Recidiverende erythema multiforme udløst af herpes simplex-virus

DEFF Research Database (Denmark)

Vestergård Grejsen, Dorthe; Henningsen, Emil

2012-01-01

We describe two cases of recurrent erythema multiforme, both associated to infection with herpes simplex virus. The importance of subclinical herpes is illustrated. Antiviral and additional treatment is described.......We describe two cases of recurrent erythema multiforme, both associated to infection with herpes simplex virus. The importance of subclinical herpes is illustrated. Antiviral and additional treatment is described....

Prospective evaluation of angiogenic, hypoxic and EGFR-related biomarkers in recurrent glioblastoma multiforme treated with cetuximab, bevacizumab and irinotecan

DEFF Research Database (Denmark)

Hasselbalch, Benedikte; Eriksen, Jesper Grau; Broholm, Helle

2010-01-01

, hypoxia and mediators of the epidermal growth factor receptor (EGFR) pathway were investigated. Tumor tissue was obtained from a previous phase II study, treating recurrent primary glioblastoma multiforme (GBM) patients with the EGFR inhibitor cetuximab in combination with bevacizumab and irinotecan...... of cetuximab. There is still an urgent need for one or more reliable and reproducible biomarkers able to predict the efficacy of anti-angiogenic therapy....

Novel multiform morphologies of hydroxyapatite: Synthesis and growth mechanism

Energy Technology Data Exchange (ETDEWEB)

Mary, I. Reeta [Department of Nanoscience and Technology, Bharathiar University, Coimbatore 641046 (India); Department of Physics, Government Arts College, Coimbatore 641018 (India); Sonia, S.; Viji, S.; Mangalaraj, D.; Viswanathan, C. [Department of Nanoscience and Technology, Bharathiar University, Coimbatore 641046 (India); Ponpandian, N., E-mail: ponpandian@buc.edu.in [Department of Nanoscience and Technology, Bharathiar University, Coimbatore 641046 (India)

2016-01-15

Graphical abstract: - Highlights: • Novel multiform morphologies of hydroxyapatite from nanoscale building blocks. • Facile hydro/solvothermal method under mild reaction conditions without the necessity of post-annealing treatment. • Growth mechanism by Ostwald ripening and self-assembly processes. - Abstract: Morphological evolution of materials becomes a prodigious challenge due to their key role in defining their functional properties and desired applications. Herein, we report the synthesis of hydroxyapatite (HAp) microstructures with multiform morphologies, such as spheres, cubes, hexagonal rods and nested bundles constructed from their respective nanoscale building blocks via a simple cost effective hydro/solvothermal method. A possible formation mechanism of diverse morphologies of HAp has been presented. Structural analysis based on X-ray diffraction (XRD) and Fourier transform infrared (FTIR) spectroscopy confirms the purity of the HAp microstructures. The multiform morphologies of HAp were corroborated by using Field emission scanning electron microscope (FESEM).

Erythema multiforme and persistent erythema as early cutaneous manifestations of Lyme disease

NARCIS (Netherlands)

Schuttelaar, M L; Laeijendecker, R; Heinhuis, R J; Van Joost, T

1997-01-01

We report two cases of borreliosis (Lyme disease) with unusual cutaneous manifestations, erythema multiforme, and persistent erythema. The lesions in both of our patients had distinctive histopathologic features. To our knowledge, this is the first report of erythema multiforme and persistent

Hemolytic anemia in two patients with glioblastoma multiforme: A possible interaction between vorinostat and dapsone.

Science.gov (United States)

Lewis, Jennifer A; Petty, William J; Harmon, Michele; Peacock, James E; Valente, Kari; Owen, John; Pirmohamed, Munir; Lesser, Glenn J

2015-06-01

Patients undergoing treatment for glioblastoma multiforme are routinely placed on prophylactic treatment for Pneumocystis jirovecii pneumonia because of significant therapy-induced lymphopenia. In patients with sulfa allergies, dapsone prophylaxis is often used due to its efficacy, long half-life, cost effectiveness, and general safety at low doses. However, dapsone may uncommonly induce a hemolytic anemia, particularly in patients deficient of glucose-6-phosphate dehydrogenase. This hemolysis is thought to be a result of oxidative stress on red blood cells induced by dapsone metabolites which produce reactive oxygen species that disrupt the red blood cell membrane and promote splenic sequestration. A single case report of dapsone-induced hemolytic anemia in a patient with glioblastoma multiforme has been reported. We present two patients with glioblastoma multiforme who developed severe hemolytic anemia shortly after initiating therapy with vorinostat, a pan-active histone deacetylase inhibitor, while on prophylactic dapsone. There are several potential mechanisms by which histone deacetylase inhibition may alter dapsone metabolism including changes in hepatic acetylation or N-glucuronidation leading to an increase in the bioavailability of dapsone's hematotoxic metabolites. In addition, vorinostat may lead to increased hemolysis through inhibition of heat shock protein-90, a chaperone protein that maintains the integrity of the red blood cell membrane cytoskeleton. The potential interaction between dapsone and vorinostat may have important clinical implications as more than 10 clinical trials evaluating drug combinations with vorinostat in patients with malignant glioma are either ongoing or planned in North America. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Micro RNAs as molecular markers of glioblastoma multiform

Energy Technology Data Exchange (ETDEWEB)

Farace, M G [Department Experimental Medicine and Biochemical Sciences, University of Tor Vergata, Rome (Italy); Finocchiaro, G [Istituto Neurologico Besta, Milan (Italy); Ricci Vitiani, L [Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanita, Rome (Italy)

2009-07-01

The aim of this project was to unravel the role that miR-221 and miR-222, of which we had already demonstrated the specific differential expression in glioblastoma multiforme compared to normal brain, play in the control of cell proliferation, with the ultimate goal to provide new insights in the molecular basis of cancer. The results of our research allowed to identify an important molecular target for miRNA-221 and miR-222, highly expressed in glioblastoma multiforme tissues and cell lines, and to precisely recognize the mRNA regions responsible for this regulation.

Micro RNAs as molecular markers of glioblastoma multiform

International Nuclear Information System (INIS)

Farace, M.G.; Finocchiaro, G.; Ricci Vitiani, L.

2009-01-01

The aim of this project was to unravel the role that miR-221 and miR-222, of which we had already demonstrated the specific differential expression in glioblastoma multiforme compared to normal brain, play in the control of cell proliferation, with the ultimate goal to provide new insights in the molecular basis of cancer. The results of our research allowed to identify an important molecular target for miRNA-221 and miR-222, highly expressed in glioblastoma multiforme tissues and cell lines, and to precisely recognize the mRNA regions responsible for this regulation

Neoadjuvant bevacizumab and irinotecan versus bevacizumab and temozolomide followed by concomitant chemoradiotherapy in newly diagnosed glioblastoma multiforme

DEFF Research Database (Denmark)

Hofland, Kenneth F; Hansen, Steinbjørn; Sorensen, Morten

2014-01-01

BACKGROUND: Surgery followed by radiotherapy and concomitant and adjuvant temozolomide is standard therapy in newly diagnosed glioblastoma multiforme (GBM). Bevacizumab combined with irinotecan produces impressive response rates in recurrent GBM. In a randomized phase II study, we investigated...... from febrile neutropenia whereas non-hematological toxicity was manageable. CONCLUSIONS: Only the Bev-Tem arm met the pre-specified level of activity of interest. Our results did not indicate any benefit from Bev-Iri in first-line therapy as opposed to Bev-Tem in terms of response and PFS....

Autopsy findings in a long-term survivor with glioblastoma multiforme. Case report

Energy Technology Data Exchange (ETDEWEB)

Yamada, Shozo; Endo, Yuzo; Takada, Koji; Usui, Masaaki; Hara, Mitsuru [Toranomon Hospital, Tokyo (Japan); Hirose, Takanori

1998-02-01

Autopsy detected no tumor tissues in a patient who died 6.5 years after the diagnosis of glioblastoma multiforme. A 54-year-old male developed left hemiparesis one month prior to admission. Computed tomography demonstrated a cystic lesion in the right frontal region with irregular ring-like enhancement. The tumor was extensively removed together with the surrounding tissues followed by irradiation (whole brain 32.4 Gy, local 28.8 Gy), and intravenous administration of interferon-{beta}. Histological examination confirmed the diagnosis of glioblastoma multiform. He died of accidental head trauma 6.5 years after surgery. Autopsy of the brain detected no evidence of glioblastoma multiform. The only findings were cerebral edema and hematoma caused by head trauma, as well as histological changes due to radiation damage. This case apparently confirms the histological disappearance of tumor tissue in a long-term survivor with glioblastoma multiform. (author)

Autopsy findings in a long-term survivor with glioblastoma multiforme. Case report

International Nuclear Information System (INIS)

Yamada, Shozo; Endo, Yuzo; Takada, Koji; Usui, Masaaki; Hara, Mitsuru; Hirose, Takanori.

1998-01-01

Autopsy detected no tumor tissues in a patient who died 6.5 years after the diagnosis of glioblastoma multiforme. A 54-year-old male developed left hemiparesis one month prior to admission. Computed tomography demonstrated a cystic lesion in the right frontal region with irregular ring-like enhancement. The tumor was extensively removed together with the surrounding tissues followed by irradiation (whole brain 32.4 Gy, local 28.8 Gy), and intravenous administration of interferon-β. Histological examination confirmed the diagnosis of glioblastoma multiform. He died of accidental head trauma 6.5 years after surgery. Autopsy of the brain detected no evidence of glioblastoma multiform. The only findings were cerebral edema and hematoma caused by head trauma, as well as histological changes due to radiation damage. This case apparently confirms the histological disappearance of tumor tissue in a long-term survivor with glioblastoma multiform. (author)

Cyclophilin B supports Myc and mutant p53-dependent survival of glioblastoma multiforme cells.

Science.gov (United States)

Choi, Jae Won; Schroeder, Mark A; Sarkaria, Jann N; Bram, Richard J

2014-01-15

Glioblastoma multiforme is an aggressive, treatment-refractory type of brain tumor for which effective therapeutic targets remain important to identify. Here, we report that cyclophilin B (CypB), a prolyl isomerase residing in the endoplasmic reticulum (ER), provides an essential survival signal in glioblastoma multiforme cells. Analysis of gene expression databases revealed that CypB is upregulated in many cases of malignant glioma. We found that suppression of CypB reduced cell proliferation and survival in human glioblastoma multiforme cells in vitro and in vivo. We also found that treatment with small molecule inhibitors of cyclophilins, including the approved drug cyclosporine, greatly reduced the viability of glioblastoma multiforme cells. Mechanistically, depletion or pharmacologic inhibition of CypB caused hyperactivation of the oncogenic RAS-mitogen-activated protein kinase pathway, induction of cellular senescence signals, and death resulting from loss of MYC, mutant p53, Chk1, and Janus-activated kinase/STAT3 signaling. Elevated reactive oxygen species, ER expansion, and abnormal unfolded protein responses in CypB-depleted glioblastoma multiforme cells indicated that CypB alleviates oxidative and ER stresses and coordinates stress adaptation responses. Enhanced cell survival and sustained expression of multiple oncogenic proteins downstream of CypB may thus contribute to the poor outcome of glioblastoma multiforme tumors. Our findings link chaperone-mediated protein folding in the ER to mechanisms underlying oncogenic transformation, and they make CypB an attractive and immediately targetable molecule for glioblastoma multiforme therapy.

Gut microbiota modulation of chemotherapy efficacy and toxicity

OpenAIRE

Alexander, James L.; Wilson, Ian D.; Teare, Julian; Marchesi, Julian Roberto; Nicholson, Jeremy K.; Kinross, James M.

2017-01-01

Evidence is growing that the gut microbiota modulates the host response to chemotherapeutic drugs, with three main clinical outcomes: facilitation of drug efficacy; abrogation and compromise of anticancer effects; and mediation of toxicity. The implication is that gut microbiota are critical to the development of personalized cancer treatment strategies and, therefore, a greater insight into prokaryotic co-metabolism of chemotherapeutic drugs is now required. This thinking is based on evidenc...

Prognostic value of plasma transforming growth factor-beta in patients with glioblastoma multiforme

NARCIS (Netherlands)

Hulshof, M. C.; Sminia, P.; Barten-van Rijbroek, A. D.; Gonzalez Gonzalez, D.

2001-01-01

We investigated whether the postoperative concentration of circulating transforming growth factor beta (TGF-beta) yields prognostic value in patients with glioblastoma multiforme (gbm). Blood was collected from 20 healthy volunteers and in 28 patients with mainly glioblastoma multiforme (gbm), both

Efficacy and toxicity of (chemo)radiotherapy for primary subglottic cancer

Energy Technology Data Exchange (ETDEWEB)

Hata, M.; Koike, I.; Odagiri, K.; Minagawa, Y.; Inoue, T. [Yokohama City Univ. Graduate School of Medicine, Yokohama (Japan). Dept. of Radiology; Taguchi, T.; Nishimura, G.; Takahashi, M.; Komatsu, M.; Sano, D. [Yokohama City Univ. Graduate School of Medicine, Yokohama (Japan). Dept. of Otorhinolaryngology

2013-01-15

Background and purpose: Primary subglottic cancer is a rare malignancy. We investigated the efficacy and toxicity of radiotherapy for subglottic cancer. Patients and methods: Nineteen patients with primary squamous cell carcinoma of the subglottis received radiotherapy, 14 of whom also underwent chemotherapy. Of the 19 patients, 15 received definitive radiotherapy to the gross tumors with total doses of 70-70.2 Gy in 35-39 fractions, and 4 underwent preoperative radiotherapy with total doses of 37.8-55.8 Gy in 21-31 fractions, followed by total laryngectomy. Results: Of the 19 patients, 5 developed local progression and 2 developed distant metastasis at the median follow-up period of 5 years. The 5-year local control and disease-free rates were 74 and 63%, respectively. Three patients died of tumor progression, and the 5-year overall and disease-free survival rates were 80 and 63%, respectively. Regarding acute toxicities, transient mucositis and dermatitis of grade 3 or lower were observed in all patients, but there were no late toxicities of grade 3 or higher. Conclusion: Radiotherapy is a safe and effective treatment for patients with primary squamous cell carcinoma of the subglottis. The use of chemotherapy together with radiotherapy may enhance treatment efficacy and contribute to larynx preservation through good local control. (orig.)

Toxicity and efficacy of lomustine and bevacizumab in recurrent glioblastoma patients

DEFF Research Database (Denmark)

Jakobsen, J N; Urup, T; Grunnet, K

2018-01-01

The combination of lomustine and bevacizumab is a commonly used salvage treatment for recurrent glioblastoma (GBM). We investigated the toxicity and efficacy of lomustine plus bevacizumab (lom-bev) in a community-based patient cohort and made a comparison to another frequently used combination...... therapy consisting of irinotecan plus bevacizumab (iri-bev). Seventy patients with recurrent GBM were treated with lomustine 90 mg/m2 every 6 weeks and bevacizumab 10 mg/kg every 2 weeks. Toxicity was registered and compared to the toxicity observed in 219 recurrent GBM patients who had previously been......-bev is a well-tolerated treatment for recurrent GBM, although hematological toxicity may be a dose limiting factor. No significant differences between lom-bev and iri-bev were observed with regard to PFS or OS. The differences in toxicity profiles between lom-bev and iri-bev could guide treatment decision...

Decontamination Efficacy and Skin Toxicity of Two Decontaminants against Bacillus anthracis.

Directory of Open Access Journals (Sweden)

Chad W Stratilo

Full Text Available Decontamination of bacterial endospores such as Bacillus anthracis has traditionally required the use of harsh or caustic chemicals. The aim of this study was to evaluate the efficacy of a chlorine dioxide decontaminant in killing Bacillus anthracis spores in solution and on a human skin simulant (porcine cadaver skin, compared to that of commonly used sodium hypochlorite or soapy water decontamination procedures. In addition, the relative toxicities of these decontaminants were compared in human skin keratinocyte primary cultures. The chlorine dioxide decontaminant was similarly effective to sodium hypochlorite in reducing spore numbers of Bacillus anthracis Ames in liquid suspension after a 10 minute exposure. After five minutes, the chlorine dioxide product was significantly more efficacious. Decontamination of isolated swine skin contaminated with Bacillus anthracis Sterne with the chlorine dioxide product resulted in no viable spores sampled. The toxicity of the chlorine dioxide decontaminant was up to two orders of magnitude less than that of sodium hypochlorite in human skin keratinocyte cultures. In summary, the chlorine dioxide based decontaminant efficiently killed Bacillus anthracis spores in liquid suspension, as well as on isolated swine skin, and was less toxic than sodium hypochlorite in cultures of human skin keratinocytes.

Human glioblastoma multiforme: p53 reactivation by a novel MDM2 inhibitor.

Directory of Open Access Journals (Sweden)

Barbara Costa

Full Text Available Cancer development and chemo-resistance are often due to impaired functioning of the p53 tumor suppressor through genetic mutation or sequestration by other proteins. In glioblastoma multiforme (GBM, p53 availability is frequently reduced because it binds to the Murine Double Minute-2 (MDM2 oncoprotein, which accumulates at high concentrations in tumor cells. The use of MDM2 inhibitors that interfere with the binding of p53 and MDM2 has become a valid approach to inhibit cell growth in a number of cancers; however little is known about the efficacy of these inhibitors in GBM. We report that a new small-molecule inhibitor of MDM2 with a spirooxoindolepyrrolidine core structure, named ISA27, effectively reactivated p53 function and inhibited human GBM cell growth in vitro by inducing cell cycle arrest and apoptosis. In immunoincompetent BALB/c nude mice bearing a human GBM xenograft, the administration of ISA27 in vivo activated p53, inhibited cell proliferation and induced apoptosis in tumor tissue. Significantly, ISA27 was non-toxic in an in vitro normal human cell model and an in vivo mouse model. ISA27 administration in combination with temozolomide (TMZ produced a synergistic inhibitory effect on GBM cell viability in vitro, suggesting the possibility of lowering the dose of TMZ used in the treatment of GBM. In conclusion, our data show that ISA27 releases the powerful antitumor capacities of p53 in GBM cells. The use of this MDM2 inhibitor could become a novel therapy for the treatment of GBM patients.

Folate Functionalized Boron Nitride Nanotubes and their Selective Uptake by Glioblastoma Multiforme Cells: Implications for their Use as Boron Carriers in Clinical Boron Neutron Capture Therapy.

Science.gov (United States)

Ciofani, Gianni; Raffa, Vittoria; Menciassi, Arianna; Cuschieri, Alfred

2008-11-25

Boron neutron capture therapy (BNCT) is increasingly being used in the treatment of several aggressive cancers, including cerebral glioblastoma multiforme. The main requirement for this therapy is selective targeting of tumor cells by sufficient quantities of (10)B atoms required for their capture/irradiation with low-energy thermal neutrons. The low content of boron targeting species in glioblastoma multiforme accounts for the difficulty in selective targeting of this very malignant cerebral tumor by this radiation modality. In the present study, we have used for the first time boron nitride nanotubes as carriers of boron atoms to overcome this problem and enhance the selective targeting and ablative efficacy of BNCT for these tumors. Following their dispersion in aqueous solution by noncovalent coating with biocompatible poly-l-lysine solutions, boron nitride nanotubes were functionalized with a fluorescent probe (quantum dots) to enable their tracking and with folic acid as selective tumor targeting ligand. Initial in vitro studies have confirmed substantive and selective uptake of these nanovectors by glioblastoma multiforme cells, an observation which confirms their potential clinical application for BNCT therapy for these malignant cerebral tumors.

Folate Functionalized Boron Nitride Nanotubes and their Selective Uptake by Glioblastoma Multiforme Cells: Implications for their Use as Boron Carriers in Clinical Boron Neutron Capture Therapy

Directory of Open Access Journals (Sweden)

Ciofani Gianni

2008-01-01

Full Text Available Abstract Boron neutron capture therapy (BNCT is increasingly being used in the treatment of several aggressive cancers, including cerebral glioblastoma multiforme. The main requirement for this therapy is selective targeting of tumor cells by sufficient quantities of10B atoms required for their capture/irradiation with low-energy thermal neutrons. The low content of boron targeting species in glioblastoma multiforme accounts for the difficulty in selective targeting of this very malignant cerebral tumor by this radiation modality. In the present study, we have used for the first time boron nitride nanotubes as carriers of boron atoms to overcome this problem and enhance the selective targeting and ablative efficacy of BNCT for these tumors. Following their dispersion in aqueous solution by noncovalent coating with biocompatible poly-l-lysine solutions, boron nitride nanotubes were functionalized with a fluorescent probe (quantum dots to enable their tracking and with folic acid as selective tumor targeting ligand. Initial in vitro studies have confirmed substantive and selective uptake of these nanovectors by glioblastoma multiforme cells, an observation which confirms their potential clinical application for BNCT therapy for these malignant cerebral tumors.

Lagrangian multiforms and multidimensional consistency

Energy Technology Data Exchange (ETDEWEB)

Lobb, Sarah; Nijhoff, Frank [Department of Applied Mathematics, University of Leeds, Leeds LS2 9JT (United Kingdom)

2009-10-30

We show that well-chosen Lagrangians for a class of two-dimensional integrable lattice equations obey a closure relation when embedded in a higher dimensional lattice. On the basis of this property we formulate a Lagrangian description for such systems in terms of Lagrangian multiforms. We discuss the connection of this formalism with the notion of multidimensional consistency, and the role of the lattice from the point of view of the relevant variational principle.

Radiotherapy and chemotherapy with or without carbogen and nicotinamide in inoperable biopsy-proven glioblastoma multiforme

International Nuclear Information System (INIS)

Simon, Jean-Marc; Noeel, Georges; Chiras, Jacques; Khe, H.-X.; Delattre, Jean-Yves; Baillet, Francois; Mazeron, Jean-Jacques

2003-01-01

Background: Nicotinamide and carbogen have been shown to enhance the radiation effect in tumour models. Purpose: Prospective evaluation of the toxicity and efficacy of carbogen and nicotinamide with external beam radiotherapy in the management of inoperable glioblastoma. Patients and methods: From April 1995 to December 1997, 33 patients with inoperable biopsy-proven glioblastoma multiforme (GBM) were enrolled in a phase II trial, to undergo radiotherapy (59.4 Gy in 1.8 Gy/fraction), intra-arterial cerebral chemotherapy (ACNU 100 mg/m 2 , three cycles), carbogen breathing (15 l/min), and nicotinamide (85 mg/kg). This experimental group was compared to a control group of 38 patients with inoperable GBM treated with radiotherapy and three cycles of nitrosourea-based chemotherapy from January 1990 to March 1995, in our institution. Results: In the experimental group, carbogen breathing was well tolerated, but only 51.5% of patients completed daily nicotinamide over the 6.5-week treatment period. Nausea and vomiting were the most frequent side effects of nicotinamide. No significant difference in overall survival was observed among the two treatment groups: median survival times were 36.7 and 35.3 weeks for patients treated with carbogen and nicotinamide, and for those treated in the control group, respectively. Conclusion: The association of carbogen and nicotinamide with radiotherapy is feasible, but tolerable only in 51.5% of patients with GBM. Carbogen and nicotinamide did not appear to modify the evolution of glioblastoma

RNA expression patterns in serum microvesicles from patients with glioblastoma multiforme and controls

Directory of Open Access Journals (Sweden)

Noerholm Mikkel

2012-01-01

Full Text Available Abstract Background RNA from exosomes and other microvesicles contain transcripts of tumour origin. In this study we sought to identify biomarkers of glioblastoma multiforme in microvesicle RNA from serum of affected patients. Methods Microvesicle RNA from serum from patients with de-novo primary glioblastoma multiforme (N = 9 and normal controls (N = 7 were analyzed by microarray analysis. Samples were collected according to protocols approved by the Institutional Review Board. Differential expressions were validated by qRT-PCR in a separate set of samples (N = 10 in both groups. Results Expression profiles of microvesicle RNA correctly separated individuals in two groups by unsupervised clustering. The most significant differences pertained to down-regulated genes (121 genes > 2-fold down in the glioblastoma multiforme patient microvesicle RNA, validated by qRT-PCR on several genes. Overall, yields of microvesicle RNA from patients was higher than from normal controls, but the additional RNA was primarily of size Conclusions Serum microvesicle RNA from patients with glioblastoma multiforme has significantly down-regulated levels of RNAs coding for ribosome production, compared to normal healthy controls, but a large overabundance of RNA of unknown origin with size

Phase I trial of erlotinib with radiation therapy in patients with glioblastoma multiforme: Results of North Central Cancer Treatment Group protocol N0177

International Nuclear Information System (INIS)

Krishnan, Sunil; Brown, Paul D.; Ballman, Karla V.; Fiveash, John B.; Uhm, Joon H.; Giannini, Caterina; Jaeckle, Kurt A.; Geoffroy, Francois J.; Nabors, L. Burt; Buckner, Jan C.

2006-01-01

Purpose: To evaluate the toxicity and maximum tolerated dose (MTD) of erlotinib plus radiation therapy (RT) in patients with glioblastoma multiforme (GBM) in a multicenter phase I trial. Methods and Materials: Patients were stratified on the basis of the use of enzyme-inducing anticonvulsants (EIACs). After resection or biopsy, patients were treated with erlotinib for 1 week before concurrent erlotinib and 6 weeks (60 Gy) of RT and maintained on erlotinib until progression. The erlotinib dose was escalated in cohorts of 3 starting at 100 mg/day. Results: Twenty patients were enrolled and 19 were evaluable for the MTD and efficacy endpoints. Of these patients, 14 were males and 5 were females, with a median age of 54 years. Seven had undergone biopsy only, 5 had subtotal resections, and 7 had gross total resections. The highest dose level was 150 mg/day erlotinib for patients not on EIACs (Group 1) and 200 mg/day for patients on EIACs (Group 2). MTD was not reached in either group. In Group 1 at 100 mg (n = 6) and at 150 mg (n = 4), only 1 dose-limiting toxicity (DLT) occurred (stomatitis at 100 mg). No DLTs have occurred in Group 2 at 100 mg (n = 3), 150 mg (n = 3), and 200 mg (n = 3). With a median follow-up of 52 weeks, progression was documented in 16 patients and 13 deaths occurred. Median time to progression was 26 weeks, and median survival was 55 weeks. Conclusion: Toxicity is acceptable at the current doses of erlotinib plus RT. The study was modified to include concurrent and adjuvant temozolomide, and accrual is in progress

RNA expression patterns in serum microvesicles from patients with glioblastoma multiforme and controls

International Nuclear Information System (INIS)

Noerholm, Mikkel; Balaj, Leonora; Limperg, Tobias; Salehi, Afshin; Zhu, Lin Dan; Hochberg, Fred H; Breakefield, Xandra O; Carter, Bob S; Skog, Johan

2012-01-01

RNA from exosomes and other microvesicles contain transcripts of tumour origin. In this study we sought to identify biomarkers of glioblastoma multiforme in microvesicle RNA from serum of affected patients. Microvesicle RNA from serum from patients with de-novo primary glioblastoma multiforme (N = 9) and normal controls (N = 7) were analyzed by microarray analysis. Samples were collected according to protocols approved by the Institutional Review Board. Differential expressions were validated by qRT-PCR in a separate set of samples (N = 10 in both groups). Expression profiles of microvesicle RNA correctly separated individuals in two groups by unsupervised clustering. The most significant differences pertained to down-regulated genes (121 genes > 2-fold down) in the glioblastoma multiforme patient microvesicle RNA, validated by qRT-PCR on several genes. Overall, yields of microvesicle RNA from patients was higher than from normal controls, but the additional RNA was primarily of size < 500 nt. Gene ontology of the down-regulated genes indicated these are coding for ribosomal proteins and genes related to ribosome production. Serum microvesicle RNA from patients with glioblastoma multiforme has significantly down-regulated levels of RNAs coding for ribosome production, compared to normal healthy controls, but a large overabundance of RNA of unknown origin with size < 500 nt

Prolonged survival when temozolomide is added to accelerated radiotherapy for glioblastoma multiforme

Energy Technology Data Exchange (ETDEWEB)

Guckenberger, Matthias; Mayer, Mario; Sweeney, Reinhart A.; Flentje, Michael [University Hospital Wuerzburg (Germany). Dept. of Radiation Oncology; Buttmann, Mathias [University Hospital Wuerzburg (Germany). Dept. of Neurology; Vince, Giles H. [University Hospital Wuerzburg (Germany). Dept. of Neurosurgery

2011-09-15

The goal of this study was to evaluate accelerated radiotherapy with and without temozolomide (TMZ) for glioblastoma multiforme (GBM). This retrospective analysis evaluated 86 patients with histologically proven GBM who were treated with accelerated radiotherapy of 1.8 Gy twice daily to a total dose of 54 Gy within 3 weeks. Median age was 62 years and median Karnofsky index was 90. A total of 41 patients received radiotherapy only from 2002-2005 and 45 patients were treated with TMZ concomitantly and after radiotherapy from 2005-2007. Median overall survival (OS) was 12.5 months and 2-year OS was 15.4%. Patient characteristics were well balanced between the two groups except for better performance status (p = 0.05) and higher frequency of retreatment for the first recurrence (p = 0.02) in the TMZ group. Age at diagnosis (HR 2.83) and treatment with TMZ (HR 0.60) were correlated with OS in the multivariate analysis: treatment with and without TMZ resulted in median OS of 16 months and 11.3 months, respectively. Hematological toxicity grade > II was observed in 2/45 patients and 5/37 patients during simultaneous radiochemotherapy and adjuvant TMZ. TMZ added to accelerated radiotherapy for GBM resulted in prolonged overall survival with low rates of severe hematological toxicity. (orig.)

Prolonged survival when temozolomide is added to accelerated radiotherapy for glioblastoma multiforme

International Nuclear Information System (INIS)

Guckenberger, Matthias; Mayer, Mario; Sweeney, Reinhart A.; Flentje, Michael; Buttmann, Mathias; Vince, Giles H.

2011-01-01

The goal of this study was to evaluate accelerated radiotherapy with and without temozolomide (TMZ) for glioblastoma multiforme (GBM). This retrospective analysis evaluated 86 patients with histologically proven GBM who were treated with accelerated radiotherapy of 1.8 Gy twice daily to a total dose of 54 Gy within 3 weeks. Median age was 62 years and median Karnofsky index was 90. A total of 41 patients received radiotherapy only from 2002-2005 and 45 patients were treated with TMZ concomitantly and after radiotherapy from 2005-2007. Median overall survival (OS) was 12.5 months and 2-year OS was 15.4%. Patient characteristics were well balanced between the two groups except for better performance status (p = 0.05) and higher frequency of retreatment for the first recurrence (p = 0.02) in the TMZ group. Age at diagnosis (HR 2.83) and treatment with TMZ (HR 0.60) were correlated with OS in the multivariate analysis: treatment with and without TMZ resulted in median OS of 16 months and 11.3 months, respectively. Hematological toxicity grade > II was observed in 2/45 patients and 5/37 patients during simultaneous radiochemotherapy and adjuvant TMZ. TMZ added to accelerated radiotherapy for GBM resulted in prolonged overall survival with low rates of severe hematological toxicity. (orig.)

Glioblastoma multiforme after radiotherapy for acromegaly

Energy Technology Data Exchange (ETDEWEB)

Piatt, J.H. Jr.; Blue, J.M.; Schold, S.C. Jr.; Burger, P.C.

1983-07-01

A case of glioblastoma multiforme that occurred 14 years after radiotherapy for acromegaly is presented. The striking correspondence between the anatomy of the tumor and the geometry of the radiation ports is suggestive of a causal relationship. Previously reported cases of radiation-associated glioma are reviewed, and a brief appraisal of the evidence for induction of these lesions by radiation is presented. The differentiation of radiation-associated neoplasms from radionecrosis is also discussed.

Glioblastoma multiforme after radiotherapy for acromegaly

International Nuclear Information System (INIS)

Piatt, J.H. Jr.; Blue, J.M.; Schold, S.C. Jr.; Burger, P.C.

1983-01-01

A case of glioblastoma multiforme that occurred 14 years after radiotherapy for acromegaly is presented. The striking correspondence between the anatomy of the tumor and the geometry of the radiation ports is suggestive of a causal relationship. Previously reported cases of radiation-associated glioma are reviewed, and a brief appraisal of the evidence for induction of these lesions by radiation is presented. The differentiation of radiation-associated neoplasms from radionecrosis is also discussed

Erythema multiforme like allergic contact dermatitis associated with laurel oil: a rare presentation.

Science.gov (United States)

Uzuncakmak, Tugba Kevser; Karadag, Ayse Serap; Izol, Belcin; Akdeniz, Necmettin; Cobanoglu, Bengu; Taskin, Secil

2015-04-16

Allergic contact dermatitis is a common skin disease, which affects approximately 20% of the population. This reaction may present with several clinical manifestations. Erythema multiforme-like allergic contact dermatitis is a rare type of non-eczematous contact dermatitis, which may lead to difficulty in diagnosis.Essential oil of Laurus nobilis is widely used in massage therapy for antiinflammatory and analgesic effects. Laurus nobilis induced contact dermatitis has been reported in the literature but an erythema multiforme-like presentation is rare.

Therapeutic efficacy of aldoxorubicin in an intracranial xenograft mouse model of human glioblastoma.

Science.gov (United States)

Marrero, Luis; Wyczechowska, Dorota; Musto, Alberto E; Wilk, Anna; Vashistha, Himanshu; Zapata, Adriana; Walker, Chelsey; Velasco-Gonzalez, Cruz; Parsons, Christopher; Wieland, Scott; Levitt, Daniel; Reiss, Krzysztof; Prakash, Om

2014-10-01

Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor with a median survival of 12 to 15 months after diagnosis. Acquired chemoresistance, high systemic toxicity, and low penetration of the blood brain barrier by many anticancer drugs contribute to the failure of anti-GBM therapies. To circumvent some of these obstacles, we tested a novel prodrug approach to evaluate anti-GBM efficacy by utilizing serum albumin-binding doxorubicin (Doxo), aldoxorubicin (Aldoxo), which is less toxic, is released from albumin in an acidic environment and accumulates in tumor tissues. A human GBM cell line that expresses a luciferase reporter (U87-luc) was stereotactically injected into the left striatum of the brain of immunodeficient mice. Following initial tumor growth for 12 days, mice were injected once a week in the tail-vein with Aldoxo [24 mg/kg or 18 mg/kg of doxorubicin equivalents-3/4 maximum tolerated dose (MTD)], Doxo [6 mg/kg (3/4 MTD)], or vehicle. Aldoxo-treated mice demonstrated significantly slower growth of the tumor when compared to vehicle-treated or Doxo-treated mice. Five out of eight Aldoxo-treated mice remained alive more than 60 days with a median survival of 62 days, while the median survival of vehicle- and Doxo-treated mice was only 26 days. Importantly, Aldoxo-treated mice exhibited high levels of Doxo within the tumor tissue, accompanied by low tumor cell proliferation (Ki67) and abundant intratumoral programmed cell death (cleaved caspase-3). Effective accumulation of Aldoxo in brain tumor tissues but not normal brain, its anti-tumor efficacy, and low toxicity, provide a strong rationale for evaluating this novel drug conjugate as a treatment for patients afflicted with GBM.

Comparative toxicity and efficacy of engineered anthrax lethal toxin variants with broad anti-tumor activities

International Nuclear Information System (INIS)

Peters, Diane E.; Hoover, Benjamin; Cloud, Loretta Grey; Liu, Shihui; Molinolo, Alfredo A.; Leppla, Stephen H.; Bugge, Thomas H.

2014-01-01

We have previously designed and characterized versions of anthrax lethal toxin that are selectively cytotoxic in the tumor microenvironment and which display broad and potent anti-tumor activities in vivo. Here, we have performed the first direct comparison of the safety and efficacy of three engineered anthrax lethal toxin variants requiring activation by either matrix-metalloproteinases (MMPs), urokinase plasminogen activator (uPA) or co-localized MMP/uPA activities. C57BL/6J mice were challenged with six doses of engineered toxins via intraperitoneal (I.P.) or intravenous (I.V.) dose routes to determine the maximum tolerated dose for six administrations (MTD6) and dose-limiting toxicities. Efficacy was evaluated using the B16-BL6 syngraft model of melanoma; mice bearing established tumors were treated with six I.P. doses of toxin and tumor measurements and immunohistochemistry, paired with terminal blood work, were used to elaborate upon the anti-tumor mechanism and relative efficacy of each variant. We found that MMP-, uPA- and dual MMP/uPA-activated anthrax lethal toxins exhibited the same dose-limiting toxicity; dose-dependent GI toxicity. In terms of efficacy, all three toxins significantly reduced primary B16-BL6 tumor burden, ranging from 32% to 87% reduction, and they also delayed disease progression as evidenced by dose-dependent normalization of blood work values. While target organ toxicity and effective doses were similar amongst the variants, the dual MMP/uPA-activated anthrax lethal toxin exhibited the highest I.P. MTD6 and was 1.5–3-fold better tolerated than the single MMP- and uPA-activated toxins. Overall, we demonstrate that this dual MMP/uPA-activated anthrax lethal toxin can be administered safely and is highly effective in a preclinical model of melanoma. This modified bacterial cytotoxin is thus a promising candidate for further clinical development and evaluation for use in treating human cancers. - Highlights: • Toxicity and anti

Comparative toxicity and efficacy of engineered anthrax lethal toxin variants with broad anti-tumor activities

Energy Technology Data Exchange (ETDEWEB)

Peters, Diane E. [Proteases and Tissue Remodeling Section, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD (United States); Program of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA (United States); Hoover, Benjamin [Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD (United States); Cloud, Loretta Grey [Proteases and Tissue Remodeling Section, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD (United States); Liu, Shihui [Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD (United States); Molinolo, Alfredo A. [Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD (United States); Leppla, Stephen H. [Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD (United States); Bugge, Thomas H., E-mail: thomas.bugge@nih.go [Proteases and Tissue Remodeling Section, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD (United States)

2014-09-01

We have previously designed and characterized versions of anthrax lethal toxin that are selectively cytotoxic in the tumor microenvironment and which display broad and potent anti-tumor activities in vivo. Here, we have performed the first direct comparison of the safety and efficacy of three engineered anthrax lethal toxin variants requiring activation by either matrix-metalloproteinases (MMPs), urokinase plasminogen activator (uPA) or co-localized MMP/uPA activities. C57BL/6J mice were challenged with six doses of engineered toxins via intraperitoneal (I.P.) or intravenous (I.V.) dose routes to determine the maximum tolerated dose for six administrations (MTD6) and dose-limiting toxicities. Efficacy was evaluated using the B16-BL6 syngraft model of melanoma; mice bearing established tumors were treated with six I.P. doses of toxin and tumor measurements and immunohistochemistry, paired with terminal blood work, were used to elaborate upon the anti-tumor mechanism and relative efficacy of each variant. We found that MMP-, uPA- and dual MMP/uPA-activated anthrax lethal toxins exhibited the same dose-limiting toxicity; dose-dependent GI toxicity. In terms of efficacy, all three toxins significantly reduced primary B16-BL6 tumor burden, ranging from 32% to 87% reduction, and they also delayed disease progression as evidenced by dose-dependent normalization of blood work values. While target organ toxicity and effective doses were similar amongst the variants, the dual MMP/uPA-activated anthrax lethal toxin exhibited the highest I.P. MTD6 and was 1.5–3-fold better tolerated than the single MMP- and uPA-activated toxins. Overall, we demonstrate that this dual MMP/uPA-activated anthrax lethal toxin can be administered safely and is highly effective in a preclinical model of melanoma. This modified bacterial cytotoxin is thus a promising candidate for further clinical development and evaluation for use in treating human cancers. - Highlights: • Toxicity and anti

Tonsillary carcinoma after temozolomide treatment for glioblastoma multiforme: treatment-related or dual-pathology?

Science.gov (United States)

Binello, E; Germano, I M

2009-08-01

Glioblastoma multiforme is a primary malignant brain tumor with a prognosis of typically less than 2 years. Standard treatment paradigms include surgery, radiation therapy and temozolomide. Little data exists for temozolomide recommendations after the first 6 months. We present a case of a patient with glioblastoma multiforme treated with surgery, radiation and chronic temozolomide for 6 years. He continues to survive glioblastoma-recurrence-free, but developed tonsillary carcinoma. This case raises the question of whether this secondary solid-organ malignancy is treatment-related or dual pathology.

Eritema multiforme mayor desencadenado por antimicrobianos

Directory of Open Access Journals (Sweden)

Ronaldo de Carvalho Raimundo

2010-03-01

Full Text Available El eritema multiforme, aparece como una enfermedad sistémica con la participación de la piel y las membranas mucosas en relación con varios factores como las infecciones bacterianas o virales, y en particular la administración de drogas, analgésicos y antibióticos en general. Se presenta un paciente masculino de 29 años de edad con eritema multiforme mayor desencadenado por antimicrobianos con la aparición de lesiones vesiculares-bulloso-ulcerosas en las regiones de los labios, encías, la lengua y la mucosa genital en tratamiento de una infección del tracto urinario con norfloxacino 400 mg por una semana. Fue realizado un tratamiento de soporte con el uso de colutorios para la higienización bucal y pomada a base de corticoide para protección de las úlceras, antihistamínicos y orientación nutricional de dieta líquida hipercalórica e hiperproteica. Este síndrome está caracterizado como un proceso eruptivo buloso agudo que compromete la calidad de vida del paciente y no hay pruebas de laboratorio específicas por lo que su diagnóstico debe estar basado en la revisión minuciosa de la anamnesis y en los hallazgos clínicos.

Comparative toxicity and efficacy of engineered anthrax lethal toxin variants with broad anti-tumor activities.

Science.gov (United States)

Peters, Diane E; Hoover, Benjamin; Cloud, Loretta Grey; Liu, Shihui; Molinolo, Alfredo A; Leppla, Stephen H; Bugge, Thomas H

2014-09-01

We have previously designed and characterized versions of anthrax lethal toxin that are selectively cytotoxic in the tumor microenvironment and which display broad and potent anti-tumor activities in vivo. Here, we have performed the first direct comparison of the safety and efficacy of three engineered anthrax lethal toxin variants requiring activation by either matrix-metalloproteinases (MMPs), urokinase plasminogen activator (uPA) or co-localized MMP/uPA activities. C57BL/6J mice were challenged with six doses of engineered toxins via intraperitoneal (I.P.) or intravenous (I.V.) dose routes to determine the maximum tolerated dose for six administrations (MTD6) and dose-limiting toxicities. Efficacy was evaluated using the B16-BL6 syngraft model of melanoma; mice bearing established tumors were treated with six I.P. doses of toxin and tumor measurements and immunohistochemistry, paired with terminal blood work, were used to elaborate upon the anti-tumor mechanism and relative efficacy of each variant. We found that MMP-, uPA- and dual MMP/uPA-activated anthrax lethal toxins exhibited the same dose-limiting toxicity; dose-dependent GI toxicity. In terms of efficacy, all three toxins significantly reduced primary B16-BL6 tumor burden, ranging from 32% to 87% reduction, and they also delayed disease progression as evidenced by dose-dependent normalization of blood work values. While target organ toxicity and effective doses were similar amongst the variants, the dual MMP/uPA-activated anthrax lethal toxin exhibited the highest I.P. MTD6 and was 1.5-3-fold better tolerated than the single MMP- and uPA-activated toxins. Overall, we demonstrate that this dual MMP/uPA-activated anthrax lethal toxin can be administered safely and is highly effective in a preclinical model of melanoma. This modified bacterial cytotoxin is thus a promising candidate for further clinical development and evaluation for use in treating human cancers. Published by Elsevier Inc.

TCGA Workshop: Genomics and Biology of Glioblastoma Multiforme (GBM) - TCGA

Science.gov (United States)

The National Cancer Institute (NCI) and National Human Genome Research Institute (NHGRI) held a workshop entitled, “Genomics and Biology of Glioblastoma Multiforme (GBM),” to review the initial GBM data from the TCGA pilot project.

First clinical results of a personalized immunotherapeutic vaccine against recurrent, incompletely resected, treatment-resistant glioblastoma multiforme (GBM) tumors, based on combined allo- and auto-immune tumor reactivity.

Science.gov (United States)

Schijns, Virgil E J C; Pretto, Chrystel; Devillers, Laurent; Pierre, Denis; Hofman, Florence M; Chen, Thomas C; Mespouille, Pascal; Hantos, Peter; Glorieux, Philippe; Bota, Daniela A; Stathopoulos, Apostolos

2015-05-28

Glioblastoma multiforme (GBM) patients have a poor prognosis. After tumor recurrence statistics suggest an imminent death within 1-4.5 months. Supportive preclinical data, from a rat model, provided the rational for a prototype clinical vaccine preparation, named Gliovac (or ERC 1671) composed of autologous antigens, derived from the patient's surgically removed tumor tissue, which is administered together with allogeneic antigens from glioma tissue resected from other GBM patients. We now report the first results of the Gliovac treatment for treatment-resistant GBM patients. Nine (9) recurrent GBM patients, after standard of care treatment, including surgery radio- and chemotherapy temozolomide, and for US patients, also bevacizumab (Avastin™), were treated under a compassionate use/hospital exemption protocol. Gliovac was given intradermally, together with human GM-CSF (Leukine(®)), and preceded by a regimen of regulatory T cell-depleting, low-dose cyclophosphamide. Gliovac administration in patients that have failed standard of care therapies showed minimal toxicity and enhanced overall survival (OS). Six-month (26 weeks) survival for the nine Gliovac patients was 100% versus 33% in control group. At week 40, the published overall survival was 10% if recurrent, reoperated patients were not treated. In the Gliovac treated group, the survival at 40 weeks was 77%. Our data suggest that Gliovac has low toxicity and a promising efficacy. A phase II trial has recently been initiated in recurrent, bevacizumab naïve GBM patients (NCT01903330). Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Stevens-Johnson syndrome progressing to toxic epidermal necrolysis with haloperidol and carbamazepine combination

Directory of Open Access Journals (Sweden)

Ajay Kumar

2011-01-01

Full Text Available Carbamazepine and other anticonvulsants are commoner cause of severe adverse cutaneous drug reactions such as erythema multiforme, toxic epidermal necrolysis (TEN, and Stevens-Johnson syndrome (SJS. We report a case of SJS rapidly progressing to TEN with a combination of haloperidol and carbamazepine in a patient with bipolar affective disorder. The pathophysiological mechanism underlying this reaction is discussed.

Vaccine-induced toxic epidermal necrolysis: A case and systematic review

OpenAIRE

Chahal, Dev; Aleshin, Maria; Turegano, Mamina; Chiu, Melvin; Worswick, Scott

2018-01-01

Background: Erythema multiforme (EM), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are cutaneous hypersensitivityreactions that develop in response to specific triggers such as medications and certain infections. Vaccines, which undergo rigorous safety testing prior to use in humans, are a rare cause of SJS/TEN and little is known about the frequency of such events and corresponding pathogenesis. Objective: Herein, we discuss a case of suspected TEN in a 19-yea...

Relative oral efficacy and acute toxicity of hydroxypyridin-4-one iron chelators in mice

International Nuclear Information System (INIS)

Porter, J.B.; Morgan, J.; Hoyes, K.P.; Burke, L.C.; Huehns, E.R.; Hider, R.C.

1990-01-01

The relationship between the oral efficacy and the acute toxicity of hydroxypyridin-4-one iron chelators has been investigated to clarify structure-function relationships of these compounds in vivo and to identify compounds with the maximum therapeutic safety margin. By comparing 59Fe excretion following oral or intraperitoneal administration of increasing doses of each chelator to iron-overloaded mice, the most effective compounds have been identified. These have partition coefficients (Kpart) above 0.3 in the iron-free form with a trend of increasing oral efficacy with increasing Kpart values (r = .6). However, this is achieved at a cost of increasing acute toxicity, as shown by a linear correlation between 59Fe excretion increase per unit dose and 1/LD50 (r = .83). A sharp increase in the LD50 values is observed for compounds with Kpart values above 1.0, suggesting that such compounds are unlikely to possess a sufficient therapeutic safety margin. Below a Kpart of 1.0, acute toxicity is relatively independent of lipid solubility. All the compounds are less toxic by the oral route than by the intraperitoneal route, although iron excretion is not significantly different by these two routes. At least five compounds (CP51, CP94, CP93, CP96, and CP21) are more effective orally than the same dose of intraperitoneal desferrioxamine (DFO) (P less than or equal to .02) or orally administered L1(CP20) (P less than or equal to .02)

Investigation of Monnose-Binding Lectin gene Polymorphism in Patients with Erythema Multiforme, Stevens-Johnson Syndrome and Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis Overlap Syndrome

Directory of Open Access Journals (Sweden)

Sevil Toka

2012-09-01

Full Text Available Objective: Monnose-Binding lectin (MBL appears to play an important role in the immune system. The genetic polymorphisms in the MBL2 gene can result in a reduction of serum levels, leading to a predisposition to recurrent infection. The aim of this study is to investigate the influence of a polymorphism in codon 54 of the MBL2 gene on the susceptibility to Erythema Multiforme, Stevens-Johnson Syndrome and Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis Overlap Syndrome (EM, SJS and SJS/TEN overlap syndrome. Material and Methods: Our study included 64 patients who were clinically and/or histopathologically diagnosed with EM, SJS, and SJS/TEN overlap syndrome and 66 healthy control subjects who were genotyped for the MBL2 gene codon 54 polymorphism using the PCR-RFLP method. For all statistical analyses, the level of significance was set at p<0.05. Results: The prevalence of the B allele was 18% in the EM, SJS and SJS/TEN patient groups and 13% in the control group. No significant differences in allele frequencies of any polymorphism were observed between the patient and control groups, although the B allele was more frequent in the patient groups (p=0.328.Conclusion: Our results provide no evidence of a relationship between MBL2 gene codon 54 polymorphism and the susceptibility to EM, SJS and SJS/TEN overlap syndrome. However, these findings should be confirmed in studies with a larger sample size.

The efficacy of Pistacia Terebinthus soap in the treatment of cetuximab-induced skin toxicity.

Science.gov (United States)

Tastekin, Didem; Tambas, Makbule; Kilic, Kemal; Erturk, Kayhan; Arslan, Deniz

2014-12-01

This open-labeled phase II, efficacy-finding study evaluated the efficiency and safety of Pistacia terebinthus soap in metastatic colorectal cancer patients who developed cetuximab induced skin toxicity. Patients who received cetuximab plus chemotherapy and developed Grade 2 or 3 skin toxicity were treated twice daily with a soap made of oil extracted from Pistacia terebinthus. During treatment, no topical or oral antibiotics, corticosteroids or other moisturizers were used. Patients were examined 1 week later and their photographs were taken. Fifteen mCRC patients who developed skin toxicity while receiving first-line CTX in combination with chemotherapy were included into the study. Eight patients were male and the median age was 58 (25-70). Sixty percent of the patients (n:9) had Grade 3 skin toxicity. Complete response rates in patients with Grade 2 and Grade 3 skin toxicities were 100 and 33%, respectively. In the remaining patients with Grade 3 toxicity the skin toxicity regressed to Grade 1. The objective response rate was 100%, and no delay, dose reduction or discontinuation of CTX treatment due to skin toxicity was necessary. Skin toxicity reoccurred in all patients when patients stopped administering the soap and therefore they used it throughout the cetuximab treatment. Pistacia terebinthus soap seemed to be used safely and effectively in the treatment of skin toxicity induced by Cetuximab.

Short course of radiation therapy in elderly patients with multiform glioblastoma

International Nuclear Information System (INIS)

Idbaih, A.; Taillibert, S.; Simon, J.M.; Lopez, S.; Lang, P.; Toubiana, T.; Feuvret, L.; Mazeron, J.J.; Idbaih, A.; Taillibert, S.; Psimaras, D.; Delattre, J.Y.; Schneble, H.M.

2008-01-01

Purpose: The optimal schedule of irradiation in elderly patients suffering from glioblastoma multiform (G.B.M.) is unsettled. Materials and methods: This study reviewed the charts of 28 consecutive G.B.M. patients aged 70 years or more with a Karnofsky Performance Status (K.P.S.) greater than or equal to 70 who received a short course of radiotherapy (40 grays in 15 fractions over three weeks). Results: The median age at surgery was 74.6 years (range, 70.1 - 85.7). No patient received prior or concomitant chemotherapy. The median progression-free survival and overall survival were 21.6 weeks (95% CI, 17.0 - 39.9) and 50.6 weeks (95% CI, 26.3 - 62.0), respectively. Even within a narrow range (< 90 or = 90), K.P.S. remained a prognostic factor (p = 0.03). Tolerance appeared acceptable in terms of K.P.S. changes and corticosteroid use during radiation therapy. Conclusion: These results support the efficacy of short schedule radiotherapy for G.B.M. in elderly patients with a good K.P.S.. (authors)

A Phase I Dose Escalation Study of Hypofractionated IMRT Field-in-Field Boost for Newly Diagnosed Glioblastoma Multiforme

Energy Technology Data Exchange (ETDEWEB)

Monjazeb, Arta M., E-mail: arta.monjazeb@ucdmc.ucdavis.edu [U.C. Davis School of Medicine, Department of Radiation Oncology, Sacramento, CA (United States); Ayala, Deandra; Jensen, Courtney [Radiation Oncology, Wake Forest University Health Sciences, Winston-Salem, NC (United States); Case, L. Douglas [Biostatistical Sciences, Wake Forest University Health Sciences, Winston-Salem, NC (United States); Bourland, J. Daniel; Ellis, Thomas L. [Neurosurgery, Wake Forest University Health Sciences, Winston-Salem, NC (United States); McMullen, Kevin P.; Chan, Michael D. [Radiation Oncology, Wake Forest University Health Sciences, Winston-Salem, NC (United States); Tatter, Stephen B. [Neurosurgery, Wake Forest University Health Sciences, Winston-Salem, NC (United States); Lesser, Glen J. [Hematology Oncology, Wake Forest University Health Sciences, Winston-Salem, NC (United States); Shaw, Edward G. [Radiation Oncology, Wake Forest University Health Sciences, Winston-Salem, NC (United States)

2012-02-01

Objectives: To describe the results of a Phase I dose escalation trial for newly diagnosed glioblastoma multiforme (GBM) using a hypofractionated concurrent intensity-modulated radiotherapy (IMRT) boost. Methods: Twenty-one patients were enrolled between April 1999 and August 2003. Radiotherapy consisted of daily fractions of 1.8 Gy with a concurrent boost of 0.7 Gy (total 2.5 Gy daily) to a total dose of 70, 75, or 80 Gy. Concurrent chemotherapy was not permitted. Seven patients were enrolled at each dose and dose limiting toxicities were defined as irreversible Grade 3 or any Grade 4-5 acute neurotoxicity attributable to radiotherapy. Results: All patients experienced Grade 1 or 2 acute toxicities. Acutely, 8 patients experienced Grade 3 and 1 patient experienced Grade 3 and 4 toxicities. Of these, only two reversible cases of otitis media were attributable to radiotherapy. No dose-limiting toxicities were encountered. Only 2 patients experienced Grade 3 delayed toxicity and there was no delayed Grade 4 toxicity. Eleven patients requiring repeat resection or biopsy were found to have viable tumor and radiation changes with no cases of radionecrosis alone. Median overall and progression-free survival for this cohort were 13.6 and 6.5 months, respectively. One- and 2-year survival rates were 57% and 19%. At recurrence, 15 patients received chemotherapy, 9 underwent resection, and 5 received radiotherapy. Conclusions: Using a hypofractionated concurrent IMRT boost, we were able to safely treat patients to 80 Gy without any dose-limiting toxicity. Given that local failure still remains the predominant pattern for GBM patients, a trial of dose escalation with IMRT and temozolomide is warranted.

A Phase I Dose Escalation Study of Hypofractionated IMRT Field-in-Field Boost for Newly Diagnosed Glioblastoma Multiforme

International Nuclear Information System (INIS)

Monjazeb, Arta M.; Ayala, Deandra; Jensen, Courtney; Case, L. Douglas; Bourland, J. Daniel; Ellis, Thomas L.; McMullen, Kevin P.; Chan, Michael D.; Tatter, Stephen B.; Lesser, Glen J.; Shaw, Edward G.

2012-01-01

Objectives: To describe the results of a Phase I dose escalation trial for newly diagnosed glioblastoma multiforme (GBM) using a hypofractionated concurrent intensity-modulated radiotherapy (IMRT) boost. Methods: Twenty-one patients were enrolled between April 1999 and August 2003. Radiotherapy consisted of daily fractions of 1.8 Gy with a concurrent boost of 0.7 Gy (total 2.5 Gy daily) to a total dose of 70, 75, or 80 Gy. Concurrent chemotherapy was not permitted. Seven patients were enrolled at each dose and dose limiting toxicities were defined as irreversible Grade 3 or any Grade 4–5 acute neurotoxicity attributable to radiotherapy. Results: All patients experienced Grade 1 or 2 acute toxicities. Acutely, 8 patients experienced Grade 3 and 1 patient experienced Grade 3 and 4 toxicities. Of these, only two reversible cases of otitis media were attributable to radiotherapy. No dose-limiting toxicities were encountered. Only 2 patients experienced Grade 3 delayed toxicity and there was no delayed Grade 4 toxicity. Eleven patients requiring repeat resection or biopsy were found to have viable tumor and radiation changes with no cases of radionecrosis alone. Median overall and progression-free survival for this cohort were 13.6 and 6.5 months, respectively. One- and 2-year survival rates were 57% and 19%. At recurrence, 15 patients received chemotherapy, 9 underwent resection, and 5 received radiotherapy. Conclusions: Using a hypofractionated concurrent IMRT boost, we were able to safely treat patients to 80 Gy without any dose-limiting toxicity. Given that local failure still remains the predominant pattern for GBM patients, a trial of dose escalation with IMRT and temozolomide is warranted.

Advanced case of glioblastoma multiforme and pregnancy. An ethical dilemma.

Science.gov (United States)

Al-Rasheedy, Intisar M; Al-Hameed, Fahad M

2015-10-01

Glioblastoma multiforme (GBM) is the most common and malignant form of the glial tumors. Advanced and treated GBM is rarely associated with pregnancy for many reasons. Glioblastoma multiforme presenting during pregnancy carries unique challenges to the patient, baby, family, and health care providers. We describe an unusual case of advanced GBM that was treated with maximum doses of chemotherapy and radiations, and she became pregnant and presented at eighteenth weeks of gestation. Her medical management was associated with a significant ethical dilemma. We managed to deliver the baby safely through cesarean section at week 28 despite the critical condition of the mother. Unfortunately, the mother died 2 weeks post delivery. We concluded that although recurrent and treated GBM is rarely associated with pregnancy and carries dismal prognosis, but if it occurs, it can still be carried, and a multidisciplinary team work is the key for successful outcome.

Therapeutic Efficacy of Aldoxorubicin in an Intracranial Xenograft Mouse Model of Human Glioblastoma

Directory of Open Access Journals (Sweden)

Luis Marrero

2014-10-01

Full Text Available Glioblastoma multiforme (GBM is the most aggressive primary brain tumor with a median survival of 12 to 15 months after diagnosis. Acquired chemoresistance, high systemic toxicity, and low penetration of the blood brain barrier by many anticancer drugs contribute to the failure of anti-GBM therapies. To circumvent some of these obstacles, we tested a novel prodrug approach to evaluate anti-GBM efficacy by utilizing serum albumin-binding doxorubicin (Doxo, aldoxorubicin (Aldoxo, which is less toxic, is released from albumin in an acidic environment and accumulates in tumor tissues. A human GBM cell line that expresses a luciferase reporter (U87-luc was stereotactically injected into the left striatum of the brain of immunodeficient mice. Following initial tumor growth for 12 days, mice were injected once a week in the tail-vein with Aldoxo [24 mg/kg or 18 mg/kg of doxorubicin equivalents—3/4 maximum tolerated dose (MTD], Doxo [6 mg/kg (3/4 MTD], or vehicle. Aldoxo-treated mice demonstrated significantly slower growth of the tumor when compared to vehicle-treated or Doxo-treated mice. Five out of eight Aldoxo-treated mice remained alive more than 60 days with a median survival of 62 days, while the median survival of vehicle- and Doxo-treated mice was only 26 days. Importantly, Aldoxo-treated mice exhibited high levels of Doxo within the tumor tissue, accompanied by low tumor cell proliferation (Ki67 and abundant intratumoral programmed cell death (cleaved caspase-3. Effective accumulation of Aldoxo in brain tumor tissues but not normal brain, its anti-tumor efficacy, and low toxicity, provide a strong rationale for evaluating this novel drug conjugate as a treatment for patients afflicted with GBM.

Impact of therapy on quality of life, neurocognitive function and their correlates in glioblastoma multiforme: a review

DEFF Research Database (Denmark)

Henriksson, Roger; Asklund, Thomas; Poulsen, Hans Skovgaard

2011-01-01

The maintenance of quality of life (QoL) in patients with high-grade glioma is an important endpoint during treatment, particularly in those with glioblastoma multiforme (GBM) given its dismal prognosis despite limited advances in standard therapy. It has proven difficult to identify new therapies...... that extend survival in patients with recurrent GBM, so one of the primary aims of new therapies is to reduce morbidity, restore or preserve neurologic functions, and the capacity to perform daily activities. Apart from temozolomide, cytotoxic chemotherapeutic agents do not appear to significantly impact...... response or survival, but produce toxicity that is likely to negatively impact QoL. New biological agents, such as bevacizumab, can induce a clinically meaningful proportion of durable responses among patients with recurrent GBM with an acceptable safety profile. Emerging evidence suggests that bevacizumab...

Chemical and Plant-Based Insect Repellents: Efficacy, Safety, and Toxicity.

Science.gov (United States)

Diaz, James H

2016-03-01

Most emerging infectious diseases today are arthropod-borne and cannot be prevented by vaccinations. Because insect repellents offer important topical barriers of personal protection from arthropod-borne infectious diseases, the main objectives of this article were to describe the growing threats to public health from emerging arthropod-borne infectious diseases, to define the differences between insect repellents and insecticides, and to compare the efficacies and toxicities of chemical and plant-derived insect repellents. Internet search engines were queried with key words to identify scientific articles on the efficacy, safety, and toxicity of chemical and plant-derived topical insect repellants and insecticides to meet these objectives. Data sources reviewed included case reports; case series; observational, longitudinal, and surveillance studies; and entomological and toxicological studies. Descriptive analysis of the data sources identified the most effective application of insect repellents as a combination of topical chemical repellents, either N-diethyl-3-methylbenzamide (formerly N, N-diethyl-m-toluamide, or DEET) or picaridin, and permethrin-impregnated or other pyrethroid-impregnated clothing over topically treated skin. The insecticide-treated clothing would provide contact-level insecticidal effects and provide better, longer lasting protection against malaria-transmitting mosquitoes and ticks than topical DEET or picaridin alone. In special cases, where environmental exposures to disease-transmitting ticks, biting midges, sandflies, or blackflies are anticipated, topical insect repellents containing IR3535, picaridin, or oil of lemon eucalyptus (p-menthane-3, 8-diol or PMD) would offer better topical protection than topical DEET alone. Copyright © 2016 Wilderness Medical Society. Published by Elsevier Inc. All rights reserved.

Phase I/II Trial of Hyperfractionated Concomitant Boost Proton Radiotherapy for Supratentorial Glioblastoma Multiforme

International Nuclear Information System (INIS)

Mizumoto, Masashi; Tsuboi, Koji; Igaki, Hiroshi; Yamamoto, Tetsuya; Takano, Shingo; Oshiro, Yoshiko; Hayashi, Yasutaka; Hashii, Haruko; Kanemoto, Ayae; Nakayama, Hidetsugu; Sugahara, Shinji; Sakurai, Hideyuki; Matsumura, Akira; Tokuuye, Koichi

2010-01-01

Purpose: To evaluate the safety and efficacy of postoperative hyperfractionated concomitant boost proton radiotherapy with nimustine hydrochloride for supratentorial glioblastoma multiforme (GBM). Methods and Materials: Twenty patients with histologically confirmed supratentorial GBM met the following criteria: (1) a Karnofsky performance status of ≥60; (2) the diameter of the enhanced area before radiotherapy was ≤40 cm; and (3) the enhanced area did not extend to the brain stem, hypothalamus, or thalamus. Magnetic resonance imaging (MRI) T 2 -weighted high area (clinical tumor volume 3 [CTV3]) was treated by x-ray radiotherapy in the morning (50.4 Gy in 28 fractions). More than 6 hours later, 250 MeV proton beams were delivered to the enhanced area plus a 10-mm margin (CTV2) in the first half of the protocol (23.1 GyE in 14 fractions) and to the enhanced volume (CTV1) in the latter half (23.1 GyE in 14 fraction). The total dose to the CTV1 was 96.6 GyE. Nimustine hydrochloride (80 mg/m2) was administered during the first and fourth weeks. Results: Acute toxicity was mainly hematologic and was controllable. Late radiation necrosis and leukoencephalopathy were each seen in one patient. The overall survival rates after 1 and 2 years were 71.1% and 45.3%, respectively. The median survival period was 21.6 months. The 1- and 2-year progression-free survival rates were 45.0% and 15.5%, respectively. The median MRI change-free survival was 11.2 months. Conclusions: Hyperfractionated concomitant boost proton radiotherapy (96.6 GyE in 56 fractions) for GBM was tolerable and beneficial if the target size was well considered. Further studies are warranted to pursue the possibility of controlling border region recurrences.

Nanoparticles of carbon allotropes inhibit glioblastoma multiforme angiogenesis in ovo

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Grodzik, Marta; Sawosz, Ewa; Wierzbicki, Mateusz

2011-01-01

The objective of the study was to determine the effect of carbon nanoparticles produced by different methods on the growth of brain tumor and the development of blood vessels. Glioblastoma multiforme cells were cultured on the chrioallantoic membrane of chicken embryo and after 7 days of incubati...

Efficacy and Toxicity of Intrathecal Liposomal Cytarabine in First-line Therapy of Childhood Acute Lymphoblastic Leukemia

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Levinsen, Mette; Harila-Saari, Arja; Grell, Kathrine

2016-01-01

We investigated efficacy and toxicity of replacing conventional triple (cytarabine, methotrexate, and hydrocortisone) intrathecal therapy (TIT) with liposomal cytarabine during maintenance therapy among 40 acute lymphoblastic leukemia patients. Twenty-eight of 29 patients in the TIT arm received...

Investigation of platinum nanoparticle properties against U87 glioblastoma multiforme

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Kutwin, Marta; Sawosz, Ewa; Jaworski, Slawomir

2017-01-01

a harmful influence on viability of U87 glioblastoma multiforme (GBM) cells, but also showed genotoxic properties as well as a pro-apoptotic effect on cancer cells. It was found that NP-Pt decreased the weight and volume of U87 GBM tumor tissue and caused pathomorphological changes in the ultrastructure...

Long-term Survival of Six Patients with Glioblastoma Multiforme: Case Series and Review of the Literature

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Shapour Omidvari

2012-04-01

Full Text Available The median overall survival in glioblastoma multiforme is usually less than one year. Long-term survival is rare and is seen in only 3%-6% of GBM patients. The present study reports the characteristics and treatment outcomes of six cases of glioblastoma multiforme with long-term survival. A literature review is also presented.Between 1990 and 2008, 217 glioblastoma multiforme patients have been treated at our center of which six cases (four males survived for three years or longer. The mean age of the six cases was 25.7 years. All patients received postoperative radiotherapy with a mean dose of 55 gray and four patients received nitrosourea-based chemotherapy.Patients' mean survival was 5.2 years. The results of this study and review of the literature have indicated that long-term (more than three years survival is exceptional and mainly observed in younger patients with good performance status and following complete surgical tumor resection.

Correlation between paclitaxel Tc > 0.05 and its therapeutic efficacy and severe toxicities in ovarian cancer patients

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Shuyao Zhang

2016-01-01

Conclusion: These results indicated that the PTX Tc > 0.05 correlated with therapeutic efficacy and drug toxicity. Therefore, monitoring the PTX Tc > 0.05 other than blood concentration of PTX is necessary to optimize individual treatment.

Survival benefit of surgery in recurrent glioblastoma multiforme.

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Choudry, Usama Khalid; Khan, Saad Akhtar; Shamim, Muhammad Shahzad

2017-12-01

There is an ongoing debate regarding role of surgery for recurrent glioblastoma multiforme (GBM). Older literature hinted at only modest survival benefits with surgery and a high rate of morbidity. However, more recent literature suggests better survival that may be attributed to better surgical techniques and better options in adjuvant treatment. Herein the authors review recent literature with regards to the possible role of surgery in recurrent GBM and also look into the key factors impacting second surgery. .

New extracellular factors in glioblastoma multiforme development: neurotensin, growth differentiation factor-15, sphingosine-1-phosphate and cytomegalovirus infection

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Korbecki, Jan; Gutowska, Izabela; Kojder, Ireneusz; Jeżewski, Dariusz; Goschorska, Marta; Łukomska, Agnieszka; Lubkowska, Anna; Chlubek, Dariusz; Baranowska-Bosiacka, Irena

2018-01-01

Recent years have seen considerable progress in understanding the biochemistry of cancer. For example, more significance is now assigned to the tumor microenvironment, especially with regard to intercellular signaling in the tumor niche which depends on many factors secreted by tumor cells. In addition, great progress has been made in understanding the influence of factors such as neurotensin, growth differentiation factor-15 (GDF-15), sphingosine-1-phosphate (S1P), and infection with cytomegalovirus (CMV) on the ‘hallmarks of cancer’ in glioblastoma multiforme. Therefore, in the present work we describe the influence of these factors on the proliferation and apoptosis of neoplastic cells, cancer stem cells, angiogenesis, migration and invasion, and cancer immune evasion in a glioblastoma multiforme tumor. In particular, we discuss the effect of neurotensin, GDF-15, S1P (including the drug FTY720), and infection with CMV on tumor-associated macrophages (TAM), microglial cells, neutrophil and regulatory T cells (Treg), on the tumor microenvironment. In order to better understand the role of the aforementioned factors in tumoral processes, we outline the latest models of intratumoral heterogeneity in glioblastoma multiforme. Based on the most recent reports, we discuss the problems of multi-drug therapy in treating glioblastoma multiforme. PMID:29467963

Liposomal n-butylidenephthalide protects the drug from oxidation and enhances its antitumor effects in glioblastoma multiforme

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Lin YL

2015-09-01

Full Text Available Yu-Ling Lin,1,2,* Kai-Fu Chang,3,* Xiao-Fan Huang,3 Che-Lun Hung,4 Shyh-Chang Chen,5 Wan-Ru Chao,6,7 Kuang-Wen Liao,1,8 Nu-Man Tsai3,9 1College of Biological Science and Technology, 2Center for Bioinformatics Research, National Chiao Tung University, Hsinchu, 3School of Medical Laboratory and Biotechnology, Chung Shan Medical University, 4Department of Computer Science and Communication Engineering, Providence University, 5Department of Pathology and Laboratory Medicine, Taichung Veterans General Hospital, 6Institute of Medicine, Chung Shan Medical University, 7Department of Pathology, Chung Shan Medical University and Chung Shan Medical University Hospital, Taichung, 8Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, Hsinchu, 9Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan *These authors contributed equally to this work Background: The natural compound n-butylidenephthalide (BP can pass through the blood–brain barrier to inhibit the growth of glioblastoma multiforme tumors. However, BP has an unstable structure that reduces its antitumor activity and half-life in vivo.Objective: The aim of this study is to design a drug delivery system to encapsulate BP to enhance its efficacy by improving its protection and delivery.Methods: To protect its structural stability against protein-rich and peroxide solutions, BP was encapsulated into a lipo-PEG-PEI complex (LPPC. Then, the cytotoxicity of BP/LPPC following preincubation in protein-rich, acid/alkaline, and peroxide solutions was analyzed by MTT. Cell uptake of BP/LPPC was also measured by confocal microscopy. The therapeutic effects of BP/LPPC were analyzed in xenograft mice following intratumoral and intravenous injections.Results: When BP was encapsulated in LPPC, its cytotoxicity was maintained following preincubation in protein-rich, acid/alkaline, and peroxide solutions. The cytotoxic activity of encapsulated BP was higher than

Metástases intrarraquidianas de glioblastoma multiforme supratentorial da infância: relato de caso Spinal cord metastatic glioblastoma multiforme of childhood: case report

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Patricia Imperatriz Porto Rondinelli

2002-09-01

Full Text Available Relatamos o caso de uma menina de onze anos de idade com glioblastoma multiforme na região têmporo-parietal direita, completamente ressecado cirurgicamente, submetida a radioterapia craniana pós-operatória. Houve recaída três meses após, em topografia distante do sítio primário, na porção caudal do canal raquidiano. Após, ocorreu evolução rápida para o óbito. A propósito desse caso, discutimos nossa experiência quanto à conduta nesses tumores e a literatura sobre o assunto.We report the case of an eleven years-old girl with a right temporo-parietal glioblastoma multiforme. The tumor was totally resected on neurossurgery, and cranial radioteraphy was applied at next. The tumor recurred three months later, far from primary site, in the caudal portion of the spinal canal. Death occurred in less than one month later. Taking into account the data of this case, we discuss our experience in the management of such tumors and the literature on the subject.

Comparison of vitamins K1, K2 and K3 effects on growth of rat glioma and human glioblastoma multiforme cells in vitro.

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Oztopçu, Pinar; Kabadere, Selda; Mercangoz, Ayşe; Uyar, Ruhi

2004-09-01

Glioblastoma multiforme is characterized as highly invasive and rapidly growing astrocytomas, and scientists have sought for efficient treatment against malignant gliomas for a long time. Therefore, we compared the respond of rat glioma (C6) and glioblastoma multiforme cells derived from two patients to vitamins K1, K2 and K3. The cells were exposed to 100, 250, 500, 750 and 1000 microM of vitamins K1 and K2, and 1, 10, 25, 50, 75 and 100 microM of vitamin K3 for 24 hours in an incubator atmosphere of 5% CO2, 37 degrees C and 100% humidity. Cell viability was estimated by MTT assay. Vitamin K1 showed no growth effect on all the glioma cells examined. Vitamin K2 did not cause any change in number of C6, however induced growth inhibition in a dose-dependent manner on glioblastoma multiforme. The IC50 values of vitamin K2 were 960 microM and 970 microM for glioblastoma multiforme, respectively. Vitamin K3 had also growth inhibitory effect in a dose-dependent manner on both C6 and glioblastoma multiforme. The IC50 values were 41 microM, 24 microM and 23 microM for vitamin K3, respectively. We concluded that vitamin K3 is more effective than vitamin K2 for inhibition of cancer cell growth, and might have an alternative value as an anticancer drug against glioblastoma multiforme.

Glioblastoma multiforme med intra- og ekstramedullær disseminering til spinalkanalen

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Hansson, Karin; Gutte Borgwardt, Henrik; Idris, Fadi

2013-01-01

Metastases to the spinal cord from glioblastoma multiforme (GBM) are uncommon, but important to have in mind when patients with a history of GBM present with symptoms that do not correlate with the primary disease pattern. We report a rare case, where a male with GBM, six months after tumour...

Erythema multiforme and Stevens-Johnson syndrome in patients receiving cranial irradiation and phenytoin

International Nuclear Information System (INIS)

Delattre, J.Y.; Safai, B.; Posner, J.B.

1988-01-01

In 15 months we encountered eight patients with intracranial tumors who developed erythema multiforme (EM) or erythema multiforme bullosa (Stevens-Johnson syndrome). All occurred shortly after use of phenytoin (DPH) and brain radiation therapy (WBRT). The clinical picture differed from the classic form of EM in that the erythema began on the scalp and spread to the extremities, progressing in three cases to extensive bullous formation. There were no cases of EM among patients who received either DPH or radiotherapy alone. The combination of DPH, WBRT, and tapering of steroids seems to predispose to EM. The pathogenesis of the disorder is probably immunologic. In the absence of seizures, anticonvulsants should not be given routinely to patients with brain tumors. When anticonvulsants are necessary in patients scheduled for WBRT, DPH may not be the drug of choice

A prospective PET study of patients with glioblastoma multiforme

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Andersen, Preben B.; Blinkenberg, M; Lassen, U

2006-01-01

OBJECTIVE: To study the post-surgical metabolic and structural cerebral changes in patients with glioblastoma multiforme (GBM). MATERIALS AND METHODS: We examined ten patients prospectively with newly diagnosed GBM. All patients were primarily treated with surgery, followed by chemotherapy...... compared with structural imaging in the prospective evaluation of GBM. We found a difference in metabolic increase and tumor growth between the two treatment regimens, although this finding has limited relevance due to the design of the study....

On the Concepts and History of Glioblastoma Multiforme - Morphology, Genetics and Epigenetics

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Stoyanov George St.

2018-03-01

Full Text Available Glioblastoma multiforme (GBM is a grade IV WHO malignant tumor with astrocytic differentiation. As one of the most common clinically diagnosed central nervous system (CNS oncological entries, there have been a wide variety of historical reports of the description and evolution of ideas regarding these tumors.

Toxicity and efficacy of carbon nanotubes and graphene: the utility of carbon-based nanoparticles in nanomedicine.

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Zhang, Yongbin; Petibone, Dayton; Xu, Yang; Mahmood, Meena; Karmakar, Alokita; Casciano, Dan; Ali, Syed; Biris, Alexandru S

2014-05-01

Carbon-based nanomaterials have attracted great interest in biomedical applications such as advanced imaging, tissue regeneration, and drug or gene delivery. The toxicity of the carbon nanotubes and graphene remains a debated issue although many toxicological studies have been reported in the scientific community. In this review, we summarize the biological effects of carbon nanotubes and graphene in terms of in vitro and in vivo toxicity, genotoxicity and toxicokinetics. The dose, shape, surface chemistry, exposure route and purity play important roles in the metabolism of carbon-based nanomaterials resulting in differential toxicity. Careful examination of the physico-chemical properties of carbon-based nanomaterials is considered a basic approach to correlate the toxicological response with the unique properties of the carbon nanomaterials. The reactive oxygen species-mediated toxic mechanism of carbon nanotubes has been extensively discussed and strategies, such as surface modification, have been proposed to reduce the toxicity of these materials. Carbon-based nanomaterials used in photothermal therapy, drug delivery and tissue regeneration are also discussed in this review. The toxicokinetics, toxicity and efficacy of carbon-based nanotubes and graphene still need to be investigated further to pave a way for biomedical applications and a better understanding of their potential applications to humans.

TC > 0.05 as a Pharmacokinetic Parameter of Paclitaxel for Therapeutic Efficacy and Toxicity in Cancer Patients.

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Xin, D S; Zhou, L; Li, C Z; Zhang, S Q; Huang, H Q; Qiu, G D; Lin, L F; She, Y Q; Zheng, J T; Chen, C; Fang, L; Chen, Zhe-Sheng; Zhang, S Y

2018-03-05

Paclitaxel (PTX) has remarkable anti-tumor activity, but it causes severe toxicities. There is an urgent need to seek an appropriate pharmacokinetic parameter of PTX to improve treatment efficacy and reduce adverse effects. To evaluate the association of pharmacokinetic parameter TC>0.05 of paclitaxel (PTX) and its therapeutic efficacy and toxicity in patients with solid tumors. A total of 295 patients with ovarian cancer, esophageal cancer, breast cancer, and non-small cell lung cancer (NSCLC), who were admitted to the Tumor Hospital of Shantou University Medical College, China, were recruited for this study. Patients received 3 weeks of PTX chemotherapy. The plasma concentrations of PTX were examined using the MyPaclitaxelTM kit. The patients' PTX TC>0.05 (the time during which PTX plasma concentration exceed 0.05 μmol/L) were calculated based on pharmacokinetic analysis. The results showed that: (1) the concentrations of PTX in these 295 patients ranged from 0.0358-0.127 μmol/L; (2) the PTX TC> 0.05 ranged from 14 to 38 h with a median time of 27 h; (3) among all treatment cycles, there was a statistically significant difference in the PTX TC>0.05 between CR+PR and SD+PD; (4) with the increasing value of TC>0.05, level of leukopenia and leukopenic fever increased; (5) high PTX TC>0.05 led to the occurrence of neutropenia, neutropenic fever, severe anemia, and severe peripheral neurotoxicity. Taken together, our results indicated that the pharmacokinetic parameter PTX TC>0.05 was an effective measure of treatment efficacy and toxicity in patients with solid tumors. Maintaining PTX TC>0.05 at 26 to 30 h could improve its efficacy and reduce the incidence of leukopenia, neutropenia, anemia, and peripheral neurotoxicity in these patients. PTX TC>0.05 is a key pharmacokinetic parameter of PTX which should be monitored to optimize individual treatment in patients with solid tumors. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Aplastic anemia as a cause of death in a patient with glioblastoma multiforme treated with temozolomide

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Kopecky, Jindrich; Priester, Peter; Slovacek, Ladislav; Petera, Jiri; Macingova, Zuzana; Kopecky, Otakar

2010-01-01

Background: Standard treatment of glioblastoma multiforme consists of postoperative radiochemotherapy with temozolomide, followed by a 6-month chemotherapy. Serious hematologic complications are rarely reported. Case Report and Results: The authors present the case of a 61-year-old female patient with glioblastoma multiforme treated with external-beam radiation therapy and concomitant temozolomide. After completion of treatment, the patient developed symptoms of serious aplastic anemia that eventually led to death due to prolonged neutro- and thrombocytopenia followed by infectious complications. Conclusion: Lethal complications following temozolomide are, per se, extremely rare, however, a total of four other cases of aplastic anemia have been reported in the literature so far. (orig.)

Aplastic anemia as a cause of death in a patient with glioblastoma multiforme treated with temozolomide

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Kopecky, Jindrich; Priester, Peter; Slovacek, Ladislav; Petera, Jiri; Macingova, Zuzana [Dept. of Clinical Oncology and Radiotherapy, Charles Univ. Hospital and Faculty of Medicine in Hradec Kralove (Czech Republic); Kopecky, Otakar [Clinical Oncology, Regional Hospital Nachod (Czech Republic)

2010-08-15

Background: Standard treatment of glioblastoma multiforme consists of postoperative radiochemotherapy with temozolomide, followed by a 6-month chemotherapy. Serious hematologic complications are rarely reported. Case Report and Results: The authors present the case of a 61-year-old female patient with glioblastoma multiforme treated with external-beam radiation therapy and concomitant temozolomide. After completion of treatment, the patient developed symptoms of serious aplastic anemia that eventually led to death due to prolonged neutro- and thrombocytopenia followed by infectious complications. Conclusion: Lethal complications following temozolomide are, per se, extremely rare, however, a total of four other cases of aplastic anemia have been reported in the literature so far. (orig.)

TSPO Imaging in Glioblastoma Multiforme

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Jensen, Per; Feng, Ling; Law, Ian

2015-01-01

-CLINDE is superior to (18)F-FET in predicting progression of glioblastoma multiforme (GBM) at follow-up. METHODS: Three patients with World Health Organization grade IV GBM were scanned with (123)I-CLINDE SPECT, (18)F-FET PET, and gadolinium-enhanced MR imaging. Molecular imaging data were compared with follow......-CLINDE (15%-30%). In contrast, VOIs of increased contrast enhancement at follow-up compared with baseline overlapped to a greater extent with baseline (123)I-CLINDE VOIs than (18)F-FET VOIs (21% vs. 8% and 72% vs. 55%). CONCLUSION: Our preliminary results suggest that TSPO brain imaging in GBM may...... be a useful tool for predicting tumor progression at follow-up and may be less susceptible to changes in blood-brain barrier permeability than (18)F-FET. Larger studies are warranted to test the clinical potential of TSPO imaging in GBM, including presurgical planning and radiotherapy....

Chronomodulation of topotecan or X-radiation treatment increases treatment efficacy without enhancing acute toxicity

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Mullins, Dana; Proulx, Denise; Saoudi, A.; Ng, Cheng E.

2005-01-01

Purpose: Topotecan (TPT), a camptothecin analog, is currently used to treat human ovarian and small-cell lung cancer and is in clinical trials for other tumor sites. However, it is unknown whether chronomodulation of TPT treatment is beneficial. We examined the effects of administering TPT or X-radiation (XR) alone at different times of the day or night. Methods: We treated mice bearing human colorectal tumor xenografts at four different times representing the early rest period (9 AM or 3 HALO [hours after light onset]), late rest period (3 PM or 9 HALO), early active period (9 PM or 15 HALO), and late active period (3 AM or 21 HALO) of the mice. We gave either TPT (12 mg/kg, injected i.p.) or XR (4 Gy, directed to the tumor) twice weekly on Days 0, 4, 7, 10 within 2 weeks. Results: Treatment with either TPT or XR at 3 AM demonstrated the greatest efficacy (measured by a tumor regrowth assay) without significantly increasing acute toxicity (assessed by a decrease in leukocyte counts or body weight). Conversely, treatment at 3 PM, in particular, showed increased toxicity without any enhanced efficacy. Conclusions: Our study provided the first evidence that chronomodulation of TPT treatments, consistent with the findings of other camptothecin analogs, is potentially clinically beneficial. Additionally, our findings suggest that chronomodulation of fractionated XR treatments is also potentially clinically beneficial

Chronomodulation of topotecan or X-radiation treatment increases treatment efficacy without enhancing acute toxicity.

Science.gov (United States)

Mullins, Dana; Proulx, Denise; Saoudi, A; Ng, Cheng E

2005-05-01

Topotecan (TPT), a camptothecin analog, is currently used to treat human ovarian and small-cell lung cancer and is in clinical trials for other tumor sites. However, it is unknown whether chronomodulation of TPT treatment is beneficial. We examined the effects of administering TPT or X-radiation (XR) alone at different times of the day or night. We treated mice bearing human colorectal tumor xenografts at four different times representing the early rest period (9 am or 3 HALO [hours after light onset]), late rest period (3 pm or 9 HALO), early active period (9 pm or 15 HALO), and late active period (3 am or 21 HALO) of the mice. We gave either TPT (12 mg/kg, injected i.p.) or XR (4 Gy, directed to the tumor) twice weekly on Days 0, 4, 7, 10 within 2 weeks. Treatment with either TPT or XR at 3 am demonstrated the greatest efficacy (measured by a tumor regrowth assay) without significantly increasing acute toxicity (assessed by a decrease in leukocyte counts or body weight). Conversely, treatment at 3 pm, in particular, showed increased toxicity without any enhanced efficacy. Our study provided the first evidence that chronomodulation of TPT treatments, consistent with the findings of other camptothecin analogs, is potentially clinically beneficial. Additionally, our findings suggest that chronomodulation of fractionated XR treatments is also potentially clinically beneficial.

Chlamydia pneumoniae infection-associated erythema multiforme

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Shinsaku Imashuku

2013-06-01

Full Text Available There is a well-known correlation between Herpes simplex (HSV infection and erythema multiforme (EM. More recently, in Japan, it was found that Chlamydia pneumoniae (Cp may promote the development of EM. All cases of Cp infection-associated EM that had been diagnosed in our clinic over the past two years (from 2011 to 2012 were analyzed. Cp infection was diagnosed on the basis of a significant increase (>2.00 in anti-Cp IgM titers, as measured by the HITAZYME-ELISA test. There were 7 cases of Cp-EM, one male and 6 females. Median age was 13 years (range 3-29 years. It is recommended that the possible involvement of Cp infection, besides HSV or Mycoplasma pneumoniae infections, should be considered in all cases of EM.

Statin use and survival following glioblastoma multiforme

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Gaist, David; Hallas, Jesper; Friis, Søren

2014-01-01

with glioblastoma multiforme (GBM). METHODS: We identified 1562 patients diagnosed with GBM during 2000-2009 from the Danish Cancer Registry and linked this cohort to Danish nationwide demographic and health registries. Within the GBM cohort, each patient recorded as using statins prior to diagnosis (defined as ≥2......-cause death associated with prediagnostic statin use. RESULTS: A total of 339 GBM patients were included in the analyses. Of these, 325 died during median follow-up of 6.9 months (interquartile range: 3.8-13.4 months). Prediagnostic statin use was associated with a reduced HR of death (0.79; 95% CI: 0......: 0.63-1.01). CONCLUSION: Long-term prediagnostic statin use may improve survival following GBM....

Clinical variables serve as prognostic factors in a model for survival from glioblastoma multiforme

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Michaelsen, Signe Regner; Christensen, Ib Jarle; Grunnet, Kirsten

2013-01-01

Although implementation of temozolomide (TMZ) as a part of primary therapy for glioblastoma multiforme (GBM) has resulted in improved patient survival, the disease is still incurable. Previous studies have correlated various parameters to survival, although no single parameter has yet been...

Nestin expression in the cell lines derived from glioblastoma multiforme

International Nuclear Information System (INIS)

Veselska, Renata; Kuglik, Petr; Cejpek, Pavel; Svachova, Hana; Neradil, Jakub; Loja, Tomas; Relichova, Jirina

2006-01-01

Nestin is a protein belonging to class VI of intermediate filaments that is produced in stem/progenitor cells in the mammalian CNS during development and is consecutively replaced by other intermediate filament proteins (neurofilaments, GFAP). Down-regulated nestin may be re-expressed in the adult organism under certain pathological conditions (brain injury, ischemia, inflammation, neoplastic transformation). Our work focused on a detailed study of the nestin cytoskeleton in cell lines derived from glioblastoma multiforme, because re-expression of nestin together with down-regulation of GFAP has been previously reported in this type of brain tumor. Two cell lines were derived from the tumor tissue of patients treated for glioblastoma multiforme. Nestin and other cytoskeletal proteins were visualized using imunocytochemical methods: indirect immunofluorescence and immunogold-labelling. Using epifluorescence and confocal microscopy, we described the morphology of nestin-positive intermediate filaments in glioblastoma cells of both primary cultures and the derived cell lines, as well as the reorganization of nestin during mitosis. Our most important result came through transmission electron microscopy and provided clear evidence that nestin is present in the cell nucleus. Detailed information concerning the pattern of the nestin cytoskeleton in glioblastoma cell lines and especially the demonstration of nestin in the nucleus represent an important background for further studies of nestin re-expression in relationship to tumor malignancy and invasive potential

Pediatric glioblastoma multiforme: A single-institution experience.

Science.gov (United States)

Ansari, Mansour; Nasrolahi, Hamid; Kani, Amir-Abbas; Mohammadianpanah, Mohammad; Ahmadloo, Niloofar; Omidvari, Shapour; Mosalaei, Ahmad

2012-07-01

Glioblastoma multiforme (GBM) is the most common astrocytoma in adults and has a poor prognosis, with a median survival of about 12 months. But, it is rare in children. We report our experience on the pediatric population (20 years or younger) with GBM. Twenty-three patients with GBM who were treated at our hospital during 1990-2008 were evaluated. The mean age was 15.2 years, and the majority of them (14/23) were male. All had received radiotherapy and some had also received chemotherapy. The mean survival was 16.0 months. Two cases survived more than 5 years. Age, radiation dose and performance status were significantly related to survival. GBM in pediatric patients were not very common in our center, and prognosis was unfavorable.

Saponin 1 induces apoptosis and suppresses NF-κB-mediated survival signaling in glioblastoma multiforme (GBM.

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Juan Li

Full Text Available Saponin 1 is a triterpeniod saponin extracted from Anemone taipaiensis, a traditional Chinese medicine against rheumatism and phlebitis. It has also been shown to exhibit significant anti-tumor activity against human leukemia (HL-60 cells and human hepatocellular carcinoma (Hep-G2 cells. Herein we investigated the effect of saponin 1 in human glioblastoma multiforme (GBM U251MG and U87MG cells. Saponin 1 induced significant growth inhibition in both glioblastoma cell lines, with a 50% inhibitory concentration at 24 h of 7.4 µg/ml in U251MG cells and 8.6 µg/ml in U87MG cells, respectively. Nuclear fluorescent staining and electron microscopy showed that saponin 1 caused characteristic apoptotic morphological changes in the GBM cell lines. Saponin 1-induced apoptosis was also verified by DNA ladder electrophoresis and flow cytometry. Additionally, immunocytochemistry and western blotting analyses revealed a time-dependent decrease in the expression and nuclear location of NF-κB following saponin 1 treatment. Western blotting data indicated a significant decreased expression of inhibitors of apoptosis (IAP family members,(e.g., survivin and XIAP by saponin 1. Moreover, saponin 1 caused a decrease in the Bcl-2/Bax ratio and initiated apoptosis by activating caspase-9 and caspase-3 in the GBM cell lines. These findings indicate that saponin 1 inhibits cell growth of GBM cells at least partially by inducing apoptosis and inhibiting survival signaling mediated by NF-κB. In addition, in vivo study also demonstrated an obvious inhibition of saponin 1 treatment on the tumor growth of U251MG and U87MG cells-produced xenograft tumors in nude mice. Given the minimal toxicities of saponin 1 in non-neoplastic astrocytes, our results suggest that saponin 1 exhibits significant in vitro and in vivo anti-tumor efficacy and merits further investigation as a potential therapeutic agent for GBM.

Saponin 1 Induces Apoptosis and Suppresses NF-κB-Mediated Survival Signaling in Glioblastoma Multiforme (GBM)

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Tang, Chi; Li, Bo; Wang, Yuangang; Gao, Zhenhui; Luo, Peng; Yin, Anan; Wang, Xiaoyang; Cheng, Guang; Fei, Zhou

2013-01-01

Saponin 1 is a triterpeniod saponin extracted from Anemone taipaiensis, a traditional Chinese medicine against rheumatism and phlebitis. It has also been shown to exhibit significant anti-tumor activity against human leukemia (HL-60 cells) and human hepatocellular carcinoma (Hep-G2 cells). Herein we investigated the effect of saponin 1 in human glioblastoma multiforme (GBM) U251MG and U87MG cells. Saponin 1 induced significant growth inhibition in both glioblastoma cell lines, with a 50% inhibitory concentration at 24 h of 7.4 µg/ml in U251MG cells and 8.6 µg/ml in U87MG cells, respectively. Nuclear fluorescent staining and electron microscopy showed that saponin 1 caused characteristic apoptotic morphological changes in the GBM cell lines. Saponin 1-induced apoptosis was also verified by DNA ladder electrophoresis and flow cytometry. Additionally, immunocytochemistry and western blotting analyses revealed a time-dependent decrease in the expression and nuclear location of NF-κB following saponin 1 treatment. Western blotting data indicated a significant decreased expression of inhibitors of apoptosis (IAP) family members,(e.g., survivin and XIAP) by saponin 1. Moreover, saponin 1 caused a decrease in the Bcl-2/Bax ratio and initiated apoptosis by activating caspase-9 and caspase-3 in the GBM cell lines. These findings indicate that saponin 1 inhibits cell growth of GBM cells at least partially by inducing apoptosis and inhibiting survival signaling mediated by NF-κB. In addition, in vivo study also demonstrated an obvious inhibition of saponin 1 treatment on the tumor growth of U251MG and U87MG cells-produced xenograft tumors in nude mice. Given the minimal toxicities of saponin 1 in non-neoplastic astrocytes, our results suggest that saponin 1 exhibits significant in vitro and in vivo anti-tumor efficacy and merits further investigation as a potential therapeutic agent for GBM. PMID:24278406

Phase I Trial of Gross Total Resection, Permanent Iodine-125 Brachytherapy, and Hyperfractionated Radiotherapy for Newly Diagnosed Glioblastoma Multiforme

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Chen, Allen M.; Chang, Susan; Pouliot, Jean; Sneed, Penny K.; Prados, Michael D.; Lamborn, Kathleen R.; Malec, Mary K.; McDermott, Michael W.; Berger, Mitchell S.; Larson, David A.

2007-01-01

Purpose: To evaluate the feasibility of gross total resection and permanent I-125 brachytherapy followed by hyperfractionated radiotherapy for patients with newly diagnosed glioblastoma. Methods and Materials: From April 1999 to May 2002, 21 patients with glioblastoma multiforme were enrolled on a Phase I protocol investigating planned gross total resection and immediate placement of permanent I-125 seeds, followed by postoperative hyperfractionated radiotherapy to a dose of 60 Gy at 100 cGy b.i.d., 5 days per week. Median age and Karnofsky performance status were 50 years (range, 32-65 years) and 90 (range, 70-100), respectively. Toxicity was assessed according to Radiation Therapy Oncology Group criteria. Results: Eighteen patients completed treatment according to protocol. The median preoperative tumor volume on magnetic resonance imaging was 18.6 cm 3 (range, 4.4-41.2 cm 3 ). The median brachytherapy dose measured 5 mm radially outward from the resection cavity was 400 Gy (range, 200-600 Gy). Ten patients underwent 12 reoperations, with 11 of 12 reoperations demonstrating necrosis without evidence of tumor. Because of high toxicity, the study was terminated early. Median progression-free survival and overall survival were 57 and 114 weeks, respectively, but not significantly improved compared with historical patients treated at University of California, San Francisco, with gross total resection and radiotherapy without brachytherapy. Conclusions: Treatment with gross total resection and permanent I-125 brachytherapy followed by hyperfractionated radiotherapy as performed in this study results in high toxicity and reoperation rates, without demonstrated improvement in survival

Difficult diagnosis of brainstem glioblastoma multiforme in a woman: a case report and review of the literature

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Lakhan Shaheen E

2009-10-01

Full Text Available Abstract Introduction Brainstem gliomas are rare in adults. They most commonly occur in the pons and are most likely to be high-grade lesions. The diagnosis of a high-grade brainstem glioma is usually reached due to the presentation of rapidly progressing brainstem, cranial nerve and cerebellar symptoms. These symptoms do, however, overlap with a variety of other central nervous system disorders. Magnetic resonance imaging is the radiographic modality of choice, but can still be misleading. Case presentation A 48-year-old Caucasian woman presented with headache and vomiting followed by cerebellar signs and confusion. Magnetic resonance imaging findings were suggestive of a demyelinating process, but the patient failed to respond to therapy. Her condition rapidly progressed and she died. At autopsy, a high-grade invasive pontine tumor was identified. Histological evaluation revealed glioblastoma multiforme. Conclusion While pontine gliomas are rare in adults, those that do occur tend to be high-grade and rapidly progressive. Progression of symptoms from non-specific findings of headache and vomiting to rapid neurological deterioration, as occurred in our patient, is common in glioblastoma multiforme. While radiographic findings are often suggestive of the underlying pathology, this case represents the possibility of glioblastoma multiforme presenting as a deceptively benign appearing lesion.

Metabolic management of glioblastoma multiforme using standard therapy together with a restricted ketogenic diet: Case Report

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Servadei Franco

2010-04-01

Full Text Available Abstract Background Management of glioblastoma multiforme (GBM has been difficult using standard therapy (radiation with temozolomide chemotherapy. The ketogenic diet is used commonly to treat refractory epilepsy in children and, when administered in restricted amounts, can also target energy metabolism in brain tumors. We report the case of a 65-year-old woman who presented with progressive memory loss, chronic headaches, nausea, and a right hemisphere multi-centric tumor seen with magnetic resonance imaging (MRI. Following incomplete surgical resection, the patient was diagnosed with glioblastoma multiforme expressing hypermethylation of the MGMT gene promoter. Methods Prior to initiation of the standard therapy, the patient conducted water-only therapeutic fasting and a restricted 4:1 (fat: carbohydrate + protein ketogenic diet that delivered about 600 kcal/day. The patient also received the restricted ketogenic diet concomitantly during the standard treatment period. The diet was supplemented with vitamins and minerals. Steroid medication (dexamethasone was removed during the course of the treatment. The patient was followed using MRI and positron emission tomography with fluoro-deoxy-glucose (FDG-PET. Results After two months treatment, the patient's body weight was reduced by about 20% and no discernable brain tumor tissue was detected using either FDG-PET or MRI imaging. Biomarker changes showed reduced levels of blood glucose and elevated levels of urinary ketones. MRI evidence of tumor recurrence was found 10 weeks after suspension of strict diet therapy. Conclusion This is the first report of confirmed GBM treated with standard therapy together with a restricted ketogenic diet. As rapid regression of GBM is rare in older patients following incomplete surgical resection and standard therapy alone, the response observed in this case could result in part from the action of the calorie restricted ketogenic diet. Further studies are needed

Phase II open-label study of nintedanib in patients with recurrent glioblastoma multiforme

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Muhic, Aida; Poulsen, Hans Skovgaard; Mau-Sørensen, Paul Morten

2013-01-01

glioblastoma multiforme (GBM) who had previously failed radiotherapy plus temozolomide as first-line therapy (STUPP), or the same regimen with subsequent bevacizumab-based therapy as second-line treatment (BEV). Patients with a performance status of 0-1, histologically proven GBM, and measurable disease (by...... GBM who had failed 1-2 prior lines of therapy....

Magnetic resonance imaging in 67 cases of glioblastoma multiform and occurrence of metastases

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Ferreira, Nelson Fortes; Barbosa, Marcelo; Amaral, Lazaro L. Faria do; Mendonca, Renato Adam; Lima, Sergio Santos

2004-01-01

The purpose of this paper is to demonstrate the main MRI characteristics of glioblastoma multiform (GBM), the most common CNS primary tumor, emphasizing its location and the occurrence of metastases. The MR imaging of 67 pathologically proven cases of glioblastoma multiform were retrospectively reviewed. The exams were realized in the period between 1995 and 2003, in one of three 1.5 Signa GE units (Milwaukee, WI). The ages of the patients ranged from 4 years to 86 years, mean 60 years, and the occurrence of the tumor was preponderant among men, with 39 cases (58%). The most common location was in the frontal lobes (47%) followed by the temporal lobes (18%) and the parietal lobes (16%). In 19% of the cases there were involvement of more than one site and long distance metastases were seen in 22% of the patients. According to the literature, the most common location of GBM was in the frontal lobe of older than 50 years old men. Metastases occurred in 22% of our cases. (author)

Copper-64 Dichloride as Theranostic Agent for Glioblastoma Multiforme: A Preclinical Study

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Cristina Ferrari

2015-01-01

Full Text Available Glioblastoma multiforme (GBM is the most common primary malignant brain tumor in adults with a median survival time less than one year. To date, there are only a limited number of effective agents available for GBM therapy and this does not seem to add much survival advantage over the conventional approach based on surgery and radiotherapy. Therefore, the development of novel therapeutic approaches to GBM is essential and those based on radionuclide therapy could be of significant clinical impact. Experimental evidence has clearly demonstrated that cancer cells have a particularly high fractional content of copper inside the nucleus compared to normal cells. This behavior can be conveniently exploited both for diagnosis and for delivering therapeutic payloads (theranostic of the radionuclide copper-64 into the nucleus of cancerous cells by intravenous administration of its simplest chemical form as dichloride salt [64Cu]CuCl2. To evaluate the potential theranostic role of [64Cu]CuCl2 in GBM, the present work reports results from a preclinical study carried out in a xenografted GBM tumor mouse model. Biodistribution data of this new agent were collected using a small-animal PET tomograph. Subsequently, groups of tumor implanted nude mice were treated with [64Cu]CuCl2 to simulate single- and multiple-dose therapy protocols, and results were analyzed to estimate therapeutic efficacy.

Therapeutic efficacy and toxicity of bolus application of chemotherapy protocol in the treatment of metastatic colorectal cancer.

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Šišić, Ibrahim; Pojskić, Belma; Mekić Abazović, Alma; Kovčin, Vladimir

2015-08-01

To compare efficacy and toxicity of bolus application of chemotherapy protocol, oxaliplatin, fluorouracil (bolus), leucovorin (folfox) between two groups of patients in the therapy of metastatic colorectal carcinoma (mCRC). A total of 63 patients were treated for mCRC in the period January 2009 - January 2010 at the Department of Oncology of the Cantonal Hospital Zenica, Bosnia and Herzegovina (first group, 30 patients) and at the Department of Oncology of the Clinical Hospital Centre Bežanijska kosa in Belgrade, Serbia, in the period January 2005 - January 2006 (second group, 33 patients). The patients were treated according the same protocol, i.v. bolus infusion, but in different day intervals (D), 1, 8, 15/28 days or D1-D5/28 days, respectively. In all patients the following factors were analyzed: tumor response, overall survival (OS), progression free survival, hematological and non-hematological toxicity . Colon was the primary localization in almost two thirds of patients. There was no statistically significant difference between the groups according to the age, hematological and non-hematological toxicity, as well as in achieved OS. Progression free survival expressed in months was in average 5 months though with a large range between minimal and maximal survival time. Both groups have shown equivalent efficacy to applied chemotherapy protocols. Overall survival in the two groups matched data from the literature. Further research should confirm success of the combination of chemotherapy protocols and their combination with the biological therapy. Copyright© by the Medical Assotiation of Zenica-Doboj Canton.

Therapeutic efficacy and toxicity of bolus application of chemotherapy protocol in the treatment of metastatic colorectal cancer

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Ibrahim Šišić

2015-08-01

Full Text Available Aim To compare efficacy and toxicity of bolus application of chemotherapy protocol, oxaliplatin, fluorouracil (bolus, leucovorin (folfox between two groups of patients in the therapy of metastatic colorectal carcinoma (mCRC. Methods A total of 63 patients were treated for mCRC in the period January 2009 – January 2010 at the Department of Oncology of the Cantonal Hospital Zenica, Bosnia and Herzegovina (first group, 30 patients and at the Department of Oncology of the Clinical Hospital Centre Bežanijska kosa in Belgrade, Serbia, in the period January 2005 – January 2006 (second group, 33 patients. The patients were treated according the same protocol, i.v. bolus infusion, but in different day intervals (D, 1, 8, 15/28 days or D1-D5/28 days, respectively. In all patients the following factors were analyzed: tumor response, overall survival (OS, progression free survival, hematological and non-hematological toxicity. Results Colon was the primary localization in almost two thirds of patients. There was no statistically significant difference between the groups according to the age, hematological and non-hematological toxicity, as well as in achieved OS. Progression free survival expressed in months was in average 5 months though with a large range between minimal and maximal survival time. Conclusion Both groups have shown equivalent efficacy to applied chemotherapy protocols. Overall survival in the two groups matched data from the literature. Further research should confirm success of the combination of chemotherapy protocols and their combination with the biological therapy.

Evaluation of preclinical single and multiple dose toxicity and efficacy of 213 Bi-labeled plasminogen activator inhibitor 2 for breast and prostate cancer

International Nuclear Information System (INIS)

Rizvi, S.; Li, Y.; Allen, B.; Littlejohn, T.; Ranson, M.; Links, M.; Irving, D.; Andrews, J.

2003-01-01

The aim of the study was to evaluate the single and multiple dose toxicity (maximum tolerated dose or MTD) regimes for 213 Bi-labeled PAI2. Dose range of 2-8 mCi/kg was used for the single dose toxicity studies. It was found that end point (20% weight loss and/or distressed behaviour) was not reached for the highest dose either with single or multiple dose injections. For multiple dose toxicity studies, the dose levels ranged between 0.4 - 2 mCi/kg, and were administered daily for 5 days. The highest level tested (2mCi/kg/day x 5) was the maximum tolerated dose as 3/6 mice succumbed to the endpoints. However, histological examination of major organs showed no adverse morphological changes. From these toxicity studies, we concluded that either a dose of 1.6mCi/kg of 213 Bi-PAI2 per day for 5 days or a single injection of 8 mCi/kg can be administered without reaching the endpoints. These dose levels were used for efficacy trials. The efficacy studies were conducted to examine if the 1.6mCi/kgday x 5 multiple dose schedule (sub-maximum tolerated dose) showed efficacy against established and early stage human breast and prostate tumours in mice. Statistical analyses of the data indicate a significant tumour growth rate delay and increased time to reach tumour size endpoint for alpha-PAI2 treatment compared to control tumours, in both pre-tumour stage and established tumour models

Enhanced antitumor efficacy and reduced systemic toxicity of sulfatide-containing nanoliposomal doxorubicin in a xenograft model of colorectal cancer.

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Jia Lin

Full Text Available Sulfatide is a glycosphingolipid known to interact with several extracellular matrix proteins, such as tenascin-C which is overexpressed in many types of cancer including that of the colon. In view of the limited success of chemotherapy in colorectal cancer and high toxicity of doxorubicin (DOX, a sulfatide-containing liposome (SCL encapsulation approach was taken to overcome these barriers. This study assessed the in vitro cytotoxicity, biodistribution, therapeutic efficacy and systemic toxicity in vivo of sulfatide-containing liposomal doxorubicin (SCL-DOX using human colonic adenocarcinoma HT-29 xenograft as the experimental model. In vitro, SCL-DOX was shown to be delivered into the nuclei and displayed prolonged retention compared with the free DOX. The use of this nanodrug delivery system to deliver DOX for treatment of tumor-bearing mice produced a much improved therapeutic efficacy in terms of tumor growth suppression and extended survival in contrast to the free drug. Furthermore, treatment of tumor-bearing mice with SCL-DOX resulted in a lower DOX uptake in the principal sites of toxicity of the free drug, namely the heart and skin, as well as reduced myelosuppression and diminished cardiotoxicity. Such natural lipid-guided nanodrug delivery systems may represent a new strategy for the development of effective anticancer chemotherapeutics targeting the tumor microenvironment for both primary tumor and micrometastases.

Hair-dye induced erythema multiforme like allergic contact dermatitis

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Mrinal Gupta

2017-04-01

Full Text Available Erythema multiforme (EM is an acute, self limited skin disease characterized by the sudden eruption of symmetrical lesions in typical targetoid fashion usually confined to face and extremities. The most commonly implicated factors include infections like herpes simplex, mycoplasma, drugs like antibiotics and anticonvulsants and vaccinations. Contact dermatitis induced EM is a rarely reported entity. Herein we present a case of a 40 year old female who presented with EM due to contact sensitivity to p-Paraphenylenediamine (PPD, a common coloring agent in hair-dyes and a potent sensitizer. Till date, there have been only a few case reports of PPD induced EM.

Multiform structures of SnO2 nanobelts

International Nuclear Information System (INIS)

Duan Junhong; Gong Jiangfeng; Huang Hongbo; Zhao Xiaoning; Cheng Guangxu; Yu Zhongzhen; Yang Shaoguang

2007-01-01

Multiform SnO 2 microstructures were synthesized by a facile thermal evaporation of tin grains. The product was characterized with a variety of techniques to obtain the structural and optical information. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) images showed a large percentage of acute angle zigzag nanobelts with perfectly periodic morphology. High resolution transmission electron microscopy (HRTEM) images and selected area electron diffraction (SAED) patterns revealed that the zigzag nanobelts were single crystalline and their zone axis was along the [010] crystal direction. The growth mechanism of zigzag nanobelts was proposed based on TEM characterization and thermodynamic analysis. The zigzag nanobelts were deduced to be formed by changing the growth direction from [101-bar] to [101] or vice versa. The photoluminescence (PL) spectroscopy of the nanobelts showed a broad and strong luminescence emission centred at 550 nm

Cerebellar giant cell glioblastoma multiforme in an adult

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Sudhansu Sekhar Mishra

2014-01-01

Full Text Available Cerebellar glioblastoma multiforme (GBM is a rare tumor that accounts for only 1% of all cases of GBM and its giant cell variant is even much rarely encountered in adults. A case of cerebellar giant cell GBM managed at our institution reporting its clinical presentation, radiological and histological findings, and treatment instituted is described. In conjunction, a literature review, including particular issues, clinical data, advances in imaging studies, pathological characteristics, treatment options, and the behavior of such malignant tumor is presented. It is very important for the neurosurgeon to make the differential diagnosis between the cerebellar GBM, and other diseases such as metastasis, anaplastic astrocytomas, and cerebellar infarct because their treatment modalities, prognosis, and outcome are different.

Efficacy of free and nanoencapsulated Eucalyptus citriodora essential oils on sheep gastrointestinal nematodes and toxicity for mice.

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Ribeiro, J C; Ribeiro, W L C; Camurça-Vasconcelos, A L F; Macedo, I T F; Santos, J M L; Paula, H C B; Araújo Filho, J V; Magalhães, R D; Bevilaqua, C M L

2014-08-29

Herbal medicines with anthelmintic effects are alternatives for the sustainable control and prevention of disease caused by gastrointestinal parasites. The nanoencapsulation of essential oils has been proposed to enhance the absorption of their constituents and improve their efficacy. The present study aimed to evaluate the efficacy of free and nanoencapsulated Eucalyptus citriodora essential oil (EcEO) on the control of gastrointestinal nematodes of small ruminants in vitro and in vivo. Chitosan was used as a matrix for the formulation of a nanoemulsion. Chromatographic and physico-chemical analyses of EcEO were performed. Egg hatch (EHT) and larval development (LDT) tests were conducted to evaluate the effectiveness of nanoencapsulated and free EcEO on the eggs and larvae of Haemonchus contortus. Acute toxicity of free and nanoencapsulated EcEO was evaluated using mice. Finally, nanoencapsulated EcEO efficacy on the control of gastrointestinal nematodes was calculated by fecal egg count reduction test (FECRT) treating 30 sheep naturally infected with 250 mg/kg of free and nanoencapsulated EcEO. In vitro tests were analyzed by an analysis of variance (ANOVA) followed by comparison with the Tukey test. The efficacy of FECRT was calculated by the BootStreet program through arithmetic average, using the formula 100 (1-XT/XC). To compare the differences between epg, the data were transformed to log(x+1) and subjected to an ANOVA to compare the significant differences between groups by Tukey's. The level of significance was P<0.05. The free (4 mg/ml concentration) and nanoencapsulated (2mg/ml concentration) EcEO inhibited larvae hatching by 97.2% and 92.8%, respectively. Free and nanoencapsulated EcEO at 8 mg/ml inhibited larval development by 99.8% and 98.1%, respectively. In the acute toxicity test, the LD10 and LD50 of free EcEO was 1999 and 2653 mg/kg, respectively, while the LD10 and LD50 of nanoencapsulated EcEO was 1121 and 1681 mg/kg, respectively

Exploratory analysis of the copy number alterations in glioblastoma multiforme.

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Pablo Freire

Full Text Available The Cancer Genome Atlas project (TCGA has initiated the analysis of multiple samples of a variety of tumor types, starting with glioblastoma multiforme. The analytical methods encompass genomic and transcriptomic information, as well as demographic and clinical data about the sample donors. The data create the opportunity for a systematic screening of the components of the molecular machinery for features that may be associated with tumor formation. The wealth of existing mechanistic information about cancer cell biology provides a natural reference for the exploratory exercise.Glioblastoma multiforme DNA copy number data was generated by The Cancer Genome Atlas project for 167 patients using 227 aCGH experiments, and was analyzed to build a catalog of aberrant regions. Genome screening was performed using an information theory approach in order to quantify aberration as a deviation from a centrality without the bias of untested assumptions about its parametric nature. A novel Cancer Genome Browser software application was developed and is made public to provide a user-friendly graphical interface in which the reported results can be reproduced. The application source code and stand alone executable are available at (http://code.google.com/p/cancergenome and (http://bioinformaticstation.org, respectively.The most important known copy number alterations for glioblastoma were correctly recovered using entropy as a measure of aberration. Additional alterations were identified in different pathways, such as cell proliferation, cell junctions and neural development. Moreover, novel candidates for oncogenes and tumor suppressors were also detected. A detailed map of aberrant regions is provided.

Exploratory analysis of the copy number alterations in glioblastoma multiforme.

Science.gov (United States)

Freire, Pablo; Vilela, Marco; Deus, Helena; Kim, Yong-Wan; Koul, Dimpy; Colman, Howard; Aldape, Kenneth D; Bogler, Oliver; Yung, W K Alfred; Coombes, Kevin; Mills, Gordon B; Vasconcelos, Ana T; Almeida, Jonas S

2008-01-01

The Cancer Genome Atlas project (TCGA) has initiated the analysis of multiple samples of a variety of tumor types, starting with glioblastoma multiforme. The analytical methods encompass genomic and transcriptomic information, as well as demographic and clinical data about the sample donors. The data create the opportunity for a systematic screening of the components of the molecular machinery for features that may be associated with tumor formation. The wealth of existing mechanistic information about cancer cell biology provides a natural reference for the exploratory exercise. Glioblastoma multiforme DNA copy number data was generated by The Cancer Genome Atlas project for 167 patients using 227 aCGH experiments, and was analyzed to build a catalog of aberrant regions. Genome screening was performed using an information theory approach in order to quantify aberration as a deviation from a centrality without the bias of untested assumptions about its parametric nature. A novel Cancer Genome Browser software application was developed and is made public to provide a user-friendly graphical interface in which the reported results can be reproduced. The application source code and stand alone executable are available at (http://code.google.com/p/cancergenome) and (http://bioinformaticstation.org), respectively. The most important known copy number alterations for glioblastoma were correctly recovered using entropy as a measure of aberration. Additional alterations were identified in different pathways, such as cell proliferation, cell junctions and neural development. Moreover, novel candidates for oncogenes and tumor suppressors were also detected. A detailed map of aberrant regions is provided.

Efficacy and toxicity management of CAR-T-cell immunotherapy: a matter of responsiveness control or tumour-specificity?

Science.gov (United States)

Alonso-Camino, Vanesa; Harwood, Seandean Lykke; Álvarez-Méndez, Ana; Alvarez-Vallina, Luis

2016-04-15

Chimaeric antigen receptor (CAR)-expressing T-cells have demonstrated potent clinical efficacy in patients with haematological malignancies. However, the use of CAR-T-cells targeting solid tumour-associated antigens (TAAs) has been limited by organ toxicities related to activation of T-cell effector functions through the CAR. Most existing CARs recognize TAAs, which are also found in normal tissues. CAR-T-cell-mediated destruction of normal tissues constitutes a major roadblock to CAR-T-cell therapy, and must be avoided or mitigated. There is a broad range of strategies for modulating antigen responsiveness of CAR-T-cells, with varying degrees of complexity. Some of them might ameliorate the acute and chronic toxicities associated with current CAR constructs. However, further embellishments to CAR therapy may complicate clinical implementation and possibly create new immunogenicity issues. In contrast, the development of CARs targeting truly tumour-specific antigens might circumvent on-target/off-tumour toxicities without adding additional complexity to CAR-T-cell therapies, but these antigens have been elusive and may require novel selection strategies for their discovery. © 2016 Authors; published by Portland Press Limited.

The suppression of manganese superoxide dismutase decreased the survival of human glioblastoma multiforme T98G cells

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Novi S. Hardiany

2017-05-01

Full Text Available Background: Glioblastoma multiforme (GBM is a primary malignant brain tumor which has poor prognosis. High incidence of oxidative stress-based therapy resistance could be related to the high antioxidant status of GBM cells. Our previous study has reported that manganese superoxide dismutase (MnSOD antioxidant expression was significantly higher in high grade glioma than in low grade. The aim of this study was to analyze the impact of MnSOD suppression toward GBM cell survival.Methods: This study is an experimental study using human glioblastoma multiforme T98G cell line. Suppression of MnSOD expression was performed using in vitro transfection MnSOD-siRNA. The MnSOD expression was analyzed by measuring the mRNA using real time RT-PCR, protein using ELISA technique, and specific activity of enzyme using inhibition of xantine oxidase. Concentration of reactive oxygen species (ROS intracellular was determined by measuring superoxide radical and hydrogen peroxide. Cell survival was analyzed by measuring viability, proliferation, and cell apoptosis.Results: In vitro transfection of MnSOD-siRNA suppressed the mRNA, protein, and specific activity of MnSOD. This treatment significantly increased the concentration of superoxide radical; however, it did not influence the concentration of hydrogen peroxide. Moreover, viability MnSOD-suppressing cell significantly decreased, accompanied by increase of cell apoptosis without affecting cell proliferation.Conclusion: The suppression of MnSOD expression leads to decrease glioblastoma multiforme cell survival, which was associated to the increase of cell apoptotic.

Prognostic factors in glioblastoma multiforme. 10 years experience of a single institution

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Hulshof, M.C.C.M.; Schimmel, E.C.; Gonzalez, D.G.; Koot, R.W.; Bosch, D.A.; Dekker, F.

2001-01-01

Background: To analyze prognostic factors in patients with a glioblastoma multiforme treated in an academic institute over the last 10 years. Patients and method: From 1988 to 1998, 198 patients with pathologically confirmed glioblastoma multiforme were analyzed. Five radiation schedules were used mainly based on pretreatment selection criteria: 1. 60 Gy in 30 fractions followed by an interstitial iridium-192 (Ir-192) boost for selected patients with a good performance and a small circumscribed tumor, 2. 66 Gy in 33 fractions for good performance patients, 3. 40 Gy in eight fractions or 4. 28 Gy in four fractions for poor prognostic patients and 5. no irradiation. Results: Median survival was 16 months, 7 months, 5.6 months, 6.6 months and 1.8 months for the groups treated with Ir-192, 66 Gy, 40 Gy, 28 Gy and the group without treatment, respectively. No significant improvement in survival was encountered over the last 10 years. At multivariate analysis patients treated with a hypofractionated scheme showed a similar survival probability and duration of palliative effect compared to the conventionally fractionated group. The poor prognostic groups receiving radiotherapy had a highly significant better survival compared to the no-treatment group. Patients treated with an Ir-192 boost had a better median survival compared to a historical group matched on selection criteria but without boost treatment (16 vs 9.7 months, n.s.). However, survival at 2 years was similar. Analysis on pretreatment characteristics at multivariate analysis revealed age, neurological performance, addition of radiotherapy, total resection, tumor size post surgery and deterioration before start of radiotherapy (borderline) as significant prognostic factors for survival. Conclusion: Despite technical developments in surgery and radiotherapy over the last 10 years, survival of patients with a glioblastoma multiforme has not improved in our institution. The analysis of prognostic factors

The management of oral erythema multiforme in juvenile patient

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Diah Savitri Ernawati

2007-12-01

Full Text Available Erythema multiforme is an acute inflammatory disease of the skin and mucous membranes that causes a variety of the skin lesionhence the name ‘multiforme’.The oral mucosa looks severely inflamed, but the feature are non specific and usually a biopsy is required in order to confirm the diagnosis. Cracked, bleeding, Crusted, swollen and ulcers of the lips is very characteristic of erythema multiforme, and lip involvement may cause significant morbidity. EM is assumed as an immune complex disorder which rises as a result of an immune response to an external agent such as herpes simplex virus or various drugs. We reported: 14-year girl, complained she suffered from painful oral ulceration for one week. One weeks advance the patient received a treatment of paracetamol and paramex for febris, headache and cough. Clinical examination of the skin showed no signs of cutaneous involvement. Other site such as the conjunctival, and genital were also free of lesions. The patients had several red-based superficial erosions on the upper and lower lips accompanied by crusting and bleeding. Intra oral findings showed multiple irregular erosions, ulcers and intense erythematous areas, mainly on the labial mucosa. The clinical diagnosis of EM was concluded by anamnesis and clinical appearance, with differential diagnosis of secondary herpes infection (herpes labialis and pemphigus vulgaris. Systemic and topical corticosteroid therapy is frequently used to treat EM Although it may partially suppress the disease. Objective: This report explains and describes the management of patients with EM which may help dentists to determine an accurate diagnosis to avoid further complication and to give medical intervention to the disease. Conclusion: Early recognition of this disease may prevent delayed diagnosis and incorrect treatment.

Eritema multiforme ampollar extenso asociado a infección por virus herpes simplex Extended Bullous Erythema Multiforme Associated To Herpes Simplex Virus Infection

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A Elgueta-Noy

2009-12-01

Full Text Available El Eritema Multiforme (EM es una reacción cutánea aguda generalmente benigna y autolimitada, asociada a la infección por Virus Herpes Simplex (HSV. Se caracteriza por lesiones polimorfas y tipo diana en extremidades y mucosas. Presentamos un paciente de 22 años con pápulas, vesículas y ampollas, que evoluciona con un 90% de la superficie corporal comprometida en tres semanas. Se realizó una reacción de polimerasa en cadena para HSV, resultando positiva en una costra. La biopsia de piel y la tinción de inmunohistoquímica positiva para linfocitos T CD4, fueron compatibles con EM ampollar asociado a HSV. Destacamos la importancia de la correlación clínico patológica, apoyada por el estudio virológico, en el diagnóstico de este caso de presentación atípica. Los hallazgos de laboratorio confirmaron lo descrito en la literatura respecto de la patogenia del EM asociado a HSV.Erythema Multiforme (EM is a generally benign and self-limited acute cutaneous reaction, associated with Herpes Simplex Virus (HSV infection. It is characterized by polymorphic "target" lesions in extremities and mucosal tissues. We report a 22-year old patient with papules, vesicles and blisters, which evolved to cover 90% of the body in three weeks. We performed a PCR study for HSV, which was positive in a crust. A skin biopsy and positive immunohistochemical stain for LT CD4+ were compatible with bullous EM associated with HSV. We underline the importance of pathological clinical correlation, reinforced by a virological study, in the diagnosis of this case with atypical symptoms. The laboratory findings confirmed literature descriptions with respect to the pathogenicity of EM associated with HSV.

A case of toxic epidermal necrolysis initially affecting the skin site of radiation therapy for an intra-cranial post-transplantation lymphoma

International Nuclear Information System (INIS)

Tanoue, Toshihide; Egawa, Kiyofumi; Fukushima, Satoshi; Wakasugi, Syoji; Ono, Tomomichi; Yoshida, Shinsuke; Kouchi, Masato; Nishi, Kazuhiko

2006-01-01

We report a case of post-transplantation lymphoma (intra-cranial EBV-related malignant lymphoma) who developed toxic epidermal necrolysis (TEN) during concomitant phenobarbital administration and radiotherapy. The erythema exsudativum multiforme-like eruption first appeared on the site of radiation and extended to approximately 35% of the body surface. After stopping radiation therapy and all medications, including immunosuppressant, anticonvulsant, and diuretic drugs, treatment was successfully administered by systemic corticosteroids including semi-pulse therapy (500 mg of methylpredonisolone sodium succinate for 3 days). (author)

Treatment efficacy and methotrexate-related toxicity in patients with rheumatoid arthritis receiving methotrexate in combination with adalimumab.

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Burmester, Gerd R; Kaeley, Gurjit S; Kavanaugh, Arthur F; Gabay, Cem; MacCarter, Daryl K; Nash, Peter; Takeuchi, Tsutomu; Goss, Sandra L; Rodila, Ramona; Chen, Kun; Kupper, Hartmut; Kalabic, Jasmina

2017-01-01

Treatment of rheumatoid arthritis (RA) with a combination of methotrexate (MTX)+adalimumab (ADA) is more effective than ADA monotherapy. We assessed the toxicity of different doses of MTX and treatment efficacy of ADA+MTX in two trials. Data originated from CONCERTO, in patients with early RA initiating ADA+ 2.5, 5, 10 or 20 mg/week MTX for 26 weeks; and MUSICA, in patients with an inadequate response to MTX initiating ADA+ 7.5 or 20 mg/week MTX for 24 weeks. Efficacy was assessed by the American College of Rheumatology 50 (ACR50). Patient-reported MTX-related toxicity information was collected at each visit on 18 prespecified MTX-related adverse events (AE) in the MTX label. In CONCERTO, ACR50 rates increased over time, ranging from 54% to 68% at week 26, while AE rates remained steady, ranging from 2.4% to 17.8% at week 26. Of 395 patients, 113 (28.6%) reported 345 MTX-related AEs, including one serious AE (SAE, excessive fatigue and/or malaise); 10 AEs (in two patients) led to study discontinuation. In MUSICA, ACR50 rates increased over time, and were 32.3% and 37.5% at week 24, while MTX-related AE rates remained steady and were 6.5% at week 24. Of 309 patients, 71 (23%) reported 185 MTX-related AEs, including 5 SAEs (four infections and one fever/chills); six AEs (in four patients) led to study discontinuation. In patients with RA initiating ADA+MTX combination, treatment efficacy was achieved and increased throughout both trials, while rates of MTX-related AEs remained steady. MTX-related AEs were observed in up to 30% of patients and most were mild. MTX was discontinued by 0.5%-1.3% of patients. MUSICA (NCT01185288), CONCERTO (NCT01185301), Post results.

Ternary copper(II) complex: NCI60 screening, toxicity studies, and evaluation of efficacy in xenograft models of nasopharyngeal carcinoma

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Chu, Tai-Lin; Abdul Aziz, Norazlin; Mohd Kornain, Noor-Kaslina; Samiulla, D. S.; Lo, Kwok-Wai; Ng, Chew-Hee

2018-01-01

Copper(II) ternary complex, [Cu(phen)(C-dmg)(H2O)]NO3 was evaluated against a panel of cell lines, tested for in vivo efficacy in nasopharyngeal carcinoma xenograft models as well as for toxicity in NOD scid gamma mice. The Cu(II) complex displayed broad spectrum cytotoxicity against multiple cancer types, including lung, colon, central nervous system, melanoma, ovarian, and prostate cancer cell lines in the NCI-60 panel. The Cu(II) complex did not cause significant induction of cytochrome P450 (CYP) 3A and 1A enzymes but moderately inhibited CYP isoforms 1A2, 2C9, 2C19, 2D6, 2B6, 2C8 and 3A4. The complex significantly inhibited tumor growth in nasopharyngeal carcinoma xenograft bearing mice models at doses which were well tolerated without causing significant or permanent toxic side effects. However, higher doses which resulted in better inhibition of tumor growth also resulted in toxicity. PMID:29329342

Glioblastoma Multiforme Presenting as Spontaneous Intracerebral Hemorrhage

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Cagatay Ozdol

2014-06-01

Full Text Available Brain tumors with concomitant intracerebral hemorrhage are rarely encountered. Hemorrhage as the initial presentation of a brain tumour may pose some diagnostic problems, especially if the tumour is small or the hemorrhage is abundant. We present a 47-year-old man who admitted to the emergency department with sudden onset headache, right blurred vision and gait disturbance. A non-contrast cranial computerized tomography scan performed immediately after his admission revealed a well circumscribed right occipitoparietal haematoma with intense peripheral edema causing compression of the ipsilateral ventricles. On 6th hour of his admission the patient%u2019s neurological status deteriorated and he subsequently underwent emergent craniotomy and microsurgical evacuation of the haematoma. The histopathological examination of the mass was consistent with a glioblastoma multiforme. Neoplasms may be hidden behind each case of spontaneous intracerebral hemorrhage. Histological sampling and investigation is mandatory in the presence of preoperative radiological features suggesting a neoplasm.

Influence of polymorphisms within the methotrexate pathway genes on the toxicity and efficacy of methotrexate in patients with juvenile idiopathic arthritis.

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Yanagimachi, Masakatsu; Naruto, Takuya; Hara, Takuma; Kikuchi, Masako; Hara, Ryoki; Miyamae, Takako; Imagawa, Tomoyuki; Mori, Masaaki; Kaneko, Tetsuji; Morita, Satoshi; Goto, Hiroaki; Yokota, Shumpei

2011-02-01

We investigated whether several polymorphisms within the methotrexate (MTX) pathway genes were related to the toxicity and efficacy of MTX in 92 Japanese patients with articular-type juvenile idiopathic arthritis (JIA). Eight gene polymorphisms within the MTX pathway genes, namely, RFC, BCRP, MTHFR (two), FPGS, γ-glutamyl hydrolase (GGH; two) and ATIC, were genotyped using TaqMan assays. Liver dysfunction was defined as an increase in alanine transaminase to five times the normal upper limit. Non-responders to MTX were defined as patients refractory to MTX and were therefore treated with biologics. The non-TT genotype at GGH T16C was associated with a high risk of liver dysfunction (P=0.028, odds ratio=6.90, 95% confidence interval 1.38-34.5), even after adjustment for the duration of MTX treatment. A longer interval from disease onset to treatment (8.5 and 21.3 months, P=0.029) and rheumatoid factor positivity (P=0.026, odds ratio=2.87, 95% confidence interval 1.11-7.39) were associated with lower efficacy of MTX. The non-TT genotype at GGH T16C was associated with a high risk of liver dysfunction, presumably because the C allele of GGH C16T may reduce the activity of GGH. The time interval before MTX treatment and rheumatoid factor positivity were associated with the efficacy of MTX treatment. The pharmacogenetics of the MTX pathway genes affects the toxicity and efficacy of MTX in Japanese JIA patients. © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.

Glioblastoma multiforme of the cerebellum: description of three cases.

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Luccarelli, G

1980-01-01

Only 43 cases of glioblastoma multiforme of the cerebellum have been reported in the literature. This report is based on the findings of 3 cerebellar glioblastomas in a review of 1,206 consecutive confirmed cases of glioblastoma operated on between 1947 and 1977 at the Istituto Neurologico of Milan, giving an incidence of 0.24%. Clinical features are similar to those of any other fast-growing subtentorial tumour. Neuroradiological studies, including CAT, are of little help in predicting the exact nature of these tumours before surgery. A correct diagnosis can be reached only by microscopic examination. Histological patterns appear in no way to differ from those of cerebral glioblastoma. The biological behaviour of these tumours is in all respects identical to that of glioblastoma of cerebral hemispheres.

Primary pontine gliobastoma multiforme: A case report and review of the literature

International Nuclear Information System (INIS)

Baik, Ji Yeon; Baek, Hye Jin; Moon, Jin Il; Cho, Soo Buem; Choi, Bo Hwa; Bae, Kyung Soo; Jeon, Kyung Nyeo; Choi, Dae Seob; Shin, Hwa Seon

2016-01-01

Glioblastoma multiforme (GBM) most commonly occurs in the pons while it is rare in the brainstem. However, diagnosis of brainstem GBM can be difficult due to its rarity and nonspecific clinical manifestations. Herein, we presented a case of a 47-year-old female patient confirmed as primary pontine GBM by histopathological examination. This case highlights that GBM should be considered in the differential diagnosis of patients with a space-occupying lesion in the brainstem as well as the importance of a meticulous radiological review with clinical suspicion

Primary pontine gliobastoma multiforme: A case report and review of the literature

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Baik, Ji Yeon; Baek, Hye Jin [Dept. of Radiology, Inje University College of Medicine, Haeundae Paik Hospital, Busan (Korea, Republic of); Moon, Jin Il; Cho, Soo Buem; Choi, Bo Hwa; Bae, Kyung Soo; Jeon, Kyung Nyeo [Dept. of Radiology, Gyeongsang National University School of Medicine, Gyeongsang National University Changwon Hospital, Changwon (Korea, Republic of); Choi, Dae Seob; Shin, Hwa Seon [Dept. of Radiology, Gyeongsang National University School of Medicine, Gyeongsang National University Hospital, Jinju (Korea, Republic of)

2016-08-15

Glioblastoma multiforme (GBM) most commonly occurs in the pons while it is rare in the brainstem. However, diagnosis of brainstem GBM can be difficult due to its rarity and nonspecific clinical manifestations. Herein, we presented a case of a 47-year-old female patient confirmed as primary pontine GBM by histopathological examination. This case highlights that GBM should be considered in the differential diagnosis of patients with a space-occupying lesion in the brainstem as well as the importance of a meticulous radiological review with clinical suspicion.

Prognostic factors in glioblastoma multiforme. 10 years experience of a single institution

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Hulshof, M C.C.M.; Schimmel, E C; Gonzalez, D G [Amsterdam Univ. (Netherlands). Dept. of Radiotherapy; Koot, R W; Bosch, D A [Amsterdam Univ. (Netherlands). Dept. of Neurosurgery; Dekker, F [Amsterdam Univ. (Netherlands). Dept. of Epidemiology

2001-06-01

Background: To analyze prognostic factors in patients with a glioblastoma multiforme treated in an academic institute over the last 10 years. Patients and method: From 1988 to 1998, 198 patients with pathologically confirmed glioblastoma multiforme were analyzed. Five radiation schedules were used mainly based on pretreatment selection criteria: 1. 60 Gy in 30 fractions followed by an interstitial iridium-192 (Ir-192) boost for selected patients with a good performance and a small circumscribed tumor, 2. 66 Gy in 33 fractions for good performance patients, 3. 40 Gy in eight fractions or 4. 28 Gy in four fractions for poor prognostic patients and 5. no irradiation. Results: Median survival was 16 months, 7 months, 5.6 months, 6.6 months and 1.8 months for the groups treated with Ir-192, 66 Gy, 40 Gy, 28 Gy and the group without treatment, respectively. No significant improvement in survival was encountered over the last 10 years. At multivariate analysis patients treated with a hypofractionated scheme showed a similar survival probability and duration of palliative effect compared to the conventionally fractionated group. The poor prognostic groups receiving radiotherapy had a highly significant better survival compared to the no-treatment group. Patients treated with an Ir-192 boost had a better median survival compared to a historical group matched on selection criteria but without boost treatment (16 vs 9.7 months, n.s.). However, survival at 2 years was similar. Analysis on pretreatment characteristics at multivariate analysis revealed age, neurological performance, addition of radiotherapy, total resection, tumor size post surgery and deterioration before start of radiotherapy (borderline) as significant prognostic factors for survival. Conclusion: Despite technical developments in surgery and radiotherapy over the last 10 years, survival of patients with a glioblastoma multiforme has not improved in our institution. The analysis of prognostic factors

Discovery of potent and selective cytotoxic activity of new quinazoline-ureas against TMZ-resistant glioblastoma multiforme (GBM).

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Elkamhawy, Ahmed; Viswanath, Ambily Nath Indu; Pae, Ae Nim; Kim, Hyeon Young; Heo, Jin-Chul; Park, Woo-Kyu; Lee, Chong-Ock; Yang, Heekyoung; Kim, Kang Ho; Nam, Do-Hyun; Seol, Ho Jun; Cho, Heeyeong; Roh, Eun Joo

2015-10-20

Herein, we report new quinazoline-urea based compounds with potent cytotoxic activities against TMZ-resistant glioblastoma multiforme (GBM) cells. Low micromolar IC₅₀ values were exhibited over a panel of three primary GBM patient-derived cell cultures belonging to proneural (GBM-1), mesenchymal (GBM-2), and classical (GBM-3) subtypes. Eight compounds showed excellent selectivity indices for GBM cells comparing to a normal astrocyte cell line. In JC-1 assay, analogues 11, 12, 20, 22, and 24 exerted promising rates of mPTP opening induction towards proneural GBM subtype. Compounds 11, 20, and 24 bound to the translocator protein 18 kDa (TSPO) in submicromolar range using [(3)H] PK-11195 binding affinity assay. A homology model was built and docked models of 11, 12, 20, 22 and 24 were generated for describing their plausible binding modes in TSPO. In 3D clonogenic assay, compound 20 manifested potent tumoricidal effects on TMZ-resistant GBM cells even at submicromolar concentrations. In addition, CYP450 and hERG assays presented a safe toxicity profile of 20. Taken as a whole, this report presents compound 20 as a potent, selective and safe GBM cytotoxic agent which constitutes a promising direction against TMZ-resistant GBM. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Jacob's ladders, Riemann's oscillators, quotient of two oscillating multiforms and set of metamorphoses of this system

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Moser, Jan

2015-01-01

In this paper we introduce complicated oscillating system, namely quotient of two multiforms based on Riemann-Siegel formula. We prove that there is an infinite set of metamorphoses of this system (=chrysalis) on critical line $\\sigma=\\frac 12$ into a butterfly (=infinite series of M\\" obius functions in the region of absolute convergence $\\sigma>1$).

Phase II study of imatinib mesylate plus hydroxyurea in adults with recurrent glioblastoma multiforme.

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Reardon, David A; Egorin, Merrill J; Quinn, Jennifer A; Rich, Jeremy N; Rich, Jeremy N; Gururangan, Sridharan; Gururangan, Idharan; Vredenburgh, James J; Desjardins, Annick; Sathornsumetee, Sith; Provenzale, James M; Herndon, James E; Dowell, Jeannette M; Badruddoja, Michael A; McLendon, Roger E; Lagattuta, Theodore F; Kicielinski, Kimberly P; Dresemann, Gregor; Sampson, John H; Friedman, Allan H; Salvado, August J; Friedman, Henry S

2005-12-20

We performed a phase II study to evaluate the combination of imatinib mesylate, an adenosine triphosphate mimetic, tyrosine kinase inhibitor, plus hydroxyurea, a ribonucleotide reductase inhibitor, in patients with recurrent glioblastoma multiforme (GBM). Patients with GBM at any recurrence received imatinib mesylate plus hydroxyurea (500 mg twice a day) orally on a continuous, daily schedule. The imatinib mesylate dose was 500 mg twice a day for patients on enzyme-inducing antiepileptic drugs (EIAEDs) and 400 mg once a day for those not on EIAEDs. Assessments were performed every 28 days. The primary end point was 6-month progression-free survival (PFS). Thirty-three patients enrolled with progressive disease after prior radiotherapy and at least temozolomide-based chemotherapy. With a median follow-up of 58 weeks, 27% of patients were progression-free at 6 months, and the median PFS was 14.4 weeks. Three patients (9%) achieved radiographic response, and 14 (42%) achieved stable disease. Cox regression analysis identified concurrent EIAED use and no more than one prior progression as independent positive prognostic factors of PFS. The most common toxicities included grade 3 neutropenia (16%), thrombocytopenia (6%), and edema (6%). There were no grade 4 or 5 events. Concurrent EIAED use lowered imatinib mesylate exposure. Imatinib mesylate clearance was decreased at day 28 compared with day 1 in all patients, suggesting an effect of hydroxyurea. Imatinib mesylate plus hydroxyurea is well tolerated and associated with durable antitumor activity in some patients with recurrent GBM.

The development of glioblastoma multiforme reactive monoclonal antibodies and their use in drug targeting

International Nuclear Information System (INIS)

Klaich, G.M.

1989-01-01

The objectives of this project were to develop monoclonal antibodies reactive with the tumor glioblastoma multiforme and to use them to study and develop new treatment modalities for this disease. A tumor antigen enriched immunogen, prepared by immunoaffinity chromatography, was compared to a whole tumor homogenate immunogen with the difference in the yield of tumor reactive, normal brain unreactive monoclonal antibodies proving to be significant. Monoclonal antibody A7, reactive with tumor tissue but unreactive with normal tissue, was isotyped to be an IgG2a immunoglobulin and could be purified to electrophoretic homogeneity by using serum-free culture conditions and protein A sepharose chromatography. Monoclonal antibody A7 is noncytotoxic as measured by the 3 H-nicotinamide release assay and binds to a 138 kd membrane antigen which is not internalized. Localization studies using 14 C-labeled monoclonal antibody A7 and the U-87 MG nude mouse xenograft model resulted in a tumor:serum ratio of 1.25:1.0 as compared to 0.29:1.0 for the negative control. A monoclonal antibody A7-doxorubicin immunoconjugate proved to be more cytotoxic than free doxorubicin in vitro while lethality studies using Swiss mice demonstrated the lack of toxicity of the immunoconjugate as compared to free doxorubicin. In vivo chemotherapy studies using the U-87 MG nude mouse xenograft failed to demonstrate any immunoconjugate anti-tumor activity which may be attributable to the route of administration

Analysis of Electronic Densities and Integrated Doses in Multiform Glioblastomas Stereotactic Radiotherapy

International Nuclear Information System (INIS)

Baron-Aznar, C.; Moreno-Jimenez, S.; Celis, M. A.; Ballesteros-Zebadua, P.; Larraga-Gutierrez, J. M.

2008-01-01

Integrated dose is the total energy delivered in a radiotherapy target. This physical parameter could be a predictor for complications such as brain edema and radionecrosis after stereotactic radiotherapy treatments for brain tumors. Integrated Dose depends on the tissue density and volume. Using CT patients images from the National Institute of Neurology and Neurosurgery and BrainScan(c) software, this work presents the mean density of 21 multiform glioblastomas, comparative results for normal tissue and estimated integrated dose for each case. The relationship between integrated dose and the probability of complications is discussed

Cellular and subcellular distribution of BSH in human glioblastoma multiforme

International Nuclear Information System (INIS)

Neumann, M.; Gabel, D.

2000-01-01

The cellular and subcellular distribution of mercaptoundecahydrododecaborate (BSH) in seven glioblastoma multiforme tissue sections of six patients having received BSH prior to surgery was investigated by light, fluorescence and electron microscopy. With use of specific antibodies against BSH its localization could be found in tissue sections predominantly (approx. 90%) in the cytoplasm of GFAP-positive cells of all but one patient. The latter was significantly younger (33 years in contrast of 46-71 (mean 60) years). In none of the tissue sections BSH could be found to a significant amount in the cell nuclei. In contrast, electron microscopy studies show BSH as well associated with the cell membrane as with the chromatin in the nucleus. (author)

Protocols for BNCT of glioblastoma multiforme at Brookhaven: Practical considerations

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Chanana, A.D.; Coderre, J.A.; Joel, D.D.; Slatkin, D.N.

1996-12-31

In this report we discuss some issues considered in selecting initial protocols for boron neutron capture therapy (BNCT) of human glioblastoma multiforme. First the tolerance of normal tissues, especially the brain, to the radiation field. Radiation doses limits were based on results with human and animal exposures. Estimates of tumor control doses were based on the results of single-fraction photon therapy and single fraction BNCT both in humans and experimental animals. Of the two boron compounds (BSH and BPA), BPA was chosen since a FDA-sanctioned protocol for distribution in humans was in effect at the time the first BNCT protocols were written and therapy studies in experimental animals had shown it to be more effective than BSH.

Evaluation of the efficacy and toxicity of protocol cisplatin, 5-fluorouracil, leucovorin compared to protocol fluorouracil, doxorubicin and mitomycin C in locally advanced and metastatic gastric cancer

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Andrić Zoran

2012-01-01

Full Text Available Introduction. Still there is no consensus on the choice of the most efficient and the least toxic chemotherapy regimen in the treatment of advanced gastric cancer. Nowadays few therapy protocols are available for treating this disease. Objective. Study was conducted to compare the efficacy and toxicity of FAM (flurouracil, doxorubicin, mitomycin C with CDDP and FU/FA (cisplatin, 5-fluorouracil, leucovorin protocols in patients with locally advanced and metastatic gastric cancer. Methods. This randomized study involved a group of 50 patients with locally advanced or metastatic gastric cancer, who had not previously undergone chemotherapy treatment. Progression free survival, overall survival and drug toxicity were evaluated. For statistical analysis chi-square test, Kaplan-Meier curve and the log rank test were used. Results. The overall response rate was 20% in the group treated with FAM and 24% in the group treated with CDDP, FU/FA (4% of patients from each group had complete response, but without significant statistical difference. Median survival was 10.9 months in the FAM group and 11.8 months in CDDP, FU/FA group, with no statistically significant difference. Non-haematological and haematological toxicities of CDDP, FU/FA were considerably less frequent than of FAM, and there was no treatment related deaths in any of the groups. Conclusion. Both investigated regimens demonstrated moderate efficacy. The study shows in favour of justified application of both protocols, while in regard to toxicity CDDP and FU/FA can be recommended as preferable treatment for locally advanced and metastatic gastric cancer. New strategies should be considered for better efficacy in the treatment of advanced gastric cancer. New strategies are necessary with the goal to achieve a better therapeutic effect.

Increased intracranial pressure in a case of spinal cervical glioblastoma multiforme: analysis of these two rare conditions

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C.M. de Castro-Costa

1994-03-01

Full Text Available The authors describe a rare case of increased intracranial hypertension consequent to a spinal cervical glioblastoma multiforme in a young patient. They analyse the physiopathology of intracranial hypertension in spinal tumors and the rarity of such kind of tumor in this location, and its clinico-pathological aspects.

Multiformity of inherent randomicity and visitation density in n symbolic dynamics

International Nuclear Information System (INIS)

Zhang Yagang; Wang Changjiang

2007-01-01

The multiformity of inherent randomicity and visitation density in n symbolic dynamics will be clarified in this paper. These stochastic symbolic sequences bear three features. The distribution of frequency, inter-occurrence times and the alignment of two random sequences are amplified in detail. The features of visitation density in surjective maps presents catholicity and the catholicity in n letters randomicity has the same measure foundation. We hope to offer a symbolic platform that satisfies these stochastic properties and to attempt to study certain properties of DNA base sequences, 20 amino acids symbolic sequences of proteid structure, and the time series that can be symbolic in finance market et al

Analysis of association between polymorphisms of MTHFR, MTHFD1 and RFC1 genes and efficacy and toxicity of methotrexate in rheumatoid arthritis patients

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Vejnovic Dubravka

2016-01-01

Full Text Available A folate analogue methotrexate (MTX is the most commonly used disease-modifying drug in the treatment of rheumatoid arthritis. However, the clinical response of RA patients treated with MTX shows interindividual differences and 30% of patients discontinue therapy due to the side effects. In a group of 184 RA patients treated with MTX we have investigated whether polymorphisms in MTHFR (rs1801133, rs1801131, MTHFD1 (rs2236225 and RFC1 (rs144320551 genes may have impact on MTX efficacy and/or adverse drugs effects (ADEs. The efficacy of the MTX therapy has been estimated using the disease activity score in 28 joints (DAS28-ESR based on EULAR criteria and relative DAS28 values (rDAS28 and all adverse drug events were recorded. Patients were genotyped for selected polymorphism by PCR-RFLP method. According to the EULAR response criteria after 6 months of MTX therapy 146 (79.3% patients were classified as responders, (17 patients (11.6% were good and 129 patients (88.4% were moderate responders and 38 patients (20.7% as non-responders. ADEs were observed in 53 (28.8% patients. The majority of ADEs were mild (36 (19.56% patients to moderate (12 (6.25% patients. Five patients (2.7% had serious ADEs. Association studies have been conducted between obtained genotypes and the efficacy and toxicity of MTX. We have observed no association between polymorphisms and efficacy or toxicity of MTX in RA patients. [Projekat Ministarstva nauke Republike Srbije, br. 175091

Hypofractionated High-Dose Irradiation with Positron Emission Tomography Data for the Treatment of Glioblastoma Multiforme

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Kazuhiro Miwa

2014-01-01

Full Text Available This research paper presents clinical outcomes of hypofractionated high-dose irradiation by intensity-modulated radiation therapy (Hypo-IMRT with 11C-methionine positron emission tomography (MET-PET data for the treatment of glioblastoma multiforme (GBM. A total of 45 patients with GBM were treated with Hypo-IMRT after surgery. Gross tumor volume (GTV was defined as the area of enhanced lesion on MRI, including MET-PET avid region; clinical target volume (CTV was the area with 5 mm margin surrounding the GTV; planning target volume (PTV was the area with 15 mm margin surrounding the CTV, including MET-PET moderate region. Hypo-IMRT was performed in 8 fractions; planning the dose for GTV was escalated to 68 Gy and that for CTV was escalated to 56 Gy, while keeping the dose delivered to the PTV at 40 Gy. Concomitant and adjuvant TMZ chemotherapy was administered. At a median follow-up of 18.7 months, median overall survival (OS was 20.0 months, and median progression-free survival was 13.0 months. The 1- and 2-year OS rates were 71.2% and 26.3%, respectively. Adjuvant TMZ chemotherapy was significantly predictive of OS on multivariate analysis. Late toxicity included 7 cases of Grade 3-4 radiation necrosis. Hypo-IMRT with MET-PET data appeared to result in favorable survival outcomes for patients with GBM.

Phase II Radiation therapy oncology group trial of weekly paclitaxel and conventional external beam radiation therapy for supratentorial glioblastoma multiforme

International Nuclear Information System (INIS)

Langer, Corey J.; Ruffer, James; Rhodes, Harker; Paulus, Rebecca; Murray, Kevin; Movsas, Benjamin; Curran, Walter

2001-01-01

Purpose: Fractionated external beam radiotherapy (EBRT) ± carmustine (BCNU) is the standard of care for patients with glioblastoma multiforme (GBM), but survival results remain poor. Preclinical studies indicate synergy between RT and paclitaxel (TAX) in astrocytoma cell lines. Phase I studies in GBM have demonstrated a maximum tolerated dose for TAX of 225 mg/m 2 /3 h/week x 6, during EBRT, with no exacerbation of typical RT-induced toxicities. The Radiation Therapy Oncology Group (RTOG) therefore mounted a Phase II study to determine the feasibility and efficacy of conventional EBRT and concurrent weekly TAX at its MTD. Patients and Methods: Sixty-two patients with histologic diagnosis of GBM were enrolled from 8/16/96 through 3/21/97 in a multi-institutional Phase II trial of EBRT and TAX 225 mg/m 2 /3 h (1-3 h before EBRT), administered the first treatment day of each RT week. Total EBRT dose was 60 Gy (200 cGy/fraction), 5 days per week. A smaller treatment field, to include gross disease plus a margin only, was used after 46 Gy. Results: Sixty-one patients (98%) were evaluable. Median age was 55 years (range, 28-78). Seventy-four percent were ≥50 years. Recursive partitioning analysis (RPA) Classes III, IV, V, VI included 10 (17%), 21 (34%), 25 (41%), and 5 (8%) patients, respectively. Gross total resection was performed in only 16%. There was no Grade 3 or 4 neutropenia or thrombocytopenia. Hypersensitivity reactions precluding further use of TAX occurred in 4 patients. There were 2 instances of late neurotoxicity (4% Grade 3 or 4). Ninety-one percent of patients received treatment per protocol. Seventy-seven percent completed prescribed treatment (6 weeks). Of 35 patients with measurable disease, CR/PR was observed in 23%, MR in 17%, and SD in 43%. Seventeen percent demonstrated progression at first follow-up. Median potential follow-up time is 20 months. Median survival is 9.7 months, with median survivals for RPA classes III, IV, V, and VI of 16.3, 10

Erythema multiforme in a patient with recurrent non-hodgkins lymphoma/chronic lymphocytic leukemia

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Siva Kumara Shankari

2012-01-01

Full Text Available Erythema multiforme major (EMM is a hypersensitivity reaction usually secondary to medications, viruses or other infections. Its presentation is fairly typical with a symmetrical distribution of vesicles, bullae or targeted lesions on the upper body, arms, legs, palms, feet and oral mucosa. The authors present a delineated case of EMM in association with chronic lymphocytic leukemia (CLL and non-Hodgkin′s lymphoma (NHL with a very unusual clinical presentation evolving overtime into a unique, almost dermatomal distribution. Typical therapies were not initially helpful and intravenous immunoglobulin antibody had to be administered.

A simple route to synthesize multiform structures of tin oxide nanobelts and optical properties investigation

International Nuclear Information System (INIS)

Cheng Chuanwei; Xu Guoyue; Zhang Haiqian; Li Yingying; Luo Yan; Zhang Peigen

2008-01-01

Multiform structures of SnO 2 nanobelts including of zigzag, branching and straight structures have been synthesized by a simple molten-salt assisted route. The obtained samples were characterized by X-ray diffraction (XRD), scanning electron microscope (SEM), transmission electron microscope (TEM) and high resolution transmission electron microscope (HRTEM). The growth mechanism of zigzag nanobelts was proposed. A strong blue emission band centered in 425 nm was observed in the photoluminescence spectrum

Efficacy and toxicity profile of carfilzomib based regimens for treatment of multiple myeloma: A systematic review.

Science.gov (United States)

Mushtaq, Adeela; Kapoor, Vikas; Latif, Azka; Iftikhar, Ahmad; Zahid, Umar; McBride, Ali; Abraham, Ivo; Riaz, Irbaz Bin; Anwer, Faiz

2018-05-01

Standard induction therapy for multiple myeloma is three-drug combination based on following classes of drugs: proteasome inhibitors, immunomodulators and steroids. Despite its notable efficacy, bortezomib has side effects like peripheral neuropathy (PNP) with reported incidence of grade ≥3 PNP between 2%-23% Schlafer et al., 2017. Carfilzomib (CFZ) has high selectivity and minimal off-target adverse effects including lower rates of PNP. CFZ is already approved for treatment of relapsed and refractory multiple myeloma (RRMM) as single agent as well as in combination with lenalidomide and/or dexamethasone. Extensive literature search identified a total of 1839 articles. Twenty-six articles (n = 5980) met the inclusion criteria, 15 in newly diagnosed multiple myeloma (NDMM) and 11 in RRMM group. CFZ demonstrates comparable or even better efficacy to bortezomib with much favorable AE profile. Deep, rapid and sustainable response using KRd with safer toxicity profile supports extension of KRd therapy to frontline therapy for all risk categories of MM. High incidence of grade ≥3 HTN underscores the importance of serial BP monitoring. In RRMM, CFZ has documented efficacy with standard 20-27mg/m2 dose. Further large-scale trials are needed to study benefit-to-risk profile of 20-56 and 20-70 mg/m2 dose of CFZ vs standard 20-27 mg/m2 dose in NDMM and RRMM. Copyright © 2018 Elsevier B.V. All rights reserved.

Coexistence of meningioma and glioblastoma multiforme in a same patient: a case report

International Nuclear Information System (INIS)

Pereira, C.; Dumont, P.; Romero, P.C.; Lima, J.P.; Caldas, J.G.; Settanni, F.

1991-01-01

Tumoral collision has been defined as a coexistence of two or more central nervous system tumors histologically distinct, in a patient not harbouring a neuro-ectodermic disease (phakomatosis). Several theories exist for explaining this phenomenon but most of them assume that there is spacial proximity between the tumors and/or ionizing radiation effects. We report the case of coexistence of meningothelial meningioma and glioblastoma multiforme in a same patient, occurring in different hemispheres on different times. The tomographic aspects of the gliomatous lesion and the difficulty in differentiating by neuroimaging among high grade gliomas and recent hemorrhagic cerebral events are discussed. (author)

Erythema multiforme and Stevens-Johnson syndrome following radiotherapy

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Yoshitake, Tadamasa; Nakamura, Katsumasa; Shioyama, Yoshiyuki

2007-01-01

Erythema multiforme (EM) and Stevens-Johnson syndrome (SJS) are thought to be hypersensitivity syndromes with various causes, and radiotherapy might be one of the causes of these syndromes. We herein report two cases of EM/SJS following radiotherapy. The first case was a 63-year-old woman with breast cancer. At the end of postoperative radiotherapy with 60 Gy, severe pruritic erythema appeared in the irradiated area and spread over the whole body. She was diagnosed with EM by a skin biopsy. The second case was a 77-year-old woman with uterine cervical cancer who underwent postoperative radiotherapy. At a dose of 30.6 Gy, pruritic redness appeared in the irradiated area and the precordial region, and it became widespread rapidly with polymorphic transformation. Although without any histological confirmation, SJS was strongly suspected because of her pruritic conjunctivitis. Because both patients were given medicines during irradiation, radiotherapy may not be the only cause of EM/SJS. However, it should be noted that radiotherapy might trigger EM/SJS. (author)

The Efficacy and Toxicity of Gefitinib in Treating Non-small Cell Lung Cancer: A Meta-analysis of 19 Randomized Clinical Trials

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Wo, Hongmei; He, Jing; Zhao, Yang; Yu, Hao; Chen, Feng; Yi, Honggang

2018-01-01

Background: This meta-analysis evaluated the efficacy and toxicity of gefitinib with other commonly used drugs in different treatment settings and epidermal growth factor receptor (EGFR) mutation status. Methods: Nineteen randomize clinical trials (RCTs) of 6,554 patients with NSCLC were pooled in this meta-analysis by random-effects or fixed-effects model, whichever is proper. Results: In first-line therapy, gefitinib showed higher odds than chemotherapy (OR = 2.19, 95% CI: 1.20-4.01), but less than other targeted therapies (OR = 0.58, 95% CI: 0.38-0.88). As non-first-line therapy, the overall survival (OS) and progression-free survival (PFS) were similar between gefitinib and controls (HR = 1.00, 95% CI: 0.93-1.08; HR = 0.91, 95% CI: 0.72-1.15), respectively. With the regard to toxicity, the incidences of dry skin, rash and pruritus were higher in gefitinib compared with controls, while gefitinib significantly reduced the incidence of hematologic toxicity. Conclusion: Gefitinib might be more efficient than chemotherapy, but less efficient than other targeted therapies in ORR, especially in EGFR mutation-positive patients. Gefitinib can decrease the odds of hematologic toxicity compared to controls. Future studies, especially those with EGFR mutation-positive patients, will be needed to confirm our findings. PMID:29721056

Prognostic significance of IDH 1 mutation in patients with glioblastoma multiforme.

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Khan, Inamullah; Waqas, Muhammad; Shamim, Muhammad Shahzad

2017-05-01

Focus of brain tumour research is shifting towards tumour genesis and genetics, and possible development of individualized treatment plans. Genetic analysis shows recurrent mutation in isocitrate dehydrogenase (IDH1) gene in most Glioblastoma multiforme (GBM) cells. In this review we evaluated the prognostic significance of IDH 1 mutation on the basis of published evidence. Multiple retrospective clinical analyses correlate the presence of IDH1 mutation in GBM with good prognostic outcomes compared to wild-type IDH1. A systematic review reported similar results. Based on the review of current literature IDH1 mutation is an independent factor for longer overall survival (OS) and progression free survival (PFS) in GBM patients when compared to wild-type IDH1. The prognostic significance opens up new avenues for treatment.

A Phase 1 trial of intravenous boronophenylalanine-fructose complex in patients with glioblastoma multiforme

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Bergland, R.; Elowitz, E.; Chadha, M.; Coderre, J.A.; Joel, D.

1996-01-01

Boron neutron capture therapy (BNCT) of glioblastoma multiforme was initially performed at the Brookhaven National Laboratory in the early 1950's While this treatment for malignant brain tumors has continued in Japan, new worldwide interest has been stimulated by the development of new and more selective boron compounds. Boronophenylalanine (BPA) is a blood-brain barrier penetrating compound that has been used in BNCT of malignant melanomas. SPA has been employed experimentally in BNCT of rat gliosarcoma and has potential use in the treatment of human glioblastoma. As a preface to clinical BNCT trials, we studied the biodistribution of SPA in patients with glioblastoma

Protective efficacy of folic acid and vitamin B12 against nicotine-induced toxicity in pancreatic islets of the rat

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Bhattacharjee Ankita

2015-06-01

Full Text Available Although cigarette smoking is associated with insulin resistance and an increased risk for type 2 diabetes, few studies have examined the effect of nicotine on the adult endocrine pancreas. In this study, male Wister rats were treated with nicotine (3 mg/kg body weight/day with or without supplementation of folic acid (36 μg/kg body weight/day or vitamin B12 (0.63 μg/kg body weight/day alone or in combination. Fasting blood glucose, insulin and HBA1C level and different oxidative and anti-oxidative stress parameters were measured and pancreatic tissue sections were stained with eosin-haematoxylene. Data were analysed by nonparametric statistics. The results revealed that nicotine induced prediabetes condition with subsequent damage to pancreatic islets in rats. Nicotine also caused oxidative stress in pancreatic tissue as evidenced by increased nitric oxide and malondialdehyde level and decreased superoxide dismutase, catalase and reduced glutathione level. Compared to vitamin B12 supplementation, folic acid blunted the nicotine-induced toxicity in pancreatic islets with higher efficacy. Further, folic acid and vitamin B12 in combination were able to confer significant protection on pancreatic islets against nicotine induced toxicity. These results suggest that supplementation of folic acid and vitamin B12 in combination may be a possible strategy of detoxification against nicotine-induced toxicity in pancreatic islets of the rat.

Glioblastoma Multiforme: A Look Inside Its Heterogeneous Nature

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Inda, Maria-del-Mar; Bonavia, Rudy; Seoane, Joan

2014-01-01

Heterogeneity is a hallmark of tumors and has a crucial role in the outcome of the malignancy, because it not only confounds diagnosis, but also challenges the design of effective therapies. There are two types of heterogeneity: inter-tumor and intra-tumor heterogeneity. While inter-tumor heterogeneity has been studied widely, intra-tumor heterogeneity has been neglected even though numerous studies support this aspect of tumor pathobiology. The main reason has been the technical difficulties, but with new advances in single-cell technology, intra-tumor heterogeneity is becoming a key area in the study of cancer. Several models try to explain the origin and maintenance of intra-tumor heterogeneity, however, one prominent model compares cancer with a tree where the ubiquitous mutations compose the trunk and mutations present in subpopulations of cells are represented by the branches. In this review we will focus on the intra-tumor heterogeneity of glioblastoma multiforme (GBM), the most common brain tumor in adults that is characterized by a marked heterogeneity at the cellular and molecular levels. Better understanding of this heterogeneity will be essential to design effective therapies against this devastating disease to avoid tumor escape

Glioblastoma Multiforme: A Look Inside Its Heterogeneous Nature

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Inda, Maria-del-Mar, E-mail: mminda@vhio.net; Bonavia, Rudy [Translational Research Program, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron University Hospital, 119-129 Passeig Vall d’Hebron, Barcelona 08035 (Spain); Seoane, Joan [Translational Research Program, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron University Hospital, 119-129 Passeig Vall d’Hebron, Barcelona 08035 (Spain); Catalan Institution of Research and Advanced Studies (ICREA), Barcelona 08035 (Spain)

2014-01-27

Heterogeneity is a hallmark of tumors and has a crucial role in the outcome of the malignancy, because it not only confounds diagnosis, but also challenges the design of effective therapies. There are two types of heterogeneity: inter-tumor and intra-tumor heterogeneity. While inter-tumor heterogeneity has been studied widely, intra-tumor heterogeneity has been neglected even though numerous studies support this aspect of tumor pathobiology. The main reason has been the technical difficulties, but with new advances in single-cell technology, intra-tumor heterogeneity is becoming a key area in the study of cancer. Several models try to explain the origin and maintenance of intra-tumor heterogeneity, however, one prominent model compares cancer with a tree where the ubiquitous mutations compose the trunk and mutations present in subpopulations of cells are represented by the branches. In this review we will focus on the intra-tumor heterogeneity of glioblastoma multiforme (GBM), the most common brain tumor in adults that is characterized by a marked heterogeneity at the cellular and molecular levels. Better understanding of this heterogeneity will be essential to design effective therapies against this devastating disease to avoid tumor escape.

Glioblastoma Multiforme: A Look Inside Its Heterogeneous Nature

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Maria-del-Mar Inda

2014-01-01

Full Text Available Heterogeneity is a hallmark of tumors and has a crucial role in the outcome of the malignancy, because it not only confounds diagnosis, but also challenges the design of effective therapies. There are two types of heterogeneity: inter-tumor and intra-tumor heterogeneity. While inter-tumor heterogeneity has been studied widely, intra-tumor heterogeneity has been neglected even though numerous studies support this aspect of tumor pathobiology. The main reason has been the technical difficulties, but with new advances in single-cell technology, intra-tumor heterogeneity is becoming a key area in the study of cancer. Several models try to explain the origin and maintenance of intra-tumor heterogeneity, however, one prominent model compares cancer with a tree where the ubiquitous mutations compose the trunk and mutations present in subpopulations of cells are represented by the branches. In this review we will focus on the intra-tumor heterogeneity of glioblastoma multiforme (GBM, the most common brain tumor in adults that is characterized by a marked heterogeneity at the cellular and molecular levels. Better understanding of this heterogeneity will be essential to design effective therapies against this devastating disease to avoid tumor escape.

Glioblastoma multiforme: a look inside its heterogeneous nature.

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Inda, Maria-Del-Mar; Bonavia, Rudy; Seoane, Joan

2014-01-27

Heterogeneity is a hallmark of tumors and has a crucial role in the outcome of the malignancy, because it not only confounds diagnosis, but also challenges the design of effective therapies. There are two types of heterogeneity: inter-tumor and intra-tumor heterogeneity. While inter-tumor heterogeneity has been studied widely, intra-tumor heterogeneity has been neglected even though numerous studies support this aspect of tumor pathobiology. The main reason has been the technical difficulties, but with new advances in single-cell technology, intra-tumor heterogeneity is becoming a key area in the study of cancer. Several models try to explain the origin and maintenance of intra-tumor heterogeneity, however, one prominent model compares cancer with a tree where the ubiquitous mutations compose the trunk and mutations present in subpopulations of cells are represented by the branches. In this review we will focus on the intra-tumor heterogeneity of glioblastoma multiforme (GBM), the most common brain tumor in adults that is characterized by a marked heterogeneity at the cellular and molecular levels. Better understanding of this heterogeneity will be essential to design effective therapies against this devastating disease to avoid tumor escape.

The effect of GABA A receptor antagonist - bicucullin - administration on the number of multiform neurons in the brain parabrachial nucleus due to pain induction of adult male rats

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Mahsa Kamali

2015-10-01

Full Text Available Background and Aim:  A lot of biological investigations are aimed to find pain decreasing or relieving substances that appear in various diseases. Parabrachial nucleus plays an important role in cognitive and emotional aspects of pain. The present study was designed to evaluate the inhibitory effect of bicuculine- as a GABA A receptor antagonist- on the number of multiform neurons in Parabrachial region of adult male rats in tonic pain model. Materials and Methods: This experimental study was carried out on 40 Wistar male rats. Based on the pain induction, the animals were divided into 8 groups (n=5. Bicuculine was administrated in doses of  50, 100, and 200 ng/rat.  Using stereotaxic method, Bicuculine was administrated to the rats` brain parabrachial area. The present study utilized Formalin test as a standard method for pain stimulations. Thereafter, Gimsa staining method was applied for histological determination of multiform cells. The obtained data was analyzed using statistical testsincluding Student-t and  one-way ANOVA. Results: Our data showed no significant changes in the number of multiform cells in Parabrachial nucleus between the animals administrated by bicuculine at the dose of 50   compared  with the controls (P>0.05. Nevertheless, the number of these cells was decreased significantly in the animals administrated by bicuculine at the doses of 100 and 200   when compared to the controls (p<0.05. Conclusion:  It was found that nociceptive stimulations cause changes in the number of multiform neurons in para- brachial nucleus. Nevertheless, higher dose administration of GABA A receptor antagonist has preventive effects on neuronal dysmorphogenesis at this brain area.

Outcome in elderly patients undergoing definitive surgery and radiation therapy for supratentorial glioblastoma multiforme at a tertiary care institution

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Mohan, Dasarahally S.; Suh, John H.; Phan, Jennifer L.; Kupelian, Patrick A.; Cohen, Bruce H.; Barnett, Gene H.

1998-01-01

Purpose: To determine the efficacy of definitive surgery and radiation in patients aged 70 years and older with supratentorial glioblastoma multiforme. Methods and Materials: We selected elderly patients (≥ 70 years) who had primary treatment for glioblastoma multiforme at our tertiary care institution from 1977 through 1996. The study group (n = 102) included 58 patients treated with definitive radiation, 19 treated with palliative radiation, and 25 who received no radiation. To compare our results with published findings, we grouped our patients according to the applicable prognostic categories developed by the Radiation Therapy Oncology Group (RTOG): RTOG group IV (n = 6), V (n = 70), and VI (n = 26). Patients were retrospectively assigned to prognostic group IV, V, or VI based on age, performance status, extent of surgery, mental status, neurologic function, and radiation dose. Treatment included surgical resection and radiation (n 49), biopsy alone (n = 25), and biopsy followed by radiation (n = 28). Patients were also stratified according to whether they were optimally treated (gross total or subtotal resection with postoperative definitive radiation) or suboptimally treated (biopsy, biopsy + radiation, surgery alone, or surgery + palliative radiation). Patients were considered to have a favorable prognosis (n = 39) if they were optimally treated and had a Karnofsky Performance Status (KPS) score of at least 70. Results: The median survival for patients according to RTOG groups IV, V, and VI was 9.2, 6.6, and 3.1 months, respectively (log-rank, p < 0.0004). The median overall survival was 5.3 months. The definitive radiation group (n = 58) had a median survival of 7.3 months compared to 4.5 months in the palliative radiation group (n = 19) and 1.2 months in the biopsy-alone group (p < 0.0001). Optimally treated patients had a median survival of 7.4 months compared to 2.4 months in those suboptimally treated (p < 0.0001). The favorable prognosis group had an

Primary glioblastoma multiforme of medulla oblongata: Case report and review of literature

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Chotai, Silky P.; Moon, Hong-Joo; Kim, Joo-Han; Kim, Jong-Hyun; Kwon, Taek-Hyun

2012-01-01

Glioblastoma multiforme (GBM) is the most common glial tumor of the adult brain. However, the primary GBM of medulla oblongata is a rarity. To the best of our knowledge, only four cases of GBM of medulla oblongata have been reported so far in the literature, and this is the second report of conventional GBM of the medulla oblongata in adults. We describe a case of 51-year-old female, who presented with a heterogeneous mass with exophytic feature located in the caudal brain stem that was approached and a near total tumor removal was achieved by median suboccipital route. A literature review with emphasis on anatomical location, radiological and histopathological findings, extent of tumor resectibility, and outcome is included. PMID:22639691

Molecular Characteristics in MRI-classified Group 1 Glioblastoma Multiforme

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William E Haskins

2013-07-01

Full Text Available Glioblastoma multiforme (GBM is a clinically and pathologically heterogeneous brain tumor. Previous study of MRI-classified GBM has revealed a spatial relationship between Group 1 GBM (GBM1 and the subventricular zone (SVZ. The SVZ is an adult neural stem cell niche and is also suspected to be the origin of a subtype of brain tumor. The intimate contact between GBM1 and the SVZ raises the possibility that tumor cells in GBM1 may be most related to SVZ cells. In support of this notion, we found that neural stem cell and neuroblast markers are highly expressed in GBM1. Additionally, we identified molecular characteristics in this type of GBM that include up-regulation of metabolic enzymes, ribosomal proteins, heat shock proteins, and c-Myc oncoprotein. As GBM1 often recurs at great distances from the initial lesion, the rewiring of metabolism and ribosomal biogenesis may facilitate cancer cells’ growth and survival during tumor migration. Taken together, combined our findings and MRI-based classification of GBM1 would offer better prediction and treatment for this multifocal GBM.

Immune phenotypes predict survival in patients with glioblastoma multiforme

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Haouraa Mostafa

2016-09-01

Full Text Available Abstract Background Glioblastoma multiforme (GBM, a common primary malignant brain tumor, rarely disseminates beyond the central nervous system and has a very bad prognosis. The current study aimed at the analysis of immunological control in individual patients with GBM. Methods Immune phenotypes and plasma biomarkers of GBM patients were determined at the time of diagnosis using flow cytometry and ELISA, respectively. Results Using descriptive statistics, we found that immune anomalies were distinct in individual patients. Defined marker profiles proved highly relevant for survival. A remarkable relation between activated NK cells and improved survival in GBM patients was in contrast to increased CD39 and IL-10 in patients with a detrimental course and very short survival. Recursive partitioning analysis (RPA and Cox proportional hazards models substantiated the relevance of absolute numbers of CD8 cells and low numbers of CD39 cells for better survival. Conclusions Defined alterations of the immune system may guide the course of disease in patients with GBM and may be prognostically valuable for longitudinal studies or can be applied for immune intervention.

Erythema Multiforme-Like Reaction Due to Rosewood: Two Case Reports

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Eylem Ceren

2008-12-01

Full Text Available Woods and their dusts can lead to various cutaneous reactions such as folliculitis, contact urticaria, irritant and allergic dermatitis. Erythema multiforme-like (EM cutaneous and respiratory system reactions such as astma and allergic rhinitis were also reported. The cutaneous reactions typically affect the areas such as the face, neck and arms exposed to the dust of the tree and usually occur on carpenters as occupational dermatitis\t. Rosewood is one of the most allergic varieties of the trees leading to contact dermatitis. It is a tropical tree and does not grow up in our country. It is especially used in the production of furniture and music instruments and imported from abroad to our country. A few cases of EM-like reaction were reported in 1976 and 1988 in the literature. Herein, two carpenters with severe EM-like skin reaction due to the rosewood, treated with systemic corticosteroids are reported for the first time in our country

Nanoparticle delivery of chemosensitizers improve chemotherapy efficacy without incurring additional toxicity

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Caster, Joseph M.; Sethi, Manish; Kowalczyk, Sonya; Wang, Edina; Tian, Xi; Nabeel Hyder, Sayed; Wagner, Kyle T.; Zhang, Ying-Ao; Kapadia, Chintan; Man Au, Kin; Wang, Andrew Z.

2015-01-01

Chemosensitizers can improve the therapeutic index of chemotherapy and overcome treatment resistance. Successful translation of chemosensitizers depends on the development of strategies that can preferentially deliver chemosensitizers to tumors while avoiding normal tissue. We hypothesized that nanoparticle (NP) formulation of chemosensitizers can improve their delivery to tumors which can in turn improve their therapeutic index. To demonstrate the proof of principle of this approach, we engineered NP formulations of two chemosensitizers, the PI3-kindase inhibitor wortmanin (Wtmn) and the PARP inhibitor olaparib. NP Wtmn and NP olaparib were evaluated as chemosensitizers using lung cancer cells and breast cancer cells respectively. We found Wtmn to be an efficient chemosensitizer in all tested lung-cancer cell lines reducing tumor cell growth between 20 and 60% compared to drug alone. NP formulation did not decrease its efficacy in vitro. Olaparib showed less consistent chemosensitization as a free drug or in NP formulation. NP Wtmn was further evaluated as a chemosensitizer using mouse models of lung cancer. We found that NP Wtmn is an effective chemosensitizer and more effective than free Wtmn showing a 32% reduction in tumor growth compared to free Wtmn when given with etoposide. Importantly, NP Wtmn was able to sensitize the multi-drug resistant H69AR cells to etoposide. Additionally, the combination of NP Wtmn and etoposide chemotherapy did not significantly increase toxicity. The present study demonstrates the proof of principle of using NP formulation of chemosensitizing drugs to improve the therapeutic index of chemotherapy.

Efficacy and toxicity of postoperative temozolomide radiochemotherapy in malignant glioma

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Kocher, M.; Kunze, S.; Eich, H.T.; Semrau, R.; Mueller, R.P. [Dept. of Radiation Oncology, Univ. of Cologne (Germany)

2005-03-01

Purpose: to evaluate the feasibility, safety and efficacy of daily temozolomide concurrent with postoperative radiotherapy in malignant glioma. Patients and methods: from 11/1999 to 03/2003, n = 81 patients aged 15-72 years (median 52 years, karnofsky score 80-100% in 83%) suffering from primary glioblastoma (n = 47), anaplastic astrocytoma (n = 6), anaplastic oligodendroglioma (n = 16), and recurrent glioma (n = 12) were treated. Patients with primary gliomas received a combination of postoperative radiotherapy (60 Gy/1.8- to 2.0-Gy fractions) and daily oral temozolomide (75 mg/m{sup 2}) at all irradiation days (30-33 doses), while recurrent tumors were treated with 45-60 Gy and temozolomide. Initially, 6/81 patients had daily temozolomide doses of 50 mg/m{sup 2}. Results: in total, 70/81 patients (86%) completed both radio- and chemotherapy. Grade 1 nausea/vomiting was seen in 28%, grade 2 in 11%, grade 3 in 1%. Antiemetics were applied in 41%. Hematologic toxicities were observed as follows: leukopenia grade 3/4 1%, lymphopenia grade 3/4 46%, thrombopenia grade 3/4 1%. Two patients under dexamethasone suffered herpes encephalitis after one and 16 doses of temozolomide (75 mg/m{sup 2}). Median survival was 15 months for glioblastoma. In oligodendroglioma patients, a 4-year survival rate of 78% was observed. Conclusion: postoperative radiochemotherapy with 30-33 daily doses of temozolomide (75 mg/m{sup 2}) is safe in patients with malignant glioma. The combined schedule is effective in oligodendroglioma patients and may prolong survival in glioblastoma. Effort should be taken to minimize corticosteroid doses, since both steroids and temozolomide lead to immunosuppression. (orig.)

Impact of gender on efficacy and acute toxicity of alkylating agent -based chemotherapy in Ewing sarcoma: secondary analysis of the Euro-Ewing99-R1 trial.

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van den Berg, Henk; Paulussen, Michael; Le Teuff, Gwénaël; Judson, Ian; Gelderblom, Hans; Dirksen, Uta; Brennan, Bernadette; Whelan, Jeremy; Ladenstein, Ruth Lydia; Marec-Berard, Perrine; Kruseova, Jarmila; Hjorth, Lars; Kühne, Thomas; Brichard, Benedicte; Wheatley, Keith; Craft, Alan; Juergens, Heribert; Gaspar, Nathalie; Le Deley, Marie-Cécile

2015-11-01

Based on the randomised Euro-EWING99-R1 trial, vincristine, adriamycin, cyclophosphamide (VAC) may be able to replace vincristine, adriamycin, ifosfamide (VAI) in the treatment of standard-risk Ewing sarcoma. However some heterogeneity of treatment effect by gender was observed. The current exploratory study aimed at investigating the influence of gender on treatment efficacy and acute toxicity. Impact of gender on event-free survival (EFS), acute toxicity by course, switches between treatment arms and cumulative dose of alkylating agents was evaluated in multivariable models adjusted for age including terms to test for heterogeneity of treatment effect by gender. The analysis of the EFS was performed on the intention-to-treat population. EFS did not significantly differ between the 509 males and 347 females (p=0.33), but an interaction in terms of efficacy was suspected between treatment and gender (p=0.058): VAC was associated with poorer EFS than VAI in males, hazard ratio (HR) (VAC/VAI)=1.37 [95% confidence interval (CI), 0.98-1.90], contrasting with HR=0.81 [95%CI, 0.53-1.24] in females. Severe toxicity was more frequent in females, whatever the toxicity type. Thirty patients switched from VAI to VAC (9/251 males, 4%, and 21/174 females, 12%) mostly due to renal toxicity, and three from VAC to VAI (2/258 males, 0.8%, and 1/173 females, 0.6%). A reduction of alkylating agent cumulative dose >20% was more frequent in females (15% versus 9%, p=0.005), with no major difference between VAC and VAI (10% versus 13%, p=0.15). Differences of acute toxicity rate and cumulative doses of alkylating agents could not explain the marginal interaction observed in the Euro-EWING99-R1 trial data. Effects of gender-dependent polymorphism/activity of metabolic enzymes (e.g. known for CYP2B6) of ifosfamide versus cyclophosphamide should be explored. External data are required to further evaluate whether there is heterogeneity of alkylating agent effect by gender. NCT00987636 and

Arginine-Glycine-Aspartic Acid-Modified Lipid-Polymer Hybrid Nanoparticles for Docetaxel Delivery in Glioblastoma Multiforme.

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Shi, Kairong; Zhou, Jin; Zhang, Qianyu; Gao, Huile; Liu, Yayuan; Zong, Taili; He, Qin

2015-03-01

Hybrid nanoparticles consisting of lipids and the biodegradable polymer, poly (D,L-lactide-co-glycolide) (PLGA), were developed for the targeted delivery of the anticancer drug, docetaxel. Transmission electron microscopic observations confirmed the presence of a lipid coating over the polymeric core. Using coumarin-6 as a fluorescent probe, the uptake efficacy of RGD conjugated lipid coated nanoparticles (RGD-L-P) by C6 cells was increased significantly, compared with that of lipid-polymer hybrid nanoparticles (L-P; 2.5-fold higher) or PLGA-nanoparticles (PLGA-P; 1.76-fold higher). The superior tumor spheroid penetration of RGD-L-P indicated that RGD-L-P could target effectively and specifically to C6 cells overexpressing integrin α(v)β3. The anti-proliferative activity of docetaxel-loaded RGD-L-P against C6 cells was increased 2.69- and 4.13-fold compared with L-P and PLGA-P, respectively. Regarding biodistribution, the strongest brain-localized fluorescence signals were detected in glioblastoma multiforme (GBM)-bearing rats treated with 1,10-Dioctadecyl-3,3,30,30-tetramethylindotricarb-ocyanine iodide (DiR)-loaded RGD-L-P, compared to rats treated with DiR-loaded L-P or PLGA-P. The median survival time of GBM-bearing rats treated with docetaxel-loaded RGD-L-P was 57 days, a fold increase of 1.43, 1.78, 3.35, and 3.56 compared with animals given L-P (P PLGA-P (P < 0.05), Taxotere (P < 0.01) and saline (P < 0.01), respectively. Collectively, these results support RGD-L-P as a promising drug delivery system for the specific targeting and the treatment of GBM.

Initial care and outcome of glioblastoma multiforme patients in 2 diverse health care scenarios in Brazil: does public versus private health care matter?.

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Loureiro, Luiz Victor Maia; Pontes, Lucíola de Barros; Callegaro-Filho, Donato; Koch, Ludmila de Oliveira; Weltman, Eduardo; Victor, Elivane da Silva; Santos, Adrialdo José; Borges, Lia Raquel Rodrigues; Segreto, Roberto Araújo; Malheiros, Suzana Maria Fleury

2014-07-01

The aim of this study was to describe the epidemiological and survival features of patients with glioblastoma multiforme treated in 2 health care scenarios--public and private--in Brazil. We retrospectively analyzed clinical, treatment, and outcome characteristics of glioblastoma multiforme patients from 2003 to 2011 at 2 institutions. The median age of the 171 patients (117 public and 54 private) was 59.3 years (range, 18-84). The median survival for patients treated in private institutions was 17.4 months (95% confidence interval, 11.1-23.7) compared with 7.1 months (95% confidence interval, 3.8-10.4) for patients treated in public institutions (P public setting (median of 64 days for the public hospital and 31 days for the private institution; P = .003). The patients at the private hospital received radiotherapy concurrent with chemotherapy in 59.3% of cases; at the public hospital, only 21.4% (P Brazil is critical.

Current status and future therapeutic perspectives of glioblastoma multiforme (GBM) therapy: A review.

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Anjum, Komal; Shagufta, Bibi Ibtesam; Abbas, Syed Qamar; Patel, Seema; Khan, Ishrat; Shah, Sayed Asmat Ali; Akhter, Najeeb; Hassan, Syed Shams Ul

2017-08-01

Glioblastoma multiforme (GBM) is the deadliest form of heterogeneous brain cancer. It affects an enormous number of patients every year and the survival is approximately 8 to 15 months. GBM has driven by complex signaling pathways and considered as a most challenging to treat. Standard treatment of GBM includes surgery, radiation therapy, chemotherapy and also the combined treatment. This review article described inter and intra- tumor heterogeneity of GMB. In addition, recent chemotherapeutic agents, with their mechanism of action have been defined. FDA-approved drugs also been focused over here and most importantly highlighting some natural and synthetic and novel anti- glioma agents, that are the main focus of researchers nowadays. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Altered expression of polycomb group genes in glioblastoma multiforme.

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Gang Li

Full Text Available The Polycomb group (PcG proteins play a critical role in histone mediated epigenetics which has been implicated in the malignant evolution of glioblastoma multiforme (GBM. By systematically interrogating The Cancer Genome Atlas (TCGA, we discovered widespread aberrant expression of the PcG members in GBM samples compared to normal brain. The most striking differences were upregulation of EZH2, PHF19, CBX8 and PHC2 and downregulation of CBX7, CBX6, EZH1 and RYBP. Interestingly, changes in EZH2, PHF19, CBX7, CBX6 and EZH1 occurred progressively as astrocytoma grade increased. We validated the aberrant expression of CBX6, CBX7, CBX8 and EZH2 in GBM cell lines by Western blotting and qRT-PCR, and further the aberrant expression of CBX6 in GBM tissue samples by immunohistochemical staining. To determine if there was functional significance to the diminished CBX6 levels in GBM, CBX6 was overexpressed in GBM cells resulting in decreased proliferative capacity. In conclusion, aberrant expression of PcG proteins in GBMs may play a role in the development or maintenance of the malignancy.

Variegated colors of pediatric glioblastoma multiforme: what to expect?

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Vivek Immanuel

2017-08-01

Full Text Available Malignant gliomas account for 35-45% of primary brain tumors; among these glioblastoma multiforme (GBM is the most common adult brain tumor constituting approximately 85%. Its incidence is quite less in the pediatric population and treatment of these patients is particularly challenging. Exposure to ionizing radiation is the only environmental factor found to have any significant association with GBM. Several genetic alterations associated with GBM in adults have been well documented such as epidermal growth factor receptor amplification, overexpression of mouse double minute 2 homolog also known as E3 ubiquitin-protein ligase, Phosphatase and tensin homolog gene mutation, loss of heterozygosity of chromosome 10p and isocitrate dehydrogenase-1 mutation. However, data on genetic mutations in pediatric GBM is still lacking. Exophytic brain stem gliomas are rare tumors and are usually associated with a poor prognosis. The most effective treatment in achieving long-term survival in such patients, is surgical excision of the tumor and then chemoradiotherapy followed by adjuvant chemotherapy by temozolomide. This schedule is the standard treatment for GBM patients. In view of the rarity of pediatric GBM, we report here a case of pontine GBM in a 5-year-old girl.

Toxicity and management in CAR T-cell therapy

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Challice L Bonifant

2016-01-01

Full Text Available T cells can be genetically modified to target tumors through the expression of a chimeric antigen receptor (CAR. Most notably, CAR T cells have demonstrated clinical efficacy in hematologic malignancies with more modest responses when targeting solid tumors. However, CAR T cells also have the capacity to elicit expected and unexpected toxicities including: cytokine release syndrome, neurologic toxicity, “on target/off tumor” recognition, and anaphylaxis. Theoretical toxicities including clonal expansion secondary to insertional oncogenesis, graft versus host disease, and off-target antigen recognition have not been clinically evident. Abrogating toxicity has become a critical step in the successful application of this emerging technology. To this end, we review the reported and theoretical toxicities of CAR T cells and their management.

Vinorelbine/carboplatin vs gemcitabine/carboplatin in advanced NSCLC shows similar efficacy, but different impact of toxicity

DEFF Research Database (Denmark)

Helbekkmo, N; Sundstrøm, S H; Aasebø, U

2007-01-01

This randomised phase III study in advanced non-small cell lung cancer (NSCLC) patients was conducted to compare vinorelbine/carboplatin (VC) and gemcitabine/carboplatin (GC) regarding efficacy, health-related quality of life (HRQOL) and toxicity. Chemonaive patients with NSCLC stage IIIB....../IV and WHO performance status 0-2 were eligible. No upper age limit was defined. Patients received vinorelbine 25 mg m(-2) or gemcitabine 1000 mg m(-2) on days 1 and 8 and carboplatin AUC4 on day 1 and three courses with 3-week cycles. HRQOL questionnaires were completed at baseline, before chemotherapy...... and every 8 weeks until 49 weeks. During 14 months, 432 patients were included (VC, n=218; GC, n=214). Median survival was 7.3 vs 6.4 months, 1-year survival 28 vs 30% and 2-year survival 7 vs 7% in the VC and GC arm, respectively (P=0.89). HRQOL, represented by global QOL, nausea/vomiting, dyspnoea...

Histological vis-a-vis biochemical assessment on the toxic level and antineoplastic efficacy of a synthetic drug Pt-ATP on experimental animal models.

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Pal, Shipra; Sadhu, Arpita Sengupta; Patra, Swarup; Mukherjea, Kalyan K

2008-11-12

Cisplatin, a platinum based anticancer drug has played a vital role in the treatment of cancers by chemical agents, but in view of the serious toxicity including nephrotoxicity of cisplatin, various other platinum based drugs have been synthesized and screened to overcome its toxicity. A Pt-ATP compound was prepared in our laboratory hoping to have reduced or no toxicity along with the potentiality of reducing neoplasm growth. A Pt-ATP compound was prepared. It was first screened for its antineoplastic efficacy. Confirming that, subsequent experiments were carried on to test its toxicity on animals, viz. Albino Swiss mice. The animals were randomly divided into four sets--Set I: Erhlich Ascites Carcinoma (EAC) challenged mice; Set II: Normal mice; Set III: Drug treated mice, Set IVA Cisplatin (CDDP) treated mice, Set IV B EAC challenged Cisplatin treated mice. Set I was used to test antineoplasticity of the drug, Set II and Set III for studying drug toxicity and Set IV was treated with CDDP. Set II was used as a control. Animals were sacrificed after 5 days, 10 days 15 days and 20 days of drug administration on the 6th, 11th, 16th and 21st days respectively for Set I, II and III. Set IVA was sacrificed only on the 16th day and Set IV B on 6th and 11th days. For Set I only tumor cell count and packed cell volume (PCV) of tumor cells were recorded. For Set II and III, aspartate aminotransferase (AST), alanine aminotransferase (ALT) assays were done using serum while blood creatinine and creatine were assayed from blood filtrate. For cytotoxicity assessment liver, spleen and kidney tissues were collected and subjected to scanning electron microscopy (SEM) after extensive treatment. Set IV A was only studied for the biochemical parameters viz. aspartate aminotransferase (AST), alanine aminotransferase (ALT) assays were done using serum while blood creatinine and creatine were assayed from blood filtrate. Set IV B was studied for tumor cell count after treatment with

The “Great Masquerader" Strikes Again: Secondary Syphilis Presentation with Erythema Multiforme (EM-Like Lesions

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Adi Brom

2014-12-01

Full Text Available Syphilis is a sexually transmitted disease known to present with highly variable manifestations, especially when left untreated. Patients who present to Internal Medicine Departments with fever and a rash are always a diagnostic challenge since mild viral diseases and life-threatening bacterial infections may manifest themselves similarly. In the following case presentation, we describe a patient with 1 month’s duration of fever and rash on the palms of the hand and soles of the feet, in the form of erythema multiforme (EM-like lesions. His disease was diagnosed as secondary syphilis, once again justifying its name: the “great masquerader".

Toxicity studies of medicinal plants used in sub-Saharan Africa.

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Boukandou Mounanga, Marlaine; Mewono, Ludovic; Aboughe Angone, Sophie

2015-11-04

In sub-Saharan Africa, traditional medicine is widely used in rural and urban areas also. This is essentially due to the prohibitive cost of pharmaceutical-based medicine and the low incomes of a major part of the population. In addition, the efficacies of many of these traditional and plant-based medicines are proven, but the fact remains that certain plants used in traditional medicine have toxic effects. It is in this perspective that we investigated by bibliographic literature on the toxicity of plants used in traditional medicine. It is crucial to gain knowledge on these plant-based medicines prepared and prescribed by practitioners, particularly in terms of toxicity, composition, specific efficacy of disease and to advise practitioners of this alternative medicine on the protection and security of patients. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Andrographolide suppresses the migratory ability of human glioblastoma multiforme cells by targeting ERK1/2-mediated matrix metalloproteinase-2 expression

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Yang, Shih-Liang; Kuo, Fu-Hsuan; Chen, Pei-Ni; Hsieh, Yi-Hsien; Yu, Nuo-Yi; Yang, Wei-En; Hsieh, Ming-Ju; Yang, Shun-Fa

2017-01-01

Glioblastoma multiforme (GBM) can be a fatal tumor because of difficulties in treating the related metastasis. Andrographolide is the bioactive component of the Andrographis paniculata. Andrographolide possesses the anti-inflammatory activity and inhibits the growth of various cancers; however, its effect on GBM cancer motility remains largely unknown. In this study, we examined the antimetastatic properties of andrographolide in human GBM cells. Our results revealed that andrographolide inhi...

Toxicity management of angiogenesis inhibitors: resolution of expert panel

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Pavel O. Rumiantsev

2017-12-01

Full Text Available On 22 June 2017 in St. Petersburg the expert panel was held on the topic “Management of toxicity of angiogenesis inhibitors”, which discussed current issues of systemic therapy of advanced differentiated thyroid cancer resistant to radioactive iodine therapy, advanced kidney cancer and questions of efficacy and safety of new target drugs in the treatment of these diseases. The reports and discussions of experts raised the following questions: 1. Own experience of using lenvatinib in patients with differentiated thyroid cancer refractory to therapy with radioactive iodine and kidney cancer. 2. Profile of efficacy and safety of modern targeted therapy with multikinase inhibitors. 3. Prophylaxis and management of predictable toxicity.

Multifuntional Nanotherapeutics for the Combinatorial Drug and Gene Therapy in the Treatment of Glioblastoma Multiforme

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Hourigan, Breanne

Glioblastoma multiforme (GBM), a grade IV glioma, is the most common primary brain tumor, affecting about 3 out of 100,000 persons per year in the United States. GBM accounts for about 80% of primary malignant brain tumors, and is also the most aggressive of malignant brain tumors. With exhaustive treatment, survival only averages between 12 and 15 months, with a 2-year survival rate less than 25%. New therapeutic strategies are necessary to improve the outcomes of this disease. Chemotherapy with temozolomide (TMZ), a DNA alkylating agent, is used as a first-line of treatment for GBM. However, GBM tumors develop resistance to TMZ over time due to increased expression of O6-methylguanine-DNA methyltransferase (MGMT), a gene responsible for DNA repair. We previously developed cationic, amphiphilic copolymer poly(lactide-co-glycolide)-g-polyethylenimine (PgP) and demonstrated its utility for nucleic acid delivery. Here, we examine the ability of PgP polyplexes to overcome TMZ resistance and improve therapeutic efficacy through combination drug and gene therapy for GBM treatment. In this study, we evaluated the ability of PgP to deliver siRNA targeting to MGMT (siMGMT), a gene responsible for drug resistance in GBM. Our results demonstrated that PgP effectively forms stable complex with siRNA and protects siRNAs from heparin competition assay, serum- and ribonuclease-mediated degradation, confirming the potential of the polyplex for in vivo delivery. Results from MTT assays showed that PgP/siRNA polyplexes exhibited minimal cytotoxicity compared to untreated cells when incubated with T98G human GBM cells. We also demonstrated that PgP/siMGMT polyplexes mediate knockdown of MGMT protein as well as a significant ˜56% and ˜68% knockdown of MGMT mRNA in T98G GBM cells compared to cells treated with PgP complexed with non-targeting siRNA (siNT) at a 60:1 and 80:1 nitrogen:phosphate (N:P) ratio, respectively. Further, co-incubation of PgP/siMGMT polyplexes with TMZ

Prospective evaluation of angiogenic, hypoxic and EGFR-related biomarkers in recurrent glioblastoma multiforme treated with cetuximab, bevacizumab and irinotecan

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Hasselbalch, Benedikte; Eriksen, Jesper Grau; Broholm, Helle

2010-01-01

, hypoxia and mediators of the epidermal growth factor receptor (EGFR) pathway were investigated. Tumor tissue was obtained from a previous phase II study, treating recurrent primary glioblastoma multiforme (GBM) patients with the EGFR inhibitor cetuximab in combination with bevacizumab and irinotecan....... Of the 37 patients with available tumor tissue, 29 were evaluable for response. We concurrently performed immunohistochemical stainings on tumor tissue from 21 GBM patients treated with bevacizumab and irinotecan. We found a tendency of correlation between the hypoxia-related markers, indicating...

Toxicity identification evaluations of produced-water effluents

International Nuclear Information System (INIS)

Sauer, T.C.; Costa, H.J.; Brown, J.S.; Ward, T.J.

1997-01-01

Toxicity identification evaluations (TIEs) were performed on 14 produced-water (PW) samples of various salinities from inland and offshore oil- and gas-production facilities operated by different companies in Wyoming, Texas, California, and Louisiana (USA) to evaluate the efficacy of TIE procedures in determining potential toxicants in PW effluents. The research involved acute (24- and 48-h) freshwater and marine toxicity tests on whole PW and PW fractions generated by standard US Environmental Protection Agency and PW-specific fractionation schemes. Factors influencing PW TIEs were investigated, such as the effect of salinity in selecting fractionation manipulations, the effect of toxicity test replication (i.e., reproducibility) in distinguishing changes in toxicities between whole PW and its fractions, and the suitability of different test species in PW TIEs. The results obtained and lessons learned from conducting these PW TIEs are presented in this article. Components, or fractions, contributing to toxicity differed for each PW with no specific fraction being consistently toxic. For most PW samples, toxicity attributed to any one fraction represented only part of the toxicity of the whole sample. However, no more than two fraction types were identified as potential toxicants in any sample. Potential toxicants identified during this study, besides salinity, included acidic and basic organic compound class fractions, particulates removed by filtration at pH 11, ammonia, hydrocarbons, hydrogen sulfide, material removed by pH change, and volatile compounds

Thermoregulatory responses to environmental toxicants: The interaction of thermal stress and toxicant exposure

International Nuclear Information System (INIS)

Leon, Lisa R.

2008-01-01

Thermal stress can have a profound impact on the physiological responses that are elicited following environmental toxicant exposure. The efficacy by which toxicants enter the body is directly influenced by thermoregulatory effector responses that are evoked in response to high ambient temperatures. In mammals, the thermoregulatory response to heat stress consists of an increase in skin blood flow and moistening of the skin surface to dissipate core heat to the environment. These physiological responses may exacerbate chemical toxicity due to increased permeability of the skin, which facilitates the cutaneous absorption of many environmental toxicants. The core temperature responses that are elicited in response to high ambient temperatures, toxicant exposure or both can also have a profound impact on the ability of an organism to survive the insult. In small rodents, the thermoregulatory response to thermal stress and many environmental toxicants (such as organophosphate compounds) is often biphasic in nature, consisting initially of a regulated reduction in core temperature (i.e., hypothermia) followed by fever. Hypothermia is an important thermoregulatory survival strategy that is used by small rodents to diminish the effect of severe environmental insults on tissue homeostasis. The protective effect of hypothermia is realized by its effects on chemical toxicity as molecular and cellular processes, such as lipid peroxidation and the formation of reactive oxygen species, are minimized at reduced core temperatures. The beneficial effects of fever are unknown under these conditions. Perspective is provided on the applicability of data obtained in rodent models to the human condition

Can high-dose fotemustine reverse MGMT resistance in glioblastoma multiforme?

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Gallo, Chiara; Buonerba, Carlo; Di Lorenzo, Giuseppe; Romeo, Valeria; De Placido, Sabino; Marinelli, Alfredo

2010-11-01

Glioblastoma multiforme (GBM), the highest grade malignant glioma, is associated with a grim prognosis-median overall survival is in the range 12-15 months, despite optimum treatment. Surgery to the maximum possible extent, external beam radiotherapy, and systemic temozolomide chemotherapy are current standard treatments for newly diagnosed GBM, with intracerebral delivery of carmustine wafers (Gliadel). Unfortunately, the effectiveness of chemotherapy can be hampered by the DNA repair enzyme O6-methylguanine methyltransferase (MGMT), which confers resistance both to temozolomide and nitrosoureas, for example fotemustine and carmustine. MGMT activity can be measured by PCR and immunohistochemistry, with the former being the current validated technique. High-dose chemotherapy can deplete MGMT levels in GBM cells and has proved feasible in various trials on temozolomide, in both newly diagnosed and recurrent GBM. We here report the unique case of a GBM patient, with high MGMT expression by immunohistochemistry, who underwent an experimental, high-dose fotemustine schedule after surgery and radiotherapy. Although treatment caused two episodes of grade 3-4 thrombocytopenia, a complete response and survival of more than three years were achieved, with a 30% increase in dose intensity compared with the standard fotemustine schedule.

Long-sustaining response in a patient with non-resectable, distant recurrence of glioblastoma multiforme treated by interstitial photodynamic therapy using 5-ALA: case report.

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Stummer, Walter; Beck, Tobias; Beyer, Wolfgang; Mehrkens, Jan Hendrik; Obermeier, Andreas; Etminan, Nima; Stepp, Herbert; Tonn, Jörg-Christian; Baumgartner, Reinhold; Herms, Jochen; Kreth, Friedrich Wilhelm

2008-03-01

Glioblastoma multiforme continues to be a devastating disease despite modest improvements in survival achieved at present, and there is an urgent need for innovative treatment concepts. Five-aminolevulinic acid (ALA) is a drug which induces protoporphyrin IX accumulation in malignant gliomas and has been explored for fluorescence-guided resections of these tumors. ALA is also under investigation as a photosensitizer. We report a case of a patient with prior left frontal glioblastoma multiforme treated by surgery, radiation and chemotherapy, who developed a remote lesion in the left insula, which was refractory to secondary treatments. In a compassionate use setting she was treated by oral application of ALA (20 mg/kg bodyweight), and stereotactic phototherapy achieved by positioning four laser diffusors using 3-dimensional irradiation planning, and a 633 nm diode laser. The lesion disappeared 24 h after therapy. Circumferential contrast enhancement was observed at 72 h, which disappeared in the course of subsequent months. Edema resolved completely. The patient is still free of recurrence 56 months after treatment, demonstrating an impressive and long-lasting response to this novel mode of therapy.

Study of efficacy and toxicity of hypofractionated thoracic radiotherapy 17 gray in 2 fractions for palliation in advanced non-small-cell lung cancer

International Nuclear Information System (INIS)

Arif, S.; Rasul, S.; Haider, N.; Mahmood, A.; Syed, A.S.; Nadeem, M.

2012-01-01

Objective: To determine the efficacy and toxicity of hypofractionated thoracic radiotherapy 17 Gray (Gy) in 2 fractions for palliation in advanced non-small-cell lung carcinoma. Study design: A quasi-experimental study. Place and duration of study: Oncology department, Combined Military Hospital, Rawalpindi, from 4th July 2008 to 4th Nov 2009. Material and Methods: Fifty four patients with histologically and/or cytologically confirmed unresectable stages III and IV non small cell lung cancer, with performance status 2 or 3 and expected survival > 2 months were treated with megavoltage radiation therapy 17 Gy in 2 fractions one week apart, with symptoms due to intrathoracic disease (cough, dyspnea and hemoptysis) and toxicity due to radiation therapy (dysphagia secondary to esophagitis) assessed as per common toxicity criteria adverse event version 3.0 on day 0 before treatment and day 30 after start of treatment. Results: Grades of cough, hemoptysis and dyspnea showed significant improvement after treatment (p<0.001). A total of 42.68% patients showed an improvement in grade of cough (23 out of 54 patients), 85.7% of patients showed improvement in grade of hemoptysis (36 out of 42 patients) and 55.65% patients showed improvement in grade of dyspnea (30 out of 54 patients). Twenty two point two percent patients (12 out of 54) showed increase in grade of dysphagia. Although, there was a statistically significant increase in grade of dysphagia after treatment but it was limited to grade 1 and 2 only. Considering that no patient had grade 3 or 4 dysphagia, this toxicity was acceptable. Conclusion: Based on our results hypofractionated thoracic radiotherapy, 17 Gy in 2 fractions, is effective with acceptable toxicity in palliation in advanced non small cell lung cancer and is recommended as it will result in shorter duration of hospital stay and low hospital stay charges. (author)

Varicella zoster with erythema multiforme in a young girl: a rare association.

Science.gov (United States)

Kishore, B Nanda; Ankadavar, Nandini S; Kamath, Ganesh H; Martis, Jacintha

2014-05-01

Erythema multiforme (EM) is an acute, self-limited, mucocutaneous disorder regarded as a hypersensitivity reaction which is triggered by various factors like infection, drugs, and food. Infectious agents are considered to be a major cause of EM other than idiopathic cause. A young girl presented with fluid-filled lesions all over the body of 3 days duration with history of similar lesions with fever in her sibling 2 weeks prior to admission. This was followed by large fluid-filled lesions with halo 3 days thereafter over the trunk, extremities suggesting target lesions of EM. The diagnosis was confirmed by cytology and positive serology. Varicella zoster virus (VZV) has rarely been reported as an etiological agent, despite its high incidence in childhood. VZV as an etiology of EM in a young girl has not been reported so far. This case was reported for its rare association of EM and varicella zoster and also for its rare presentation in a young girl.

Therapeutic Potential of Curcumin for the Treatment of Brain Tumors

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Neil V. Klinger

2016-01-01

Full Text Available Brain malignancies currently carry a poor prognosis despite the current multimodal standard of care that includes surgical resection and adjuvant chemotherapy and radiation. As new therapies are desperately needed, naturally occurring chemical compounds have been studied for their potential chemotherapeutic benefits and low toxicity profile. Curcumin, found in the rhizome of turmeric, has extensive therapeutic promise via its antioxidant, anti-inflammatory, and antiproliferative properties. Preclinical in vitro and in vivo data have shown it to be an effective treatment for brain tumors including glioblastoma multiforme. These effects are potentiated by curcumin’s ability to induce G2/M cell cycle arrest, activation of apoptotic pathways, induction of autophagy, disruption of molecular signaling, inhibition of invasion, and metastasis and by increasing the efficacy of existing chemotherapeutics. Further, clinical data suggest that it has low toxicity in humans even at large doses. Curcumin is a promising nutraceutical compound that should be evaluated in clinical trials for the treatment of human brain tumors.

Modeling the Treatment of Glioblastoma Multiforme and Cancer Stem Cells with Ordinary Differential Equations.

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Abernathy, Kristen; Burke, Jeremy

2016-01-01

Despite improvements in cancer therapy and treatments, tumor recurrence is a common event in cancer patients. One explanation of recurrence is that cancer therapy focuses on treatment of tumor cells and does not eradicate cancer stem cells (CSCs). CSCs are postulated to behave similar to normal stem cells in that their role is to maintain homeostasis. That is, when the population of tumor cells is reduced or depleted by treatment, CSCs will repopulate the tumor, causing recurrence. In this paper, we study the application of the CSC Hypothesis to the treatment of glioblastoma multiforme by immunotherapy. We extend the work of Kogan et al. (2008) to incorporate the dynamics of CSCs, prove the existence of a recurrence state, and provide an analysis of possible cancerous states and their dependence on treatment levels.

Boron neutron capture therapy (BNCT) for glioblastoma multiforme using the epithermal neutron beam at the Brookhaven Medical Research Reactor

International Nuclear Information System (INIS)

Capala, J.; Diaz, A.Z.; Chadha, M.

1997-01-01

The abstract describes evaluation of boron neutron capture therapy (BNCT) for two groups of glioblastoma multiforme patients. From September 1994 to February 1996 15 patients have been treated. In September 1997 another 34 patients were examined. Authors determined a safe starting dose for BNCT using epithermal neutrons and BPA-F. They have also evaluated adverse effects of BNCT at this starting dose. Therapeutic effectiveness of this starting dose has been evaluated. No significant side effects from BPA-F infusion or BNCT treatment were observed in normal brains

Boron neutron capture therapy (BNCT) for glioblastoma multiforme using the epithermal neutron beam at the Brookhaven Medical Research Reactor

Energy Technology Data Exchange (ETDEWEB)

Capala, J. [Brookhaven National Lab., Upton, NY (United States); Diaz, A.Z.; Chadha, M. [Univ. Hospital, State Univ. of New York, NY (United States)] [and others

1997-12-31

The abstract describes evaluation of boron neutron capture therapy (BNCT) for two groups of glioblastoma multiforme patients. From September 1994 to February 1996 15 patients have been treated. In September 1997 another 34 patients were examined. Authors determined a safe starting dose for BNCT using epithermal neutrons and BPA-F. They have also evaluated adverse effects of BNCT at this starting dose. Therapeutic effectiveness of this starting dose has been evaluated. No significant side effects from BPA-F infusion or BNCT treatment were observed in normal brains.

Pharmacokinetics, Biodistribution, and Toxicity Evaluation of Anti-SEMA3A (F11) in In Vivo Models.

Science.gov (United States)

Lee, Jaehyun; Kim, Donggeon; Son, Eunju; Yoo, Su-Ji; Sa, Jason K; Shin, Yong Jae; Yoon, Yeup; Nam, DO-Hyun

2018-05-01

The aim of our study was to investigate the pharmacokinetics (PK), tissue distribution and toxicity of F11 antibody to semaphorin 3A in mouse models and explore its anti-angiogenic and tumor-inhibitory effect. Patient-derived xenograft (PDX) models were established via subcutaneous implantation of glioblastoma multiforme (GBM) cells and treated with F11. F11 significantly attenuated tumor growth and angiogenesis in the GBM PDX model. Within the range of administered doses, the PK of F11 in serum demonstrated a linear fashion, consistent with general PK profiles of soluble antigen-targeting antibodies. Additionally, the clearance level was detected at between 4.63 and 7.12 ml/d/kg, while the biological half-life was measured at 6.9 and 9.4 days. Tissue distribution of F11 in kidney, liver and heart was consistent with previously reported antibody patterns. However, the presence of F11 in the brain was an interesting finding. Collectively, our results revealed angiogenic and tumor-inhibitory effect of F11 antibody and its potential therapeutic use within a clinical framework based on PK, biodistribution and toxicity evaluation in mouse models. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

The novel Hsp90 inhibitor NXD30001 induces tumor regression in a genetically engineered mouse model of glioblastoma multiforme.

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Zhu, Haihao; Woolfenden, Steve; Bronson, Roderick T; Jaffer, Zahara M; Barluenga, Sofia; Winssinger, Nicolas; Rubenstein, Allan E; Chen, Ruihong; Charest, Al

2010-09-01

Glioblastoma multiforme (GBM) has an abysmal prognosis. We now know that the epidermal growth factor receptor (EGFR) signaling pathway and the loss of function of the tumor suppressor genes p16Ink4a/p19ARF and PTEN play a crucial role in GBM pathogenesis: initiating the early stages of tumor development, sustaining tumor growth, promoting infiltration, and mediating resistance to therapy. We have recently shown that this genetic combination is sufficient to promote the development of GBM in adult mice. Therapeutic agents raised against single targets of the EGFR signaling pathway have proven rather inefficient in GBM therapy, showing the need for combinatorial therapeutic approaches. An effective strategy for concurrent disruption of multiple signaling pathways is via the inhibition of the molecular chaperone heat shock protein 90 (Hsp90). Hsp90 inhibition leads to the degradation of so-called client proteins, many of which are key effectors of GBM pathogenesis. NXD30001 is a novel second generation Hsp90 inhibitor that shows improved pharmacokinetic parameters. Here we show that NXD30001 is a potent inhibitor of GBM cell growth in vitro consistent with its capacity to inhibit several key targets and regulators of GBM biology. We also show the efficacy of NXD30001 in vivo in an EGFR-driven genetically engineered mouse model of GBM. Our findings establish that the Hsp90 inhibitor NXD30001 is a therapeutically multivalent molecule, whose actions strike GBM at the core of its drivers of tumorigenesis and represent a compelling rationale for its use in GBM treatment.

Global diffusion tensor imaging derived metrics differentiate glioblastoma multiforme vs. normal brains by using discriminant analysis: introduction of a novel whole-brain approach.

Science.gov (United States)

Roldan-Valadez, Ernesto; Rios, Camilo; Cortez-Conradis, David; Favila, Rafael; Moreno-Jimenez, Sergio

2014-06-01

Histological behavior of glioblastoma multiforme suggests it would benefit more from a global rather than regional evaluation. A global (whole-brain) calculation of diffusion tensor imaging (DTI) derived tensor metrics offers a valid method to detect the integrity of white matter structures without missing infiltrated brain areas not seen in conventional sequences. In this study we calculated a predictive model of brain infiltration in patients with glioblastoma using global tensor metrics. Retrospective, case and control study; 11 global DTI-derived tensor metrics were calculated in 27 patients with glioblastoma multiforme and 34 controls: mean diffusivity, fractional anisotropy, pure isotropic diffusion, pure anisotropic diffusion, the total magnitude of the diffusion tensor, linear tensor, planar tensor, spherical tensor, relative anisotropy, axial diffusivity and radial diffusivity. The multivariate discriminant analysis of these variables (including age) with a diagnostic test evaluation was performed. The simultaneous analysis of 732 measures from 12 continuous variables in 61 subjects revealed one discriminant model that significantly differentiated normal brains and brains with glioblastoma: Wilks' λ = 0.324, χ(2) (3) = 38.907, p tensor and linear tensor. These metrics might be clinically applied for diagnosis, follow-up, and the study of other neurological diseases.

Postoperative treatment of glioblastoma multiforme with radiation therapy plus concomitant and adjuvant temozolomide : A mono-institutional experience of 215 patients

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Pramod Kumar Julka

2013-01-01

Full Text Available Objective: To study the clinical results and prognostic factors of patients with glioblastoma multiforme (GBM treated by postoperative radiation therapy (PORT and concomitant temozolomide followed by adjuvant temozolomide. Methods: From 2005 to 2008, 215 patients (median age 48 years with GBM were treated with PORT plus temozolomide chemotherapy. Radiation therapy (RT was employed with a dose of 60 Gy in 30 fractions over 6 weeks by conventional fractionation with concomitant temozolomide (75 mg/m 2 /day. Adjuvant therapy consisted of 6 cycles of temozolomide (150 mg/m 2 for 5 days, 28 days cycle. The primary end point of the study was overall survival (OS, and the secondary end points were progression free survival (PFS and toxicity. OS was determined with respect to different variables to study the prognostic significance. Results: Median follow up was 11 months (range 2-50 months. Median OS and PFS were 13 months and 11 months respectively. The 1-year and 2-year OS was 44% and 18% respectively. There was no statistical significant impact of age, sex, KP score, anatomical location and extent of surgery. Presentation without seizures (on univariate analysis and 6 cycles of adjuvant temozolomide therapy (on univariate as well as multivariate analysis were found significant prognostic factors. Sixteen patients developed grade III-IV neutropenia/thrombocytopenia during the course of RT. Conclusion: Our results authenticate the role of concomitant and adjuvant temozolomide chemotherapy in combination with PORT for the management of GBM patients. We strongly recommend complete 6 cycle of adjuvant temozolomide since it significantly improved the survival in our study.

Use of ERC-1671 Vaccine in a Patient with Recurrent Glioblastoma Multiforme after Progression during Bevacizumab Therapy: First Published Report.

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Bota, Daniela A; Alexandru-Abrams, Daniela; Pretto, Chrystel; Hofman, Florence M; Chen, Thomas C; Fu, Beverly; Carrillo, Jose A; Schijns, Virgil Ejc; Stathopoulos, Apostolos

2015-01-01

Glioblastoma multiforme is a highy aggressive tumor that recurs despite resection, focal beam radiation, and temozolamide chemotherapy. ERC-1671 is an experimental treatment strategy that uses the patient's own immune system to attack the tumor cells. The authors report preliminary data on the first human administration of ERC-1671 vaccination under a single-patient, compassionate-use protocol. The patient survived for ten months after the vaccine administration without any other adjuvant therapy and died of complications related to his previous chemotherapies.

Inhibition of GLO1 in Glioblastoma Multiforme Increases DNA-AGEs, Stimulates RAGE Expression, and Inhibits Brain Tumor Growth in Orthotopic Mouse Models

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Rahul Jandial

2018-01-01

Full Text Available Cancers that exhibit the Warburg effect may elevate expression of glyoxylase 1 (GLO1 to detoxify the toxic glycolytic byproduct methylglyoxal (MG and inhibit the formation of pro-apoptotic advanced glycation endproducts (AGEs. Inhibition of GLO1 in cancers that up-regulate glycolysis has been proposed as a therapeutic targeting strategy, but this approach has not been evaluated for glioblastoma multiforme (GBM, the most aggressive and difficult to treat malignancy of the brain. Elevated GLO1 expression in GBM was established in patient tumors and cell lines using bioinformatics tools and biochemical approaches. GLO1 inhibition in GBM cell lines and in an orthotopic xenograft GBM mouse model was examined using both small molecule and short hairpin RNA (shRNA approaches. Inhibition of GLO1 with S-(p-bromobenzyl glutathione dicyclopentyl ester (p-BrBzGSH(Cp2 increased levels of the DNA-AGE N2-1-(carboxyethyl-2′-deoxyguanosine (CEdG, a surrogate biomarker for nuclear MG exposure; substantially elevated expression of the immunoglobulin-like receptor for AGEs (RAGE; and induced apoptosis in GBM cell lines. Targeting GLO1 with shRNA similarly increased CEdG levels and RAGE expression, and was cytotoxic to glioma cells. Mice bearing orthotopic GBM xenografts treated systemically with p-BrBzGSH(Cp2 exhibited tumor regression without significant off-target effects suggesting that GLO1 inhibition may have value in the therapeutic management of these drug-resistant tumors.

Inhibition of GLO1 in Glioblastoma Multiforme Increases DNA-AGEs, Stimulates RAGE Expression, and Inhibits Brain Tumor Growth in Orthotopic Mouse Models.

Science.gov (United States)

Jandial, Rahul; Neman, Josh; Lim, Punnajit P; Tamae, Daniel; Kowolik, Claudia M; Wuenschell, Gerald E; Shuck, Sarah C; Ciminera, Alexandra K; De Jesus, Luis R; Ouyang, Ching; Chen, Mike Y; Termini, John

2018-01-30

Cancers that exhibit the Warburg effect may elevate expression of glyoxylase 1 (GLO1) to detoxify the toxic glycolytic byproduct methylglyoxal (MG) and inhibit the formation of pro-apoptotic advanced glycation endproducts (AGEs). Inhibition of GLO1 in cancers that up-regulate glycolysis has been proposed as a therapeutic targeting strategy, but this approach has not been evaluated for glioblastoma multiforme (GBM), the most aggressive and difficult to treat malignancy of the brain. Elevated GLO1 expression in GBM was established in patient tumors and cell lines using bioinformatics tools and biochemical approaches. GLO1 inhibition in GBM cell lines and in an orthotopic xenograft GBM mouse model was examined using both small molecule and short hairpin RNA (shRNA) approaches. Inhibition of GLO1 with S -( p -bromobenzyl) glutathione dicyclopentyl ester ( p- BrBzGSH(Cp)₂) increased levels of the DNA-AGE N ²-1-(carboxyethyl)-2'-deoxyguanosine (CEdG), a surrogate biomarker for nuclear MG exposure; substantially elevated expression of the immunoglobulin-like receptor for AGEs (RAGE); and induced apoptosis in GBM cell lines. Targeting GLO1 with shRNA similarly increased CEdG levels and RAGE expression, and was cytotoxic to glioma cells. Mice bearing orthotopic GBM xenografts treated systemically with p -BrBzGSH(Cp)₂ exhibited tumor regression without significant off-target effects suggesting that GLO1 inhibition may have value in the therapeutic management of these drug-resistant tumors.

Dual Inhibition of PDK1 and Aurora Kinase A: An Effective Strategy to Induce Differentiation and Apoptosis of Human Glioblastoma Multiforme Stem Cells.

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Daniele, Simona; Sestito, Simona; Pietrobono, Deborah; Giacomelli, Chiara; Chiellini, Grazia; Di Maio, Danilo; Marinelli, Luciana; Novellino, Ettore; Martini, Claudia; Rapposelli, Simona

2017-01-18

The poor prognosis of glioblastoma multiforme (GBM) is mainly attributed to drug resistance mechanisms and to the existence of a subpopulation of glioma stem cells (GSCs). Multitarget compounds able to both affect different deregulated pathways and the GSC subpopulation could escape tumor resistance and, most importantly, eradicate the stem cell reservoir. In this respect, the simultaneous inhibition of phosphoinositide-dependent kinase-1 (PDK1) and aurora kinase A (AurA), each one playing a pivotal role in cellular survival/migration/differentiation, could represent an innovative strategy to overcome GBM resistance and recurrence. Herein, the cross-talk between these pathways was investigated, using the single-target reference compounds MP7 (PDK1 inhibitor) and Alisertib (AurA inhibitor). Furthermore, a new ligand, SA16, was identified for its ability to inhibit the PDK1 and the AurA pathways at once, thus proving to be a useful tool for the simultaneous inhibition of the two kinases. SA16 blocked GBM cell proliferation, reduced tumor invasiveness, and triggered cellular apoptosis. Most importantly, the AurA/PDK1 blocker showed an increased efficacy against GSCs, inducing their differentiation and apoptosis. To the best of our knowledge, this is the first report on combined targeting of PDK1 and AurA. This drug represents an attractive multitarget lead scaffold for the development of new potential treatments for GBM and GSCs.

Level of Notch activation determines the effect on growth and stem cell-like features in glioblastoma multiforme neurosphere cultures

DEFF Research Database (Denmark)

Kristoffersen, Karina; Villingshøj, Mette; Poulsen, Hans Skovgaard

2013-01-01

Brain cancer stem-like cells (bCSC) are cancer cells with neural stem cell (NSC)-like properties found in glioblastoma multiforme (GBM) and they are assigned a central role in tumor initiation, progression and relapse. The Notch pathway is important for maintenance and cell fate decisions...... in the normal NSC population. Notch signaling is often deregulated in GBM and recent results suggest that this pathway plays a significant role in bCSC as well. We therefore wished to further elucidate the role of Notch activation in GBM-derived bCSC....

Correlação clínico-topográfica em glioblastomas multiformes nas síndromes motoras: significados fisiopatológicos Clinical topographic findings in glioblastoma multiforme and the relation with motor impairment

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Rita de Cássia G. Lucena

2006-06-01

Full Text Available O glioblastoma multiforme (GBM é o tumor glial com maior grau de malignidade. Acomete principalmente os hemisférios cerebrais apresentando sintomas e sinais focais ou gerais, relacionados ao tamanho, localização e taxa de crescimento tumoral. OBJETIVO: Analisar a relação do déficit motor com a topografia do GBM. MÉTODO: Foram estudados 43 casos de GBM, referidos quanto à idade, sexo, localização e a síndrome motora. RESULTADOS: O tumor predominou em adultos (média de 55 anos, sexo masculino (55,82%, localização frontal (aproximadamente 40%. A hemiparesia prevaleceu como distúrbio motor, somente não ocorrendo em 2 casos de lesão frontal, 2 temporais, 1 parietal, 1 occipital e 1 fronto-temporal. CONCLUSÃO: Os achados clínico-topográficos favorecem os efeitos infiltrativos (lesões extensas como responsáveis pela síndrome motora em detrimento aos efeitos compressivos (lesões localizadas.Glioblastoma multiforme (GBM is the glial tumor with the highest grade of malignity. It mainly affects the cerebral hemispheres, presenting general or focal signs and symptoms, which depend on the size, the location of the lesion and rate of growth of the tumor. OBJECTIVE: To analyze the relationship between motor impairment and GBM topography. METHOD: We studied 43 cases of GBM, related to the age, gender, localization and motor impairment. RESULTS: The occurrence of the tumor was preponderant in adults (mean age 55 years old, men (55.82%, and frontal lobe (approximately 40%. The principal motor impairment was hemiparesis, with the exception of 2 cases in the frontal lobe, 2 temporal, 1 parietal, 1 occipital and 1 frontotemporal. CONCLUSION: The clinical-topographic findings lead to consider the infiltrative effects (broad lesions are responsible for the motor impairment rather than compressive effects (located lesions.

Treatment of newly diagnosed glioblastoma multiforme with carmustine, cisplatin and etoposide followed by radiotherapy. A phase II study

DEFF Research Database (Denmark)

Lassen, U; Kristjansen, P E; Wagner, A

1999-01-01

fractions. Twenty-nine patients with newly diagnosed glioblastoma multiforme (GBM), mean age 50 (27-66) and performance status (PS) 0-2 were included. Using the Macdonald criteria 33% had partial remission (PR), 41% stable disease (SD) and 26% progressive disease (PD) after chemotherapy. After additional...... (6.0-9.1) and median survival was 11.4 months (10.1-12.7). We conclude that this regimen is effective and feasible in patients with GBM. The short course pre-irradiatory chemotherapy may be less cumbersome than adjuvant chemotherapy and the regimen may be even more active in grade III gliomas....

Salmonella enterica serovar Enteritidis brain abscess mimicking meningitis after surgery for glioblastoma multiforme: a case report and review of the literature

OpenAIRE

Luciani, L?a; Dubourg, Gr?gory; Graillon, Thomas; Honnorat, Estelle; Lepidi, Hubert; Drancourt, Michel; Seng, Piseth; Stein, Andreas

2016-01-01

Background Salmonella brain abscess associated with brain tumor is rare. Only 11 cases have been reported to date. Here we report a case of brain abscess caused by Salmonella enterica serovar Enteritidis mimicking post-surgical meningitis in a patient with glioblastoma multiforme. Case presentation A 60-year-old Algerian woman was admitted through an emergency department for a 4-day history of headache, nausea and vomiting, and behavioral disorders. Surgery for cerebral tumor excision was per...

Immunogenicity to therapeutic proteins: impact on PK/PD and efficacy.

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Chirmule, Narendra; Jawa, Vibha; Meibohm, Bernd

2012-06-01

The development of therapeutic proteins requires the understanding of the relationship between the dose, exposure, efficacy, and toxicity of these molecules. Several intrinsic and extrinsic factors contribute to the challenges for measuring therapeutic proteins in a precise and accurate manner. In addition, induction of an immune response to therapeutic protein results in additional complexities in the analysis of the pharmacokinetic profile, toxicity, safety, and efficacy of this class of molecules. Assessment of immunogenicity of therapeutic proteins is a required aspect of regulatory filings for a licensing application and for the safe and efficacious use of these compounds. A systematic strategy and well-defined criteria for measuring anti-drug antibodies (ADA) have been established, to a large extent, through coordinated efforts. These recommendations are based on risk assessment and include the determination of ADA content (concentration/titer), affinity, immunoglobulin isotype/subtype, and neutralization capacity. This manuscript reviews the requirements necessary for understanding the nature of an ADA response in order to discern the impact of immunogenicity on pharmacokinetics/pharmacodynamics and efficacy.

Attenuating the toxicity of cisplatin by using selenosulfate with reduced risk of selenium toxicity as compared with selenite

International Nuclear Information System (INIS)

Zhang Jinsong; Peng Dungeng; Lu Hongjuan; Liu Qingliang

2008-01-01

It has been reported that high doses of sodium selenite can reduce side effects of cisplatin (CDDP) without compromising its antitumor activity, thus substantially enhancing the cure rate in tumor-bearing mice. However, the toxicity of selenite at high doses should be a concern. The present study revealed that selenosulfate had much lower toxicity, but possessed equal efficacy in selenium (Se) utilization, as compared with selenite at similar doses when used for the intervention of CDDP. In addition, Se accumulation in whole blood and kidney of mice treated with selenosulfate was highly correlated with the survival rate of mice treated with CDDP (both r > 0.96 and both p < 0.05), suggesting that whole blood Se is a potential clinical biomarker to predict host tolerance to CDDP. In either Se-deficient or -sufficient mice bearing solid tumors of hepatoma 22 (H22), selenosulfate did not disturb the therapeutic effect of CDDP on tumors but effectively attenuated the toxicity of CDDP. Furthermore, in a highly malignant cancer model, with Se-sufficient mice bearing ascitic H22 cells, 8 or 10 mg/kg CDDP alone only achieved a null or 25% cure rate, whereas coadministration of selenosulfate with the above two doses of CDDP achieved cure rates of 87.5% or 75%. These results together argue for consideration of selenosulfate as an agent to enhance the therapeutic efficacy of CDDP

Nanoparticles of carbon allotropes inhibit glioblastoma multiforme angiogenesis in ovo

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Grodzik M

2011-11-01

Full Text Available Marta Grodzik1, Ewa Sawosz1, Mateusz Wierzbicki1, Piotr Orlowski1, Anna Hotowy2, Tomasz Niemiec1, Maciej Szmidt3, Katarzyna Mitura4, André Chwalibog21Division of Biotechnology and Biochemistry of Nutrition, Warsaw University of Life Sciences, Warsaw, Poland; 2Department of Basic Animal and Veterinary Science, University of Copenhagen, Copenhagen, Denmark; 3Division of Histology and Embryology, Warsaw University of Life Sciences, Warsaw, Poland; 4Department of Biomedical Engineering, Koszalin University of Technology, Koszalin, PolandAbstract: The objective of the study was to determine the effect of carbon nanoparticles produced by different methods on the growth of brain tumor and the development of blood vessels. Glioblastoma multiforme cells were cultured on the chorioallantoic membrane of chicken embryo and after 7 days of incubation, were treated with carbon nanoparticles administered in ovo to the tumor. Both types of nanoparticles significantly decreased tumor mass and volume, and vessel area. Quantitative real-time polymerase chain reaction analysis showed downregulated fibroblast growth factor-2 and vascular endothelial growth factor expression at the messenger ribonucleic acid level. The present results demonstrate antiangiogenic activity of carbon nanoparticles, making them potential factors for anticancer therapy.Keywords: cancer, nanoparticle, embryo, angiogenesis, FGF-2, VEGF

Cancer stem cells from a rare form of glioblastoma multiforme involving the neurogenic ventricular wall

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Li Shengwen

2012-09-01

Full Text Available Abstract Background The cancer stem cell (CSC hypothesis posits that deregulated neural stem cells (NSCs form the basis of brain tumors such as glioblastoma multiforme (GBM. GBM, however, usually forms in the cerebral white matter while normal NSCs reside in subventricular and hippocampal regions. We attempted to characterize CSCs from a rare form of glioblastoma multiforme involving the neurogenic ventricular wall. Methods We described isolating CSCs from a GBM involving the lateral ventricles and characterized these cells with in vitro molecular biomarker profiling, cellular behavior, ex vivo and in vivo techniques. Results The patient’s MRI revealed a heterogeneous mass with associated edema, involving the left subventricular zone. Histological examination of the tumor established it as being a high-grade glial neoplasm, characterized by polygonal and fusiform cells with marked nuclear atypia, amphophilic cytoplasm, prominent nucleoli, frequent mitotic figures, irregular zones of necrosis and vascular hyperplasia. Recurrence of the tumor occurred shortly after the surgical resection. CD133-positive cells, isolated from the tumor, expressed stem cell markers including nestin, CD133, Ki67, Sox2, EFNB1, EFNB2, EFNB3, Cav-1, Musashi, Nucleostemin, Notch 2, Notch 4, and Pax6. Biomarkers expressed in differentiated cells included Cathepsin L, Cathepsin B, Mucin18, Mucin24, c-Myc, NSE, and TIMP1. Expression of unique cancer-related transcripts in these CD133-positive cells, such as caveolin-1 and −2, do not appear to have been previously reported in the literature. Ex vivo organotypic brain slice co-culture showed that the CD133+ cells behaved like tumor cells. The CD133-positive cells also induced tumor formation when they were stereotactically transplanted into the brains of the immune-deficient NOD/SCID mice. Conclusions This brain tumor involving the neurogenic lateral ventricular wall was comprised of tumor-forming, CD133-positive cancer

Toxicity of essential oil compounds against Exorista sorbillans ...

African Journals Online (AJOL)

Essential oils of Ageratum conyzoides and Ocimum species are potential candidates for management of Exorista sorbillans (Wiedemann) (Diptera: Culicidae), a serious pest of silkworm. Considering that the pure compounds in essential oil may exhibit efficacy against the parasitoid, contact and topical toxicity of 22 essential ...

Glioblastoma multiforme and papillary thyroid carcinoma - A rare combination of multiple primary malignancies

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Swaroopa Pulivarthi

2015-01-01

Full Text Available We are describing a 19-year-old white woman who presented with two synchronous primary cancers, namely glioblastoma multiforme and papillary thyroid cancer. The patient was admitted with dizziness, headache, and vomiting. CT head revealed acute intraparenchymal hematoma in the right cingulate gyrus and the splenium of the corpus callosum. Carotid and cerebral angiogram were unremarkable. MRI of the brain demonstrated a non-enhancing and non-hemorrhagic component of the lesion along the lateral margin of the hemorrhage just medial to the atrium of the right lateral ventricle that was suspicious for a tumor or metastasis. Brain biopsy confirmed it as glioblastoma mutiforme. CT chest was done to rule out primary cancer that revealed a 11 mm hypodense lesion in the left lobe of the thyroid and ultrasound-guided fine-needle aspiration biopsy confirmed it as papillary thyroid carcinoma. We should evaluate for multiple primary malignancies in young patients who are found to have primary index cancer.

Erythema multiforme-like eruption from a slimming drug preparation cutaneous adverse drug reaction

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Linda Tognetti

2011-01-01

Full Text Available We report a case of a 34-year-old woman presenting with an erythema multiforme (EM-like eruption. Lesions developed after a 12-day treatment with a slimming drug preparation (food integrator with thermogenic activity and a herbal remedy (pilosella tincture. Serological investigations excluded viral or bacterial infections. Patch testing with galenic preparations of both drugs demonstrated sensitization to the slimming drug preparation. According to literature reports and immune-chemical properties, those components that are likely to have triggered the skin eruption are clorazepate dipotassium and theobromine. Their interaction with other two constituents such as pseudoephedrine hydrochloride and dehydrocholic acid may have caused the adverse reaction by means of a summation effect. There are no reports specifically about EM caused by a slimming drug preparation and no studies have identified thermogenic pills as cause of EM/EM-like eruption. Weight-loss compounds in slimming preparations should be kept in mind as a possible cause of drug-induced EM-like eruption.

Influence of toxic bait type and starvation on worker and queen mortality in laboratory colonies of Argentine ant (Hymenoptera: Formicidae).

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Mathieson, Melissa; Toft, Richard; Lester, Philip J

2012-08-01

The efficacy of toxic baits should be judged by their ability to kill entire ant colonies, including the colony queen or queens. We studied the efficacy of four toxic baits to the Argentine ant, Linepithema humile (Mayr) (Hymenoptera: Formicidae). These baits were Xstinguish that has the toxicant fipronil, Exterm-an-Ant that contains both boric acid and sodium borate, and Advion ant gel and Advion ant bait arena that both have indoxacarb. Experimental nests contained 300 workers and 10 queen ants that were starved for either 24 or 48 h before toxic bait exposure. The efficacy of the toxic baits was strongly influenced by starvation. In no treatment with 24-h starvation did we observe 100% worker death. After 24-h starvation three of the baits did not result in any queen deaths, with only Exterm-an-Ant producing an average of 25% mortality. In contrast, 100% queen and worker mortality was observed in colonies starved for 48 h and given Xstinguish or Exterm-an-Ant. The baits Advion ant gel and Advion ant bait arena were not effective against Argentine ants in these trials, resulting in ants are likely to be starved. Our results suggest queen mortality must be assessed in tests for toxic bait efficacy. Our data indicate that of these four baits, Xstinguish and Exterm-an-Ant are the best options for control of Argentine ants in New Zealand.

Connection between cell phone use, p53 gene expression in different zones of glioblastoma multiforme and survival prognoses

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Reza Akhavan-Sigari

2014-08-01

Full Text Available The aim of this paper is to investigate p53 gene expression in the central and peripheral zones of glioblastoma multiforme using a real-time reverse transcription polymerase chain reaction (RT-PCR technique in patients who use cell phones ≥3 hours a day and determine its relationship to clinicopathological findings and overall survival. Sixty-three patients (38 males and 25 females, diagnosed with glioblastoma multiforme (GBM, underwent tumor resection between 2008 and 2011. Patient ages ranged from 25 to 88 years, with a mean age of 55. The levels of expression of p53 in the central and peripheral zone of the GBM were quantified by RT-PCR. Data on p53 gene expression from the central and peripheral zone, the related malignancy and the clinicopatholagical findings (age, gender, tumor location and size, as well as overall survival, were analyzed. Forty-one out of 63 patients (65% with the highest level of cell phone use (≥3 hours/day had higher mutant type p53 expression in the peripheral zone of the glioblastoma; the difference was statistically significant (P=0.034. Results from the present study on the use of mobile phones for ≥3 hours a day show a consistent pattern of increased risk for the mutant type of p53 gene expression in the peripheral zone of the glioblastoma, and that this increase was significantly correlated with shorter overall survival time. The risk was not higher for ipsilateral exposure. We found that the mutant type of p53 gene expression in the peripheral zone of the glioblastoma was increased in 65% of patients using cell phones ≥3 hours a day.

EGFR gene overexpression retained in an invasive xenograft model by solid orthotopic transplantation of human glioblastoma multiforme into nude mice.

Science.gov (United States)

Yi, Diao; Hua, Tian Xin; Lin, Huang Yan

2011-03-01

Orthotopic xenograft animal model from human glioblastoma multiforme (GBM) cell lines often do not recapitulate an extremely important aspect of invasive growth and epidermal growth factor receptor (EGFR) gene overexpression of human GBM. We developed an orthotopic xenograft model by solid transplantation of human GBM into the brain of nude mouse. The orthotopic xenografts sharing the same histopathological features with their original human GBMs were highly invasive and retained the overexpression of EGFR gene. The murine orthotopic GBM models constitute a valuable in vivo system for preclinical studies to test novel therapies for human GBM.

Transgenic nude mouse with green fluorescent protein expression-based human glioblastoma multiforme animal model with EGFR expression and invasiveness.

Science.gov (United States)

Tan, Guo-Wei; Lan, Fo-Lin; Gao, Jian-Guo; Jiang, Cai-Mou; Zhang, Yi; Huang, Xiao-Hong; Ma, Yue-Hong; Shao, He-Dui; He, Xue-Yang; Chen, Jin-Long; Long, Jian-Wu; Xiao, Hui-Sheng; Guo, Zhi-Tong; Diao, Yi

2012-08-01

Previously, we developed an orthotopic xenograft model of human glioblastoma multiforme (GBM) with high EGFR expression and invasiveness in Balb/c nu/nu nude mice. Now we also developed the same orthotopic xenograft model in transgenic nude mice with green fluorescent protein (GFP) expression. The present orthotopic xenografts labeled by phycoerythrin fluorescing red showed high EGFR expression profile, and invasive behavior under a bright green-red dual-color fluorescence background. A striking advantage in the present human GBM model is that the change of tumor growth can be observed visually instead of sacrificing animals in our further antitumor therapy studies.

Biodistribution, toxicity and efficacy of a boronated porphyrin for boron neutron capture therapy

International Nuclear Information System (INIS)

Miura, Michiko; Micca, P.; Fairchild, R.; Slatkin, D.; Gabel, D.

1992-01-01

Boron-containing porphyrins may be useful for boron neutron capture therapy (BNCT) in the treatment of brain tumors. Porphyrins have been shown to accumulate in tumor tissue and to be essentially excluded from normal brain. However, problems of toxicity may prevent some boron-containing porphyrins from being considered for BNCT. The authors have synthesized the boronated porphyrin 2,4-bis-vinyl-o-nidocarboranyl-deuteroporphyrin IX (VCDP). Preliminary studies in tumor-bearing mice showed considerable uptake of boron at a total dose of 150 μg/gbw with low mortality. They now report that a total dose to mice of ∼ 275 μg VCDP/gbw administered in multiple intraperitoneal (ip) injections can provide 40-50μg B per gram of tumor with acceptable toxicity. Toxicity experiments and a preliminary trial of BNCT in mice given such doses are also reported

Myelin structure is a key difference in the x-ray scattering signature between meningioma, schwannoma and glioblastoma multiforme

International Nuclear Information System (INIS)

Falzon, G; Pearson, S; Murison, R; Hall, C; Siu, K; Round, A; Schueltke, E; Kaye, A H; Lewis, R

2007-01-01

Small angle x-ray scattering (SAXS) patterns of benign and malignant brain tumour tissue were examined. Independent component analysis was used to find a feature set representing the images collected. A set of coefficients was then used to describe each image, which allowed the use of the statistical technique of flexible discriminant analysis to discover a hidden order in the data set. The key difference was found to be in the intensity and spectral content of the second and fourth order myelin scattering peaks. This has clearly demonstrated that significant differences in the structure of myelin exist in the highly malignant glioblastoma multiforme as opposed to the benign: meningioma and schwannoma

Chemotherapeutic treatment efficacy and sensitivity are increased by adjuvant alternating electric fields (TTFields)

International Nuclear Information System (INIS)

Kirson, Eilon D; Goldsher, Dorit; Wasserman, Yoram; Palti, Yoram; Schneiderman, Rosa S; Dbalý, Vladimír; Tovaryš, František; Vymazal, Josef; Itzhaki, Aviran; Mordechovich, Daniel; Gurvich, Zoya; Shmueli, Esther

2009-01-01

The present study explores the efficacy and toxicity of combining a new, non-toxic, cancer treatment modality, termed Tumor Treating Fields (TTFields), with chemotherapeutic treatment in-vitro, in-vivo and in a pilot clinical trial. Cell proliferation in culture was studied in human breast carcinoma (MDA-MB-231) and human glioma (U-118) cell lines, exposed to TTFields, paclitaxel, doxorubicin, cyclophosphamide and dacarbazine (DTIC) separately and in combinations. In addition, we studied the effects of combining chemotherapy with TTFields in an animal tumor model and in a pilot clinical trial in recurrent and newly diagnosed GBM patients. The efficacy of TTFields-chemotherapy combination in-vitro was found to be additive with a tendency towards synergism for all drugs and cell lines tested (combination index ≤ 1). The sensitivity to chemotherapeutic treatment was increased by 1–3 orders of magnitude by adjuvant TTFields therapy (dose reduction indexes 23 – 1316). Similar findings were seen in an animal tumor model. Finally, 20 GBM patients were treated with TTFields for a median duration of 1 year. No TTFields related systemic toxicity was observed in any of these patients, nor was an increase in Temozolomide toxicity seen in patients receiving combined treatment. In newly diagnosed GBM patients, combining TTFields with Temozolomide treatment led to a progression free survival of 155 weeks and overall survival of 39+ months. These results indicate that combining chemotherapeutic cancer treatment with TTFields may increase chemotherapeutic efficacy and sensitivity without increasing treatment related toxicity

Enhancement of Radiotherapeutic Efficacy by Paclitaxel-Loaded ph-Sensitive Block Copolymer Micelles

International Nuclear Information System (INIS)

Jinhyang, C.; Jaesook, P.; Dong-Hoon, J.

2012-01-01

Radiotherapy (RT) is a major modality for cancer treatment, but its efficacy is often compromised by the resistance caused by tumor-specific microenvironment including acidosis and hypoxia. For an effective RT, concurrent administration of radiosensitizer with RT has been emphasized. However, most anticancer agents enhancing radiotherapeutic efficacy have obstacles such as poor solubility and severe toxicity. Paclitaxel (PTX), a well-known radiosensitizer, is insoluble in water and needs toxic solvent like Cremophor EL. Nano materials in drug delivery systems have been utilized for improving the drawbacks of anti-cancer drugs. Solubilization, tumor accumulation, and toxicity attenuation of drug by nano materials are suitable for enhancement of radiotherapeutic efficacy. In this study, PTX was incorporated into ph-sensitive block copolymer micelle (psm-PTX), polyethylene glycol-graft-poly(β-amino ester), and pre clinically evaluated for its effect on RT. The size of psm-PTX was 125. 4.4±nm at ph 7.4. psm-PTX released PTX rapidly in the acidic condition (ph 6.5), while it was reasonably stable in the physiologic condition (ph 7.4). The clonogenic assay showed that psm-PTX greatly sensitized human non-small-cell lung cancer A549 cells to radiation. In the xenograft tumor model, the combination of psm-PTX and radiation significantly delayed the tumor growth. These results demonstrated the feasibility of psm-PTX to enhance the chemo radiotherapeutic efficacy.

[F-18]-fluorodeoxyglucose positron emission tomography for targeting radiation dose escalation for patients with glioblastoma multiforme: Clinical outcomes and patterns of failure

International Nuclear Information System (INIS)

Douglas, James G.; Stelzer, Keith J.; Mankoff, David A.; Tralins, Kevin S.; Krohn, Kenneth A.; Muzi, Mark; Silbergeld, Daniel L.; Rostomily, Robert C.; Scharnhorst, Jeffrey B.S.; Spence, Alexander M.

2006-01-01

Purpose: [F-18]-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging for brain tumors has been shown to identify areas of active disease. Radiation dose escalation in the treatment of glioblastoma multiforme may lead to improved disease control. Based on these premises, we initiated a prospective study of FDG-PET for the treatment planning of radiation dose escalation for the treatment of glioblastoma multiforme. Methods and Materials: Forty patients were enrolled. Patients were treated with standard conformal fractionated radiotherapy with volumes defined by MRI imaging. When patients reached a dose of 45-50.4 Gy, they underwent FDG-PET imaging for boost target delineation, for an additional 20 Gy (2 Gy per fraction) to a total dose of 79.4 Gy (n = 30). Results: The estimated 1-year and 2-year overall survival (OS) for the entire group was 70% and 17%, respectively, with a median overall survival of 70 weeks. The estimated 1-year and 2-year progression-free survival (PFS) was 18% and 3%, respectively, with a median of 24 weeks. No significant improvements in OS or PFS were observed for the study group in comparison to institutional historical controls. Conclusions: Radiation dose escalation to 79.4 Gy based on FDG-PET imaging demonstrated no improvement in OS or PFS. This study establishes the feasibility of integrating PET metabolic imaging into radiotherapy treatment planning

Drug eruption (erythema multiforme type) following chemoradiotherapy with mitomycin C and 5-fluorouracil administration for squamous cell carcinoma of the anal canal

International Nuclear Information System (INIS)

Arikawa, Shunji; Uchida, Masafumi; Ogoh, Etsuyo

2010-01-01

We report a case of drug eruption (erythema multiforme type) in a 54-year-old woman, following concurrent chemoradiotherapy for squamous cell carcinoma of the anal canal. Chemotherapy comprised one cycle of mitomycin C 10 mg/m 2 /day (intravenous bolus injection) on day 1 and 5-fluorouracil (5-FU) 1, 000 mg/m 2 /day (continuous intravenous infusion) on days 1-4 of radiotherapy. External irradiation of the pelvic space was performed, using daily fractions of 1.5 Gy (total dose, 33 Gy). From day 4 after chemoradiotherapy, erythema appeared proximal to the forearm site used for drug administration. On day 6, erythema was noted on the trunk, hip and thigh. We suspected erythema multiforme based on the appearance of wheals and target lesions of the skin and a patient history of chemoradiotherapy. Steroids were administered orally, which resolved systemic eruption at week 2. The patient also experienced grade 3 leukocytopenia, neutropenia, thrombopenia, diarrhea, and anorexia. Although we could not provide sufficient chemotherapy and radiation therapy due to severe side effects, squamous cell carcinoma of the anal canal responded extremely well with a marked decrease in complete response. We surmise that the drug eruption was associated with 5-FU. Concurrent chemoradiotherapy is safe and effective for squamous cell carcinoma of the anal canal, but care is required to prevent drug eruption during treatment. (author)

Toxicity and efficacy of re-irradiation of high-grade glioma in a phase I dose- and volume escalation trial

DEFF Research Database (Denmark)

Møller, Søren; Munck Af Rosenschöld, Per; Costa, Junia

2017-01-01

.1-3.5) and the median overall survival was 7.0 months (95%CI: 3.5-10.5). Early side effects were mild and included headache and fatigue. Seven patients were progression-free beyond 10 weeks and were evaluable for late toxicity. Among these patients, three (43%) suffered late adverse events which included radionecrosis......INTRODUCTION: The purpose of this study was to evaluate the safety and efficacy of PET and MRI guided re-irradiation of recurrent high-grade glioma (HGG) and to assess the impact of radiotherapy dose, fractionation and irradiated volume. MATERIAL AND METHODS: Patients with localized, recurrent HGG...... (grades III-IV) and no other treatment options were eligible for a prospective phase I trial. Gross tumor volumes for radiotherapy were defined using T1-contrast enhanced MRI and (18)F-fluoro-ethyl tyrosine PET. Radiotherapy was delivered using volumetric modulated arc therapy with a 2-mm margin. The dose...

Preclinical evaluations of norcantharidin-loaded intravenous lipid microspheres with low toxicity.

Science.gov (United States)

Lin, Xia; Zhang, Bo; Zhang, Keru; Zhang, Yu; Wang, Juan; Qi, Na; Yang, Shenshen; He, Haibing; Tang, Xing

2012-12-01

The aim of this study was to perform a systematic preclinical evaluation of norcantharidin (NCTD)-loaded intravenous lipid microspheres (NLM). Pharmacokinetics, biodistribution, antitumor efficacy and drug safety assessment (including acute toxicity, subchronic toxicity, hemolysis testing, intravenous stimulation and injection anaphylaxis) of NLM were carried out in comparison with the commercial product disodium norcantharidate injection (NI). The pharmacokinetics of NLM in rats was similar to that of NI, and a non-linear correlation was observed between AUC and dose. A comparable antitumor efficacy of NLM and NI was observed in mice inoculated with A549, BEL7402 and BCAP-37 cell lines. It was worth noting that the NLM produced a lower drug concentration in heart compared with NI, and significantly reduced the cardiac and renal toxicity. The LD(50) of NLM was twice higher than that of NI. In NLM, over 80% of NCTD was loaded in the lipid phase or bound with phospholipids. Thus, NCTD was sequestered by direct contacting with body fluids and largely avoided distribution into tissues, consequently leading to significantly reduced cardiac and renal toxicity. These preclinical results suggested that NLM could be a useful potential carrier for parenteral administration of NCTD, while providing a superior safety profile.

Simulation of glioblastoma multiforme (GBM) tumor cells using ising model on the Creutz Cellular Automaton

Science.gov (United States)

Züleyha, Artuç; Ziya, Merdan; Selçuk, Yeşiltaş; Kemal, Öztürk M.; Mesut, Tez

2017-11-01

Computational models for tumors have difficulties due to complexity of tumor nature and capacities of computational tools, however, these models provide visions to understand interactions between tumor and its micro environment. Moreover computational models have potential to develop strategies for individualized treatments for cancer. To observe a solid brain tumor, glioblastoma multiforme (GBM), we present a two dimensional Ising Model applied on Creutz cellular automaton (CCA). The aim of this study is to analyze avascular spherical solid tumor growth, considering transitions between non tumor cells and cancer cells are like phase transitions in physical system. Ising model on CCA algorithm provides a deterministic approach with discrete time steps and local interactions in position space to view tumor growth as a function of time. Our simulation results are given for fixed tumor radius and they are compatible with theoretical and clinic data.

Phase 1/2 Trials of Temozolomide, Motexafin Gadolinium, and 60-Gy Fractionated Radiation for Newly Diagnosed Supratentorial Glioblastoma Multiforme: Final Results of RTOG 0513

Energy Technology Data Exchange (ETDEWEB)

Brachman, David G., E-mail: david.brachman@dignityhealth.org [Arizona Oncology Services Foundation, Scottsdale, Arizona (United States); Barrow Neurological Institute, St. Joseph' s Hospital and Medical Center, Phoenix, Arizona (United States); Pugh, Stephanie L. [Radiation Therapy Oncology Group Statistical Center, Philadelphia, Pennsylvania (United States); Ashby, Lynn S. [Barrow Neurological Institute, St. Joseph' s Hospital and Medical Center, Phoenix, Arizona (United States); Thomas, Theresa A. [Arizona Oncology Services Foundation, Scottsdale, Arizona (United States); Dunbar, Erin M. [University of Florida College of Medicine, Gainesville, Florida (United States); Narayan, Samir [St. Joseph Mercy Hospital, Ann Arbor, Michigan (United States); Robins, H. Ian [University of Wisconsin Hospital, Madison, Wisconsin (United States); Bovi, Joseph A. [Medical College of Wisconsin, Milwaukee, Wisconsin (United States); Rockhill, Jason K. [University of Washington Medical Center, Seattle, Washington (United States); Won, Minhee [Barrow Neurological Institute, St. Joseph' s Hospital and Medical Center, Phoenix, Arizona (United States); Curran, Walter P. [Emory University, Atlanta, Georgia (United States)

2015-04-01

Purpose: The purpose of phase 1 was to determine the maximum tolerated dose (MTD) of motexafin gadolinium (MGd) given concurrently with temozolomide (TMZ) and radiation therapy (RT) in patients with newly diagnosed supratentorial glioblastoma multiforme (GBM). Phase 2 determined whether this combination improved overall survival (OS) and progression-free survival (PFS) in GBM recursive partitioning analysis class III to V patients compared to therapies for recently published historical controls. Methods and Materials: Dose escalation in phase 1 progressed through 3 cohorts until 2 of 6 patients experienced dose-limiting toxicity or a dose of 5 mg/kg was reached. Once MTD was established, a 1-sided 1-sample log-rank test at significance level of .1 had 85% power to detect a median survival difference (13.69 vs 18.48 months) with 60 deaths over a 12-month accrual period and an additional 18 months of follow-up. OS and PFS were estimated using the Kaplan-Meier method. Results: In phase 1, 24 patients were enrolled. The MTD established was 5 mg/kg, given intravenously 5 days a week for the first 10 RT fractions, then 3 times a week for the duration of RT. The 7 patients enrolled in the third dose level and the 94 enrolled in phase 2 received this dose. Of these 101 patients, 87 were eligible and evaluable. Median survival time was 15.6 months (95% confidence interval [CI]: 12.9-17.6 months), not significantly different from that of the historical control (P=.36). Median PFS was 7.6 months (95% CI: 5.7-9.6 months). One patient (1%) experienced a grade 5 adverse event possibly related to therapy during the concurrent phase, and none experience toxicity during adjuvant TMZ therapy. Conclusions: Treatment was well tolerated, but median OS did not reach improvement specified by protocol compared to historical control, indicating that the combination of standard RT with TMZ and MGd did not achieve a significant survival advantage.

Salmonella enterica serovar Enteritidis brain abscess mimicking meningitis after surgery for glioblastoma multiforme: a case report and review of the literature.

Science.gov (United States)

Luciani, Léa; Dubourg, Grégory; Graillon, Thomas; Honnorat, Estelle; Lepidi, Hubert; Drancourt, Michel; Seng, Piseth; Stein, Andreas

2016-07-07

Salmonella brain abscess associated with brain tumor is rare. Only 11 cases have been reported to date. Here we report a case of brain abscess caused by Salmonella enterica serovar Enteritidis mimicking post-surgical meningitis in a patient with glioblastoma multiforme. A 60-year-old Algerian woman was admitted through an emergency department for a 4-day history of headache, nausea and vomiting, and behavioral disorders. Surgery for cerebral tumor excision was performed and histopathological analysis revealed glioblastoma multiforme. On the seventh day post-surgery, she presented a sudden neurological deterioration with a meningeal syndrome, confusion, and fever of 39.8°C. Her cerebrospinal fluid sample and blood cultures were positive for S. enterica Enteritidis. She was treated with ceftriaxone and ciprofloxacin. On the 17th day post-surgery, she presented a new neurological disorder and purulent discharge from the surgical wound. Brain computed tomography revealed a large cerebral abscess located at the operative site. Surgical drainage of the abscess was performed and microbial cultures of surgical deep samples were positive for the same S. enterica Enteritidis isolate. She recovered and was discharged 6 weeks after admission. In this case report, a brain abscess was initially diagnosed as Salmonella post-surgical meningitis before the imaging diagnosis of the brain abscess. The diagnosis of brain abscess should be considered in all cases of non-typhoidal Salmonella meningitis after surgery for brain tumor. Surgical brain abscess drainage followed by prolonged antibiotic treatment remains a major therapeutic option.

Vaccine-induced toxic epidermal necrolysis: A case and systematic review.

Science.gov (United States)

Chahal, Dev; Aleshin, Maria; Turegano, Mamina; Chiu, Melvin; Worswick, Scott

2018-01-15

Erythema multiforme (EM), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are cutaneous hypersensitivityreactions that develop in response to specific triggers such as medications and certain infections. Vaccines, which undergo rigorous safety testing prior to use in humans, are a rare cause of SJS/TEN and little is known about the frequency of such events and corresponding pathogenesis. Herein, we discuss a case of suspected TEN in a 19-year-old woman who received the meningococcal B vaccine (the first report of such an association) and conduct a systematic review of the associated literature. We also discuss management of this patient with a single dose of etanercept. Relevant literature was searched using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method. A total of 29 articles reporting EM, SJS, or TEN following vaccination were included from >5 countries. Of the 29, 22 articles reported EM, 6/29 reported SJS, and 4/29 reported TEN (3 articlesreported cases of both EM and SJS/TEN). We suggest consideration of vaccines as an etiology for cases of SJS or TEN that begin with an EM-like presentation, and provide further evidence for the use of etanercept as a viable treatment for TEN.

The classification and application of toxic Chinese materia medica.

Science.gov (United States)

Liu, Xinmin; Wang, Qiong; Song, Guangqing; Zhang, Guangping; Ye, Zuguang; Williamson, Elizabeth M

2014-03-01

Many important drugs in the Chinese materia medica (CMM) are known to be toxic, and it has long been recognized in classical Chinese medical theory that toxicity can arise directly from the components of a single CMM or may be induced by an interaction between combined CMM. Traditional Chinese Medicine presents a unique set of pharmaceutical theories that include particular methods for processing, combining and decocting, and these techniques contribute to reducing toxicity as well as enhancing efficacy. The current classification of toxic CMM drugs, traditional methods for processing toxic CMM and the prohibited use of certain combinations, is based on traditional experience and ancient texts and monographs, but accumulating evidence increasingly supports their use to eliminate or reduce toxicity. Modern methods are now being used to evaluate the safety of CMM; however, a new system for describing the toxicity of Chinese herbal medicines may need to be established to take into account those herbs whose toxicity is delayed or otherwise hidden, and which have not been incorporated into the traditional classification. This review explains the existing classification and justifies it where appropriate, using experimental results often originally published in Chinese and previously not available outside China. Copyright © 2013 John Wiley & Sons, Ltd.

The use of hypofractionated intensity-modulated irradiation in the treatment of glioblastoma multiforme: preliminary results of a prospective trial.

Science.gov (United States)

Sultanem, Khalil; Patrocinio, Horacio; Lambert, Christine; Corns, Robert; Leblanc, Richard; Parker, William; Shenouda, George; Souhami, Luis

2004-01-01

Despite major advances in treatment modalities, the prognosis of patients with glioblastoma multiforme (GBM) remains poor. Exploring hypofractionated regimens to replace the standard 6-week radiotherapy schedule is an attractive strategy as an attempt to prevent accelerated tumor cell repopulation. There is equally interest in dose escalation to the gross tumor volume where the majority of failures occur. We report our preliminary results using hypofractionated intensity-modulated accelerated radiotherapy regimen in the treatment of patients with GBM. Between July 1998 and December 2001, 25 patients with histologically proven diagnosis of GBM, Karnofsky performance status > or =60, and a postoperative tumor volume step-and-shoot technique), 60 Gy in 20 daily fractions of 3 Gy each were given to the GTV, whereas the planning target volume received a minimum of 40 Gy in 20 fractions of 2 Gy each at its periphery. Treatments were delivered over a 4-week period using 5 daily fractions per week. Dose was prescribed at the isocenter (ICRU point). Three beam angles were used in all of the cases. Treatments were well tolerated. Acute toxicity was limited to increased brain edema during radiotherapy in 2 patients who were on tapering doses of corticosteroids. This was corrected by increasing the steroid dose. At a median follow-up of 8.8 months, no late toxicity was observed. One patient experienced visual loss at 9 months after completion of treatment. MRI suggested nonspecific changes to the optic chiasm. On review of the treatment plan, the total dose to the optic chiasm was confirmed to be equal to or less than 40 Gy in 20 fractions. When Radiation Therapy Oncology Group recursive partitioning analysis was used, 10 patients were class III-IV, and 15 patients were class V-VI. To date, 21 patients have had clinical and/or radiologic evidence of disease progression, and 16 patients have died. The median survival was 9.5 months (range: 2.8-22.9 months), the 1-year survival

Fostering efficacy and toxicity evaluation of traditional Chinese medicine and natural products: Chick embryo as a high throughput model bridging in vitro and in vivo studies.

Science.gov (United States)

Wu, Tong; Yu, Gui-Yuan; Xiao, Jia; Yan, Chang; Kurihara, Hiroshi; Li, Yi-Fang; So, Kwok-Fai; He, Rong-Rong

2018-04-19

Efficacy and safety assessments are essential thresholds for drug candidates from preclinical to clinical research. Conventional mammalian in vivo models cannot offer rapid pharmacological and toxicological screening, whereas cell-based or cell-free in vitro systems often lead to inaccurate results because of the lack of physiological environment. Within the avian species, gallus gallus is the first bird to have its genome sequencing. Meantime, chick embryo is an easily operating, relatively transparent and extensively accessible model, whose physiological and pathological alterations can be visualized by egg candler, staining and image technologies. These features facilitate chick embryo as a high-throughput screening platform bridging in vivo and in vitro gaps in the pharmaceutical research. Due to the complicated ingredients and multiple-targets natures of traditional Chinese medicine (TCM), testing the efficacy and safety of TCM by in vitro methods are laborious and inaccurate, while testing in mammalian models consume massive cost and time. As such, the productive living organism chick embryo serves as an ideal biological system for pharmacodynamics studies of TCM. Herein, we comprehensively update recent progresses on the specialty of chick embryo in evaluation of efficacy and toxicity of drugs, with special concerns of TCM. Copyright © 2018 Elsevier Ltd. All rights reserved.

Phase II, two-arm RTOG trial (94-11) of bischloroethyl-nitrosourea plus accelerated hyperfractionated radiotherapy (64.0 or 70.4 Gy) based on tumor volume (> 20 or ≤ 20 cm2, respectively) in the treatment of newly-diagnosed radiosurgery-ineligible glioblastoma multiforme patients

International Nuclear Information System (INIS)

Coughlin, C.; Scott, C.; Langer, C.; Coia, L.; Curran, W.; Rubin, P.

2000-01-01

Purpose: To compare survivorship, and acute and delayed toxicities following radiation therapy (RT) of radiosurgery-ineligible glioblastoma multiforme (GBM) patients treated with tumor volume-influenced, high-dose accelerated, hyperfractionated RT plus bischloroethyl-nitrosourea (BCNU), using prior RTOG malignant glioblastoma patients as historical controls. Methods and Materials: One hundred four of 108 patients accrued from June 1994 through May 1995 from 26 institutions were analyzable. Patients were histologically confirmed with GBM, and previously untreated. Treatment assignment (52 patients/arm) was based on tumor mass (TM), defined as the product of the maximum diameter and greatest perpendicular dimension of the titanium-gadolinium-enhanced postoperative MRI: Arm A, 64 Gy, TM > 20 cm 2 ; or Arm B, 70.4 Gy, TM ≤ 20 cm 2 . Both Arms A and B received BCNU (80 mg/m 2 , under hyperhydration) days 1-3, 56-58, then 4 cycles, each 8 weeks, for a total of 6 treatment series. Results: During the 24 months immediately post-treatment, the overall median survival was 9.1 months in Arm A (64 Gy) and 11.0 months in Arm B (70.4 Gy). Median survival in recursive partitioning analysis (RPA) Class III/IV was 10.4 months in Arm A and 12.2 months in Arm B, while RPA Class V/VI was 7.6 months in Arm A and 6.1 months in Arm B. There were no grade 4 neurological toxicities in Arm A; 2 grade 4 neurological toxicities were observed in Arm B (1 motor deficit, 1 necrosis at 157 days post-treatment). Conclusion: This strategy of high-dose, accelerated hyperfractionated radiotherapy shortens overall RT treatment times while allowing dose escalation, and it provides the potential for combination with currently available, as well as newer, chemotherapy agents. Survival is comparable with previously published RTOG data, and toxicities are within acceptable limits.

Comparing predictive models of glioblastoma multiforme built using multi-institutional and local data sources.

Science.gov (United States)

Singleton, Kyle W; Hsu, William; Bui, Alex A T

2012-01-01

The growing amount of electronic data collected from patient care and clinical trials is motivating the creation of national repositories where multiple institutions share data about their patient cohorts. Such efforts aim to provide sufficient sample sizes for data mining and predictive modeling, ultimately improving treatment recommendations and patient outcome prediction. While these repositories offer the potential to improve our understanding of a disease, potential issues need to be addressed to ensure that multi-site data and resultant predictive models are useful to non-contributing institutions. In this paper we examine the challenges of utilizing National Cancer Institute datasets for modeling glioblastoma multiforme. We created several types of prognostic models and compared their results against models generated using data solely from our institution. While overall model performance between the data sources was similar, different variables were selected during model generation, suggesting that mapping data resources between models is not a straightforward issue.

Subcutaneous tissue metastasis from glioblastoma multiforme: A case report and review of the literature.

Science.gov (United States)

Frade Porto, Natalia; Delgado Fernández, Juan; García Pallero, María de Los Ángeles; Penanes Cuesta, Juan Ramón; Pulido Rivas, Paloma; Gil Simoes, Ricardo

2018-05-16

Glioblastoma multiforme is the most common primary brain tumor, despite an aggressive clinical course, less than 2% of patients develop extraneural metastasis. We present a 72-year-old male diagnosed with a right temporal glioblastoma due to headache. He underwent total gross resection surgery and after that the patient was treated with adyuvant therapy. Five months after the patient returned with trigeminal neuralgia, and MRI showed an infratemporal cranial mass which infiltrates masticator space, the surrounding bone, the temporal muscle and superior cervical and parotid lymph nodes. The patient underwent a new surgery reaching partial resection of the temporal lesion. After that the patient continued suffering from disabling trigeminal neuralgia, that's why because of the bad clinical situation and the treatment failure we decided to restrict therapeutic efforts. The patient died 3 weeks after the diagnosis of extracranial metastasis. Copyright © 2018 Sociedad Española de Neurocirugía. Publicado por Elsevier España, S.L.U. All rights reserved.

The use of positron emission tomography in BNCT treatment planning for metastatic malignant melanoma and glioblastoma multiforme

International Nuclear Information System (INIS)

Kabalka, G.; Nichols, T.; Smith, G.; Miller, L.; Kahn, M.

2000-01-01

Positron emission tomography (PET) evaluations of six glioblastoma multiforme (GBM) and one metastatic melanoma (MM) patient have been carried out utilizing fluorine-18 labeled p-boronophenylalanine. Four of the GBM patients were imaged both prior to and post BNCT. In one GBM patient, biopsy derived boron distribution data compared favorably to the PET derived data. The PET data have been used as input to dosimetry calculations and the results vary from those obtained using current protocols. In addition, PET images of the thorax would indicate that the utility of PET for staging tumors for BNCT may extend beyond the brain. However, higher than anticipated levels of activity in the lungs (as also seen in salivary glands) indicate the more effective BNCT agents will be required. (author)

Comparative metal oxide nanoparticle toxicity using embryonic zebrafish

Directory of Open Access Journals (Sweden)

Leah C. Wehmas

2015-01-01

Full Text Available Engineered metal oxide nanoparticles (MO NPs are finding increasing utility in the medical field as anticancer agents. Before validation of in vivo anticancer efficacy can occur, a better understanding of whole-animal toxicity is required. We compared the toxicity of seven widely used semiconductor MO NPs made from zinc oxide (ZnO, titanium dioxide, cerium dioxide and tin dioxide prepared in pure water and in synthetic seawater using a five-day embryonic zebrafish assay. We hypothesized that the toxicity of these engineered MO NPs would depend on physicochemical properties. Significant agglomeration of MO NPs in aqueous solutions is common making it challenging to associate NP characteristics such as size and charge with toxicity. However, data from our agglomerated MO NPs suggests that the elemental composition and dissolution potential are major drivers of toxicity. Only ZnO caused significant adverse effects of all MO particles tested, and only when prepared in pure water (point estimate median lethal concentration = 3.5–9.1 mg/L. This toxicity was life stage dependent. The 24 h toxicity increased greatly (∼22.7 fold when zebrafish exposures started at the larval life stage compared to the 24 h toxicity following embryonic exposure. Investigation into whether dissolution could account for ZnO toxicity revealed high levels of zinc ion (40–89% of total sample were generated. Exposure to zinc ion equivalents revealed dissolved Zn2+ may be a major contributor to ZnO toxicity.

Hydroxocobalamin as a Cyanide Antidote: Empirical use , Safety, Efficacy, and Considerations for Stockpiling

International Nuclear Information System (INIS)

Hall, A. H.

2007-01-01

Cyanide is a well-known toxic terrorism agent and is a major cause of mortality and morbidity in smoke inhalation victims. Terrorist attacks could start enclosed-space fires with cyanide-poisoned victims, even if cyanide itself was not utilized. Cyanide poisoning cannot be emergent confirmed by laboratory analysis and treatment with safe and efficacious antidotes must be administered empirically. Hydroxocobalamin has been recently approved by the US FDA and is a safe and efficacious antidote. Its efficacy is comparable to that of other, more toxic, cyanide antidotes. Its mechanism of action involves both direct cyanide chelation (forming non-toxic cyanocobalamin which is excreted in the urine) and nitric oxide scavenging. Adverse effects are usually limited to transient dark red-brown discoloration of urine, skin, sclera, and mucous membranes. Antidotal doses have not caused allergic reactions in cyanide-poisoned patients and only minor and easily-treated allergic reactions occurred in 2 of 136 normal volunteers. Transient, asymptomatic hypertension and reflex bradycardia have occurred in some normal volunteers, but not in seriously ill smoke inhalation victims not having significant cyanide poisoning. Hydroxocobalamin is a safe and efficacious antidote and can be empirically administered in pre-hospital or emergency department settings. It is therefore suitable for inclusion in national or multinational medication stockpiles and is already included in some national programs in the European Union.(author)

Glioblastoma multiforme subterfuge as acute cerebral hemorrhage: A case report and literature review

Directory of Open Access Journals (Sweden)

Seidu A. Richard

2018-04-01

Full Text Available Hemorrhagic related Glioblastoma multiforme (GBM are rare and characterizes with severe clinical scuffle. The etiology of this presentation although not well known is believed to be multifactorial. We present a case as well as review on the pathogenesis of evolution of the hematoma into ring enhancing features of GBM on imaging studies. We present a case of 28 years old man who suddenly went into coma for 9 hours preceded with seizures that latest for 10 minutes. He had no focal neurological signs. CT-Scans images indicated acute cerebral hemorrhage near the frontal horn of the left ventricle with brain edema about the hemorrhagic lesion and MRI done a week later revealed a cerebral ring enhancing lesion. The lesion was partially resected during surgery and immunohistochemical staining confirmed GBM (WHO, grade 4. The diagnosis of intratumoral hemorrhage in GBM was very challenging at the initial stages but with time the hematoma evolved into ring enhancing images typical of GBM. It’s not every intracranial hematoma that is of pure vascular origin.

ORAL LESIONS OF DRUG INDUCED ERYTHEMA MULTIFORME and ndash; REPORT OF THREE CASES

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Shruthi Hegde

2013-09-01

Full Text Available Abstract: Erythema multiforme (EM is an acute, self-limited, and sometimes recurring skin condition considered to be a hypersensitivity reaction associated with certain infections and medications. A range of medications can trigger the EM. Non-steroidal anti-inflammatory drugs (NSAIDS which are most commonly prescribed for pain relief can also produce rare adverse reactions such as EM. EM is clinically characterized by a and lsquo; and lsquo;minor'' form and a and lsquo; and lsquo;major'' form. Only few reports have stated about oral EM as the third variant of EM. However it is unclear whether EM involving only oral mucosa is a separate entity or is a part of minor form of EM. In this report three cases of EM are discussed , in which two cases involved exclusively oral mucosal lesions and in one case skin manifestations along with oral mucosa was observed. Also the uncommon adverse effects of NSAIDS is highlighted in this report along with its management. [J Contemp Med 2013; 3(3.000: 193-196

Treatment outcome and prognostic factors of adult glioblastoma multiforme.

Science.gov (United States)

Ahmadloo, Niloofar; Kani, Amir-Abbas; Mohammadianpanah, Mohammad; Nasrolahi, Hamid; Omidvari, Shapour; Mosalaei, Ahmad; Ansari, Mansour

2013-03-01

This study aimed to report the characteristics, prognostic factors and treatment outcome of 223 patients with glioblastoma multiforme (GBM). This retrospective study was carried out by reviewing the medical records of 223 adult patients diagnosed at a tertiary academic hospital between 1990 and 2008. Patients' follow up ranged from 1 to 69 months (median 11 months). Surgery was attempted in all patients in whom complete resection in 15 patients (7%), subtotal resection in 77 patients (34%), partial resection in 73 patients (33%) and biopsy alone in 58 patients (26%) were done. In addition, we performed a literature review of PubMed to find out and analyze major related series. In all, we collected and analyzed the data of 33 major series including more than 11,000 patients with GBM. There were 141 men and 82 women. The median progression free- and overall survival were 6 (95% CI=5.711-8.289) and 11 (95% CI=9.304-12.696) months respectively. In univariate analysis for overall survival, age (P=0.003), tumor size (P<0.013), performance status (P<0.001), the extent of surgical resection (P=0.009), dose of radiation (P<0.001), and adjuvant chemotherapy (P<0.001) were prognostic factors. However, in multivariate analysis, only radiation dose, extent of surgical resection, and adjuvant chemotherapy were independent prognostic factors for overall survival. The prognosis of adult patients with GBM remains poor; however, complete surgical resection and adjuvant treatments improve progression-free and overall survival. Copyright © 2012. Production and hosting by Elsevier B.V.

Treatment outcome and prognostic factors of adult glioblastoma multiforme

International Nuclear Information System (INIS)

Ahmadloo, N.; Mohammadianpanah, M.; Nasrolahi, H.; Omidvari, Sh.; Ansari, M.; Kani, A.A.; Mosalaei, A.

2013-01-01

Introduction: This study aimed to report the characteristics, prognostic factors and treatment outcome of 223 patients with glioblastoma multiforme (GBM). Subjects and method: This retrospective study was carried out by reviewing the medical records of 223 adult patients diagnosed at a tertiary academic hospital between 1990 and 2008. Patients’ follow up ranged from 1 to 69 months (median 11 months). Surgery was attempted in all patients in whom complete resection in 15 patients (7%), subtotal resection in 77 patients (34%), partial resection in 73 patients (33%) and biopsy alone in 58 patients (26%) were done. In addition, we performed a literature review of Pub Med to find out and analyze major related series. In all, we collected and analyzed the data of 33 major series including more than 11,000 patients with GB M. Results: There were 141 men and 82 women. The median progression free- and overall survival were 6 (95% Cl = 5.711-8.289) and 11 (95% Cl = 9.304-12.696) months respectively. In univariate analysis for overall survival, age (P = 0.003), tumor size (P < 0.013), performance status (P < 0.001), the extent of surgical resection (P - 0.009), dose of radiation (P < 0.001), and adjuvant chemotherapy (P < 0.001) were prognostic factors. However, in multivariate analysis, only radiation dose, extent of surgical resection, and adjuvant chemotherapy were independent prognostic factors for overall survival. Conclusion: The prognosis of adult patients with GBM remains poor; however, complete surgical resection and adjuvant treatments improve progression-free and overall survival

Percutaneous ethanol injection treatment in benign thyroid lesions: role and efficacy.

Science.gov (United States)

Guglielmi, Rinaldo; Pacella, Claudio Maurizio; Bianchini, Antonio; Bizzarri, Giancarlo; Rinaldi, Roberta; Graziano, Filomena Maria; Petrucci, Lucilla; Toscano, Vincenzo; Palma, Enzo; Poggi, Maurizio; Papini, Enrico

2004-02-01

To establish the role of percutaneous ethanol injection (PEI) treatment in benign thyroid lesions by evaluating: (1) the long-term efficacy and side effects of the treatment, (2) the factors predictive of efficacy of PEI, and (3) the cost effectiveness of the procedure. Fifty-eight recurrent cystic nodules, 95 autonomously functioning nodules (AFTN), and 17 hyperfunctioning nodules causing thyrotoxicosis (toxic nodules) were treated by PEI from 1990 to 1996 in our center. Ultrasound (US) and color flow doppler (CFD) examinations were carried out before and after each treatment. In patients with AFTN, serum thyrotropin (TSH), free triiodothyronine (FT3), free thyroxine (FT4), thyroid peroxidase antibody (TPOAb) levels were tested before and after PEI. All patients were independently reexamined by two external reviewers after a minimum follow-up of 5 years (median, 6.9 years). The median number of treatments was 2.0 (range, 1.0-4.0) for cystic nodules, 4 (range, 2.0-6.0) for AFTN, and 5 (range, 3.0-7.0) for toxic nodules. At the 5-year evaluation cystic nodules showed a volume reduction greater than 75% versus baseline in 86.2% of cases and an improvement of local symptoms in 91.4% of cases. AFTN presented serum TSH within normal limits in 60.0% of patients. Toxic nodules showed a detectable serum TSH and normal FT3 and FT4 values in 35.3% of cases. Two cases of transient dysphonia were observed. In cystic lesions no significant correlation was found between the baseline and the final volume (r2 = 0.17) and no significant predictor of treatment efficacy was found. However, unilocularity was associated with a lower number of treatments than multilocularity (median, 2.0 vs. 3.0). Independent predictors of clinical efficacy in both AFTN and toxic nodules were a baseline volume less than 5.0 mL and a fluid component greater than 30% (odds ratio [OR] = 6.1 and 3.3, respectively). Most recurrent cystic lesions of the thyroid can be cured by PEI, which should become the

Comparison between anti-CEA and anti-HER2 212Pb-labeled mAbs during α-RIT of small volume peritoneal carcinomatosis - Role of activity distribution on therapeutic efficacy and toxicity?

International Nuclear Information System (INIS)

Elgqvist, J.; Boudousq, V.; Bobyk, L.; Busson, M.; Lozza, C.; Navarro-Teulon, I.; Pouget, J.P.; Maquaire, P.; Torgue, J.

2015-01-01

Full text of publication follows. Objectives: we investigated the role of internalizing/non-internalizing monoclonal antibodies (mAbs) on the final outcome (efficacy/toxicity) of mice treated with alpha radioimmunotherapy (α- RIT) using 212 Pb-labeled mAbs. The relationship between distribution of radioactivity at the tissue level and biological parameters was also assessed. Methods: nude mice bearing 2-3 mm peritoneal nodules obtained by xenograft of A-431 tumor cells, expressing low and high level of HER2 and CEA receptors, respectively, were intraperitoneally (i.p.) injected with increasing activities (370-1480 kBq; 37 MBq/mg) of either 35A7 (non-internalising anti-CEA), Trastuzumab (internalizing anti-HER2) or PX (non-specific) 212 Pb-labeled mAbs. Control groups were injected with corresponding amount of unlabeled mAbs or with NaCl. Tumor growth was followed by bioluminescence and median survival (MS) of control and treated mice was determined. 212 Pb-35A7 and 212 Pb-Trastuzumab biodistribution was used to determine the cumulative uptake of radioactivity (UOR) in organs and tumors. Mean absorbed doses were calculated using the MIRD formalism. Haematological, liver and kidney toxicities were also assessed. Distribution of radioactivity at the tissue level was determined by digital micro-autoradiography and the relationship with biological markers of tissue damage was investigated using immunohistochemistry. Results: a mild and transient haematological toxicity in groups treated with the highest amount of activity was observed. MS of the groups treated either with internalizing or non-internalizing 212 Pb-labeled mAbs was significantly improved compared to those treated with non-specific 212 Pb-PX or those only given unlabeled mAbs or just NaCl. MS ranged from 42 days to 94 days using various activity levels of anti-CEA 212 Pb-35A7 while MS was not reached over the follow-up period of 130 days for mice treated with anti-HER2 212 Pb-Trastuzumab. However, UOR and

Role of 5-ALA in improving extent of tumour resection in patients with Glioblastoma Multiforme.

Science.gov (United States)

Waqas, Muhammad; Khan, Inamullah; Shamim, Muhammad Shahzad

2017-10-01

Goal of surgery for patients with Glioblastoma Multiforme (GBM) is gross total resection with no new neurological deficits. Surgical resection is often restricted due the difficulty in differentiating the tumour from surrounding normal brain using either naked eye, or standard intra-operative white light microscopy. GBM uptakes orally administered 5-ALA becomes fluorescent when viewed by a special light, and this property has been used to improve intra-operative tumour identification. This technique should therefore allow better extent of tumour resection. The hypothesis has been tested through several studies and even though most studies are of low quality, they strongly favour the use of 5- ALA in improving the extent of resection when compared to white light microscopy. A systematic review on the topic had a similar conclusion. Few studies have also hinted on a high false negative rate with the use of this technique..

Protective efficacy of various carbonyl compounds and their metabolites, and nutrients against acute toxicity of some cyanogens in rats: biochemical and physiological studies

Directory of Open Access Journals (Sweden)

Bhattacharya Rahul

2017-09-01

Full Text Available Cyanogens are widely used in industries and their toxicity is mainly due to cyanogenesis. The antidotes for cyanide are usually instituted for the management of cyanogen poisoning. The present study reports the protective efficacy of 14 carbonyl compounds and their metabolites, and nutrients (1.0 g/kg; oral; +5 min against acute oral toxicity of acetonitrile (ATCN, acrylonitrile (ACN, malononitrile (MCN, propionitrile (PCN, sodium nitroprusside (SNP, succinonitrile (SCN, and potassium ferricyanide (PFCN in rats. Maximum protection index was observed for alpha-ketoglutarate (A-KG against MCN and PCN (5.60, followed by dihydroxyacetone (DHA against MCN (2.79. Further, MCN (0.75 LD50 caused significant increase in cyanide concentration in brain, liver and kidney and inhibition of cytochrome c oxidase activity in brain and liver, which favorably responded to A-KG and DHA treatment. Up-regulation of inducible nitric oxide synthase by MCN, PCN and SNP, and uncoupling protein by PCN and SNP observed in the brain was abolished by A-KG administration. However, no DNA damage was detected in the brain. MCN and SNP significantly decreased the mean arterial pressure, heart rate, respiratory rate and neuromuscular transmission, which were resolved by A-KG. The study suggests a beneficial effect of A-KG in the treatment of acute cyanogen poisoning.

Anthelmintic effect of thymol and thymol acetate on sheep gastrointestinal nematodes and their toxicity in mice

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Weibson Paz Pinheiro André

Full Text Available Abstract Thymol is a monoterpene and acetylation form of this compound can reduce the toxicity and enhance its biological effects. The objective of this study was to evaluate the effect of thymol and thymol acetate (TA on egg, larva and adult Haemonchus contortus and the cuticular changes, acute toxicity in mice and the efficacy on sheep gastrointestinal nematodes. In vitro tests results were analyzed by analysis of variance (ANOVA and followed by comparison with Tukey test or Bonferroni. The efficacy of in vivo test was calculated by the BootStreet program. In the egg hatch test (EHT, thymol (0.5 mg/mL and TA (4 mg/mL inhibited larval hatching by 98% and 67.1%, respectively. Thymol and TA (8 mg/mL inhibited 100% of larval development. Thymol and TA (800 µg/mL reduced the motility of adult worms, by 100% and 83.4%, respectively. Thymol caused cuticular changes in adult worm teguments. In the acute toxicity test, the LD50 of thymol and TA were 1,350.9 mg/kg and 4,144.4 mg/kg, respectively. Thymol and TA reduced sheep egg count per gram of faeces (epg by 59.8% and 76.2%, respectively. In in vitro tests thymol presented better anthelmintic activity than TA. However TA was less toxic and in in vivo test efficacy was similar.

A comprehensive characterization of mitochondrial DNA mutations in glioblastoma multiforme.

Science.gov (United States)

Vidone, Michele; Clima, Rosanna; Santorsola, Mariangela; Calabrese, Claudia; Girolimetti, Giulia; Kurelac, Ivana; Amato, Laura Benedetta; Iommarini, Luisa; Trevisan, Elisa; Leone, Marco; Soffietti, Riccardo; Morra, Isabella; Faccani, Giuliano; Attimonelli, Marcella; Porcelli, Anna Maria; Gasparre, Giuseppe

2015-06-01

Glioblastoma multiforme (GBM) is the most malignant brain cancer in adults, with a poor prognosis, whose molecular stratification still represents a challenge in pathology and clinics. On the other hand, mitochondrial DNA (mtDNA) mutations have been found in most tumors as modifiers of the bioenergetics state, albeit in GBM a characterization of the mtDNA status is lacking to date. Here, a characterization of the burden of mtDNA mutations in GBM samples was performed. First, investigation of tumor-specific vs. non tumor-specific mutations was carried out with the MToolBox bioinformatics pipeline by analyzing 45 matched tumor/blood samples, from whole genome or whole exome sequencing datasets obtained from The Cancer Genome Atlas (TCGA) consortium. Additionally, the entire mtDNA sequence was obtained in a dataset of 104 fresh-frozen GBM samples. Mitochondrial mutations with potential pathogenic interest were prioritized based on heteroplasmic fraction, nucleotide variability, and in silico prediction of pathogenicity. A preliminary biochemical analysis of the activity of mitochondrial respiratory complexes was also performed on fresh-frozen GBM samples. Although a high number of mutations was detected, we report that the large majority of them does not pass the prioritization filters. Therefore, a relatively limited burden of pathogenic mutations is indeed carried by GBM, which did not appear to determine a general impairment of the respiratory chain. This article is part of a Directed Issue entitled: Energy Metabolism Disorders and Therapies. Copyright © 2015 Elsevier Ltd. All rights reserved.

What’s the clinical significance of adding diffusion and perfusion MRI in the differentiation of glioblastoma multiforme and solitary brain metastasis?

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Amr F. Mourad

2017-09-01

Full Text Available Objective: To evaluate the additional diagnostic value of diffusion and perfusion MRI in the differentiation of glioblastoma multiforme (GBM and solitary brain metastasis. Patients and methods: This retrospective study included 24 patients with histologically proven brain tumors who underwent conventional MRI with analysis of diffusion (DWI and perfusion (PWI MRI findings of each tumor. The Apparent Diffusion Coefficient (ADC values were calculated in the minimum (ADC-MIN, mean (ADC-MEAN, and maximum (ADC-MAX in all the tumors and the peritumoral regions. The PWI data was expressed as maximum regional cerebral blood volume (rCBV of the tumors and peritumoral regions. Results: After adding diffusion and perfusion to conventional MRI findings, we found that the accuracy of differentiation between glioblastoma multiforme (GBM and solitary metastasis increased from 70% to 90%.There is a significant difference in DWI signal intensity between GBM and metastatic tumors (P < 0.05. The ADC values of GBM were lower than that of metastatic tumors. On perfusion MRI, the maximum rCBV of the peritumoral region (rCBVP of GBM was higher than that of brain metastases (P < 0.001. Conclusion: The addition of diffusion and perfusion to the MRI protocol increases the accuracy of differentiation between GBM and solitary brain metastasis and should be considered routinely. Keywords: Diffusion MRI, Perfusion MRI, GBM, Solitary brain metastases

The Protective Efficacy Of Extract Of Hibiscus Sabdariffa (Karkade) Calyces Against Alcohol Toxicity In Male Albino Rats

International Nuclear Information System (INIS)

Ali, E.A.; Ali, E.A.; Shahen, E.M.; El Madawy, S.A.

2013-01-01

Hibiscus sabdariffa (HS), Malvacea family, is a medicinal plant with a worldwide fame. Its benefit effect on some physiological parameters as blood picture, blood pressure, fasting blood sugar, lipid profile, liver and kidney functions, electrolytes and antioxidant capacity is mentioned in several recent studies. The purpose of this study was to assess the efficacy of this plant in protecting from alcohol toxicity in rats. Thirty two adult male albino rats were divided into four equal groups: group 1 received water orally for 30 days, group 2 received ethanol (5 ml/kg/day) for 30 days, both group 3 and group 4 received Hibiscus sabdariffa (100 mg/kg/day) orally for 30 days and then group 4 received ethanol (5 ml/kg/day) orally for another 30 days. Serum hepatic markers (aspartate and alanine minotransferases; AST and ALT), alkaline phosphatase (ALP) and gamma glutamyl transferase (GGT) were increased significantly by alcohol abuse with no observed improvement in treatment with HS. Significant reduction in total protein and albumin was observed in alcohol abuse which improved with HS treatment and showed significant increase as compared with both control and alcohol treated groups. Serum kidney markers (urea, creatinine and uric acid) were increased in alcohol abuse and only creatinine and uric acid nearly returned to normal levels with HS treatment while urea level remains high. Serum glucose was increased significantly in alcohol abuse and significantly decreased in group 3 (HS treated) and group 4 (HS + ethanol). Serum total cholesterol, triglycerides, high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C) and atherogenic index were increased significantly while HDL-C was significantly reduced in alcohol abuse. HS treatment resulted in significant increase in HDL-C and therefore decreased atherogenic index in both group 3 and group 4 which indicated protective effect of HS for coronary heart diseases. These results lead to the

Use of toxicity assays for evaluating the effectiveness of groundwater remediation with Fenton’s reagent

DEFF Research Database (Denmark)

Kusk, Kresten Ole; Bennedsen, Lars; Christophersen, Mette

2011-01-01

evaluates in situ chemical oxidation (ISCO) using modified Fenton’s reagent (H2O2 + chelated Fe2+) as a groundwater remedy. Three injections were performed over a period to test treatment efficacy. Performance monitoring samples were collected from two depths both prior to and during treatment, and analyzed...... treatment with Fenton’s reagent the toxicity had increased and now needed 7100 times dilution to reduce toxicity to the LC10 probably due to mobilization of metals. It is concluded that toxicity assay is a useful tool for evaluating samples from contaminated sites and that toxicity assays and chemical...

Intraoperative MRI to guide the resection of primary supratentorial glioblastoma multiforme - a quantitative radiological analysis

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Schneider, Jens P.; Rubach, Matthias; Schulz, Thomas; Dietrich, Juergen; Zimmer, Claus; Kahn, Thomas [University of Leipzig, Diagnostic Radiology, Leipzig (Germany); Trantakis, Christos; Winkler, Dirk; Renner, Christof [University of Leipzig, Department of Neurosurgery, Leipzig (Germany); Schober, Ralf; Geiger, Kathrin [University of Leipzig, Department of Neuropathology, Leipzig (Germany); Brosteanu, Oana [Coordination Centre for Clinical Trials, Leipzig (Germany)

2005-07-01

Patients with supratentorial high-grade glioma underwent surgery within a vertically open 0.5-T magnetic resonance (MR) system to evaluate the efficacy of intraoperative MR guidance in achieving gross-total resection. For 31 patients, preoperative clinical data and MR findings were consistent with the putative diagnosis of a high-grade glioma, in 23 cases in eloquent regions. Tumor resections were carried out within a 0.5-T MR SIGNA SP/i (GE Medical Systems, USA). The resection of the lesion was carried out using fully MR compatible neurosurgical equipment and was stopped at the point when the operation was considered complete by the surgeon viewing the operation field with the microscope. We repeated imaging to determine the residual tumor volume only visible with MRI. Areas of tissue that were abnormal on these images were localized in the bed of resection by using interactive MR guidance. The procedure of resection, imaging control and interactive image guidance was repeated where necessary. Almost all tissue with abnormal characteristics was resected, with the exception of tissue localized in eloquent brain areas. The diagnosis of glioblastoma was confirmed in all 31 cases. When comparing the tumor volume before resection and at the point where the neurosurgeon would otherwise have terminated surgery (''first control''), residual tumor tissue was detectable in 29/31 patients; the mean residual tumor volume was 30.7{+-}24%. After repeated resections under interactive image guidance the mean residual tumor volume was 15.1%. At this step we found tumor remnants only in 20/31 patients. The perioperative morbidity (12.9%) was low. Twenty-seven patients underwent sufficient postoperative radiotherapy. We found a significant difference (log{sub rank}p=0.0037) in the mean survival times of the two groups with complete resection (n=10, median survival time 537 days) and incomplete resection (n=17, median survival time 237 days). The resection of

Role of Intra-operative MRI (iMRI) in Improving Extent of Resection and Survival in Patients with Glioblastoma Multiforme.

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Khan, Inamullah; Waqas, Muhammad; Shamim, Muhammad Shahzad

2017-07-01

Multiple intraoperative aids have been introduced to improve the extent of resection (EOR) in Glioblastoma Multiforme (GBM) patients, avoiding any new neurological deficits. Intraoperative MRI (iMRI) has been debated for its utility and cost for nearly two decades in neurosurgical literature. Review of literature suggests improved EOR in GBM patients who underwent iMRI assisted surgical resections leading to higher overall survival (OS) and progression free survival (PFS). iMRI provides real time intraoperative imaging with reasonable quality. Higher risk for new postoperative deficits with increased EOR is not reported in any study using iMRI. The level of evidence regarding prognostic benefits of iMRI is still of low quality..

A Limited Structural Modification Results in a Significantly More Efficacious Diazachrysene-Based Filovirus Inhibitor

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Rekha G. Panchal

2012-08-01

Full Text Available Ebola (EBOV and Marburg (MARV filoviruses are highly infectious pathogens causing deadly hemorrhagic fever in humans and non-human primates. Promising vaccine candidates providing immunity against filoviruses have been reported. However, the sporadic nature and swift progression of filovirus disease underlines the need for the development of small molecule therapeutics providing immediate antiviral effects. Herein we describe a brief structural exploration of two previously reported diazachrysene (DAAC-based EBOV inhibitors. Specifically, three analogs were prepared to examine how slight substituent modifications would affect inhibitory efficacy and inhibitor-mediated toxicity during not only EBOV, but also MARV cellular infection. Of the three analogs, one was highly efficacious, providing IC₅₀ values of 0.696 µM ± 0.13 µM and 2.76 µM ± 0.21 µM against EBOV and MARV infection, respectively, with little or no associated cellular toxicity. Overall, the structure-activity and structure-toxicity results from this study provide a framework for the future development of DAAC-based filovirus inhibitors that will be both active and non-toxic in vivo.

Combined stereotactic biopsy and stepping-source interstitial irradiation of glioblastoma multiforme.

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Brehmer, Stefanie; Guthier, Christian V; Clausen, Sven; Schneider, Frank; Schulte, Dirk-Michael; Benker, Matthias; Bludau, Frederic; Glatting, Gerhard; Marx, Alexander; Schmiedek, Peter; Hesser, Jürgen; Wenz, Frederik; Giordano, Frank A

2018-04-01

Patients diagnosed with glioblastoma multiforme receiving stereotactic biopsy only either due to tumor localization or impaired clinical status face a devastating prognosis with very short survival times. One strategy to provide an initial cytoreductive and palliative therapy at the time of the stereotactic biopsy is interstitial irradiation through the pre-defined trajectory of the biopsy channel. We designed a novel treatment planning system and evaluated the treatment potential of a fixed-source and a stepping-source algorithm for interstitial radiosurgery on non-spherical glioblastoma in direct adjacency to risk structures. Using both setups, we show that radiation doses delivered to 100% of the gross tumor volume shifts from sub-therapeutic (10-12 Gy) to sterilizing single doses (25-30 Gy) when using the stepping source algorithm due to improved sparing of organs-at-risk. Specifically, the maximum doses at the brain stem were 100% of the PTV dose when a fixed central source and 38% when a stepping-source algorithm was used. We also demonstrated precision of intracranial target points and stability of superficial and deep trajectories using both a phantom and a body donor study. Our setup now for the first time provides a basis for a clinical proof-of-concept trial and may widen palliation options for patients with limited life expectancy that should not undergo time-consuming therapies.

Efficacy and toxicity of adjuvant chemotherapy in elderly patients with colorectal cancer

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Lund, C M; Nielsen, D; Dehlendorff, Christian

2016-01-01

BACKGROUND: Elderly patients with primary colorectal cancer (CRC) are less frequently treated with adjuvant chemotherapy than younger patients due to concerns regarding toxicity and efficiency. We investigated how age, performance status (PS) and comorbidity influence treatment outcomes. PATIENTS...... AND METHODS: A retrospective single-centre study of 529 patients with stages II-III CRC treated with adjuvant chemotherapy (5-fluorouracil/capecitabine+/÷oxaliplatin) from 2001 to 2011 at Herlev Hospital, Denmark. Baseline characteristics, chemotherapy and outcome were analysed with respect to age after......-dependent difference in 3-year disease-free survival (DFS; HR 1.09, 95% CI 0.80 to 1.47, p=0.59), in grade 3-5 toxicity (29% vs 28%, p=0.86) or in 10-year CRC mortality (28%, HR 1.07, p=0.71). In elderly patients, a reduction in chemotherapy dose intensity compared with full dose had no impact on DFS or CRC mortality...

Abatement by Naringenin of Doxorubicin-Induced Cardiac Toxicity in Rats

International Nuclear Information System (INIS)

Arafa, H.M.; Abd-Ellah, M.F.; Hafez, H.F.

2005-01-01

Doxorubicin is one of the most active cytotoxic agents in current use. It has proven efficacy in various malignancies either alone or combined with other cytocidal agents. The clinical usefulness of the anthracycline drug has been precluded by cardiac toxicity. Many therapeutic interventions have been attempted to improve the therapeutic benefits of the drug. Few, however, have been efficacious in this setting. Purpose: We have addressed in the current study the possible protective effects of naringenin, a flavonoid known to have anti-oxidant properties, on doxorubicin induced cardiac toxicity in male Swiss albino rats. Methods: Forty male Swiss albino rats were used in this study. Naringenin (25 mg/kg body weight) was administered daily by gavage for 7 consecutive days before a cumulative single dose of doxorubicin (15 mg/kg body weight, ip). Doxorubicin induced marked biochemical alterations characteristic of cardiac toxicity including, elevated activities of serum total lactate dehydrogenase (LDH) and creatine phosphokinase (CPK), enhanced lipid peroxidation measured as malonaldehyde (MDA). The anthracycline drug has also reduced the cardiac enzymatic activities of superoxide dismutase (SOD), glutathione-Stransferase (GST) and catalase (CAT). Besides, it reduced significantly the reduced glutathione (GSH) level, but it increased the total NO content in heart tissue. Prior administration of naringenin ahead of doxorubicin challenge ameliorated all these biochemical markers. Taken together, one could conclude that naringenin has a protective role in the abatement of doxorubicin-induced cardiac toxicity that resides, at least in part, on its anti-radical effects and regulatory role on NO production

Boron neutron capture therapy of glioblastoma multiforme using the p- boronophenylalanine-fructose complex and epithermal neutrons

International Nuclear Information System (INIS)

Coderre, J.A.; Chanana, A.D.; Joel, D.D.; Liu, H.B.; Slatkin, D.N.; Wielopolski, L.; Bergland, R.; Elowitz, E.; Chadha, M.

1994-01-01

The amino acid analogue p-boronophenylalanine (BPA) is under investigation as a neutron capture agent for BNCT of glioblastoma multiforme. A series of patients undergoing surgical removal of tumor received BPA orally as the free amino acid. Favorable tumor/blood boron concentration ratios were obtained but the absolute amount of boron in the tumor would have been insufficient for BNCT. BPA can be solubilized at neutral pH by complexation with fructose (BPA-F). Studies with rats suggest that intraperitoneal injection of BPA-F complex produces a much higher tumor boron concentration to rat intracerebral 9L gliosarcoma that were possible with oral BPA. Higher boron concentrations have allowed higher tumor radiation doses to be delivered while maintaining the dose to the normal brain vascular endothelium below the threshold of tolerance. The experience to date of the administration of BPA-F to one patient is provided in this report

Boron neutron capture therapy of glioblastoma multiforme using the p- boronophenylalanine-fructose complex and epithermal neutrons

Energy Technology Data Exchange (ETDEWEB)

Coderre, J.A.; Chanana, A.D.; Joel, D.D.; Liu, H.B.; Slatkin, D.N.; Wielopolski, L. [Brookhaven National Lab., Upton, NY (United States); Bergland, R.; Elowitz, E. [Beth Israel Medical Center, New York, NY (United States). Dept. of Neurosurgery; Chadha, M. [Beth Israel Medical Center, New York, NY (United States). Dept. of Radiation Oncology

1994-12-31

The amino acid analogue p-boronophenylalanine (BPA) is under investigation as a neutron capture agent for BNCT of glioblastoma multiforme. A series of patients undergoing surgical removal of tumor received BPA orally as the free amino acid. Favorable tumor/blood boron concentration ratios were obtained but the absolute amount of boron in the tumor would have been insufficient for BNCT. BPA can be solubilized at neutral pH by complexation with fructose (BPA-F). Studies with rats suggest that intraperitoneal injection of BPA-F complex produces a much higher tumor boron concentration to rat intracerebral 9L gliosarcoma that were possible with oral BPA. Higher boron concentrations have allowed higher tumor radiation doses to be delivered while maintaining the dose to the normal brain vascular endothelium below the threshold of tolerance. The experience to date of the administration of BPA-F to one patient is provided in this report.

Acute and Subacute Toxicity Evaluation of Corn Silk Extract.

Science.gov (United States)

Ha, Ae Wha; Kang, Hyeon Jung; Kim, Sun Lim; Kim, Myung Hwan; Kim, Woo Kyoung

2018-03-01

Many studies have reported therapeutic efficacy of corn silk extract. However, research on its toxicity and safe dose range is limited. Thus, the objective of this study was to determine the acute and subacute toxicity of corn silk extract in ICR mice. To determine acute toxicity, corn silk extract containing high levels of maysin was orally administered to mice at a dose of 0 or 2,000 mg/kg. Clinical symptoms, mortality, and body weight changes were recorded for 14 days. To determine subacute toxicity, corn silk extract was orally administered to mice over a 4-week period, and then body weight, water and food consumption, and organ weight were determined. In addition, urine and serum analyses were performed. In the acute toxicity study, no death or abnormal symptoms was observed in all treatment groups during the study period. Body weights did not show any significant change compared to those of the control group. Lethal dose of corn silk extract was estimated to be more than 2,000 mg/kg. In the 4-week subacute toxicity study, there was no corn silk extract related toxic effect on body weight, water intake, food consumption, urine parameters, clinical chemistry, or organ weight. Histopathological examination showed no abnormality related to the administration of corn silk extract at 500 mg/kg. The maximum non-toxic dose of corn silk extract containing high levels of maysin was found to be more than 500 mg/kg.

Irinotecan-loaded double-reversible thermogel with improved antitumor efficacy without initial burst effect and toxicity for intramuscular administration.

Science.gov (United States)

Din, Fakhar Ud; Kim, Dong Wuk; Choi, Ju Yeon; Thapa, Raj Kumar; Mustapha, Omer; Kim, Dong Shik; Oh, Yu-Kyoung; Ku, Sae Kwang; Youn, Yu Seok; Oh, Kyung Taek; Yong, Chul Soon; Kim, Jong Oh; Choi, Han-Gon

2017-05-01

Intramuscularly administered, anti-tumour drugs induce severe side effects due to their direct contact with body tissues and initial burst effect. In this study, to solve this problem, a novel double-reversible thermogel system (DRTG) for the intramuscular administration of irinotecan was developed. This irinotecan-loaded DRTG was prepared by dispersing the irinotecan-loaded thermoreversible solid lipid nanoparticles (SLNs) in the thermoreversible hydrogel. In DRTG, the former was solid at 25°C but converted to liquid at 36.5°C; in contrast, the latter existed in a liquid form but transformed to gel state in the body. The DRTG was easily administered intramuscularly. Its particle size and drug content were not noticeably changeable, resulting that it was stable at 40°C for at least 6months. Compared to the irinotecan-loaded solution and conventional hydrogel, the DRTG significantly delayed drug release, leading to a reduced burst effect. Moreover, it showed decreased C max and maintained the sustained plasma concentrations at a relatively low level for the long period of 60h in rats, resulting in ameliorated side effects of the anti-tumour drug. Furthermore, it gave significantly improved anti-tumour efficacy in tumour-bearing mice compared to the hydrogel but, unlike the conventional hydrogel, induced no body weight loss and local damage to the muscle. Thus, this DRTG with improved antitumor efficacy without initial burst effect and toxicity could provide a potential pharmaceutical system for the intramuscular administration of irinotecan. Intramuscularly administered, anti-tumour drugs induce severe side effects due to their direct contact with body tissues and initial burst effect. To solve this problem, we developed a novel double-reversible thermogel system (DRTG) for the intramuscular administration of irinotecan. Unlike the conventional hydrogel, the DRTG is a dispersion of the irinotecan-loaded thermoreversible solid lipid nanoparticles in the

Raman spectroscopy for diagnosis of glioblastoma multiforme

Science.gov (United States)

Clary, Candace Elise

Glioblastoma multiforme (GBM), the most common and most fatal malignant brain tumor, is highly infiltrative and incurable. Although improved prognosis has been demonstrated by surgically resecting the bulk tumor, a lack of clear borders at the tumor margins complicates the selection decision during surgery. This dissertation investigates the potential of Raman spectroscopy for distinguishing between normal and malignant brain tissue and sets the groundwork for a surgical diagnostic guide for resection of gross malignant gliomas. These studies revealed that Raman spectroscopy was capable of discriminating between normal scid mouse brain tissue and human xenograft tumors induced in those mice. The spectra of normal and malignant tissue were normalized by dividing by the respective magnitudes of the peaks near 1440 cm -1. Spectral differences include the shape of the broad peaks near 1440 cm-1 and 1660 cm-1 and the relative magnitudes of the peaks at 1264 cm-1, 1287 cm-1, 1297 cm-1, 1556 cm -1, 1586 cm-1, 1614 cm-1, and 1683 cm-1. From these studies emerged questions regarding how to objectively normalize and compare spectra for future automation. Some differences in the Raman spectra were shown to be inherent in the disease states of the cells themselves via differences in the Raman spectra of normal human astrocytes in culture and cultured cells derived from GBM tumors. The spectra of astrocytes and glioma cells were normalized by dividing by the respective magnitudes of the peaks near 1450 cm-1. The differences between the Raman spectra of normal and transformed cells include the ratio of the 1450 cm-1/1650 cm-1 peaks and the relative magnitudes of the peaks at 1181 cm-1, 1191 cm-1, 1225 cm-1, 1263 cm -1, 1300 cm-1, 1336 cm-1, 1477 cm-1, 1494 cm-1, and 1695 cm -1. Previous Raman spectroscopic studies of biological cells have shown that the magnitude of the Raman signal decreases over time, indicating sample damage. Cells exposed to laser excitation at similar power

Virgin coconut oil supplementation ameliorates cyclophosphamide-induced systemic toxicity in mice.

Science.gov (United States)

Nair, S S; Manalil, J J; Ramavarma, S K; Suseela, I M; Thekkepatt, A; Raghavamenon, A C

2016-02-01

Virgin coconut oil (VCO) is an unrefined kernal oil, prepared from Cocos nucifera L., having substantial nutritional and medicinal value. Experimental studies have suggested its antioxidant, anti-inflammatory, immunostimulatory and hypolipidemic effects. The present study assesses its effect on formalin-induced chronic inflammation and cyclophosphamide (CTX)-induced systemic toxicity in murine models. Oral administration of VCO effectively reduced formalin-induced paw oedema in mice with more or less similar efficacy as that of diclofenac. The CTX-induced hike in blood urea, creatinine, thiobarbituric acid reactive substances (TBARS) and liver marker enzymes in mice was marginally decreased by VCO (8 g/kg body weight) ingestion orally. The liver and kidney catalase, superoxide dismutase and glutathione peroxidase activities, together with cellular glutathione and TBARS levels, were found to be improved in these animals. Overall the study reveals the protective efficacy of VCO against secondary toxicity induced by CTX possibly through its antioxidant and anti-inflammatory properties. © The Author(s) 2015.

Efficacy and toxicity of iodine disinfection of Atlantic salmon eggs

Science.gov (United States)

Chalupnicki, M.A.; Ketola, H.G.; Starliper, C.E.; Gallagher, D.

2011-01-01

Recent interest in the restoration of Atlantic salmon Salmo salar in the Great Lakes has given rise to new culture techniques and management programs designed to reduce pathogen transmission while stabilizing and enhancing wild populations. We examined the toxicity of iodine to Atlantic salmon eggs and its effectiveness as a disinfectant against bacteria on egg surfaces. We spawned and fertilized eight gravid Atlantic salmon from Cayuga Lake, New York, and exposed their eggs to 10 concentrations of iodine (5, 10, 50, 75, 100, 500, 750, 1,000, 5,000, and 7,500 mg/L) for 30 min during water hardening. An additional subsample of unfertilized eggs was also exposed to some of the same concentrations of iodine (5, 10, 50, 75, and 100 mg/L) to determine the efficiency of disinfection. Viable eggs were only obtained from four females. Survival of eggs to the eyed stage and hatch tended to be reduced at iodine concentrations of 50 and 75 mg/L and was significantly reduced at concentrations of 100 mg/L iodine or more. We calculated the concentrations of iodine that killed 50% of the Atlantic salmon eggs at eye-up and hatch to be 175 and 85 mg/L, respectively. Aeromonas veronii, A. schubertii, A. hydrophila, A. caviae, Plesiomonas shiggeloides, and Citrobacter spp. were the predominant bacteria present on the surface of green eggs and were significantly reduced by an iodine immersion. The use of iodine as a disinfectant on Atlantic salmon eggs was effective at low concentrations (50–75 mg/L), for which toxicity to Atlantic salmon was minimal.

Acute and subacute toxicity of 18F-FDG

International Nuclear Information System (INIS)

Dantas, Danielle Maia

2013-01-01

Before starting clinical trials of a new drug, it is necessary to perform a battery of safety tests for assessing human risk. Radiopharmaceuticals like any new drug must be tested taking into account its specificity, duration of treatment and especially the toxicity of both parties, the unlabeled molecule and its radionuclide, apart from impurities emanating from radiolysis. Regulatory agencies like the Food and Drug Administration - USA (FDA) and the European Medicine Agency (EMEA), establish guidelines for the regulation of production and research of radiopharmaceuticals. In Brazil the production of radiopharmaceuticals was not regulated until the end of 2009, when were established by the National Agency for Sanitary Surveillance (ANVISA) resolutions No. 63, which refers to the Good Manufacturing Practices of Radiopharmaceuticals and No. 64 which seeks the registration of record radiopharmaceuticals. To obtain registration of radiopharmaceuticals are necessary to prove the quality, safety, efficacy and specificity of the drug . For the safety of radiopharmaceuticals must be presented studies of acute toxicity, subacute and chronic toxicity as well as reproductive, mutagenic and carcinogenic. Nowadays IPEN-CNEN/SP produces one of the most important radiopharmaceutical of nuclear medicine, the 18 F-FDG, which is used in many clinical applications, particularly in the diagnosis and staging of tumors. The objective of this study was to evaluate the systemic toxicity (acute/ subacute) radiopharmaceutical 18 F-FDG in an in vivo test system, as recommended by the RDC No. 64, which will serve as a model for protocols toxicity of radiopharmaceuticals produced at IPEN. The following tests were performed: tests of acute and subacute toxicity, biodistribution studies of 18 F-FDG, comet assay and reproductive toxicity. In acute toxicity, healthy rats were injected . (author)

Evaluation of early imaging response criteria in glioblastoma multiforme

International Nuclear Information System (INIS)

Gladwish, Adam; Koh, Eng-Siew; Hoisak, Jeremy; Lockwood, Gina; Millar, Barbara-Ann; Mason, Warren; Yu, Eugene; Laperriere, Normand J; Ménard, Cynthia

2011-01-01

Early and accurate prediction of response to cancer treatment through imaging criteria is particularly important in rapidly progressive malignancies such as Glioblastoma Multiforme (GBM). We sought to assess the predictive value of structural imaging response criteria one month after concurrent chemotherapy and radiotherapy (RT) in patients with GBM. Thirty patients were enrolled from 2005 to 2007 (median follow-up 22 months). Tumor volumes were delineated at the boundary of abnormal contrast enhancement on T1-weighted images prior to and 1 month after RT. Clinical Progression [CP] occurred when clinical and/or radiological events led to a change in chemotherapy management. Early Radiologic Progression [ERP] was defined as the qualitative interpretation of radiological progression one month post-RT. Patients with ERP were determined pseudoprogressors if clinically stable for ≥6 months. Receiver-operator characteristics were calculated for RECIST and MacDonald criteria, along with alternative thresholds against 1 year CP-free survival and 2 year overall survival (OS). 13 patients (52%) were found to have ERP, of whom 5 (38.5%) were pseudoprogressors. Patients with ERP had a lower median OS (11.2 mo) than those without (not reached) (p < 0.001). True progressors fared worse than pseudoprogressors (median survival 7.2 mo vs. 19.0 mo, p < 0.001). Volume thresholds performed slightly better compared to area and diameter thresholds in ROC analysis. Responses of > 25% in volume or > 15% in area were most predictive of OS. We show that while a subjective interpretation of early radiological progression from baseline is generally associated with poor outcome, true progressors cannot be distinguished from pseudoprogressors. In contrast, the magnitude of early imaging volumetric response may be a predictive and quantitative metric of favorable outcome

ABT-888 enhances cytotoxic effects of temozolomide independent of MGMT status in serum free cultured glioma cells

NARCIS (Netherlands)

R.K. Balvers (Rutger); M.L.M. Lamfers (Martine); J.J. Kloezeman (Jenneke); A. Kleijn (Anne); L.M.E. Berghauser Pont (Lotte); C.M.F. Dirven (Clemens); S. Leenstra (Sieger)

2015-01-01

textabstractBackground: The current standard of care for Glioblastoma Multiforme (GBM) consists of fractionated focal irradiation with concomitant temozolomide (TMZ) chemotherapy. A promising strategy to increase the efficacy of TMZ is through interference with the DNA damage repair machinery, by

A phase I/II trial of hydroxychloroquine in conjunction with radiation therapy and concurrent and adjuvant temozolomide in patients with newly diagnosed glioblastoma multiforme.

Science.gov (United States)

Rosenfeld, Myrna R; Ye, Xiaobu; Supko, Jeffrey G; Desideri, Serena; Grossman, Stuart A; Brem, Steven; Mikkelson, Tom; Wang, Daniel; Chang, Yunyoung C; Hu, Janice; McAfee, Quentin; Fisher, Joy; Troxel, Andrea B; Piao, Shengfu; Heitjan, Daniel F; Tan, Kay-See; Pontiggia, Laura; O'Dwyer, Peter J; Davis, Lisa E; Amaravadi, Ravi K

2014-08-01

Preclinical studies indicate autophagy inhibition with hydroxychloroquine (HCQ) can augment the efficacy of DNA-damaging therapy. The primary objective of this trial was to determine the maximum tolerated dose (MTD) and efficacy of HCQ in combination with radiation therapy (RT) and temozolomide (TMZ) for newly diagnosed glioblastoma (GB). A 3 + 3 phase I trial design followed by a noncomparative phase II study was conducted in GB patients after initial resection. Patients received HCQ (200 to 800 mg oral daily) with RT and concurrent and adjuvant TMZ. Quantitative electron microscopy and immunoblotting were used to assess changes in autophagic vacuoles (AVs) in peripheral blood mononuclear cells (PBMC). Population pharmacokinetic (PK) modeling enabled PK-pharmacodynamic correlations. Sixteen phase I subjects were evaluable for dose-limiting toxicities. At 800 mg HCQ/d, 3/3 subjects experienced Grade 3 and 4 neutropenia and thrombocytopenia, 1 with sepsis. HCQ 600 mg/d was found to be the MTD in this combination. The phase II cohort (n = 76) had a median survival of 15.6 mos with survival rates at 12, 18, and 24 mo of 70%, 36%, and 25%. PK analysis indicated dose-proportional exposure for HCQ. Significant therapy-associated increases in AV and LC3-II were observed in PBMC and correlated with higher HCQ exposure. These data establish that autophagy inhibition is achievable with HCQ, but dose-limiting toxicity prevented escalation to higher doses of HCQ. At HCQ 600 mg/d, autophagy inhibition was not consistently achieved in patients treated with this regimen, and no significant improvement in overall survival was observed. Therefore, a definitive test of the role of autophagy inhibition in the adjuvant setting for glioma patients awaits the development of lower-toxicity compounds that can achieve more consistent inhibition of autophagy than HCQ.

Efficacy and toxicity of replication-competent adenovirus-mediated double suicide gene therapy in combination with radiation therapy in an orthotopic mouse prostate cancer model

International Nuclear Information System (INIS)

Freytag, Svend O.; Paielli, Dell; Wing, Mark; Rogulski, Ken; Brown, Steve; Kolozsvary, Andy; Seely, John; Barton, Ken; Dragovic, Alek; Kim, Jae Ho

2002-01-01

Purpose: The purpose of this study was to evaluate the efficacy and toxicity of replication-competent adenovirus-mediated double suicide gene therapy in an adjuvant setting with external beam radiation therapy (EBRT) in an experimental prostate cancer model in preparation for a Phase I clinical study in humans. Methods: For efficacy studies, i.m. DU145 and intraprostatic LNCaP C4-2 tumors were established in immune-deficient mice. Tumors were injected with the lytic, replication-competent Ad5-CD/TKrep adenovirus containing a cytosine deaminase (CD)/herpes simplex virus thymidine kinase (HSV-1 TK) fusion gene. Two days later, mice were administered 1 week of 5-fluorocytosine + ganciclovir (GCV) prodrug therapy and fractionated doses of EBRT (trimodal therapy). Tumor control rate of trimodal therapy was compared to that of EBRT alone. For toxicology studies, immune-competent male mice received a single intraprostatic injection (10 10 vp) of the replication-competent Ad5-CD/TKrep adenovirus. Two days later, mice were administered 4 weeks of 5-fluorocytosine + GCV prodrug therapy and 56 Gy EBRT to the pelvic region. The toxicity of trimodal therapy was assessed by histopathologic analysis of major organs and clinical chemistries. Results: In both the i.m. DU145 and intraprostatic LNCaP C4-2 tumor models, trimodal therapy significantly improved primary tumor control beyond that of EBRT alone. In the DU145 model, trimodal therapy resulted in a tumor growth delay (70 days) that was more than twice that (32 days) of EBRT alone. Whereas EBRT failed to eradicate DU145 tumors, trimodal therapy resulted in 25% tumor cure. In the LNCaP C4-2 tumor model, EBRT slowed the growth of intraprostatic tumors, but resulted in no tumor cures, and 57% of the mice developed retroperitoneal lymph node metastases at 3 months. By contrast, trimodal therapy resulted in 44% tumor cure and reduced significantly the percentage (13%) of lymph node metastases relative to EBRT alone. Overall

Patterns of failure for glioblastoma multiforme following concurrent radiation and temozolomide

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Dobelbower, Michael C.; Burnett, Omer L. III; Haytt, Mark D.; Fiveash, John B.; Nordal, Robert A.; Nabors, Louis B.; Markert, James M.

2011-01-01

To analyse patterns of failure in patients with glioblastoma multiforme treated with concurrent radiation and temozolomide. A retrospective review of patients treated with concurrent radiation and temozolomide was performed. Twenty patients treated at the University of Alabama at Birmingham, with biopsy-proven disease, documented disease progression after treatment, and adequate radiation dosimetry and imaging records were included in the study. Patients generally received 46 Gy to the primary tumour and surrounding oedema plus 1 cm, and 60 Gy to the enhancing tumour plus 1 cm. MRIs documenting failure after therapy were fused to the original treatment plans. Contours of post-treatment tumour volumes were generated from MRIs showing tumour failure and were overlaid onto the original isodose curves. The recurrent tumours were classified as in-field, marginal or regional. Recurrences were also evaluated for distant failure. Of the 20 documented failures, all patients had some component of failure at the primary site. Eighteen patients (90%) failed in-field, 2 patients (10%) had marginal failures, and no regional failures occurred. Four patients (20%) had a component of distant failure in which an independent satellite lesion was located completely outside of the 95% isodose curve. Radiation concurrent with temozolomide appears to be associated with a moderate risk of distant brain failure in addition to the high rate of local failure. The risk of distant failure was consistent with that observed with radiation alone, suggesting that temozolomide does not act to reduce distant brain failure but to improve local control.

Development of CAR T cells designed to improve antitumor efficacy and safety

OpenAIRE

Jaspers, Janneke E.; Brentjens, Renier J.

2017-01-01

Chimeric antigen receptor (CAR) T cell therapy has shown promising efficacy against hematologic malignancies. Antitumor activity of CAR T cells, however, needs to be improved to increase therapeutic efficacy in both hematologic and solid cancers. Limitations to overcome are ‘on-target, off-tumor’ toxicity, antigen escape, short CAR T cell persistence, little expansion, trafficking to the tumor and inhibition of T cell activity by an inhibitory tumor microenvironment. Here we will discuss how ...

Efficacy and safety evaluation of icotinib in patients with advanced non-small cell lung cancer.

Science.gov (United States)

Gu, Aiqin; Shi, Chunlei; Xiong, Liwen; Chu, Tianqing; Pei, Jun; Han, Baohui

2013-02-01

To evaluate the efficacy and safety of icotinib hydrochloride in patients with advanced non-small cell lung cancer (NSCLC). A total of 89 patients with stage IIIB or IV NSCLC received icotinib at a dose of 125 mg administered 3 times a day. Icotinib treatment was continued until disease progression or development of unacceptable toxicity. A total of 89 patients were assessable. In patients treated with icotinib, the overall response rate (RR) was 36.0% (32/89), and the disease control rate (DCR) was 69.7% (62/89). RR and DCR were significantly improved in patients with adenocarcinoma versus non-adenocarcinoma (Picotinib hydrochloride in the treatment of advanced NSCLC is efficacious and safe, and its toxic effects are tolerable.

In silico studies on marine actinomycetes as potential inhibitors for Glioblastoma multiforme

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Kirubakaran, Palani; Kothapalli, Roopa; Singh, Kh Dhanachandra; Nagamani, Selvaraman; Arjunan, Subramanian; Muthusamy, Karthikeyan

2011-01-01

Glioblastoma multiforme (GBM) is considered to be the most common and often deadly disorder which affects the brain. It is caused by the over expression of proteins such as ephrin type-A receptor 2 (EphA2), epidermal growth factor receptor (EGFR) and EGFRvIII. These 3 proteins are considered to be the potential therapeutic targets for GBM. Among these, EphA2 is reported to be over-expressed in ˜90% of GBM. Herein we selected 35 compounds from marine actinomycetes, 5 in vitro and in vivo studied drug candidates and 4 commercially available drugs for GBM which were identified from literature and analysed by using comparative docking studies. Based on the glide scores and other in silico parameters available in Schrödinger, two selected marine actinomycetes compounds which include Tetracenomycin D and Chartreusin exhibited better binding energy among all the compounds studied in comparative docking. In this study we have demonstrated the inhibition of the 3 selected targets by the two bioactive compounds from marine actinomycetes through in-silico docking studies. Furthermore molecular dynamics simulation were also been performed to check the stability and the amino acids interacted with the 3 molecular targets (EphA2 receptor, EGFR, EGFRvIII) for GBM. Our results suggest that Tetracinomycin D and Chartreusin are the novel and potential inhibitor for the treatment of GBM. PMID:21584184

A phase II trial with bevacizumab and irinotecan for patients with primary brain tumors and progression after standard therapy

DEFF Research Database (Denmark)

Møller, Søren; Grunnet, Kirsten; Hansen, Steinbjørn

2012-01-01

The combination of irinotecan and bevacizumab has shown efficacy in the treatment of recurrent glioblastoma multiforme (GBM). A prospective, phase II study of 85 patients with various recurrent brain tumors was carried out. Primary endpoints were progression free survival (PFS) and response rate....

Cetuximab, bevacizumab, and irinotecan for patients with primary glioblastoma and progression after radiation therapy and temozolomide

DEFF Research Database (Denmark)

Hasselbalch, Benedikte; Lassen, Ulrik; Hansen, Steinbjørn

2010-01-01

The aim of this clinical trial was to investigate safety and efficacy when combining cetuximab with bevacizumab and irinotecan in patients with recurrent primary glioblastoma multiforme (GBM). Patients were included with recurrent primary GBM and progression within 6 months of ending standard tre...

Surprisal analysis of Glioblastoma Multiform (GBM) microRNA dynamics unveils tumor specific phenotype.

Science.gov (United States)

Zadran, Sohila; Remacle, Francoise; Levine, Raphael

2014-01-01

Gliomablastoma multiform (GBM) is the most fatal form of all brain cancers in humans. Currently there are limited diagnostic tools for GBM detection. Here, we applied surprisal analysis, a theory grounded in thermodynamics, to unveil how biomolecule energetics, specifically a redistribution of free energy amongst microRNAs (miRNAs), results in a system deviating from a non-cancer state to the GBM cancer -specific phenotypic state. Utilizing global miRNA microarray expression data of normal and GBM patients tumors, surprisal analysis characterizes a miRNA system response capable of distinguishing GBM samples from normal tissue biopsy samples. We indicate that the miRNAs contributing to this system behavior is a disease phenotypic state specific to GBM and is therefore a unique GBM-specific thermodynamic signature. MiRNAs implicated in the regulation of stochastic signaling processes crucial in the hallmarks of human cancer, dominate this GBM-cancer phenotypic state. With this theory, we were able to distinguish with high fidelity GBM patients solely by monitoring the dynamics of miRNAs present in patients' biopsy samples. We anticipate that the GBM-specific thermodynamic signature will provide a critical translational tool in better characterizing cancer types and in the development of future therapeutics for GBM.

The Radiologic Features of Cystic versus Noncystic Glioblastoma Multiforme as Significant Prognostic Factors

International Nuclear Information System (INIS)

Choi, Seung Joon; Hwang, Hee Young; Kim, Na Rae; Lee, Sheen Woo; Kim, Jeong Ho; Choi, Hye Young; Kim, Hyung Sik

2010-01-01

The purpose of this study was to determine the preoperative radiological characteristic and survival differences of glioblastoma multiforme (GBM) with and without cysts. Twenty-one GBMs were collected retrospectively; these tumors were pathologic confirmed as GBM. Based on the preoperative MR imaging, we compared the cystic GBMs with the noncystic GBMs according to the the tumor size, the tumor interface, the tumor wall thickness and peritumoral edema. Seven cases were classified as cystic GBMs and fourteen were noncystic GBMs. The cystic GBMs had a well-defined tumor interface, a less than 2 cm thickness of the tumor wall and less than 40 cm 3 thick peritumoral edema as compared to that of the noncystic GBMs. There was a statistically significant difference in age between the patients with cystic tumors and those with noncystic tumors. For the patients with cystic GBMs and noncystic GBMs, median survival time after surgery was 43.8 months and 12.5 months, respectively. The cystic GBMs had a well-defined tumor interface, a thin wall and minimal edema, as compared with that of the noncystic GBMs. The patients with cystic GBMs were significantly younger and they had more favorable survival outcomes than did the patients with noncystic GBMs

Prognostic relevance of cytochrome C oxidase in primary glioblastoma multiforme.

Directory of Open Access Journals (Sweden)

Corinne E Griguer

Full Text Available Patients with primary glioblastoma multiforme (GBM have one of the lowest overall survival rates among cancer patients, and reliable biomarkers are necessary to predict patient outcome. Cytochrome c oxidase (CcO promotes the switch from glycolytic to OXPHOS metabolism, and increased CcO activity in tumors has been associated with tumor progression after chemotherapy failure. Thus, we investigated the relationship between tumor CcO activity and the survival of patients diagnosed with primary GBM. A total of 84 patients with grade IV glioma were evaluated in this retrospective cohort study. Cumulative survival was calculated by the Kaplan-Meier method and analyzed by the log-rank test, and univariate and multivariate analyses were performed with the Cox regression model. Mitochondrial CcO activity was determined by spectrophotometrically measuring the oxidation of cytochrome c. High CcO activity was detected in a subset of glioma tumors (∼30%, and was an independent prognostic factor for shorter progression-free survival and overall survival [P = 0.0087 by the log-rank test, hazard ratio = 3.57 for progression-free survival; P<0.001 by the log-rank test, hazard ratio = 10.75 for overall survival]. The median survival time for patients with low tumor CcO activity was 14.3 months, compared with 6.3 months for patients with high tumor CcO activity. High CcO activity occurs in a significant subset of high-grade glioma patients and is an independent predictor of poor outcome. Thus, CcO activity may serve as a useful molecular marker for the categorization and targeted therapy of GBMs.

Glioblastoma multiforme in Klippel-Trenaunay-Weber syndrome: a case report.

Science.gov (United States)

Yilmaz, Tevfik; Cikla, Ulas; Kirst, Alice; Baskaya, Mustafa K

2015-04-17

Klippel-Trenaunay-Weber syndrome (KTWS) is a rare syndrome in which patients usually present with cutaneous hemangiomas, venous varicosities, and bone and soft tissue hypertrophy of the affected limb. Intracranial lesions in patients with KTWS are extremely rare, and are generally reported as single cases in the literature. We describe a rare case, where a patient with KTWS was found with a hemorrhagic grade IV astrocytoma. Although central nervous system abnormalities such as intracranial aneurysms and cerebral and spinal cord cavernomas have been described in patients with KTWS, to the best of our knowledge, this is the first report of an association between glioblastoma multiforme (grade IV astrocytoma) and KTWS in the English-language medical literature. A 61-year-old white Caucasian man with a history of KTWS presented with seizures. Left upper and lower extremity hypertrophy, left foot, leg and ear gigantism and left-sided abdominal capillary hemangiomas were noted in the physical examination. Cranial computed tomography (CT) and magnetic resonance imaging (MRI) were obtained, showing a heterogeneous lesion in the cingulate gyrus, with peripheral and central areas of T1 hyperintensity and layering T2 hypointensity consistent with a hemorrhage. A right parasagittal frontal craniotomy was performed with an interhemispheric approach. We had difficulty controlling the bleeding with bipolar electrocautery during surgery and finally were able to stop the bleeding using surgicel and gelfoam. Postoperative cranial CT and MRI scans showed intraparenchymal hemorrhage centered within the medial right frontal lobe. There was no increase in hematoma size in consecutive CT scans. Co-occurrence of vascular abnormalities with KWTS should be taken into consideration to avoid perilous preoperative and postoperative complications.

Identification of repaglinide as a therapeutic drug for glioblastoma multiforme

International Nuclear Information System (INIS)

Xiao, Zui Xuan; Chen, Ruo Qiao; Hu, Dian Xing; Xie, Xiao Qiang; Yu, Shang Bin; Chen, Xiao Qian

2017-01-01

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with a median survival time of only 14 months after treatment. It is urgent to find new therapeutic drugs that increase survival time of GBM patients. To achieve this goal, we screened differentially expressed genes between long-term and short-term survived GBM patients from Gene Expression Omnibus database and found gene expression signature for the long-term survived GBM patients. The signaling networks of all those differentially expressed genes converged to protein binding, extracellular matrix and tissue development as revealed in BiNGO and Cytoscape. Drug repositioning in Connectivity Map by using the gene expression signature identified repaglinide, a first-line drug for diabetes mellitus, as the most promising novel drug for GBM. In vitro experiments demonstrated that repaglinide significantly inhibited the proliferation and migration of human GBM cells. In vivo experiments demonstrated that repaglinide prominently prolonged the median survival time of mice bearing orthotopic glioma. Mechanistically, repaglinide significantly reduced Bcl-2, Beclin-1 and PD-L1 expression in glioma tissues, indicating that repaglinide may exert its anti-cancer effects via apoptotic, autophagic and immune checkpoint signaling. Taken together, repaglinide is likely to be an effective drug to prolong life span of GBM patients. - Highlights: • Gene expression signarue in long-term survived GBM patients are identified from Gene Expression Omnibus database. • Repaglinide is identified as a survival-related drug for GBM via drug repositioning in CMap. • Repaglinide effectively kills GBM cells, inhibits GBM cell migration and increases survival of mice bearing orthotopic glioma. • Repaglinide reduces Bcl-2, Beclin-1 and PD-L1 in GBM tissues.

Safety and clinical efficacy of tenvermectin, a novel antiparasitic 16-membered macrocyclic lactone antibiotics.

Science.gov (United States)

Fei, Chenzhong; She, Rufeng; Li, Guiyu; Zhang, Lifang; Fan, Wushun; Xia, Suhan; Xue, Feiqun

2018-05-30

Tenvermectin (TVM) is a novel 16-membered macrocyclic lactone antibiotics, which contains component TVM A and TVM B. However there is not any report on safety and clinical efficacy of TVM for developing as a potential drug. In order to understand the part of safety and clinical efficacy of TVM, we conducted the acute toxicity test, the standard bacterial reverse mutation (Ames) test and the clinical deworming test. In the acute toxicity studies, TVM, TVM A and ivermectin (IVM) were administrated once by oral gavage to mice and rats. Results showed that the oral LD 50 values of TVM, TVM A and IVM in mice were 74.41, 106.95 and 53.06 mg/kg respectively. The oral LD 50 values of TVM and TVM A in rats were determined to be 164.22 and 749.34 mg/kg respectively. TVM and IVM are moderately toxic substances, meanwhile the TVM A belongs to low toxic compounds, implying that the acute toxicity is highly related to the length of side chain of TVM at position C25. In the Ames test, results showed that TVM did not induce mutagenicity in Salmonella typhimurium TA97a, TA98, TA100, TA102 and TA1535 with and without metabolic activation system, speculating that the mutagenicity is probably not related to the side chain at position C25 of 16-membered macrocyclic lactone antibiotics. In the efficacy trail of TVM against swine nematodes, growing pigs natural infection of Ascaris suum and Trichuris suis were treated with a single subcutaneous injection 0.3 mg/kg b.w.. Results showed that TVM and IVM had excellent effect in expelling Ascaris suum, and TVM had potential efficacy against Trichuris suis, however IVM had no effect on Trichuris suis. This study suggests that the side chain of TVM at position C25 may have important biological functions, which is one of the key sites of the studies on structure-activity relationship of 16-membered macrocyclic lactone compounds. TVM is a new compound exhibited some advantages worthy of developing. Copyright © 2018 Elsevier B.V. All

A Prospective Comparative Study of the Toxicity Profile of 5-Flurouracil, Adriamycin, Cyclophosphamide Regime VS Adriamycin, Paclitaxel Regime in Patients with Locally Advanced Breast Carcinoma

Science.gov (United States)

Pillai, Pradeep Sadasivan; Jayakumar, Krishnan Nair Lalithamma

2015-01-01

Introduction A 5-flurouracil, Adriamycin, Cyclophosphamide (FAC) and Adriamycin, Paclitaxel (AT) are two popular chemotherapeutic regimens for treatment of breast carcinoma. The most time tested and popular regimen is FAC. It is extensively studied for efficacy and toxicity. But data regarding toxicity profile and efficacy of AT regimen is sparse. Aim To study the toxicity profile, severity of toxicities and clinical response rate of FAC and AT regimens in patients with locally advanced breast carcinoma. Materials and Methods A prospective observational study with 50 patients in each treatment arm. Study duration was 12 months from November 2012 to October 2013. Consecutive patients with locally advanced breast carcinoma receiving treatment with either FAC or AT regimen, satisfying inclusion criteria were enrolled into the study after getting informed written consent. Prior to initiation of treatment detailed medical history was taken from all patients. General clinical examination, examination of organ systems and local examination of breast lump were done. After each cycle of chemotherapy and after completion of treatment patients were interviewed and examined for clinical response and toxicities. Toxicities were graded with WHO toxicity grading criteria. All data were entered in a structured proforma. At least 50% reduction in tumour size was taken as adequate clinical response. Statistical Analysis Data was analysed using Chi-square test with help of Excel 2007 and SPSS-16 statistical software. Results Different pattern of toxicities were seen with FAC and AT regimens. Anaemia, thrombocytopenia, stomatitis, hyperpigmentation, photosensitivity and diarrhoea were more common with patients receiving FAC regimen. Leucopenia, peripheral neuropathy, myalgia, arthralgia, vomiting and injection site reactions were more common in AT regimen. Both FAC and AT regimens gave 100% clinical response. Conclusion FAC and AT regimens are equally efficacious but have different

Whole acute toxicity removal from industrial and domestic effluents treated by electron beam radiation: emphasis on anionic surfactants

International Nuclear Information System (INIS)

Moraes, M.C.F.; Romanelli, M.F; Sena, H.C.; Pasqualini da Silva, G.; Sampa, M.H.O.; Borrely, S.I.

2004-01-01

Electron beam radiation has been applied to improve real industrial and domestic effluents received by Suzano wastewater treatment plant. Radiation efficacy has been evaluated as toxicity reduction, using two biological assays. Three sites were sampled and submitted for toxicity assays, anionic surfactant determination and electron beam irradiation. This paper shows the reduction of acute toxicity for both test-organisms, the marine bacteria Vibrio fischeri and the crustacean Daphnia similis. The raw toxic effluents exibitted from 0.6 ppm up to 11.67 ppm for anionic surfactant before being treated by the electron beam. Radiation processing resulted in reduction of the acute toxicity as well as surfactant removal. The final biological effluent was in general less toxic than other sites but the presence of anionic surfactants was evidenced

Whole acute toxicity removal from industrial and domestic effluents treated by electron beam radiation: emphasis on anionic surfactants

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Moraes, M.C.F. E-mail: mariacristinafm@uol.com.br; Romanelli, M.F; Sena, H.C.; Pasqualini da Silva, G.; Sampa, M.H.O.; Borrely, S.I

2004-10-01

Electron beam radiation has been applied to improve real industrial and domestic effluents received by Suzano wastewater treatment plant. Radiation efficacy has been evaluated as toxicity reduction, using two biological assays. Three sites were sampled and submitted for toxicity assays, anionic surfactant determination and electron beam irradiation. This paper shows the reduction of acute toxicity for both test-organisms, the marine bacteria Vibrio fischeri and the crustacean Daphnia similis. The raw toxic effluents exibitted from 0.6 ppm up to 11.67 ppm for anionic surfactant before being treated by the electron beam. Radiation processing resulted in reduction of the acute toxicity as well as surfactant removal. The final biological effluent was in general less toxic than other sites but the presence of anionic surfactants was evidenced.

SU-F-R-17: Advancing Glioblastoma Multiforme (GBM) Recurrence Detection with MRI Image Texture Feature Extraction and Machine Learning

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Yu, V; Ruan, D; Nguyen, D; Kaprealian, T; Chin, R; Sheng, K [UCLA School of Medicine, Los Angeles, CA (United States)

2016-06-15

Purpose: To test the potential of early Glioblastoma Multiforme (GBM) recurrence detection utilizing image texture pattern analysis in serial MR images post primary treatment intervention. Methods: MR image-sets of six time points prior to the confirmed recurrence diagnosis of a GBM patient were included in this study, with each time point containing T1 pre-contrast, T1 post-contrast, T2-Flair, and T2-TSE images. Eight Gray-level co-occurrence matrix (GLCM) texture features including Contrast, Correlation, Dissimilarity, Energy, Entropy, Homogeneity, Sum-Average, and Variance were calculated from all images, resulting in a total of 32 features at each time point. A confirmed recurrent volume was contoured, along with an adjacent non-recurrent region-of-interest (ROI) and both volumes were propagated to all prior time points via deformable image registration. A support vector machine (SVM) with radial-basis-function kernels was trained on the latest time point prior to the confirmed recurrence to construct a model for recurrence classification. The SVM model was then applied to all prior time points and the volumes classified as recurrence were obtained. Results: An increase in classified volume was observed over time as expected. The size of classified recurrence maintained at a stable level of approximately 0.1 cm{sup 3} up to 272 days prior to confirmation. Noticeable volume increase to 0.44 cm{sup 3} was demonstrated at 96 days prior, followed by significant increase to 1.57 cm{sup 3} at 42 days prior. Visualization of the classified volume shows the merging of recurrence-susceptible region as the volume change became noticeable. Conclusion: Image texture pattern analysis in serial MR images appears to be sensitive to detecting the recurrent GBM a long time before the recurrence is confirmed by a radiologist. The early detection may improve the efficacy of targeted intervention including radiosurgery. More patient cases will be included to create a generalizable

177Lu-immunotherapy of experimental peritoneal carcinomatosis shows comparable effectiveness to 213Bi-immunotherapy, but causes toxicity not observed with 213Bi

International Nuclear Information System (INIS)

Seidl, Christof; Zoeckler, Christine; Beck, Roswitha; Senekowitsch-Schmidtke, Reingard; Quintanilla-Martinez, Leticia; Bruchertseifer, Frank

2011-01-01

213 Bi-d9MAb-immunoconjugates targeting gastric cancer cells have effectively cured peritoneal carcinomatosis in a nude mouse model following intraperitoneal injection. Because the β-emitter 177 Lu has proven to be beneficial in targeted therapy, 177 Lu-d9MAb was investigated in this study in order to compare its therapeutic efficacy and toxicity with those of 213 Bi-d9MAb. Nude mice were inoculated intraperitoneally with HSC45-M2 gastric cancer cells expressing d9-E-cadherin and were treated intraperitoneally 1 or 8 days later with different activities of specific 177 Lu-d9MAb immunoconjugates targeting d9-E-cadherin or with nonspecific 177 Lu-d8MAb. Therapeutic efficacy was evaluated by monitoring survival for up to 250 days. For evaluation of toxicity, both biodistribution of 177 Lu-d9MAb and blood cell counts were determined at different time points and organs were examined histopathologically. Treatment with 177 Lu-immunoconjugates (1.85, 7.4, 14.8 MBq) significantly prolonged survival. As expected, treatment on day 1 after tumour cell inoculation was more effective than treatment on day 8, and specific 177 Lu-d9MAb conjugates were superior to nonspecific 177 Lu-d8MAb. Treatment with 7.4 MBq of 177 Lu-d9MAb was most successful, with 90% of the animals surviving longer than 250 days. However, treatment with therapeutically effective activities of 177 Lu-d9MAb was not free of toxic side effects. In some animals lymphoblastic lymphoma, proliferative glomerulonephritis and hepatocarcinoma were seen but were not observed after treatment with 213 Bi-d9MAb at comparable therapeutic efficacy. The therapeutic efficacy of 177 Lu-d9MAb conjugates in peritoneal carcinomatosis is impaired by toxic side effects. Because previous therapy with 213 Bi-d9MAb revealed comparable therapeutic efficacy without toxicity it should be preferred for the treatment of peritoneal carcinomatosis. (orig.)

Strong adverse prognostic impact of hyperglycemic episodes during adjuvant chemoradiotherapy of glioblastoma multiforme

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Mayer, Arnulf; Vaupel, Peter; Stockinger, Marcus; Schmidberger, Heinz [University Medical Center, Department of Radiooncology and Radiotherapy, Mainz (Germany); Struss, Hans-Garlich [University Medical Center, Department of Laboratory Medicine, Mainz (Germany); Giese, Alf [University Medical Center, Department of Neurosurgery, Mainz (Germany)

2014-10-15

In comparison to normal brain tissue, glioblastomas exhibit significantly increased glucose uptake. Brain edema is a common complication during adjuvant chemoradiotherapy, leading to a requirement for glucocorticoid treatment. Glucocorticoid treatment frequently causes considerable deregulation of blood glucose levels. Therefore, episodes of hyperglycemia may contribute to radio- and/or chemoresistance. This study comprises a retrospective analysis of the influence of hyperglycemic episodes (HEs) during adjuvant therapy on the overall survival of 106 glioblastoma multiforme patients. The occurrence of one or more deregulated blood glucose value(s) > 10 mM is associated with a reduction in median overall survival from 16.7 to 8.8 months. A significantly poorer overall survival of patients with hyperglycemia could also be detected in subgroup analyses of patients with complete tumor resection and complete treatment according to the EORTC 22891/26891 trial protocol, as well as in a multivariate Cox proportional hazards analysis. A history of diabetes mellitus had no influence on prognosis. Our data suggest that the observed negative impact of elevated blood glucose levels on overall survival may not solely be explained by the patients' poorer general condition; the elevated blood glucose concentration itself may play a pathogenetic role. This could be due to increased activity of antioxidant systems, elevated expression of DNA damage response proteins and protection of hypoxic tumor cells against apoptosis combined with hypoxia-mediated radioresistance. A possible prognostic impact of elevated blood glucose levels during the period of adjuvant (chemo-) radiotherapy of glioblastoma should be evaluated in a prospective clinical trial. (orig.) [German] Glioblastome zeigen im Vergleich mit normalem Gehirngewebe eine deutlich vermehrte Glukoseaufnahme. Im Rahmen der adjuvanten Radio(chemo)therapie von Glioblastomen treten vielfach Hirnoedeme auf, die eine

Bilateral posterior RION after concomitant radiochemotherapy with temozolomide in a patient with glioblastoma multiforme: a case report

International Nuclear Information System (INIS)

Schreiber, Stefanie; Prox-Vagedes, Vanessa; Elolf, Erck; Brueggemann, Ines; Gademann, Guenther; Galazky, Imke; Bartels, Claudius

2010-01-01

Radiation induced optic neuropathy (RION) is a rare but severe consequence of radiation therapy that is associated with adjuvant chemotherapy, specifically therapy with vincristine or nitrosoureas. However, there is very little evidence regarding the occurrence of RION after concomitant radiochemotherapy with temozolomide. The case of a 63 year old woman with glioblastoma multiforme and concomitant radiochemotherapy with temozolomide is described. Due to a slight depressive episode the patient also took hypericum perforatum. Five months after cessation of fractionated radiation and adjuvant chemotherapy with temozolomide (cumulative dose of 11040 mg) the patient developed bilateral amaurosis due to RION. Tumor regrowth was excluded by magnetic resonance imaging. After the application of gadolinium a pathognomonic contrast enhancement of both prechiasmatic optic nerves could be observed. In this patient, the occurrence of RION may have been the result of radiosensitization by temozolomide, which could have been strengthened by hypericin. Consequently, physicians should avoid a concomitant application of hypericum perforatum and radiochemotherapy

Bilateral posterior RION after concomitant radiochemotherapy with temozolomide in a patient with glioblastoma multiforme: a case report

Directory of Open Access Journals (Sweden)

Gademann Guenther

2010-10-01

Full Text Available Abstract Background Radiation induced optic neuropathy (RION is a rare but severe consequence of radiation therapy that is associated with adjuvant chemotherapy, specifically therapy with vincristine or nitrosoureas. However, there is very little evidence regarding the occurrence of RION after concomitant radiochemotherapy with temozolomide. Case Presentation The case of a 63 year old woman with glioblastoma multiforme and concomitant radiochemotherapy with temozolomide is described. Due to a slight depressive episode the patient also took hypericum perforatum. Five months after cessation of fractionated radiation and adjuvant chemotherapy with temozolomide (cumulative dose of 11040 mg the patient developed bilateral amaurosis due to RION. Tumor regrowth was excluded by magnetic resonance imaging. After the application of gadolinium a pathognomonic contrast enhancement of both prechiasmatic optic nerves could be observed. Conclusions In this patient, the occurrence of RION may have been the result of radiosensitization by temozolomide, which could have been strengthened by hypericin. Consequently, physicians should avoid a concomitant application of hypericum perforatum and radiochemotherapy.

Multicentre trial on the efficacy and toxicity of single-dose samarium-153-ethylene diamine tetramethylene phosphonate as a palliative treatment for painful skeletal metastases in China

International Nuclear Information System (INIS)

Tian Jia-he; Zhang Jin-ming; He Yi-jie; Hou Qing-tian; Oyang Qiao-hong; Wang Jian-min; Chuan Ling

1999-01-01

A multicentre trial was organized in China as part of an international coordinated research project to study the efficacy and toxicity of single-dose samarium-153 ethylene diamine tetramethylene phosphonate (EDTMP) as a palliative treatment for painful skeletal metastases. One hundred and five patients with painful bone metastases from various primaries were treated with 153 Sm-EDTMP at a dose of 37 MBq/kg(group I) or 18.5 MBq/kg (group II). The effects were evaluated according to change in daily analgesic consumption, pain score, sum of effect product (SEP), Physician's Global Assessment (PGA), blood counts, and organ function tests conducted regularly for 16 weeks. Fifty-eight of 70 patients in group I and 30 of 35 in group II had a positive response, with SEPs of 22.29±14.47 and 20.13±13.90 respectively. Of 72 patients who had been receiving analgesics, 63 reduced their consumption. PGA showed that the Karnofsky score (KS) increased from 58.54±25.90 to 71.67±26.53, indicating improved general condition, but the difference was not significant. Among subgroups of patients, only those with breast cancer showed a significant change in the Karnofsky score after treatment. Inter-group differences were found for net change in KS between patients with lung and patients with breast cancer, and between patients with lung and patients with oesophageal cancer. Seventeen patients showed no response. No serious side-effects were noted, except for falls in the white blood cell (nadir 1.5 x 10 9 /l) and platelet (nadir 6.0 x 10 10 /l) counts in 44/105 and 34/105 cases, respectively. Ten patients had an abnormal liver function test. Response and side-effects were both independent of dose. In conclusion, 153 Sm-EDTMP provided effective palliation in 83.8% of patients with painful bone metastases; the major toxicity was temporary myelosuppression. Further studies are needed to identify better ways of determining the appropriate dose in the individual case and the efficacy of

Biological efficacy and toxic effect of emergency water disinfection process based on advanced oxidation technology.

Science.gov (United States)

Tian, Yiping; Yuan, Xiaoli; Xu, Shujing; Li, Rihong; Zhou, Xinying; Zhang, Zhitao

2015-12-01

An innovative and removable water treatment system consisted of strong electric field discharge and hydrodynamic cavitation based on advanced oxidation technologies was developed for reactive free radicals producing and waterborne pathogens eliminating in the present study. The biological efficacy and toxic effects of this advanced oxidation system were evaluated during water disinfection treatments. Bench tests were carried out with synthetic microbial-contaminated water, as well as source water in rainy season from a reservoir of Dalian city (Liaoning Province, China). Results showed that high inactivation efficiency of Escherichia coli (>5 log) could be obtained for synthetic contaminated water at a low concentration (0.5-0.7 mg L(-1)) of total oxidants in 3-10 s. The numbers of wild total bacteria (108 × 10(3) CFU mL(-1)) and total coliforms (260 × 10(2) MPN 100 mL(-1)) in source water greatly reduced to 50 and 0 CFU mL(-1) respectively after treated by the advanced oxidation system, which meet the microbiological standards of drinking water, and especially that the inactivation efficiency of total coliforms could reach 100%. Meanwhile, source water qualities were greatly improved during the disinfection processes. The values of UV254 in particular were significantly reduced (60-80%) by reactive free radicals. Moreover, the concentrations of possible disinfection by-products (formaldehyde and bromide) in treated water were lower than detection limits, indicating that there was no harmful effect on water after the treatments. These investigations are helpful for the ecotoxicological studies of advanced oxidation system in the treatments of chemical polluted water or waste water. The findings of this work suggest that the developed water treatment system is ideal in the acute phases of emergencies, which also could offer additional advantages over a wide range of applications in water pollution control.

Profile of trifluridine/tipiracil hydrochloride in the treatment of metastatic colorectal cancer: efficacy, safety, and place in therapy

Directory of Open Access Journals (Sweden)

Sunakawa Y

2017-09-01

Full Text Available Yu Sunakawa, Naoki Izawa, Takuro Mizukami, Yoshiki Horie, Mami Hirakawa, Hiroyuki Arai, Takashi Ogura, Takashi Tsuda, Takako Eguchi Nakajima Department of Clinical Oncology, St Marianna University School of Medicine, Kawasaki, Japan Abstract: TAS-102, with its robust survival efficacy and feasible toxicity, is one of the standard salvage-line treatments for patients with metastatic colorectal cancer (mCRC. No definitive data are available to determine which drug should be administered first during salvage-line treatment. Therefore, it is imperative that we establish the sequence of administration by considering drug toxicity profiles based on patient characteristics, such as age, performance status, comorbidities, tolerability to previous treatments, and patient preferences. The identification of predictive biomarkers in response to TAS-102 or its toxicity is urgently needed for better patient selection. Moreover, to strengthen efficacy or relieve toxicity, combinations with other agents, which could potentially emerge as standard treatment regimens, have been investigated and compared to existing active regimens for mCRC. Keywords: TAS-102, metastatic colorectal cancer, regorafenib, biomarker

In vivo anti-plasmodial activities and toxic impacts of lime extract of a ...

African Journals Online (AJOL)

specified accurate dosage and clear knowledge of the toxic impacts of their constituent compounds on body organs may be an impediment to the usage of the plants despite the acclaimed efficacy. Ethanolic extracts of. Clerodendrum violaceum leaves considerably reversed the alterations caused by malaria infection in liver ...

Use of pharmacogenomics in predicting bleomycin-induced pulmonary toxicity in testicular cancer patients.

NARCIS (Netherlands)

Nuver, J; Van Zweeden, M; Holzik, ML; Meijer, C; Hoekstra, H; Suurmeijer, A; Hofstra, R; Groen, H; Sleijfer, D; Gietema, J

2004-01-01

4531 Background:Use of bleomycin, important for treatment efficacy in testicular cancer, is limited by its pulmonary toxicity. Bleomycin is mainly excreted by the kidneys, but can also be inactivated by bleomycin hydrolase (BLH). An A1450G polymorphic site in the BLH gene results in an amino acid

Transcranial sonography: integration into target volume definition for glioblastoma multiforme

International Nuclear Information System (INIS)

Vordermark, Dirk; Becker, Georg; Flentje, Michael; Richter, Susanne; Goerttler-Krauspe, Irene; Koelbl, Oliver

2000-01-01

Purpose: Recent studies indicate that transcranial sonography (TCS) reliably displays the extension of malignant brain tumors. The effect of integrating TCS into radiotherapy planning for glioblastoma multiforme (GBM) was investigated herein. Methods and Materials: Thirteen patients subtotally resected for GBM underwent TCS during radiotherapy planning and were conventionally treated (54 to 60 Gy). Gross tumor volumes (GTVs) and stereotactic boost planning target volumes (PTVs, 3-mm margin) were created, based on contrast enhancement on computed tomography (CT) only (PTV CT ) or the combined CT and TCS information (PTV CT+TCS ). Noncoplonar conformal treatment plans for both PTVs were compared. Tumor progression patterns and preoperative magnetic resonance imaging (MRI) were related to both PTVs. Results: A sufficient temporal bone window for TCS was present in 11 of 13 patients. GTVs as defined by TCS were considerably larger than the respective CT volumes: Of the composite GTV CT+TCS (median volume 42 ml), 23%, 13%, and 66% (medians) were covered by the overlap of both methods, CT only and TCS only, respectively. Median sizes of PTV CT and PTV CT+TCS were 34 and 74 ml, respectively. Addition of TCS to CT information led to a median increase of the volume irradiated within the 80% isodose by 32 ml (median factor 1.51). PTV CT+TCS volume was at median 24% of a 'conventional' MRI(T2)-based PTV. Of eight progressions analyzed, three and six occurred inside the 80% isodose of the plans for PTV CT and for PTV CT+TCS , respectively. Conclusion: Addition of TCS tumor volume to the contrast-enhancing CT volume in postoperative radiotherapy planning for GBM increases the treated volume by a median factor of 1.5. Since a high frequency of marginal recurrences is reported from dose-escalation trials of this disease, TCS may complement established methods in PTV definition

Maintenance of EGFR and EGFRvIII expressions in an in vivo and in vitro model of human glioblastoma multiforme

DEFF Research Database (Denmark)

Stockhausen, Marie-Thérése; Broholm, Helle; Villingshøj, Mette

2011-01-01

Glioblastoma multiforme (GBM) is the most common, and most aggressive primary brain tumor among adults. A vast majority of the tumors express high levels of the epidermal growth factor receptor (EGFR) as a consequence of gene amplification. Furthermore, gene amplification is often associated...... with mutation of EGFR, and the constitutive activated deletion variant EGFRvIII is the most common EGFR mutation found in GBM. Activated EGFR signaling, through overexpression and/or mutation, is involved in increased tumorigenic potential. As such, EGFR is an attractive target for GBM therapy. However......, clinical studies with EGFR inhibitors have shown inconsistent results, and as such, further knowledge regarding the role of EGFR and EGFRvIII in GBM is needed. For this, an appropriate in vivo/in vitro tumor model is required. Here, we report the establishment of an experimental GBM model in which...

Radiotherapy with concurrent or sequential temozolomide in elderly patients with glioblastoma multiforme

International Nuclear Information System (INIS)

Hashem, Sameh A.; Salem, Ahmed; Al-Rashdan, Abdulla

2012-01-01

The objective of this article was to evaluate therapeutic outcomes of elderly patients with glioblastoma multiforme (GBM) treated by surgery followed by combined modality therapy and compare achievable outcomes to those of a younger age population. Seventy-eight adult patients with histologically confirmed grade IV astrocytoma were treated at King Hussein Cancer Center (Amman, Jordan) between September 2004 and December 2008. Records were retrospectively reviewed and included 55 males and 23 females between 19 and 78 years of age (median age 50 years). This case series included 20 patients aged 60 years or older. All patients underwent craniotomy followed radiotherapy and concurrent or sequential temozolomide. The follow-up ranged from 1 to 56 months (median 9.4 months). The median survival for the whole cohort was 13.8 months. The median survival for patients less than 60 years was 14.3 months and for patients 60 years or older was 12.3 months (P = 0.19). Among elderly patients, radical surgical resection (P = 0.002), concurrent delivery of chemoradiation (0.041) and radiotherapy dose ≥5400 cGy (P = 0.0001) conferred statistically significant improvements in overall survival. Management of GBM in elderly patients should include maximal surgical resection followed by radiotherapy and temozolomide whenever medically feasible. Outcomes comparable to those obtained in younger age groups can be expected. Our results indicate that concurrent chemoradiation is superior to sequential chemoradiation in these patients.

Volumetric Spectroscopic Imaging of Glioblastoma Multiforme Radiation Treatment Volumes

Energy Technology Data Exchange (ETDEWEB)

Parra, N. Andres [Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, Florida (United States); Maudsley, Andrew A. [Department of Radiology, University of Miami Miller School of Medicine, Miami, Florida (United States); Gupta, Rakesh K. [Department of Radiology and Imaging, Fortis Memorial Research Institute, Gurgaon, Haryana (India); Ishkanian, Fazilat; Huang, Kris [Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, Florida (United States); Walker, Gail R. [Biostatistics and Bioinformatics Core Resource, Sylvester Cancer Center, University of Miami Miller School of Medicine, Miami, Florida (United States); Padgett, Kyle [Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, Florida (United States); Department of Radiology, University of Miami Miller School of Medicine, Miami, Florida (United States); Roy, Bhaswati [Department of Radiology and Imaging, Fortis Memorial Research Institute, Gurgaon, Haryana (India); Panoff, Joseph; Markoe, Arnold [Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, Florida (United States); Stoyanova, Radka, E-mail: RStoyanova@med.miami.edu [Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, Florida (United States)

2014-10-01

Purpose: Magnetic resonance (MR) imaging and computed tomography (CT) are used almost exclusively in radiation therapy planning of glioblastoma multiforme (GBM), despite their well-recognized limitations. MR spectroscopic imaging (MRSI) can identify biochemical patterns associated with normal brain and tumor, predominantly by observation of choline (Cho) and N-acetylaspartate (NAA) distributions. In this study, volumetric 3-dimensional MRSI was used to map these compounds over a wide region of the brain and to evaluate metabolite-defined treatment targets (metabolic tumor volumes [MTV]). Methods and Materials: Volumetric MRSI with effective voxel size of ∼1.0 mL and standard clinical MR images were obtained from 19 GBM patients. Gross tumor volumes and edema were manually outlined, and clinical target volumes (CTVs) receiving 46 and 60 Gy were defined (CTV{sub 46} and CTV{sub 60}, respectively). MTV{sub Cho} and MTV{sub NAA} were constructed based on volumes with high Cho and low NAA relative to values estimated from normal-appearing tissue. Results: The MRSI coverage of the brain was between 70% and 76%. The MTV{sub NAA} were almost entirely contained within the edema, and the correlation between the 2 volumes was significant (r=0.68, P=.001). In contrast, a considerable fraction of MTV{sub Cho} was outside of the edema (median, 33%) and for some patients it was also outside of the CTV{sub 46} and CTV{sub 60}. These untreated volumes were greater than 10% for 7 patients (37%) in the study, and on average more than one-third (34.3%) of the MTV{sub Cho} for these patients were outside of CTV{sub 60}. Conclusions: This study demonstrates the potential usefulness of whole-brain MRSI for radiation therapy planning of GBM and revealed that areas of metabolically active tumor are not covered by standard RT volumes. The described integration of MTV into the RT system will pave the way to future clinical trials investigating outcomes in patients treated based on

Feasibility, toxicity, and efficacy of short induction chemotherapy of docetaxel plus cisplatin or carboplatin (TP) followed by concurrent chemoradiotherapy for organ preservation in advanced cancer of the hypopharynx, larynx, and base of tongue. Early results

International Nuclear Information System (INIS)

Semrau, Sabine; Klautke, Gunther; Fietkau, Rainer; Waldfahrer, Frank; Iro, Heinrich; Lell, Michael; Uder, Michael; Linke, Rainer; Kuwert, Torsten

2011-01-01

Concurrent chemoradiotherapy (CRT) is standard treatment for advanced head and neck cancer. Whether short induction chemotherapy (ICT) provides additional benefit or, in particular, predictive benefit for the response to chemoradiotherapy is an open question. The present study aimed to assess the feasibility, toxicity, and efficacy of induction with docetaxel and platinum salt (TP) and subsequent CRT. A total of 25 patients with functionally inoperable cancer of the base of the tongue, hypopharynx, or larynx received 1 cycle of docetaxel (75 mg/m 2 , day 1) combined with either cisplatin (30 mg/m 2 , days 1-3; n = 23) or carboplatin (AUC 1.5 days 1-3; n = 2). Responders (n = 22, > 30% tumor reduction, graded by endoscopy) and 1 non-responder received CRT (target dose: 69-72 Gy) with cisplatin/paclitaxel, carboplatin/paclitaxel, or cisplatin/docetaxel. All patients completed ICT with acceptable toxicity (leukocytopenia grade 4: 8%). The remission rate of the primary tumor was 88% (22/25 patients). There was no need to delay CRT due to toxicity in any case. Each patient received the full radiation dose. Of the patients, 56% received > 80% of the chemotherapy. The acute toxicity of CRT was moderate, no grade 4 toxicities occurred, while grade 3 toxicities included the following: infection (39%), dermatitis (13%), leukocytopenia (30%), and thrombocytopenia (4%). The local control rate was 84.6% ± 8.5% and the survival rate was 89.6% ± 7.2% at 12 months. Organ preservation was possible in 22/23 (95%) cases. Short induction with a TP regimen and subsequent CRT with a taxan is feasible and associated with an encouraging local control rate. (orig.)

Oral administration of amphotericin B nanoparticles: antifungal activity, bioavailability and toxicity in rats.

Science.gov (United States)

Radwan, Mahasen A; AlQuadeib, Bushra T; Šiller, Lidija; Wright, Matthew C; Horrocks, Benjamin

2017-11-01

Amphotericin B (AMB) is used most commonly in severe systemic life-threatening fungal infections. There is currently an unmet need for an efficacious (AMB) formulation amenable to oral administration with better bioavailability and lower nephrotoxicity. Novel PEGylated polylactic-polyglycolic acid copolymer (PLGA-PEG) nanoparticles (NPs) formulations of AMB were therefore studied for their ability to kill Candida albicans (C. albicans). The antifungal activity of AMB formulations was assessed in C. albicans. Its bioavalability was investigated in nine groups of rats (n = 6). Toxicity was examined by an in vitro blood hemolysis assay, and in vivo nephrotoxicity after single and multiple dosing for a week by blood urea nitrogen (BUN) and plasma creatinine (PCr) measurements. The MIC of AMB loaded to PLGA-PEG NPs against C. albicans was reduced two to threefold compared with free AMB. Novel oral AMB delivery loaded to PLGA-PEG NPs was markedly systemically available compared to Fungizone® in rats. The addition of 2% of GA to the AMB formulation significantly (p bioavailability from 1.5 to 10.5% and the relative bioavailability was > 790% that of Fungizone®. The novel AMB formulations showed minimal toxicity and better efficacy compared to Fungizone®. No nephrotoxicity in rats was detected after a week of multiple dosing of AMB NPs based on BUN and PCr, which remained at normal levels. An oral delivery system of AMB-loaded to PLGA-PEG NPs with better efficacy and minimal toxicity was formulated. The addition of glycyrrhizic acid (GA) to AMB NPs formulation resulted in a significant oral absorption and improved bioavailability in rats.

Ceriodaphnia and Chironomus in situ toxicity tests assessing the wastewater treatment efficacy of constructed wetlands

International Nuclear Information System (INIS)

Barjaktarovic, L.; Nix, P.; Gulley, J.

1995-01-01

In situ toxicity tests were designed for Ceriodaphnia dubia and Chironomus tentans as part of a larger study designed to assess the effectiveness of constructed wetlands for the treatment of wastewater produced by oil production at Suncor OSG. The artificial wetlands were 50m long by 3m wide, with three replicates of the control and the treatment. Each wetland had four sample sites equidistant along its length, creating a gradient of treatment from site A being the most toxic to site D being the least toxic. Each test was conducted twice during the summer of 1994. Both the Ceriodaphnia and Chironomus test cages were a flow through design to allow for maximal exposure to the water within the wetlands. Mortality and reproduction were used as endpoints for Ceriodaphnia, whereas mortality and growth were used as endpoints for the Chironomus test. Test durations were fifteen and ten days respectively. Chironomus had very high mortality along the entire wetlands whereas Ceriodaphnia survival and fecundity increased along the length of the treatment wetlands. Both organisms had low mortality and high growth/fecundity in the control wetlands

Toxicity prediction of compounds from turmeric (Curcuma longa L).

Science.gov (United States)

Balaji, S; Chempakam, B

2010-10-01

Turmeric belongs to the ginger family Zingiberaceae. Currently, cheminformatics approaches are not employed in any of the spices to study the medicinal properties traditionally attributed to them. The aim of this study is to find the most efficacious molecule which does not have any toxic effects. In the present study, toxicity of 200 chemical compounds from turmeric were predicted (includes bacterial mutagenicity, rodent carcinogenicity and human hepatotoxicity). The study shows out of 200 compounds, 184 compounds were predicted as toxigenic, 136 compounds are mutagenic, 153 compounds are carcinogenic and 64 compounds are hepatotoxic. To cross validate our results, we have chosen the popular curcumin and found that curcumin and its derivatives may cause dose dependent hepatotoxicity. The results of these studies indicate that, in contrast to curcumin, few other compounds in turmeric which are non-mutagenic, non-carcinogenic, non-hepatotoxic, and do not have any side-effects. Hence, the cost-effective approach presented in this paper could be used to filter toxic compounds from the drug discovery lifecycle. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

Acute toxicity and efficacy of postoperative combined modality therapy for adenocarcinoma of the pancreas

International Nuclear Information System (INIS)

Davis, Brian J.; Raben, Adam; Casper, Ephraim; Minsky, Bruce D.

1996-01-01

PURPOSE: To examine the acute toxicity and outcome in patients (pts) treated with combined modality therapy following resection of adenocarcinoma of the pancreas. MATERIALS AND METHODS: From 2/88 to 2/96, 34 pts (M:20, F:14) received postoperative combined modality therapy following a pancreatic resection. Tumor location included; head only: 28, head and ampulla: 1, ampulla only: 1, body and tail: 2, and tail only: 2. Postoperative stages included: stage I: 7 (21%) and stage III: 27 (79%). Pts were referred for combined modality therapy based on surgeon preference. In general, pts were treated who had one or more adverse prognostic factors. These included positive local/regional lymph nodes (79%), positive margins (50%) or disease invasive into adjacent structures (85 %). Radiation fields included the original primary tumor bed (based on preoperative CT scans) and peri-pancreatic and para-aortic lymph nodes adjacent to vertebral bodies T10 through L3. No attempt was made to include the entire pancreas in the radiation field. Patients received 5040 cGy at 180 cGy/day using a 3 or 4 field technique and CT-based treatment planning. Concurrent bolus 5-FU (375-500 mg/m 2 ) was delivered on the first three and last three days of radiation. Post-radiation maintenance bolus 5-FU was given to 7 patients for a median of 6 cycles. A toxicity assessment using the NCI toxicity criteria was performed at each weekly visit and 4 weeks following the completion of combined modality therapy. The median follow-up was 13 months (range: 2-36 months). Patterns of failure as a component of failure were assessed by radiographic criteria and, in 2 pts, by intraoperative evaluation for symptomatic progression of disease. Local/regional failure was defined as recurrence within the radiation field. Distant failure included liver, peritoneal seeding, and extra-abdominal sites. Actuarial survival was calculated from the time of surgery using the Kaplan-Meier method. RESULTS: The only grade 3

Establishment, maintenance and in vitro and in vivo applications of primary human glioblastoma multiforme (GBM) xenograft models for translational biology studies and drug discovery.

Science.gov (United States)

Carlson, Brett L; Pokorny, Jenny L; Schroeder, Mark A; Sarkaria, Jann N

2011-03-01

Development of clinically relevant tumor model systems for glioblastoma multiforme (GBM) is important for advancement of basic and translational biology. One model that has gained wide acceptance in the neuro-oncology community is the primary xenograft model. This model entails the engraftment of patient tumor specimens into the flank of nude mice and subsequent serial passage of these tumors in the flank of mice. These tumors are then used to establish short-term explant cultures or intracranial xenografts. This unit describes detailed procedures for establishment, maintenance, and utilization of a primary GBM xenograft panel for the purpose of using them as tumor models for basic or translational studies.

Palbociclib: A new hope in the treatment of breast cancer.

Science.gov (United States)

Palanisamy, R Priyadharsini

2016-01-01

Breast cancer being one of the common cancers has high morbidity and mortality. Despite the conventional treatment, the burden of the disease increases year after year. There is a need for newer drugs that target the different mechanisms in the pathogenesis. The interaction of cyclins with cyclin dependent kinases (CDKs) plays a major role in the abnormal cell cycle in cancer and it is considered to be an important target. Palbociclib is a CDK inhibitor currently approved for the treatment of breast cancer. The preclinical studies with breast cancer lines were sensitive to palbociclib and the clinical trials phase I, phase II (PALOMA 1), and phase III (PALOMA 2, 3, PENTELOPE, PEARL) showed that the drug was efficacious when combined other conventional drugs for breast cancer. Palbociclib was also been tested in various other germ cell tumors, melanoma, multiple myeloma, glioblastoma multiforme etc., The major adverse effect of the drug includes hematological toxicity mainly neutropenia, gastrointestinal adverse effects.

Medicinal plants and natural products in amelioration of arsenic toxicity: a short review.

Science.gov (United States)

Bhattacharya, Sanjib

2017-12-01

Chronic arsenic toxicity (arsenicosis) is considered a serious public health menace worldwide, as there is no specific, safe, and efficacious therapeutic management of arsenicosis. To collate the studies on medicinal plants and natural products with arsenic toxicity ameliorative effect, active pre-clinically and/or clinically. Literature survey was carried out by using Google, Scholar Google and Pub-Med. Only the scientific journal articles found on the internet for last two decades were considered. Minerals and semi-synthetic or synthetic analogs of natural products were excluded. Literature study revealed that 34 medicinal plants and 14 natural products exhibited significant protection from arsenic toxicity, mostly in preclinical trials and a few in clinical studies. This research could lead to development of a potentially useful agent in clinical management of arsenicosis in humans.

A functional study of EGFR and Notch signaling in brain cancer stem-like cells from glioblastoma multiforme (Ph.d.)

DEFF Research Database (Denmark)

Kristoffersen, Karina

2013-01-01

Glioblastoma Multiforme (GBM) is the most common and aggressive brain tumor in adults with a median survival for newly diagnosed GBM patients at less than 1.5 year. Despite intense treatment efforts the vast majority of patients will experience relapse and much research today is therefore searching...... for new molecular and cellular targets that can improve the prognosis for GBM patients. One such target is the brain cancer stem-like cells (bCSC) that are believed to be responsible for tumor initiation, progression, treatment resistance and ultimately relapse. bCSC are identified based...... on their resemblance to normal neural stem cells (NSC) and their tumorigenic potential. Like for NSC, the epidermal growth factor receptor (EGFR) and Notch receptor signaling pathways are believed to be important for the maintenance of bCSC. These pathways as such present promising targets in a future anti-bCSC GBM...

Toxicity of emamectin benzoate to Cydia pomonella (L.) and Cydia molesta (Busck) (Lepidoptera: Tortricidae): laboratory and field tests.

Science.gov (United States)

Ioriatti, Claudio; Anfora, Gianfranco; Angeli, Gino; Civolani, Stefano; Schmidt, Silvia; Pasqualini, Edison

2009-03-01

Emamectin benzoate is a novel macrocyclic lactone insecticide derived from naturally occurring avermectin molecules isolated by fermentation from the soil microorganism Streptomyces avermitilis Kim & Goodfellow. The present study aims to evaluate the toxicity of emamectin benzoate to codling moth, Cydia pomonella (L.), and oriental fruit moth, C. molesta (Busck), under laboratory and semi-field conditions. Dose response bioassays showed that emamectin benzoate had a high level of intrinsic toxicity to early-stage larvae of both species, and that contact activity might contribute significantly to mortality. In the semi-field trials, residual toxicity lasted for more than 1 week. Ovicidal activity was recorded only for C. pomonella (approximately 30%), irrespective of the concentrations tested. Field trials confirmed the efficacy of emamectin benzoate on codling moth when applied at 7 day intervals. Fruit damage, both from the first and second generations, was comparable with that on treatment with chlorpyrifos-ethyl, used as a chemical reference. Emamectin benzoate may be considered a valuable tool for the control of codling moth as a component of an IPM programme. Its collective advantages are: high efficacy, lack of cross-resistance with currently used products, control of secondary pests such as oriental fruit moth and selective toxicity that spares beneficials. 2008 Society of Chemical Industry

Hypofractionated Intensity-Modulated Radiotherapy for Carcinoma of the Prostate: Analysis of Toxicity

International Nuclear Information System (INIS)

Coote, Joanna H.; Wylie, James P.; Cowan, Richard A.; Logue, John P.; Swindell, Ric; Livsey, Jacqueline E.

2009-01-01

Purpose: Dose escalation for prostate cancer improves biological control but with a significant increase in late toxicity. Recent estimates of low α/β ratio for prostate cancer suggest that hypofractionation may result in biological advantage. Intensity-modulated radiotherapy (IMRT) should enable dose escalation to the prostate while reducing toxicity to local organs. We report late toxicity data of a hypofractionated IMRT regime. Methods and Materials: Eligible men had T2-3N0M0 adenocarcinoma prostate, and either Gleason score ≥ 7 or prostate-specific antigen 20-50 ng/L. Patients received 57-60 Gy to prostate in 19-20 fractions using five-field IMRT. All received hormonal therapy for 3 months before radiotherapy to a maximum of 6 months. Toxicity was assessed 2 years postradiotherapy using the RTOG criteria, LENT/SOMA, and UCLA prostate index assessment tools. Results: Acute toxicity was favorable with no RTOG Grade 3 or 4 toxicity. At 2 years, there was 4% Grade 2 bowel and 4.25% Grade 2 bladder toxicity. There was no Grade 3 or 4 bowel toxicity; one patient developed Grade 3 bladder toxicity. UCLA data showed a slight improvement in urinary function at 2 years compared with pretreatment. LENT/SOMA assessments demonstrated general worsening of bowel function at 2 years. Patients receiving 60 Gy were more likely to develop problems with bowel function than those receiving 57 Gy. Conclusions: These data demonstrate that hypofractionated radiotherapy using IMRT for prostate cancer is well tolerated with minimal late toxicity at 2 years posttreatment. Ongoing studies are looking at the efficacy of hypofractionated regimes with respect to biological control.

Nab-paclitaxel for the treatment of breast cancer: efficacy, safety, and approval

Directory of Open Access Journals (Sweden)

Iwase H

2011-07-01

Full Text Available Yutaka Yamamoto1, Ichiro Kawano2, Hirotaka Iwase11Department of Breast and Endocrine Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; 2Department of Surgery, Asahino General Hospital, Kumamoto, JapanAbstract: Nanoparticle albumin-bound paclitaxel (nab-paclitaxel is a novel formulation of paclitaxel that does not require solvents such as polyoxyethylated castor oil and ethanol. Use of these solvents has been associated with toxic response, including hypersensitivity reactions and prolonged sensory neuropathy, as well as a negative impact in relation to the therapeutic index of paclitaxel. nab-paclitaxel displays greater antitumor activity and less toxicity than solvent-base paclitaxel. In a phase I trial of single nab-paclitaxel, the maximum tolerated dose was 300 mg/m2 with the dose limiting toxicities being sensory neuropathy, stomatitis, and superficial keratopathy. In the metastatic setting, a pivotal comparative randomized phase III study demonstrated that nab-paclitaxel (at 260 mg/m2 over 30 minutes infusion without premedication every 3 weeks mediated a superior objective response rate and prolonged time to progression compared with solvent-based paclitaxel (at 175 mg/m2 over a 3-hour injection with standard premedication. The nab-paclitaxel-treated group showed a higher incidence of sensory neuropathy than the solvent-based paclitaxel group. However, these adverse side effects rapidly resolved after interruption of treatment and dose reduction. Weekly administration of nab-paclitaxel was also more active and displayed less toxicity compared with 100 mg/m2 docetaxel given triweekly. Nab-paclitaxel has already been approved in 42 countries for the treatment of metastatic breast cancer previously treated with anthracycline, based on confirmation of the efficacy and manageable toxicity in the metastatic setting. This review summarizes the most relevant knowledge on nab-paclitaxel for treating breast cancer

Different biokinetics of nanomedicines linking to their toxicity; an overview

Directory of Open Access Journals (Sweden)

Abdollahi Mohammad

2013-02-01

Full Text Available Abstract In spite of the extreme rise to the knowledge of nanotechnology in pharmaceutical sciences, there are currently limited experimental works studying the interactions between nanoparticles (NPs and the biological system. Adjustment of size and surface area plays the main role in the reaction between NPs and cells leading to their increased entrance into cells through skin, gastrointestinal and respiratory system. Moreover, change in physicochemical reactivity of NPs causes them to interact with circulatory and cellular proteins differentially leading to the altered parameters of their biokinetics, including adsorption, distribution, translocation, transformation, and elimination. A direct relationship between the surface area, reactive oxygen species generating capability, and proinflammatory effects of NPs have been found in respiratory tract toxicity. Additionally, complement-mediated hypersensitivity reactions to liposomes and other lipid-based nanodrugs have been well defined. Inhalation studies of some NPs have confirmed the translocation of inhaled materials to extra pulmonary organs such as central nervous system (CNS via olfactory neurons and induction of inflammatory response. Injectable uncoated NPs have a tendency to remain on the injection site while the poly ethanol glycol (PEG-coated NPs can be notably drained from the injection site to get as far as the lymph nodes where they accumulate. This confirms the existence of channels within the extracellular matrix for NPs to move along. Furthermore, induction of DNA strand breaks and formation of micronuclei have been recorded for exposure to some NPs such as single-walled carbon nanotubes. In the recent years, most of the studies have simply outlined better efficacy of nanodrugs, but few discussed their possible toxic reactions specially if used chronically. Therefore, we emphasize that this part of the nanoscience must not be undermined and toxicologists must be sensitive to

One-to-one comparison of sunscreen efficacy, aesthetics and potential nanotoxicity

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Barnard, Amanda S.

2010-04-01

Numerous reports have described the superior properties of nanoparticles and their diverse range of applications. Issues of toxicity, workplace safety and environmental impact have also been a concern. Here we show a theoretical comparison of how the size of titanium dioxide nanoparticles and their concentration in sunscreens can affect efficacy, aesthetics and potential toxicity from free radical production. The simulation results reveal that, unless very small nanoparticles can be shown to be safe, there is no combination of particle size and concentration that will deliver optimal performance in terms of sun protection and aesthetics. Such a theoretical method complements well the experimental approach for identifying these characteristics.

Acute Oral Mammalian Toxicity and Effect of Solvents on Efficacy of Maerua edulis (Gilg. & Ben. De Wolf against Rhipicephalus (Boophilus decoloratus Koch, 1844 (Acarina: Ixodidae, Tick Larvae

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Emmanuel T. Nyahangare

2016-01-01

Full Text Available Efficacy and toxicity of aqueous and organic solvents extracts of Maerua edulis against ticks and mice, respectively, were determined. Ground leaves were extracted separately using cold water, cold water plus surfactant (1% v/v liquid soap, hot water plus surfactant, hexane, or methanol to make 25% w/v stock solutions from which serial dilutions of 5, 10, 20, and 25% were made. For each concentration, 20 Rhipicephalus decoloratus tick larvae were put in filter papers impregnated with extracts and incubated for 48 h at 27°C and 85–90% RH for mortality observation after 24 h and 48 h. In the toxicity experiment, hot water plus surfactant treatments of 5, 10, 20, and 25% (w/v M. edulis were administered in suspension per os to sexually mature Balb/C mice and observed for clinical signs and mortality for 72 h. Larvae mortality was highest (>98% in methanol-extracted M. edulis treatments (20 and 25%, which was not different from the amitraz-based control (Tickbuster®. Mortality was also higher in the hot water than in cold water plus surfactant treatments (P<0.05. No postadministration adverse health effects were observed in the mice. These results suggest that M. edulis is an effective tick remedy best extracted using methanol or hot water plus surfactant.

The toxicity of vanadium on gastrointestinal, urinary and reproductive system, and its influence on fertility and fetuses malformations

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Aleksandra Wilk

2017-09-01

Additionally, this research identifies the doses of vanadium which lead to pathological alterations becoming visible within tissues. Moreover, this study includes information about the protective efficacy of some substances in view of the toxicity of vanadium.

Patterns of failure for glioblastoma multiforme following limited-margin radiation and concurrent temozolomide

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Gebhardt, Brian J; Dobelbower, Michael C; Ennis, William H; Bag, Asim K; Markert, James M; Fiveash, John B

2014-01-01

To analyze patterns of failure in patients with glioblastoma multiforme (GBM) treated with limited-margin radiation therapy and concurrent temozolomide. We hypothesize that patients treated with margins in accordance with Adult Brain Tumor Consortium guidelines (ABTC) will demonstrate patterns of failure consistent with previous series of patients treated with 2–3 cm margins. A retrospective review was performed of patients treated at the University of Alabama at Birmingham for GBM between 2000 and 2011. Ninety-five patients with biopsy-proven disease and documented disease progression after treatment were analyzed. The initial planning target volume includes the T1-enhancing tumor and surrounding edema plus a 1 cm margin. The boost planning target volume includes the T1-enhancing tumor plus a 1 cm margin. The tumors were classified as in-field, marginal, or distant if greater than 80%, 20-80%, or less than 20% of the recurrent volume fell within the 95% isodose line, respectively. The median progression-free survival from the time of diagnosis to documented failure was 8 months (range 3–46). Of the 95 documented recurrences, 77 patients (81%) had an in-field component of treatment failure, 6 (6%) had a marginal component, and 27 (28%) had a distant component. Sixty-three patients (66%) demonstrated in-field only recurrence. The low rate of marginal recurrence suggests that wider margins would have little impact on the pattern of failure, validating the use of limited margins in accordance ABTC guidelines

Sphingosine 1-phosphate (S1P) signaling in glioblastoma multiforme-A systematic review.

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Mahajan-Thakur, Shailaja; Bien-Möller, Sandra; Marx, Sascha; Schroeder, Henry; Rauch, Bernhard H

2017-11-17

The multifunctional sphingosine-1-phosphate (S1P) is a lipid signaling molecule and central regulator in the development of several cancer types. In recent years, intriguing information has become available regarding the role of S1P in the progression of Glioblastoma multiforme (GBM), the most aggressive and common brain tumor in adults. S1P modulates numerous cellular processes in GBM, such as oncogenesis, proliferation and survival, invasion, migration, metastasis and stem cell behavior. These processes are regulated via a family of five G-protein-coupled S1P receptors (S1PR1-5) and may involve mainly unknown intracellular targets. Distinct expression patterns and multiple intracellular signaling pathways of each S1PR subtype enable S1P to exert its pleiotropic cellular actions. Several studies have demonstrated alterations in S1P levels, the involvement of S1PRs and S1P metabolizing enzymes in GBM pathophysiology. While the tumorigenic actions of S1P involve the activation of several kinases and transcription factors, the specific G-protein (Gi, Gq, and G12/13)-coupled signaling pathways and downstream mediated effects in GBM remain to be elucidated in detail. This review summarizes the recent findings concerning the role of S1P and its receptors in GBM. We further highlight the current insights into the signaling pathways considered fundamental for regulating the cellular processes in GMB and ultimately patient prognosis.

Leucaena toxicity: a new perspective on the most widely used forage tree legume

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Michael J. Halliday

2013-09-01

Full Text Available The tree legume Leucaena leucocephala (leucaena is a high quality ruminant feed, vitally important for livestock production in the tropics, despite the presence of mimosine in the leaves. This toxic non-protein amino acid has the potential to limit productivity and adversely affect the health of animals. In the 1980s, the ruminal bacterium Synergistes jonesii was discovered and subsequently distributed in Australia as an oral inoculum to overcome these toxic effects. However, in recent times, a number of factors, including: surveys of the status of toxicity worldwide; improved understanding of the chemistry and mode of action of the toxins; new techniques for molecular sequencing; and concerns about the efficacy of the in vitro inoculum; have cast doubt on some past understanding of leucaena toxicity and provide new insights into the geographical spread of S. jonesii. There is also confusion and ignorance regarding the occurrence and significance of toxicity in many countries worldwide. Ongoing research into the taxonomy and ecology of the Synergistetes phylum, improved methods of inoculation, and improved management solutions, along with aware-ness-raising extension activities, are vital for the future success of leucaena feeding systems.

Toxicity and profile and objective response of Paclitaxel in metastatic breast cancer

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Ansari, T.N.; Mahmood, A; Rasul, S.; Syed, A.S.

2005-01-01

Objective: To evaluate the efficacy and toxicity of 1-hour weekly Paclitaxel in metastatic breast cancer along with evaluation of overall survival. Patients and Methods: Thirty six patients were enrolled in the study. All patients with histologically confirmed and bi- dimensionally measurable metastatic breast cancer who had received previously either chemotherapy or hormone therapy were included in the study. Paclitaxel was administered in 1-hour weekly infusion in a dose of 100 mg/m/sup 2/ for 12 doses. Results: All patients had received previous chemotherapy with either CAF or CMF. Twenty five patients had also received hormone therapy, 61% had two or more metastatic sites involved, and lung was the common site of involvement. Complete response was observed in 4 (11.1 %) patients, partial response in 14 (38.8%) patients, with an overall response rate of 50.0%. Clinical benefit was 94.4% and median overall survival was 11 months. Treatment was well-tolerated with no grade 3 or 4 toxicity. Common side effects were arthralgias, myalgias and neutropenia. Conclusion: Treatment with 1-hour weekly infusion of Paclitaxel is a well-tolerated chemotherapy with a substantial degree of efficacy in patients with metastatic breast cancer. (author)

Cyclophilin B Supports Myc and Mutant p53 Dependent Survival of Glioblastoma Multiforme Cells

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Choi, Jae Won; Schroeder, Mark A.; Sarkaria, Jann N.; Bram, Richard J.

2014-01-01

Glioblastoma multiforme (GBM) is an aggressive, treatment-refractory type of brain tumor for which effective therapeutic targets remain important to identify. Here we report that cyclophilin B (CypB), a prolyl isomerase residing in the endoplasmic reticulum (ER), provides an essential survival signal in GBM cells. Analysis of gene expression databases revealed that CypB is upregulated in many cases of malignant glioma. We found that suppression of CypB reduced cell proliferation and survival in human GBM cells in vitro and in vivo. We also found that treatment with small molecule inhibitors of cyclophilins, including the approved drug cyclosporine, greatly reduced the viability of GBM cells. Mechanistically, depletion or pharmacologic inhibition of CypB caused hyperactivation of the oncogenic RAS-MAPK pathway, induction of cellular senescence signals, and death resulting from loss of MYC, mutant p53, Chk1 and JAK/STAT3 signaling. Elevated reactive oxygen species, ER expansion and abnormal unfolded protein responses in CypB-depleted GBM cells indicated that CypB alleviates oxidative and ER stresses and coordinates stress adaptation responses. Enhanced cell survival and sustained expression of multiple oncogenic proteins downstream of CypB may thus contribute to the poor outcome of GBM tumors. Our findings link chaperone-mediated protein folding in the ER to mechanisms underlying oncogenic transformation, and they make CypB an attractive and immediately targetable molecule for GBM therapy. PMID:24272483

Semi-automated segmentation of a glioblastoma multiforme on brain MR images for radiotherapy planning.

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Hori, Daisuke; Katsuragawa, Shigehiko; Murakami, Ryuuji; Hirai, Toshinori

2010-04-20

We propose a computerized method for semi-automated segmentation of the gross tumor volume (GTV) of a glioblastoma multiforme (GBM) on brain MR images for radiotherapy planning (RTP). Three-dimensional (3D) MR images of 28 cases with a GBM were used in this study. First, a sphere volume of interest (VOI) including the GBM was selected by clicking a part of the GBM region in the 3D image. Then, the sphere VOI was transformed to a two-dimensional (2D) image by use of a spiral-scanning technique. We employed active contour models (ACM) to delineate an optimal outline of the GBM in the transformed 2D image. After inverse transform of the optimal outline to the 3D space, a morphological filter was applied to smooth the shape of the 3D segmented region. For evaluation of our computerized method, we compared the computer output with manually segmented regions, which were obtained by a therapeutic radiologist using a manual tracking method. In evaluating our segmentation method, we employed the Jaccard similarity coefficient (JSC) and the true segmentation coefficient (TSC) in volumes between the computer output and the manually segmented region. The mean and standard deviation of JSC and TSC were 74.2+/-9.8% and 84.1+/-7.1%, respectively. Our segmentation method provided a relatively accurate outline for GBM and would be useful for radiotherapy planning.

Understanding cytoskeleton regulators in glioblastoma multiforme for therapy design

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Masoumi S

2016-09-01

Full Text Available Samaneh Masoumi,1,*, Aditya Harisankar,2,* Aileen Gracias,3 Fabian Bachinger,1 Temesgen Fufa,1,4 Gayathri Chandrasekar,5 Frank Gaunitz,4 Julian Walfridsson,2 Satish S Kitambi1 1Department of Microbiology Tumor and Cell Biology, 2Center for Hematology and Regenerative Medicine, Department of Medicine, 3Department of Neuroscience, Karolinska Institutet, Solna, Sweden; 4Department of Neurosurgery, University Hospital, Leipzig, Germany; 5Department of Biosciences and Nutrition, Karolinska Institutet, Solna, Sweden *These authors contributed equally to this work Abstract: The cellular cytoskeleton forms the primary basis through which a cell governs the changes in size, shape, migration, proliferation, and forms the primary means through which the cells respond to their environment. Indeed, cell and tissue morphologies are used routinely not only to grade tumors but also in various high-content screening methods with an aim to identify new small molecules with therapeutic potential. This study examines the expression of various cytoskeleton regulators in glioblastoma multiforme (GBM. GBM is a very aggressive disease with a low life expectancy even after chemo- and radiotherapy. Cancer cells of GBM are notorious for their invasiveness, ability to develop resistance to chemo- and radiotherapy, and to form secondary site tumors. This study aims to gain insight into cytoskeleton regulators in GBM cells and to understand the effect of various oncology drugs, including temozolomide, on cytoskeleton regulators. We compare the expression of various cytoskeleton regulators in GBM-derived tumor and normal tissue, CD133-postive and -negative cells from GBM and neural cells, and GBM stem-like and differentiated cells. In addition, the correlation between the expression of cytoskeleton regulators with the clinical outcome was examined to identify genes associated with longer patient survival. This was followed by a small molecule screening with US Food and Drug

Improved Outcomes with Intensity Modulated Radiation Therapy Combined with Temozolomide for Newly Diagnosed Glioblastoma Multiforme

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Noel J. Aherne

2014-01-01

Full Text Available Purpose. Glioblastoma multiforme (GBM is optimally treated by maximal debulking followed by combined chemoradiation. Intensity modulated radiation therapy (IMRT is gaining widespread acceptance in other tumour sites, although evidence to support its use over three-dimensional conformal radiation therapy (3DCRT in the treatment of gliomas is currently lacking. We examined the survival outcomes for patients with GBM treated with IMRT and Temozolomide. Methods and Materials. In all, 31 patients with GBM were treated with IMRT and 23 of these received chemoradiation with Temozolomide. We correlated survival outcomes with patient functional status, extent of surgery, radiation dose, and use of chemotherapy. Results. Median survival for all patients was 11.3 months, with a median survival of 7.2 months for patients receiving 40.05 Gray (Gy and a median survival of 17.4 months for patients receiving 60 Gy. Conclusions. We report one of the few series of IMRT in patients with GBM. In our group, median survival for those receiving 60 Gy with Temozolomide compared favourably to the combined therapy arm of the largest randomised trial of chemoradiation versus radiation to date (17.4 months versus 14.6 months. We propose that IMRT should be considered as an alternative to 3DCRT for patients with GBM.

Improved outcomes with intensity modulated radiation therapy combined with temozolomide for newly diagnosed glioblastoma multiforme.

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Aherne, Noel J; Benjamin, Linus C; Horsley, Patrick J; Silva, Thomaz; Wilcox, Shea; Amalaseelan, Julan; Dwyer, Patrick; Tahir, Abdul M R; Hill, Jacques; Last, Andrew; Hansen, Carmen; McLachlan, Craig S; Lee, Yvonne L; McKay, Michael J; Shakespeare, Thomas P

2014-01-01

Purpose. Glioblastoma multiforme (GBM) is optimally treated by maximal debulking followed by combined chemoradiation. Intensity modulated radiation therapy (IMRT) is gaining widespread acceptance in other tumour sites, although evidence to support its use over three-dimensional conformal radiation therapy (3DCRT) in the treatment of gliomas is currently lacking. We examined the survival outcomes for patients with GBM treated with IMRT and Temozolomide. Methods and Materials. In all, 31 patients with GBM were treated with IMRT and 23 of these received chemoradiation with Temozolomide. We correlated survival outcomes with patient functional status, extent of surgery, radiation dose, and use of chemotherapy. Results. Median survival for all patients was 11.3 months, with a median survival of 7.2 months for patients receiving 40.05 Gray (Gy) and a median survival of 17.4 months for patients receiving 60 Gy. Conclusions. We report one of the few series of IMRT in patients with GBM. In our group, median survival for those receiving 60 Gy with Temozolomide compared favourably to the combined therapy arm of the largest randomised trial of chemoradiation versus radiation to date (17.4 months versus 14.6 months). We propose that IMRT should be considered as an alternative to 3DCRT for patients with GBM.

Phase II Study of Short-Course Radiotherapy Plus Concomitant and Adjuvant Temozolomide in Elderly Patients With Glioblastoma

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Minniti, Giuseppe, E-mail: Giuseppe.Minniti@ospedalesantandrea.it [Department of Radiation Oncology, Sant' Andrea Hospital, University ' La Sapienza,' Rome (Italy); Department of Neurological Sciences, Neuromed Institute, Pozzilli (Italy); Lanzetta, Gaetano [Department of Neurological Sciences, Neuromed Institute, Pozzilli (Italy); Scaringi, Claudia [Department of Radiation Oncology, Sant' Andrea Hospital, University ' La Sapienza,' Rome (Italy); Caporello, Paola [Department of Medical Oncology, Sant' Andrea Hospital, University ' La Sapienza,' Rome (Italy); Salvati, Maurizio [Department of Neurosurgery, Umberto I Hospital, University ' La Sapienza,' Rome (Italy); Arcella, Antonella [Department of Neurological Sciences, Neuromed Institute, Pozzilli (Italy); De Sanctis, Vitaliana [Department of Radiation Oncology, Sant' Andrea Hospital, University ' La Sapienza,' Rome (Italy); Giangaspero, Felice [Department of Neurological Sciences, Neuromed Institute, Pozzilli (Italy); Department of Pathology, Umberto I Hospital, University ' La Sapienza,' Rome (Italy); Enrici, Riccardo Maurizi [Department of Radiation Oncology, Sant' Andrea Hospital, University ' La Sapienza,' Rome (Italy)

2012-05-01

Purpose: Radiotherapy (RT) and chemotherapy may prolong survival in older patients (age {>=}70 years) with glioblastoma multiforme (GBM), although the survival benefits remain poor. This Phase II multicenter study was designed to evaluate the efficacy and safety of an abbreviated course of RT plus concomitant and adjuvant temozolomide (TMZ) in older patients with GBM. Patients and Methods: Seventy-one eligible patients 70 years of age or older with newly diagnosed GBM and a Karnofsky performance status {>=}60 were treated with a short course of RT (40 Gy in 15 fractions over 3 weeks) plus TMZ at the dosage of 75 mg/m{sup 2} per day followed by 12 cycles of adjuvant TMZ (150-200 mg/m{sup 2} for 5 days during each 28-day cycle). The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival and toxicity. Results: The Median OS was 12.4 months, and the 1-year and 2-year OS rates were 58% and 20%, respectively. The median and 1-year rates of progression-free survival were 6 months and 20%, respectively. All patients completed the planned programme of RT. Grade 3 or 4 adverse events occurred in 16 patients (22%). Grade 3 and 4 neutropenia and/or thrombocytopenia occurred in 10 patients (15%), leading to the interruption of treatment in 6 patients (8%). Nonhematologic Grade 3 toxicity was rare, and included fatigue in 4 patients and cognitive disability in 1 patient. Conclusions: A combination of an abbreviated course of RT plus concomitant and adjuvant TMZ is well tolerated and may prolong survival in elderly patients with GBM. Future randomized studies need to evaluate the efficacy and toxicity of different schedules of RT in association with chemotherapy.

Stereotactic intracranial implantation and in vivo bioluminescent imaging of tumor xenografts in a mouse model system of glioblastoma multiforme.

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Baumann, Brian C; Dorsey, Jay F; Benci, Joseph L; Joh, Daniel Y; Kao, Gary D

2012-09-25

Glioblastoma multiforme (GBM) is a high-grade primary brain cancer with a median survival of only 14.6 months in humans despite standard tri-modality treatment consisting of surgical resection, post-operative radiation therapy and temozolomide chemotherapy. New therapeutic approaches are clearly needed to improve patient survival and quality of life. The development of more effective treatment strategies would be aided by animal models of GBM that recapitulate human disease yet allow serial imaging to monitor tumor growth and treatment response. In this paper, we describe our technique for the precise stereotactic implantation of bio-imageable GBM cancer cells into the brains of nude mice resulting in tumor xenografts that recapitulate key clinical features of GBM. This method yields tumors that are reproducible and are located in precise anatomic locations while allowing in vivo bioluminescent imaging to serially monitor intracranial xenograft growth and response to treatments. This method is also well-tolerated by the animals with low perioperative morbidity and mortality.

Light-activated phenalen-1-one bactericides: efficacy, toxicity and mechanism compared with benzalkonium chloride.

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Muehler, Denise; Sommer, Kerstin; Wennige, Sara; Hiller, Karl-Anton; Cieplik, Fabian; Maisch, Tim; Späth, Andreas

2017-11-01

Five photoactive compounds with variable elongated alkyl-substituents in a phenalen-1-one structure were examined in view of structural similarity to the antimicrobial agent benzalkonium chloride (BAC). All phenalen-1-ones and BAC were evaluated for their antimicrobial properties against Staphylococcus aureus, methicillin-resistant S. aureus, Escherichia coli, Pseudomonas aeruginosa and for their eukaryotic toxicity against normal human epidermal keratinocyte (NHEK) cells to narrow down the BAC-like effect and the photodynamic effect depending on the chemical structure. All compounds were investigated for effective concentration ranges, where a bacterial reduction of 5 log 10 is achieved, while an NHEK survival of 80% is ensured. Effective concentration ranges were found for four out of five photoactive compounds, but not for BAC and the compound with BAC-like alkyl chain length. Chain length size and polar area of the respective head-groups of phenalen-1-one compounds or BAC showed an influence on the incorporation inside lipid membranes and thus, head-groups may have an impact on the toxicity of antimicrobials.

Structurally-diverse, PPARγ-activating environmental toxicants induce adipogenesis and suppress osteogenesis in bone marrow mesenchymal stromal cells

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Watt, James; Schlezinger, Jennifer J.

2015-01-01

Environmental obesogens are a newly recognized category of endocrine disrupting chemicals that have been implicated in contributing to the rising rates of obesity in the United States. While obesity is typically regarded as an increase in visceral fat, adipocyte accumulation in the bone has been linked to increased fracture risk, lower bone density, and osteoporosis. Exposure to environmental toxicants that activate peroxisome proliferator activated receptor γ (PPARγ), a critical regulator of the balance of differentiation between adipogenesis and osteogenesis, may contribute to the increasing prevalence of osteoporosis. However, induction of adipogenesis and suppression of osteogenesis are separable activities of PPARγ, and ligands may selectively alter these activities. It currently is unknown whether suppression of osteogenesis is a common toxic endpoint of environmental PPARγ ligands. Using a primary mouse bone marrow culture model, we tested the hypothesis that environmental toxicants acting as PPARγ agonists divert the differentiation pathway of bone marrow-derived multipotent mesenchymal stromal cells towards adipogenesis and away from osteogenesis. The toxicants tested included the organotins tributyltin and triphenyltin, a ubiquitous phthalate metabolite (mono-(2-ethylhexyl) phthalate, MEHP), and two brominated flame retardants (tetrabromobisphenol-a, TBBPA, and mono-(2-ethylhexyl) tetrabromophthalate, METBP). All of the compounds activated PPARγ1 and 2. All compounds increased adipogenesis (lipid accumulation, Fabp4 expression) and suppressed osteogenesis (alkaline phosphatase activity, Osx expression) in mouse primary bone marrow cultures, but with different potencies and efficacies. Despite structural dissimilarities, there was a strong negative correlation between efficacies to induce adipogenesis and suppress osteogenesis, with the organotins being distinct in their exceptional ability to suppress osteogenesis. As human exposure to a mixture of

Radioimmunotherapy targeting the extra domain B of fibronectin in C6 rat gliomas: a preliminary study about the therapeutic efficacy of iodine-131-labeled SIP(L19)

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Spaeth, Nicolas; Wyss, Matthias T.; Pahnke, Jens; Biollaz, Gregoire; Trachsel, Eveline; Drandarov, Konstantin; Treyer, Valerie; Weber, Bruno; Neri, Dario; Buck, Alfred

2006-01-01

Despite aggressive treatment protocols, patients suffering from glioblastoma multiforme still experience poor outcome. Therefore, new adjuvant therapeutic options such as radioimmunotherapy (RIT) have been studied and have resulted in significant survival benefit. In this study, we assessed the efficacy of a novel radioimmunotherapeutic approach targeting the extra domain B (EDB) of fibronectin, a marker of angiogenesis, in glioma-bearing rats. Methods: C6 gliomas were induced intracerebrally in Wistar rats. Ten to 11 days later, 220-360 MBq of iodine-131-labeled anti-EDB SIP(L19) ('small immunoprotein') was administered intravenously into nine animals, yielding a radiation dose of 13-21 Gy. Another nine rats served as controls. Then the following parameters were compared: median survival time, tumor size and histology. Results: Histological examination of the tumors revealed typical glioblastoma characteristics. Eleven of 18 rats developed a tumor size bigger than 150 mm 3 . When these animals were used for survival analysis, median survival did significantly differ between groups [22 days (therapy; n=7) vs. 16 days (control; n=4); P 131 I-SIP(L19)-RIT showed promising potential in treating C6 gliomas, warranting further studies. However, larger trials with preferentially higher doses are needed to confirm this finding and, potentially, to further increase the efficacy of this treatment

Thyroid cancer in toxic and non-toxic multinodular goiter

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Cerci C

2007-01-01

Full Text Available Background : Many authors have claimed that hyperthyroidism protects against thyroid cancer and believed that the incidence of malignancy is lower in patients with toxic multinodular goiter (TMG than in those with non-toxic multinodular goiter. But in recent studies, it was reported that the incidence of malignancy with TMG is not as low as previously thought. Aim : To compare the thyroid cancer incidence in patients with toxic and non-toxic multinodular goiter. Settings and Design : Histology reports of patients treated surgically with a preoperative diagnosis of toxic and non-toxic multinodular goiter were reviewed to identify the thyroid cancer incidence. Patients having a history of neck irradiation or radioactive iodine therapy were excluded from the study. Materials and Methods : We reviewed 294 patients operated between 2001-2005 from toxic and non-toxic multinodular goiter. One hundred and twenty-four of them were toxic and 170 were non-toxic. Hyperthyroidism was diagnosed by elevated tri-iodothyroinine / thyroxine ratios and low thyroid-stimulating hormone with clinical signs and symptoms. All patients were evaluated with ultrasonography and scintigraphy and fine needle aspiration biopsy. Statistical Analysis Used : Significance of the various parameters was calculated by using ANOVA test. Results : The incidence of malignancy was 9% in the toxic and 10.58% in the non-toxic multinodular goiter group. Any significant difference in the incidence of cancer and tumor size between the two groups could not be detected. Conclusions : The incidence of malignancy in toxic multinodular goiter is not very low as thought earlier and is nearly the same in non-toxic multinodular goiter.

Phase II Pilot Study of Bevacizumab in Combination with Temozolomide and Regional Radiation Therapy for Up-Front Treatment of Patients With Newly Diagnosed Glioblastoma Multiforme: Interim Analysis of Safety and Tolerability

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Lai, Albert; Filka, Emese; McGibbon, Bruce; Nghiemphu, Phioanh Leia; Graham, Carrie; Yong, William H.; Mischel, Paul; Liau, Linda M.; Bergsneider, Marvin; Pope, Whitney; Selch, Michael; Cloughesy, Tim

2008-01-01

Purpose: To assess interim safety and tolerability of a 10-patient, Phase II pilot study using bevacizumab (BV) in combination with temozolomide (TMZ) and regional radiation therapy (RT) in the up-front treatment of patients with newly diagnosed glioblastoma. Methods and Materials: All patients received standard external beam regional RT of 60.0 Gy in 30 fractions started within 3 to 5 weeks after surgery. Concurrently TMZ was given daily at 75 mg/m 2 for 42 days during RT, and BV was given every 2 weeks at 10 mg/kg starting with the first day of RT/TMZ. After a 2-week interval upon completion of RT, the post-RT phase commenced with resumption of TMZ at 150 to 200 mg/m 2 for 5 days every 4 weeks and continuation of BV every 2 weeks. Results: For these 10 patients, toxicities were compiled until study discontinuation or up to ∼40 weeks from initial study treatment for those remaining on-study. In terms of serious immediate or delayed neurotoxicity, 1 patient developed presumed radiation-induced optic neuropathy. Among the toxicities that could be potentially treatment related, relatively high incidences of fatigue, myelotoxicity, wound breakdown, and deep venous thrombosis/pulmonary embolism were observed. Conclusion: The observed toxicities were acceptable to continue enrollment toward the overall target group of 70 patients. Preliminary efficacy analysis shows encouraging mean progression-free survival. At this time data are not sufficient to encourage routine off-label use of BV combined with TMZ/RT in the setting of newly diagnosed glioblastoma without longer follow-up, enrollment of additional patients, and thorough efficacy assessment

Radiation Therapy Dose Escalation for Glioblastoma Multiforme in the Era of Temozolomide

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Badiyan, Shahed N.; Markovina, Stephanie; Simpson, Joseph R.; Robinson, Clifford G.; DeWees, Todd [Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri (United States); Tran, David D.; Linette, Gerry [Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri (United States); Jalalizadeh, Rohan [Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri (United States); Dacey, Ralph; Rich, Keith M.; Chicoine, Michael R.; Dowling, Joshua L.; Leuthardt, Eric C.; Zipfel, Gregory J.; Kim, Albert H. [Department of Neurosurgery, Washington University School of Medicine, St. Louis, Missouri (United States); Huang, Jiayi, E-mail: jhuang@radonc.wustl.edu [Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri (United States)

2014-11-15

Purpose: To review clinical outcomes of moderate dose escalation using high-dose radiation therapy (HDRT) in the setting of concurrent temozolomide (TMZ) in patients with newly diagnosed glioblastoma multiforme (GBM), compared with standard-dose radiation therapy (SDRT). Methods and Materials: Adult patients aged <70 years with biopsy-proven GBM were treated with SDRT (60 Gy at 2 Gy per fraction) or with HDRT (>60 Gy) and TMZ from 2000 to 2012. Biological equivalent dose at 2-Gy fractions was calculated for the HDRT assuming an α/β ratio of 5.6 for GBM. Results: Eighty-one patients received SDRT, and 128 patients received HDRT with a median (range) biological equivalent dose at 2-Gy fractions of 64 Gy (61-76 Gy). Overall median follow-up time was 1.10 years, and for living patients it was 2.97 years. Actuarial 5-year overall survival (OS) and progression-free survival (PFS) rates for patients that received HDRT versus SDRT were 12.4% versus 13.2% (P=.71), and 5.6% versus 4.1% (P=.54), respectively. Age (P=.001) and gross total/near-total resection (GTR/NTR) (P=.001) were significantly associated with PFS on multivariate analysis. Younger age (P<.0001), GTR/NTR (P<.0001), and Karnofsky performance status ≥80 (P=.001) were associated with improved OS. On subset analyses, HDRT failed to improve PFS or OS for those aged <50 years or those who had GTR/NTR. Conclusion: Moderate radiation therapy dose escalation above 60 Gy with concurrent TMZ does not seem to improve clinical outcomes for patients with GBM.

Mdr1a plays a crucial role in regulating the analgesic effect and toxicity of aconitine by altering its pharmacokinetic characteristics

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Zhu, Lijun; Wu, Jinjun; Zhao, Min; Song, Wenjie; Qi, Xiaoxiao; Wang, Ying [International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006 (China); Lu, Linlin [International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006 (China); State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau (SAR) 999078 (China); Liu, Zhongqiu, E-mail: liuzq@gzucm.edu.cn [International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006 (China); State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau (SAR) 999078 (China)

2017-04-01

Aconitine (AC) is the primary bioactive/toxic alkaloid in plants of the Aconitum species. Our previous study demonstrated that Mdr1 was involved in efflux of AC. However, the mechanism by which Mdr1 regulates the efficacy/toxicity of AC in vivo remains unclear. The present study aimed to determine the effects of Mdr1a on the efficacy/toxicity and pharmacokinetics of AC in wild-type and Mdr1a{sup −/−} FVB mice. After oral administration of AC, significantly higher analgesic effect was observed in Mdr1a{sup −/−} mice (49% to 105%) compared to wild-type mice (P < 0.05). The levels of s100-β protein and creatine kinase, which indicate cerebral and myocardial damage, respectively, were also significantly increased (P < 0.05) in Mdr1a{sup −/−} mice. Histopathological examination revealed that the Mdr1a{sup −/−} mice suffered from evident cerebral and myocardial damages, but the wild-type mice did not. These findings suggested that Mdr1a deficiency significantly promoted the analgesic effect of AC and exacerbated its toxicity. Pharmacokinetic experiments showed that T{sub 1/2} of AC in the Mdr1a{sup −/−} mice was significantly higher (from 87% to 300%) than that in wild-type mice (P < 0.05). The distribution of AC in the brain of Mdr1a{sup −/−} mice was 2- to 32-fold higher than that in the brains of wild-type mice (P < 0.05). Toxic reactions were more severe in Mdr1a{sup −/−} mice compared to wild-type mice. In conclusion, Mdr1a deficiency significantly enhanced the analgesic effect of AC and exacerbated its toxicity by upregulating its distribution to the brain and decreasing its plasma elimination rate. Thus, Mdr1a dysfunction may cause severe AC poisoning. - Highlights: • The efficacy and toxicity of aconitine were significantly enhanced in Mdr1a{sup −/−} mice. • The distribution of aconitine to the brain was remarkably increased in Mdr1a{sup −/−} mice. • The elimination rate of aconitine was significantly decreased in Mdr1a

Limited clinical efficacy of azacitidine in transfusion-dependent, growth factor-resistant, low- and Int-1-risk MDS

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Holm, Mette; Dybedahl, I; Holm, Mette

2014-01-01

This prospective phase II study evaluated the efficacy of azacitidine (Aza)+erythropoietin (Epo) in transfusion-dependent patients with lower-risk myelodysplastic syndrome (MDS). Patients ineligible for or refractory to full-dose Epo+granulocyte colony stimulation factors for >8 weeks and a trans...... patients, but efficacy is limited, toxicity substantial and most responses of short duration. This treatment cannot be generally recommended in lower-risk MDS. Mutational screening revealed a high frequency of mutations....

Systematic review of the effect of intravenous lipid emulsion therapy for local anesthetic toxicity

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Høgberg, Lotte Christine Groth; Bania, Theodore C; Lavergne, Valéry

2016-01-01

BACKGROUND: Following national and regional recommendations, intravenous lipid emulsion (ILE) has become established in clinical practice as a treatment for acute local anesthetic (LA) toxicity, although evidence of efficacy is limited to animal studies and human case reports. A collaborative lipid......-defined inclusion and exclusion criteria. Pre-treatment experiments, pharmacokinetic studies not involving toxicity and studies that did not address antidotal use of ILE were excluded. RESULTS: We included 113 studies and reports. Of these, 76 were human and 38 animal studies. One publication included both a human...... case report and an animal study. Human studies included one randomized controlled crossover trial involving 16 healthy volunteers. The subclinical LA toxicity design did not show a difference in the effects of ILE versus saline. There was one case series and 73 case reports of ILE use in the context...

Nanomedicine for therapeutic drug therapy: Approaches to increase the efficacy of drug therapy with nanoemulsion delivery and reduce the toxicity of quantum dots

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Kambalapally, Swetha Reddy

The advancement of nanotechnology has paved the way for novel nanoscale materials for use in a wide range of applications. The use of these nanomaterials in biomedicine facilitates the improvement of existing technologies for disease prevention and treatment through diagnostics, tumor detection, drug delivery, medical imaging and vaccine development. Nanotechnology delivery systems for therapeutic uses includes the formulation of nanoparticles in emulsions. These novel delivery systems can improve drug efficacy by their ability to enhance bioavailability, minimize drug side effects, decrease drug toxicity, provide targeted site delivery and increase circulation of the drug in the blood. Additionally, these delivery systems also improve the drug stability and encapsulation efficiency. In the Introduction, this thesis will describe a novel technique for the preparation of nanoemulsions which was utilized in drug delivery and diagnostic applications. This novel Phase Inversion Temperature (PIT) method is a solvent and polymer-free and low energy requiring emulsification method, typically utilizing oils stabilized by nonionic surfactants to prepare water in oil (W/O) emulsions. The correlation between the particle size, zeta potential and the emulsion stability is described. The use of this nanoemulsion delivery system for pharmaceuticals and nutraceuticals by utilizing in vitro systems was investigated. Using the PIT method, a self assembling nanoemulsion (SANE) of gamma Tocotrienols (gammaT3), a component of Vitamin E family has been demonstrated to reduce cholesterol accumulation in HepG-2 cells. The nanoemulsion is stable and the particle size is around 20 nm with a polydispersity index (PDI) of 0.065. The effect of the nano gammaT3 on the metabolism of cholesterol, HMG-CoA activity and Apo-B levels were evaluated in an in vitro system utilizing HepG2 cells. A new class of nanoparticles, Quantum dots (QDs) has shown immense potential as novel nanomaterials used as

Management of advanced pancreatic cancer with gemcitabine plus erlotinib: efficacy and safety results in clinical practice.

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Diaz Beveridge, Robert; Alcolea, Vicent; Aparicio, Jorge; Segura, Ángel; García, Jose; Corbellas, Miguel; Fonfría, María; Giménez, Alejandra; Montalar, Joaquin

2014-01-10

The combination of gemcitabine and erlotinib is a standard first-line treatment for unresectable, locally advanced or metastatic pancreatic cancer. We reviewed our single centre experience to assess its efficacy and toxicity in clinical practice. Clinical records of patients with unresectable, locally advanced or metastatic pancreatic cancer who were treated with the combination of gemcitabine and erlotinib were reviewed. Univariate survival analysis and multivariate analysis were carried out to indentify independent predictors factors of overall survival. Our series included 55 patients. Overall disease control rate was 47%: 5% of patients presented complete response, 20% partial response and 22% stable disease. Median overall survival was 8.3 months). Cox regression analysis indicated that performance status and locally advanced versus metastatic disease were independent factors of overall survival. Patients who developed acne-like rash toxicity, related to erlotinib administration, presented a higher survival than those patients who did not develop this toxicity. Gemcitabine plus erlotinib doublet is active in our series of patients with advanced pancreatic cancer. This study provides efficacy and safety results similar to those of the pivotal phase III clinical trial that tested the same combination.

In vitro evaluation of the effects of graphene platelets on glioblastoma multiforme cells

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Jaworski, Slawomir; Sawosz, Ewa; Grodzik, Marta

2013-01-01

Graphene is a single atom-thick material with exciting potential. It can be used in many fields, from electronics to biomedicine. However, little is known about its toxicity and biocompatibility. Herein, we report a study on the toxicity of graphene platelets (GPs) by examining the influence of G...

Investigating the heterogeneity of alkylating agents' efficacy and toxicity between sexes: A systematic review and meta-analysis of randomized trials comparing cyclophosphamide and ifosfamide (MAIAGE study).

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Fresneau, Brice; Hackshaw, A; Hawkins, D S; Paulussen, M; Anderson, J R; Judson, I; Litière, S; Dirksen, U; Lewis, I; van den Berg, H; Gaspar, N; Gelderblom, H; Whelan, J; Boddy, A V; Wheatley, K; Pignon, J P; De Vathaire, F; Le Deley, M C; Le Teuff, G

2017-08-01

A marginal interaction between sex and the type of alkylating agent was observed for event-free survival in the Euro-EWING99-R1 randomized controlled trial (RCT) comparing cyclophosphamide and ifosfamide in Ewing sarcoma. To further evaluate this interaction, we performed an individual patient data meta-analysis of RCTs assessing cyclophosphamide versus ifosfamide in any type of cancer. A literature search produced two more eligible RCTs (EICESS92 and IRS-IV). The endpoints were progression-free survival (PFS, main endpoint) and overall survival (OS). The hazard ratios (HRs) of the treatment-by-sex interaction and their 95% confidence interval (95% CI) were assessed using stratified multivariable Cox models. Heterogeneity of the interaction across age categories and trials was explored. We also assessed this interaction for severe acute toxicity using logistic models. The meta-analysis comprised 1,528 pediatric and young adult sarcoma patients from three RCTs: Euro-EWING99-R1 (n = 856), EICESS92 (n = 155), and IRS-IV (n = 517). There were 224 PFS events in Euro-EWING99-R1 and 200 in the validation set (EICESS92 + IRS-IV), and 171 and 154 deaths in each dataset, respectively. The estimated treatment-by-sex interaction for PFS in Euro-EWING99-R1 (HR = 1.73, 95% CI = 1.00-3.00) was not replicated in the validation set (HR = 0.97, 95% CI = 0.55-1.72), without heterogeneity across trials (P = 0.62). In the pooled analysis, the treatment-by-sex interaction was not significant (HR = 1.31, 95% CI = 0.89-1.95, P = 0.17), without heterogeneity across age categories (P = 0.88) and trials (P = 0.36). Similar results were observed for OS. No significant treatment-by-sex interaction was observed for leucopenia/neutropenia (P = 0.45), infection (P = 0.64), or renal toxicity (P = 0.20). Our meta-analysis did not confirm the hypothesis of a treatment-by-sex interaction on efficacy or toxicity outcomes. © 2017 Wiley Periodicals, Inc.

Differential Radiosensitizing Potential of Temozolomide in MGMT Promoter Methylated Glioblastoma Multiforme Cell Lines

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Nifterik, Krista A. van; Berg, Jaap van den; Stalpers, Lukas J.A.; Lafleur, M. Vincent M.; Leenstra, Sieger; Slotman, Ben J.; Hulsebos, Theo J.M.; Sminia, Peter

2007-01-01

Purpose: To investigate the radiosensitizing potential of temozolomide (TMZ) for human glioblastoma multiforme (GBM) cell lines using single-dose and fractionated γ-irradiation. Methods and Materials: Three genetically characterized human GBM cell lines (AMC-3046, VU-109, and VU-122) were exposed to various single (0-6 Gy) and daily fractionated doses (2 Gy per fraction) of γ-irradiation. Repeated TMZ doses were given before and concurrent with irradiation treatment. Immediately plated clonogenic cell-survival curves were determined for both the single-dose and the fractionated irradiation experiments. To establish the net effect of clonogenic cell survival and cell proliferation, growth curves were determined, expressed as the number of surviving cells. Results: All three cell lines showed MGMT promoter methylation, lacked MGMT protein expression, and were sensitive to TMZ. The isotoxic TMZ concentrations used were in a clinically feasible range of 10 μmol/L (AMC-3046), 3 μmol/L (VU-109), and 2.5 μmol/L (VU-122). Temozolomide was able to radiosensitize two cell lines (AMC 3046 and VU-122) using single-dose irradiation. A reduction in the number of surviving cells after treatment with the combination of TMZ and fractionated irradiation was seen in all three cell lines, but only AMC 3046 showed a radiosensitizing effect. Conclusions: This study on TMZ-sensitive GBM cell lines shows that TMZ can act as a radiosensitizer and is at least additive to γ-irradiation. Enhancement of the radiation response by TMZ seems to be independent of the epigenetically silenced MGMT gene

Low-dose fractionated radiotherapy and concomitant chemotherapy for recurrent or progressive glioblastoma. Final report of a pilot study

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Balducci, M.; Diletto, B.; Chiesa, S.; D' Agostino, G.R.; Gambacorta, M.A.; Ferro, M.; Valentini, V. [Catholic University of the Sacred Heart, Department of Radiation Oncology, Rome (Italy); Colosimo, C. [Catholic University of the Sacred Heart, Department of Radiology, Rome (Italy); Maira, G.; Anile, C. [Catholic University of the Sacred Heart, Department of Neurosurgery, Rome (Italy)

2014-04-15

Evaluated in this study were the feasibility and the efficacy of concurrent low dose fractionated radiotherapy (LD-FRT) and chemotherapy as palliative treatment for recurrent/progressive glioblastoma multiforme (GBM). Eligible patients had recurrent or progressive GBM, Karnofsky performance status ≥70, prior surgery, and standard radiochemotherapy treatment. Recurrence/progression disease during temozolomide (TMZ) received cisplatin (CDDP; 30 mg/m{sup 2} on days 1, 8, 15), fotemustine (FTM; 40 mg/m{sup 2} on days 2, 9, 16), and concurrent LD-FRT (0.3 Gy twice daily); recurrence/progression after 4 months from the end of adjuvant TMZ were treated by TMZ (150/200 mg/m{sup 2} on days 1-5) concomitant with LD-FRT (0.4 Gy twice daily). Primary endpoints were safety and toxicity. A total of 32 patients were enrolled. Hematologic toxicity G1-2 was observed in 18.7% of patients and G3-4 in 9.4%. One patient (3.1%) had complete response, 3 (9.4%) had partial response, 8 (25%) had stable disease for at least 8 weeks, while 20 patients (62.5%) experienced progressive disease. The clinical benefit was 37.5%. Median progression-free survival (PFS) and overall survival (OS) were 5 and 8 months, respectively. Survival rate at 12 months was of 27.8%. LD-FRT and chemotherapy for recurrent/progressive GBM have a good toxicity profile and clinical outcomes, even though further investigation of this novel palliative treatment approach is warranted. (orig.)

Radiotherapy for pituitary adenomas: Long-term efficacy and toxicity

International Nuclear Information System (INIS)

Erridge, Sara C.; Conkey, David S.; Stockton, Diane; Strachan, Mark W.J.; Statham, Patrick F.X.; Whittle, Ian R.; Grant, Robin; Kerr, Gillian R.; Gregor, Anna

2009-01-01

Background: Radiotherapy for pituitary adenomas is an effective treatment but remains controversial due to toxicity concerns. Materials and methods: A retrospective audit of patients referred for radiotherapy during 1974-2003 was conducted, the case records were examined and data linkage to cancer registry and hospital discharge records was performed to assess the overall survival (OS), progression-free survival (PFS) and late effects (hormone deficiency, reduced vision, second cancer and stroke). Results: Three hundred and eighty-five patients had radiotherapy (median 45 Gy). The OS was 74% and 49%, PFS was 97% and 96%, at 10 and 20 years, respectively. No specific factors influenced local control. Additional hormone deficiencies occurred in 19% (ACTH) and 26% (TSH). Actuarial rate optic neuropathy at 10 years was 0.8%. Seventy-eight patients had a stroke, a RR for a matched Scottish population of 1.45 (CI 1.05-1.18, p = 0.03) men and 2.22 (1.56-3.08, p < 0.01) women. Four intra-cranial tumours were identified; 20-year actuarial risk 1.9% (CI 0-2.6%), a RR of 5.65 (0.53-20.77, p = 0.10) men and 9.94 (0.94-36.56, p = 0.04) women. Conclusions: This treatment is effective with good local control rates at 20 years. A significant proportion developed hypo-pituitarism. The risk of optic neuropathy was low but risk of stroke increased, particularly in women who had slight increased risk of intra-cranial tumours.

Comparing two polymeric biguanides: chemical distinction, antiseptic efficacy and cytotoxicity of polyaminopropyl biguanide and polyhexamethylene biguanide.

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Rembe, Julian-Dario; Fromm-Dornieden, Carolin; Schäfer, Nadine; Böhm, Julia K; Stuermer, Ewa K

2016-08-01

In this study, polyaminopropyl biguanide (PAPB) was compared to the molecularly closely related polyhexamethylene biguanide (PHMB) with respect to chemical relationship, antiseptic efficacy and cytotoxicity in vitro. Cytotoxicity for human keratinocytes (HaCaTs) and murine fibroblasts (L929) was determined according to ISO EN 10993-5 for both substances. Antimicrobial efficacy tests were performed via determination of the MBC, quantitative suspension method for substances and investigation of two PAPB- or PHMB-containing dressings against Staphyloccoccus aureus, Escherichia coli and Pseudomonas aeruginosa, according to international standards. Prior mass spectrometry was performed for chemical differentiation of the investigated substances. PHMB showed high toxicity even in low concentrations for both tested cell lines and a high antimicrobial efficacy against S. aureus and E. coli. In the case of PAPB, no or only low cytotoxicity was detected after 72 h, whilst comparable antibacterial features are lacking, as PAPB showed no relevant antimicrobial effects. Even though chemically closely related, PAPB proved to be ineffective in bacterial eradication, whilst PHMB showed a high efficacy. The discovery and establishment of safe and effective alternative antiseptics are important issues for the treatment of infected wounds. In particular, rising bacterial resistances to established agents, as well as ongoing discussions of potential toxic or carcinogenic effects emphasize this necessity. Nevertheless, the presented results highlight that even small changes in the chemical structure of related agents such as PHMB and PAPB can dramatically affect their efficacy and, therefore, need to be carefully distinguished and assessed side by side.

Quality of Radiomic Features in Glioblastoma Multiforme: Impact of Semi-Automated Tumor Segmentation Software.

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Lee, Myungeun; Woo, Boyeong; Kuo, Michael D; Jamshidi, Neema; Kim, Jong Hyo

2017-01-01

The purpose of this study was to evaluate the reliability and quality of radiomic features in glioblastoma multiforme (GBM) derived from tumor volumes obtained with semi-automated tumor segmentation software. MR images of 45 GBM patients (29 males, 16 females) were downloaded from The Cancer Imaging Archive, in which post-contrast T1-weighted imaging and fluid-attenuated inversion recovery MR sequences were used. Two raters independently segmented the tumors using two semi-automated segmentation tools (TumorPrism3D and 3D Slicer). Regions of interest corresponding to contrast-enhancing lesion, necrotic portions, and non-enhancing T2 high signal intensity component were segmented for each tumor. A total of 180 imaging features were extracted, and their quality was evaluated in terms of stability, normalized dynamic range (NDR), and redundancy, using intra-class correlation coefficients, cluster consensus, and Rand Statistic. Our study results showed that most of the radiomic features in GBM were highly stable. Over 90% of 180 features showed good stability (intra-class correlation coefficient [ICC] ≥ 0.8), whereas only 7 features were of poor stability (ICC NDR ≥1), while above 35% of the texture features showed poor NDR (software tools provided sufficiently reliable tumor segmentation and feature stability; thus helping to overcome the inherent inter-rater and intra-rater variability of user intervention. However, certain aspects of feature quality, including NDR and redundancy, need to be assessed for determination of representative signature features before further development of radiomics.

Activation of PPARγ mediates icaritin-induced cell cycle arrest and apoptosis in glioblastoma multiforme.

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Liu, Yongji; Shi, Ling; Liu, Yuan; Li, Peng; Jiang, Guoping; Gao, Xiaoning; Zhang, Yongbin; Jiang, Chuanwu; Zhu, Weiping; Han, Hongxing; Ju, Fang

2018-04-01

Glioblastoma multiforme (GBM) is the most prevalent primary malignancy of the brain. This study was designed to investigate whether icaritin exerts anti-neoplastic activity against GBM in vitro. Cell Counting Kit-8 (CCK-8) assay was utilized to examine the viability of GBM cells. The apoptotic cell population was measured by flow cytometry analysis. Cell cycle distribution was detected by flow cytometry as well. Western blot analysis was performed to examine the level of biomarker proteins in GBM cells. Levels of PPARγ mRNA and protein were detected by qPCR and western blot analysis, respectively. To examine the role of PPARγ in the anti-neoplastic activity of icaritin, PPARγ antagonist GW9662 or PPARγ siRNA was used. The activity of PPARγ was determined by DNA binding and luciferase assays. Our findings revealed that icaritin markedly suppresses cell growth in a dose-dependent and time-dependent fashion. The cell population at the G0/G1 phase of the cell cycle was significantly increased following icaritin treatment. Meanwhile, icaritin promoted apoptotic cell death in T98G and U87MG cells. Further investigation showed upregulation of PPARγ played a key role in the anti-neoplastic activities of icaritin. Moreover, our result demonstrated activation of AMPK signaling by icaritin mediated the modulatory effect of icaritin on PPARγ. Our results suggest the PPARγ may mediate anti-neoplastic activities against GBM. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Docetaxel-loaded solid lipid nanoparticles suppress breast cancer cells growth with reduced myelosuppression toxicity

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Yuan Q

2014-10-01

Full Text Available Qing Yuan,1 Jing Han,1,2 Wenshu Cong,1 Ying Ge,3 Dandan Ma,1,3,4 Zhaoxia Dai,3,4 Yaping Li,5 Xiaolin Bi1,3,4 1CAS Key Laboratory for Biological Effects of Nanomaterials and Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing, 2School of Life Sciences, Anhui University, Hefei, 3Cancer Center, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, 4Graduate School, Dalian Medical University, Dalian, 5Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, People’s Republic of China Abstract: Docetaxel is an adjuvant chemotherapy drug widely used to treat multiple solid tumors; however, its toxicity and side effects limit its clinical efficacy. Herein, docetaxel-loaded solid lipid nanoparticles (DSNs were developed to reduce systemic toxicity of docetaxel while still keeping its anticancer activity. To evaluate its anticancer activity and toxicity, and to understand the molecular mechanisms of DSNs, different cellular, molecular, and whole genome transcription analysis approaches were utilized. The DSNs showed lower cytotoxicity compared with the commercial formulation of docetaxel (Taxotere® and induced more apoptosis at 24 hours after treatment in vitro. DSNs can cause the treated cancer cells to arrest in the G2/M phase in a dose-dependent manner similar to Taxotere. They can also suppress tumor growth very effectively in a mice model with human xenograft breast cancer. Systemic analysis of gene expression profiles by microarray and subsequent verification experiments suggested that both DSNs and Taxotere regulate gene expression and gene function, including DNA replication, DNA damage response, cell proliferation, apoptosis, and cell cycle regulation. Some of these genes expressed differentially at the protein level although their messenger RNA expression level was similar under Taxotere and DSN treatment. Moreover, DSNs improved the main side effect of Taxotere by greatly

In vivo bioluminescence imaging validation of a human biopsy-derived orthotopic mouse model of glioblastoma multiforme.

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Jarzabek, Monika A; Huszthy, Peter C; Skaftnesmo, Kai O; McCormack, Emmet; Dicker, Patrick; Prehn, Jochen H M; Bjerkvig, Rolf; Byrne, Annette T

2013-05-01

Glioblastoma multiforme (GBM), the most aggressive brain malignancy, is characterized by extensive cellular proliferation, angiogenesis, and single-cell infiltration into the brain. We have previously shown that a xenograft model based on serial xenotransplantation of human biopsy spheroids in immunodeficient rodents maintains the genotype and phenotype of the original patient tumor. The present work further extends this model for optical assessment of tumor engraftment and growth using bioluminescence imaging (BLI). A method for successful lentiviral transduction of the firefly luciferase gene into multicellular spheroids was developed and implemented to generate optically active patient tumor cells. Luciferase-expressing spheroids were injected into the brains of immunodeficient mice. BLI photon counts and tumor volumes from magnetic resonance imaging (MRI) were correlated. Luciferase-expressing tumors recapitulated the histopathologic hallmarks of human GBMs and showed proliferation rates and microvessel density counts similar to those of wild-type xenografts. Moreover, we detected widespread invasion of luciferase-positive tumor cells in the mouse brains. Herein we describe a novel optically active model of GBM that closely mimics human pathology with respect to invasion, angiogenesis, and proliferation indices. The model may thus be routinely used for the assessment of novel anti-GBM therapeutic approaches implementing well-established and cost-effective optical imaging strategies.

In Vivo Bioluminescence Imaging Validation of a Human Biopsy–Derived Orthotopic Mouse Model of Glioblastoma Multiforme

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Monika A. Jarzabek

2013-05-01

Full Text Available Glioblastoma multiforme (GBM, the most aggressive brain malignancy, is characterized by extensive cellular proliferation, angiogenesis, and single-cell infiltration into the brain. We have previously shown that a xenograft model based on serial xenotransplantation of human biopsy spheroids in immunodeficient rodents maintains the genotype and phenotype of the original patient tumor. The present work further extends this model for optical assessment of tumor engraftment and growth using bioluminescence imaging (BLI. A method for successful lentiviral transduction of the firefly luciferase gene into multicellular spheroids was developed and implemented to generate optically active patient tumor cells. Luciferase-expressing spheroids were injected into the brains of immunodeficient mice. BLI photon counts and tumor volumes from magnetic resonance imaging (MRI were correlated. Luciferase-expressing tumors recapitulated the histopathologic hallmarks of human GBMs and showed proliferation rates and microvessel density counts similar to those of wild-type xenografts. Moreover, we detected widespread invasion of luciferase-positive tumor cells in the mouse brains. Herein we describe a novel optically active model of GBM that closely mimics human pathology with respect to invasion, angiogenesis, and proliferation indices. The model may thus be routinely used for the assessment of novel anti-GBM therapeutic approaches implementing well-established and cost-effective optical imaging strategies.

5-ALA Fluorescence Image Guided Resection of Glioblastoma Multiforme: A Meta-Analysis of the Literature

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Samy Eljamel

2015-05-01

Full Text Available Background: Glioblastoma multiforme (GBM is one of the most deadly cancers in humans. Despite recent advances in anti-cancer therapies, most patients with GBM die from local disease progression. Fluorescence image guided surgical resection (FIGR was recently advocated to enhance local control of GBM. This is meta-analyses of 5-aminolevulinic (5-ALA induced FIGR. Materials: Review of the literature produced 503 potential publications; only 20 of these fulfilled the inclusion criteria of this analysis, including a total of 565 patients treated with 5-ALA-FIGR reporting on its outcomes and 800 histological samples reporting 5-ALA-FIGR sensitivity and specificity. Results: The mean gross total resection (GTR rate was 75.4% (95% CI: 67.4–83.5, p < 0.001. The mean time to tumor progression (TTP was 8.1 months (95% CI: 4.7–12, p < 0.001. The mean overall survival gain reported was 6.2 months (95% CI: −1–13, p < 0.001. The specificity was 88.9% (95% CI: 83.9–93.9, p < 0.001 and the sensitivity was 82.6% (95% CI: 73.9–91.9, p < 0.001. Conclusion: 5-ALA-FIGR in GBM is highly sensitive and specific, and imparts significant benefits to patients in terms of improved GTR and TTP.

Association of Glioblastoma Multiforme Stem Cell Characteristics, Differentiation, and Microglia Marker Genes with Patient Survival

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Sandra Bien-Möller

2018-01-01

Full Text Available Patients with glioblastoma multiforme (GBM are at high risk to develop a relapse despite multimodal therapy. Assumedly, glioma stem cells (GSCs are responsible for treatment resistance of GBM. Identification of specific GSC markers may help to develop targeted therapies. Here, we performed expression analyses of stem cell (ABCG2, CD44, CD95, CD133, ELF4, Nanog, and Nestin as well as differentiation and microglia markers (GFAP, Iba1, and Sparc in GBM compared to nonmalignant brain. Furthermore, the role of these proteins for patient survival and their expression in LN18 stem-like neurospheres was analyzed. At mRNA level, ABCG2 and CD95 were reduced, GFAP was unchanged; all other investigated markers were increased in GBM. At protein level, CD44, ELF4, Nanog, Nestin, and Sparc were elevated in GBM, but only CD133 and Nestin were strongly associated with survival time. In addition, ABCG2 and GFAP expression was decreased in LN18 neurospheres whereas CD44, CD95, CD133, ELF4, Nanog, Nestin, and Sparc were upregulated. Altogether only CD133 and Nestin were associated with survival rates. This raises concerns regarding the suitability of the other target structures as prognostic markers, but makes both CD133 and Nestin candidates for GBM therapy. Nevertheless, a search for more specific marker proteins is urgently needed.

Association of Glioblastoma Multiforme Stem Cell Characteristics, Differentiation, and Microglia Marker Genes with Patient Survival

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Balz, Ellen; Herzog, Susann; Plantera, Laura; Vogelgesang, Silke; Seifert, Carolin; Bialke, Angela; Venugopal, Chitra; Singh, Sheila K.; Hoffmann, Wolfgang; Schroeder, Henry W. S.

2018-01-01

Patients with glioblastoma multiforme (GBM) are at high risk to develop a relapse despite multimodal therapy. Assumedly, glioma stem cells (GSCs) are responsible for treatment resistance of GBM. Identification of specific GSC markers may help to develop targeted therapies. Here, we performed expression analyses of stem cell (ABCG2, CD44, CD95, CD133, ELF4, Nanog, and Nestin) as well as differentiation and microglia markers (GFAP, Iba1, and Sparc) in GBM compared to nonmalignant brain. Furthermore, the role of these proteins for patient survival and their expression in LN18 stem-like neurospheres was analyzed. At mRNA level, ABCG2 and CD95 were reduced, GFAP was unchanged; all other investigated markers were increased in GBM. At protein level, CD44, ELF4, Nanog, Nestin, and Sparc were elevated in GBM, but only CD133 and Nestin were strongly associated with survival time. In addition, ABCG2 and GFAP expression was decreased in LN18 neurospheres whereas CD44, CD95, CD133, ELF4, Nanog, Nestin, and Sparc were upregulated. Altogether only CD133 and Nestin were associated with survival rates. This raises concerns regarding the suitability of the other target structures as prognostic markers, but makes both CD133 and Nestin candidates for GBM therapy. Nevertheless, a search for more specific marker proteins is urgently needed. PMID:29535786

Antifouling efficacy of a controlled depletion paint formulation with acetophenone

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Sangmok Jung

2017-12-01

Full Text Available Biofouling is an inevitable problem that occurs continually on marine fishing vessels and other small crafts. The nature of the antifouling (AF coatings used to prevent biofouling on these small vessels is of great environmental concern. Therefore, the efficacy of a non-toxic AF candidate, acetophenone, was evaluated in preliminary laboratory assays using marine bacteria, diatom and Ulva spores. At a low concentration of 100 μg cm–2 of acetophenone, spore attachment of a green fouling alga was significantly reduced (p < 0.01. Similarly, 40% acetophenone coatings significantly inhibited diatom attachment. This new non-toxic AF agent was incorporated into controlled depletion paint (CDP. Fouling coverage (%, biomass, and fouling resistance (% were estimated. On CDP coatings made with acetophenone (40%, a significant decrease in fouling biomass was estimated (p < 0.01.

23Na-MRI of recurrent glioblastoma multiforme after intraoperative radiotherapy: technical note

International Nuclear Information System (INIS)

Haneder, Stefan; Buesing, Karen A.; Schoenberg, Stefan O.; Ong, Melissa M.; Giordano, Frank A.; Wenz, Frederik; Konstandin, Simon; Schad, Lothar R.; Brehmer, Stefanie; Schmiedek, Peter

2015-01-01

We report the first case of an intraoperative radiotherapy (IORT) in a patient with recurrent glioblastoma multiforme (GBM) who was followed up with a novel magnetic resonance imaging (MRI) method - 23 Na-MRI - in comparison to a standard contrast-enhanced 1 H-MRI and 18 F-FET-PET. A 56-year-old female patient with diagnosed GBM in July 2012 underwent tumor resection, radiochemotherapy, and three cycles of chemotherapy. After a relapse, 6 months after the initial diagnosis, an IORT was recommended which was performed in March 2013 using the INTRABEAM system (Carl Zeiss Meditec AG, Germany) with a 3-cm applicator and a surface dose of 20 Gy. Early post-operative contrast-enhanced and 1-month follow-up 1 H-MRI and a 18 F-FET-PET were performed. In addition, an IRB-approved 23 Na-MRI was performed on a 3.0-T MR scanner (MAGNETOM TimTrio, Siemens Healthcare, Germany). After re-surgery and IORT in March 2013, only a faint contrast enhancement but considerable surrounding edema was visible at the medio-posterior resection margins. In April 2013, new and progressive contrast enhancement, edema, 23 Na content, and increased uptake in the 18 F-FET-PET were visible, indicating tumor recurrence. Increased sodium content within the area of contrast enhancement was found in the 23 Na-MRI, but also exceeding this area, very similar to the increased uptake depicted in the 18 F-FET-PET. The clearly delineable zone of edema in both examinations exhibits a lower 23 Na content compared to areas with suspected proliferating tumor tissue. 23 Na-MRI provided similar information in the suspicious area compared to 18 F-FET-PET, exceeding conventional 1 H-MRI. Still, 23 Na-MRI remains an investigational technique, which is worth to be further evaluated. (orig.)

Using Acetaminophen's Toxicity Mechanism to Enhance Cisplatin Efficacy in Hepatocarcinoma and Hepatoblastoma Cell Lines

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Alexander J. Neuwelt

2009-10-01

Conclusions: Our results suggest that a chemotherapeutic regimen containing both AAP and CDDP with delayed NAC rescue has the potential to enhance chemotherapeutic efficacy while decreasing adverse effects. This would be a promising approach particularly for hepatoblastomas regardless of cellular CYP2E1 protein level but could also be beneficial in other malignancies.

Nitrosourea efficacy in high-grade glioma: a survival gain analysis summarizing 504 cohorts with 24193 patients.

Science.gov (United States)

Wolff, Johannes E A; Berrak, Su; Koontz Webb, Susannah E; Zhang, Ming

2008-05-01

Even though past studies have suggested efficacy of nitrosourea drugs in patients with high-grade glioma and temozolomide has recently been shown significantly to be beneficial, no conclusive comparisons between these agents have been published. We performed a survival gain analysis of 364 studies describing 24,193 patients with high-grade glioma treated in 504 cohorts, and compared the effects of drugs. The most frequent diagnoses were glioblastoma multiforme (GBM) (72%) and anaplastic astrocytoma (22%). The mean overall survival (mOS) was 14.1 months. The outcome was influenced by several of the known prognostic factors including the histological grade, if the tumors were newly diagnosed or recurrent, the completeness of resection, patients' age, and gender. This information allowed the calculation of a predicted mOS for each cohort based on their prognostic factors independent of treatment. Survival gain to characterize the influence of treatment was subsequently defined and validated as the difference between the observed and the predicted mOS. In 62 CCNU-treated cohorts and 15 ACNU-treated cohorts the survival gain was 5.3 months and 8.9 months (P < 0.0005), respectively. No detectable survival gain for patients treated with various BCNU-containing regimens was found. Conclusion CCNU- and ACNU-containing regimens were superior to BCNU containing regiments.

Nitric oxide released from JS-K induces cell death by mitotic catastrophe as part of necrosis in glioblastoma multiforme.

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Günzle, Jessica; Osterberg, Nadja; Saavedra, Joseph E; Weyerbrock, Astrid

2016-09-01

The nitric oxide (NO) donor JS-K is specifically activated by glutathione S-transferases (GSTs) in GST-overexpressing cells. We have shown the induction of cell death in glioblastoma multiforme (GBM) cells at high JS-K doses but the mechanism remains unclear. The aim of this study was to determine whether NO-induced cell death is triggered by induction of apoptotic or necrotic pathways. For the first time, we demonstrate that NO induces cell death via mitotic catastrophe (MC) with non-apoptotic mechanisms in GBM cells. Moreover, the level of morphological changes indicating MC correlates with increased necrosis. Therefore, we conclude that MC is the main mechanism by which GBM cells undergo cell death after treatment with JS-K associated with necrosis rather than apoptosis. In addition, we show that PARP1 is not an exclusive marker for late apoptosis but is also involved in MC. Activating an alternative way of cell death can be useful for the multimodal cancer therapy of GBM known for its strong anti-apoptotic mechanisms and drug resistance.

Enhanced tumor control of human Glioblastoma Multiforme xenografts with the concomitant use of radiotherapy and an attenuated herpes simplex-1 virus (ASTRO research fellowship)

International Nuclear Information System (INIS)

Song, Paul Y.; Sibley, Gregory S.; Advani, Sunil; Hallahan, Dennis; Hyland, John; Kufe, Donald W.; Chou, Joany; Roizman, Bernard; Weichselbaum, Ralph R.

1996-01-01

Purpose: Glioblastoma Multiforme remains one of the most incurable of human tumors. The current treatment outcomes are dismal. There are several recent reports which suggest that some human glioblastoma xenografts implanted in the brains of athymic mice may be potentially cured with the use of an attenuated herpes simplex-1 virus alone. We have chosen a replication competent, non-neurovirulent HSV-1 mutant, designated R3616 to determine whether there is an interactive cell killing and enhanced tumor control with radiotherapy in the treatment of a human glioblastoma xenograft. Materials and Methods: In vivo, 1 mm 3 pieces of U-87 human glioblastoma cell line xenografts were implanted into the right hind limb of athymic mice and grown to > 200 mm 3 . A total of 112 mice were then equally distributed within four treatment arms (see chart below) based upon tumor volume. Xenografts selected to receive virus as part of the therapy were inoculated with three injections of 2 x 10 7 plaque forming units (PFU) of R3616 virus given on day 1, 2, and 3 for a total dose of 6 x 10 7 PFU. R3616 is a non-neurovirulent HSV-1 mutant created by the deletion of the γ 34.5 gene. Local field irradiation was delivered on day 2 (20 Gy) and day 3 (25 Gy). The mice were then followed for 60 days during which time the xenografts were measured twice weekly. A clinically non-palpable tumor (< 10% original volume) was scored as a cure. In addition percent-fractional tumor volume (FTV) and mean tumor volume (MTV) were calculated for each group. Results: Conclusion: While our tumor control with R3616 alone is similar to that reported in the literature, we have seen significantly enhanced tumor control and cell killing with the addition of RT suggesting a synergistic interaction between an oncolytic virus and radiation in the treatment of human glioblastoma multiforme xenografts

Toxicity identification evaluation methods for identification of toxicants in refinery effluents

International Nuclear Information System (INIS)

Barten, K.A.; Mount, D.R.; Hackett, J.R.

1993-01-01

During the last five years, the authors have used Toxicity Identification Evaluation (TIE) methods to characterize and identify the source(s) of toxicity in effluents from dozens of municipal and industrial facilities. In most cases, specific chemicals responsible for toxicity have been identified. Although generally successful, the initial experience was that for several refinery effluents, they were able only to qualitatively characterize the presence of organic toxicants; standard toxicant identification procedures were not able to isolate specific organic chemicals. They believe that organic toxicity in these refinery effluents is caused by multiple organic compounds rather than by just a few; evidence for this includes an inability to isolate toxicity in a small number of fractions using liquid chromatography and the presence of very large numbers of compounds in isolated fractions. There is also evidence that the toxicant(s) may be ionic, in that the toxicity of whole effluent and isolated fractions often show increasing toxicity with decreasing pH. Finally, positive-pressure filtration has also reduced toxicity in some samples. In this presentation the authors summarize their experiences with refinery effluents, focusing on typical patterns they have observed and alternative procedures they have used to better understand the nature of these toxicants

Treatment of textile effluent in a developed phytoreactor with immobilized bacterial augmentation and subsequent toxicity studies on Etheostoma olmstedi fish

Energy Technology Data Exchange (ETDEWEB)

Watharkar, Anuprita D. [Department of Biotechnology, Shivaji University, Kolhapur (India); Khandare, Rahul V. [School of Life Sciences, North Maharashtra University, Jalgaon (India); Waghmare, Pankajkumar R.; Jagadale, Ashwini D.; Govindwar, Sanjay P. [Department of Biochemistry, Shivaji University, Kolhapur (India); Jadhav, Jyoti P., E-mail: jpj_biochem@unishivaji.ac.in [Department of Biotechnology, Shivaji University, Kolhapur (India); Department of Biochemistry, Shivaji University, Kolhapur (India)

2015-02-11

Graphical abstract: - Highlights: • A phytoreactor was developed and augmented with immobilized bacteria. • This consortium showed enhanced treatment than the individual species. • Oxido-reductases from P. crinitum and B. pumilus could decolorize the effluent. • Characterization of effluent samples endorsed the efficacy of consortial strategy. • Toxicity studies revealed the less toxic nature of the consortium treated effluent. - Abstract: A static hydroponic bioreactor using nursery grown plants of Pogonatherum crinitum along with immobilized Bacillus pumilus cells was developed for the treatment of textile wastewater. Independent reactors with plants and immobilized cells were also kept for performance and efficacy evaluation. The effluent samples characterized before and after their treatment showed that the plant–bacterial consortium reactor was more efficient than those of individual plant and bacterium reactors. COD, BOD, ADMI, conductivity, turbidity, TDS and TSS of the textile effluent was found to be reduced by 78, 70, 93, 4, 90, 13 and 70% respectively within 12 d by the consortial set. HPTLC analysis revealed the transformation of the textile effluent to new products. The phytotoxicity study on Phaeseolus mungo and Sorghum vulgare seeds showed reduced toxicity of treated effluents. The animal toxicity study performed on Etheostoma olmstedi fishes showed the toxic nature of untreated effluent giving extreme stress to fishes leading to death. Histology of fish gills exposed to treated effluent was found to be less affected. The oxidative stress related enzymes like superoxide dismutase and catalase were found to show decreased activities and less lipid peroxidation in fishes exposed to treated effluent.

Treatment of textile effluent in a developed phytoreactor with immobilized bacterial augmentation and subsequent toxicity studies on Etheostoma olmstedi fish

International Nuclear Information System (INIS)

Watharkar, Anuprita D.; Khandare, Rahul V.; Waghmare, Pankajkumar R.; Jagadale, Ashwini D.; Govindwar, Sanjay P.; Jadhav, Jyoti P.

2015-01-01

Graphical abstract: - Highlights: • A phytoreactor was developed and augmented with immobilized bacteria. • This consortium showed enhanced treatment than the individual species. • Oxido-reductases from P. crinitum and B. pumilus could decolorize the effluent. • Characterization of effluent samples endorsed the efficacy of consortial strategy. • Toxicity studies revealed the less toxic nature of the consortium treated effluent. - Abstract: A static hydroponic bioreactor using nursery grown plants of Pogonatherum crinitum along with immobilized Bacillus pumilus cells was developed for the treatment of textile wastewater. Independent reactors with plants and immobilized cells were also kept for performance and efficacy evaluation. The effluent samples characterized before and after their treatment showed that the plant–bacterial consortium reactor was more efficient than those of individual plant and bacterium reactors. COD, BOD, ADMI, conductivity, turbidity, TDS and TSS of the textile effluent was found to be reduced by 78, 70, 93, 4, 90, 13 and 70% respectively within 12 d by the consortial set. HPTLC analysis revealed the transformation of the textile effluent to new products. The phytotoxicity study on Phaeseolus mungo and Sorghum vulgare seeds showed reduced toxicity of treated effluents. The animal toxicity study performed on Etheostoma olmstedi fishes showed the toxic nature of untreated effluent giving extreme stress to fishes leading to death. Histology of fish gills exposed to treated effluent was found to be less affected. The oxidative stress related enzymes like superoxide dismutase and catalase were found to show decreased activities and less lipid peroxidation in fishes exposed to treated effluent

Pim1 kinase is upregulated in glioblastoma multiforme and mediates tumor cell survival

Science.gov (United States)

Herzog, Susann; Fink, Matthias Alexander; Weitmann, Kerstin; Friedel, Claudius; Hadlich, Stefan; Langner, Sönke; Kindermann, Katharina; Holm, Tobias; Böhm, Andreas; Eskilsson, Eskil; Miletic, Hrvoje; Hildner, Markus; Fritsch, Michael; Vogelgesang, Silke; Havemann, Christoph; Ritter, Christoph Alexander; Meyer zu Schwabedissen, Henriette Elisabeth; Rauch, Bernhard; Hoffmann, Wolfgang; Kroemer, Heyo Klaus; Schroeder, Henry; Bien-Möller, Sandra

2015-01-01

Background The current therapy for glioblastoma multiforme (GBM), the most aggressive and common primary brain tumor of adults, involves surgery and a combined radiochemotherapy that controls tumor progression only for a limited time window. Therefore, the identification of new molecular targets is highly necessary. Inhibition of kinases has become a standard of clinical oncology, and thus the oncogenic kinase Pim1 might represent a promising target for improvement of GBM therapy. Methods Expression of Pim1 and associated signaling molecules was analyzed in human GBM samples, and the potential role of this kinase in patients' prognosis was evaluated. Furthermore, we analyzed the in vivo role of Pim1 in GBM cell growth in an orthotopic mouse model and examined the consequences of Pim1 inhibition in vitro to clarify underlying pathways. Results In comparison with normal brain, a strong upregulation of Pim1 was demonstrated in human GBM samples. Notably, patients with short overall survival showed a significantly higher Pim1 expression compared with GBM patients who lived longer than the median. In vitro experiments with GBM cells and analysis of patients' GBM samples suggest that Pim1 regulation is dependent on epidermal growth factor receptor. Furthermore, inhibition of Pim1 resulted in reduced cell viability accompanied by decreased cell numbers and increased apoptotic cells, as seen by elevated subG1 cell contents and caspase-3 and -9 activation, as well as modulation of several cell cycle or apoptosis regulatory proteins. Conclusions Altogether, Pim1 could be a novel therapeutic target, which should be further analyzed to improve the outcome of patients with aggressive GBM. PMID:25155357

Introducing Toxics

OpenAIRE

David C. Bellinger

2013-01-01

With this inaugural issue, Toxics begins its life as a peer-reviewed, open access journal focusing on all aspects of toxic chemicals. We are interested in publishing papers that present a wide range of perspectives on toxicants and naturally occurring toxins, including exposure, biomarkers, kinetics, biological effects, fate and transport, treatment, and remediation. Toxics differs from many other journals in the absence of a page or word limit on contributions, permitting authors to present ...

Osthole Suppresses the Migratory Ability of Human Glioblastoma Multiforme Cells via Inhibition of Focal Adhesion Kinase-Mediated Matrix Metalloproteinase-13 Expression

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Cheng-Fang Tsai

2014-03-01

Full Text Available Glioblastoma multiforme (GBM is the most common type of primary and malignant tumor occurring in the adult central nervous system. GBM often invades surrounding regions of the brain during its early stages, making successful treatment difficult. Osthole, an active constituent isolated from the dried C. monnieri fruit, has been shown to suppress tumor migration and invasion. However, the effects of osthole in human GBM are largely unknown. Focal adhesion kinase (FAK is important for the metastasis of cancer cells. Results from this study show that osthole can not only induce cell death but also inhibit phosphorylation of FAK in human GBM cells. Results from this study show that incubating GBM cells with osthole reduces matrix metalloproteinase (MMP-13 expression and cell motility, as assessed by cell transwell and wound healing assays. This study also provides evidence supporting the potential of osthole in reducing FAK activation, MMP-13 expression, and cell motility in human GBM cells.

Reinduction of Bevacizumab in Combination with Pegylated Liposomal Doxorubicin in a Patient with Recurrent Glioblastoma Multiforme Who Progressed on Bevacizumab/Irinotecan

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Mohammed Almubarak

2008-01-01

Full Text Available Glioblastoma multiforme (GBM carries a dismal prognosis despite the current standard of multimodality treatments. Recent studies showed promising results to a regimen consisting of a VEGF inhibitor, (bevacizumab and a topoisomerase I inhibitor (irinotecan [BI] in recurrent GBM. However, those patients with GBM who progress on BI will succumb to their disease generally in a very short period of time. We report a case of a 56-year-old male patient with GBM who declined surgical resection and received chemoradiation with temozolomide. This treatment was withheld secondary to significant thrombocytopenia. Subsequently, he achieved stable disease for 10 months with a regimen consisting of thalidomide and tamoxifen before progressing. This was followed by bevacizumab with irinotecan [BI], for which he had a significant partial response for 8 months with subsequent progression. Reinducing the patient with bevacizumab in combination with a pegylated liposomal doxorubicin [PLD] (a topoisomerase II inhibitor demonstrated antitumor activity with significant shrinkage of contrast enhancing mass and peritumoral edema.

Toroidal-spiral particles for codelivery of anti-VEGFR-2 antibody and irinotecan: a potential implant to hinder recurrence of glioblastoma multiforme.

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Sharma, Vishal; Köllmer, Melanie; Szymusiak, Magdalena; Nitsche, Ludwig C; Gemeinhart, Richard A; Liu, Ying

2014-03-10

Heterogeneous toroidal-spiral particles (TSPs) were generated by polymer droplet sedimentation, interaction, and cross-linking. TSPs provide a platform for encapsulation and release of multiple compounds of different sizes and physicochemical properties. As a model system, we demonstrate the encapsulation and independently controlled release of an anti-VEGFR-2 antibody and irinotecan for the treatment of glioblastoma multiforme. The anti-VEGFR-2 antibody was released from the TS channels and its binding to HUVECs was confirmed by confocal microscopy and flow cytometry, suggesting active antibody encapsulation and release. Irinotecan, a small molecule drug, was released from the dense polymer matrix of poly(ethylene glycol) diacrylate (MW ~ 700 g/mol; PEGDA 700). Released irinotecan inhibited the proliferation of U251 malignant glioma cells. Since the therapeutic compounds are released through different pathways, specifically diffusion through the polymer matrix versus TS channels, the release rate can be controlled independently through the design of the structure and material of particle components.

Toxic shock syndrome

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Staphylococcal toxic shock syndrome; Toxic shock-like syndrome; TSLS ... Toxic shock syndrome is caused by a toxin produced by some types of staphylococcus bacteria. A similar problem, called toxic shock- ...

Our Approach to Toxic Epidermal Necrolysis and Review of Current Treatment Alternatives

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Fatih Uygur

2008-09-01

Full Text Available Toxic epidermal necrolysis (TEN is a clinical entity which has a 30 to 40 % mortality rate, with necrolysis affecting the entire epidermis. Antibiotics, nonsteroidal anti-inflammatory drugs and anticonvulsants are offender drugs in TEN etiology. A standard treatment protocol with proven efficacy is still lacking. In this study, current treatment practice and our treatment strategy for TEN is discussed and eight patients treated in our clinic between the years 2001 and 2008 are reviewed.

Acute toxicity of chlorantraniliprole to non-target crayfish (Procambarus clarkii) associated with rice-crayfish cropping systems.

Science.gov (United States)

Barbee, Gary C; McClain, W Ray; Lanka, Srinivas K; Stout, Michael J

2010-09-01

Chlorantraniliprole, a novel anthranilic diamide insecticide, was recently introduced into the United States where rice-crayfish crop rotations are practiced to control rice water weevil (Lissorhoptrus oryzophilus Kuschel) infestations. Chlorantraniliprole has high margins of mammalian safety and excellent insecticidal efficacy, but its toxicity to non-target crayfish is uncertain. In this study, the acute toxicity of chlorantraniliprole to the red swamp crayfish Procambarus clarkii Girard was determined using aquatic and feeding assays. The aquatic 96 h median lethal toxicity (LC(50)) data indicate that technical-grade chlorantraniliprole is highly toxic (US EPA category) to crayfish with an LC(50) of 951 microg L(-1) (95% CL = 741-1118 microg L(-1)). A no observed effect concentration (NOEC) of 480 microg L(-1) was recorded. Neither the 36 day chronic feeding study, where crayfish fed on chlorantraniliprole-treated rice seed in aquaria, nor the 144 h acute feeding test, where crayfish fed on rice seeds treated with chlorantraniliprole, produced mortality or abnormal behavior. Chlorantraniliprole is three orders of magnitude less acutely toxic to P. clarkii than lambda-cyhalothrin and etofenprox, two pyrethroid insecticides also used in rice, and is less likely to cause acute crayfish toxicity in rice pond ecosystems. Based on acute toxicity data, the use of chlorantraniliprole should be more compatible with rice-crayfish crop rotations than pyrethroids. (c) 2010 Society of Chemical Industry.

Anaerobic biodegradability and toxicity of complex or toxicant wastewater

International Nuclear Information System (INIS)

Wills Betancur, B.A.

1995-01-01

As a first approximation to wastewater classification in susceptibility terms to treatment by anaerobic biological system, anaerobic biodegradability trials are accomplished to leached of sanitary landfill, to wastewater of coffee grain wet treatment plant and to wastewater of fumaric acid recuperation plant. In the last Plant, anaerobic toxicity trials and lethal toxicity on the Daphnia pulex micro-crustacean are made too. Anaerobic biological trials are made continuing the Wageningen University (Holland) Methodology (1.987). Lethal toxicity biological trials are made following the Standard Methods for the Examination of Water and Wastewater(18th edition, 1992). In development of this investigation project is found that fumaric acid recuperation plant leached it has a low anaerobic biodegradability, a high anaerobic toxicity and a high lethal toxicity over Daphnia pulex, for such reasons this leached is cataloged as complex and toxic wastewater. The other hand, wastewater of coffee grain wet treatment plant and wastewater of sanitary landfill they are both highly biodegradability and not-toxic, for such reasons these wastewaters are cataloged as susceptible to treatment by anaerobic biological system

New synthetic peptide with efficacy for heparin reversal and low toxicity and immunogenicity in comparison to protamine sulfate

Energy Technology Data Exchange (ETDEWEB)

Li, Tong; Meng, Zhiyun; Zhu, Xiaoxia; Gan, Hui; Gu, Ruolan; Wu, Zhuona; Li, Jian; Zheng, Ying; Liu, Taoyun; Han, Peng; Han, Su; Dou, Guifang, E-mail: douguifang@vip.sina.com

2015-11-20

Protamine sulfate (PS), the only clinically approved antidote to unfractionated heparin (UFH), is widely used for cardiopulmonary surgery or other extracorporeal circulation situations. However, the applications of PS have accompanied various severe side-effects. In this study, we presented a novel synthesized peptide compound (RRRRR-RRRRR-RRRRR-sulfate, R15S) served as a safer UFH antidote. Comparison studies were conducted between PS and R15S on efficacy and safety, aided by heparin neutralization studies, drug toxicity studies and anaphylactic analysis. Our research demonstrated that R15S contained comparable UFH neutralization activity in vitro and in rats in vivo as to active partial thromboplastin time (APTT) and anti-FXa assays. There was no cytotoxicity for R15S at 60 μg mg{sup −1} or below and the median lethal dose (LD{sub 50}) of R15S in mice was 35.4 mg kg{sup −1}, both of which were similar to that of PS. Furthermore, R15S exhibited no immunogenicity while it was obvious in guinea pigs immunized with PS. The level of cross-reactivity to anti-PS antibodies of R15S was about 30%. Both of which indicated much safer properties of R15S than PS. In conclusion, we presented a promising candidate R15S for UFH reversal, which is effective in neutralizing UFH and potentially safer in use. - Highlights: • R15 sulfate has a comparable unfractionated heparin neutralization activity to PS. • R15 sulfate avoided severe anaphylactic responses which happened to PS in clinical use. • R15 sulfate could provide a stricter quality control compared to PS which may vary with different batches.

The influence of lysosomal stability of silver nanomaterials on their toxicity to human cells.

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Setyawati, Magdiel Inggrid; Yuan, Xun; Xie, Jianping; Leong, David Tai

2014-08-01

How silver nanomaterials (Ag NMs) could induce toxicity has been debated heatedly by many researchers. We utilized Ag nanoclusters (Ag NCs) with the same size and ligand protection but different core surface speciation. Ag(+)-rich NCs (Ag(+)-R NCs) and their counterpart, the reduced Ag(0)-rich NCs (Ag(0)-R NCs) are synthesized to represent possible dichotomous stages in silver nanomaterial degradation process. Here we show Ag(0)-R NCs induce higher cellular toxicity when compared to Ag(+)-R NCs. This cellular toxicity is brought about via the modulation of reactive oxygen species (ROS) in cells as a result of the more rapid release of Ag species from Ag(0)-R NCs and subsequent oxidation into Ag(+) in the lysosomal compartment. The weaker Ag(0)-R bond greatly potentiated the release of Ag species in the acidic and enzymatic processes within the lysosomes. Since lysosomes are absent in bacteria, increasing silver nanomaterials stability may lower toxicity in mammalian cells whilst not reducing their efficacy to fight bacteria; this redesign can result in a safer silver nanomaterial. Copyright © 2014 Elsevier Ltd. All rights reserved.

Antioxidant Capacity, Cytotoxicity, and Acute Oral Toxicity of Gynura bicolor

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Wuen Yew Teoh

2013-01-01

Full Text Available Gynura bicolor (Compositae which is widely used by the locals as natural remedies in folk medicine has limited scientific studies to ensure its efficacy and nontoxicity. The current study reports the total phenolic content, antioxidant capacity, cytotoxicity, and acute oral toxicity of crude methanol and its fractionated extracts (hexane, ethyl acetate, and water of G. bicolor leaves. Five human colon cancer cell lines (HT-29, HCT-15, SW480, Caco-2, and HCT 116, one human breast adenocarcinoma cell line (MCF7, and one human normal colon cell line (CCD-18Co were used to evaluate the cytotoxicity of G. bicolor. The present findings had clearly demonstrated that ethyl acetate extract of G. bicolor with the highest total phenolic content among the extracts showed the strongest antioxidant activity (DPPH radical scavenging assay and metal chelating assay, possessed cytotoxicity, and induced apoptotic and necrotic cell death, especially towards the HCT 116 and HCT-15 colon cancer cells. The acute oral toxicity study indicated that methanol extract of G. bicolor has negligible level of toxicity when administered orally and has been regarded as safe in experimental rats. The findings of the current study clearly established the chemoprevention potential of G. bicolor and thus provide scientific validation on the therapeutic claims of G. bicolor.

FNAB cytology of extra-cranial metastasis of glioblastoma multiforme may resemble a lung primary: A diagnostic pitfall

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Dincer HE

2005-01-01

Full Text Available Abstract Background As extra-cranial metastasis of glioblastoma multiforme (GBM is rare, it may create a diagnostic dilemma especially during interpretation of fine needle aspiration biopsy (FNAB cytology. Case presentation We present transbronchial FNAB findings in a 62-year-old smoker with lung mass clinically suspicious for a lung primary. The smears of transbronchial FNAB showed groups of cells with ill-defined cell margins and cytological features overlapping with poorly differentiated non-small cell carcinoma. The tumor cells demonstrated lack of immunoreactivity for cytokeratin, thyroid transcription factor-1, and usual neuroendocrine markers, synaptophysin and chromogranin in formalin-fixed cellblock sections. However, they were immunoreactive for the other neuroendocrine immunomarker, CD56, suggesting neural nature of the cells. Further scrutiny of clinical details revealed a history of GBM, 13 months status-post surgical excision with radiation therapy and systemic chemotherapy. The tumor recurred 7 months earlier and was debulked surgically and with intra-cranial chemotherapy. Additional evaluation of tumor cells for glial fibrillary acidic protein (GFAP immunoreactivity with clinical details resulted in final interpretation of metastatic GBM. Conclusion Lack of clinical history and immunophenotyping may lead to a diagnostic pitfall with possible misinterpretation of metastatic GBM as poorly differentiated non-small cell carcinoma of lung in a smoker.

Monitoring and Management of Toxicities of Novel B Cell Signaling Agents.

Science.gov (United States)

Rhodes, Joanna; Mato, Anthony; Sharman, Jeff P

2018-04-11

B cell signaling agents, including ibrutinib, idelalisib, and the BCL-2 inhibitor venetoclax have become an integral part of therapy for patients with non-Hodgkin's lymphomas. The toxicity profiles of these medications is distinct from chemoimmunotherapy. Here, we will review the mechanism of action of these drugs, their efficacy, and toxicity management. Ibrutinib use is associated with increased risk of atrial fibrillation and bleeding which can be managed using dose interruptions and modifications. Patients on idelalisib require close clinical and frequent laboratory monitoring, particularly of liver function tests to ensure there are no serious adverse events. Monitoring for infections is important in patients on both idelalisib and ibrutinib. Venetoclax requires close clinical and laboratory monitoring to prevent significant tumor lysis. Targeted B cell receptor therapies each have unique side effect profiles which require careful clinical monitoring. As we continue to use these therapies, optimal management strategies will continue to be elucidated.

Pharmacogenetics predictive of response and toxicity in acute lymphoblastic leukemia therapy.

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Mei, Lin; Ontiveros, Evelena P; Griffiths, Elizabeth A; Thompson, James E; Wang, Eunice S; Wetzler, Meir

2015-07-01

Acute lymphoblastic leukemia (ALL) is a relatively rare disease in adults accounting for no more than 20% of all cases of acute leukemia. By contrast with the pediatric population, in whom significant improvements in long term survival and even cure have been achieved over the last 30years, adult ALL remains a significant challenge. Overall survival in this group remains a relatively poor 20-40%. Modern research has focused on improved pharmacokinetics, novel pharmacogenetics and personalized principles to optimize the efficacy of the treatment while reducing toxicity. Here we review the pharmacogenetics of medications used in the management of patients with ALL, including l-asparaginase, glucocorticoids, 6-mercaptopurine, methotrexate, vincristine and tyrosine kinase inhibitors. Incorporating recent pharmacogenetic data, mainly from pediatric ALL, will provide novel perspective of predicting response and toxicity in both pediatric and adult ALL therapies. Copyright © 2015 Elsevier Ltd. All rights reserved.

Brown coal derived humate inhibits contact hypersensitivity; An efficacy, toxicity and teratogenicity study in rats

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Van Rensburg, C.E.J.; Snyman, J.R.; Mokoele, T.; Cromarty, A.D. [University of Pretoria, Pretoria (South Africa). Faculty of Health Science

2007-10-15

The effects of two humate products were compared to that of prednisolone on a contact hypersensitivity rat model. Rats, sensitized with dinitrofluorobenzene (DNFB), were placed on a daily oral treatment of 61 mg/kg BW of humate derived from either leonardite or bituminous coal or on prednisolone at one mg/kg BW and challenged 6 days later with a topical application of DNFB to the right ear. The inflamed ears were measured daily. In a toxicity study rats were exposed to daily oral treatment of leonardite humate at 1,000 mg/kg BW for 1 month. A teratogenicity study was done where pregnant rats were treated with 500 mg/kg BW on days 5 to 17 of pregnancy. Only the leonardite humate compared favourably with prednisolone in suppressing contact hypersensitivity. No signs of toxicity were observed and weight gain was normal during the 6-day and 1 month treatments and during the teratogenicity study with the leonardite humate. However, the rats on the other two products experienced slower weight gain. The identification of a naturally occurring nontoxic compound with anti-inflammatory activity is exciting and merits further evaluation in the treatment of patients suffering from inflammatory conditions.

Benzodiazepines and antipsychotic medications for treatment of acute cocaine toxicity in animal models--a systematic review and meta-analysis.

Science.gov (United States)

Heard, Kennon; Cleveland, Nathan R; Krier, Shay

2011-11-01

There are no controlled human studies to determine the efficacy of benzodiazepines or antipsychotic medications for prevention or treatment of acute cocaine toxicity. The only available controlled data are from animal models and these studies have reported inconsistent benefits. The objective of this study was to quantify the reported efficacy of benzodiazepines and antipsychotic medication for the prevention of mortality due to cocaine poisoning. We conducted a systematic review to identify English language articles describing experiments that compared a benzodiazepine or antipsychotic medication to placebo for the prevention of acute cocaine toxicity in an animal model. We then used these articles in a meta-analysis with a random-effects model to quantify the absolute risk reduction observed in these experiments. We found 10 articles evaluating antipsychotic medications and 15 articles evaluating benzodiazepines. Antipsychotic medications reduced the risk of death by 27% (95% CI, 15.2%-38.7%) compared to placebo and benzodiazepines reduced the risk of death by 52% (42.8%-60.7%) compared to placebo. Both treatments showed evidence of a dose-response effect, and no experiment found a statistically significant increase in risk of death. We conclude that both benzodiazepines and antipsychotic medications are effective for the prevention of lethality from cocaine toxicity in animal models.

Stereotactic radiotherapy of meningiomas. Symptomatology, acute and late toxicity

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Henzel, M.; Gross, M.W.; Failing, T.; Strassmann, G.; Engenhart-Cabillic, R. [Dept. of Radiation Oncology, Univ. of Gisssen (Germany); Dept. of Radiation Oncology, Marburg Univ. (Germany); Hamm, K.; Surber, G.; Kleinert, G. [Dept. of Stereotactic Neurosurgery and Radiosurgery, Helios Klinikum Erfurt (Germany)

2006-07-15

Background and purpose: stereotactic radiosurgery (SRS) is well established in the treatment of skull base meningiomas, but this therapy approach is limited to small tumors only. The fractionated stereotactic radiotherapy (SRT) offers an alternative treatment option. This study aims at local control, symptomatology, and toxicity. Patients and methods: between 1997-2003, 224 patients were treated with SRT (n= 183), hypofractionated SRT (n = 30), and SRS (n = 11). 95/224 were treated with SRT/SRS alone. 129/224 patients underwent previous operations. Freedom from progression and overall survival, toxicity, and symptomatology were evaluated systematically. Additionally, tumor volume (TV) shrinkage was analyzed three-dimensionally within the planning system. Results: the median follow-up was 36 months (range, 12-100 months). Overall survival and freedom from progression for 5 years were 92.9% and 96.9%. Quantitative TV reduction was 26.2% and 30.3% 12 and 18 months after SRT/SRS (p < 0.0001). 95.9% of the patients improved their symptoms or were stable. Clinically significant acute toxicity (CTC III ) was rarely seen (2.5%). Clinically significant late morbidity (III -IV ) or new cranial nerve palsies did not occur. Conclusion: SRT offers an additional treatment option of high efficacy with only few side effects. In the case of large tumor size (> 4 ml) and adjacent critical structures (< 2 mm), SRT is highly recommended. (orig.)

Graphene Functionalized with Arginine Decreases the Development of Glioblastoma Multiforme Tumor in a Gene-Dependent Manner

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Ewa Sawosz

2015-10-01

Full Text Available Our previous studies revealed that graphene had anticancer properties in experiments in vitro with glioblastoma multiforme (GBM cells and in tumors cultured in vivo. We hypothesized that the addition of arginine or proline to graphene solutions might counteract graphene agglomeration and increase the activity of graphene. Experiments were performed in vitro with GBM U87 cells and in vivo with GBM tumors cultured on chicken embryo chorioallantoic membranes. The measurements included cell morphology, mortality, viability, tumor morphology, histology, and gene expression. The cells and tumors were treated with reduced graphene oxide (rGO and rGO functionalized with arginine (rGO + Arg or proline (rGO + Pro. The results confirmed the anticancer effect of graphene on GBM cells and tumor tissue. After functionalization with amino acids, nanoparticles were distributed more specifically, and the flakes of graphene were less agglomerated. The molecule of rGO + Arg did not increase the expression of TP53 in comparison to rGO, but did not increase the expression of MDM2 or the MDM2/TP53 ratio in the tumor, suggesting that arginine may block MDM2 expression. The expression of NQO1, known to be a strong protector of p53 protein in tumor tissue, was greatly increased. The results indicate that the complex of rGO + Arg has potential in GBM therapy.

Graphene Functionalized with Arginine Decreases the Development of Glioblastoma Multiforme Tumor in a Gene-Dependent Manner

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Sawosz, Ewa; Jaworski, Sławomir; Kutwin, Marta; Vadalasetty, Krishna Prasad; Grodzik, Marta; Wierzbicki, Mateusz; Kurantowicz, Natalia; Strojny, Barbara; Hotowy, Anna; Lipińska, Ludwika; Jagiełło, Joanna; Chwalibog, André

2015-01-01

Our previous studies revealed that graphene had anticancer properties in experiments in vitro with glioblastoma multiforme (GBM) cells and in tumors cultured in vivo. We hypothesized that the addition of arginine or proline to graphene solutions might counteract graphene agglomeration and increase the activity of graphene. Experiments were performed in vitro with GBM U87 cells and in vivo with GBM tumors cultured on chicken embryo chorioallantoic membranes. The measurements included cell morphology, mortality, viability, tumor morphology, histology, and gene expression. The cells and tumors were treated with reduced graphene oxide (rGO) and rGO functionalized with arginine (rGO + Arg) or proline (rGO + Pro). The results confirmed the anticancer effect of graphene on GBM cells and tumor tissue. After functionalization with amino acids, nanoparticles were distributed more specifically, and the flakes of graphene were less agglomerated. The molecule of rGO + Arg did not increase the expression of TP53 in comparison to rGO, but did not increase the expression of MDM2 or the MDM2/TP53 ratio in the tumor, suggesting that arginine may block MDM2 expression. The expression of NQO1, known to be a strong protector of p53 protein in tumor tissue, was greatly increased. The results indicate that the complex of rGO + Arg has potential in GBM therapy. PMID:26512645

Exploring the Q-marker of "sweat soaking method" processed radix Wikstroemia indica: Based on the "effect-toxicity-chemicals" study.

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Feng, Guo; Chen, Yun-Long; Li, Wei; Li, Lai-Lai; Wu, Zeng-Guang; Wu, Zi-Jun; Hai, Yue; Zhang, Si-Chao; Zheng, Chuan-Qi; Liu, Chang-Xiao; He, Xin

2018-06-01

Radix Wikstroemia indica (RWI), named "Liao Ge Wang" in Chinese, is a kind of toxic Chinese herbal medicine (CHM) commonly used in Miao nationality of South China. "Sweat soaking method" processed RWI could effectively decrease its toxicity and preserve therapeutic effect. However, the underlying mechanism of processing is still not clear, and the Q-markers database for processed RWI has not been established. Our study is to investigate and establish the quality evaluation system and potential Q-markers based on "effect-toxicity-chemicals" relationship of RWI for quality/safety assessment of "sweat soaking method" processing. The variation of RWI in efficacy and toxicity before and after processing was investigated by pharmacological and toxicological studies. Cytotoxicity test was used to screen the cytotoxicity of components in RWI. The material basis in ethanol extract of raw and processed RWI was studied by UPLC-Q-TOF/MS. And the potential Q-markers were analyzed and predicted according to "effect-toxicity-chemical" relationship. RWI was processed by "sweat soaking method", which could preserve efficacy and reduce toxicity. Raw RWI and processed RWI did not show significant difference on the antinociceptive and anti-inflammatory effect, however, the injury of liver and kidney by processed RWI was much weaker than that by raw RWI. The 20 compounds were identified from the ethanol extract of raw product and processed product of RWI using UPLC-Q-TOF/MS, including daphnoretin, emodin, triumbelletin, dibutyl phthalate, Methyl Paraben, YH-10 + OH and matairesinol, arctigenin, kaempferol and physcion. Furthermore, 3 diterpenoids (YH-10, YH-12 and YH-15) were proved to possess the high toxicity and decreased by 48%, 44% and 65%, respectively, which could be regarded as the potential Q-markers for quality/safety assessment of "sweat soaking method" processed RWI. A Q-marker database of processed RWI by "sweat soaking method" was established according to the results

Efficacy of Pistacia khinjuk Fruits on Viability of Hydatid Cyst Protoscoleces and Its Acute Toxicity in Mice Model

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Hossein MAHMOUDVAND

2016-10-01

Full Text Available Background: This investigation aimed to evaluate the in vitro scolicidal effects of Pistacia khinjuk methanolic extract against protoscoleces of hydatid cysts and its acute toxicity in mice NMRI model.Methods: Protoscoleces were aseptically extracted from sheep livers having hydatid cysts. Various concentrations of the essential oil (12.5- 100 mg/mL were used for 10 to 60 min. Viability of protoscoleces was confirmed using eosin exclusion test (0.1% eosin staining. Twenty-four male NMRI mice were used to assess the acute toxicity of P. khinjuk.Results: P. khinjuk extract at the concentrations of 100 mg/mL after 10 min of exposure killed 100% of protoscoleces. Similarly, the mean of mortality rate of protoscoleces after 20 min of exposure to the concentration of 50 mg/mL was 100%. The LD50 of the intraperitoneal injection of the P. khinjuk methanolic extract was 2.8 g/kg and the maximum non-fatal dose was 1.7 g/kg.Conclusion: The findings demonstrated effective scolicidal effects of P. khinjuk extract with no considerable toxicity that might be a natural source for the producing of new scolicidal agent.

Introducing Toxics

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David C. Bellinger

2013-04-01

Full Text Available With this inaugural issue, Toxics begins its life as a peer-reviewed, open access journal focusing on all aspects of toxic chemicals. We are interested in publishing papers that present a wide range of perspectives on toxicants and naturally occurring toxins, including exposure, biomarkers, kinetics, biological effects, fate and transport, treatment, and remediation. Toxics differs from many other journals in the absence of a page or word limit on contributions, permitting authors to present their work in as much detail as they wish. Toxics will publish original research papers, conventional reviews, meta-analyses, short communications, theoretical papers, case reports, commentaries and policy perspectives, and book reviews (Book reviews will be solicited and should not be submitted without invitation. Toxins and toxicants concern individuals from a wide range of disciplines, and Toxics is interested in receiving papers that represent the full range of approaches applied to their study, including in vitro studies, studies that use experimental animal or non-animal models, studies of humans or other biological populations, and mathematical modeling. We are excited to get underway and look forward to working with authors in the scientific and medical communities and providing them with a novel venue for sharing their work. [...

In Vitro and In Vivo Toxicity of Garcinia or Hydroxycitric Acid: A Review

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Li Oon Chuah

2012-01-01

Full Text Available Obesity is one of the pandemic chronic diseases commonly associated with health disorders such as heart attack, high blood pressure, diabetes or even cancer. Among the current natural products for obesity and weight control, Garcinia or more specifically hydroxycitric acid (HCA extracted from Garcinia has been widely used. The evaluation of the potential toxicity of weight control supplement is of the utmost importance as it requires long term continuous consumption in order to maintain its effects. Majority of reports demonstrated the efficacy of Garcinia/HCA without any toxicity found. However, a few clinical toxicity reports on weight-loss diet supplements of which some were combinations that included Garcinia/HCA as an active ingredient showed potential toxicity towards spermatogenesis. Nonetheless, it cannot be concluded that Garcinia/HCA is unsafe. Those products which have been reported to possess adverse effects are either polyherbal or multi-component in nature. To date, there is no case study or report showing the direct adverse effect of HCA. The structure, mechanism of action, long history of the use of Garcinia/HCA and comprehensive scientific evidence had shown “no observed adverse effect level (NOAEL” at levels up to 2800 mg/day, suggesting its safety for use.

CYP39A1 polymorphism is associated with toxicity during intensive induction chemotherapy in patients with advanced head and neck cancer

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Melchardt, Thomas; Hufnagl, Clemens; Magnes, Teresa; Weiss, Lukas; Hutarew, Georg; Neureiter, Daniel; Schlattau, Alexander; Moser, Gerhard; Gaggl, Alexander; Tränkenschuh, Wolfgang; Greil, Richard; Egle, Alexander

2015-01-01

Induction chemotherapy incorporating docetaxel, cisplatin and 5- fluorouracil before radiotherapy may improve the outcome of patients with advanced head and neck cancer. Nevertheless, the addition of docetaxel increases hematological toxicity and infectious complications. Therefore, genetic markers predicting toxicity and efficacy of this treatment regimen may help to identify patients, who would have the most benefit from this intensive treatment. A cohort of 78 patients with advanced head and neck cancer treated with induction chemotherapy was assessed for clinical outcome and toxicity during treatment with curative intention. Genetic polymorphisms primary associated with treatment efficacy (ERCC2-rs13181, rs1799793, ERCC1-rs3212986, rs11615, XRCC1-rs25487) or with docetaxel caused toxicity (CYP39A1-rs7761731, SLCO1B3-rs11045585) were evaluated in all patients. The results of these analyses were correlated with the clinical outcome of the patients (loco regional control, progression free survival, overall survival) and treatment related toxicity during induction chemotherapy. Median progression free survival and overall survival was 20 and 31 months in an intention to treat analysis, respectively. Overall response rate to induction chemotherapy was high with 78.1 % of all patients. None of the polymorphisms tested was associated with the clinical outcome of the patients. Genotype A of the CYP39A1 rs7761731 polymorphism was associated with a higher incidence of leucopenia and infections or death during induction chemotherapy. Intensive induction chemotherapy results in a high response rate in the majority of patients. None of the polymorphisms tested was associated with the clinical outcome of the patients. The CYP39A1 polymorphism rs7761731 may help to identify patients at high risk for treatment related toxicity

Flavanone silibinin treatment attenuates nitrogen mustard-induced toxic effects in mouse skin

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Jain, Anil K.; Tewari-Singh, Neera; Inturi, Swetha; Kumar, Dileep [Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045 (United States); Orlicky, David J. [Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045 (United States); Agarwal, Chapla [Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045 (United States); White, Carl W. [Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045USA (United States); Agarwal, Rajesh, E-mail: Rajesh.Agarwal@UCDenver.edu [Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045 (United States)

2015-05-15

Currently, there is no effective antidote to prevent skin injuries by sulfur mustard (SM) and nitrogen mustard (NM), which are vesicating agents with potential relevance to chemical warfare, terrorist attacks, or industrial/laboratory accidents. Our earlier report has demonstrated the therapeutic efficacy of silibinin, a natural flavanone, in reversing monofunctional alkylating SM analog 2-chloroethyl ethyl sulfide-induced toxic effects in mouse skin. To translate this effect to a bifunctional alkylating vesicant, herein, efficacy studies were carried out with NM. Topical application of silibinin (1 or 2 mg) 30 min after NM exposure on the dorsal skin of male SKH-1 hairless mice significantly decreased NM-induced toxic lesions at 24, 72 or 120 h post-exposure. Specifically, silibinin treatment resulted in dose-dependent reduction of NM-induced increase in epidermal thickness, dead and denuded epidermis, parakeratosis and microvesication. Higher silibinin dose also caused a 79% and 51%reversal in NM-induced increases in myeloperoxidase activity and COX-2 levels, respectively. Furthermore, silibinin completely prevented NM-induced H2A.X phosphorylation, indicating reversal of DNA damage which could be an oxidative DNA damage as evidenced by high levels of 8-oxodG in NM-exposed mouse skin that was significantly reversed by silibinin. Together, these findings suggest that attenuation of NM-induced skin injury by silibinin is due to its effects on the pathways associated with DNA damage, inflammation, vesication and oxidative stress. In conclusion, results presented here support the optimization of silibinin as an effective treatment of skin injury by vesicants. - Highlights: • Silibinin treatment attenuated nitrogen mustard (NM)-induced skin injury. • Silibinin affects pathways associated with DNA damage, inflammation and vesication. • The efficacy of silibinin could also be associated with oxidative stress. • These results support testing and optimization of

Discovering less toxic ionic liquids by using the Microtox® toxicity test.

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Hernández-Fernández, F J; Bayo, J; Pérez de los Ríos, A; Vicente, M A; Bernal, F J; Quesada-Medina, J

2015-06-01

New Microtox® toxicity data of 16 ionic liquids of different cationic and anionic composition were determined. The ionic liquids 1-butyl-1-methylpyrrolidinium trifluoromethanesulfonate, [BMPyr(+)][TFO(-)], 1-butyl-1-methylpyrrolidinium chloride, [BMPyr(+)][Cl(-)], hydroxypropylmethylimidazolium fluoroacetate, [HOPMIM(+)][FCH2COO(-)], and hydroxypropylmethylimidazolium glycolate [HOPMIM(+)][glycolate(-)] were found to be less toxic than conventional organic solvent such as chloroform or toluene, accoding the Microtox® toxicity assays. The toxicity of pyrrolidinium cation was lower than the imidazolium and pyridinium ones. It was found that the inclusion of an hydroxyl group in the alkyl chain length of the cation also reduce the toxicity of the ionic liquid. To sum up, the Microtox® toxicity assays can be used as screening tool to easily determined the toxicity of a wide range of ionic liquids and the toxicity data obtained could allow the obtention of structure-toxicity relationships to design less toxic ionic liquids. Copyright © 2015 Elsevier Inc. All rights reserved.

Irradiation with visible light enhances the antibacterial toxicity of silver nanoparticles produced by laser ablation

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Ratti, Matthew; Naddeo, J. J.; Tan, Yuying; Griepenburg, Julianne C.; Tomko, John; Trout, Cory; O'Malley, Sean M.; Bubb, Daniel M.; Klein, Eric A.

2016-04-01

The rise of antibiotic-resistant bacteria is a rapidly growing global health concern. According to the Center for Disease Control, approximately 2 million illnesses and 23,000 deaths per year occur in the USA due to antibiotic resistance. In recent years, there has been a surge in the use of metal nanoparticles as coatings for orthopedic implants, wound dressings, and food packaging, due to their antimicrobial properties. In this report, we demonstrate that the antibacterial efficacy of silver nanoparticles (AgNPs) is enhanced with exposure to light from the visible spectrum. We find that the increased toxicity is due to augmented silver ion release and bacterial uptake. Interestingly, silver ion toxicity does not appear to depend on the formation of reactive oxygen species. Our findings provide a novel paradigm for using light to regulate the toxicity of AgNPs which may have a significant impact in the development of new antimicrobial therapeutics.

Microfluidics for Antibiotic Susceptibility and Toxicity Testing

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Jing Dai

2016-10-01

Full Text Available The recent emergence of antimicrobial resistance has become a major concern for worldwide policy makers as very few new antibiotics have been developed in the last twenty-five years. To prevent the death of millions of people worldwide, there is an urgent need for a cheap, fast and accurate set of tools and techniques that can help to discover and develop new antimicrobial drugs. In the past decade, microfluidic platforms have emerged as potential systems for conducting pharmacological studies. Recent studies have demonstrated that microfluidic platforms can perform rapid antibiotic susceptibility tests to evaluate antimicrobial drugs’ efficacy. In addition, the development of cell-on-a-chip and organ-on-a-chip platforms have enabled the early drug testing, providing more accurate insights into conventional cell cultures on the drug pharmacokinetics and toxicity, at the early and cheaper stage of drug development, i.e., prior to animal and human testing. In this review, we focus on the recent developments of microfluidic platforms for rapid antibiotics susceptibility testing, investigating bacterial persistence and non-growing but metabolically active (NGMA bacteria, evaluating antibiotic effectiveness on biofilms and combinatorial effect of antibiotics, as well as microfluidic platforms that can be used for in vitro antibiotic toxicity testing.

Invariant delineation of nuclear architecture in glioblastoma multiforme for clinical and molecular association.

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Chang, Hang; Han, Ju; Borowsky, Alexander; Loss, Leandro; Gray, Joe W; Spellman, Paul T; Parvin, Bahram

2013-04-01

Automated analysis of whole mount tissue sections can provide insights into tumor subtypes and the underlying molecular basis of neoplasm. However, since tumor sections are collected from different laboratories, inherent technical and biological variations impede analysis for very large datasets such as The Cancer Genome Atlas (TCGA). Our objective is to characterize tumor histopathology, through the delineation of the nuclear regions, from hematoxylin and eosin (H&E) stained tissue sections. Such a representation can then be mined for intrinsic subtypes across a large dataset for prediction and molecular association. Furthermore, nuclear segmentation is formulated within a multi-reference graph framework with geodesic constraints, which enables computation of multidimensional representations, on a cell-by-cell basis, for functional enrichment and bioinformatics analysis. Here, we present a novel method, multi-reference graph cut (MRGC), for nuclear segmentation that overcomes technical variations associated with sample preparation by incorporating prior knowledge from manually annotated reference images and local image features. The proposed approach has been validated on manually annotated samples and then applied to a dataset of 377 Glioblastoma Multiforme (GBM) whole slide images from 146 patients. For the GBM cohort, multidimensional representation of the nuclear features and their organization have identified 1) statistically significant subtypes based on several morphometric indexes, 2) whether each subtype can be predictive or not, and 3) that the molecular correlates of predictive subtypes are consistent with the literature. Data and intermediaries for a number of tumor types (GBM, low grade glial, and kidney renal clear carcinoma) are available at: http://tcga.lbl.gov for correlation with TCGA molecular data. The website also provides an interface for panning and zooming of whole mount tissue sections with/without overlaid segmentation results for quality

Differential Expression of Circular RNAs in Glioblastoma Multiforme and Its Correlation with Prognosis

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Junle Zhu

2017-04-01

Full Text Available OBJECTIVE: The present study aimed to explore the expression profiles of circular RNAs (circRNAs in glioblastoma multiforme (GBM in an attempt to identify potential core genes in the pathogenesis of this tumor. METHODS: Differentially expressed circRNAs were screened between tumor tissues from five GBM patients and five normal brain samples using Illumina Hiseq. Bioinformatics analysis was used to analyze their potential function. CircBRAF was further detected in different WHO grades glioma tissues and normal brain tissues. Kaplan-Meier curves and multivariate Cox's analysis were used to analyze the association between circBRAF expression level and prognosis of glioma patients. RESULTS: A total of 1411 differentially expressed circRNAs were identified in GBM patients including 206 upregulated circRNAs and 1205 downregulated circRNAs. Differential expression of circRNAs was closely associated with the biological process and molecular function. The downregulated circRNAs were mainly associated with ErbB and Neurotrophin signaling pathways. Moreover, the expression level of circBRAF in normal brain tissues was significantly higher than that in glioma tissues (P < .001. CircBRAF was significantly lower in glioma patients with high pathological grade (WHO III & IV than those with low grade (WHO I & II (P < .001. Cox analysis revealed that high circBRAF expression was an independent biomarker for predicting good progression-free survival and overall survival in glioma patients (HR = 0.413, 95% CI 0.201-0.849; HR = 0.299, 95% CI 0.135-0.661; respectively. CONCLUSION: The present study identified a profile of dysregulated circRNAs in GBM. Bioinformatics analysis showed that dysregulated circRNAs might be associated with tumorigenesis and development of GBM. In addition, circBRAF could severe as a biomarker for predicting pathological grade and prognosis in glioma patients.

In vivo and in vitro toxicity of nanogold conjugated snake venom protein toxin GNP-NKCT1

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Partha Pratim Saha

2014-01-01

Full Text Available Research on nanoparticles has created interest among the biomedical scientists. Nanoparticle conjugation aims to target drug delivery, increase drug efficacy and imaging for better diagnosis. Toxicity profile of the nanoconjugated molecules has not been studied well. In this communication, the toxicity profile of snake venom cytotoxin (NKCT1, an antileukemic protein toxin, was evaluated after its conjugation with gold nanoparticle (GNP-NKCT1. Gold nanoparticle conjugation with NKCT1 was done with NaBH4 reduction method. The conjugated product GNP-NKCT1 was found less toxic than NKCT1 on isolated rat lymphocyte, mice peritoneal macrophage, in culture, which was evident from the MTT/Trypan blue assay. Peritoneal mast cell degranulation was in the order of NKCT1 > GNP-NKCT1. The in vitro cardiotoxicity and neurotoxicity were increased in case of NKCT1 than GNP-NKCT1. On isolated kidney tissue, NKCT1 released significant amount of ALP and γ-GT than GNP-NKCT1. Gold nanoconjugation with NKCT1 also reduced the lethal activity in mice. In vivo acute/sub-chronic toxicity studies in mice showed significant increase in molecular markers due to NKCT1 treatment, which was reduced by gold nanoconjugation. Histopathology study showed decreased toxic effect of NKCT1 in kidney tissue after GNP conjugation. The present study confirmed that GNP conjugation significantly decreased the toxicity profile of NKCT1. Further studies are in progress to establish the molecular mechanism of GNP induced toxicity reduction.

Toxicity of fluoride to aquatic species and evaluation of toxicity modifying factors.

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Pearcy, Krysta; Elphick, James; Burnett-Seidel, Charlene

2015-07-01

The present study was performed to investigate the toxicity of fluoride to a variety of freshwater aquatic organisms and to establish whether water quality variables contribute substantively to modifying its toxicity. Water hardness, chloride, and alkalinity were tested as possible toxicity modifying factors for fluoride using acute toxicity tests with Hyalella azteca and Oncorhynchus mykiss. Chloride appeared to be the major toxicity modifying factor for fluoride in these acute toxicity tests. The chronic toxicity of fluoride was evaluated with a variety of species, including 3 fish (Pimephales promelas, O. mykiss, and Salvelinus namaycush), 3 invertebrates (Ceriodaphnia dubia, H. azteca, and Chironomus dilutus), 1 plant (Lemna minor), and 1 alga (Pseudokirchneriella subcapitata). Hyalella azteca was the most sensitive species overall, and O. mykiss was the most sensitive species of fish. The role of chloride as a toxicity modifying factor was inconsistent between species in the chronic toxicity tests. © 2015 SETAC.

Too much of a good thing: a retrospective study of β-lactam concentration-toxicity relationships.

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Imani, Sahand; Buscher, Hergen; Marriott, Debbie; Gentili, Sheridan; Sandaradura, Indy

2017-10-01

To determine the existence of concentration-toxicity relationships for common β-lactam antibiotic adverse effects and define thresholds above which toxicity is more likely. Retrospective review of consecutive patients treated with piperacillin, meropenem or flucloxacillin who underwent therapeutic drug monitoring (TDM) at St Vincent's Hospital (Sydney, Australia) between January 2013 and December 2015. Adverse events investigated included neurotoxicity, nephrotoxicity, hepatotoxicity and opportunistic Clostridium difficile infection. Toxicity was measured using observational grading criteria, clinical assessment and relevant serum biomarkers. These findings were correlated with trough TDM measurements at the time of toxicity presentation. TDM results from 378 patients (piperacillin = 223, meropenem = 94 and flucloxacillin = 61) were investigated. There was no difference in baseline patient characteristics across antibiotic groups. A statistically significant elevation in mean serum trough concentrations (Cmin) was found in patients diagnosed with neurotoxicity (piperacillin, P 361.4 mg/L; meropenem, Cmin >64.2 mg/L; flucloxacillin, Cmin >125.1 mg/L) or nephrotoxicity (piperacillin, Cmin >452.65 mg/L; meropenem, Cmin >44.45 mg/L) varied across antibiotics. Our data reveal an association between toxic concentrations for a number of β-lactam agents and neurotoxic/nephrotoxic effects. We have defined threshold concentrations above which these toxicities become more likely. Clinicians should balance concerns for therapeutic efficacy with potential toxicity when considering aggressive therapy. © The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Pre-clinical analysis of changes in intra-cellular biochemistry of glioblastoma multiforme (GBM) cells due to c-Myc silencing.

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Rajagopalan, Vishal; Vaidyanathan, Muthukumar; Janardhanam, Vanisree Arambakkam; Bradner, James E

2014-10-01

Glioblastoma Multiforme (GBM) is an aggressive form of brain Tumor that has few cures. In this study, we analyze the anti-proliferative effects of a new molecule JQ1 against GBMs induced in Wistar Rats. JQ1 is essentially a Myc inhibitor. c-Myc is also known for altering the biochemistry of a tumor cell. Therefore, the study is intended to analyze certain other oncogenes associated with c-Myc and also the change in cellular biochemistry upon c-Myc inhibition. The quantitative analysis of gene expression gave a co-expressive pattern for all the three genes involved namely; c-Myc, Bcl-2, and Akt. The cellular biochemistry analysis by transmission electron microscopy revealed high glycogen and lipid aggregation in Myc inhibited cells and excessive autophagy. The study demonstrates the role of c-Myc as a central metabolic regulator and Bcl-2 and Akt assisting in extending c-Myc half-life as well as in regulation of autophagy, so as to regulate cell survival on the whole. The study also demonstrates that transient treatment by JQ1 leads to aggressive development of tumor and therefore, accelerating death, emphasizing the importance of dosage fixation, and duration for clinical use in future.

Methyl-hydroxylamine as an efficacious antibacterial agent that targets the ribonucleotide reductase enzyme.

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Esther Julián

Full Text Available The emergence of multidrug-resistant bacteria has encouraged vigorous efforts to develop antimicrobial agents with new mechanisms of action. Ribonucleotide reductase (RNR is a key enzyme in DNA replication that acts by converting ribonucleotides into the corresponding deoxyribonucleotides, which are the building blocks of DNA replication and repair. RNR has been extensively studied as an ideal target for DNA inhibition, and several drugs that are already available on the market are used for anticancer and antiviral activity. However, the high toxicity of these current drugs to eukaryotic cells does not permit their use as antibacterial agents. Here, we present a radical scavenger compound that inhibited bacterial RNR, and the compound's activity as an antibacterial agent together with its toxicity in eukaryotic cells were evaluated. First, the efficacy of N-methyl-hydroxylamine (M-HA in inhibiting the growth of different Gram-positive and Gram-negative bacteria was demonstrated, and no effect on eukaryotic cells was observed. M-HA showed remarkable efficacy against Mycobacterium bovis BCG and Pseudomonas aeruginosa. Thus, given the M-HA activity against these two bacteria, our results showed that M-HA has intracellular antimycobacterial activity against BCG-infected macrophages, and it is efficacious in partially disassembling and inhibiting the further formation of P. aeruginosa biofilms. Furthermore, M-HA and ciprofloxacin showed a synergistic effect that caused a massive reduction in a P. aeruginosa biofilm. Overall, our results suggest the vast potential of M-HA as an antibacterial agent, which acts by specifically targeting a bacterial RNR enzyme.

Methyl-hydroxylamine as an efficacious antibacterial agent that targets the ribonucleotide reductase enzyme.

Science.gov (United States)

Julián, Esther; Baelo, Aida; Gavaldà, Joan; Torrents, Eduard

2015-01-01

The emergence of multidrug-resistant bacteria has encouraged vigorous efforts to develop antimicrobial agents with new mechanisms of action. Ribonucleotide reductase (RNR) is a key enzyme in DNA replication that acts by converting ribonucleotides into the corresponding deoxyribonucleotides, which are the building blocks of DNA replication and repair. RNR has been extensively studied as an ideal target for DNA inhibition, and several drugs that are already available on the market are used for anticancer and antiviral activity. However, the high toxicity of these current drugs to eukaryotic cells does not permit their use as antibacterial agents. Here, we present a radical scavenger compound that inhibited bacterial RNR, and the compound's activity as an antibacterial agent together with its toxicity in eukaryotic cells were evaluated. First, the efficacy of N-methyl-hydroxylamine (M-HA) in inhibiting the growth of different Gram-positive and Gram-negative bacteria was demonstrated, and no effect on eukaryotic cells was observed. M-HA showed remarkable efficacy against Mycobacterium bovis BCG and Pseudomonas aeruginosa. Thus, given the M-HA activity against these two bacteria, our results showed that M-HA has intracellular antimycobacterial activity against BCG-infected macrophages, and it is efficacious in partially disassembling and inhibiting the further formation of P. aeruginosa biofilms. Furthermore, M-HA and ciprofloxacin showed a synergistic effect that caused a massive reduction in a P. aeruginosa biofilm. Overall, our results suggest the vast potential of M-HA as an antibacterial agent, which acts by specifically targeting a bacterial RNR enzyme.

Predictors of Chemotherapy-Induced Toxicity and Treatment Outcomes in Elderly Versus Younger Patients With Metastatic Castration-Resistant Prostate Cancer

DEFF Research Database (Denmark)

Kongsted, Per; Svane, Inge Marie; Lindberg, Henriette

2016-01-01

records from 421 consecutive patients treated with first-line docetaxel (75 mg/m(2) every 3 weeks) and low-dose prednisolone from 2007 to 2013 at Herlev University Hospital were reviewed. Common Terminology Criteria for Adverse Events, version 4.0, and the Prostate Cancer Working Group 2 guidelines were...... used to evaluate treatment-related toxicity and efficacy. Logistic and Cox regression models were used to predict toxicity and survival. RESULTS: Age ≥ 75 years (odds ratio [OR], 2.33), baseline levels of hemoglobin (OR, 0.89), and previous metastatic epidural spinal cord compression (MESCC; OR, 1...

Quality of radiomic features in glioblastoma multiforme: Impact of semi-automated tumor segmentation software

International Nuclear Information System (INIS)

Lee, Myung Eun; Kim, Jong Hyo; Woo, Bo Yeong; Ko, Micheal D.; Jamshidi, Neema

2017-01-01

The purpose of this study was to evaluate the reliability and quality of radiomic features in glioblastoma multiforme (GBM) derived from tumor volumes obtained with semi-automated tumor segmentation software. MR images of 45 GBM patients (29 males, 16 females) were downloaded from The Cancer Imaging Archive, in which post-contrast T1-weighted imaging and fluid-attenuated inversion recovery MR sequences were used. Two raters independently segmented the tumors using two semi-automated segmentation tools (TumorPrism3D and 3D Slicer). Regions of interest corresponding to contrast-enhancing lesion, necrotic portions, and non-enhancing T2 high signal intensity component were segmented for each tumor. A total of 180 imaging features were extracted, and their quality was evaluated in terms of stability, normalized dynamic range (NDR), and redundancy, using intra-class correlation coefficients, cluster consensus, and Rand Statistic. Our study results showed that most of the radiomic features in GBM were highly stable. Over 90% of 180 features showed good stability (intra-class correlation coefficient [ICC] ≥ 0.8), whereas only 7 features were of poor stability (ICC NDR ≥1), while above 35% of the texture features showed poor NDR (< 1). Features were shown to cluster into only 5 groups, indicating that they were highly redundant. The use of semi-automated software tools provided sufficiently reliable tumor segmentation and feature stability; thus helping to overcome the inherent inter-rater and intra-rater variability of user intervention. However, certain aspects of feature quality, including NDR and redundancy, need to be assessed for determination of representative signature features before further development of radiomics

Toxicity alarm: Case history

International Nuclear Information System (INIS)

Hogan, D.; Retallack, J.

1993-01-01

In late fall 1991, the Novacor petrochemical plant near Joffre, Alberta experienced a toxicity alarm, the first since its startup 14 years ago. Fish exposed to a normal toxicity test were stressed within 2 h and showed 100% mortality after 24 h. A history of the events leading up to, during, and after the toxicity alarm is presented. The major effluent sources were three cooling water systems. Although these sources are well characterized, the event causes were not immediately clear. Initial toxic screening indicated that one was very toxic, another moderately toxic, and the third not toxic at all. All three systems utilized the same chemical treatment program to avoid fouling: stabilized phosphates with minor variants. The most toxic of the cooling systems operated at 10-12 cycles, had three chemicals for biocide control, and had three makeup streams. Toxic and nontoxic system characteristics were compared. An in-depth modified toxicity identification and evaluation program was then performed to identify and evaluate the cause of the toxicity alarm for future prevention. The most probable causes of toxicity were identified by elimination. The combination of high numbers of cycles, hydrocarbons in the makeup water, and bromine added as an antifoulant resulted in formation of aromatic bromamines which are capable of causing the toxic condition experienced. 2 tabs

Irinotecan and bevacizumab in recurrent glioblastoma multiforme

DEFF Research Database (Denmark)

Jakobsen, Jan Nyrop; Hasselbalch, Benedikte; Stockhausen, Marie-Thérése

2011-01-01

treatment with BVZ and irinotecan provides impressive response rates (RR), it is still uncertain if this treatment translates into improved clinical benefit in GBM patients. AREAS COVERED: This review discusses the clinical efficacy, safety and difficulties regarding response evaluation when treating...... with BVZ and CPT-11 in recurrent GBM. Particular attention is placed on the literature and a discussion on whether treatment with BVZ and CPT-11 improves clinical outcome. Antiangiogenic treatment has led to difficulties when evaluating objective response by the conventional MacDonald criteria....... In the present paper the authors discuss selected key aspects of this treatment modality. A literature search was performed using PubMed in February 2011. EXPERT OPINION: BVZ + irinotecan leads to high RR and to an increased 6-month progression-free survival. However, no improvement in median overall survival...

Antimony Toxicity

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Shyam Sundar

2010-12-01

Full Text Available Antimony toxicity occurs either due to occupational exposure or during therapy. Occupational exposure may cause respiratory irritation, pneumoconiosis, antimony spots on the skin and gastrointestinal symptoms. In addition antimony trioxide is possibly carcinogenic to humans. Improvements in working conditions have remarkably decreased the incidence of antimony toxicity in the workplace. As a therapeutic, antimony has been mostly used for the treatment of leishmaniasis and schistosomiasis. The major toxic side-effects of antimonials as a result of therapy are cardiotoxicity (~9% of patients and pancreatitis, which is seen commonly in HIV and visceral leishmaniasis co-infections. Quality control of each batch of drugs produced and regular monitoring for toxicity is required when antimonials are used therapeutically.

Vegetated Treatment Systems for Removing Contaminants Associated with Surface Water Toxicity in Agriculture and Urban Runoff.

Science.gov (United States)

Anderson, Brian S; Phillips, Bryn M; Voorhees, Jennifer P; Cahn, Michael

2017-05-15

Urban stormwater and agriculture irrigation runoff contain a complex mixture of contaminants that are often toxic to adjacent receiving waters. Runoff may be treated with simple systems designed to promote sorption of contaminants to vegetation and soils and promote infiltration. Two example systems are described: a bioswale treatment system for urban stormwater treatment, and a vegetated drainage ditch for treating agriculture irrigation runoff. Both have similar attributes that reduce contaminant loading in runoff: vegetation that results in sorption of the contaminants to the soil and plant surfaces, and water infiltration. These systems may also include the integration of granulated activated carbon as a polishing step to remove residual contaminants. Implementation of these systems in agriculture and urban watersheds requires system monitoring to verify treatment efficacy. This includes chemical monitoring for specific contaminants responsible for toxicity. The current paper emphasizes monitoring of current use pesticides since these are responsible for surface water toxicity to aquatic invertebrates.

Differential toxicity and influence of salinity on acute toxicity of ...

African Journals Online (AJOL)

Differential toxicity and influence of salinity on acute toxicity of copper sulphate and lead nitrate against Oreochromis niloticus. KA Bawa-Allah, F Osuala, J Effiong. Abstract. This study investigated the salinity-tolerance of Oreochromis niloticus and the influence of salinity changes on the acute toxicities of copper sulphate ...

DNM3, p65 and p53 from exosomes represent potential clinical diagnosis markers for glioblastoma multiforme

Science.gov (United States)

Yang, Jian-kai; Song, Jian; Huo, Hao-ran; Zhao, Yin-long; Zhang, Guang-yu; Zhao, Zong-mao; Sun, Guo-zhu; Jiao, Bao-hua

2017-01-01

Background: Glioblastoma multiforme (GBM) is the most aggressive and deadly primary brain cancer that arises from astrocytes and classified as grade IV. Recently, exosomes have been reported as an essential mediator in diverse cancer carcinogenesis and metastasis. However, their role in GBM is still unclear. In this study, we aimed to investigate whether blood exosomes can be potential clinical diagnostic markers for GBM. Methods: We used a xenograft orthotopic mouse model to detect the differentially expressed genes in the brain and blood exosomes of original/recurrent GBM. Results: We found that recurrent GBM had stronger growth capacity and lethality than original GBM in the mouse model. A gene microarray of original tumors and blood exosomes from GBM orthotopic xenografts results showed that DNM3, p65 and CD117 expressions increased, whereas PTEN and p53 expressions decreased in both original tumors and blood exosomes. In the recurrent GBM tumor model, DNM3 and p65 showed increased expressions, whereas ST14 and p53 showed decreased expressions in tumor and blood exosomes of the recurrent GBM mouse model. Conclusion: In summary, we found that DNM3, p65 and p53 had a similar trend in brain and blood exosomes both for original and recurrent GBM, and could serve as potential clinical diagnostic markers for GBM. PMID:29449895

Classification of baseline toxicants for QSAR predictions to replace fish acute toxicity studies.

Science.gov (United States)

Nendza, Monika; Müller, Martin; Wenzel, Andrea

2017-03-22

Fish acute toxicity studies are required for environmental hazard and risk assessment of chemicals by national and international legislations such as REACH, the regulations of plant protection products and biocidal products, or the GHS (globally harmonised system) for classification and labelling of chemicals. Alternative methods like QSARs (quantitative structure-activity relationships) can replace many ecotoxicity tests. However, complete substitution of in vivo animal tests by in silico methods may not be realistic. For the so-called baseline toxicants, it is possible to predict the fish acute toxicity with sufficient accuracy from log K ow and, hence, valid QSARs can replace in vivo testing. In contrast, excess toxicants and chemicals not reliably classified as baseline toxicants require further in silico, in vitro or in vivo assessments. Thus, the critical task is to discriminate between baseline and excess toxicants. For fish acute toxicity, we derived a scheme based on structural alerts and physicochemical property thresholds to classify chemicals as either baseline toxicants (=predictable by QSARs) or as potential excess toxicants (=not predictable by baseline QSARs). The step-wise approach identifies baseline toxicants (true negatives) in a precautionary way to avoid false negative predictions. Therefore, a certain fraction of false positives can be tolerated, i.e. baseline toxicants without specific effects that may be tested instead of predicted. Application of the classification scheme to a new heterogeneous dataset for diverse fish species results in 40% baseline toxicants, 24% excess toxicants and 36% compounds not classified. Thus, we can conclude that replacing about half of the fish acute toxicity tests by QSAR predictions is realistic to be achieved in the short-term. The long-term goals are classification criteria also for further groups of toxicants and to replace as many in vivo fish acute toxicity tests as possible with valid QSAR

Efficacy and toxicological studies of cremophor EL free alternative paclitaxel formulation.

Science.gov (United States)

Utreja, Puneet; Jain, Subheet; Yadav, Subodh; Khandhuja, K L; Tiwary, A K

2011-11-01

In the present study, Cremophor EL free paclitaxel elastic liposomal formulation consisting of soya phosphatidylcholine and biosurfactant sodium deoxycholate was developed and optimized. The toxicological profile, antitumor efficacy and hemolytic toxicity of paclitaxel elastic liposomal formulation in comparison to Cremophor EL based marketed formulation were evaluated. Paclitaxel elastic liposomal formulations were prepared and characterized in vitro, ex-vivo and in vivo. Single dose toxicity study of paclitaxel elastic liposomal and marketed formulation was carried out in dose range of 10, 20, 40, 80, 120, 160 and 200 mg/kg. Cytotoxicity of developed formulation was evaluated using small cell lung cancer cell line (A549). Antitumor activity of developed formulation was compared with the marketed formulation using Cytoselect™ 96-well cell transformation assay. In vivo administration of paclitaxel elastic liposomal formulation into mice showed 6 fold increase in Maximum Tolerated Dose (MTD) in comparison to the marketed formulation. Similarly, LD50 (141.6 mg/kg) was also found to increase significantly than the marketed formulation (16.7 mg/kg). Result of antitumor assay revealed a high reduction of tumor density with paclitaxel elastic liposomal formulation. Reduction in hemolytic toxicity was also observed with paclitaxel elastic liposomal formulation in comparison to the marketed formulation. The carrier based approach for paclitaxel delivery demonstrated significant reduction in toxicity as compared to the Cremophor EL based marketed formulation following intra-peritoneal administration in mice model. The reduced toxicity and enhanced anti-cancer activity of elastic liposomal formulation strongly indicate its potential for safe and effective delivery of paclitaxel.

Efficacy of Brazilian Propolis against Herpes Simplex Virus Type 1 Infection in Mice and Their Modes of Antiherpetic Efficacies

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Tomomi Shimizu

2011-01-01

Full Text Available Ethanol extracts (AF-06, 07, and 08, 10 mg/kg of Brazilian propolis were administered orally to cutaneously herpes simplex virus type 1 (HSV-1-infected mice three times daily on days 0 to 6 after infection to evaluate their efficacies against HSV-1 infection and significantly limited development of herpetic skin lesions. AF-07 and 08 significantly reduced virus titers in brain and/or skin on day 4 without toxicity, but AF-08 had no anti-HSV-1 activity in vitro. AF-06 and 08 significantly enhanced delayed-type hypersensitivity (DTH to inactivated HSV-1 antigen in infected mice. Oral AF-08-administration significantly augmented interferon (IFN-γ production by HSV-1 antigen from splenocytes of HSV-1-infected mice, while direct exposure of splenocytes of infected mice to AF-06 significantly elevated IFN-γ production in vitro. Thus, AF-08 might have components that are active in vivo even after oral administration and those of AF-06 might be active only in vitro. Because DTH is a major host defense for intradermal HSV-1 infection, augmentation of DTH response by AF-06 or 08, directly or indirectly, respectively, may contribute to their efficacies against HSV-1 infection. In addition, AF-06 and 07 possibly contain anti-HSV-1 components contributing to their efficacies. Such biological activities of Brazilian propolis may be useful to analyze its pharmacological actions.

Efficacy of fungal decolorization of a mixture of dyes belonging to different classes

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Wioletta Przystas

2015-06-01

Full Text Available Dyes are the most difficult constituents to remove by conventional biological wastewater treatment. Colored wastewater is mainly eliminated by physical and chemical procedures, which are very expensive and have drawbacks. Therefore, the advantage of using biological processes, such as the biotransformation of dyes, is that they may lead to complete mineralization or formation of less toxic products. To prove the possibility of using fungal processes for decolorization and other applications, the analysis of the toxicity of the processes' products is required. The decolorization of the mixture of two dyes from different classes - triphenylmethane brilliant green and azo Evans blue (GB - total concentration 0.08 g/L, proportion 1:1 w/w - by Pleurotus ostreatus (BWPH and MB, Gloeophyllum odoratum (DCa, RWP17 (Polyporus picipes and Fusarium oxysporum (G1 was studied. Zootoxicity (Daphnia magna and phytotoxicity (Lemna minor changes were estimated at the end of the experiment. The mixture of dyes was significantly removed by all the strains that were tested with 96 h of experimental time. However, differences among strains from the same species (P. ostreatus were noted. Shaking improved the efficacy and rate of the dye removal. In static samples, the removal of the mixture reached more than 51.9% and in shaken samples, more than 79.2%. Tests using the dead biomass of the fungi only adsorbed up to 37% of the dye mixture (strain BWPH, which suggests that the process with the living biomass involves the biotransformation of the dyes. The best results were reached for the MB strain, which removed 90% of the tested mixture under shaking conditions. Regardless of the efficacy of the dye removal, toxicity decreased from class V to class III in tests with D. magna. Tests with L. minor control samples were classified as class IV, and samples with certain strains were non-toxic. The highest phytotoxicity decrease was noted in shaken samples where the

Correlation of FCGR3A and EGFR germline polymorphisms with the efficacy of cetuximab in KRAS wild-type metastatic colorectal cancer

NARCIS (Netherlands)

Pander, Jan; Gelderblom, Hans; Antonini, Ninja F.; Tol, Jolien; van Krieken, Johan H. J. M.; van der Straaten, Tahar; Punt, Cornelis J. A.; Guchelaar, Henk-Jan

2010-01-01

Next to KRAS mutation status, additional predictive markers are needed for the response to cetuximab in patients with metastatic colorectal cancer (mCRC). Previous studies indicated that germline polymorphisms in specific genes may predict efficacy and toxicity of cetuximab in mCRC patients.

Toxicity assays applied for evaluation of ionizing radiation and zeolites adsorption as treatment technologies for coloured effluent

International Nuclear Information System (INIS)

Higa, Marcela Cantelli

2008-01-01

Textile industry is one raising commercial activity in Brazil. This activity has been generating important environmental interferences such as colour and bad biological effects into aquatic environment. Liquid textile effluents are toxic to lived organisms and may present low biological degradability. Although foreseen at federal regulation, the effluent quality is not controlled by toxicity assays in the country. These assays are carried out to determine the potential effects of chemical substances and effluents to cause negative effects to the exposed organisms. The present work aimed whole toxicity evaluation as well as the applicability of two different treatment techniques: ionizing radiation and zeolite adsorption. The efficacy of them were evaluated using eco toxicity bases and real effluents. Two different industries from Sao Paulo State contributed to this project supplying their real effluents. The samples were collected at a Textile Industry and at a Chemical Industry (dying producer) and after the measurement of whole toxicity the samples were submitted to treatments. Toxicity assays were carried out for Daphnia similis and for Vibrio fischeri. Sample irradiations were performed at an Electron Beam Accelerator at CTR/IPEN. Zeolites treatment is an P and D activity from CQMA/IPEN which contributed to this Project. Zeolites v/ere prepared from fly ash previously being used as an adsorber material. Both treatments (electron irradiation and zeolite adsorption) resulted on important toxicity and colour reduction. Concerning irradiation the effluents from chemical industry required higher radiation doses than that from textile activity. The radiation dose to be suggested is 40 kGy (toxicity reduction > 60%) for the chemical effluents and 0.5 kGy for the textile effluents (toxicity reduction > 90%). When zeolite adsorption was evaluated the Z1M6 resulted in 85%o v/hole toxicity reduction and ZC6 resulted in very low efficiency for the effluents of chemical

Image Guided Hypofractionated Radiotherapy by Helical Tomotherapy for Prostate Carcinoma: Toxicity and Impact on Nadir PSA

Directory of Open Access Journals (Sweden)

Salvina Barra

2014-01-01

Full Text Available Aim. To evaluate the toxicity of a hypofractionated schedule for primary radiotherapy (RT of prostate cancer as well as the value of the nadir PSA (nPSA and time to nadir PSA (tnPSA as surrogate efficacy of treatment. Material and Methods. Eighty patients underwent hypofractionated schedule by Helical Tomotherapy (HT. A dose of 70.2 Gy was administered in 27 daily fractions of 2.6 Gy. Acute and late toxicities were graded on the RTOG/EORTC scales. The nPSA and the tnPSA for patients treated with exclusive RT were compared to an equal cohort of 20 patients treated with conventional fractionation and standard conformal radiotherapy. Results. Most of patients (83% did not develop acute gastrointestinal (GI toxicity and 50% did not present genitourinary (GU toxicity. After a median follow-up of 36 months only grade 1 of GU and GI was reported in 6 and 3 patients as late toxicity. Average tnPSA was 30 months. The median value of nPSA after exclusive RT with HT was 0.28 ng/mL and was significantly lower than the median nPSA (0.67 ng/mL of the conventionally treated cohort (P=0.02. Conclusions. Hypofractionated RT schedule with HT for prostate cancer treatment reports very low toxicity and reaches a low level of nPSA that might correlate with good outcomes.

Efficacy Study of Novel Diamidine Compounds in a Trypanosoma evansi Goat Model

Science.gov (United States)

Gillingwater, Kirsten; Gutierrez, Carlos; Bridges, Arlene; Wu, Huali; Deborggraeve, Stijn; Ali Ekangu, Rosine; Kumar, Arvind; Ismail, Mohamed; Boykin, David; Brun, Reto

2011-01-01

Three diamidines (DB 75, DB 867 and DB 1192) were selected and their ability to cure T. evansi experimentally infected goats was investigated. A toxicity assessment and pharmacokinetic analysis of these compounds were additionally carried out. Goats demonstrated no signs of acute toxicity, when treated with four doses of 1 mg/kg/day (total dose 4 mg/kg). Complete curative efficacy of experimentally infected goats was seen in the positive control group treated with diminazene at 5 mg/kg and in the DB 75 and DB 867 groups treated at 2.5 mg/kg. Drug treatment was administered once every second day for a total of seven days. Complete cure was also seen in the group of goats treated with DB 75 at 1.25 mg/kg. DB 1192 was incapable of curing goats at either four-times 2.5 mg/kg or 1.25 mg/kg. Pharmacokinetic analysis clearly demonstrated that the treatment failures of DB 1192 were due to sub-therapeutic compound levels in goat plasma, whilst compound levels for DB 75 and DB 867 remained well within the therapeutic window. In conclusion, two diamidine compounds (DB 75 and DB 867) presented comparable efficacy at lower doses than the standard drug diminazene and could be considered as potential clinical candidates against T. evansi infection. PMID:21698106

Antihepatotoxic efficacy of Mangifera indica L. polysaccharides against cyclophosphamide in rats.

Science.gov (United States)

Fahmy, Sohair R; Amien, Ahmed I; Abd-Elgleel, Fathi M; Elaskalany, Sara M

2016-01-25

The present study aims to evaluate the possible protective role of polysaccharides extracted from the Egyptian mango Mangifera indica L. (MPS) and/or silymarine against cyclophosphamide (CP) toxicity in male albino rats. The MPS and/or silymarin significantly decreased the activities of serum ASAT and ALAT. However, MPS (1000 mg/kg) normalized their activities towards the normal levels recording 28.75 and 78.75 U/ml respectively. The recorded data also showed the antioxidant effect of MPS by decreasing the level of malondialdehyde (MDA) and increasing the level of reduced glutathione (GSH) as well as normalized the activities of the antioxidant enzyme GST and SOD. Histopathological examinations also confirmed the protective efficacy of MPS against liver toxicity of CP. In conclusion, the recorded results of the present study support the protective role of MPS and/or silymarin against CP-induced hepatic damage. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Andrographolide suppresses the migratory ability of human glioblastoma multiforme cells by targeting ERK1/2-mediated matrix metalloproteinase-2 expression.

Science.gov (United States)

Yang, Shih-Liang; Kuo, Fu-Hsuan; Chen, Pei-Ni; Hsieh, Yi-Hsien; Yu, Nuo-Yi; Yang, Wei-En; Hsieh, Ming-Ju; Yang, Shun-Fa

2017-12-01

Glioblastoma multiforme (GBM) can be a fatal tumor because of difficulties in treating the related metastasis. Andrographolide is the bioactive component of the Andrographis paniculata . Andrographolide possesses the anti-inflammatory activity and inhibits the growth of various cancers; however, its effect on GBM cancer motility remains largely unknown. In this study, we examined the antimetastatic properties of andrographolide in human GBM cells. Our results revealed that andrographolide inhibited the invasion and migration abilities of GBM8401 and U251 cells. Furthermore, andrographolide inhibited matrix metalloproteinase (MMP)-2 activity and expression. Real-time PCR and promoter activity assays indicated that andrographolide inhibited MMP-2 expression at the transcriptional level. Such inhibitory effects were associated with the suppression of CREB DNA-binding activity and CREB expression. Mechanistically, andrographolide inhibited the cell motility of GBM8401 cells through the extracellular-regulated kinase (ERK) 1/2 pathway, and the blocking of the ERK 1/2 pathway could reverse MMP-2-mediated cell motility. In conclusion, CREB is a crucial target of andrographolide for suppressing MMP-2-mediated cell motility in GBM cells. Therefore, a combination of andrographolide and an ERK inhibitor might be a good strategy for preventing GBM metastasis.

Cocaine Hydrolase Gene Transfer Demonstrates Cardiac Safety and Efficacy against Cocaine-Induced QT Prolongation in Mice

OpenAIRE

Murthy, Vishakantha; Reyes, Santiago; Geng, Liyi; Gao, Yang; Brimijoin, Stephen

2016-01-01

Cocaine addiction is associated with devastating medical consequences, including cardiotoxicity and risk-conferring prolongation of the QT interval. Viral gene transfer of cocaine hydrolase engineered from butyrylcholinesterase offers therapeutic promise for treatment-seeking drug users. Although previous preclinical studies have demonstrated benefits of this strategy without signs of toxicity, the specific cardiac safety and efficacy of engineered butyrylcholinesterase viral delivery remains...

Dose-escalated intensity-modulated radiotherapy and irradiation of subventricular zones in relation to tumor control outcomes of patients with glioblastoma multiforme

Directory of Open Access Journals (Sweden)

Kusumawidjaja G

2016-03-01

Full Text Available Grace Kusumawidjaja,1 Patricia Zhun Hong Gan,1 Whee Sze Ong,2 Achiraya Teyateeti,3 Pittaya Dankulchai,3 Daniel Yat Harn Tan,1 Eu Tiong Chua,1 Kevin Lee Min Chua,1 Chee Kian Tham,4 Fuh Yong Wong,1 Melvin Lee Kiang Chua1,5 1Division of Radiation Oncology, National Cancer Centre, Singapore; 2Division of Clinical Trials and Epidemiological Sciences, National Cancer Centre, Singapore; 3Department of Radiology, Division of Radiation Oncology, Faculty of Medicine Siriraj Hospital, Mahidol University, Thailand; 4Division of Medical Oncology, National Cancer Centre, Singapore; 5Duke-NUS Graduate Medical School, Singapore Background: Glioblastoma multiforme (GBM is the most aggressive primary brain tumor with high relapse rate. In this study, we aimed to determine if dose-escalated (DE radiotherapy improved tumor control and survival in GBM patients. Methods: We conducted a retrospective analysis of 49 and 23 newly-diagnosed histology-proven GBM patients, treated with DE radiotherapy delivered in 70 Gy (2.33 Gy per fraction and conventional doses (60 Gy, respectively, between 2007 and 2013. Clinical target volumes for 70 and 60 Gy were defined by 0.5 and 2.0 cm expansion of magnetic resonance imaging T1-gadolinium-enhanced tumor/surgical cavity, respectively. Bilateral subventricular zones (SVZ were contoured on a co-registered pre-treatment magnetic resonance imaging and planning computed tomography dataset as a 5 mm wide structure along the lateral margins of the lateral ventricles. Survival outcomes of both cohorts were compared using log-rank test. Radiation dose to SVZ in the DE cohort was evaluated. Results: Median follow-up was 13.6 and 15.1 months for the DE- and conventionally-treated cohorts, respectively. Median overall survival (OS of patients who received DE radiotherapy was 15.2 months (95% confidence interval [CI] =11.0–18.6, while median OS of the latter cohort was 18.4 months (95% CI =12.5–31.4, P=0.253. Univariate analyses of

Toxicity and residual efficacy of chlorantraniliprole, spinetoram, and emamectin benzoate to obliquebanded leafroller (Lepidoptera: Tortricidae).

Science.gov (United States)

Sial, Ashfaq A; Brunner, Jay F

2010-08-01

Studies were conducted to determine the residual toxicity of spinetoram, chlorantraniliprole, and emamectin benzoate to obliquebanded leafroller, Choristoneura rosaceana (Harris) (Lepidoptera: Tortricidae). Larvae were exposed to apple (Malus spp.) foliage collected at different intervals after an airblast sprayer application at the manufacturer-recommended field rate and half the field rate. A mortality of 100% was recorded at field rate applications of spinetoram, chlorantraniliprole, and emamectin benzoate through 59, 38, and 10 d after treatment (DAT), respectively. Significantly less foliage was consumed by C. rosaceana larvae surviving in the emamectin, chlorantraniliprole, and spinetoram treatments compared with those exposed to untreated foliage. Third-instar C. rosaceana exposed to fresh residues on terminal foliage showed 100% mortality after 5-d exposure to spinetoram residues and after 10-d exposure to chlorantraniliprole and emamectin benzoate. The effects of larval movement from foliage with fresh residues was examined by transferring neonate larvae from foliage treated with spinetoram, chlorantraniliprole, or emamectin benzoate to untreated foliage after various exposure intervals. An exposure of 1, 3, and 6 d was required for spinetoram, chlorantraniliprole, and emamectin benzoate to cause 100% mortality at the field rate, respectively. The higher the concentration of chlorantraniliprole and emamectin benzoate, the less exposure time was necessary to cause high levels of mortality in C. rosaceana neonates. Our results indicate that these novel insecticides are highly toxic to C. rosaceana larvae. Implications of these results for C. rosaceana management programs are discussed.

Evaluation of the anthelmintic activity and toxicity of an aqueous extract of Chenopodium ambrosioides in goats

Directory of Open Access Journals (Sweden)

Gisele Dias da Silva

2016-10-01

Full Text Available ABSTRACT. da Silva G.D., Botura M.B., de Lima H.G., de Oliveira J.V.A., Moreira E.L.T., Santos F.O., de Souza T.S., de Almeida M.A.O. & Batatinha M.J.M. Evaluation of the anthelmintic activity and toxicity of an aqueous extract of Chenopodium ambrosioides in goats. [Avaliação da atividade anti-helmíntica e toxicidade do extrato aquoso de Chenopodium ambrosioides em caprinos.] Revista Brasileira de Medicina Veterinária, 38(Supl.1:156-162, 2016. Programa de Pós-Graduação em Ci- ência Animal nos Trópicos, Universidade Federal da Bahia, Av. Ademar de Barros, 500, Ondina, Salvador, BA 40170-110, Brasil. E-mail: mjmb@ufba.br The objective of this study was to evaluate the anthelmintic activity of an aqueous extract (AE from Chenopodium ambrosioides on goat gastrointestinal nematodes (GINs and its toxic effects. The anthelmintic activity in vitro was investigated using the inhibition of egg hatching assay (EHA, while cytotoxicity on Vero cells was evaluated using the MTT test. In vivo, thirty goats that were naturally infected with GINs were divided into three groups: group I, treated with a daily dose of AE C. ambrosioides (700mg/kg for eight days; group II (positive control, treated with a single dose of levamisole phosphate (6.3mg/kg; and Group III, untreated (negative control. Treatment efficacy was assessed on the basis of egg counts (FEC, faecal cultures and post-mortem worm burden counts. Clinical and laboratory evaluations were performed to detect toxic effects associated with treatment. In the EHA, the EC50 and EC90 corresponded to 1.6 and 1.9mg/mL, respectively. The AE promoted a slight reduction in cell viability in the cytotoxicity test. The AE reduced (p <0.05 the number of infective larvae of the genera Haemonchus and Oesophagostomum. The anthelmintic treatment of goats with AE C.ambrosioides resulted in moderate efficacy against infective larvae, but revealed neither ovicidal nor toxic activity towards adult nematodes. No toxic

SU-F-T-392: Superior Brainstem and Cochlea Sparing with VMAT for Glioblastoma Multiforme

Energy Technology Data Exchange (ETDEWEB)

Briere, TM; McAleer, MF; Levy, LB; Yang, JN; Anderson, MD [Cancer Ctr., Houston, TX (United States)

2016-06-15

Purpose: Volumetric arc therapy (VMAT) can provide similar target coverage and normal tissue sparing as IMRT but with shorter treatment times. At our institution VMAT was adopted for the treatment glioblastoma multiforme (GBM) after a small number of test plans demonstrated its non-inferiority. In this study, we compare actual clinical treatment plans for a larger cohort of patients treated with either VMAT or IMRT. Methods: 90 GBM patients were included in this study, 45 treated with IMRT and 45 with VMAT. All planning target volumes (PTVs) were prescribed a dose of 50 Gy, with a simultaneous integrated boost to 60 Gy. Most IMRT plans used 5 non-coplanar beams, while most VMAT plans used 2 coplanar beams. Statistical analysis was performed using Fisher’s exact test or the Wilcoxon-Mann-Whitney rank sum test. Included in the analysis were patient and treatment characteristics as well as the doses to the target volumes and organs at risk. Results: Treatment times for the VMAT plans were reduced by 5 minutes compared with IMRT. The PTV coverage was similar, with at least 95% covered for all plans, while the median boost PTV dose differed by 0.1 Gy between the IMRT and VMAT cohorts. The doses to the brain, optic chiasm, optic nerves and eyes were not significantly different. The mean dose to the brainstem, however, was 9.4 Gy less with VMAT (p<0.001). The dose to the ipsilateral and contralateral cochleae were respectively 19.7 and 9.5 Gy less (p<0.001). Conclusion: Comparison of clinical treatment plans for separate IMRT and VMAT cohorts demonstrates that VMAT can save substantial treatment time while providing similar target coverage and superior sparing of the brainstem and cochleae. To our knowledge this is the first study to demonstrate this benefit of VMAT in the management of GBM.

Involvement of miRNAs in the differentiation of human glioblastoma multiforme stem-like cells.

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Beatriz Aldaz

Full Text Available Glioblastoma multiforme (GBM-initiating cells (GICs represent a tumor subpopulation with neural stem cell-like properties that is responsible for the development, progression and therapeutic resistance of human GBM. We have recently shown that blockade of NFκB pathway promotes terminal differentiation and senescence of GICs both in vitro and in vivo, indicating that induction of differentiation may be a potential therapeutic strategy for GBM. MicroRNAs have been implicated in the pathogenesis of GBM, but a high-throughput analysis of their role in GIC differentiation has not been reported. We have established human GIC cell lines that can be efficiently differentiated into cells expressing astrocytic and neuronal lineage markers. Using this in vitro system, a microarray-based high-throughput analysis to determine global expression changes of microRNAs during differentiation of GICs was performed. A number of changes in the levels of microRNAs were detected in differentiating GICs, including over-expression of hsa-miR-21, hsa-miR-29a, hsa-miR-29b, hsa-miR-221 and hsa-miR-222, and down-regulation of hsa-miR-93 and hsa-miR-106a. Functional studies showed that miR-21 over-expression in GICs induced comparable cell differentiation features and targeted SPRY1 mRNA, which encodes for a negative regulator of neural stem-cell differentiation. In addition, miR-221 and miR-222 inhibition in differentiated cells restored the expression of stem cell markers while reducing differentiation markers. Finally, miR-29a and miR-29b targeted MCL1 mRNA in GICs and increased apoptosis. Our study uncovers the microRNA dynamic expression changes occurring during differentiation of GICs, and identifies miR-21 and miR-221/222 as key regulators of this process.

Quality of radiomic features in glioblastoma multiforme: Impact of semi-automated tumor segmentation software

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Lee, Myung Eun; Kim, Jong Hyo [Center for Medical-IT Convergence Technology Research, Advanced Institutes of Convergence Technology, Seoul National University, Suwon (Korea, Republic of); Woo, Bo Yeong [Dept. of Transdisciplinary Studies, Graduate School of Convergence Science and Technology, Seoul National University, Suwon (Korea, Republic of); Ko, Micheal D.; Jamshidi, Neema [Dept. of Radiological Sciences, University of California, Los Angeles, Los Angeles (United States)

2017-06-15

The purpose of this study was to evaluate the reliability and quality of radiomic features in glioblastoma multiforme (GBM) derived from tumor volumes obtained with semi-automated tumor segmentation software. MR images of 45 GBM patients (29 males, 16 females) were downloaded from The Cancer Imaging Archive, in which post-contrast T1-weighted imaging and fluid-attenuated inversion recovery MR sequences were used. Two raters independently segmented the tumors using two semi-automated segmentation tools (TumorPrism3D and 3D Slicer). Regions of interest corresponding to contrast-enhancing lesion, necrotic portions, and non-enhancing T2 high signal intensity component were segmented for each tumor. A total of 180 imaging features were extracted, and their quality was evaluated in terms of stability, normalized dynamic range (NDR), and redundancy, using intra-class correlation coefficients, cluster consensus, and Rand Statistic. Our study results showed that most of the radiomic features in GBM were highly stable. Over 90% of 180 features showed good stability (intra-class correlation coefficient [ICC] ≥ 0.8), whereas only 7 features were of poor stability (ICC < 0.5). Most first order statistics and morphometric features showed moderate-to-high NDR (4 > NDR ≥1), while above 35% of the texture features showed poor NDR (< 1). Features were shown to cluster into only 5 groups, indicating that they were highly redundant. The use of semi-automated software tools provided sufficiently reliable tumor segmentation and feature stability; thus helping to overcome the inherent inter-rater and intra-rater variability of user intervention. However, certain aspects of feature quality, including NDR and redundancy, need to be assessed for determination of representative signature features before further development of radiomics.

Marital status, treatment, and survival in patients with glioblastoma multiforme: a population based study.

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Chang, Susan M; Barker, Fred G

2005-11-01

Social factors influence cancer treatment choices, potentially affecting patient survival. In the current study, the authors studied the interrelations between marital status, treatment received, and survival in patients with glioblastoma multiforme (GM), using population-based data. The data source was the Surveillance, Epidemiology, and End Results (SEER) Public Use Database, 1988-2001, 2004 release, all registries. Multivariate logistic, ordinal, and Cox regression analyses adjusted for demographic and clinical variables were used. Of 10,987 patients with GM, 67% were married, 31% were unmarried, and 2% were of unknown marital status. Tumors were slightly larger at the time of diagnosis in unmarried patients (49% of unmarried patients had tumors larger than 45 mm vs. 45% of married patients; P = 0.004, multivariate analysis). Unmarried patients were less likely to undergo surgical resection (vs. biopsy; 75% of unmarried patients vs. 78% of married patients) and were less likely to receive postoperative radiation therapy (RT) (70% of unmarried patients vs. 79% of married patients). On multivariate analysis, the odds ratio (OR) for resection (vs. biopsy) in unmarried patients was 0.88 (95% confidence interval [95% CI], 0.79-0.98; P = 0.02), and the OR for RT in unmarried patients was 0.69 (95% CI, 0.62-0.77; P Unmarried patients more often refused both surgical resection and RT. Unmarried patients who underwent surgical resection and RT were found to have a shorter survival than similarly treated married patients (hazard ratio for unmarried patients, 1.10; P = 0.003). Unmarried patients with GM presented with larger tumors, were less likely to undergo both surgical resection and postoperative RT, and had a shorter survival after diagnosis when compared with married patients, even after adjustment for treatment and other prognostic factors. (c) 2005 American Cancer Society.

Efficacy and Safety of Leucine Supplementation in the Elderly.

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Borack, Michael S; Volpi, Elena

2016-12-01

Leucine supplementation has grown in popularity due to the discovery of its anabolic effects on cell signaling and protein synthesis in muscle. The current recommendation is a minimum intake of 55 mg ⋅ kg -1 . d -1 Leucine acutely stimulates skeletal muscle anabolism and can overcome the anabolic resistance of aging. The value of chronic leucine ingestion for muscle growth is still unclear. Most of the research into leucine consumption has focused on efficacy. To our knowledge, very few studies have sought to determine the maximum safe level of intake. Limited evidence suggests that intakes of ≤1250 mg ⋅ kg -1 . d -1 do not appear to have any health consequences other than short-term elevated plasma ammonia concentrations. Similarly, no adverse events have been reported for the leucine metabolite β-hydroxy-β-methylbutyrate (HMB), although no studies have tested HMB toxicity in humans. Therefore, future research is needed to evaluate leucine and HMB toxicity in the elderly and in specific health conditions. © 2016 American Society for Nutrition.

Poly-epsilon-caprolactone nanoparticles enhance ursolic acid in vivo efficacy against Trypanosoma cruzi infection.

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Abriata, Juliana Palma; Eloy, Josimar O; Riul, Thalita Bachelli; Campos, Patricia Mazureki; Baruffi, Marcelo Dias; Marchetti, Juliana Maldonado

2017-08-01

Despite affecting millions of people worldwide, Chagas disease is still neglected by the academia and industry and the therapeutic option available, benznidazole, presents limited efficacy and side effects. Within this context, ursolic acid may serve as an option for treatment, however has low bioavailability, which can be enhanced through the encapsulation in polymeric nanoparticles. Therefore, herein we developed ursolic acid-loaded nanoparticles with poly-ε-caprolactone by the nanoprecipitation method and characterized them for particle size, zeta potential, polydispersity, encapsulation efficiency, morphology by scanning electron microscopy and thermal behavior by differential scanning calorimetry. Results indicated that an appropriate ratio of organic phase/aqueous phase and polymer/drug is necessary to produce smaller particles, with low polydispersity, negative zeta potential and high drug encapsulation efficiency. In vitro studies indicated the safety of the formulation against fibroblast culture and its efficacy in killing T. cruzi. Very importantly, the in vivo study revealed that the ursolic acid-loaded nanoparticle is as potent as the benznidazole group to control parasitemia, which could be attributed to improved bioavailability of the encapsulated drug. Finally, the toxicity evaluation showed that while benznidazole group caused liver toxicity, the nanoparticles were safe, indicating that this formulation is promising for future evaluation. Copyright © 2017 Elsevier B.V. All rights reserved.

The efficacy and nephrotoxicity associated with colistin use in an intensive care unit in Vietnam: Use of colistin in a population of lower body weight

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Nguyen Gia Binh

2015-06-01

Conclusion: A personalized dosing protocol of colistin was effective, with low nephrotoxicity, among critically ill Vietnamese patients with low body weight. Further studies are warranted for assessing the efficacy and toxicity in a larger cohort.

Toxicity of polymeric nanoparticles in vivo and in vitro

Science.gov (United States)

Voigt, Nadine; Henrich-Noack, Petra; Kockentiedt, Sarah; Hintz, Werner; Tomas, Jürgen; Sabel, Bernhard A.

2014-06-01

Polybutylcyanoacrylate nanoparticles (PBCA NPs) are candidates for a drug delivery system, which can cross the blood-brain barrier (BBB). Because little is known about their toxicity, we exposed cells to PBCA NPs in vitro and in vivo and monitored their life and death assays. PBCA NPs were fabricated with different surfactants according to the mini-emulsion technique. Viabilities of HeLa and HEK293 cells after NP incubation were quantified by analysing cellular metabolic activity (MTT-test). We then repetitively injected i.v. rhodamine-labelled PBCA NP variations into rats and monitored the survival and morphology of retrogradely labelled neurons by in vivo confocal neuroimaging (ICON) for five weeks. To test for carrier-efficacy and safety, PBCA NPs loaded with Kyotorphin were injected in rats, and a hot plate test was used to quantify analgesic effects. In vitro, we found dose-dependent cell death which was, however, only detectable at very high doses and mainly seen in the cultures incubated with NPs fabricated with the tensids SDS and Tween. However, the in vivo experiments did not show any NP-induced neuronal death, even with particles which were toxic at high dose in vitro, i.e. NPs with Tween and SDS. The increased pain threshold at the hot plate test demonstrated that PBCA NPs are able to cross the BBB and thus comprise a useful tool for drug delivery into the central nervous system (CNS). Our findings showing that different nanoparticle formulations are non-toxic have important implications for the value of NP engineering approaches in medicine.

The addition of temozolomide does not change the pattern of progression glioblastoma multiforme post-radiotherapy

International Nuclear Information System (INIS)

Gunjur, Ashray; Bressel, Mathias; Ryan, Gail

2012-01-01

To determine whether the pattern of progressive disease (PD) for glioblastoma multiforme (GBM) patients has changed with the introduction of the current standard of care protocol – postoperative conformal radiotherapy to a dose of 60 Gray in 30 fractions with concurrent low-dose (75–100 mg/m 2 ) temozolomide, followed by six cycles of adjuvant high-dose (150–200 mg/m 2 ) temozolomide – as compared with radiotherapy alone. For GBM patients commencing combined modality treatment between October 2005 and August 2009, the MRI scan confirming progression (if any) was co-registered with the original planning CT scan, and progression site(s) marked. Coverage of the composite progression volume (PDvol) by the original 95% prescription isodose volume was obtained from dose-volume histogram (DVH) data, and assigned as ‘central’, ‘in field’, ‘marginal’ and ‘out of field’, corresponding to >95%, >80%, 20–80% and <20% coverage. Of 68 consecutive patients identified, 54 (79.4%) had documented PD. Of the 47 (87%) evaluable patients, 43 (91%) had in field progression with 36 (77%) of these being central. Of the remaining four cases, three (6%) had marginal progression, and only one patient (2%) had out of field progression. Median overall and progression-free survival were 11.6 and 6.6 months, respectively. The pattern of progression in our GBM patients does not appear to have been altered by the addition of temozolomide. The overwhelming majority of first PD occurred within the original radiotherapy planning target volume, as is the case in patients treated with radiotherapy alone. Major changes to radiotherapy volumes are not indicated, with alternative strategies required to improve outcomes.

Acquired MET expression confers resistance to EGFR inhibition in a mouse model of glioblastoma multiforme.

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Jun, H J; Acquaviva, J; Chi, D; Lessard, J; Zhu, H; Woolfenden, S; Bronson, R T; Pfannl, R; White, F; Housman, D E; Iyer, L; Whittaker, C A; Boskovitz, A; Raval, A; Charest, A

2012-06-21

Glioblastoma multiforme (GBM) is an aggressive brain tumor for which there is no cure. Overexpression of wild-type epidermal growth factor receptor (EGFR) and loss of the tumor suppressor genes Ink4a/Arf and PTEN are salient features of this deadly cancer. Surprisingly, targeted inhibition of EGFR has been clinically disappointing, demonstrating an innate ability for GBM to develop resistance. Efforts at modeling GBM in mice using wild-type EGFR have proven unsuccessful to date, hampering endeavors at understanding molecular mechanisms of therapeutic resistance. Here, we describe a unique genetically engineered mouse model of EGFR-driven gliomagenesis that uses a somatic conditional overexpression and chronic activation of wild-type EGFR in cooperation with deletions in the Ink4a/Arf and PTEN genes in adult brains. Using this model, we establish that chronic activation of wild-type EGFR with a ligand is necessary for generating tumors with histopathological and molecular characteristics of GBMs. We show that these GBMs are resistant to EGFR kinase inhibition and we define this resistance molecularly. Inhibition of EGFR kinase activity using tyrosine kinase inhibitors in GBM tumor cells generates a cytostatic response characterized by a cell cycle arrest, which is accompanied by a substantial change in global gene expression levels. We demonstrate that an important component of this pattern is the transcriptional activation of the MET receptor tyrosine kinase and that pharmacological inhibition of MET overcomes the resistance to EGFR inhibition in these cells. These findings provide important new insights into mechanisms of resistance to EGFR inhibition and suggest that inhibition of multiple targets will be necessary to provide therapeutic benefit for GBM patients.

Efficacy of adsorbents (bentonite and diatomaceous earth) and turmeric (Curcuma longa) in alleviating the toxic effects of aflatoxin in chicks.

Science.gov (United States)

Dos Anjos, F R; Ledoux, D R; Rottinghaus, G E; Chimonyo, M

2015-01-01

A study was conducted to determine the efficacy of bentonite clay (BC), diatomaceous earth (DE) and turmeric powder (TUM) in alleviating the toxic effects of aflatoxin B1 (AFB1). A total of 250 Ross-308 d-old male broiler chicks were assigned to 10 dietary treatments (5 replicates of 5 chicks) from hatch to d 21. Dietary treatments were: basal diet; basal diet plus AFB1 (2 mg) or BC (0.75%), or DE (0.75%), or TUM (200 mg/kg curcuminoids) and different combinations of AFB1, BC, DE and TUM. Feed intake (FI), body weight gain (BWG) and feed gain (FG) of the birds fed on BC or DE separately were not different from control birds. Birds fed on TUM only had similar FI and FG but lower BWG than control chicks. Aflatoxin B1 reduced FI, BWG and serum concentrations of glucose, albumin, total protein calcium, but increased FG and relative liver and kidney weights. Chicks fed on the combination of AFB1 and BC had similar FI and FG to control chicks. Chicks fed on the combination of DE and AFB1 had lower FI (23.1%) and BWG (28.6%) compared with control chicks. Chicks fed on the combination of TUM and AFB1 also had decreased FI (26.2 %) and BWG (31%) compared with control chicks. Chicks fed on the combination of AFB1, BC and TUM consumed significantly higher amounts of feed compared with chicks fed on only AF, but gained less when compared with control diet chicks. Chicks fed on the combination of AFB1, DE and TUM diet had poorer growth performance than those fed on AFB1 alone. None of the combination diets reduced the severity of liver lesions.

Sediment toxicity assessment in the Lagoon of Venice (Italy) using Paracentrotus lividus (Echinodermata: Echinoidea) fertilization and embryo bioassays.

Science.gov (United States)

Volpi Ghirardini, A; Arizzi Novelli, A; Tagliapietra, D

2005-09-01

The capacity of two toxicity bioassays (fertilization and embryo toxicity tests) to discriminate sediment toxicity using the sea urchin Paracentrotus lividus was tested in five stations with different levels of pollution in the Lagoon of Venice. Two stations were located in estuarine sites, two in the industrial zone, and one in a site at the top of our quality gradient (reference). Elutriate was chosen as sediment matrix to assess the potential effects of bioavailable pollutants in the water column as a consequence of sediment resuspension (dredging and dumping, fishing gear, etc.). An experimental design based on Quality Assurance/Quality Control procedures (QA/QC) was adopted in order to set the methodological basis for an effective use of these bioassays in monitoring programs. Results revealed both higher embriotoxicity than spermiotoxicity in all stations and the efficacy of combined use of both toxicity bioassays in discriminating differing pollution/bioavailability between stations and periods. The good representativeness of the integrated sampling scheme and the standardization of all experimental phases yielded high precision of results. Clear Toxicity Fingerprints were evidenced for the investigated sites through the combined use of both bioassays. A good fit between ecotoxicological data and chemical contamination levels was found, except for unnatural sediment texture.

Toxic substances alert program

Science.gov (United States)

Junod, T. L.

1978-01-01

A toxicity profile is provided, of 187 toxic substances procured by NASA Lewis Research Center during a 3 1/2 year period, including 27 known or suspected carcinogens. The goal of the program is to assure that the center's health and safety personnel are aware of the procurement and use of toxic substances and to alert and inform the users of these materials as to the toxic characteristics and the control measures needed to ensure their safe use. The program also provides a continuing record of the toxic substances procured, who procured them, what other toxic substances the user has obtained in the past, and where similar materials have been used elsewhere at the center.

1H NMR-based serum metabolomics reveals erythromycin-induced liver toxicity in albino Wistar rats

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Atul Rawat

2016-01-01

Full Text Available Introduction: Erythromycin (ERY is known to induce hepatic toxicity which mimics other liver diseases. Thus, ERY is often used to produce experimental models of drug-induced liver-toxicity. The serum metabolic profiles can be used to evaluate the liver-toxicity and to further improve the understanding of underlying mechanism. Objective: To establish the serum metabolic patterns of Erythromycin induced hepatotoxicity in albino wistar rats using 1H NMR based serum metabolomics. Experimental: Fourteen male rats were randomly divided into two groups (n = 7 in each group: control and ERY treated. After 28 days of intervention, the metabolic profiles of sera obtained from ERY and control groups were analyzed using high-resolution 1D 1H CPMG and diffusion-edited nuclear magnetic resonance (NMR spectra. The histopathological and SEM examinations were employed to evaluate the liver toxicity in ERY treated group. Results: The serum metabolic profiles of control and ERY treated rats were compared using multivariate statistical analysis and the metabolic patterns specific to ERY-induced liver toxicity were established. The toxic response of ERY was characterized with: (a increased serum levels of Glucose, glutamine, dimethylamine, malonate, choline, phosphocholine and phospholipids and (b decreased levels of isoleucine, leucine, valine, alanine, glutamate, citrate, glycerol, lactate, threonine, circulating lipoproteins, N-acetyl glycoproteins, and poly-unsaturated lipids. These metabolic alterations were found to be associated with (a decreased TCA cycle activity and enhanced fatty acid oxidation, (b dysfunction of lipid and amino acid metabolism and (c oxidative stress. Conclusion and Recommendations: Erythromycin is often used to produce experimental models of liver toxicity; therefore, the established NMR-based metabolic patterns will form the basis for future studies aiming to evaluate the efficacy of anti-hepatotoxic agents or the hepatotoxicity of new

Studies of the ionizing radiation effects on the effluents acute toxicity due to anionic surfactants

International Nuclear Information System (INIS)

Moraes, Maria Cristina Franco de

2004-01-01

Several studies have shown the negative effects of surfactants, as detergents active substance, when discharged on biological sewage wastewater treatment plants. High toxicity may represent a lower efficiency for biological treatment. When surfactants are in aquatic environment they may induce a loss of grease revetment on birds (feather). Depending on the surfactant concentration, several damages to all biotic systems can happen. Looking for an alternative technology for wastewater treatment, efficient for surfactant removal, the present work applied ionizing radiation as an advanced oxidation process for affluents and effluents from Suzano Treatment Station. Such wastewater samples were submitted to radiation using an electron beam from a Dynamic Electron Beam Accelerator from Instituto de Pesquisas Energeticas e Nucleares. In order to assess this proposed treatment efficacy, it was performed acute toxicity evaluation with two test-organisms, the crustacean Daphnia similis and the luminescent bacteria Vibrio fischeri. The studied effluents were: one from a chemical industry (IND), three from sewage plant (affluents - GG, GM and Guaio) and the last biologically treated secondary effluent (EfF), discharged at Tiete river. The applied radiation doses varied from 3 kGy to 50 kGy, being 50 kGy enough for surfactant degradation contained at industrial effluent. For GG, GM and Guaio samples, doses of 6 kGy and 10 kGy were efficient for surfactant and toxicity reduction, representing an average removal that varied from 71.80% to 82.76% and toxicity from 30% to 91% for most the effluents. The final effluent was less toxic than the others and the radiation induced an average 11% removal for anionic surfactant. The industrial effluents were also submitted to an aeration process in order to quantify the contribution of surfactant to the whole sample toxicity, once it was partially removed as foam and several fractions were evaluated for toxicity. (author)

Topical efficacy of dimercapto-chelating agents against lewisite-induced skin lesions in SKH-1 hairless mice

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Mouret, Stéphane, E-mail: stephane.mouret@irba.fr [Département de Toxicologie et Risques Chimiques, Institut de Recherche Biomédicale des Armées, Centre de Recherches du Service de Santé des Armées, 24 avenue Maquis du Grésivaudan, 38700 La Tronche (France); Wartelle, Julien; Emorine, Sandy; Bertoni, Marine; Nguon, Nina; Cléry-Barraud, Cécile [Département de Toxicologie et Risques Chimiques, Institut de Recherche Biomédicale des Armées, Centre de Recherches du Service de Santé des Armées, 24 avenue Maquis du Grésivaudan, 38700 La Tronche (France); Dorandeu, Frédéric [Département de Toxicologie et Risques Chimiques, Institut de Recherche Biomédicale des Armées, Centre de Recherches du Service de Santé des Armées, 24 avenue Maquis du Grésivaudan, 38700 La Tronche (France); Ecole du Val-de-Grâce, 1 place Alphonse Laveran, Paris (France); Boudry, Isabelle [Département de Toxicologie et Risques Chimiques, Institut de Recherche Biomédicale des Armées, Centre de Recherches du Service de Santé des Armées, 24 avenue Maquis du Grésivaudan, 38700 La Tronche (France)

2013-10-15

Lewisite is a potent chemical warfare arsenical vesicant that can cause severe skin lesions. Today, lewisite exposure remains possible during demilitarization of old ammunitions and as a result of deliberate use. Although its cutaneous toxicity is not fully elucidated, a specific antidote exists, the British anti-lewisite (BAL, dimercaprol) but it is not without untoward effects. Analogs of BAL, less toxic, have been developed such as meso-2,3-dimercaptosuccinic acid (DMSA) and have been employed for the treatment of heavy metal poisoning. However, efficacy of DMSA against lewisite-induced skin lesions remains to be determined in comparison with BAL. We have thus evaluated in this study the therapeutic efficacy of BAL and DMSA in two administration modes against skin lesions induced by lewisite vapor on SKH-1 hairless mice. Our data demonstrate a strong protective efficacy of topical application of dimercapto-chelating agents in contrast to a subcutaneous administration 1 h after lewisite exposure, with attenuation of wound size, necrosis and impairment of skin barrier function. The histological evaluation also confirms the efficacy of topical application by showing that treatments were effective in reversing lewisite-induced neutrophil infiltration. This protective effect was associated with an epidermal hyperplasia. However, for all the parameters studied, BAL was more effective than DMSA in reducing lewisite-induced skin injury. Together, these findings support the use of a topical form of dimercaprol-chelating agent against lewisite-induced skin lesion within the first hour after exposure to increase the therapeutic management and that BAL, despite its side-effects, should not be abandoned. - Highlights: • Topically applied dimercapto-chelating agents reduce lewisite-induced skin damage. • One topical application of BAL or DMSA is sufficient to reverse lewisite effects. • Topical BAL is more effective than DMSA to counteract lewisite-induced skin damage.

Effect of YH0618 soup on chemotherapy-induced toxicity in patients with cancer who have completed chemotherapy: study protocol for a randomized controlled trial.

Science.gov (United States)

You, Jie-Shu; Chen, Jian-Ping; Chan, Jessie S M; Lee, Ho-Fun; Wong, Mei-Kuen; Yeung, Wing-Fai; Lao, Li-Xing

2016-07-26

The incidence of cancer has been staying at a high level worldwide in recent years. With advances in cancer diagnosis and therapy strategy, the survival rate of patients with cancer has been increasing, but the side effects of these treatments, especially chemotherapy, are obvious even when the chemotherapy ceases. YH0618, a prescription, has showed efficacy in reducing chemotherapy-induced toxicity through long clinical practice. However, there is no scientific research exploring the effects of YH0618 in patients with cancer. Therefore, using a randomized controlled trial, this study will explore the efficacy of YH0618 on ameliorating chemotherapy-induced toxicity including dermatologic toxicity, myelosuppression, hepatotoxicity and nephrotoxicity and improving fatigue in cancer patients who have completed chemotherapy. This is a prospective assessor-blinded, parallel, randomized controlled trial. Patients with cancer at any stage who have completed chemotherapy within two weeks will be randomly divided into group A (YH0618) and group B (wait-list) using a 1:1 allocation ratio. The chemotherapeutic agents include taxanes or anthracyclines. Subjects assigned to group A will receive YH0618 soup 6 days a week for 6 weeks and uncontrolled follow-up for 6 weeks, while group B are required to wait for 6 weeks before receiving YH0618 intervention. The primary outcome of this study is the incidence of protocol-specified grade ≥2 dermatologic toxicities graded by NCI CTCAE Chinese version 4.0 and changes of fingernail color, face skin color and tongue color evaluated by the L*a*b system within 6 weeks. There are some secondary outcomes associated with dermatologic toxicity including fatigue and clinical objective examination. There are few scientific and safe methods in ameliorating chemotherapy-induced toxicity. The proposed study may provide direct and convincing evidence to support YH0618 as an adjuvant treatment for reducing chemotherapy-induced toxicity, which

Toxicity classification and evaluation of four pharmaceuticals classes: antibiotics, antineoplastics, cardiovascular, and sex hormones

International Nuclear Information System (INIS)

Sanderson, Hans; Brain, Richard A.; Johnson, David J.; Wilson, Christian J.; Solomon, Keith R.

2004-01-01

Four different classes of environmental concern are quantitatively and qualitatively assessed for environmental hazards; antibiotics (n = 226), antineoplastics (n = 81), cardiovascular (n = 272), and sex hormones (n 92). These along with an ECOSAR scan of all pharmaceuticals (n = 2848) were then classified according to the OECD aquatic toxicity classification system. The predicted species susceptibility is: daphnid > fish > algae, and the predicted rank order of relative toxicity: sex hormones > cardiovascular antibiotics > antineoplastics (Table 1). Generally, a relatively large proportion (1/3) of all pharmaceuticals are potentially very toxic to aquatic organisms (Table 2). The qualitative risk assessment ranking relative to probability and potential severity for human and environmental health effects is: antibiotics > sex hormones > cardiovascular > antineoplastics. (Q)SARs and pharmacodynamic information should be used to prioritize and steer experimental risk assessments of pharmaceuticals, and potentially, also be used in new drug discovery optimizing efficacy and in minimising environmental hazards of new products. Nuclear receptors are relatively well conserved in evolution. Currently, antibacterial resistance represents the most significant human health hazard, and potentially the largest non-target organism hazard is sex hormones acting as endocrine modulators in wildlife. Data for the individual compounds are accessible via http://www.uoguelph.ca/~hsander/

{sup 23}Na-MRI of recurrent glioblastoma multiforme after intraoperative radiotherapy: technical note

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Haneder, Stefan; Buesing, Karen A.; Schoenberg, Stefan O.; Ong, Melissa M. [Heidelberg University, Institute of Clinical Radiology and Nuclear Medicine, University Medical Center Mannheim, Medical Faculty Mannheim, Mannheim (Germany); Giordano, Frank A.; Wenz, Frederik [University of Heidelberg, Department of Radiation Oncology, University Medical Center Mannheim, Mannheim (Germany); Konstandin, Simon; Schad, Lothar R. [Heidelberg University, Computer Assisted Clinical Medicine, Mannheim (Germany); Brehmer, Stefanie; Schmiedek, Peter [Heidelberg University, Department of Neurosurgery, University Medical Center Mannheim, Mannheim (Germany)

2015-03-01

We report the first case of an intraoperative radiotherapy (IORT) in a patient with recurrent glioblastoma multiforme (GBM) who was followed up with a novel magnetic resonance imaging (MRI) method - {sup 23}Na-MRI - in comparison to a standard contrast-enhanced {sup 1}H-MRI and {sup 18}F-FET-PET. A 56-year-old female patient with diagnosed GBM in July 2012 underwent tumor resection, radiochemotherapy, and three cycles of chemotherapy. After a relapse, 6 months after the initial diagnosis, an IORT was recommended which was performed in March 2013 using the INTRABEAM system (Carl Zeiss Meditec AG, Germany) with a 3-cm applicator and a surface dose of 20 Gy. Early post-operative contrast-enhanced and 1-month follow-up {sup 1}H-MRI and a {sup 18}F-FET-PET were performed. In addition, an IRB-approved {sup 23}Na-MRI was performed on a 3.0-T MR scanner (MAGNETOM TimTrio, Siemens Healthcare, Germany). After re-surgery and IORT in March 2013, only a faint contrast enhancement but considerable surrounding edema was visible at the medio-posterior resection margins. In April 2013, new and progressive contrast enhancement, edema, {sup 23}Na content, and increased uptake in the {sup 18}F-FET-PET were visible, indicating tumor recurrence. Increased sodium content within the area of contrast enhancement was found in the {sup 23}Na-MRI, but also exceeding this area, very similar to the increased uptake depicted in the {sup 18}F-FET-PET. The clearly delineable zone of edema in both examinations exhibits a lower {sup 23}Na content compared to areas with suspected proliferating tumor tissue. {sup 23}Na-MRI provided similar information in the suspicious area compared to {sup 18}F-FET-PET, exceeding conventional {sup 1}H-MRI. Still, {sup 23}Na-MRI remains an investigational technique, which is worth to be further evaluated. (orig.)

Mixture toxicity of wood preservative products in the fish embryo toxicity test.

Science.gov (United States)

Coors, Anja; Dobrick, Jan; Möder, Monika; Kehrer, Anja

2012-06-01

Wood preservative products are used globally to protect wood from fungal decay and insects. We investigated the aquatic toxicity of five commercial wood preservative products, the biocidal active substances and some formulation additives contained therein, as well as six generic binary mixtures of the active substances in the fish embryo toxicity test (FET). Median lethal concentrations (LC50) of the single substances, the mixtures, and the products were estimated from concentration-response curves and corrected for concentrations measured in the test medium. The comparison of the experimentally observed mixture toxicity with the toxicity predicted by the concept of concentration addition (CA) showed less than twofold deviation for all binary mixtures of the active substances and for three of the biocidal products. A more than 60-fold underestimation of the toxicity of the fourth product by the CA prediction was detected and could be explained fully by the toxicity of one formulation additive, which had been labeled as a hazardous substance. The reason for the 4.6-fold underestimation of toxicity of the fifth product could not be explained unambiguously. Overall, the FET was found to be a suitable screening tool to verify whether the toxicity of formulated wood preservatives can reliably be predicted by CA. Applied as a quick and simple nonanimal screening test, the FET may support approaches of applying component-based mixture toxicity predictions within the environmental risk assessment of biocidal products, which is required according to European regulations. Copyright © 2012 SETAC.

Prognostic value of the Glasgow Prognostic Score for glioblastoma multiforme patients treated with radiotherapy and temozolomide.

Science.gov (United States)

Topkan, Erkan; Selek, Ugur; Ozdemir, Yurday; Yildirim, Berna A; Guler, Ozan C; Ciner, Fuat; Mertsoylu, Huseyin; Tufan, Kadir

2018-04-25

To evaluate the prognostic value of the Glasgow Prognostic Score (GPS), the combination of C-reactive protein (CRP) and albumin, in glioblastoma multiforme (GBM) patients treated with radiotherapy (RT) and concurrent plus adjuvant temozolomide (GPS). Data of newly diagnosed GBM patients treated with partial brain RT and concurrent and adjuvant TMZ were retrospectively analyzed. The patients were grouped into three according to the GPS criteria: GPS-0: CRP L and albumin > 35 g/L; GPS-1: CRP L and albumin L or CRP > 10 mg/L and albumin > 35 g/L; and GPS-2: CRP > 10 mg/L and albumin L. Primary end-point was the association between the GPS groups and the overall survival (OS) outcomes. A total of 142 patients were analyzed (median age: 58 years, 66.2% male). There were 64 (45.1%), 40 (28.2%), and 38 (26.7%) patients in GPS-0, GPS-1, and GPS-2 groups, respectively. At median 15.7 months follow-up, the respective median and 5-year OS rates for the whole cohort were 16.2 months (95% CI 12.7-19.7) and 9.5%. In multivariate analyses GPS grouping emerged independently associated with the median OS (P GPS grouping and the RTOG RPA classification were found to be strongly correlated in prognostic stratification of GBM patients (correlation coefficient: 0.42; P GPS appeared to be useful in prognostic stratification of GBM patients into three groups with significantly different survival durations resembling the RTOG RPA classification.

Tocilizumab: A Review of Its Safety and Efficacy in Rheumatoid Arthritis

Directory of Open Access Journals (Sweden)

Graeme Jones

2010-01-01

Full Text Available Recent years have seen many exciting developments in the treatment of rheumatoid arthritis. Tocilizumab (TCZ is a monoclonal antibody which inhibits the interleukin-6 receptor. After initial studies in Japan, it has been extensively studied in five multicentre clinical trials. This report summarises the key efficacy and toxicity findings from the major clinical trials. TCZ works quickly and effectively in rheumatoid arthritis either as monotherapy or in combination with other agents in early disease, DMARD inadequate responders, seronegative disease and after anti-TNF failure. The toxicity profile is manageable but includes infections (most notably skin and soft tissue, increases in serum cholesterol, transient decreases in neutrophil count and abnormal liver function tests (especially in combination with methotrexate. In summary, there is sufficient evidence to make TCZ a first line biologic therapy for rheumatoid arthritis especially for those who are unable to take methotrexate or who fail anti-TNF therapy.

Predicting molybdenum toxicity to higher plants: Estimation of toxicity threshold values

Energy Technology Data Exchange (ETDEWEB)

McGrath, S.P., E-mail: steve.mcgrath@bbsrc.ac.u [Soil Science Department, Centre for Soils and Ecosystems Function, Rothamsted Research, Harpenden, Hertfordshire AL5 2JQ (United Kingdom); Mico, C.; Zhao, F.J.; Stroud, J.L. [Soil Science Department, Centre for Soils and Ecosystems Function, Rothamsted Research, Harpenden, Hertfordshire AL5 2JQ (United Kingdom); Zhang, H.; Fozard, S. [Division of Environmental Science, Lancaster University, Lancaster LA1 4YQ (United Kingdom)

2010-10-15

Four plant species (oilseed rape, Brassica napus L.; red clover, Trifolium pratense L.; ryegrass, Lolium perenne L.; and tomato, Lycopersicon esculentum L.) were tested on ten soils varying widely in soil properties to assess molybdenum (Mo) toxicity. A larger range (66-fold-609-fold) of added Mo concentrations resulting in 50% inhibition of yield (ED{sub 50}) was found among soils than among plant species (2-fold-38-fold), which illustrated that the soils differed widely in the expression of Mo toxicity. Toxicity thresholds based on soil solution Mo narrowed the variation among soils compared to thresholds based on added Mo concentrations. We conclude that plant bioavailability of Mo in soil depends on Mo solubility, but this alone did not decrease the variability in observed toxicity enough to be used in risk assessment and that other soil properties influencing Mo toxicity to plants need to be considered. - Mo toxicity thresholds varied widely in different soils and therefore soil properties need to be taken into account in order to assess the risk of Mo exposure.

Establishment and Biological Characterization of a Panel of Glioblastoma Multiforme (GBM) and GBM Variant Oncosphere Cell Lines.

Science.gov (United States)

Binder, Zev A; Wilson, Kelli M; Salmasi, Vafi; Orr, Brent A; Eberhart, Charles G; Siu, I-Mei; Lim, Michael; Weingart, Jon D; Quinones-Hinojosa, Alfredo; Bettegowda, Chetan; Kassam, Amin B; Olivi, Alessandro; Brem, Henry; Riggins, Gregory J; Gallia, Gary L

2016-01-01

Human tumor cell lines form the basis of the majority of present day laboratory cancer research. These models are vital to studying the molecular biology of tumors and preclinical testing of new therapies. When compared to traditional adherent cell lines, suspension cell lines recapitulate the genetic profiles and histologic features of glioblastoma multiforme (GBM) with higher fidelity. Using a modified neural stem cell culture technique, here we report the characterization of GBM cell lines including GBM variants. Tumor tissue samples were obtained intra-operatively and cultured in neural stem cell conditions containing growth factors. Tumor lines were characterized in vitro using differentiation assays followed by immunostaining for lineage-specific markers. In vivo tumor formation was assayed by orthotopic injection in nude mice. Genetic uniqueness was confirmed via short tandem repeat (STR) DNA profiling. Thirteen oncosphere lines derived from GBM and GBM variants, including a GBM with PNET features and a GBM with oligodendroglioma component, were established. All unique lines showed distinct genetic profiles by STR profiling. The lines assayed demonstrated a range of in vitro growth rates. Multipotency was confirmed using in vitro differentiation. Tumor formation demonstrated histologic features consistent with high grade gliomas, including invasion, necrosis, abnormal vascularization, and high mitotic rate. Xenografts derived from the GBM variants maintained histopathological features of the primary tumors. We have generated and characterized GBM suspension lines derived from patients with GBMs and GBM variants. These oncosphere cell lines will expand the resources available for preclinical study.

[Toxicity of the combination of salinomycin and tiamulin in swine].

Science.gov (United States)

Wendt, M; Büsing, S; Bollwahn, W

1997-09-01

The toxicity of the combination of salinomycin (sal.) and tiamulin (tia.) was investigated in dependence upon dosage and feeding method. In addition the efficacy of a safe dose for prophylactic treatment of dysentery was controlled. Following feed medications were tested for toxic effects in pigs: a) 3 mg sal. + 5 mg tia./kg BW, b) 3 mg sal. + 3 mg tia./kg BW, c) 3 mg sal. + 1 mg tia./kg BW, d) 3 mg sal./kg BW, e) 10 mg tia./kg BW, f) 30 mg tia./kg BW. The daily dose was given for 2 weeks by restricted feeding (twice a day) either as bolus or mixed in the whole ration or by feeding ad libitum. Animals were controlled for clinical symptoms and activities of creatine phosphokinase (CK) and aspartate aminotransferase (ASAT) were evaluated daily. Main clinical signs of poisoning were loss of appetite and locomotor disturbances and could be noticed for dosages of 8, 6 and 4 mg sal. + tia./kg BW. Activities of CK and ASAT were increased dose-related, the feeding method also had an influence on the degree of intoxication. Some animals showed locomotor disturbances without any corresponding changes of CK and ASAT levels. Single pigs remaining without any symptoms even at high dosage pointed to differences in individual susceptibility. Toxicity was not found to be age dependent. Feed medication with 60 ppm sal. + 20 ppm tia. (feeding ad libitum) did not result in any signs of toxicity, however, the transmission of Serpulina hyodysenteriae from infected pigs to healthy, treated control animals could not be inhibited efficiently. Therefore the simultaneous application of salinomycin and tiamulin should be avoided generally, because the risk of intoxication is high and subtherapeutical dosage has an insufficient effectiveness against Serpulina hyodysenteriae.

An empirical study of the toxic capsule crisis in China: risk perceptions and behavioral responses.

Science.gov (United States)

Feng, Tianjun; Keller, L Robin; Wu, Ping; Xu, Yifan

2014-04-01

The outbreak of the toxic capsule crisis during April 2012 aroused widespread public concern about the risk of chromium-contaminated capsules and drug safety in China. In this article, we develop a conceptual model to investigate risk perceptions of the pharmaceutical drug capsules and behavioral responses to the toxic capsule crisis and the relationship between associated factors and these two variables. An online survey was conducted to test the model, including questions on the measures of perceived efficacy of the countermeasures, trust in the State FDA (Food and Drug Administration), trust in the pharmaceutical companies, trust in the pharmaceutical capsule producers, risk perception, concern, need for information, information seeking, and risk avoidance. In general, participants reported higher levels of risk perception, concern, and risk avoidance, and lower levels of trust in the three different stakeholders. The results from the structural equation modeling procedure suggest that perceived efficacy of the countermeasures is a predictor of each of the three trust variables; however, only trust in the State FDA has a dampening impact on risk perception. Both risk perception and information seeking are significant determinants of risk avoidance. Risk perception is also positively related to concern. Information seeking is positively related to both concern and need for information. The theoretical and policy implications are also discussed. © 2013 Society for Risk Analysis.

Sodium selenosulfate at an innocuous dose markedly prevents cisplatin-induced gastrointestinal toxicity

Energy Technology Data Exchange (ETDEWEB)

Li, Jun; Sun, Kang [School of Tea and Food Science, Anhui Agricultural University, Hefei 230036, Anhui (China); Ni, Lijuan; Wang, Xufang [School of Chemistry and Materials of Science, University of Science and Technology of China, Hefei 230052, Anhui (China); Wang, Dongxu [School of Tea and Food Science, Anhui Agricultural University, Hefei 230036, Anhui (China); Zhang, Jinsong, E-mail: zjs@ahau.edu.cn [School of Tea and Food Science, Anhui Agricultural University, Hefei 230036, Anhui (China)

2012-02-01

Our previous studies in mice revealed that two weeks short-term toxicity of sodium selenosulfate was significantly lower than that of sodium selenite, but selenium repletion efficacy of both compounds was equivalent. In addition, we showed that sodium selenosulfate reduced nephrotoxicity of cisplatin (CDDP) without compromising its anticancer activity, thus leading to a dramatic increase of cancer cure rate from 25% to 75%. Hydration has been used in clinical practice to reduce CDDP-induced nephrotoxicity, but it cannot mitigate CDDP-induced gastrointestinal toxicity. The present work investigated whether sodium selenosulfate is a potential preventive agent for the gastrointestinal toxicity. In tumor-bearing mice, sodium selenosulfate was administered at a dose of 9.5 μmol/kg daily for 11 days, CDDP alone resulted in diarrhea by 88% on day 12, whereas the co-administration of CDDP and sodium selenosulfate dramatically reduced diarrhea to 6% (p < 0.0001). Such a prominent protective effect promoted us to evaluate the safety potential of long-term sodium selenosulfate application. Mice were administered with sodium selenosulfate or sodium selenite for 55 days at the doses of 12.7 and 19 μmol/kg. The low-dose sodium selenite caused growth suppression and hepatotoxicity which were aggravated by the high-dose, leading to 40% mortality rate, but no toxic symptoms were observed in the two sodium selenosulfate groups. Altogether these results clearly show that sodium selenosulfate at an innocuous dose can markedly prevent CDDP-induced gastrointestinal toxicity. -- Highlights: ►Cisplatin resulted in diarrhea in mice by 88%. ►i.p. selenosulfate at 9.5 μmol/kg daily for 11 days reduced diarrhea to 6%. ►i.p. selenosulfate at 19 μmol/kg daily for 55 days was not toxic. ►i.p. selenite at 19 μmol/kg daily for 55 days was lethal. ►Innocuous dose of selenosulfate greatly prevents cisplatin-induced diarrhea.

Sodium selenosulfate at an innocuous dose markedly prevents cisplatin-induced gastrointestinal toxicity

International Nuclear Information System (INIS)

Li, Jun; Sun, Kang; Ni, Lijuan; Wang, Xufang; Wang, Dongxu; Zhang, Jinsong

2012-01-01

Our previous studies in mice revealed that two weeks short-term toxicity of sodium selenosulfate was significantly lower than that of sodium selenite, but selenium repletion efficacy of both compounds was equivalent. In addition, we showed that sodium selenosulfate reduced nephrotoxicity of cisplatin (CDDP) without compromising its anticancer activity, thus leading to a dramatic increase of cancer cure rate from 25% to 75%. Hydration has been used in clinical practice to reduce CDDP-induced nephrotoxicity, but it cannot mitigate CDDP-induced gastrointestinal toxicity. The present work investigated whether sodium selenosulfate is a potential preventive agent for the gastrointestinal toxicity. In tumor-bearing mice, sodium selenosulfate was administered at a dose of 9.5 μmol/kg daily for 11 days, CDDP alone resulted in diarrhea by 88% on day 12, whereas the co-administration of CDDP and sodium selenosulfate dramatically reduced diarrhea to 6% (p < 0.0001). Such a prominent protective effect promoted us to evaluate the safety potential of long-term sodium selenosulfate application. Mice were administered with sodium selenosulfate or sodium selenite for 55 days at the doses of 12.7 and 19 μmol/kg. The low-dose sodium selenite caused growth suppression and hepatotoxicity which were aggravated by the high-dose, leading to 40% mortality rate, but no toxic symptoms were observed in the two sodium selenosulfate groups. Altogether these results clearly show that sodium selenosulfate at an innocuous dose can markedly prevent CDDP-induced gastrointestinal toxicity. -- Highlights: ►Cisplatin resulted in diarrhea in mice by 88%. ►i.p. selenosulfate at 9.5 μmol/kg daily for 11 days reduced diarrhea to 6%. ►i.p. selenosulfate at 19 μmol/kg daily for 55 days was not toxic. ►i.p. selenite at 19 μmol/kg daily for 55 days was lethal. ►Innocuous dose of selenosulfate greatly prevents cisplatin-induced diarrhea.

TH-302, a hypoxia-activated prodrug with broad in vivo preclinical combination therapy efficacy: optimization of dosing regimens and schedules.

Science.gov (United States)

Liu, Qian; Sun, Jessica D; Wang, Jingli; Ahluwalia, Dharmendra; Baker, Amanda F; Cranmer, Lee D; Ferraro, Damien; Wang, Yan; Duan, Jian-Xin; Ammons, W Steve; Curd, John G; Matteucci, Mark D; Hart, Charles P

2012-06-01

Subregional hypoxia is a common feature of tumors and is recognized as a limiting factor for the success of radiotherapy and chemotherapy. TH-302, a hypoxia-activated prodrug selectively targeting hypoxic regions of solid tumors, delivers a cytotoxic warhead to the tumor, while maintaining relatively low systemic toxicity. The antitumor activity, different dosing sequences, and dosing regimens of TH-302 in combination with commonly used conventional chemotherapeutics were investigated in human tumor xenograft models. Seven chemotherapeutic drugs (docetaxel, cisplatin, pemetrexed, irinotecan, doxorubicin, gemcitabine, and temozolomide) were tested in combination with TH-302 in eleven human xenograft models, including non-small cell lung cancer (NSCLC), colon cancer, prostate cancer, fibrosarcoma, melanoma, and pancreatic cancer. The antitumor activity of docetaxel, cisplatin, pemetrexed, irinotecan, doxorubicin, gemcitabine, and temozolomide was increased when combined with TH-302 in nine out of eleven models tested. Administration of TH-302 2-8 h prior to the other chemotherapeutics yielded superior efficacy versus other sequences tested. Simultaneous administration of TH-302 and chemotherapeutics increased toxicity versus schedules with dosing separations. In a dosing optimization study, TH-302 administered daily at 50 mg/kg intraperitoneally for 5 days per week in the H460 NSCLC model showed the optimal response with minimal toxicity. TH-302 enhances the activity of a wide range of conventional anti-neoplastic agents in a broad panel of in vivo xenograft models. These data highlight in vivo effects of schedule and order of drug administration in regimen efficacy and toxicity and have relevance to the design of human regimens incorporating TH-302.

Serum thymidine kinase--a marker of bone marrow toxicity during treatment with zidovudine

DEFF Research Database (Denmark)

Pedersen, C; Ingeberg, S; Teglbjaerg, L S

1989-01-01

Serum thymidine kinase (S-TK) was measured weekly in 16 randomly selected patients with AIDS or AIDS-related complex (ARC; Centers for Disease Control group IV A or group IV C-2) who participated in a controlled study of the efficacy of zidovudine therapy. S-TK increased significantly (P less than...... 0.01) in the zidovudine group, whereas it remained stable in the placebo (control) group. On the basis of this observation, the value of S-TK measurements as a predictor of bone marrow toxicity during zidovudine therapy was investigated in 42 patients with AIDS or ARC who received zidovudine as part...... of their usual treatment. There was a significant association between S-TK, haemoglobin and neutrophil counts measured after the first 4 weeks of therapy and the risk of developing bone marrow toxicity during the following 6 months. Combined, measurements of S-TK and neutrophil counts seem to be well suited...

Pharmacokinetic/pharmacodynamic modeling of cardiac toxicity in human acute overdoses: utility and limitations.

Science.gov (United States)

Mégarbane, Bruno; Aslani, Arsia Amir; Deye, Nicolas; Baud, Frédéric J

2008-05-01

Hypotension, cardiac failure, QT interval prolongation, dysrhythmias, and conduction disturbances are common complications of overdoses with cardiotoxicants. Pharmacokinetic/pharmacodynamic (PK/PD) relationships are useful to assess diagnosis, prognosis, and treatment efficacy in acute poisonings. To review the utility and limits of PK/PD studies of cardiac toxicity. Discussion of various models, mainly those obtained in digitalis, cyanide, venlafaxine and citalopram poisonings. A sigmoidal E(max) model appears adequate to represent the PK/PD relationships in cardiotoxic poisonings. PK/PD correlations investigate the discrepancies between the time course of the effect magnitude and its evolving concentrations. They may help in understanding the mechanisms of occurrence as well as disappearance of a cardiotoxic effect. When data are sparse, population-based PK/PD modeling using computer-intensive algorithms is helpful to estimate population mean values of PK parameters as well as their individual variability. Further PK/PD studies are needed in medical toxicology to allow understanding of the meaning of blood toxicant concentration in acute poisonings and thus improve management.

Neurological Toxicity in Metastatic Colorectal Cancer Patients Treated with Modified FOLFOX6 plus Bevacizumab

Directory of Open Access Journals (Sweden)

Satoshi Otsu

2014-01-01

Full Text Available This study was conducted to investigate the toxicity and efficacy of modified FOLFOX6 plus bevacizumab in patients with metastatic colorectal cancer with particular regard to oxaliplatin-induced neuropathy. Toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE (version 3.0. The evaluation was especially focused on grade 2 oxaliplatin-induced neuropathy. The estimated median treatment time to occurrence of grade 2 sensory neuropathy was 7.3 months. The estimated median cumulative dose to occurrence of grade 2 sensory neuropathy was 931 mg/m 2 . This study clarified the treatment time from first dose as well as the cumulative dose of oxaliplatin leading to grade 2 neuropathy. It may be important to institute some clinical countermeasures when grade 2 neuropathy occurs so as to reduce the chance of progression to irreversible grade 3 neuropathy.

Intervention of ginger or propolis ameliorates methotrexate-induced ileum toxicity.

Science.gov (United States)

Abdul-Hamid, Manal; Salah, Marwa

2016-02-01

The long-term clinical use of methotrexate (MTX) is restricted due to its severe intestinal toxicity. The protective effect of ginger or propolis on the toxicity induced by MTX is relatively less understood, so the possible protective effect of ginger or propolis, used separately, was investigated. A total of 60 male albino rats were divided into six groups as follows: (1) control group; (2) ginger group; (3) propolis group; (4) MTX group; (5) ginger + MTX group; and (6) propolis + MTX group. The present results show that MTX caused ileum injury, including shortening and fusion of the villi, inflammatory cell infiltration and goblet cell depletion. Administration of ginger or propolis ameliorated the MTX-induced ileum injury as shown by histological, immunohistochemical and ultrastructural investigations and statistical analysis. This is revealed by intact villi, which shows marked increase in brown colouration of proliferating cell nuclear antigen positive nuclei in the crypts region, improvement in the number of goblet cells and brush border length of ileum. The current results conclude the efficacy and safety of ginger and propolis, which may be due to their antioxidant properties. © The Author(s) 2013.

MicroRNA-139-5p acts as a tumor suppressor by targeting ELTD1 and regulating cell cycle in glioblastoma multiforme

Energy Technology Data Exchange (ETDEWEB)

Dai, Shouping [Department of Diagnostic Imaging, Linyi People' s Hospital, Linyi, Shandong 276000 (China); Wang, Xianjun [Department of Neurology, Linyi People' s Hospital, Linyi, Shandong 276000 (China); Li, Xiao [Department of Pathology, First Affiliated Hospital of Nanjing Medical University, Nanjing (China); Cao, Yuandong, E-mail: yuandongcao@sina.com [Department of Radiotherapy, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province (China)

2015-11-13

MicroRNA-139-5p was identified to be significantly down-regulated in glioblastoma multiform (GBM) by miRNA array. In this report we aimed to clarify its biological function, molecular mechanisms and direct target gene in GBM. Twelve patients with GBM were analyzed for the expression of miR-139-5p by quantitative RT-PCR. miR-139-5p overexpression was established by transfecting miR-139-5p-mimic into U87MG and T98G cells, and its effects on cell proliferation were studied using MTT assay and colony formation assays. We concluded that ectopic expression of miR-139-5p in GBM cell lines significantly suppressed cell proliferation and inducing apoptosis. Bioinformatics coupled with luciferase and western blot assays also revealed that miR-139-5p suppresses glioma cell proliferation by targeting ELTD1 and regulating cell cycle. - Highlights: • miR-139-5p is downregulated in GBM. • miR-139-5p regulates cell proliferation through inducing apoptosis. • miR-139-5p regulates glioblastoma tumorigenesis by targeting 3′UTR of ELTD1. • miR-139-5p is involved in cell cycle regulation.

Toxic Elements

DEFF Research Database (Denmark)

Hajeb, Parvaneh; Shakibazadeh, Shahram; Sloth, Jens Jørgen

2016-01-01

Food is considered the main source of toxic element (arsenic, cadmium, lead, and mercury) exposure to humans, and they can cause major public health effects. In this chapter, we discuss the most important sources for toxic element in food and the foodstuffs which are significant contributors to h...

Effect of Common Species of Florida Landscaping Plants on the Efficacy of Attractive Toxic Sugar Baits Against Aedes albopictus.

Science.gov (United States)

Seeger, Kelly E; Scott, Jodi M; Muller, Gunter C; Qualls, Whitney A; Xue, Rui-De

2017-06-01

Attractive toxic sugar bait (ATSB) was applied to 5 different types of commonly found plants in landscaping of northeastern Florida. The ATSB applications were assessed for possible plant effects and preference against Aedes albopictus in semifield evaluations. Positive and negative controls consisted of plants sprayed with attractive sugar bait (no toxicant) and plants with nothing applied. Bioassays were conducted on stems with leaf clippings and on full plants to assess any difference in mosquito mortality on the different plants. Plants utilized in these evaluations were Indian hawthorne, Yaupon holly, Japanese privet, Loropetalum ruby, and podocarpus. In both assays, no significant difference was observed in the effect of ATSBs on adult female mosquitoes based on the type of plant. ATSB could be applied to common landscape plants for adult Ae. albopictus control.

Acute toxicity study of tilmicosin-loaded hydrogenated castor oil-solid lipid nanoparticles

Directory of Open Access Journals (Sweden)

Xie Shuyu

2011-11-01

Full Text Available Abstract Background Our previous studies demonstrated that tilmicosin-loaded hydrogenated castor oil solid lipid nanoparticles (Til-HCO-SLN are a promising formulation for enhanced pharmacological activity and therapeutic efficacy in veterinary use. The purpose of this work was to evaluate the acute toxicity of Til-HCO-SLN. Methods Two nanoparticle doses were used for the study in ICR mice. The low dose (766 mg/kg.bw with tilmicosin 7.5 times of the clinic dosage and below the median lethal dose (LD50 was subcutaneously administered twice on the first and 7th day. The single high dose (5 g/kg.bw was the practical upper limit in an acute toxicity study and was administered subcutaneously on the first day. Blank HCO-SLN, native tilmicosin, and saline solution were included as controls. After medication, animals were monitored over 14 days, and then necropsied. Signs of toxicity were evaluated via mortality, symptoms of treatment effect, gross and microscopic pathology, and hematologic and biochemical parameters. Results After administration of native tilmicosin, all mice died within 2 h in the high dose group, in the low dose group 3 died after the first and 2 died after the second injections. The surviving mice in the tilmicosin low dose group showed hypoactivity, accelerated breath, gloomy spirit and lethargy. In contrast, all mice in Til-HCO-SLN and blank HCO-SLN groups survived at both low and high doses. The high nanoparticle dose induced transient clinical symptoms of treatment effect such as transient reversible action retardation, anorexy and gloomy spirit, increased spleen and liver coefficients and decreased heart coefficients, microscopic pathological changes of liver, spleen and heart, and minor changes in hematologic and biochemical parameters, but no adverse effects were observed in the nanoparticle low dose group. Conclusions The results revealed that the LD50 of Til-HCO-SLN and blank HCO-SLN exceeded 5 g/kg.bw and thus the

Management of cisplatin toxicity and chromosomal aberration by vitamin E in male rats

International Nuclear Information System (INIS)

Ali, S.E.; Mohamed, N.E.; Salama, M.A.

2007-01-01

Cisplatin is one of the most active antineoplastic drugs showing a broad therapeutic activity spectrum against different types of human neoplasms. To elvaute the subacute toxicity of the drug and to test the probable preventive effect of vitamin E in rats, forty-eight male albino rats were used in this study. Animals were classified into four groups, control, vitamin E, cisplatin and vitamin E with cisplatin. Vitamin E was administered orally at a dose of 2 mg/rat for two weeks prior to cisplatin intraperitoneal injection (5 mg/kg as a single dose) and then administration of vitamin E which was continued for two another weeks (end of experiment). The changes in body weight, counts of RBC and WBC, lipid peroxide, Na + , K + , chromosomal aberration and aldosterone hormone were recorded. Cisplatin administration caused 57.4% and 60% mortality at 3 and 5 weeks intervals. Regular intake of vitamin E induced significant role against the physiological disorders and chromosomal alterations occurred after cisplatin drug administration. The present study is directed to demonstrate the toxic effect of cisplatin on mortality, body weight, blood cells, aldosterone hormone, lipid peroxidation, Na + , K + , urea, creatinia as well as on chromosomal pattern and the efficacy of vitamin E in modulating cisplatin toxicity

Preclinical renal cancer chemopreventive efficacy of geraniol by modulation of multiple molecular pathways

International Nuclear Information System (INIS)

Ahmad, Shiekh Tanveer; Arjumand, Wani; Seth, Amlesh; Nafees, Sana; Rashid, Summya; Ali, Nemat; Sultana, Sarwat

2011-01-01

Graphical abstract: Diagrammatic presentation of the hypothesis of the article in a concise manner. It reveals the chemopreventive efficacy of GOH possibly through the modulation of multiple molecular targets. GOH inhibits ROS generation, NFκB and PCNA expression thereby abrogating inflammation and proliferation of tubular cells of kidney. Whereas, GOH induces effector caspase-3 expression both through mitochondrial signalling pathway and death receptor signalling pathway. Highlights: → Geraniol modulates renal carcinogenesis in Wistar rats. → It abrogates Fe-NTA induced oxidative stress, inflammation and hyperproliferation. → Promotes apoptosis via induction of both mitochondrial and death receptor pathway. → Thus, inhibits renal carcinogenesis by modulating multiple molecular targets. -- Abstract: In the present study, we have evaluated the chemopreventive potential of geraniol (GOH), an acyclic monoterpene alcohol against ferric nitrilotriacetate (Fe-NTA) induced renal oxidative stress and carcinogenesis in Wistar rats. Chronic treatment of Fe-NTA induced oxidative stress, inflammation and cellular proliferation in Wistar rats. The chemopreventive efficacy of GOH was studied in terms of xenobiotic metabolizing enzyme activities, LPO, redox status, serum toxicity markers and the expression of putative nephrotoxicity biomarker Kim-1, tumor suppressor gene P53, inflammation, cell proliferation and apoptosis related genes in the kidney tissue. Oral administration of GOH at doses of 100 and 200 mg/kg b wt effectively suppressed renal oxidative stress and tumor incidence. Chemopreventive effects of GOH were associated with upregulation of xenobiotic metabolizing enzyme activities and down regulation of serum toxicity markers. GOH was able to down regulate expression of Kim-1, NFκB, PCNA, P53 along with induction of apoptosis. However, higher dose of GOH was more effective in modulating these multiple molecular targets both at transcriptional and protein

Randomized Phase III Trial to Test Accelerated Versus Standard Fractionation in Combination With Concurrent Cisplatin for Head and Neck Carcinomas in the Radiation Therapy Oncology Group 0129 Trial: Long-Term Report of Efficacy and Toxicity

Science.gov (United States)

Nguyen-Tan, Phuc Felix; Zhang, Qiang; Ang, K. Kian; Weber, Randal S.; Rosenthal, David I.; Soulieres, Denis; Kim, Harold; Silverman, Craig; Raben, Adam; Galloway, Thomas J.; Fortin, André; Gore, Elizabeth; Westra, William H.; Chung, Christine H.; Jordan, Richard C.; Gillison, Maura L.; List, Marcie; Le, Quynh-Thu

2014-01-01

Purpose We tested the efficacy and toxicity of cisplatin plus accelerated fractionation with a concomitant boost (AFX-C) versus standard fractionation (SFX) in locally advanced head and neck carcinoma (LA-HNC). Patients and Methods Patients had stage III to IV carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx. Radiation therapy schedules were 70 Gy in 35 fractions over 7 weeks (SFX) or 72 Gy in 42 fractions over 6 weeks (AFX-C). Cisplatin doses were 100 mg/m2 once every 3 weeks for two (AFX-C) or three (SFX) cycles. Toxicities were scored by using National Cancer Institute Common Toxicity Criteria 2.0 and the Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer criteria. Overall survival (OS) and progression-free survival (PFS) rates were estimated by using the Kaplan-Meier method and were compared by using the one-sided log-rank test. Locoregional failure (LRF) and distant metastasis (DM) rates were estimated by using the cumulative incidence method and Gray's test. Results In all, 721 of 743 patients were analyzable (361, SFX; 360, AFX-C). At a median follow-up of 7.9 years (range, 0.3 to 10.1 years) for 355 surviving patients, no differences were observed in OS (hazard ratio [HR], 0.96; 95% CI, 0.79 to 1.18; P = .37; 8-year survival, 48% v 48%), PFS (HR, 1.02; 95% CI, 0.84 to 1.24; P = .52; 8-year estimate, 42% v 41%), LRF (HR, 1.08; 95% CI, 0.84 to 1.38; P = .78; 8-year estimate, 37% v 39%), or DM (HR, 0.83; 95% CI, 0.56 to 1.24; P = .16; 8-year estimate, 15% v 13%). For oropharyngeal cancer, p16-positive patients had better OS than p16-negative patients (HR, 0.30; 95% CI, 0.21 to 0.42; P < .001; 8-year survival, 70.9% v 30.2%). There were no statistically significant differences in the grade 3 to 5 acute or late toxicities between the two arms and p-16 status. Conclusion When combined with cisplatin, AFX-C neither improved outcome nor increased late toxicity in patients with LA-HNC. Long-term high survival

Phase II Trial of Radiosurgery to Magnetic Resonance Spectroscopy–Defined High-Risk Tumor Volumes in Patients With Glioblastoma Multiforme

International Nuclear Information System (INIS)

Einstein, Douglas B.; Wessels, Barry; Bangert, Barbara; Fu, Pingfu; Nelson, A. Dennis; Cohen, Mark; Sagar, Stephen; Lewin, Jonathan; Sloan, Andrew; Zheng Yiran; Williams, Jordonna; Colussi, Valdir; Vinkler, Robert; Maciunas, Robert

2012-01-01

Purpose: To determine the efficacy of a Gamma Knife stereotactic radiosurgery (SRS) boost to areas of high risk determined by magnetic resonance spectroscopy (MRS) functional imaging in addition to standard radiotherapy for patients with glioblastoma (GBM). Methods and Materials: Thirty-five patients in this prospective Phase II trial underwent surgical resection or biopsy for a GBM followed by SRS directed toward areas of MRS-determined high biological activity within 2 cm of the postoperative enhancing surgical bed. The MRS regions were determined by identifying those voxels within the postoperative T2 magnetic resonance imaging volume that contained an elevated choline/N-acetylaspartate ratio in excess of 2:1. These voxels were marked, digitally fused with the SRS planning magnetic resonance image, targeted with an 8-mm isocenter per voxel, and treated using Radiation Therapy Oncology Group SRS dose guidelines. All patients then received conformal radiotherapy to a total dose of 60 Gy in 2-Gy daily fractions. The primary endpoint was overall survival. Results: The median survival for the entire cohort was 15.8 months. With 75% of recursive partitioning analysis (RPA) Class 3 patients still alive 18 months after treatment, the median survival for RPA Class 3 has not yet been reached. The median survivals for RPA Class 4, 5, and 6 patients were 18.7, 12.5, and 3.9 months, respectively, compared with Radiation Therapy Oncology Group radiotherapy-alone historical control survivals of 11.1, 8.9, and 4.6 months. For the 16 of 35 patients who received concurrent temozolomide in addition to protocol radiotherapeutic treatment, the median survival was 20.8 months, compared with European Organization for Research and Treatment of Cancer historical controls of 14.6 months using radiotherapy and temozolomide. Grade 3/4 toxicities possibly attributable to treatment were 11%. Conclusions: This represents the first prospective trial using selective MRS-targeted functional SRS

CTLA-4 blockade with ipilimumab: biology, safety, efficacy, and future considerations

International Nuclear Information System (INIS)

Camacho, Luis H

2015-01-01

Melanoma remains a critical public health problem worldwide. Patients with stage IV disease have very poor prognosis and their 1-year survival rate is only 25%. Until recently, systemic treatments with a positive impact on overall survival (OS) had remained elusive. In recent years, the United States Food and Drug Administration (FDA) – approved several novel agents targeting the RAS/RAF/MEK/ERK pathway (vemurafenib, dabrafenib, and trametinib) – critical in cell division and proliferation of melanoma, and an immune checkpoint inhibitor (ipilimumab) directed against the cytotoxic T lymphocyte Antigen - (CTLA-4). Moreover, recent reports of clinical trials studying other immune checkpoint modulating agents will most likely result in their FDA approval within the next months. This review focuses on ipilimumab, its safety and efficacy, and future considerations. Ipilimumab has demonstrated a positive OS impact after a several-year follow-up. It is also recognized that due to its mechanism of action, the response patterns to ipilimumab can differ from those observed in patients following treatment with conventional cytotoxic agents and even the most recently approved BRAF inhibitors. Most patients (84.8%) experience drug-related adverse events (AEs) of any grade; most of these are mild to moderate and immune mediated. However, a minority of patients may also experience severe and life-threatening AEs. In clinical studies, AEs were managed according to guidelines that emphasized close clinical monitoring and early use of corticosteroids when appropriate. Preliminary results have taught us the potential greater toxicity when in combination with vemurafenib, and the greater antitumor efficacy when combined with nivolumab, a monoclonal antibody directed against programmed death receptor-1 (PD-1), another immune checkpoint inhibitor. Future challenges include the optimization of dosing and toxicities when used as a single agent, and studying the safety and efficacy of

CXCR4 expression varies significantly among different subtypes of glioblastoma multiforme (GBM) and its low expression or hypermethylation might predict favorable overall survival.

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Ma, Xinlong; Shang, Feng; Zhu, Weidong; Lin, Qingtang

2017-09-01

CXCR4 is an oncogene in glioblastoma multiforme (GBM) but the mechanism of its dysregulation and its prognostic value in GBM have not been fully understood. Bioinformatic analysis was performed by using R2 and the UCSC Xena browser based on data from GSE16011 in GEO datasets and in GBM cohort in TCGA database (TCGA-GBM). Kaplan Meier curves of overall survival (OS) were generated to assess the association between CXCR4 expression/methylation and OS in patients with GBM. GBM patients with high CXCR4 expression had significantly worse 5 and 10 yrs OS (p GBM subtypes, there was an inverse relationship between overall DNA methylation and CXCR4 expression. CXCR4 expression was significantly lower in CpG island methylation phenotype (CIMP) group than in non CIMP group. Log rank test results showed that patients with high CXCR4 methylation (first tertile) had significantly better 5 yrs OS (p = 0.038). CXCR4 expression is regulated by DNA methylation in GBM and its low expression or hypermethylation might indicate favorable OS in GBM patients.

A toxicity reduction evaluation for an oily waste treatment plant exhibiting episodic effluent toxicity.

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Erten-Unal, M; Gelderloos, A B; Hughes, J S

1998-07-30

A Toxicity Reduction Evaluation (TRE) was conducted on the oily wastewater treatment plant (Plant) at a Naval Fuel Depot. The Plant treats ship and ballast wastes, berm water from fuel storage areas and wastes generated in the fuel reclamation plant utilizing physical/chemical treatment processes. In the first period of the project (Period I), the TRE included chemical characterization of the plant wastewaters, monitoring the final effluent for acute toxicity and a thorough evaluation of each treatment process and Plant operating procedures. Toxicity Identification Evaluation (TIE) procedures were performed as part of the overall TRE to characterize and identify possible sources of toxicity. Several difficulties were encountered because the effluent was saline, test organisms were marine species and toxicity was sporadic and unpredictable. The treatability approach utilizing enhancements, improved housekeeping, and operational changes produced substantial reductions in the acute toxicity of the final effluent. In the second period (Period II), additional acute toxicity testing and chemical characterization were performed through the Plant to assess the long-term effects of major unit process improvements for the removal of toxicity. The TIE procedures were also modified for saline wastewaters to focus on suspected class of toxicants such as surfactants. The TRE was successful in reducing acute toxicity of the final effluent through process improvements and operational modifications. The results indicated that the cause of toxicity was most likely due to combination of pollutants (matrix effect) rather than a single pollutant.

Protective Efficacy of Emodin against γ-Rays Induced Acute Hepatorenal Injury in Rats

International Nuclear Information System (INIS)

Ibrahim, S.I.; Lotfi, S.A.

2011-01-01

Emodin(C 16 H 12 O 5 ), an active principle extracted from Rheum palmatum. Its protective effect was evaluated against γ-rays-induced biochemical alterations in rats. The purpose of recent study is to demonstrate protective efficacy of emodin against γ-rays induced acute hepatorenal injury in rats.γ -irradiation (6 Gy) caused significant elevation in the release of serum alanine and aspartate transaminases, (ALT and AST), alkaline phosphatase (SALP), lactate dehydrogenase (LDH), bilirubin (Br) and glucose (Gu) with concomitant decrease in haemoglobin (Hb) after 24 h of its exposure. Toxicant exposure intensified the lipid peroxidation (LPO, measured as MDA units), total cholesterol (TC) and activity of acid phosphatase (TAC) and altered glutathione status (GSH), activities of adenosine triphosphatase (ATP), alkaline phosphatase (TALP), glutamate dehydrogenase (GDH) as well as major cellular constituents; total proteins (TP) and glycogen (Gn) in liver and kidney, compared to control measures. Emodin, oral treatment, significantly lessened the toxicity by protecting γ-rays-induced alterations in various blood and tissue biochemical variables, compared to irradiated groups. Thus, the study concluded that emodin at a dose of 40 mg/ kg body wt possesses optimum hepatorenal protective ability in γ-irradiated toxicant rats

Toxicity and cosmetic outcome of three-dimensional conformal radiotherapy for accelerated partial breast irradiation

International Nuclear Information System (INIS)

Gatti, M.; Bresciani, S.; Ponzone, R.; Panaia, R.; Salatino, A.; Stasi, M.; Gabriele, P.

2011-01-01

Full text of publication follows: Purpose.- To analyse the incidence and severity of acute and late normal tissue toxicity and cosmetic outcome using three - dimensional conformal radiotherapy to deliver accelerated partial breast irradiation. Patients and Methods.- 70 patients with stage I disease were treated with three-dimensional conformal radiotherapy for accelerated partial breast irradiation, in an approved protocol. The prescribed dose was 34 Gy in all patients delivered in 10 fractions over 5 consecutive days. On all CT scans gross tumor volume (GTV ) was defined around surgical clips. A 1.5 cm margin was added in order to account for clinical target volume (CTV) . A margin of 1 cm was added to CTI to define the planning target volume (PTV). The dose-volume constraints were followed in accordance with the specifications as dictated in the NSABP/RTOG protocol. After treatment, patients underwent a clinical and cosmetic evaluation every 3 months. Late toxicity was evaluated according to the RTOG grading schema. The cosmetic assessment was performed by the physicians using the controlateral untreated breast as the reference (Harvard scale). Results.- Median patient age was 66 years (range 51-80). Median follow-up was 15 months (range 6-46). Tumor size was 2 cm in 4(6%). The mean value of the ratio between the PTV and the whole ipsilateral breast volume was 38 % and the median percentage whole breast volume that received 95 % of prescribed dose was 34% (range 16%-55%). The rate of G1 and G2 acute skin toxicity was 28% and 2% respectively and the late toxicity was 17% (G1). G2 or greater toxicities were not observed. The most pronounced G1 late toxicity was subcutaneous fibrosis, developed in 3 patients. The cosmetic outcome was excellent in 83% and good in 17%. Conclusion.- Accelerated partial breast irradiation using three-dimensional conformal radiotherapy is technically feasible with very low acute and late toxicity. Long-term results are needed to assess

What is the value of emission tomography studies in patients with a primary glioblastoma multiforme treated by 192Ir brachytherapy?

International Nuclear Information System (INIS)

Koot, R.W.; Bosch, D.A.; Habraken, J.B.A.; Hulshof, M.C.C.M.; Paans, A.M.J.; Pruim, J.

2008-01-01

We studied the use of 201 thallium SPECT and L-[1- 11 C]-tyrosine PET in patients with a primary glioblastoma multiforme treated with 192 Ir brachytherapy after surgery and external beam radiation therapy. We hypothesised that the patients most likely to benefit from further surgery after deterioration would be those with radiation necrosis and would be recognised by a negative emission tomography scan. Twenty-one patients underwent 201 thallium SPECT performed before brachytherapy, and this was repeated in 19 patients when recurrence was suspected. Nine patients also underwent a PET scan at the same time. Nine patients underwent a second operation. SPECT and PET were highly concordant concerning the prediction of radionecrosis and/or tumor recurrence. Repeat surgery did not lead to a significant increase in survival. There was no significant association between the duration of survival and tumor-to-background ratio but the number studied was small. Both SPECT and PET showed highly active lesions, which were proved to be recurrent tumor by clinical and histological follow-up. Although PET and SPECT are both highly sensitive in detecting active tumor tissue, emission tomography was not clinically valuable in the investigation of patients with a primary glioblastoma treated with brachytherapy. (author)

Clinical outcomes and toxicity of proton beam therapy for advanced cholangiocarcinoma

International Nuclear Information System (INIS)

Makita, Chiyoko; Kikuchi, Yasuhiro; Hareyama, Masato; Murakami, Masao; Fuwa, Nobukazu; Hata, Masaharu; Inoue, Tomio; Nakamura, Tatsuya; Takada, Akinori; Takayama, Kanako; Suzuki, Motohisa; Ishikawa, Yojiro; Azami, Yusuke; Kato, Takahiro; Tsukiyama, Iwao

2014-01-01

We examined the efficacy and toxicity of proton beam therapy (PBT) for treating advanced cholangiocarcinoma. The clinical data and outcomes of 28 cholangiocarcinoma patients treated with PBT between January 2009 and August 2011 were retrospectively examined. The Kaplan–Meier method was used to estimate overall survival (OS), progression-free survival (PFS), and local control (LC) rates, and the log-rank test to analyze the effects of different clinical and treatment variables on survival. Acute and late toxicities were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. The median age of the 17 male and 11 female patients was 71 years (range, 41 to 84 years; intrahepatic/peripheral cholangiocarcinoma, n = 6; hilar cholangiocarcinoma/Klatskin tumor, n = 6; distal extrahepatic cholangiocarcinoma, n = 3; gallbladder cancer, n = 3; local or lymph node recurrence, n = 10; size, 20–175 mm; median 52 mm). The median radiation dose was 68.2 Gy (relative biological effectiveness [RBE]) (range, 50.6 to 80 Gy (RBE)), with delivery of fractions of 2.0 to 3.2 Gy (RBE) daily. The median follow-up duration was 12 months (range, 3 to 29 months). Fifteen patients underwent chemotherapy and 8 patients, palliative biliary stent placement prior to PBT. OS, PFS, and LC rates at 1 year were 49.0%, 29.5%, and 67.7%, respectively. LC was achieved in 6 patients, and was better in patients administered a biologically equivalent dose of 10 (BED10) > 70 Gy compared to those administered < 70 Gy (83.1% vs. 22.2%, respectively, at 1 year). The variables of tumor size and performance status were associated with survival. Late gastrointestinal toxicities grade 2 or greater were observed in 7 patients <12 months after PBT. Cholangitis was observed in 11 patients and 3 patients required stent replacement. Relatively high LC rates after PBT for advanced cholangiocarcinoma can be achieved by delivery of a BED10 > 70 Gy. Gastrointestinal

Estimation of toxicity using the Toxicity Estimation Software Tool (TEST)

Science.gov (United States)

Tens of thousands of chemicals are currently in commerce, and hundreds more are introduced every year. Since experimental measurements of toxicity are extremely time consuming and expensive, it is imperative that alternative methods to estimate toxicity are developed.

Children's Ability to Recognise Toxic and Non-Toxic Fruits

Science.gov (United States)

Fancovicova, Jana; Prokop, Pavol

2011-01-01

Children's ability to identify common plants is a necessary prerequisite for learning botany. However, recent work has shown that children lack positive attitudes toward plants and are unable to identify them. We examined children's (aged 10-17) ability to discriminate between common toxic and non-toxic plants and their mature fruits presented in…

Phase I trial of verubulin (MPC-6827) plus carboplatin in patients with relapsed glioblastoma multiforme.

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Grossmann, Kenneth F; Colman, Howard; Akerley, Wallace A; Glantz, Michael; Matsuoko, Yuko; Beelen, Andrew P; Yu, Margaret; De Groot, John F; Aiken, Robert D; Olson, Jeffrey J; Olsen, Jeffery J; Evans, Brent A; Jensen, Randy L

2012-11-01

Verubulin (MPC-6827) is a microtubule-destabilizing agent that achieves high concentrations in the brain. Verubulin disrupts newly formed blood vessels in xenografts. We determined the safety and tolerability of verubulin administered in combination with carboplatin in patients with relapsed glioblastoma multiforme (GBM). Three pre-selected doses of verubulin were tested: 2.1, 2.7, and 3.3 mg/m(2) in a standard "3+3" design. Verubulin was given every second week of a 6-week cycle in the 2.1 mg/m(2) cohort or weekly for 3 weeks of a 4-week cycle in subsequent cohorts. Carboplatin was administered intravenously at an area under the curve (AUC) dosage 4 every 2 weeks for the 2.1 mg/m(2) cohort or on day 1 of each 4-week cycle in subsequent cohorts. Nineteen patients with GBM in first or second relapse were enrolled. Four patients (21 %) experienced a grade 3 or greater verubulin- or carboplatin-related adverse event, including hypesthesia, cerebral ischemia, anemia, and thrombocytopenia. The mean plasma half life of verubulin was 3.2 h (SD = 0.82). Two patients achieved at least a partial response by Macdonald criteria. One of these patients remains progression free and off treatment more than 24 months beyond his initiation of verubulin. Five patients had stable disease. Median progression-free survival (PFS) across all patients was 8 weeks, and the 6-month PFS rate was 21 %. The combination of verubulin at the previously determined single-agent maximum tolerated dose of 3.3 mg/m(2) with carboplatin in patients with recurrent/refractory GBM is safe and well tolerated. In this patient population with a highly vascularized tumor, no cerebral hemorrhage was observed.

Impact of CD133 positive stem cell proportion on survival in patients with glioblastoma multiforme

International Nuclear Information System (INIS)

Kase, Marju; Minajeva, Ave; Niinepuu, Kristi; Kase, Sandra; Vardja, Markus; Asser, Toomas; Jaal, Jana

2013-01-01

The aim of the study was to assess the impact of CD133-positive (CD133+) cancer stem cell proportions on treatment results of glioblastoma multiforme (GBM) patients. Patients with GBM (n = 42) received postoperative radiotherapy (± chemotherapy). Surgically excised GBM tissue sections were immunohistochemically examined for CD133 expression. The proportions of CD133+ GBM cells were determined (%). The proportion of CD133+ GBM stem cells was established by 2 independent researchers whose results were in good accordance (R = 0.8, p < 0.01). Additionally, CD133 expression levels were correlated with patients overall survival. The proportion of CD133+ cells varied between patients, being from 0.5% to 82%. Mean and median proportions of CD133+ cells of the entire study group were 33% ± 24% (mean ± SD) and 28%, respectively. Clinical data do not support the association between higher proportion of stem cells and the aggressiveness of GBM. Median survival time of the study group was 10.0 months (95% CI 9.0–11.0). The survival time clearly depended on the proportion of CD133+ cells (log rank test, p = 0.02). Median survival times for patients with low (< median) and high (≥ median) proportion of CD133+ cells were 9.0 months (95% CI 7.6–10.5) and 12.0 months (95% CI 9.3–14.7), respectively. In multivariate analysis, the proportion of CD133+ cells emerged as a significant independent predictor for longer overall survival (HR 2.0, 95% CI 1.0–3.8, p = 0.04). In patients with higher stem cell proportion, significantly longer survival times after postoperative radiotherapy were achieved. Underlying reasons and possible higher sensitivity of GBM stem cells to fractionated radio-therapy should be clarified in further studies

Toxic substances handbook

Science.gov (United States)

Junod, T. L.

1979-01-01

Handbook, published in conjunction with Toxic Substances Alert Program at NASA Lewis Research Center, profiles 187 toxic chemicals in their relatively pure states and include 27 known or suspected carcinogens.

Oxidative Stress and Nano-Toxicity Induced by TiO2 and ZnO on WAG Cell Line.

Directory of Open Access Journals (Sweden)

Akhilesh Dubey

Full Text Available Metallic nanoparticles are widely used in cosmetics, food products and textile industry. These particles are known to cause respiratory toxicity and epithelial inflammation. They are eventually released to aquatic environment necessitating toxicity studies in cells from respiratory organs of aquatic organisms. Hence, we have developed and characterized a new cell line, WAG, from gill tissue of Wallago attu for toxicity assessment of TiO2 and ZnO nanoparticles. The efficacy of the cell line as an in vitro system for nanoparticles toxicity studies was established using electron microscopy, cytotoxicity assays, genotoxicity assays and oxidative stress biomarkers. Results obtained with MTT assay, neutral red uptake assay and lactate dehydrogenase assay showed acute toxicity to WAG cells with IC50 values of 25.29 ± 0.12, 34.99 ± 0.09 and 35.06 ± 0.09 mg/l for TiO2 and 5.716 ± 0.1, 3.160 ± 0.1 and 5.57 ± 0.12 mg/l for ZnO treatment respectively. The physicochemical properties and size distribution of nanoparticles were characterized using electron microscopy with integrated energy dispersive X-ray spectroscopy and Zetasizer. Dose dependent increase in DNA damage, lipid peroxidation and protein carbonylation along with a significant decrease in activity of Superoxide Dismutase, Catalase, total Glutathione levels and total antioxidant capacity with increasing concentration of exposed nanoparticles indicated that the cells were under oxidative stress. The study established WAG cell line as an in vitro system to study toxicity mechanisms of nanoparticles on aquatic organisms.

Toxicity evaluation and prediction of toxic chemicals on activated sludge system.

Science.gov (United States)

Cai, Bijing; Xie, Li; Yang, Dianhai; Arcangeli, Jean-Pierre

2010-05-15

The gaps of data for evaluating toxicity of new or overloaded organic chemicals on activated sludge system resulted in the requirements for methodology of toxicity estimation. In this study, 24 aromatic chemicals typically existed in the industrial wastewater were selected and classified into three groups of benzenes, phenols and anilines. Their toxicity on activated sludge was then investigated. Two indexes of IC(50-M) and IC(50-S) were determined respectively from the respiration rates of activated sludge with different toxicant concentration at mid-term (24h) and short-term (30min) time intervals. Experimental results showed that the group of benzenes was the most toxic, followed by the groups of phenols and anilines. The values of IC(50-M) of the tested chemicals were higher than those of IC(50-S). In addition, quantitative structure-activity relationships (QSARs) models developed from IC(50-M) were more stable and accurate than those of IC(50-S). The multiple linear models based on molecular descriptors and K(ow) presented better reliability than single linear models based on K(ow). Among these molecular descriptors, E(lumo) was the most important impact factor for evaluation of mid-term toxicity. Copyright (c) 2009 Elsevier B.V. All rights reserved.

Efficacy of piroxicam plus cisplatin-loaded PLGA nanoparticles in inducing apoptosis in mesothelioma cells.

Science.gov (United States)

Menale, Ciro; Piccolo, Maria Teresa; Favicchia, Ilaria; Aruta, Maria Grazia; Baldi, Alfonso; Nicolucci, Carla; Barba, Vincenzo; Mita, Damiano Gustavo; Crispi, Stefania; Diano, Nadia

2015-02-01

Combined treatment based on cisplatin-loaded Poly(D,L-lactic-co-glicolic)acid (PLGA) nanoparticles (NP-C) plus the NSAID piroxicam was used as novel treatment for mesothelioma to reduce side effects related to cisplatin toxicity. PLGA nanoparticles were prepared by double emulsion solvent evaporation method. Particle size, drug release profile and in vitro cellular uptake were characterized by TEM, DLS, LC/MS and fluorescence microscopy. MSTO-211H cell line was used to analyse NP-C biological efficacy by FACS and protein analysis. Cisplatin was encapsulated in 197 nm PLGA nanoparticles with 8.2% drug loading efficiency and 47% encapsulation efficiency. Cisplatin delivery from nanoparticles reaches 80% of total encapsulated drug in 14 days following a triphasic trend. PLGA nanoparticles in MSTO-211H cells were localized in the perinuclear space NP-C in combination with piroxicam induced apoptosis using a final cisplatin concentration 1.75 fold less than free drug. Delivered cisplatin cooperated with piroxicam in modulating cell cycle regulators as caspase-3, p53 and p21. Cisplatin loaded PLGA nanoparticles plus piroxicam showed a good efficacy in exerting cytotoxic activity and inducing the same molecular apoptotic effects of the free drugs. Sustained cisplatin release allowed to use less amount of drug, decreasing toxic side effects. This novel approach could represent a new strategy for mesothelioma treatment.

Response and toxicity of photodynamic therapy for canine bladder carcinoma

International Nuclear Information System (INIS)

Beck, E.R.; Dunstan, R.W.

1992-01-01

This investigation was to determine PDT efficacy and tolerance (both short term and long term) in dogs with spontaneously occurring transitional cell carcinoma of the urinary bladder. All patients were T2-T3, N x , M o . 27 dogs were given Photofrin II at 3.0 mg/kg IV, and 72 hours later doses of 632 nm light from 5-25 J/cm 2 . In 25/27 dogs, PDT resulted in complete remission of stranguria, hematuria and pollackiuria within one week of treatment. Gross hematuria increased in 7 dogs for the first 2 days following treatment, but then disappeared completely. Duration of clinical remission varied from 5-25 weeks after single treatment, within a median duration of 10 weeks. Doses of light from 5-10 J/cm 2 were well tolerated, with only mild toxicity for 1-3 days. Moderate toxicity showed in some dogs given 10-15 J/cm 2 . In all dogs given 25 J/cm 2 and 46% of those given 15 J/cm 2 , severe abdominal cramping, fecal incontinence, perforations and sepsis was seen. A second PDT treatment of 10-15 J/cm 2 following recurrence of clinical signs was administered to 9 dogs, without an increase in toxicity beyond that seen following the first treatment. Median duration of this second remission was 8 weeks, with a range of 5-12 weeks. 4-5 multiple PDT treatments were given to 4 dogs without any clinical symptoms of decreased bladder function. Each treatment produced an additional remission of variable length. (author). 14 refs., 1 fig., 1 tab

Semifield testing of a bioremediation tool for atrazine-contaminated soils: evaluating the efficacy on soil and aquatic compartments.

Science.gov (United States)

Chelinho, Sónia; Moreira-Santos, Matilde; Silva, Cátia; Costa, Catarina; Viana, Paula; Viegas, Cristina A; Fialho, Arsénio M; Ribeiro, Rui; Sousa, José Paulo

2012-07-01

The present study evaluated the bioremediation efficacy of a cleanup tool for atrazine-contaminated soils (Pseudomonas sp. ADP plus citrate [P. ADP + CIT]) at a semifield scale, combining chemical and ecotoxicological information. Three experiments representing worst-case scenarios of atrazine contamination for soil, surface water (due to runoff), and groundwater (due to leaching) were performed in laboratory simulators (100 × 40 × 20 cm). For each experiment, three treatments were set up: bioremediated, nonbioremediated, and a control. In the first, the soil was sprayed with 10 times the recommended dose (RD) for corn of Atrazerba and with P. ADP + CIT at day 0 and a similar amount of P. ADP at day 2. The nonbioremediated treatment consisted of soil spraying with 10 times the RD of Atrazerba (day 0). After 7 d of treatment, samples of soil (and eluates), runoff, and leachate were collected for ecotoxicological tests with plants (Avena sativa and Brassica napus) and microalgae (Pseudokirchneriella subcapitata) species. In the nonbioremediated soils, atrazine was very toxic to both plants, with more pronounced effects on plant growth than on seed emergence. The bioremediation tool annulled atrazine toxicity to A. sativa (86 and 100% efficacy, respectively, for seed emergence and plant growth). For B. napus, results point to incomplete bioremediation. For the microalgae, eluate and runoff samples from the nonbioremediated soils were extremely toxic; a slight toxicity was registered for leachates. After only 7 d, the ecotoxicological risk for the aquatic compartments seemed to be diminished with the application of P. ADP + CIT. In aqueous samples obtained from the bioremediated soils, the microalgal growth was similar to the control for runoff samples and slightly lower than control (by 11%) for eluates. Copyright © 2012 SETAC.

Determination of leachate toxicity through acute toxicity using Daphnia pulex and anaerobic toxicity assays

OpenAIRE

Carabalí-Rivera, Y. S; Barba-Ho, L. E; Torres-Lozada, P

2017-01-01

ABSTRACT The municipal solid waste (MSW) of large cities, in particular the ones of developing countries, is mainly disposed in landfills (LFs), whose inadequate management generates the emission of greenhouse gases and the production of leachates with high concentrations of organic and inorganic matter and, occasionally heavy metals. In this study, the toxicity of the leachates from an intermediate-age municipal landfill was evaluated by ecotoxicity and anaerobic toxicity tests. The acute to...

Evaluation of the Efficacy of ME1111 in the Topical Treatment of Dermatophytosis in a Guinea Pig Model

Science.gov (United States)

Long, L.; Hager, C.

2016-01-01

The treatment of dermatophytoses, including onychomycosis, has come a long way over the past few decades with the introduction of oral antifungals (e.g., terbinafine and itraconazole). However, with these advancements in oral therapies come several undesirable effects, such as kidney and liver toxicity, along with drug-drug interactions. Consequently, there is a need for new topical agents that are effective against dermatophytosis. ME1111 is a topical antifungal under development. In this study, the in vivo efficacy of ME1111 was compared to that of ciclopirox in the topical treatment of dermatophytosis caused by Trichophyton mentagrophytes using a guinea pig model. Animals were treated with the topical antifungals starting at 3 days postinfection, with each agent being applied once daily for seven consecutive days. After the treatment period, the clinical and mycological efficacies were evaluated. The data showed that both antifungals demonstrated significant clinical and mycological efficacies; however, ME1111 showed clinical efficacy superior to that of ciclopirox (46.9% and 25.0%, respectively, with a P value of <0.001). The potent efficacy of ME1111 could be attributed to its properties, such as low keratin binding. PMID:26833160

Toxic clinical hypoxic radiation sensitizers plus radiation-induced toxicity

International Nuclear Information System (INIS)

Richmond, R.C.

1984-01-01

The operational definition espoused twelve years ago that clinical hypoxic radiation sensitizers should be nontoxic interferes with the recognition and research of useful radiation sensitizers. Eight years ago the toxic antitumor drug cis-dichlorodiammineplatinum(II) was reported to be a hypoxic radiation sensitizer and the selective antitumor action of this drug was stressed as potentially creating tumor-targeted radiation sensitization. This rationale of oxidative antitumor drugs as toxic and targeted clinical sensitizers is useful, and has led to the study reported here. The antitumor drug cis-(1,1-cyclobutane-dicarboxylato)diammineplatinum(II), or JM-8, is being tested in clinical trials. Cells of S. typhimurium in PBS in the presence of 0.2mM JM-8 are found to be sensitized to irradiation under hypoxic, but not oxic, conditions. JM-8 is nontoxic to bacteria at this concentration, but upon irradiation the JM-8 solution becomes highly toxic. This radiation induced toxicity of JM-8 preferentially develops from hypoxic solution, and thus contributes to the rationale of hypoxic tumor cell destruction

The early toxicity of escalated versus standard dose conformal radiotherapy with neo-adjuvant androgen suppression for patients with localised prostate cancer: Results from the MRC RT01 trial (ISRCTN47772397)

International Nuclear Information System (INIS)

Dearnaley, David P.; Sydes, Matthew R.; Langley, Ruth E.; Graham, John D.; Huddart, Robert A.; Syndikus, Isabel; Matthews, John H.L.; Scrase, Christopher D.; Jose, Chakiath C.; Logue, John; Stephens, Richard J.

2007-01-01

Background: Five-year disease-free survival rates for localised prostate cancer following standard doses of conventional radical external beam radiotherapy are around 80%. Conformal radiotherapy (CFRT) raises the possibility that radiotherapy doses can be increased and long-term efficacy outcomes improved, with safety an important consideration. Methods: MRC RT01 is a randomised controlled trial of 862 men with localised prostate cancer comparing Standard CFRT (64 Gy/32 f) versus Escalated CFRT (74 Gy/37 f), both administered with neo-adjuvant androgen suppression. Early toxicity was measured using physician-reported instruments (RTOG, LENT/SOM, Royal Marsden Scales) and patient-reported questionnaires (MOS SF-36, UCLA Prostate Cancer Index, FACT-P). Results: Overall early radiotherapy toxicity was similar, apart from increased bladder, bowel and sexual toxicity, in the Escalated Group during a short immediate post-radiotherapy period. Toxicity in both groups had abated by week 12. Using RTOG Acute Toxicity scores, cumulative Grade ≥2 bladder and bowel toxicity was 38% and 30% for Standard Group and 39% and 33% in Escalated Group, respectively. Urinary frequency (Royal Marsden Scale) improved in both groups from pre-androgen suppression to 6 months post-radiotherapy (p < 0.001), but bowel and sexual functioning deteriorated. This pattern was supported by patient-completed assessments. Six months after starting radiotherapy the incidence of RTOG Grade ≥2 side-effects was low (<1%); but there were six reports of rectal ulceration (6 Escalated Group), six haematuria (5 Escalated Group) and eight urethral stricture (6 Escalated Group). Conclusions: The two CFRT schedules with neo-adjuvant androgen suppression have broadly similar early toxicity profiles except for the immediate post-RT period. At 6 months and compared to before hormone therapy, bladder symptoms improved, whereas bowel and sexual symptoms worsened. These assessments of early treatment safety will be

18F-Fluorothymidine-Pet Imaging of Glioblastoma Multiforme: Effects of Radiation Therapy on Radiotracer Uptake and Molecular Biomarker Patterns

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Sanjay Chandrasekaran

2013-01-01

Full Text Available Introduction. PET imaging is a useful clinical tool for studying tumor progression and treatment effects. Conventional 18F-FDG-PET imaging is of limited usefulness for imaging Glioblastoma Multiforme (GBM due to high levels of glucose uptake by normal brain and the resultant signal-to-noise intensity. 18F-Fluorothymidine (FLT in contrast has shown promise for imaging GBM, as thymidine is taken up preferentially by proliferating cells. These studies were undertaken to investigate the effectiveness of 18F-FLT-PET in a GBM mouse model, especially after radiation therapy (RT, and its correlation with useful biomarkers, including proliferation and DNA damage. Methods. Nude/athymic mice with human GBM orthografts were assessed by microPET imaging with 18F-FDG and 18F-FLT. Patterns of tumor PET imaging were then compared to immunohistochemistry and immunofluorescence for markers of proliferation (Ki-67, DNA damage and repair (γH2AX, hypoxia (HIF-1α, and angiogenesis (VEGF. Results. We confirmed that 18F-FLT-PET uptake is limited in healthy mice but enhanced in the intracranial tumors. Our data further demonstrate that 18F-FLT-PET imaging usefully reflects the inhibition of tumor by RT and correlates with changes in biomarker expression. Conclusions. 18F-FLT-PET imaging is a promising tumor imaging modality for GBM, including assessing RT effects and biologically relevant biomarkers.

Separations chemistry of toxic metals

International Nuclear Information System (INIS)

Smith, P.; Barr, M.; Barrans, R.

1996-01-01

Sequestering and removing toxic metal ions from their surroundings is an increasingly active area of research and is gaining importance in light of current environmental contamination problems both within the DOE complex and externally. One method of separating metal ions is to complex them to a molecule (a ligand or chelator) which exhibits specific binding affinity for a toxic metal, even in the presence of other more benign metals. This approach makes use of the sometimes subtle differences between toxic and non-toxic metals resulting from variations in size, charge and shape. For example, toxic metals such as chromium, arsenic, and technetium exist in the environment as oxyanions, negatively charged species with a characteristic tetrahedral shape. Other toxic metals such as actinides and heavy metals are positively charged spheres with specific affinities for particular donor atoms such as oxygen (for actinides) and nitrogen (for heavy metals). In most cases the toxic metals are found in the presence of much larger quantities of less toxic metals such as sodium, calcium and iron. The selectivity of the chelators is critical to the goal of removing the toxic metals from their less toxic counterparts. The approach was to build a ligand framework that complements the unique characteristics of the toxic metal (size, charge and shape) while minimizing interactions with non-toxic metals. The authors have designed ligands exhibiting specificity for the target metals; they have synthesized, characterized and tested these ligands; and they have shown that they exhibit the proposed selectivity and cooperative binding effects

Efficacy, safety and tolerability of sildenafil in Brazilian hypertensive patients on multiple antihypertensive drugs

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Denilson C. Albuquerque

2005-08-01

Full Text Available OBJECTIVE: To evaluate the efficacy, safety and tolerability of sildenafil among Brazilian patients with hypertension treated with combinations of anti-hypertensive drugs. MATERIALS AND METHODS: One hundred twenty hypertensive men aged 30 to 81 years old under treatment with 2 or more anti-hypertensive drugs and with erectile dysfunction (ED lasting for at least 6 months were enrolled at 7 research centers in Brazil. Patients were randomized to receive treatment with either sildenafil or placebo taken 1 hour before sexual intercourse (initial dose of 50 mg, adjusted to 25 mg or 100 mg according to efficacy and toxicity. During the following 8 weeks, patients were evaluated regarding vital signs, adverse events, therapeutic efficacy, satisfaction with treatment and use of concurrent medications. RESULTS: The primary evaluation of efficacy, which was based on responses to questions 3 and 4 of the International Index of Erectile Function, showed significant differences regarding treatment with sildenafil (p = 0.0002 and p < 0.0001, respectively. In the assessment of global efficacy, 87% of the patients treated with sildenafil reported improved erections, as compared with 37% of patients given placebos (p < 0.0001. The other secondary evaluations supported the results favoring sildenafil. The most frequent adverse events among patients treated with sildenafil were headaches (11.4%, vasodilation (11.4% and dyspepsia (6.5%. There were no significant changes in blood pressure measurements in both groups. CONCLUSION: Sildenafil is efficacious and safe for the treatment of hypertensive patients with ED who receive concurrent combinations of anti-hypertensive drugs.

Experimental Assays to Assess the Efficacy of Vinegar and Other Topical First-Aid Approaches on Cubozoan (Alatina alata) Tentacle Firing and Venom Toxicity.

Science.gov (United States)

Yanagihara, Angel A; Wilcox, Christie; King, Rebecca; Hurwitz, Kikiana; Castelfranco, Ann M

2016-01-11

Despite the medical urgency presented by cubozoan envenomations, ineffective and contradictory first-aid management recommendations persist. A critical barrier to progress has been the lack of readily available and reproducible envenomation assays that (1) recapitulate live-tentacle stings; (2) allow quantitation and imaging of cnidae discharge; (3) allow primary quantitation of venom toxicity; and (4) employ rigorous controls. We report the implementation of an integrated array of three experimental approaches designed to meet the above-stated criteria. Mechanistically overlapping, yet distinct, the three approaches comprised (1) direct application of test solutions on live tentacles (termed tentacle solution assay, or TSA) with single image- and video-microscopy; (2) spontaneous stinging assay using freshly excised tentacles overlaid on substrate of live human red blood cells suspended in agarose (tentacle blood agarose assays, or TBAA); and (3) a "skin" covered adaptation of TBAA (tentacle skin blood agarose assay, or TSBAA). We report the use and results of these assays to evaluate the efficacy of topical first-aid approaches to inhibit tentacle firing and venom activity. TSA results included the potent stimulation of massive cnidae discharge by alcohols but only moderate induction by urine, freshwater, and "cola" (carbonated soft drink). Although vinegar, the 40-year field standard of first aid for the removal of adherent tentacles, completely inhibited cnidae firing in TSA and TSBAA ex vivo models, the most striking inhibition of both tentacle firing and subsequent venom-induced hemolysis was observed using newly-developed proprietary formulations (Sting No More™) containing copper gluconate, magnesium sulfate, and urea.

Immunotoxicity, genotoxicity and epigenetic toxicity of nanomaterials: New strategies for toxicity testing?

Science.gov (United States)

Dusinska, Maria; Tulinska, Jana; El Yamani, Naouale; Kuricova, Miroslava; Liskova, Aurelia; Rollerova, Eva; Rundén-Pran, Elise; Smolkova, Bozena

2017-11-01

The unique properties of nanomaterials (NMs) are beneficial in numerous industrial and medical applications. However, they could also induce unintended effects. Thus, a proper strategy for toxicity testing is essential in human hazard and risk assessment. Toxicity can be tested in vivo and in vitro; in compliance with the 3Rs, alternative strategies for in vitro testing should be further developed for NMs. Robust, standardized methods are of great importance in nanotoxicology, with comprehensive material characterization and uptake as an integral part of the testing strategy. Oxidative stress has been shown to be an underlying mechanism of possible toxicity of NMs, causing both immunotoxicity and genotoxicity. For testing NMs in vitro, a battery of tests should be performed on cells of human origin, either cell lines or primary cells, in conditions as close as possible to an in vivo situation. Novel toxicity pathways, particularly epigenetic modification, should be assessed along with conventional toxicity testing methods. However, to initiate epigenetic toxicity screens for NM exposure, there is a need to better understand their adverse effects on the epigenome, to identify robust and reproducible causal links between exposure, epigenetic changes and adverse phenotypic endpoints, and to develop improved assays to monitor epigenetic toxicity. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Radionuclide toxicity

International Nuclear Information System (INIS)

Galle, P.

1982-01-01

The aim of this symposium was to review the radionuclide toxicity problems. Five topics were discussed: (1) natural and artificial radionuclides (origin, presence or emission in the environment, human irradiation); (2) environmental behaviour of radionuclides and transfer to man; (3) metabolism and toxicity of radionuclides (radioiodine, strontium, rare gas released from nuclear power plants, ruthenium-activation metals, rare earths, tritium, carbon 14, plutonium, americium, curium and einsteinium, neptunium, californium, uranium) cancerogenous effects of radon 222 and of its danghter products; (4) comparison of the hazards of various types of energy; (5) human epidemiology of radionuclide toxicity (bone cancer induction by radium, lung cancer induction by radon daughter products, liver cancer and leukaemia following the use of Thorotrast, thyroid cancer; other site of cancer induction by radionuclides) [fr

hERG1 channels are overexpressed in glioblastoma multiforme and modulate VEGF secretion in glioblastoma cell lines

Science.gov (United States)

Masi, A; Becchetti, A; Restano-Cassulini, R; Polvani, S; Hofmann, G; Buccoliero, A M; Paglierani, M; Pollo, B; Taddei, G L; Gallina, P; Di Lorenzo, N; Franceschetti, S; Wanke, E; Arcangeli, A

2005-01-01

Recent studies have led to considerable advancement in our understanding of the molecular mechanisms that underlie the relentless cell growth and invasiveness of human gliomas. Partial understanding of these mechanisms has (1) improved the classification for gliomas, by identifying prognostic subgroups, and (2) pointed to novel potential therapeutic targets. Some classes of ion channels have turned out to be involved in the pathogenesis and malignancy of gliomas. We studied the expression and properties of K+ channels in primary cultures obtained from surgical specimens: human ether a gò-gò related (hERG)1 voltage-dependent K+ channels, which have been found to be overexpressed in various human cancers, and human ether a gò-gò-like 2 channels, that share many of hERG1's biophysical features. The expression pattern of these two channels was compared to that of the classical inward rectifying K+ channels, IRK, that are widely expressed in astrocytic cells and classically considered a marker of astrocytic differentiation. In our study, hERG1 was found to be specifically overexpressed in high-grade astrocytomas, that is, glioblastoma multiforme (GBM). In addition, we present evidence that, in GBM cell lines, hERG1 channel activity actively contributes to malignancy by promoting vascular endothelial growth factor secretion, thus stimulating the neoangiogenesis typical of high-grade gliomas. Our data provide important confirmation for studies proposing the hERG1 channel as a molecular marker of tumour progression and a possible target for novel anticancer therapies. PMID:16175187

Pediatric Toxic Shock Syndrome

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Jennifer Yee

2017-09-01

Full Text Available Audience: This scenario was developed to educate emergency medicine residents on the diagnosis and management of a pediatric patient with toxic shock syndrome. The case is also appropriate for teaching of medical students and advanced practice providers, as well as a review of the principles of crisis resource management, teamwork, and communication. Introduction: Toxic shock syndrome is a low-frequency, high-acuity scenario requiring timely identification and aggressive management. If patients suffering from this condition are managed incorrectly, they may progress into multi-organ dysfunction and potentially death. Toxic shock syndrome has been associated with Streptococcus and Staphylococcus aureus (Staph. Approximately half of Staph cases are associated with menstruation, which was first described in the 1970s-1980s and was associated with the use of absorbent tampons.1 Group A Streptococcus may cause complications such as necrotizing fasciitis and gangrenous myositis.2 Pediatric patients may present critically ill from toxic shock syndrome. Providers need to perform a thorough history and physical exam to discern the source of infection. Management requires aggressive care with antibiotics and IV fluids. Objectives: By the end of this simulation session, the learner will be able to: 1 Recognize toxic shock syndrome. 2 Review the importance of a thorough physical exam. 3 Discuss management of toxic shock syndrome, including supportive care and the difference in antibiotic choices for streptococcal and staphylococcal toxic shock syndrome. 4 Appropriately disposition a patient suffering from toxic shock syndrome. 5 Communicate effectively with team members and nursing staff during a resuscitation of a critically ill patient. Method: This session was conducted using high-fidelity simulation, followed by a debriefing session and lecture on toxic shock syndrome.

Metabolomics and its application to the evaluation of the efficacy and toxicity of traditional Chinese herb medicines.

Science.gov (United States)

Shi, Jian; Cao, Bei; Wang, Xin-Wen; Aa, Ji-Ye; Duan, Jin-Ao; Zhu, Xuan-Xuan; Wang, Guang-Ji; Liu, Chang-Xiao

2016-07-15

Traditional Chinese herb medicines (TCHMs) have been used in the treatment of a variety of diseases for thousands of years in Asian countries. The active components of TCHMs usually exert combined synergistic therapeutic effects on multiple targets, but with less potential therapeutic effect based on routine indices than Western drugs. These complex effects make the assessment of the efficacy of TCHMs and the clarification of their underlying mechanisms very challenging, and therefore hinder their wider application and acceptance. Metabolomics is a crucial part of systems biology. It allows the quantitative measurement of large numbers of the low-molecular endogenous metabolites involved in metabolic pathways, and thus reflects the fundamental metabolism status of the body. Recently, dozens of metabolomic studies have been devoted to prove the efficacy/safety, explore the underlying mechanisms, and identify the potential biomarkers to access the action targets of TCHMs, with fruitful results. This article presents an overview of these studies, focusing on the progress made in exploring the pharmacology and toxicology of various herbal medicines. Copyright © 2015 Elsevier B.V. All rights reserved.

Applicability of the Pinus bark (Pinus elliottii for the adsorption of toxic heavy metals from aqueous solutions - doi: 10.4025/actascitechnol.v34i1.9585

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Affonso Celso Gonçalves Junior

2011-11-01

Full Text Available  Current research evaluates the efficaciousness of pine (Pinus elliottii bark as adsorbent of the toxic heavy metals cadmium (Cd, lead (Pb and chromium (Cr from aqueous solutions, at two pH conditions: 5.0 and 7.0. Approximately 500 mg of adsorbent material and 50 mL of solution contaminated by Cd, Pb and Cr at different concentrations prepared from standard solutions of each metal were added in 125 mL Erlenmeyer flasks.  Flasks were stirred during 3h at 200 rpm at 25ºC. Further, 10 mL aliquots were then retrieved and concentration of metal Cd, Pb and Cr determined by AAS. Adsorption isotherms for each metal were consequently obtained and linearized according to Langmuir and Freundlich’s mathematical models. Results show that the Pinus bark was efficacious in the removal of toxic heavy metals Cd, Pb and Cr from contaminated solutions and that the bark’s adsorption capacity depended on pH solution.

Synthesis, Characterization, and In Vivo Efficacy of Shell Cross-Linked Nanoparticle Formulations Carrying Silver Antimicrobials as Aerosolized Therapeutics

Science.gov (United States)

2014-01-01

The use of nebulizable, nanoparticle-based antimicrobial delivery systems can improve efficacy and reduce toxicity for treatment of multi-drug-resistant bacteria in the chronically infected lungs of cystic fibrosis patients. Nanoparticle vehicles are particularly useful for applying broad-spectrum silver-based antimicrobials, for instance, to improve the residence time of small-molecule silver carbene complexes (SCCs) within the lung. Therefore, we have synthesized multifunctional, shell cross-linked knedel-like polymeric nanoparticles (SCK NPs) and capitalized on the ability to independently load the shell and core with silver-based antimicrobial agents. We formulated three silver-loaded variants of SCK NPs: shell-loaded with silver cations, core-loaded with SCC10, and combined loading of shell silver cations and core SCC10. All three formulations provided a sustained delivery of silver over the course of at least 2–4 days. The two SCK NP formulations with SCC10 loaded in the core each exhibited excellent antimicrobial activity and efficacy in vivo in a mouse model of Pseudomonas aeruginosa pneumonia. SCK NPs with shell silver cation-load only, while efficacious in vitro, failed to demonstrate efficacy in vivo. However, a single dose of core SCC10-loaded SCK NPs (0.74 ± 0.16 mg Ag) provided a 28% survival advantage over sham treatment, and administration of two doses (0.88 mg Ag) improved survival to 60%. In contrast, a total of 14.5 mg of Ag+ delivered over 5 doses at 12 h intervals was necessary to achieve a 60% survival advantage with a free-drug (SCC1) formulation. Thus, SCK NPs show promise for clinical impact by greatly reducing antimicrobial dosage and dosing frequency, which could minimize toxicity and improve patient adherence. PMID:23718195

Electronic Cigarette Toxicity.

Science.gov (United States)

Payne, J Drew; Michaels, David; Orellana-Barrios, Menfil; Nugent, Kenneth

2017-04-01

Electronic cigarettes (e-cigarettes) are often advertised as a healthier product when compared with traditional cigarettes. Currently, there are limited data to support this and only a threat of federal regulation from the US Food and Drug Administration. Calls to poison control centers about e-cigarette toxicity, especially in children, and case reports of toxic exposures have increased over the past 3 years. This research letter reports the frequency of hazardous exposures to e-cigarettes and characterizes the reported adverse health effects associated with e-cigarette toxicity.

Evaluation of nano-specific toxicity of zinc oxide, copper oxide, and silver nanoparticles through toxic ratio

Energy Technology Data Exchange (ETDEWEB)

Zhang, Weicheng; Liu, Xiawei; Bao, Shaopan; Xiao, Bangding; Fang, Tao, E-mail: fangt@ihb.ac.cn [Chinese Academy of Sciences, Institute of Hydrobiology (China)

2016-12-15

For safety and environmental risk assessments of nanomaterials (NMs) and to provide essential toxicity data, nano-specific toxicities, or excess toxicities, of ZnO, CuO, and Ag nanoparticles (NPs) (20, 20, and 30 nm, respectively) to Escherichia coli and Saccharomyces cerevisiae in short-term (6 h) and long-term (48 h) bioassays were quantified based on a toxic ratio. ZnO NPs exhibited no nano-specific toxicities, reflecting similar toxicities as ZnO bulk particles (BPs) (as well as zinc salt). However, CuO and Ag NPs yielded distinctly nano-specific toxicities when compared with their BPs. According to their nano-specific toxicities, the capability of these NPs in eliciting hazardous effects on humans and the environment was as follows: CuO > Ag > ZnO NPs. Moreover, long-term bioassays were more sensitive to nano-specific toxicity than short-term bioassays. Overall, nano-specific toxicity is a meaningful measurement to evaluate the environmental risk of NPs. The log T{sub e}{sup particle} value is a useful parameter for quantifying NP nano-specific toxicity and enabling comparisons of international toxicological data. Furthermore, this value could be used to determine the environmental risk of NPs.

Increasing the safety and efficacy of chimeric antigen receptor T cell therapy

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Hua Li

2017-04-01

Full Text Available Abstract Chimeric antigen receptor (CAR T cell therapy is a promising cancer treatment that has recently been undergoing rapid development. However, there are still some major challenges, including precise tumor targeting to avoid off-target or “on-target/off-tumor” toxicity, adequate T cell infiltration and migration to solid tumors and T cell proliferation and persistence across the physical and biochemical barriers of solid tumors. In this review, we focus on the primary challenges and strategies to design safe and effective CAR T cells, including using novel cutting-edge technologies for CAR and vector designs to increase both the safety and efficacy, further T cell modification to overcome the tumor-associated immune suppression, and using gene editing technologies to generate universal CAR T cells. All these efforts promote the development and evolution of CAR T cell therapy and move toward our ultimate goal—curing cancer with high safety, high efficacy, and low cost.

Cyclophosphamide-induced pulmonary toxicity

International Nuclear Information System (INIS)

Siemann, D.W.; Macler, L.; Penney, D.P.

1986-01-01

Unlike radiation effects, pulmonary toxicity following drug treatments may develop soon after exposure. The dose-response relationship between Cyclophosphamide and lung toxicity was investigated using increased breathing frequency assays used successfully for radiation induced injury. The data indicate that release of protein into the alveolus may play a significant role in Cy induced pulmonary toxicity. Although the mechanism responsible for the increased alveolar protein is as yet not identified, the present findings suggest that therapeutic intervention to inhibit protein release may be an approach to protect the lungs from toxic effects. (UK)

TOXICITY BEHAVIORS IN ORGANIZATIONS: STUDY OF RELIABILITY AND VALIDITY OF TOXIC EMOTIONAL EXPERIENCES SCALE

OpenAIRE

Bektas, Meral; Erkal, Pinar

2016-01-01

In toxic organizations which are mostly destructive instead of being constrictive towards its employees, toxicity behaviors emerge as a result of the formal and informal relationships. Toxicity behaviors are often negatively affect motivation, job satisfaction or performance of the employees in workplace. Basic toxicity behaviors in organizations are: extreme jealousy, biting words, emphasis  superiority emphasis, getting angry, offending employees, strict control, heavy job workload, limited...

Antimony Toxicity

OpenAIRE

Sundar, Shyam; Chakravarty, Jaya

2010-01-01

Antimony toxicity occurs either due to occupational exposure or during therapy. Occupational exposure may cause respiratory irritation, pneumoconiosis, antimony spots on the skin and gastrointestinal symptoms. In addition antimony trioxide is possibly carcinogenic to humans. Improvements in working conditions have remarkably decreased the incidence of antimony toxicity in the workplace. As a therapeutic, antimony has been mostly used for the treatment of leishmaniasis and schistosomiasis. The...

Concurrent radiotherapy with temozolomide vs. concurrent radiotherapy with a cisplatinum-based polychemotherapy regimen. Acute toxicity in pediatric high-grade glioma patients

International Nuclear Information System (INIS)

Seidel, Clemens; Kortmann, Rolf D.; Bueren, Andre O. von; Bojko, Sabrina; Hoffmann, Marion; Kramm, Christof M.; Pietsch, Torsten; Gielen, Gerrit H.; Warmuth-Metz, Monika; Bison, Brigitte

2018-01-01

As the efficacy of all pediatric high-grade glioma (HGG) treatments is similar and still disappointing, it is essential to also investigate the toxicity of available treatments. Prospectively recorded hematologic and nonhematologic toxicities of children treated with radiochemotherapy in the HIT GBM-C/D and HIT-HGG-2007 trials were compared. Children aged 3-18 years with histologically proven HGG (WHO grade III and IV tumors) or unequivocal radiologic diagnosis of diffuse intrinsic pontine glioma (DIPG) were included in these trials. The HIT-HGG-2007 protocol comprised concomitant radiochemotherapy with temozolomide, while cisplatinum/etoposide (PE) and PE plus ifosfamide (PEI) in combination with weekly vincristine injections were applied during radiochemotherapy in the HIT GBM-C/D protocol. Regular blood counts and information about cellular nadirs were available from 304 patients (leukocytes) and 306 patients (thrombocytes), respectively. Grade 3-4 leukopenia was much more frequent in the HIT GBM-C/D cohort (n = 88, 52%) vs. HIT-HGG-2007 (n = 13, 10%; P <0.001). Grade 3-4 thrombopenia was also more likely in the HIT GBM-C/D cohort (n = 21, 12% vs. n = 3,2%; P <0.001). Grade 3-4 leukopenia appeared more often in children aged 3-7 years (n = 38/85, 45%) than in children aged 8-12 years (n = 39/120, 33%) and 13-18 years (24/100, 24%; P =0.034). In addition, sickness was more frequent in the HIT GBM-C/D cohort (grade 1-2: 44%, grade 3-4: 6% vs. grade 1-2: 28%, grade 3-4: 1%; P <0.001). Radiochemotherapy involving cisplatinum-based polychemotherapy is more toxic than radiotherapy in combination with temozolomide. Without evidence of differences in therapeutic efficacy, the treatment with lower toxicity, i. e., radiotherapy with temozolomide should be used. (orig.) [de

Rectal toxicity profile after transperineal interstitial permanent prostate brachytherapy: Use of a comprehensive toxicity scoring system and identification of rectal dosimetric toxicity predictors

International Nuclear Information System (INIS)

Shah, Jinesh N.; Ennis, Ronald D.

2006-01-01

Purpose: To better understand rectal toxicity after prostate brachytherapy, we employed the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE version 3.0), a comprehensive system with distinct and separately reported gastrointestinal adverse event items (unlike Radiation Therapy Oncology Group morbidity scoring), to evaluate item-specific postimplant rectal toxicities. Methods and Materials: We analyzed 135 patients treated with brachytherapy ± hormonal therapy, using CTCAE v3.0 to score acute/late rectal toxicities (median follow-up, 41 months). Dosimetric parameters were evaluated for ability to predict toxicities. Results: Use of CTCAE yielded a novel rectal toxicity profile consisting of diarrhea, incontinence, urgency, proctitis, pain, spasms, and hemorrhage event rates. No item had a 25 (percent of rectal volume receiving 25% of prescribed prostate dose) ≤ 25% vs. 60% for %V 25 > 25% (p 1 ≤ 40% vs. 44% for %V 1 > 40% (p = 0.007). Conclusions: A comprehensive understanding of item-specific postimplant rectal toxicities was obtained using CTCAE. Rectal %V 25 > 25% and %V 1 > 40% predicted worse late diarrhea and maximum toxicity, respectively

QIAD assay for quantitating a compound’s efficacy in elimination of toxic Aβ oligomers

Science.gov (United States)

Brener, Oleksandr; Dunkelmann, Tina; Gremer, Lothar; van Groen, Thomas; Mirecka, Ewa A.; Kadish, Inga; Willuweit, Antje; Kutzsche, Janine; Jürgens, Dagmar; Rudolph, Stephan; Tusche, Markus; Bongen, Patrick; Pietruszka, Jörg; Oesterhelt, Filipp; Langen, Karl-Josef; Demuth, Hans-Ulrich; Janssen, Arnold; Hoyer, Wolfgang; Funke, Susanne A.; Nagel-Steger, Luitgard; Willbold, Dieter

2015-01-01

Strong evidence exists for a central role of amyloid β-protein (Aβ) oligomers in the pathogenesis of Alzheimer’s disease. We have developed a fast, reliable and robust in vitro assay, termed QIAD, to quantify the effect of any compound on the Aβ aggregate size distribution. Applying QIAD, we studied the effect of homotaurine, scyllo-inositol, EGCG, the benzofuran derivative KMS88009, ZAβ3W, the D-enantiomeric peptide D3 and its tandem version D3D3 on Aβ aggregation. The predictive power of the assay for in vivo efficacy is demonstrated by comparing the oligomer elimination efficiency of D3 and D3D3 with their treatment effects in animal models of Alzheimer´s disease. PMID:26394756

Evaluation in zebrafish model of the toxicity of rhodamine B-conjugated crotamine, a peptide potentially useful for diagnostics and therapeutics.

Science.gov (United States)

Chan, Judy Yuet-Wa; Zhou, Hefeng; Kwan, Yiu Wa; Chan, Shun Wan; Radis-Baptista, Gandhi; Lee, Simon Ming-Yuen

2017-11-01

Crotamine is defensin-like cationic peptide from rattlesnake venom that possesses anticancer, antimicrobial, and antifungal properties. Despite these promising biological activities, toxicity is a major concern associated with the development of venom-derived peptides as therapeutic agents. In the present study, we used zebrafish as a system model to evaluate the toxicity of rhodamine B-conjugated (RhoB) crotamine derivative. The lethal toxic concentration of RhoB-crotamine was as low as 4 μM, which effectively kill zebrafish larvae in less than 10 min. With non-lethal concentrations (<1 μM), crotamine caused malformation in zebrafish embryos, delayed or completely halted hatching, adversely affected embryonic developmental programming, decreased the cardiac functions, and attenuated the swimming distance of zebrafish. The RhoB-crotamine translocated across vitelline membrane and accumulated in zebrafish yolk sac. These results demonstrate the sensitive responsivity of zebrafish to trial crotamine analogues for the development of novel therapeutic peptides with improved safety, bioavailability, and efficacy profiles. © 2017 Wiley Periodicals, Inc.

Trichothecenes: structure-toxic activity relationships.

Science.gov (United States)

Wu, Qinghua; Dohnal, Vlastimil; Kuca, Kamil; Yuan, Zonghui

2013-07-01

Trichothecenes comprise a large family of structurally related toxins mainly produced by fungi belonging to the genus Fusarium. Among trichothecenes, type A and type B are of the most concern due to their broad and highly toxic nature. In order to address structure-activity relationships (SAR) of trichothecenes, relationships between structural features and biological effects of trichothecene mycotoxins in mammalian systems are summarized in this paper. The double bond between C-9-C-10 and the 12,13-epoxide ring are essential structural features for trichothecene toxicity. Removal of these groups results in a complete loss of toxicity. A hydroxyl group at C-3 enhances trichothecene toxicity, while this activity decreases gradually when C-3 is substituted with either hydrogen or an acetoxy group. The presence of a hydroxyl group at C-4 promotes slightly lower toxicity than an acetoxy group at the same position. The toxicity for type B trichothecenes decreases if the substituent at C-4 is changed from acetoxy to hydroxyl or hydrogen at C-4 position. The presence of hydroxyl and hydrogen groups on C-15 decreases the trichothecene toxicity in comparison with an acetoxy group attached to this carbon. Trichothecenes toxicity increases when a macrocyclic ring exists between the C-4 and C-15. At C-8 position, an oxygenated substitution at C-8 is essential for trichothecene toxicity, indicating a decrease in the toxicity if substituent change from isovaleryloxy through hydrogen to the hydroxyl group. The presence of a second epoxy ring at C-7-C-8 reduces the toxicity, whereas epoxidation at C-9-C-10 of some macrocyclic trichothecenes increases the activity. Conjugated trichothecenes could release their toxic precursors after hydrolysis in animals, and present an additional potential risk. The SAR study of trichothecenes should provide some crucial information for a better understanding of trichothecene chemical and biological properties in food contamination.

Hydroxyurea for the Treatment of Sickle Cell Disease: Efficacy, Barriers, Toxicity, and Management in Children

Science.gov (United States)

Strouse, John J.; Heeney, Matthew M.

2012-01-01

Hydroxyurea is the only approved medication in the United States for the treatment of sickle cell anemia (HbSS) and is widely used in children despite an indication limited to adults. We review the evidence of efficacy and safety in children with reference to pivotal adult studies. This evidence and expert opinion form the basis for recommended guidelines for the use of hydroxyurea in children including indications, dosing, therapeutic and safety monitoring, and interventions to improve adherence. However, there are substantial gaps in our knowledge to be addressed by on-going and planned studies in children. PMID:22517797

Evaluation of a low-cost adsorbent for removal of toxic metal ions from wastewater of an electroplating factory.

Science.gov (United States)

Sousa, Francisco W; Sousa, Marcelo James; Oliveira, Isadora R N; Oliveira, André G; Cavalcante, Rivelino M; Fechine, Pierre B A; Neto, Vicente O S; de Keukeleire, Denis; Nascimento, Ronaldo F

2009-08-01

In this study, sugar cane residue or bagasse was used for removal of toxic metal ions from wastewater of an electroplating factory located in northeast Brazil. Prior acid treatment increased the adsorption efficacies in batch wise experiments. The microstructure of the material before and after the treatment was investigated by X-ray diffraction, infrared spectroscopy and scanning electron microscopy. Column operations showed that removals of Cu(2+), Ni(2+) and Zn(2+) from wastewater (in the absence of cyanide) were 95.5%, 96.3.0%, and 97.1%, respectively. Regeneration of the adsorbent obtained in acid indicated that the efficiencies decreased only after the fourth cycle of re-use. Acid-treated sugar cane bagasse can be considered a viable alternative to common methods to remove toxic metal ions from aqueous effluents of electroplating industries.

Comparative cardiac toxicity of anthracyclines in vitro and in vivo in the mouse.

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Stefano Toldo

Full Text Available PURPOSE: The antineoplastic efficacy of anthracyclines is limited by their cardiac toxicity. In this study, we evaluated the toxicity of doxorubicin, non-pegylated liposomal-delivered doxorubicin, and epirubicin in HL-1 adult cardiomyocytes in culture as well as in the mouse in vivo. METHODS: The cardiomyocytes were incubated with the three anthracyclines (1 µM to assess reactive oxygen generation, DNA damage and apoptotic cell death. CF-1 mice (10/group received doxorubicin, epirubicin or non-pegylated liposomal-doxorubicin (10 mg/kg and cardiac function was monitored by Doppler echocardiography to measure left ventricular ejection fraction (LVEF, heart rate (HR and cardiac output (CO both prior to and 10 days after drug treatment. RESULTS: In HL-1 cells, non-pegylated liposomal-doxorubicin generated significantly less reactive oxygen species (ROS, as well as less DNA damage and apoptosis activation when compared with doxorubicin and epirubicin. Cultured breast tumor cells showed similar sensitivity to the three anthracyclines. In the healthy mouse, non-pegylated liposomal doxorubicin showed a minimal and non-significant decrease in LVEF with no change in HR or CO, compared to doxorubicin and epirubicin. CONCLUSION: This study provides evidence for reduced cardiac toxicity of non-pegylated-liposomal doxorubicin characterized by attenuation of ROS generation, DNA damage and apoptosis in comparison to epirubicin and doxorubicin.

Glioprotective Effects of Ashwagandha Leaf Extract against Lead Induced Toxicity

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Praveen Kumar

2014-01-01

Full Text Available Withania somnifera (Ashwagandha, also known as Indian Ginseng, is a well-known Indian medicinal plant due to its antioxidative, antistress, antigenotoxic, and immunomodulatory properties. The present study was designed to assess and establish the cytoprotective potential of Ashwagandha leaf aqueous extract against lead induced toxicity. Pretreatment of C6 cells with 0.1% Ashwagandha extract showed cytoprotection against 25 μM to 400 μM concentration of lead nitrate. Further pretreatment with Ashwagandha extract to lead nitrate exposed cells (200 μM resulted in normalization of glial fibrillary acidic protein (GFAP expression as well as heat shock protein (HSP70, mortalin, and neural cell adhesion molecule (NCAM expression. Further, the cytoprotective efficacy of Ashwagandha extract was studied in vivo. Administration of Ashwagandha extract provided significant protection to lead induced altered antioxidant defense that may significantly compromise normal cellular function. Ashwagandha also provided a significant protection to lipid peroxidation (LPx levels, catalase, and superoxide dismutase (SOD but not reduced glutathione (GSH contents in brain tissue as well as peripheral organs, liver and kidney, suggesting its ability to act as a free radical scavenger protecting cells against toxic insult. These results, thus, suggest that Ashwagandha water extract may have the potential therapeutic implication against lead poisoning.

Assessing the toxic effects of ethylene glycol ethers using Quantitative Structure Toxicity Relationship models

International Nuclear Information System (INIS)

Ruiz, Patricia; Mumtaz, Moiz; Gombar, Vijay

2011-01-01

Experimental determination of toxicity profiles consumes a great deal of time, money, and other resources. Consequently, businesses, societies, and regulators strive for reliable alternatives such as Quantitative Structure Toxicity Relationship (QSTR) models to fill gaps in toxicity profiles of compounds of concern to human health. The use of glycol ethers and their health effects have recently attracted the attention of international organizations such as the World Health Organization (WHO). The board members of Concise International Chemical Assessment Documents (CICAD) recently identified inadequate testing as well as gaps in toxicity profiles of ethylene glycol mono-n-alkyl ethers (EGEs). The CICAD board requested the ATSDR Computational Toxicology and Methods Development Laboratory to conduct QSTR assessments of certain specific toxicity endpoints for these chemicals. In order to evaluate the potential health effects of EGEs, CICAD proposed a critical QSTR analysis of the mutagenicity, carcinogenicity, and developmental effects of EGEs and other selected chemicals. We report here results of the application of QSTRs to assess rodent carcinogenicity, mutagenicity, and developmental toxicity of four EGEs: 2-methoxyethanol, 2-ethoxyethanol, 2-propoxyethanol, and 2-butoxyethanol and their metabolites. Neither mutagenicity nor carcinogenicity is indicated for the parent compounds, but these compounds are predicted to be developmental toxicants. The predicted toxicity effects were subjected to reverse QSTR (rQSTR) analysis to identify structural attributes that may be the main drivers of the developmental toxicity potential of these compounds.