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Sample records for liver tumor drug

  1. Tumor and liver drug uptake following hepatic artery and portal vein infusion

    International Nuclear Information System (INIS)

    Sigurdson, E.R.; Ridge, J.A.; Kemeny, N.; Daly, J.M.

    1987-01-01

    Anatomic dye injection studies of the blood supply of colorectal hepatic metastases suggest that tumors are supplied predominantly by the hepatic artery. Using 13 N amino acids with dynamic gamma camera imaging in patients with colorectal hepatic metastases, it has been shown that hepatic artery infusion results in a significantly greater nutrient delivery to tumor compared with portal vein infusion. However, direct measurements of drug levels in tumor following hepatic artery and portal vein infusion in humans have not previously been reported. Patients with metastatic colorectal cancer confined to the liver received fluorodeoxyuridine (FUdR) through the hepatic artery or through the portal vein. All patients had previously failed systemic chemotherapy. Five patients with hepatic artery catheters were matched (by age, serum lactic dehydrogenase levels, percent hepatic replacement, and tumor size) with five patients with portal vein catheters. At operation, 3 H-FUdR (1 microCi/kg) and /sup 99m/Tc-macroaggregated albumin (MAA) (6 mCi) were injected into the hepatic artery or portal vein. Liver and tumor biopsies were obtained two and five minutes later. 3 H and /sup 99m/Tc were measured per gram tissue by scintillation and gamma counting. The mean liver levels following hepatic artery infusion (23.9 +/- 11.4 nmol/g) and portal vein infusion (18.4 +/- 14.5 nmol/g) did not differ. However, the mean tumor FUdR level following hepatic artery infusion was 12.4 +/- 12.2 nmol/g, compared with a mean tumor FUdR level following portal vein infusion of 0.8 +/- 0.7 nmol/g (P less than .01). This low level of tumor drug uptake after portal vein infusion of FUdR predicts minimal tumor response to treatment via this route. Thus, regional chemotherapy for established colorectal hepatic metastases should be administered through the hepatic artery

  2. Hepatic Arterial Chemoembolization Using Drug-Eluting Beads in Gastrointestinal Neuroendocrine Tumor Metastatic to the Liver

    International Nuclear Information System (INIS)

    Gaur, Shantanu K.; Friese, Jeremy L.; Sadow, Cheryl A.; Ayyagari, Rajasekhara; Binkert, Christoph A.; Schenker, Matthew P.; Kulke, Matthew; Baum, Richard

    2011-01-01

    Purpose: This study was designed to evaluate short ( 3 months) follow-up in patients with metastatic neuroendocrine tumor to the liver who underwent hepatic arterial chemoembolization with drug-eluting beads at a single institution. Methods: Institutional review board approval was obtained for this retrospective review. All patients who were treated with 100–300 or 300–500 μm drug-eluting LC Beads (Biocompatibles, UK) preloaded with doxorubicin (range, 50–100 mg) for GI neuroendocrine tumor metastatic to the liver from June 2004 to June 2009 were included. CT and MRI were evaluated for progression using Response Evaluation Criteria In Solid Tumors (RECIST) or European Association for the Study of the Liver (EASL) criteria. Short-term ( 3 months) imaging response was determined and Kaplan–Meier survival curves were plotted. Results: Thirty-eight drug-eluting bead chemoembolization procedures were performed on 32 hepatic lobes, comprising 21 treatment cycles in 18 patients. All procedures were technically successful with two major complications (biliary injuries). At short-term follow-up (<3 months), 22 of 38 (58%) procedures and 10 of 21 (48%) treatment cycles produced an objective response (OR) with the remainder having stable disease (SD). At intermediate-term follow-up (mean, 445 days; range, 163–1247), 17 of 26 (65%) procedures and 8 of 14 (57%) treatment cycles produced an OR. Probability of progressing was approximately 52% at 1 year with a median time to progression of 419 days. Conclusions: Drug-eluting bead chemoembolization is a reasonable alternative to hepatic arterial embolization and chemoembolization for the treatment of metastatic neuroendocrine tumor to the liver.

  3. Liver Tumors (For Parents)

    Science.gov (United States)

    ... Staying Safe Videos for Educators Search English Español Liver Tumors KidsHealth / For Parents / Liver Tumors What's in this article? Types of Tumors ... Cancerous) Tumors Symptoms Diagnosis Treatment Coping Print The liver is the body's largest solid organ. Lying next ...

  4. Benign Liver Tumors

    Science.gov (United States)

    ... Legacy Society Make Gifts of Stock Donate Your Car Personal Fundraising Partnership & Support Share Your Story Spread the Word Give While You Shop Contact Us Donate Now Benign Liver Tumors Back ...

  5. Quantification of drug-loaded magnetic nanoparticles in rabbit liver and tumor after in vivo administration

    Energy Technology Data Exchange (ETDEWEB)

    Tietze, Rainer; Jurgons, Roland; Lyer, Stefan; Schreiber, Eveline [Department of Otorhinolaryngology, Head and Neck Surgery, Friedrich-Alexander-University Erlangen-Nuernberg, Waldstr. 1, 91054 Erlangen (Germany); Wiekhorst, Frank; Eberbeck, Dietmar; Richter, Heike; Steinhoff, Uwe; Trahms, Lutz [Physikalisch-Technische Bundesanstalt, Berlin (Germany); Alexiou, Christoph [Department of Otorhinolaryngology, Head and Neck Surgery, Friedrich-Alexander-University Erlangen-Nuernberg, Waldstr. 1, 91054 Erlangen (Germany)], E-mail: C.Alexiou@web.de

    2009-05-15

    Magnetic nanoparticles have been investigated for biomedical applications for more than 30 years. The development of biocompatible nanosized drug delivery systems for specific targeting of therapeutics is imminent in medical research, especially for treating cancer and vascular diseases. We used drug-labeled magnetic iron oxide nanoparticles, which were attracted to an experimental tumor in rabbits with an external magnetic field (magnetic drug targeting, MDT). Aim of this study was to detect and quantify the biodistribution of the magnetic nanoparticles by magnetorelaxometry. The study shows higher amount of nanoparticles in the tumor after intraarterial application and MDT compared to intravenous administration.

  6. [Local treatment of liver tumors

    DEFF Research Database (Denmark)

    Pless, T.K.; Skjoldbye, Bjørn Ole

    2008-01-01

    Local treatment of non-resectable liver tumors is common. This brief review describes the local treatment techniques used in Denmark. The techniques are evaluated according to the evidence in literature. The primary local treatment is Radiofrequency Ablation of both primary liver tumors and liver...

  7. Benign Liver Tumors

    Science.gov (United States)

    ... Liver Function Tests Clinical Trials Liver Transplant FAQs Medical Terminology Diseases of the Liver Alagille Syndrome Alcohol-Related ... the Liver The Progression of Liver Disease FAQs Medical Terminology HOW YOU CAN HELP Sponsorship Ways to Give ...

  8. Drugs Approved for Liver Cancer

    Science.gov (United States)

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for liver cancer. The list includes generic names and brand names. The drug names link to NCI’s Cancer Drug Information summaries.

  9. A Novel Antihepatitis Drug, Bicyclol, Prevents Liver Carcinogenesis in Diethylnitrosamine-Initiated and Phenobarbital-Promoted Mice Tumor Model

    Directory of Open Access Journals (Sweden)

    Hua Sun

    2012-01-01

    Full Text Available Bicyclol, an antihepatitis drug developed by Chinese scientists, has been shown to prevent the malignant transformation induced by 3-methylcholanthrene and 12-O-tetradecanoylphorbol-13-acetate in WB-F344 rat liver epithelial cells. This study provides further evidence on its role as a chemopreventive agent in experimental mice with diethylnitrosamine- (DEN- initiated and phenobarbital- (PB- promoted liver carcinoma. Liver tissue and serum were collected. In the two-stage model of hepatocarcinogenesis in mice, oral administration of bicyclol (100, 200 mg/kg before DEN injection showed significant reduction in the incidence of hepatocellular foci, nodules, or carcinoma. Histopathological examination revealed that there was no hepatocellular carcinoma (HCC and hepatoma formation in the mice pretreated with bicyclol (200 mg/kg at week 20, while the mice treated with DEN/PB developed 33.3% HCC and 55.6% hepatoma. Furthermore, the serum levels of alanine aminotransferase (ALT, alkaline phosphatase (ALP, and α-fetal protein (AFP in serum significantly increased in the DEN/PB model group in comparison with the control group. Pretreatment with bicyclol showed a marked reduction in the above condition. Bicyclol also decreased the expression of AFP and proliferating cell nuclear antigen level in the liver tissue and attenuated the decrease in body weight. In this study, we also found that 10 weeks after stopping the administration of PB and drugs, the control and bicyclol-treated (200 mg/kg animals showed no HCC and hepatoma formation at the time of termination whereas DEN/PB-induced mice developed 100% hepatoma and 50% HCC. These results further indicate that bicyclol has the chemopreventive potential for liver carcinogenesis induced by carcinogens.

  10. Pediatric liver tumors - a pictorial review

    International Nuclear Information System (INIS)

    Jha, Priyanka; Tavri, Sidhartha; Patel, Chirag; Gooding, Charles; Daldrup-Link, Heike; Chawla, Soni C.

    2009-01-01

    Hepatic masses constitute about 5-6% of all intra-abdominal masses in children. The majority of liver tumors in children are malignant; these malignant liver tumors constitute the third most common intra-abdominal malignancy in the pediatric age group after Wilms' tumor and neuroblastoma. Only about one third of the liver tumors are benign. A differential diagnosis of liver tumors in children can be obtained based on the age of the child, clinical information (in particular AFP) and imaging characteristics. The purpose of this review is to report typical clinical and imaging characteristics of benign and malignant primary liver tumors in children. (orig.)

  11. Dynamic contrast-enhanced MRI using a macromolecular MR contrast agent (P792): Evaluation of antivascular drug effect in a rabbit VX2 liver tumor model

    Energy Technology Data Exchange (ETDEWEB)

    Park, Hee Sun [Dept. of Radiology, Konkuk University School of Medicine, Seoul (Korea, Republic of); Han, Joon Koo; Lee, Jeong Min; Woo, Sung Min; Choi, Byung Ihn [Seoul National University Hospital, Seoul (Korea, Republic of); Kim, Young Il [Dept. of Radiology, Sheikh Khalifa Specialty Hospital, Ras Al Khaimah (United Arab Emirates); Choi, Jin Young [Dept. of Radiology, Yonsei University College of Medicine, Seoul (Korea, Republic of)

    2015-10-15

    To evaluate the utility of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) using macromolecular contrast agent (P792) for assessment of vascular disrupting drug effect in rabbit VX2 liver tumor models. This study was approved by our Institutional Animal Care and Use Committee. DCE-MRI was performed with 3-T scanner in 13 VX2 liver tumor-bearing rabbits, before, 4 hours after, and 24 hours after administration of vascular disrupting agent (VDA), using gadomelitol (P792, n = 7) or low molecular weight contrast agent (gadoterate meglumine [Gd-DOTA], n = 6). P792 was injected at a of dose 0.05 mmol/kg, while that of Gd-DOTA was 0.2 mmol/kg. DCE-MRI parameters including volume transfer coefficient (Ktrans) and initial area under the gadolinium concentration-time curve until 60 seconds (iAUC) of tumors were compared between the 2 groups at each time point. DCE-MRI parameters were correlated with tumor histopathology. Reproducibility in measurement of DCE-MRI parameters and image quality of source MR were compared between groups. P792 group showed a more prominent decrease in Ktrans and iAUC at 4 hours and 24 hours, as compared to the Gd-DOTA group. Changes in DCE-MRI parameters showed a weak correlation with histologic parameters (necrotic fraction and microvessel density) in both groups. Reproducibility of DCE-MRI parameters and overall image quality was not significantly better in the P792 group, as compared to the Gd-DOTA group. Dynamic contrast-enhanced magnetic resonance imaging using a macromolecular contrast agent shows changes of hepatic perfusion more clearly after administration of the VDA. Gadolinium was required at smaller doses than a low molecular contrast agent.

  12. Dynamic contrast-enhanced MRI using a macromolecular MR contrast agent (P792): Evaluation of antivascular drug effect in a rabbit VX2 liver tumor model

    International Nuclear Information System (INIS)

    Park, Hee Sun; Han, Joon Koo; Lee, Jeong Min; Woo, Sung Min; Choi, Byung Ihn; Kim, Young Il; Choi, Jin Young

    2015-01-01

    To evaluate the utility of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) using macromolecular contrast agent (P792) for assessment of vascular disrupting drug effect in rabbit VX2 liver tumor models. This study was approved by our Institutional Animal Care and Use Committee. DCE-MRI was performed with 3-T scanner in 13 VX2 liver tumor-bearing rabbits, before, 4 hours after, and 24 hours after administration of vascular disrupting agent (VDA), using gadomelitol (P792, n = 7) or low molecular weight contrast agent (gadoterate meglumine [Gd-DOTA], n = 6). P792 was injected at a of dose 0.05 mmol/kg, while that of Gd-DOTA was 0.2 mmol/kg. DCE-MRI parameters including volume transfer coefficient (Ktrans) and initial area under the gadolinium concentration-time curve until 60 seconds (iAUC) of tumors were compared between the 2 groups at each time point. DCE-MRI parameters were correlated with tumor histopathology. Reproducibility in measurement of DCE-MRI parameters and image quality of source MR were compared between groups. P792 group showed a more prominent decrease in Ktrans and iAUC at 4 hours and 24 hours, as compared to the Gd-DOTA group. Changes in DCE-MRI parameters showed a weak correlation with histologic parameters (necrotic fraction and microvessel density) in both groups. Reproducibility of DCE-MRI parameters and overall image quality was not significantly better in the P792 group, as compared to the Gd-DOTA group. Dynamic contrast-enhanced magnetic resonance imaging using a macromolecular contrast agent shows changes of hepatic perfusion more clearly after administration of the VDA. Gadolinium was required at smaller doses than a low molecular contrast agent

  13. Drugs Approved for Wilms Tumor

    Science.gov (United States)

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for Wilms tumor and other childhood kidney cancers. The list includes generic names and brand names. The drug names link to NCI's Cancer Drug Information summaries.

  14. Drug-induced liver injuries

    African Journals Online (AJOL)

    2011-06-02

    Jun 2, 2011 ... liver failure in the developed world and a prominent aetiological factor ... most drugs is not known and several epidemiological studies have had major ... eosinophilia, are also pointers towards the cause of the injury and are.

  15. Drug-induced liver injury

    DEFF Research Database (Denmark)

    Nielsen, Mille Bækdal; Ytting, Henriette; Skalshøi Kjær, Mette

    2017-01-01

    OBJECTIVE: The idiosyncratic subtype of drug-induced liver injury (DILI) is a rare reaction to medical treatment that in severe cases can lead to acute liver failure and death. The aim of this study was to describe the presentation and outcome of DILI and to identify potential predictive factors...... that DILI may be severe and run a fatal course, and that bilirubin and INR levels may predict poor outcome....

  16. Hyperdensity liver tumor on plain CT

    Energy Technology Data Exchange (ETDEWEB)

    Hirota, Shozo; Hanaguri, Katsuro [Kochi Municipal Central Hospital (Japan); Shimizu, Masahumi; Sako, Masao; Harada, Yasushi

    1984-12-01

    Most liver tumors on plain CT have been recognized as low density or iso-density masses. Sometimes calcified high density masses were shown on plain CT in case of cysts or metastatic liver tumors. However, hyperdensity mass of the liver on CT, of which the density was a little higher than surrounding tissues, was very rare. Recently 7 patients with hyperdensity liver masses on plain CT were experienced: 6 hepatocellular carcinomas and 1 hepatic cavernous hemangioma. A single hyperdensity mass was shown in 4 patients, a hyperdensity mass of multiple hepatic tumors was shown in 2 patients, and some hyperdensity masses of multiple hepatic tumors were shown in 1 patient. Lesions are classified in 3 types according to the appearance of hyperdensity masses: diffuse hyperdensity all over the mass, ring like hyperdensity, creascent like hyperdensity. Intravenous contrast enhancement was performed in 2 patients: one with a primary hepatocellular carcinoma, and another with a hepatic cavernous hemangioma. In the former case the tumor margin had changed unclear, in the latter case the tumor was markedly enhanced. Our results revealed that hyperdensity liver tumors were divided into 2 types: One type, shown in a cavernous hemangioma with fatty liver, demonstrated relative hyperdensity due to lower density of the surrounding tissue. Another type, shown in 6 hepatocellular carcinomas, showed hyperdensity since the density of the tumor was hyperdensity relative to the surrounding tissue of the liver. It was suggested that the tumor with the latter type had been strongly probable of malignant one, and been recommended to receive further examination. Cause of hyperdensity was thought to be due to hemorrhage, though microcalcification could not be denyed. In Japan, no hyperdensity liver tumor had been reported partly due to a wide window width with which CT photographs were taken.

  17. Radiofrequency Ablation of Liver Tumors

    Science.gov (United States)

    ... have had a surgical procedure in which the liver bile duct has been connected to a loop of bowel are at much greater risk of developing a liver abscess after ablation. Women should always inform their ...

  18. Transarterial chemoembolization for primary and metastatic liver tumors

    Directory of Open Access Journals (Sweden)

    Popov M.V.

    2016-12-01

    Full Text Available The literature review presents the methodology of transarterial chemoembolization (TACE — widely used method of treatment of primary and secondary liver tumors. The TACE role as a neoadjuvant therapy and the role in the management of unresectable primary and secondary liver tumors are shown. The morphofunctional basis of TACE, benefits of superselective intra-arterial administration of cytostatic agents especially in combination with ischemic impact on a tumor are described. The subject of the choice of the chemotherapeutic agent is also touched; modern drug-loaded microspheres which allow the use of higher doses of the chemotherapeutic drug without increasing systemic effect and prolong its effect on tumor are described. Lack of correlation of presence and severity of a post-embolization syndrome with success of the procedure is noted.

  19. Tumor Heterogeneity and Drug Resistance

    International Nuclear Information System (INIS)

    Kucerova, L.; Skolekova, S.; Kozovska, Z.

    2015-01-01

    New generation of sequencing methodologies revealed unexpected complexity and genomic alterations linked with the tumor subtypes. This diversity exists across the tumor types, histologic tumor subtypes and subsets of the tumor cells within the same tumor. This phenomenon is termed tumor heterogeneity. Regardless of its origin and mechanisms of development it has a major impact in the clinical setting. Genetic, phenotypic and expression pattern diversity of tumors plays critical role in the selection of suitable treatment and also in the prognosis prediction. Intratumoral heterogeneity plays a key role in the intrinsic and acquired chemoresistance to cytotoxic and targeted therapies. In this review we focus on the mechanisms of intratumoral and inter tumoral heterogeneity and their relationship to the drug resistance. Understanding of the mechanisms and spatiotemporal dynamics of tumor heterogeneity development before and during the therapy is important for the ability to design individual treatment protocols suitable in the given molecular context. (author)

  20. Radiofrequency hyperthermia for advanced malignant liver tumors

    International Nuclear Information System (INIS)

    Nagata, Y.; Okuno, Y.; Mitsumori, M.; Akuta, K.; Nishimura, Y.; Masunaga, S.; Kanamori, S.; Fujishiro, M.; Hiraoka, M.; Takahashi, M.; Abe, M.

    1996-01-01

    Purpose: To evaluate thermometry and the clinical results of radiofrequency (RF) thermotherapy for advanced malignant liver tumors. Materials and Methods One-hundred and seventy-three patients with malignant liver tumors treated between 1983 and 1995 underwent hyperthermia. Surgery were contraindicated in all patients. The 173 tumors consisted of 114 hepatocellular carcinomas(HCCs), and 59 non-HCCs(45 metastatic liver tumors and 12 cholangiocarcinomas). Eight MHz RF capacitive heating equipment was used for hyperthermia. Two opposing 25-cm or 30-cm electrodes were generally used for heating liver tumors. Our standard protocol was to administer hyperthermia 40-50 minutes twice a week to a total of 8 sessions. Temperature of the liver tumor was measured by microthermocouples. In each patient, a single catheter was inserted into the liver tumor through the normal liver. Transcatheter arterial embolization, radiotherapy, immunotherapy, and chemotherapy were combined with hyperthermia depending on the patient's liver function and tumor location. The therapeutic efficacy was evaluated by the change in tumor size assessed by computed tomography (CT) three or four months after the completion of treatment. Results One-hundred and forty (81%) of 173 patients underwent hyperthermia more than 4 times. Thermometry could be performed in 77(55%) of these 140 patients. Neither systolic nor diastolic blood pressure changed significantly after hyperthermia. However, pulse rate significantly increased from 82.8 ± 1.1 to 96.5 ± 1.3 beats/min. Only 21 patients (11%) showed a decrease in pulse rate after hyperthermia. Body temperature increased from 36.3 ±0.1 to 37.4±0.2 after hyperthermia. Sequelae of hyperthermia included focal fat burning in 20 (12%), gastric ulceration in 4 (2%), and liver necrosis in 1(1%). Sequelae of thermometry were severe peritoneal pain in 7 (11%), intraperitoneal hematoma in 1(1%), and pneumothorax in one (1%) patient. The maximal tumor temperature

  1. [Epithelioid hemangioendothelioma: an uncommon liver tumor].

    Science.gov (United States)

    Pareja, Eugenia; Cortés, Miriam; Rayon, Miguel; Moya, Angel; Mir, Jose

    2010-01-01

    We report the case of a female patient who was referred to our unit because of a solid liver tumor, suggestive of metastasis. After biopsy, the patient was diagnosed with epithelioid hemangioendothelioma of the liver. Epithelioid hemangioendothelioma is a rare entity with an unpredictable, potentially fatal, clinical course and outcome. Due to its rarity, this entity should be considered when a solitary hepatic lesion is detected and should be included in the differential diagnosis with liver metastases. We highlight the infrequency of this tumor, its presentation as a solitary hepatic lesion and the indication of surgical treatment. We describe the clinical and pathological characteristics of epithelioid hemangioendothelioma of the liver and report a new case of this entity. The distinct therapeutic options are discussed. Copyright 2010 Elsevier España, S.L. All rights reserved.

  2. Oncologic results of laparoscopic liver resection for malignant liver tumors.

    Science.gov (United States)

    Akyuz, Muhammet; Yazici, Pinar; Yigitbas, Hakan; Dural, Cem; Okoh, Alexis; Aliyev, Shamil; Aucejo, Federico; Quintini, Cristiano; Fung, John; Berber, Eren

    2016-02-01

    There are scant data regarding oncologic outcomes of laparoscopic liver resection (LLR). The aim of this study is to analyze the oncologic outcomes of LLR for malignant liver tumors (MLT). This was a prospective IRB-approved study of 123 patients with MLT undergoing LLR. Kaplan-Meier disease-free (DFS) and overall survival (OS) was calculated. Tumor type was colorectal in 61%, hepatocellular cancer in 21%, neuroendocrine in 5% and others in 13%. Mean tumor size was 3.2 ± 1.9 cm and number of tumors 1.6 ± 1.2. A wedge resection or segmentectomy was performed in 63.4%, bisegmentectomy in 24.4%, and hemihepatectomy in 12.2%. Procedures were totally laparoscopic in 67% and hand-assisted in 33%. Operative time was 235.2 ± 94.3 min, and conversion rate 7.3%. An R0 resection was achieved in 90% of patients and 94% of tumors. Median hospital stay was 3 days. Morbidity was 22% and mortality 0.8%. For patients with colorectal liver metastasis, DFS and OS at 2 years was 47% and 88%, respectively. This study shows that LLR is a safe and efficacious treatment for selected patients with MLT. Complete resection and margin recurrence rate are comparable to open series in the literature. © 2015 Wiley Periodicals, Inc.

  3. Nonacetaminophen Drug-Induced Acute Liver Failure.

    Science.gov (United States)

    Thomas, Arul M; Lewis, James H

    2018-05-01

    Acute liver failure of all causes is diagnosed in between 2000 and 2500 patients annually in the United States. Drug-induced acute liver failure is the leading cause of acute liver failure, accounting for more than 50% of cases. Nonacetaminophen drug injury represents 11% of all cases in the latest registry from the US Acute Liver Failure Study Group. Although rare, acute liver failure is clinically dramatic when it occurs, and requires a multidisciplinary approach to management. In contrast with acetaminophen-induced acute liver failure, non-acetaminophen-induced acute liver failure has a more ominous prognosis with a lower liver transplant-free survival. Copyright © 2018 Elsevier Inc. All rights reserved.

  4. Differential diagnosis of liver tumors. 7

    International Nuclear Information System (INIS)

    Gratz, K.F.; Schober, Otmar; Ringe, Burckhard

    1991-01-01

    Liver own tumors were classified by histological criteria considering the tissue origin. hemangioma and hemangioendothelioma are of mesenchymal origin, the focal nodular hyperplasia (FNH), the hepato-blastoma, hepatocellular adenoma (HCA) or carcinoma (HCC), intrahepatic bile duct cystadenoma or carcinoma are epithelial tumors. Only the hemangioma and the FNH have an unhesitating prognosis. All the other tumors should be diagnosed definitively by histological examination. This means, the tumor has to be resected if possible. To answer the question of resectability radionuclide procedures contribute little. US, transmission tomography, magnetic resonance imaging and angiography are necessary in this case. This chapter deals with findings and problems involved with the use of radionuclide methods. (author). 28 refs.; 5 figs.; 6 tabs

  5. Segmentation of liver tumors on CT images

    International Nuclear Information System (INIS)

    Pescia, D.

    2011-01-01

    This thesis is dedicated to 3D segmentation of liver tumors in CT images. This is a task of great clinical interest since it allows physicians benefiting from reproducible and reliable methods for segmenting such lesions. Accurate segmentation would indeed help them during the evaluation of the lesions, the choice of treatment and treatment planning. Such a complex segmentation task should cope with three main scientific challenges: (i) the highly variable shape of the structures being sought, (ii) their similarity of appearance compared with their surrounding medium and finally (iii) the low signal to noise ratio being observed in these images. This problem is addressed in a clinical context through a two step approach, consisting of the segmentation of the entire liver envelope, before segmenting the tumors which are present within the envelope. We begin by proposing an atlas-based approach for computing pathological liver envelopes. Initially images are pre-processed to compute the envelopes that wrap around binary masks in an attempt to obtain liver envelopes from estimated segmentation of healthy liver parenchyma. A new statistical atlas is then introduced and used to segmentation through its diffeomorphic registration to the new image. This segmentation is achieved through the combination of image matching costs as well as spatial and appearance prior using a multi-scale approach with MRF. The second step of our approach is dedicated to lesions segmentation contained within the envelopes using a combination of machine learning techniques and graph based methods. First, an appropriate feature space is considered that involves texture descriptors being determined through filtering using various scales and orientations. Then, state of the art machine learning techniques are used to determine the most relevant features, as well as the hyper plane that separates the feature space of tumoral voxels to the ones corresponding to healthy tissues. Segmentation is then

  6. Rare primary malignant tumors of the liver

    International Nuclear Information System (INIS)

    Dahan, H.; Zoppardo, P.; Chagnon, S.; Vilgrain, V.; Blery, M.

    1991-01-01

    Angiosarcoma, epithelioid hemangio-endothelioma (EHE) and fibrolamellar carcinoma (FLC) are far less frequent malignant primary tumors of the liver than liver-cell carcinoma, and usually do not occur in a chronic liver disease. Their diagnosis is histological but a few radiological criteria are suggestive: in younger subjects, a solitary, hypervascularized mass containing calcifications and/or a central fibrous scar suggests an FLC; nodular lesions merging into patches, scattered about the periphery, containing calcified clusters and showing a low and late contrast enhancement after injections suggest an EHE; lastly, in case of occupational exposure, an heterogeneous, hypervascularized mass with a centripetal blush but containing central areas that are opacified early should suggest angiosarcoma. (4 figs) [fr

  7. Drugs Approved for Gastrointestinal Stromal Tumors

    Science.gov (United States)

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for gastrointestinal stromal tumors (GIST). The list includes generic names and brand names. The drug names link to NCI's Cancer Drug Information summaries.

  8. Brain tumor-targeted drug delivery strategies

    Directory of Open Access Journals (Sweden)

    Xiaoli Wei

    2014-06-01

    Full Text Available Despite the application of aggressive surgery, radiotherapy and chemotherapy in clinics, brain tumors are still a difficult health challenge due to their fast development and poor prognosis. Brain tumor-targeted drug delivery systems, which increase drug accumulation in the tumor region and reduce toxicity in normal brain and peripheral tissue, are a promising new approach to brain tumor treatments. Since brain tumors exhibit many distinctive characteristics relative to tumors growing in peripheral tissues, potential targets based on continuously changing vascular characteristics and the microenvironment can be utilized to facilitate effective brain tumor-targeted drug delivery. In this review, we briefly describe the physiological characteristics of brain tumors, including blood–brain/brain tumor barriers, the tumor microenvironment, and tumor stem cells. We also review targeted delivery strategies and introduce a systematic targeted drug delivery strategy to overcome the challenges.

  9. Distribution of the anticancer drugs doxorubicin, mitoxantrone and topotecan in tumors and normal tissues.

    Science.gov (United States)

    Patel, Krupa J; Trédan, Olivier; Tannock, Ian F

    2013-07-01

    Pharmacokinetic analyses estimate the mean concentration of drug within a given tissue as a function of time, but do not give information about the spatial distribution of drugs within that tissue. Here, we compare the time-dependent spatial distribution of three anticancer drugs within tumors, heart, kidney, liver and brain. Mice bearing various xenografts were treated with doxorubicin, mitoxantrone or topotecan. At various times after injection, tumors and samples of heart, kidney, liver and brain were excised. Within solid tumors, the distribution of doxorubicin, mitoxantrone and topotecan was limited to perivascular regions at 10 min after administration and the distance from blood vessels at which drug intensity fell to half was ~25-75 μm. Although drug distribution improved after 3 and 24 h, there remained a significant decrease in drug fluorescence with increasing distance from tumor blood vessels. Drug distribution was relatively uniform in the heart, kidney and liver with substantially greater perivascular drug uptake than in tumors. There was significantly higher total drug fluorescence in the liver than in tumors after 10 min, 3 and 24 h. Little to no drug fluorescence was observed in the brain. There are marked differences in the spatial distributions of three anticancer drugs within tumor tissue and normal tissues over time, with greater exposure to most normal tissues and limited drug distribution to many cells in tumors. Studies of the spatial distribution of drugs are required to complement pharmacokinetic data in order to better understand and predict drug effects and toxicities.

  10. Withaferin A Suppresses Liver Tumor Growth in a Nude Mouse ...

    African Journals Online (AJOL)

    Purpose: To investigate the effect of withaferin A on tumor growth and metastasis in liver in a nude mouse model. Methods: Withaferin A was injected through a portal vein to the orthotopic liver tumor in a nude mice model. Xenogen in vivo imaging system was used to monitor tumor growth and metastasis. The effect of ...

  11. Shared liver-like transcriptional characteristics in liver metastases and corresponding primary colorectal tumors.

    Science.gov (United States)

    Cheng, Jun; Song, Xuekun; Ao, Lu; Chen, Rou; Chi, Meirong; Guo, You; Zhang, Jiahui; Li, Hongdong; Zhao, Wenyuan; Guo, Zheng; Wang, Xianlong

    2018-01-01

    Background & Aims : Primary tumors of colorectal carcinoma (CRC) with liver metastasis might gain some liver-specific characteristics to adapt the liver micro-environment. This study aims to reveal potential liver-like transcriptional characteristics associated with the liver metastasis in primary colorectal carcinoma. Methods: Among the genes up-regulated in normal liver tissues versus normal colorectal tissues, we identified "liver-specific" genes whose expression levels ranked among the bottom 10% ("unexpressed") of all measured genes in both normal colorectal tissues and primary colorectal tumors without metastasis. These liver-specific genes were investigated for their expressions in both the primary tumors and the corresponding liver metastases of seven primary CRC patients with liver metastasis using microdissected samples. Results: Among the 3958 genes detected to be up-regulated in normal liver tissues versus normal colorectal tissues, we identified 12 liver-specific genes and found two of them, ANGPTL3 and CFHR5 , were unexpressed in microdissected primary colorectal tumors without metastasis but expressed in both microdissected liver metastases and corresponding primary colorectal tumors (Fisher's exact test, P colorectal tumors may express some liver-specific genes which may help the tumor cells adapt the liver micro-environment.

  12. Possibility of sandwiched liver surgery with molecular targeting drugs, cetuximab and bevacizumab on colon cancer liver metastases: a case report

    Directory of Open Access Journals (Sweden)

    Toyama Yoichi

    2012-06-01

    Full Text Available Abstract A 31-year-old man with sigmoid colon cancer with concomitant simultaneous multiple liver metastases had received FOLFIRI (leucovorin, fluorouracil and irinotecan and FOLFOX6 (leucovorin, fluorouracil and oxaliplatin after an ordinary sigmoidectomy. However, his serum carcinoembryonic antigen (CEA level increased rapidly during the fifteen months after the operation while he was on FOLFOX6. Abdominal computed tomography revealed expanding multiple liver tumors. As the third line chemotherapy, a combination therapy of cetuximab with irinotecan was given, which markedly reduced his levels of serum CEA, and the size and number of liver tumors. He underwent lateral segmentectomy of the liver and microwave coagulation of the liver metastases in the remnant liver. Thereafter, a good quality of life with tumor dormancy was obtained for 6 months. However, his serum CEA started to rise again in the absence of liver tumors. Therefore, FOLFOX6 with bevacizumab was chosen as the fourth line chemotherapy, and the serum CEA was reduced with tumor dormancy. A good quality of life was obtained again at 3 years after the first surgery. This report indicates the effectiveness of sandwiched liver surgery with the molecular targeting drugs cetuximab and bevacizumab on multiple liver metastases of colon cancer, and suggests the possibility of a regimen consisting of bevacizumab following cetuximab.

  13. Heme synthesis in normal mouse liver and mouse liver tumors

    International Nuclear Information System (INIS)

    Stout, D.L.; Becker, F.F.

    1990-01-01

    Hepatic cancers from mice and rats demonstrate decreased levels of delta-aminolevulinic acid synthase, the rate-limiting enzyme in the heme synthetic pathway, and increased heme oxygenase, the heme-catabolizing enzyme. These findings suggest that diminution of P-450, b5, and catalase in these lesions may result from a heme supply that is limited by decreased heme synthesis and increased heme catabolism. Heme synthesis was measured in mouse liver tumors (MLT) and adjacent tumor-free lobes (BKG) by administering the radiolabeled heme precursors 55 FeCl3 and [2- 14 C]glycine and subsequently extracting the heme for determination of specific activity. Despite reduced delta-aminolevulinic acid synthase activity in MLT, both tissues incorporated [2-14C]glycine into heme at similar rates. At early time points, heme extracted from MLT contained less 55Fe than that from BKG. This was attributed to the findings that MLT took up 55Fe at a slower rate than BKG and had larger iron stores than BKG. The amount of heme per milligram of protein was also similar in both tissues. These findings militate against the hypothesis that diminished hemoprotein levels in MLT result from limited availability of heme. It is probable, therefore, that decreased hemoprotein levels in hepatic tumors are linked to a general program of dedifferentiation associated with the cancer phenotype. Diminution of hemoprotein in MLT may result in a relatively increased intracellular heme pool. delta-Aminolevulinic acid synthase and heme oxygenase are, respectively, negatively and positively regulated by heme. Thus, their alteration in MLT may be due to the regulatory influences of the heme pool

  14. Gallium uptake in benign tumor of liver: case report

    International Nuclear Information System (INIS)

    Belanger, M.A.; Beauchamp, J.M.; Neitzschman, H.R.

    1975-01-01

    A case of positive tracer localization in a benign tumor of the liver on a 67 Ga-citrate scan is reported. The authors were unable to find any previous reports of positive localization of gallium in this type of liver tumor. (U.S.)

  15. Portal Vein Tumor Thrombus of Liver Metastasis from Lung Cancer

    Directory of Open Access Journals (Sweden)

    Ryoko Ogawa

    2009-01-01

    Full Text Available We report a case of liver metastasis of lung carcinoma with portal vein tumor thrombus (PVTT. Although the primary lesion of lung tumor remained unchanged, the patient rapidly developed wide-spread metastases and formed PVTT of liver metastasis. The primary lesion showed features of mixed Clara and bronchial surface epithelial cell component type adenocarcinoma with small foci of micropapillary pattern. Micropapillary pattern was observed in the metastatic lesions in the liver and PVTT. Micropapillary pattern lung adenocarcinoma may develop rapid metastases and cause PVTT associated with liver metastasis. We should perform a detailed examination to establish correct diagnosis.

  16. Contrast-enhanced Ultrasound for Non-tumor Liver Diseases

    Directory of Open Access Journals (Sweden)

    H Maruyama

    2012-03-01

    Full Text Available Contrast-enhanced ultrasound (CEUS is a simple, safe and reliable technique for the clinical management of patients with various liver diseases. Although the major target of the technique may be focal hepatic lesions, it is also effective for the diagnosis of non-tumor liver diseases, such as grading hepatic fibrosis, characterization of chronic liver diseases and diagnosis of portal vein thrombosis. This review article aimed to overview the recent application of CEUS in the assessment of non-tumor liver diseases. Keywords: Cirrhosis, contrast agent, fibrosis, idiopathic portal hypertension, microbubble, portal vein thrombosis, ultrasound.

  17. [Regression and therapy-resistance of primary liver tumors and liver metastases after regional chemotherapy and local tumor ablation].

    Science.gov (United States)

    Fischer, H-P

    2005-05-01

    High dosage regional chemotherapy, chemoembolization and other methods of regional treatment are commonly used to treat unresectable primary liver malignancies and liver metastases. In liver malignancies of childhood neoadjuvant chemotherapy is successfully combined with surgical treatment. Chemotherapy and local tumor ablation lead to characteristic histomorphologic changes: Complete destruction of the tumor tissue and its vascular bed is followed by encapsulated necroses. After selective eradication of the tumor cells under preservation of the fibrovasular bed the tumor is replaced by hypocellular edematous and fibrotic tissue. If completely damaged tumor tissue is absorbed quickly, the tumor area is replaced by regenerating liver tissue. Obliterating fibrohyalinosis of tumor vessels, and perivascular edema or necrosis indicate tissue damage along the vascular bed. Degenerative pleomorphism of tumor cells, steatosis, hydropic swelling and Malloryhyalin in HCC can represent cytologic findings of cytotoxic cellular damage. Macroscopic type of HCC influences significantly the response to treatment. Multinodular HCC often contain viable tumor nodules close to destroyed nodules after treatment. Encapsulated uninodular tumors undergo complete necrosis much easier. Large size and a tumor capsule limitate the effect of percutaneous injection of ethanol into HCC. In carcinomas with an infiltrating border, especially in metastases of adenocarcinomas and hepatic cholangiocarcinoma cytostatic treatment damages the tumor tissue mainly in the periphery. Nevertheless the infiltrating rim, portal veins, lymphatic spaces and bile ducts as well as the angle between liver capsule, tumor nodule and bordering parenchyma are the main refugees of viable tumor tissue even after high dosage regional chemotherapy. This local resistance is caused by special local conditions of vascularization and perfusion. These residues are the source of local tumor progression and distant metastases

  18. Autopsy case with malignant liver tumor caused by thorotrast

    Energy Technology Data Exchange (ETDEWEB)

    Sugiwara, T; Katayama, K; Shinta, K [Matsue City Hospital, Shimane (Japan); Yamazaki, I

    1975-03-01

    This paper reported the roentgenographic, laparoscopic and autopsy findings of a patient with thorotrast liver complicated with malignant liver tumor, which was considered to develop 35 years after the infusion of thorotrast. Laboratory findings of a 67-year-old man, who got a war wound before 35 years and received angiography by using thorotrast at that time, indicated marked symptoms of liver parenchymal disturbance, biliary occlusion and malignant liver tumor. X-ray examination revealed arborescent and reticular abnormal shadow in the liver and the spleen and spotted shadow at the liver hilus. Laparoscopic findings revealed reticulate grayish-yellow particles adhered to the recessus of the nodules in the surface of the liver. Liver biopsy showed deposition of thorotrast granules and necrosis and scar formation of the hepatic cells. Microautoradiography revealed ..cap alpha..-track from the region where thorotrast was deposited. Postmortem findings revealed thorotrast liver cirrhosis, primary liver tumor (reticulo-endothelial sarcoma), circular calcium deposit in the hepatic duct, the bile duct and the portal vein, and cholangitis, demonstrating delayed disturbance by thorotrast.

  19. Idiosyncratic Drug-Induced Liver Injury: Is Drug-Cytokine Interaction the Linchpin?

    Science.gov (United States)

    Roth, Robert A; Maiuri, Ashley R; Ganey, Patricia E

    2017-02-01

    Idiosyncratic drug-induced liver injury continues to be a human health problem in part because drugs that cause these reactions are not identified in current preclinical testing and because progress in prevention is hampered by incomplete knowledge of mechanisms that underlie these adverse responses. Several hypotheses involving adaptive immune responses, inflammatory stress, inability to adapt to stress, and multiple, concurrent factors have been proposed. Yet much remains unknown about how drugs interact with the liver to effect death of hepatocytes. Evidence supporting hypotheses implicating adaptive or innate immune responses in afflicted patients has begun to emerge and is bolstered by results obtained in experimental animal models and in vitro systems. A commonality in adaptive and innate immunity is the production of cytokines, including interferon-γ (IFNγ). IFNγ initiates cell signaling pathways that culminate in cell death or inhibition of proliferative repair. Tumor necrosis factor-α, another cytokine prominent in immune responses, can also promote cell death. Furthermore, tumor necrosis factor-α interacts with IFNγ, leading to enhanced cellular responses to each cytokine. In this short review, we propose that the interaction of drugs with these cytokines contributes to idiosyncratic drug-induced liver injury, and mechanisms by which this could occur are discussed. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

  20. Liver Effects of Clinical Drugs Differentiated in Human Liver Slices

    Directory of Open Access Journals (Sweden)

    Alison E. M. Vickers

    2017-03-01

    Full Text Available Drugs with clinical adverse effects are compared in an ex vivo 3-dimensional multi-cellular human liver slice model. Functional markers of oxidative stress and mitochondrial function, glutathione GSH and ATP levels, were affected by acetaminophen (APAP, 1 mM, diclofenac (DCF, 1 mM and etomoxir (ETM, 100 μM. Drugs targeting mitochondria more than GSH were dantrolene (DTL, 10 μM and cyclosporin A (CSA, 10 μM, while GSH was affected more than ATP by methimazole (MMI, 500 μM, terbinafine (TBF, 100 μM, and carbamazepine (CBZ 100 μM. Oxidative stress genes were affected by TBF (18%, CBZ, APAP, and ETM (12%–11%, and mitochondrial genes were altered by CBZ, APAP, MMI, and ETM (8%–6%. Apoptosis genes were affected by DCF (14%, while apoptosis plus necrosis were altered by APAP and ETM (15%. Activation of oxidative stress, mitochondrial energy, heat shock, ER stress, apoptosis, necrosis, DNA damage, immune and inflammation genes ranked CSA (75%, ETM (66%, DCF, TBF, MMI (61%–60%, APAP, CBZ (57%–56%, and DTL (48%. Gene changes in fatty acid metabolism, cholestasis, immune and inflammation were affected by DTL (51%, CBZ and ETM (44%–43%, APAP and DCF (40%–38%, MMI, TBF and CSA (37%–35%. This model advances multiple dosing in a human ex vivo model, plus functional markers and gene profile markers of drug induced human liver side-effects.

  1. Localization of liver tumors in freehand 3D laparoscopic ultrasound

    Science.gov (United States)

    Shahin, O.; Martens, V.; Besirevic, A.; Kleemann, M.; Schlaefer, A.

    2012-02-01

    The aim of minimally invasive laparoscopic liver interventions is to completely resect or ablate tumors while minimizing the trauma caused by the operation. However, restrictions such as limited field of view and reduced depth perception can hinder the surgeon's capabilities to precisely localize the tumor. Typically, preoperative data is acquired to find the tumor(s) and plan the surgery. Nevertheless, determining the precise position of the tumor is required, not only before but also during the operation. The standard use of ultrasound in hepatic surgery is to explore the liver and identify tumors. Meanwhile, the surgeon mentally builds a 3D context to localize tumors. This work aims to upgrade the use of ultrasound in laparoscopic liver surgery. We propose an approach to segment and localize tumors intra-operatively in 3D ultrasound. We reconstruct a 3D laparoscopic ultrasound volume containing a tumor. The 3D image is then preprocessed and semi-automatically segmented using a level set algorithm. During the surgery, for each subsequent reconstructed volume, a fast update of the tumor position is accomplished via registration using the previously segmented and localized tumor as a prior knowledge. The approach was tested on a liver phantom with artificial tumors. The tumors were localized in approximately two seconds with a mean error of less than 0.5 mm. The strengths of this technique are that it can be performed intra-operatively, it helps the surgeon to accurately determine the location, shape and volume of the tumor, and it is repeatable throughout the operation.

  2. Treatment of pancreatic neuroendocrine tumor with liver metastases

    Directory of Open Access Journals (Sweden)

    LI Zhao

    2015-05-01

    Full Text Available Pancreatic neuroendocrine tumor (pNET is a rare type of pancreatic tumors. The incidence of pNET shows a gradually increasing trend in recent years. The most common organ of distant metastases is the liver. Surgical resection is still the optimal treatment for resectable, well-differentiated liver metastases with no evidence of extrahepatic spread. For unresectable patients, a combination of multiple modalities, such as transarterial chemoembolization, radiofrequency ablation, systemic chemotherapy, and molecular targeted therapy, can prolong the survival time of patients. Liver transplantation should be strictly evaluated on an individual basis.

  3. Intra-Arterial Treatment of Primary and Metastatic Liver Tumors

    NARCIS (Netherlands)

    Buijs, M.A.M.; Vossen, J.A.

    2009-01-01

    The aims of this thesis were, first, to investigate the toxicities associated with trans-arterial chemoembolization (TACE) of liver tumors and to evaluate the use of MR imaging in characterizing tumor response after this locoregional therapy, second, to further develop intra-arterial therapy of

  4. Computed tomography of liver tumors, 2

    International Nuclear Information System (INIS)

    Naito, Akira; Fukuoka, Haruhito; Kashiwado, Kouzou; Ichiki, Toshio; Makidono, Yoko

    1984-01-01

    Differential diagnosis between hepatocellular carcinoma and metastatic hepatic tumor was attempted using dynamic CT scanning. Homogeneous and patchy types were peculiar to hepatocellular carcinoma, and ring-like type to metastatic hepatic tumor. However, with no enhancement, hepatocellular carcinoma could not be denied. Hepatocellular carcinoma was characterized by the enhancement shown on the early stage of dynamic CT. Ring enhancement was not visualized on dynamic CT but visualized on conventional contrast enhanced CT in hepatocellular carcinomas; it was visualized on conventional contrast enhanced CT and on dynamic CT in metastatic hepatic tumors. (Namekawa, K.)

  5. Liver tumors, correlation of computed tomography (CT) and pathology

    Energy Technology Data Exchange (ETDEWEB)

    Okazaki, Atsushi; Niibe, Hideo; Mitsuhashi, Norio

    1984-09-01

    Computed tomographic and pathologic correlation was studied in 12 autopsied cases with 11 cases of metastatic liver tumors and 1 case of hepatocellular carcinoma. Despite of proliferative patterns of the tumors, nodular low attenuations on CT showed scattered nodular lesions and geographic low attenuations on CT showed groups of multiple small nodular lesions, macroscopically. Abnormal areas of low attenuation were generally diminished by drip infusion contrast enhancement, which was more significant on tumors of infiltrative proliferation. Tumors of infiltrative proliferation revealed little degeneration of surrounding liver cells and abnormal areas of low attenuation were more distinct before contrast enhancement. Tumors of expansive proliferation revealed obvious degeneration of surrounding liver cells and a case having about 200 layers of degenerated liver cells revealed more distinct after contrast enhancement. The central lower density areas in abnormal areas of low attenuation on CT coincided with liquefactive necroses with scanty capillary. vessels and fibrotic changes, histopathologically. But coagulative necroses without decrease of surrouding blood flows were not visualized on CT. CT could not demonstrate the liquefactive necroses in more small nodules than 2 cm in diameter. (J.P.N.).

  6. Liver regeneration and restoration of liver function after partial hepatectomy in patients with liver tumors

    NARCIS (Netherlands)

    Jansen, P. L.; Chamuleau, R. A.; van Leeuwen, D. J.; Schipper, H. G.; Busemann-Sokole, E.; van der Heyde, M. N.

    1990-01-01

    Liver regeneration and restoration of liver function were studied in six patients who underwent partial hepatectomy with removal of 30-70% of the liver. Liver volume and liver regeneration were studied by single-photon computed tomography (SPECT), using 99mTc-colloid as tracer. The method was

  7. Stereotactic Body Radiation Therapy for Patients with Heavily Pretreated Liver Metastases and Liver Tumors

    Energy Technology Data Exchange (ETDEWEB)

    Lanciano, Rachelle; Lamond, John; Yang, Jun; Feng, Jing; Arrigo, Steve; Good, Michael; Brady, Luther, E-mail: rlancmd@gmail.com [Philadelphia CyberKnife, Drexel University, Havertown, PA (United States)

    2012-03-09

    We present our initial experience with CyberKnife stereotactic body radiation therapy (SBRT) in a heavily pretreated group of patients with liver metastases and primary liver tumors. From October 2007 to June 2009, 48 patients were treated at the Philadelphia CyberKnife Center for liver metastases or primary liver tumors. We report on 30 patients with 41 discrete lesions (1–4 tumors per patient) who received an ablative radiation dose (BED ≥ 79.2 Gy10 = 66 Gy EQD2). The treatment goal was to achieve a high SBRT dose to the liver tumor while sparing at least 700 cc of liver from radiation doses above 15 Gy. Twenty-three patients were treated with SBRT for metastatic cancer to the liver; the remainder (n = 7) were primary liver tumors. Eighty-seven percent of patients had prior systemic chemotherapy with a median 24 months from diagnosis to SBRT; 37% had prior liver directed therapy. Local control was assessed for 28 patients (39 tumors) with 4 months or more follow-up. At a median follow-up of 22 months (range, 10–40 months), 14/39 (36%) tumors had documented local failure. A decrease in local failure was found with higher doses of SBRT (p = 0.0237); 55% of tumors receiving a BED ≤ 100 Gy10 (10/18) had local failure compared with 19% receiving a BED > 100 Gy10 (4/21). The 2-year actuarial rate of local control for tumors treated with BED > 100 Gy10 was 75% compared to 38% for those patients treated with BED ≤ 100 Gy10 (p = 0.04). At last follow-up, 22/30 patients (73%) had distant progression of disease. Overall, seven patients remain alive with a median survival of 20 months from treatment and 57 months from diagnosis. To date, no patient experienced persistent or severe adverse effects. Despite the heavy pretreatment of these patients, SBRT was well tolerated with excellent local control rates when adequate doses (BED > 100 Gy10) were used. Median survival was limited secondary to development of further metastatic disease in the majority of patients.

  8. Solitary fibrous tumor of the liver: a case report

    Directory of Open Access Journals (Sweden)

    Ying Li-Xiong

    2011-03-01

    Full Text Available Abstract Hepatic solitary fibrous tumor (SFT is a rare tumor originating from the mesenchyme. Here we report a new case of SFT in the liver and review the clinical presentation, radiological and operative findings, diagnosis, treatment, and outcome. The patient was a 59-year-old man who presented with progressive fatigue for 3 months and an abdominal mass for 3 days. On laboratory tests, no abnormality was detected except that abdominal ultrasonography revealed a 9.0 × 6.2 cm hypoechogenic mass in the left lobe of the liver. A computed tomographic scan confirmed a hypodense lesion in the left lobe of the liver. The patient underwent left hepatectomy. SFT was diagnosed on the basis of histopathological findings. The patient was free from all symptoms and had no signs of local recurrence after 24 months' follow up.

  9. Drug-induced liver injury due to antibiotics.

    Science.gov (United States)

    Björnsson, Einar S

    Drug-induced liver injury (DILI) is an important differential diagnosis in patients with abnormal liver tests and normal hepatobiliary imaging. Of all known liver diseases, the diagnosis of DILI is probably one of the most difficult one to be established. In all major studies on DILI, antibiotics are the most common type of drugs that have been reported. The clinical phenotype of different types of antibiotics associated with liver injury is highly variable. Some widely used antibiotics such as amoxicillin-clavulanate have been shown to have a delayed onset on liver injury and recently cefazolin has been found to lead to liver injury 1-3 weeks after exposure of a single infusion. The other extreme is the nature of nitrofurantoin-induced liver injury, which can occur after a few years of treatment and lead to acute liver failure (ALF) or autoimmune-like reaction. Most patients with liver injury associated with use of antibiotics have a favorable prognosis. However, patients with jaundice have approximately 10% risk of death from liver failure and/or require liver transplantation. In rare instances, the hepatoxicity can lead to chronic injury and vanishing bile duct syndrome. Given, sometimes very severe consequences of the adverse liver reactions, it cannot be over emphasized that the indication for the different antibiotics should be evidence-based and symptoms and signs of liver injury from the drugs should lead to prompt cessation of therapy.

  10. Acute Liver Failure from Tumor Necrosis Factor-α Antagonists: Report of Four Cases and Literature Review.

    Science.gov (United States)

    Kok, Beverley; Lester, Erica L W; Lee, William M; Hanje, A James; Stravitz, R Todd; Girgis, Safwat; Patel, Vaishali; Peck, Joshua R; Esber, Christopher; Karvellas, Constantine J

    2018-03-21

    Tumor necrosis factor-α antagonists (anti-TNF-α) have been associated with drug-induced liver injury. However, cases of anti-TNF-α-associated acute liver failure have only been rarely reported. To identify cases of anti-TNF-α-associated acute liver failure and evaluate patterns of liver injury and common characteristics to the cases. The United States Acute Liver Failure Study Group database was searched from 1998 to 2014. Four subjects were identified. A PubMed search for articles that reported anti-TNF-α-associated acute liver failure identified five additional cases. The majority of individuals affected were female (eight of nine cases). Age of individual ranged from 20 to 53 years. The most common anti-TNF-α agent associated with acute liver failure was infliximab (n = 8). The latency between initial drug exposure and acute liver failure ranged from 3 days to over a year. Of the nine cases, six required emergency LT. Liver biopsy was obtained in seven cases with a preponderance toward cholestatic-hepatitic features; none showed clear autoimmune features. Anti-TNF-α-associated acute liver failure displays somewhat different characteristics compared with anti-TNF-α-induced drug-induced liver injury. Infliximab was implicated in the majority of cases. Cholestatic-hepatitic features were frequently found on pre-transplant and explant histology.

  11. Drug-induced liver injury associated with HIV medications.

    Science.gov (United States)

    Jain, Mamta K

    2007-08-01

    Antiretroviral therapy (ART) for HIV infection frequently has been associated with elevated liver enzyme levels. Determining the cause of elevated liver enzyme levels in patients who have HIV is difficult because ART usually consists of three different drugs, patients may be taking additional hepatotoxic medications and patients who have HIV often suffer from other liver diseases. Several agents, however, are recognized as having noteworthy and specific patterns of toxicity. This article reviews the different HIV drug classes, incidence of elevated liver enzyme values by class and by individual drug, risk factors, specific toxicities, and possible mechanisms of injury.

  12. Inflammatory angiomyolipoma of the liver: a rare hepatic tumor

    Directory of Open Access Journals (Sweden)

    Liu Yang

    2012-09-01

    Full Text Available Abstract Angiomyolipoma (AML is a rare mesenchymal neoplasm of the tumor, composed of a varying heterogeneous mixture of three tissue components: blood vessels, smooth muscle and adipose cells. Hepatic AML may demonstrate a marked histological diversity. We herein present one case of hepatic AML exhibiting prominent inflammatory cells in the background, which happened in a 61-year-old Chinese female patient, without signs of tuberous sclerosis. Histologically, the striking feature was the infiltration of numerous inflammatory cells in the background, including small lymphocytes, plasma cells, and eosnophils. The tumor cells were spindled and histiocytoid in shape, with slightly eosinophilic cytoplasm, and arranged along the vessels or scattered among the inflammatory background. Sinusoid structure was obviously seen in the tumor. Mature adipocytes and thick-walled blood vessels were focally observed at the boundaries between the tumor and surrounding liver tissues. The tumor cells were positive immunostaining for HMB-45, Melan-A, and smooth muscle actin. The inflammatory AML should be distinguished from other tumors with inflammatory background such as inflammatory myofibroblastic tumor and follicular dendritic cell tumor and deserves wider recognition for its occurrence as a primary hepatic tumor. Virtual slides The virtual slide(s for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1828633072762370

  13. Use of Semiflexible Applicators for Radiofrequency Ablation of Liver Tumors

    International Nuclear Information System (INIS)

    Gaffke, G.; Gebauer, B.; Knollmann, F.D.; Helmberger, T.; Ricke, J.; Oettle, H.; Felix, R.; Stroszczynski, C.

    2006-01-01

    Purpose. To evaluate the feasibility and potential advantages of the radiofrequency ablation of liver tumors using new MRI-compatible semiflexible applicators in a closed-bore high-field MRI scanner. Methods. We treated 8 patients with 12 malignant liver tumors of different origin (5 colorectal carcinoma, 2 cholangiocellular carcinoma, 1 breast cancer) under MRI guidance. Radiofrequency ablation (RFA) was performed using 5 cm Rita Starburst Semi-Flex applicators (Rita Medical Systems, Milwaukee, WI, USA) which are suitable for MR- and CT-guided interventions and a 150 W RF generator. All interventions were performed in a closed-bore 1.5 T high-field MRI scanner for MRI-guided RFA using fast T1-weighted gradient echo sequences and T2-weighted ultra-turbo spin echo sequences. Control and follow-up MRI examinations were performed on the next day, at 6 weeks, and every 3 months after RFA. Control MRI were performed as double-contrast MRI examinations (enhancement with iron oxide and gadopentetate dimeglumine). All interventions were performed with the patient under local anesthesia and analgo-sedation. Results. The mean diameter of the treated hepatic tumors was 2.4 cm (±0.6 cm, range 1.0-3.2 cm). The mean diameter of induced necrosis was 3.1 cm (±0.4 cm). We achieved complete ablation in all patients. Follow-up examinations over a duration of 7 months (±1.3 months, range 4-9 month) showed a local control rate of 100% in this group of patients. All interventions were performed without major complications; only 2 subcapsular hematomas were documented. Conclusion. RFA of liver tumors using semiflexible applicators in closed-bore 1.5 T scanner systems is feasible. These applicators might simplify the RFA of liver tumors under MRI control. The stiff distal part of the applicator facilitates its repositioning

  14. Is Diaphragm Motion a Good Surrogate for Liver Tumor Motion?

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Juan [Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina (United States); School of Information Science and Engineering, Shandong University, Jinan, Shandong (China); Cai, Jing [Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina (United States); Wang, Hongjun [School of Information Science and Engineering, Shandong University, Jinan, Shandong (China); Chang, Zheng; Czito, Brian G. [Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina (United States); Bashir, Mustafa R. [Department of Radiology, Duke University Medical Center, Durham, North Carolina (United States); Palta, Manisha [Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina (United States); Yin, Fang-Fang, E-mail: fangfang.yin@duke.edu [Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina (United States)

    2014-11-15

    Purpose: To evaluate the relationship between liver tumor motion and diaphragm motion. Methods and Materials: Fourteen patients with hepatocellular carcinoma (10 of 14) or liver metastases (4 of 14) undergoing radiation therapy were included in this study. All patients underwent single-slice cine–magnetic resonance imaging simulations across the center of the tumor in 3 orthogonal planes. Tumor and diaphragm motion trajectories in the superior–inferior (SI), anterior–posterior (AP), and medial–lateral (ML) directions were obtained using an in-house-developed normalized cross-correlation–based tracking technique. Agreement between the tumor and diaphragm motion was assessed by calculating phase difference percentage, intraclass correlation coefficient, and Bland-Altman analysis (Diff). The distance between the tumor and tracked diaphragm area was analyzed to understand its impact on the correlation between the 2 motions. Results: Of all patients, the mean (±standard deviation) phase difference percentage values were 7.1% ± 1.1%, 4.5% ± 0.5%, and 17.5% ± 4.5% in the SI, AP, and ML directions, respectively. The mean intraclass correlation coefficient values were 0.98 ± 0.02, 0.97 ± 0.02, and 0.08 ± 0.06 in the SI, AP, and ML directions, respectively. The mean Diff values were 2.8 ± 1.4 mm, 2.4 ± 1.1 mm, and 2.2 ± 0.5 mm in the SI, AP, and ML directions, respectively. Tumor and diaphragm motions had high concordance when the distance between the tumor and tracked diaphragm area was small. Conclusions: This study showed that liver tumor motion had good correlation with diaphragm motion in the SI and AP directions, indicating diaphragm motion in the SI and AP directions could potentially be used as a reliable surrogate for liver tumor motion.

  15. Liver regeneration and restoration of liver function after partial hepatectomy in patients with liver tumors

    International Nuclear Information System (INIS)

    Jansen, P.L.M.; Chamuleau, R.A.F.; Leeuwen, D.J. van; Schippor, H.G.; Busemann-Sokole, E.; Heyde, M.N. van der

    1990-01-01

    Liver regeneration and restoration of liver function were studied in six patients who underwent partial hepatectomy with removal of 30-70% of the liver. Liver volume and liver regeneration were studied by single photon computed tomography (SPECT), using 99m Tc-colloid as tracer. The method was assessed in 11 patients by comparing the pre- and post-operative volume measurement with the volume of the resected liver mass. Liver function was determined by measuring the galactose elimination capacity and the caffeine clearance. After a postoperative follow-up period of 50 days, the liver had regenerated maximally to a volume of 75 ± 2% of the preoperative liver mass. Maximal restoration of liver function was achieved 120 days after operation and amounted to 75 ± 10% for the caffeine clearance and to 100 ± 25% for the galactose elimination capacity. This study shows that SPECT is a useful method for assessing liver regeneration in patients after partial hepatectomy. The study furthermore shows that caffeine clearance correlates well with total liver volume, whereas the galactose elimination capacity overestimates total liver volume after partial hepatectomy. 22 refs

  16. Tumor targeting using liposomal antineoplastic drugs

    Directory of Open Access Journals (Sweden)

    Jörg Huwyler

    2008-03-01

    Full Text Available Jörg Huwyler1, Jürgen Drewe2, Stephan Krähenbühl21University of Applied Sciences Northwestern Switzerland, Institute of Pharma Technology, Muttenz, Switzerland; 2Department of Research and Division of Clinical Pharmacology, University Hospital Basel, Basel, SwitzerlandAbstract: During the last years, liposomes (microparticulate phospholipid vesicles have beenused with growing success as pharmaceutical carriers for antineoplastic drugs. Fields of application include lipid-based formulations to enhance the solubility of poorly soluble antitumordrugs, the use of pegylated liposomes for passive targeting of solid tumors as well as vector-conjugated liposomal carriers for active targeting of tumor tissue. Such formulation and drug targeting strategies enhance the effectiveness of anticancer chemotherapy and reduce at the same time the risk of toxic side-effects. The present article reviews the principles of different liposomal technologies and discusses current trends in this field of research.Keywords: tumor targeting, antineoplastic drugs, liposomes, pegylation, steric stabilization, immunoliposomes

  17. Thrombocytopenia and liver damage induced by actinomycin-D following radiotherapy in a patient with Wilms' tumor

    International Nuclear Information System (INIS)

    Watanabe, Takeshi; Kibe, Norio; Kawano, Yoshifumi; Yazawa, Kenji; Shiraga, Hiroshi; Hosoya, Ryota; Ohya, Tatsuo; Nishimura, Kozo; Yokoyama, Johtaro

    1985-01-01

    A two-year-old girl with Wilms' tumor received radiotherapy of 25.5 Gy to the right abdomen, followed by vincristine and actinomycin-D (Act). The patient developed general fatigue, anemia, thrombocytopenia, and liver damage associated with ascites. She improved by conservative therapy of two week duration. From the literature, it is suggested that such drug-related liver damage tends to occur when irradiation is given before chemotherapy, including Act. (Namekawa, K.)

  18. Evaluation of selective boron absorption in liver tumors

    International Nuclear Information System (INIS)

    Chiaraviglio, D.; Grazia, F. De; Zonta, A.; Altieri, S.; Pedroni, P.; Braghieri, B.; Fossati, F.; Pinelli, T.; Perotti, A.; Specchiarello, S.; Perlini, G.; Rief, H.

    1988-01-01

    The first step was a pharmacokinetic study to identify substances which are good boron transporters and are therefore able to provide a high concentration of the nuclide with respect to the healthy hepatic tissue in the MHN. For this purpose the tumor M5076/73 (M5), which matastasizes spontaneously in liver, was inoculated subcutaneously in a group of C57B1/6 mice. Thirty days after the inoculation, when 90% of the liver was invaded by metastases, a boric acid 0.3 M solution enriched to 96% 10 B was injected into the caudal vein. The mice were sacrificed and the liver was frozen for measurements. Boron concentration in the various samples was achieved by measuring the energy distribution of α particles produced in the nuclear reaction 10 B(n, α) 7 Li induced by a thermal neutron beam extracted from the Triga Mark II reactor,

  19. Pyrrolizidine Alkaloids: Metabolic Activation Pathways Leading to Liver Tumor Initiation.

    Science.gov (United States)

    Fu, Peter P

    2017-01-17

    Pyrrolizidine alkaloids (PAs) and PA N-oxides are a class of phytochemical carcinogens contained in over 6000 plant species spread around the world. It has been estimated that approximately half of the 660 PAs and PA N-oxides that have been characterized are cytotoxic, genotoxic, and tumorigenic. It was recently determined that a genotoxic mechanism of liver tumor initiation mediated by PA-derived DNA adducts is a common metabolic activation pathway of a number of PAs. We proposed this set of PA-derived DNA adducts could be a common biological biomarker of PA exposure and a potential biomarker of PA-induced liver tumor formation. We have also found that several reactive secondary pyrrolic metabolites can dissociate and interconvert to other secondary pyrrolic metabolites, resulting in the formation of the same exogenous DNA adducts. This present perspective reports the current progress on these new findings and proposes future research needed for obtaining a greater understanding of the role of this activation pathway and validating the use of this set of PA-derived DNA adducts as a biological biomarker of PA-induced liver tumor initiation.

  20. Determination of Radiation Absorbed Dose to Primary Liver Tumors and Normal Liver Tissue Using Post Radioembolization 90Y PET

    Directory of Open Access Journals (Sweden)

    Shyam Mohan Srinivas

    2014-10-01

    Full Text Available Background: Radioembolization with Yttrium-90 (90Y microspheres is becoming a more widely used transcatheter treatment for unresectable hepatocellular carcinoma (HCC. Using post-treatment 90Y PET/CT scans,the distribution of microspheres within the liver can be determined and quantitatively assessesed . We studied the radiation dose of 90Y delivered to liver and treated tumors.Methods: This retrospective study of 56 patients with HCC, including analysis of 98 liver tumors, measured and correlated the dose of radiation delivered to liver tumors and normal liver tissue using glass microspheres (TheraSpheres® to the frequency of complications with mRECIST. 90Y PET/CT and triphasic liver CT scans were used to contour treated tumor and normal liver regions and determine their respective activity concentrations. An absorbed dose factor was used to convert the measured activity concentration (Bq/mL to an absorbed dose (Gy.Results: The 98 studied tumors received a mean dose of 169 Gy (mode 90-120 Gy;range 0-570 Gy. Tumor response by mRECIST criteria was performed for 48 tumors that had follow up scans. There were 21 responders (mean dose 215 Gy and 27 nonresponders (mean dose 167 Gy. The association between mean tumor absorbed dose and response suggests a trend but did not reach statistical significance (p=0.099. Normal liver tissue received a mean dose of 67 Gy (mode 60-70 Gy; range 10-120 Gy. There was a statistically significant association between absorbed dose to normal liver and the presence of two or more severe complications (p=0.036.Conclusion: Our cohort of patients showed a possible dose response trend for the tumors. Collateral dose to normal liver is nontrivial and can have clinical implications. These methods help us understand whether patient adverse events, treatment success, or treatment failure can be attributed to the dose which the tumor or normal liver received.

  1. Rb and p53 Liver Functions Are Essential for Xenobiotic Metabolism and Tumor Suppression.

    Directory of Open Access Journals (Sweden)

    Sathidpak Nantasanti

    Full Text Available The tumor suppressors Retinoblastoma (Rb and p53 are frequently inactivated in liver diseases, such as hepatocellular carcinomas (HCC or infections with Hepatitis B or C viruses. Here, we discovered a novel role for Rb and p53 in xenobiotic metabolism, which represent a key function of the liver for metabolizing therapeutic drugs or toxins. We demonstrate that Rb and p53 cooperate to metabolize the xenobiotic 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC. DDC is metabolized mainly by cytochrome P450 (Cyp3a enzymes resulting in inhibition of heme synthesis and accumulation of protoporphyrin, an intermediate of heme pathway. Protoporphyrin accumulation causes bile injury and ductular reaction. We show that loss of Rb and p53 resulted in reduced Cyp3a expression decreased accumulation of protoporphyrin and consequently less ductular reaction in livers of mice fed with DDC for 3 weeks. These findings provide strong evidence that synergistic functions of Rb and p53 are essential for metabolism of DDC. Because Rb and p53 functions are frequently disabled in liver diseases, our results suggest that liver patients might have altered ability to remove toxins or properly metabolize therapeutic drugs. Strikingly the reduced biliary injury towards the oxidative stress inducer DCC was accompanied by enhanced hepatocellular injury and formation of HCCs in Rb and p53 deficient livers. The increase in hepatocellular injury might be related to reduce protoporphyrin accumulation, because protoporphrin is well known for its anti-oxidative activity. Furthermore our results indicate that Rb and p53 not only function as tumor suppressors in response to carcinogenic injury, but also in response to non-carcinogenic injury such as DDC.

  2. Optimization of localized 19F magnetic resonance spectroscopy for the detection of fluorinated drugs in the human liver.

    NARCIS (Netherlands)

    Klomp, D.W.J.; Laarhoven, H.W.M. van; Kentgens, A.P.M.; Heerschap, A.

    2003-01-01

    Fluorine MR spectroscopy ((19)F MRS) is an indispensable tool for assessing the pharmacokinetics of fluorinated drugs. Since the metabolism of 5-fluorouracil (5FU), a frequently used cytotoxic drug, is expected to be different in normal liver and in tumor tissue, spatial localization is required for

  3. Optimization of localized 19F magnetic resonance spectroscopy for the detection of fluorinated drugs in the human liver

    NARCIS (Netherlands)

    Klomp, Dennis W. J.; van Laarhoven, Hanneke W. M.; Kentgens, Arno P. M.; Heerschap, Arend

    2003-01-01

    Fluorine MR spectroscopy ((19)F MRS) is an indispensable tool for assessing the pharmacokinetics of fluorinated drugs. Since the metabolism of 5-fluorouracil (5FU), a frequently used cytotoxic drug, is expected to be different in normal liver and in tumor tissue, spatial localization is required for

  4. Bioengineered Liver Models for Drug Testing and Cell Differentiation Studies

    Directory of Open Access Journals (Sweden)

    Gregory H. Underhill

    2018-01-01

    Full Text Available In vitro models of the human liver are important for the following: (1 mitigating the risk of drug-induced liver injury to human beings, (2 modeling human liver diseases, (3 elucidating the role of single and combinatorial microenvironmental cues on liver cell function, and (4 enabling cell-based therapies in the clinic. Methods to isolate and culture primary human hepatocytes (PHHs, the gold standard for building human liver models, were developed several decades ago; however, PHHs show a precipitous decline in phenotypic functions in 2-dimensional extracellular matrix–coated conventional culture formats, which does not allow chronic treatment with drugs and other stimuli. The development of several engineering tools, such as cellular microarrays, protein micropatterning, microfluidics, biomaterial scaffolds, and bioprinting, now allow precise control over the cellular microenvironment for enhancing the function of both PHHs and induced pluripotent stem cell–derived human hepatocyte-like cells; long-term (4+ weeks stabilization of hepatocellular function typically requires co-cultivation with liver-derived or non–liver-derived nonparenchymal cell types. In addition, the recent development of liver organoid culture systems can provide a strategy for the enhanced expansion of therapeutically relevant cell types. Here, we discuss advances in engineering approaches for constructing in vitro human liver models that have utility in drug screening and for determining microenvironmental determinants of liver cell differentiation/function. Design features and validation data of representative models are presented to highlight major trends followed by the discussion of pending issues that need to be addressed. Overall, bioengineered liver models have significantly advanced our understanding of liver function and injury, which will prove useful for drug development and ultimately cell-based therapies.

  5. The Role of Tumor Necrosis Factor- alpha and Resistin in Nonalcoholic Fatty Liver Disease

    International Nuclear Information System (INIS)

    Alkady, M.M.

    2011-01-01

    Nonalcoholic fatty liver disease (NAFLD) represents one of the most common liver diseases. It is strongly associated with obesity and insulin resistance and is thought to be a part of the metabolic syndrome. It can progress from simple fatty liver to steatohepatitis, cirrhosis and liver failure. Adipocytokines, synthesized in adipose tissue, are involved in the pathophysiology of many acute and chronic liver diseases. The aim of this study was to investigate the role of Tumor Necrosis Factor-alpha (TNF-alpha) and resistin in the pathogenesis of NAFLD and their correlation to the severity of the disease. Serum concentration of TNF-alpha and resistin were measured in 20 patients with NAFLD and 20 healthy controls with ELISA method. The results of this study revealed that serum levels of both adipokines were significantly elevated in NAFLD patients than controls (P<0.01). Moreover, they were significantly higher in patients with nonalcoholic steatohepatitis than in patients with simple fatty liver. There was a significant positive correlation between TNF-alpha, resistin and each of AST, ALT and HOMA. Similarly, the results showed a significant positive correlation between the two studied adipokines, TNF-alpha and resistin (P<0.001). We conclude that TNF-alpha and resistin have a role in the pathogenesis of NAFLD and they may be promising markers for the progressin to steatohepatitis and inhibition of their activities by drugs may be a new approach for the treatment of NAFLD

  6. Recellularization of rat liver: An in vitro model for assessing human drug metabolism and liver biology.

    Directory of Open Access Journals (Sweden)

    Matthew J Robertson

    Full Text Available Liver-like organoids that recapitulate the complex functions of the whole liver by combining cells, scaffolds, and mechanical or chemical cues are becoming important models for studying liver biology and drug metabolism. The advantages of growing cells in three-dimensional constructs include enhanced cell-cell and cell-extracellular matrix interactions and preserved cellular phenotype including, prevention of de-differentiation. In the current study, biomimetic liver constructs were made via perfusion decellularization of rat liver, with the goal of maintaining the native composition and structure of the extracellular matrix. We optimized our decellularization process to produce liver scaffolds in which immunogenic residual DNA was removed but glycosaminoglycans were maintained. When the constructs were recellularized with rat or human liver cells, the cells remained viable, capable of proliferation, and functional for 28 days. Specifically, the cells continued to express cytochrome P450 genes and maintained their ability to metabolize a model drug, midazolam. Microarray analysis showed an upregulation of genes involved in liver regeneration and fibrosis. In conclusion, these liver constructs have the potential to be used as test beds for studying liver biology and drug metabolism.

  7. Predisposing Factors of Liver Necrosis after Transcatheter Arterial Chemoembolization in Liver Metastases from Neuroendocrine Tumor

    Energy Technology Data Exchange (ETDEWEB)

    Joskin, Julien, E-mail: j.joskin@gmail.com; Baere, Thierry de, E-mail: Thierry.DEBAERE@igr.fr [Institut Gustave Roussy, Department of Interventional Radiology (France); Auperin, Anne, E-mail: Anne.AUPERIN@igr.fr [Institut Gustave Roussy, Department of Epidemiology (France); Tselikas, Lambros, E-mail: lambros.tselikas@gmail.com; Guiu, Boris, E-mail: boris.guiu@chu-dijon.fr; Farouil, Geoffroy, E-mail: g.farouil@gmail.com [Institut Gustave Roussy, Department of Interventional Radiology (France); Boige, Valérie, E-mail: boige@igr.fr; Malka, David, E-mail: david.malka@igr.fr [Institut Gustave Roussy, Department of Digestive Oncology (France); Leboulleux, Sophie, E-mail: sophie.leboulleux@igr.fr [Institut Gustave Roussy, Department of Nuclear Medicine and Endocrine Oncology (France); Ducreux, Michel, E-mail: ducreux@igr.fr [Institut Gustave Roussy, Department of Digestive Oncology (France); Baudin, Eric, E-mail: baudin@igr.fr [Institut Gustave Roussy, Department of Nuclear Medicine and Endocrine Oncology (France); Deschamps, Frédéric, E-mail: frederic.deschamps@igr.fr [Institut Gustave Roussy, Department of Interventional Radiology (France)

    2015-04-15

    PurposeTo investigate predictive factors for liver necrosis after transcatheter arterial chemoembolization (TACE) of neuroendocrine liver metastases.MethodsA total of 164 patients receiving 374 TACE were reviewed retrospectively to analyze predictive factors of liver necrosis. We analyzed patient age and sex; metastasis number and location; percentage of liver involvement; baseline liver function test; and pretreatment imaging abnormalities such as bile duct dilatation (BDD), portal vein narrowing (PVN), and portal vein thrombosis (PVT). We analyzed TACE technique such as Lipiodol or drug-eluting beads (DEB) as the drug’s vector; dose of chemotherapy; diameter of DEB; and number, frequency, and selectivity of TACE.ResultsLiver necrosis developed after 23 (6.1 %) of 374 TACE. In multivariate analysis, DEB > 300 μm in size induced more liver necrosis compared to Lipiodol (odds ratio [OR] 35.20; p < 0.0001) or with DEB < 300 μm in size (OR 19.95; p < 0.010). Pretreatment BDD (OR 119.64; p < 0.0001) and PVT (OR 9.83; p = 0.030) were predictive of liver necrosis. BDD or PVT responsible for liver necrosis were present before TACE in 59 % (13 of 22) and were induced by a previous TACE in 41 % (9 of 22) of cases.ConclusionDEB > 300 μm in size, BDD, and PVT are responsible for increased rate of liver necrosis after TACE. Careful analysis of BDD or PVT on pretreatment images as well as images taken between two courses can help avoid TACE complications.

  8. The risk of liver tumors in dogs and man from radioactive aerosols

    International Nuclear Information System (INIS)

    Muggenburg, B.A.; Boecker, B.B.; Hahn, F.F.; Griffith, W.G.; McClellan, R.O.

    1986-01-01

    Life-span studies in progress using beagle dogs that inhaled relatively soluble or relatively insoluble forms of radionuclides will provide information from which we may project the risk to humans for liver cancer from inhaled radioactive material. Twenty-two liver tumors have been observed in dogs exposed to beta-emitting radionuclides, mainly 144 Ce, and one liver tumor in a dog exposed to 238 Pu. Two liver cancers were also observed in control dogs. The risk of liver cancer in dogs that inhaled beta-emitting radionuclides was calculated to be 90 liver cancers per million rads. The risk of liver cancers in dogs in our studies and in studies at the University of Utah, when compared to the incidence of liver tumors in humans exposed to Thorotrast, suggest that the risk of liver cancer from an inhaled beta-emitting radionuclide in people is about 30 liver cancers per million person-rads. 19 refs., 3 tabs

  9. Microcirculation of the liver and hepatic tumors: implication for intervention

    International Nuclear Information System (INIS)

    Matsui, O.

    2012-01-01

    Full text:To understand the microcirculation of the liver and hepatic tumors is important for the precise imaging diagnosis and intervention of hepatic diseases. In this presentation, blood flow imaging features of dynamic MDCT in various hepatic lesions or variations as described below will be discussed based on the angiography-assisted CT imaging and pathophysiologic correlations. (1) Portal venous obstruction (segmental staining) and microangioarchtecture of the liver; Because of compensatory blood flow from the hepatic artery to the distal portion of the portal vein through the peribiliary vascular plexus (PBP), the obstructed segment shows early enhancement on dynamic CT (segmental staining). In diffuse intrahepatic portal vein obstruction, peripheral (zone) enhancement can be seen, resulting in 'central hypertrophy' in chronic stage. (2) Pseudolesion and/or pseudotumor due to third inflow into the liver; According to CT during arterial portography (CTAP)-based analysis, the third inflow includes flow from an aberrant right gastric vein (or pancreatico-duodeno-gastric vein), cystic veins, veins of Sappey, and aberrant left gastric vein. These veins usually connect directly to the intrahepatic portal venules. The areas receiving the third inflow often show pseudolesions or pseudotumors. (3) Microcirculation of hepatocellular carcinoma (HCC) and dynamic MDCT features; By single level dynamic thin-section CT during the bolus injection of a small amount of contrast medium, we revealed in vivo hemodynamics in hypervascular classical HCC, namely, the arterial blood flow into the tumor drains into surrounding hepatic sinusoids (corona enhancement, wash out). Histological examination revealed continuity between a tumor sinusoid and a portal venule in the pseudocapsule (encapsulated HCC) or surrounding hepatic sinusoids (HCC without pseudocapsule). The drainage area is the first site of the intrahepatic metastasis of HCC, and daughter nodules are commonly seen in this

  10. Treatment of Liver Tumors with Lipiodol TACE: Technical Recommendations from Experts Opinion

    Energy Technology Data Exchange (ETDEWEB)

    Baere, Thierry de, E-mail: thierry.debaere@gustaveroussy.fr [Gustave Roussy, Department of Interventional Radiology (France); Arai, Yasuaki, E-mail: arai-y3111@mvh.biglobe.ne.jp [National Cancer Center, Department of Diagnostic Radiology (Japan); Lencioni, Riccardo, E-mail: riccardo.lencioni@med.unipi.it [Pisa University School of Medicine, Division of Diagnostic Imaging and Intervention (R.L.) (Italy); Geschwind, Jean-Francois, E-mail: jfg@jhmi.edu [The Johns Hopkins Hospital, Vascular and Interventional Radiology (United States); Rilling, William, E-mail: wrilling@mcw.edu [Medical College of Wisconsin, Division of Vascular and Interventional Radiology Rm2803 (United States); Salem, Riad, E-mail: r-salem@northwestern.edu [Northwestern University, Department of Radiology (United States); Matsui, Osamu, E-mail: matsuio@med.kanazawa-u.ac.jp [Kanazawa University Graduate School of Medical Sciences, Department of Advanced Medical Imaging (Japan); Soulen, Michael C., E-mail: michael.soulen@uphs.upenn.edu [University of Pennsylvania, Division of Interventional Radiology (MCS) (United States)

    2016-03-15

    Transarterial chemoembolization with Lipiodol (Lipiodol TACE), also called conventional TACE, was developed in the early 1980s and widely adopted worldwide after randomized control trials and meta-analysis demonstrated superiority of Lipiodol TACE to best supportive care. Presently, there is no level one evidence that other TACE techniques are superior to Lipiodol TACE for intermediate stage hepatocellular carcinoma (HCC), which includes patients with preserved liver function and nonsurgical large or multinodular HCC without distant metastases. In addition, TACE is part of the treatment for progressive or symptomatic liver metastases from gastroenteropancreatic neuroendocrine tumors. When injected into the hepatic artery, Lipiodol has the unique property of selective uptake and retention in hyperarterialyzed liver tumors. Lipiodol/drug emulsion followed by particle embolization has been demonstrated to improve the pharmacokinetic of the drug and tumor response. Radio opacity of Lipiodol helps to monitor treatment delivery, with retention of Lipiodol serving as an imaging biomarker for tumor response. For 30 years, Lipiodol TACE has been inconsistently referenced in many publications with various levels of details for the method of preparation and administration, with reported progressive outcomes following improvements in the technique and the devices used to deliver the treatment and better patient selection. Consequently, there is no consensus on the standard method of TACE regarding the use of anticancer agents, embolic material, technical details, and the treatment schedule. In order to develop an internationally validated technical recommendation to standardize the Lipiodol TACE procedure, a worldwide panel of experts participated in a consensus meeting held on May 10, 2014.

  11. Linc00210 drives Wnt/β-catenin signaling activation and liver tumor progression through CTNNBIP1-dependent manner.

    Science.gov (United States)

    Fu, Xiaomin; Zhu, Xiaoyan; Qin, Fujun; Zhang, Yong; Lin, Jizhen; Ding, Yuechao; Yang, Zihe; Shang, Yiman; Wang, Li; Zhang, Qinxian; Gao, Quanli

    2018-03-14

    Liver tumor initiating cells (TICs) have self-renewal and differentiation properties, accounting for tumor initiation, metastasis and drug resistance. Long noncoding RNAs are involved in many physiological and pathological processes, including tumorigenesis. DNA copy number alterations (CNA) participate in tumor formation and progression, while the CNA of lncRNAs and their roles are largely unknown. LncRNA CNA was determined by microarray analyses, realtime PCR and DNA FISH. Liver TICs were enriched by surface marker CD133 and oncosphere formation. TIC self-renewal was analyzed by oncosphere formation, tumor initiation and propagation. CRISPRi and ASO were used for lncRNA loss of function. RNA pulldown, western blot and double FISH were used to identify the interaction between lncRNA and CTNNBIP1. Using transcriptome microarray analysis, we identified a frequently amplified long noncoding RNA in liver cancer termed linc00210, which was highly expressed in liver cancer and liver TICs. Linc00210 copy number gain is associated with its high expression in liver cancer and liver TICs. Linc00210 promoted self-renewal and tumor initiating capacity of liver TICs through Wnt/β-catenin signaling. Linc00210 interacted with CTNNBIP1 and blocked its inhibitory role in Wnt/β-catenin activation. Linc00210 silencing cells showed enhanced interaction of β-catenin and CTNNBIP1, and impaired interaction of β-catenin and TCF/LEF components. We also confirmed linc00210 copy number gain using primary hepatocellular carcinoma (HCC) samples, and found the correlation between linc00210 CNA and Wnt/β-catenin activation. Of interest, linc00210, CTNNBIP1 and Wnt/β-catenin signaling targeting can efficiently inhibit tumor growth and progression, and liver TIC propagation. With copy-number gain in liver TICs, linc00210 is highly expressed along with liver tumorigenesis. Linc00210 drives the self-renewal and propagation of liver TICs through activating Wnt/β-catenin signaling. Linc00210

  12. Mechanism of tumor and liver concentration of /sup 67/Ga: /sup 67/Ga binding substances in tumor tissues and liver

    Energy Technology Data Exchange (ETDEWEB)

    Ando, A; Ando, I; Hiraki, T; Takeshita, M; Hisada, K

    1983-01-01

    Tumor-bearing animals were administered with /sup 67/Ga citrate and tumor homogenates, from which nuclear fraction was removed, and mitochondrial fraction of the host livers were digested with protease (pronase P). After digestion, the supernatants of the reaction mixtures were applied to a Sephadex G-100 column. Resultant eluates were analyzed for radioactivity, protein, uronic acid and sialic acids. Three peaks of radioactivity were obtained by gel filtration. The first peak eluted in the void volume contained a species whose molecular weight exceeded 40,000. The second peak consisted of substances with molecular weights of 9400-40,000. Radioactivity in the third peak was from liberated gallium-67. /sup 67/Ga in the second peak was bound to acid mucopolysaccharide and/or the sulfated carbohydrate chain of sulfated glycoprotein. It was thought that /sup 67/Ga in the first peak might be bound to some acid mucopolysaccharides. Considering the results of cellulose acetate electrophoresis, /sup 67/Ga in the second peak seemed to be bound to acid mucopolysaccharide which contained no uronic acids, and/or to the sulfated carbohydrate chain of sulfated glycoprotein. It was concluded that /sup 67/Ga was bound to the acid mucopolysaccharides and/or the sulfated carbohydrate chain of sulfated glycoprotein in tumor tissues and liver lysosomes.

  13. Liver Status Assessment by Spectrally and Time Resolved IR Detection of Drug Induced Breath Gas Changes

    Directory of Open Access Journals (Sweden)

    Tom Rubin

    2016-05-01

    Full Text Available The actual metabolic capacity of the liver is crucial for disease identification, liver therapy, and liver tumor resection. By combining induced drug metabolism and high sensitivity IR spectroscopy of exhaled air, we provide a method for quantitative liver assessment at bedside within 20 to 60 min. Fast administration of 13C-labelled methacetin induces a fast response of liver metabolism and is tracked in real-time by the increase of 13CO2 in exhaled air. The 13CO2 concentration increase in exhaled air allows the determination of the metabolic liver capacity (LiMAx-test. Fluctuations in CO2 concentration, pressure and temperature are minimized by special gas handling, and tracking of several spectrally resolved CO2 absorption bands with a quantum cascade laser. Absorption measurement of different 12CO2 and 13CO2 rotation-vibration transitions in the same time window allows for multiple referencing and reduction of systematic errors. This FLIP (Fast liver investigation package setup is being successfully used to plan operations and determine the liver status of patients.

  14. Radiofrequency ablation of liver tumors (II): clinical application and outcomes.

    Science.gov (United States)

    Vanagas, Tomas; Gulbinas, Antanas; Pundzius, Juozas; Barauskas, Giedrius

    2010-01-01

    Radiofrequency ablation is one of the alternatives in the management of liver tumors, especially in patients who are not candidates for surgery. The aim of this article is to review applicability of radiofrequency ablation achieving complete tumor destruction, utility of imaging techniques for patients' follow-up, indications for local ablative procedures, procedure-associated morbidity and mortality, and long-term results in patients with different tumors. The success of local thermal ablation consists in creating adequate volumes of tissue destruction with adequate "clear margin," depending on improved delivery of radiofrequency energy and modulated tissue biophysiology. Different volumes of coagulation necrosis are achieved applying different types of electrodes, pulsing energy sources, utilizing sophisticated ablation schemes. Some additional methods are used to increase the overall deposition of energy through alterations in tissue electrical conductivity, to improve heat retention within the tissue, and to modulate tolerance of tumor tissue to hyperthermia. Contrast-enhanced computed tomography, magnetic resonance imaging, ultrasound or positron emission tomography are applied to control the effectiveness of radiofrequency ablation. The long-term results of radiofrequency ablation are controversial.

  15. Clinical evaluation of thyroxine-binding globulin (TBG) as a marker of liver tumors

    Energy Technology Data Exchange (ETDEWEB)

    Terui, S

    1984-03-01

    This investigation was undertaken to evaluate thyroxine-binding globulin (TGB) as a marker of liver tumors, in conjection with the liver scintigram. Of 30 patients with primary hepatocellular carcinoma (PHC), 22 (73.3%) showed significantly higher TBG concentrations. Eight patients (26.7%) showed normal TBG concentrations. In the case of 27 our of 30 patients with definite liver tumors, defects were apparent on the scintigrams. But seven of them had normal TBG concentrations in spite of the defects on the scintigrams. Out of 33 postoperative patients with liver metastasis, 28 (84%) had a raised TBG concentration. Only five (15.2%) had a normal TBG level. In 31 patients (93.9%) out of 33 with liver metastasis, a definite diagnosis was made on the basis of the liver scintigram. In 28 (90.3%) of these 31 people, the TBG concentration was higher than normal. Among 63 patients with liver tumors, both primary and metastatic, the test sensitivity for liver tumors was 92.1% (58/63) based on the accuracy of the liver scintigram. It was 79.4% (50/63) based on the TBG measurement. Why TBG increases to such an extent in spite of the euthyroid state remains unexplained. But it may be concluded that elevated TBG with positive liver scintigram furnishes a sensitive, fairly reliable, nonspecific tumor marker to determine liver tumors, especially in the case of liver metastasis.

  16. Clinical evaluation of thyroxine-binding globulin (TBG) as a marker of liver tumors

    International Nuclear Information System (INIS)

    Terui, S.

    1984-01-01

    This investigation was undertaken to evaluate thyroxine-binding globulin (TGB) as a marker of liver tumors, in conjection with the liver scintigram. Of 30 patients with primary hepatocellular carcinoma (PHC), 22 (73.3%) showed significantly higher TBG concentrations. Eight patients (26.7%) showed normal TBG concentrations. In the case of 27 our of 30 patients with definite liver tumors, defects were apparent on the scintigrams. But seven of them had normal TBG concentrations in spite of the defects on the scintigrams. Out of 33 postoperative patients with liver metastasis, 28 (84%) had a raised TBG concentration. Only five (15.2%) had a normal TBG level. In 31 patients (93.9%) out of 33 with liver metastasis, a definite diagnosis was made on the basis of the liver scintigram. In 28 (90.3%) of these 31 people, the TBG concentration was higher than normal. Among 63 patients with liver tumors, both primary and metastatic, the test sensitivity for liver tumors was 92.1% (58/63) based on the accuracy of the liver scintigram. It was 79.4% (50/63) based on the TBG measurement. Why TBG increases to such an extent in spite of the euthyroid state remains unexplained. But it may be concluded that elevated TBG with positive liver scintigram furnishes a sensitive, fairly reliable, nonspecific tumor marker to determine liver tumors, especially in the case of liver metastasis. (orig.)

  17. An Update on Drug-induced Liver Injury.

    Science.gov (United States)

    Devarbhavi, Harshad

    2012-09-01

    Idiosyncratic drug-induced liver injury (DILI) is an important cause of morbidity and mortality following drugs taken in therapeutic doses. Hepatotoxicity is a leading cause of attrition in drug development, or withdrawal or restricted use after marketing. No age is exempt although adults and the elderly are at increased risk. DILI spans the entire spectrum ranging from asymptomatic elevation in transaminases to severe disease such as acute hepatitis leading to acute liver failure. The liver specific Roussel Uclaf Causality Assessment Method is the most validated and extensively used for determining the likelihood that an implicated drug caused DILI. Asymptomatic elevation in liver tests must be differentiated from adaptation. Drugs producing DILI have a signature pattern although no single pattern is characteristic. Antimicrobial and central nervous system agents including antiepileptic drugs are the leading causes of DILI worldwide. In the absence of a diagnostic test or a biomarker, the diagnosis rests on the evidence of absence of competing causes such as acute viral hepatitis, autoimmune hepatitis and others. Recent studies show that antituberculosis drugs given for active or latent disease are still a major cause of drug-induced liver injury in India and the West respectively. Presence of jaundice signifies a severe disease and entails a worse outcome. The pathogenesis is unclear and is due to a mix of host, drug metabolite and environmental factors. Research has evolved from incriminating candidate genes to genome wide analysis studies. Immediate cessation of the drug is key to prevent or minimize progressive damage. Treatment is largely supportive. N-acetylcysteine is the antidote for paracetamol toxicity. Carnitine has been tried in valproate injury whereas steroids and ursodeoxycholic acid may be used in DILI associated with hypersensitivity or cholestatic features respectively. This article provides an overview of the epidemiology, the patterns of

  18. Targeted drug delivery and penetration into solid tumors.

    Science.gov (United States)

    Corti, Angelo; Pastorino, Fabio; Curnis, Flavio; Arap, Wadih; Ponzoni, Mirco; Pasqualini, Renata

    2012-09-01

    Delivery and penetration of chemotherapeutic drugs into tumors are limited by a number of factors related to abnormal vasculature and altered stroma composition in neoplastic tissues. Coupling of chemotherapeutic drugs with tumor vasculature-homing peptides or administration of drugs in combination with biological agents that affect the integrity of the endothelial lining of tumor vasculature is an appealing strategy to improve drug delivery to tumor cells. Promising approaches to achieve this goal are based on the use of Asn-Gly-Arg (NGR)-containing peptides as ligands for drug delivery and of NGR-TNF, a peptide-tumor necrosis factor-α fusion protein that selectively alters drug penetration barriers and that is currently tested in a randomized Phase III trial in patients with malignant pleural mesothelioma. © 2011 Wiley Periodicals, Inc.

  19. Traditional Chinese Medicine and Herb-induced Liver Injury: Comparison with Drug-induced Liver Injury.

    Science.gov (United States)

    Jing, Jing; Teschke, Rolf

    2018-03-28

    Cases of suspected herb-induced liver injury (HILI) caused by herbal Traditional Chinese Medicines (TCMs) and of drug-induced liver injury (DILI) are commonly published in the scientific literature worldwide. As opposed to the multiplicity of botanical chemicals in herbal TCM products, which are often mixtures of several herbs, conventional Western drugs contain only a single synthetic chemical. It is therefore of interest to study how HILI by TCM and DILI compare with each other, and to what extent results from each liver injury type can be transferred to the other. China is among the few countries with a large population using synthetic Western drugs as well as herbal TCM. Therefore, China is well suited to studies of liver injury comparing drugs with TCM herbs. Despite some concordance, recent analyses of liver injury cases with verified causality, using the Roussel Uclaf Causality Assessment Method, revealed major differences in HILI caused by TCMs as compared to DILI with respect to the following features: HILI cases are less frequently observed as compared to DILI, have a smaller proportion of females and less unintentional rechallenge events, and present a higher rate of hepatocellular injury features. Since many results were obtained among Chinese residents who had access to and had used Western drugs and TCM herbs, such ethnic homogeneity supports the contention that the observed differences of HILI and DILI in the assessed population are well founded.

  20. Clinical evaluation of high-resolution CT, 1. CT diagnosis of liver tumors and its limit

    Energy Technology Data Exchange (ETDEWEB)

    Araki, T [Tokyo Univ. (Japan). Faculty of Medicine

    1980-03-01

    To estimate diagnostic accuracy of CT in liver tumors, CT diagnosis in 120 patients with primary hepatocellular carcinoma was discussed. As a result, primary hepatocellular carcinoma less than 2 cm in diameter could not be visualized by CT. Even tumors between 4 and 8 cm in diameter showed false negative caused by isodense tumors on images of 4 patients. To improve the detectability of liver tumors by CT, the higher resolution of low contrast regions on images are required. As a method to improve qualitative diagnosis of liver tumors, rapid intravenous injection of contrast medium was performed on 42 patients with liver tumors, As a result, images reflecting vascularity of tumors were obtained, and the differential diagnosis was possible to some extent by observing the movement of the contrast. Especially, cavernous hemangioma could be distinguished from hepatocellular carcinoma, because cavernous hemangioma showed specific images and could be diagnosed accurately.

  1. Brachytherapy Using Elastin-Like Polypeptides with (131)I Inhibit Tumor Growth in Rabbits with VX2 Liver Tumor.

    Science.gov (United States)

    Liu, Xinpei; Shen, Yiming; Zhang, Xuqian; Lin, Rui; Jia, Qiang; Chang, Yixiang; Liu, Wenge; Liu, Wentian

    2016-10-01

    Brachytherapy is a targeted type of radiotherapy utilized in the treatment of cancers. Elastin-like polypeptides are a unique class of genetically engineered peptide polymers that have several attractive properties for brachytherapy. To explore the feasibility and application of brachytherapy for VX2 liver tumor using elastin-like polypeptides with (131)I so as to provide reliable experimental evidence for a new promising treatment of liver cancer. Elastin-like polypeptide as carrier was labeled with (131)I using the iodogen method. Ten eligible rabbits with VX2 liver tumor were randomly divided into the treatment group (n = 5) and control group (n = 5). The treatment group received brachytherapy using elastin-like polypeptide with (131)I, and in the control group, elastin-like polypeptide was injected into the VX2 liver tumor as a control. Periodic biochemical and imaging surveillances were required to assess treatment efficacy. The stability of elastin-like polypeptide with (131)I in vitro was maintained at over 96.8 % for 96 h. Biochemistry and imaging indicated brachytherapy using elastin-like polypeptide with (131)I for liver tumor can improve liver function and inhibit tumor growth (P Elastin-like polypeptide can be an ideal carrier of (131)I and have high labeling efficiency, radiochemical purity and stability. Brachytherapy using elastin-like polypeptide with (131)I for liver tumor is a useful therapy that possesses high antitumor efficacy advantages.

  2. CT perfusion of the liver during selective hepatic arteriography. Pure arterial blood perfusion of liver tumor and parenchyma

    International Nuclear Information System (INIS)

    Komemushi, Atsushi; Tanigawa, Noboru; Kojima, Hiroyuki; Kariya, Shuji; Sawada, Satoshi

    2003-01-01

    The purpose of this study was to quantify pure arterial blood perfusion of liver tumor and parenchyma by using CT perfusion during selective hepatic arteriography. A total of 44 patients underwent liver CT perfusion study by injection of contrast medium via the hepatic artery. CT-perfusion parameters including arterial blood flow, arterial blood volume, and arterial mean transit time in the liver parenchyma and liver tumor were calculated using the deconvolution method. The CT-perfusion parameters and vascularity of the tumor were compared. A complete analysis could be performed in 36 of the 44 patients. For liver tumor and liver parenchyma, respectively, arterial blood flow was 184.6±132.7 and 41.0±27.0 ml/min/100 g, arterial blood volume was 19.4±14.6 and 4.8±4.2 ml/100 g, and arterial mean transit time was 8.9±4.2 and 10.2±5.3 sec. Arterial blood flow and arterial blood volume correlated significantly with the vascularity of the tumor; however no correlation was detected between arterial mean transit time and the vascularity of the tumor. This technique could be used to quantify pure hepatic arterial blood perfusion. (author)

  3. Tumor induced hepatic myeloid derived suppressor cells can cause moderate liver damage.

    Directory of Open Access Journals (Sweden)

    Tobias Eggert

    Full Text Available Subcutaneous tumors induce the accumulation of myeloid derived suppressor cells (MDSC not only in blood and spleens, but also in livers of these animals. Unexpectedly, we observed a moderate increase in serum transaminases in mice with EL4 subcutaneous tumors, which prompted us to study the relationship of hepatic MDSC accumulation and liver injury. MDSC were the predominant immune cell population expanding in livers of all subcutaneous tumor models investigated (RIL175, B16, EL4, CT26 and BNL, while liver injury was only observed in EL4 and B16 tumor-bearing mice. Elimination of hepatic MDSC in EL4 tumor-bearing mice using low dose 5-fluorouracil (5-FU treatment reversed transaminase elevation and adoptive transfer of hepatic MDSC from B16 tumor-bearing mice caused transaminase elevation indicating a direct MDSC mediated effect. Surprisingly, hepatic MDSC from B16 tumor-bearing mice partially lost their damage-inducing potency when transferred into mice bearing non damage-inducing RIL175 tumors. Furthermore, MDSC expansion and MDSC-mediated liver injury further increased with growing tumor burden and was associated with different cytokines including GM-CSF, VEGF, interleukin-6, CCL2 and KC, depending on the tumor model used. In contrast to previous findings, which have implicated MDSC only in protection from T cell-mediated hepatitis, we show that tumor-induced hepatic MDSC themselves can cause moderate liver damage.

  4. Tumor induced hepatic myeloid derived suppressor cells can cause moderate liver damage.

    Science.gov (United States)

    Eggert, Tobias; Medina-Echeverz, José; Kapanadze, Tamar; Kruhlak, Michael J; Korangy, Firouzeh; Greten, Tim F

    2014-01-01

    Subcutaneous tumors induce the accumulation of myeloid derived suppressor cells (MDSC) not only in blood and spleens, but also in livers of these animals. Unexpectedly, we observed a moderate increase in serum transaminases in mice with EL4 subcutaneous tumors, which prompted us to study the relationship of hepatic MDSC accumulation and liver injury. MDSC were the predominant immune cell population expanding in livers of all subcutaneous tumor models investigated (RIL175, B16, EL4, CT26 and BNL), while liver injury was only observed in EL4 and B16 tumor-bearing mice. Elimination of hepatic MDSC in EL4 tumor-bearing mice using low dose 5-fluorouracil (5-FU) treatment reversed transaminase elevation and adoptive transfer of hepatic MDSC from B16 tumor-bearing mice caused transaminase elevation indicating a direct MDSC mediated effect. Surprisingly, hepatic MDSC from B16 tumor-bearing mice partially lost their damage-inducing potency when transferred into mice bearing non damage-inducing RIL175 tumors. Furthermore, MDSC expansion and MDSC-mediated liver injury further increased with growing tumor burden and was associated with different cytokines including GM-CSF, VEGF, interleukin-6, CCL2 and KC, depending on the tumor model used. In contrast to previous findings, which have implicated MDSC only in protection from T cell-mediated hepatitis, we show that tumor-induced hepatic MDSC themselves can cause moderate liver damage.

  5. Malignant rhabdoid tumor of the liver: a case report and literature review

    Directory of Open Access Journals (Sweden)

    Satoru Oita

    2015-03-01

    Full Text Available Malignant rhabdoid tumor (MRT is a rare and aggressive malignancy associated with poor outcomes. MRT of the liver is even rarer, and little information has been described. We report the case of an 8-month-old boy with MRT of the liver. The tumor showed aggressive progression despite a multidisciplinary approach, and the patient died due to multiple organ failure 14 days after admission. Autopsy revealed the liver tumor and multiple metastases with negative immunohistochemistry for INI1/BAF47. A review of 53 cases of pediatric MRT of the liver is provided.

  6. Neuroendocrine Tumors: A Focus on Liver Metastatic Lesions

    Energy Technology Data Exchange (ETDEWEB)

    Limouris, Georgios S., E-mail: nucleard@aretaieio.uoa.gr [Athens University Medical Faculty, Nuclear Medicine Division, Radiology Department, Aretaieion University Hospital, Athens (Greece)

    2012-02-28

    Transhepatic radionuclide infusion has been introduced as a new treatment approach for unresectable liver neuroendocrine metastatic lesions with the prerequisite of a positive In-111 Pentetreotide (Octreoscan). Patients with multiple liver neuroendocrine metastases can be locally treated after selective hepatic artery catheterization and infusion of radiolabeled somatostatin analogs, and in case of extra-hepatic secondary spread, after simple i.v. application. According to the world wide references, the average dose per session to each patient is 6.3 ± 0.3 GBq (∼160–180 mCi) of In-111-DTPA-Phe1-Pentetreotide, 10- to 12-fold in total, administered monthly or of 4.1 ± 0.2 GBq (∼105–116 mCi) of Y-90 DOTA TOC, threefold in total, or of 7.0 ± 0.4 GBq (∼178–200 mCi) of Lu-177 DOTA TATE, fourfold to sixfold in total (the choice of which being based on the tumor size, assessed by CT or MRI). Follow-up at monthly intervals has to be performed by means of ultrasonography (US). Treatment response has to be assessed according to the WHO criteria (RECIST or SWOG).

  7. Yttrium-90 radioembolization using TheraSphere in the management of primary and secondary liver tumors.

    Science.gov (United States)

    Riaz, A; Lewandowski, R J; Kulik, L; Salem, R

    2009-06-01

    Locoregional therapies, such as transarterial chemoembolization, radioembolization and thermal ablation (e.g., radiofrequency ablation) are establishing their roles in the management of liver malignancies. With yYttrium-90 radioembolization therapy (90Y) radionuclide labeled microspheres are injected into the tumor feeding artery. This allows the delivery of a high radioactive dose to the tumor with minimal toxicity to normal tissues. 90Y has demonstrated to be safe and effective in the management of liver tumors. Authors present a review of the literature available for the use of TheraSphere for radioembolization in the management of liver tumors.

  8. Spirulina maxima Protects Liver From Isoniazid and Rifampicin Drug Toxicity.

    Science.gov (United States)

    Jatav, Santosh Kumar; Kulshrestha, Archana; Zacharia, Anish; Singh, Nita; Tejovathi, G; Bisen, P S; Prasad, G B K S

    2014-07-01

    Hepatotoxicity associated with isoniazid and rifampicin is one of the major impediments in antituberculosis therapy. The present study explored the prophylactic and therapeutic efficacies of Spirulina maxima in isoniazid and rifampicin induced hepatic damage in a rat model. Hepatic damage induced in Wistar rats by isoniazid and rifampicin resulted in significant alterations in biomarkers of liver function, namely, bilirubin, aspartate transaminase, alanine transaminase, alkaline phosphatase, and oxidative stress markers such as superoxide dismutase, catalase, glutathione, and thiobarbituric acid reactive substances. Co-administration of Spirulina maxima along with antituberculosis drugs protected liver from hepatotoxicity due to isoniazid and rifampicin. Administration of Spirulina maxima consecutively for 2 weeks to hepatodamaged animals resulted in restoration of hepatic function as evident from normalization of serum markers of liver function. Thus, the present study revealed remarkable prophylactic and therapeutic potential of Spirulina maxima. Co-administration of Spirulina maxima and antituberculosis drugs is advantageous as it provides extra nutritional benefit. © The Author(s) 2014.

  9. Microencapsulation of anti-tumor, antibiotic and thrombolytic drugs in microgravity

    Science.gov (United States)

    Morrison, Dennis R.; Mosier, Benjamin; Cassanto, John

    1994-01-01

    Encapsulation of cytotoxic or labile drugs enables targeted delivery and sustained release kinetics that are not available with intravenous injection. A new liquid-liquid diffusion process has been developed for forming unique microcapsules that contain both aqueous and hydrocarbon soluble drugs. Microgravity experiments, on sounding rockets (1989-92) and Shuttle missions STS-52 (1992) and STS-56 (1993) using an automated Materials Dispersion Apparatus, produced multi-lamellar microcapsules containing both Cis-platinum (anti-tumor drug) and iodinated poppy seed oil (a radiocontrast medium), surrounded by a polyglyceride skin. Microcapsules formed with amoxicillin (antibiotic) or urokinase (a clot dissolving enzyme), co-encapsulated with IPO, are still intact after two years. Microcapsules were formed with the drug so concentrated that crystals formed inside. Multi-layered microspheres, with both hydrophobic drug compartments, can enable diffusion of complementary drugs from the same microcapsule, e.g. antibiotics and immuno-stimulants to treat resistant infections or multiple fibrinolytic drugs to dissolve emboli. Co-encapsulation of enough radio-contrast medium enables oncologists to monitor the delivery of anti-tumor microcapsules to target tumors using computerized tomography and radiography that would track the distribution of microcapsules after release from the intra-arterial catheter. These microcapsules could have important applications in chemotheraphy of certain liver, kidney, brain and other tumors.

  10. Chimeric mice with humanized liver: Application in drug metabolism and pharmacokinetics studies for drug discovery.

    Science.gov (United States)

    Naritomi, Yoichi; Sanoh, Seigo; Ohta, Shigeru

    2018-02-01

    Predicting human drug metabolism and pharmacokinetics (PK) is key to drug discovery. In particular, it is important to predict human PK, metabolite profiles and drug-drug interactions (DDIs). Various methods have been used for such predictions, including in vitro metabolic studies using human biological samples, such as hepatic microsomes and hepatocytes, and in vivo studies using experimental animals. However, prediction studies using these methods are often inconclusive due to discrepancies between in vitro and in vivo results, and interspecies differences in drug metabolism. Further, the prediction methods have changed from qualitative to quantitative to solve these issues. Chimeric mice with humanized liver have been developed, in which mouse liver cells are mostly replaced with human hepatocytes. Since human drug metabolizing enzymes are expressed in the liver of these mice, they are regarded as suitable models for mimicking the drug metabolism and PK observed in humans; therefore, these mice are useful for predicting human drug metabolism and PK. In this review, we discuss the current state, issues, and future directions of predicting human drug metabolism and PK using chimeric mice with humanized liver in drug discovery. Copyright © 2017 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

  11. 'Obligate' anaerobic Salmonella strain YB1 suppresses liver tumor growth and metastasis in nude mice.

    Science.gov (United States)

    Li, Chang-Xian; Yu, Bin; Shi, Lei; Geng, Wei; Lin, Qiu-Bin; Ling, Chang-Chun; Yang, Mei; Ng, Kevin T P; Huang, Jian-Dong; Man, Kwan

    2017-01-01

    The antitumor properties of bacteria have been demonstrated over the past decades. However, the efficacy is limited and unclear. Furthermore, systemic infection remains a serious concern in bacteria treatment. In this study, the effect of YB1, a rationally designed 'obligate' anaerobic Salmonella typhimurium strain, on liver tumor growth and metastasis in a nude mouse orthotopic liver tumor model was investigated. The orthotopic liver tumor model was established in nude mice using the hepatocellular carcinoma cell line MHCC-97L. Two weeks after orthotopic liver tumor implantation, YB1, SL7207 and saline were respectively administered through the tail vein of the mice. Longitudinal monitoring of tumor growth and metastasis was performed using Xenogen IVIS, and direct measurements of tumor volume were taken 3 weeks after treatment. In vitro , MHCC-97L and PLC cells were incubated with YB1 or SL7207 under anaerobic conditions. YB1 was observed to invade tumor cells and induce tumor cell apoptosis and death. The results revealed that all mice in the YB1 group were alive 3 weeks after YB1 injection while all mice in the SL7207 group died within 11 days of the SL7207 injection. The body weight decreased by ~9% on day 1 after YB1 injection and but subsequently recovered. Liver tumor growth and metastases were significantly inhibited following YB1 treatment. By contrast to the control group, a large number of Gr1-positive cells were detected on days 1 to 21 following YB1 treatment. Furthermore, YB1 also effectively invaded tumor cells and induced tumor cell apoptosis and death. In conclusion, YB1 suppressed liver tumor growth and metastasis in a nude mice liver tumor model. The potential mechanism may be through enhancing innate immune response and inducing tumor cell apoptosis and cell death.

  12. Drug-Loaded Microspheres for the Treatment of Liver Cancer: Review of Current Results

    International Nuclear Information System (INIS)

    Kettenbach, Joachim; Stadler, Alfred; Katzler, Isabella v.; Schernthaner, Ruediger; Blum, Melanie; Lammer, Johannes; Rand, Thomas

    2008-01-01

    Transarterial chemoembolization (TACE) involves the emulsification of a chemotherapeutic agent in a viscous drug carrier, delivered intra-arterially to liver tumor for maximum effect. TACE reduces arterial inflow, diminishes washout of the chemotherapeutic agent, and decreases systemic exposure. Despite evidence of some clinical success with TACE, a new type of microspheres with drug-eluting capabilities may offer a precisely controlled and sustainable release of the chemotherapeutic agent into the tumor bed. In animal trials tumor necrosis (approaching 100%) was greatest at 7 days, with significantly lower plasma concentrations of doxorubicin than in control animals treated with doxorubicin intra-arterially. Clinically, drug-eluting microspheres loaded with doxorubicin, either at 75 mg/m 2 or at a fixed dose of 150 mg, were used recently and no severe disorders of the hepatic function were observed postprocedure, while a substantial reduction of the fetoprotein levels occurred. An interim analysis of the first 15 patients from the Hong Kong group at 3 months showed an objective response rate of 61.54% and 53.84% according to EASL criteria and RECIST criteria, respectively, and a survival rate of 93.3%. In this paper we present how to use microspheres loaded with doxorubicin and review their clinical value and preliminary performance for treatment of unresectable liver cancer

  13. Mouse Precision-Cut Liver Slices as an ex Vivo Model To Study Idiosyncratic Drug-Induced Liver Injury

    NARCIS (Netherlands)

    Hadi, Mackenzie; Chen, Yixi; Starokozhko, Viktoriia; Groothuis, Geny M. M.; Merema, M.T.

    Idiosyncratic drug-induced liver injury (IDILI) has been the top reason for withdrawing drugs from the market or for black box warnings. IDILI may arise from the interaction of a drug's reactive metabolite with a mild inflammation that renders the liver more sensitive to injury resulting in

  14. Tumor and liver uptake models of /sup 67/Ga-citrate

    Energy Technology Data Exchange (ETDEWEB)

    Ando, A; Ando, I; Sanada, S; Hiraki, T; Hisada, K

    1985-03-01

    After administration /sup 67/Ga concentrates with time in lysosomes from the cytoplasm of liver cells. The lysosomal role in the accumulation of /sup 67/Ga in the liver cell is weakened upon transformation of the liver cell into a malignant tumor cell. In malignant tumors (except for hepatoma) the lysosome does not play a major role in the tumor concentration of /sup 67/Ga. /sup 67/Ga is bound to acid mucopolysaccharides (keratan polysulfate, etc.) in both tumor and liver. In liver cells, large amounts of /sup 67/Ga are transported into lysosomes with these acid mucopolysaccharides, and in hepatoma cells, quite large amounts of /sup 67/Ga are transported into lysosomes with these acid mucopolysaccharides. In malignant tumor cells (except for hepatoma) the effect is much smaller, the acid mucopolysaccharides transporting very little /sup 67/Ga into lysosome. The /sup 67/Ga is concentrated in viable tumor tissue within malignant tissue but hardly at all in necrotic tumor tissue, and concentrates avidly in inflammatory infiltration around tumor cells. Plenty of /sup 67/Ga is found in liver but very little in connective tissue associated with the liver.

  15. Drug targeting to tumors: principles, pitfalls and (pre-) clinical progress

    NARCIS (Netherlands)

    Lammers, Twan Gerardus Gertudis Maria; Kiessling, F.; Hennink, W.E.; Storm, Gerrit

    2012-01-01

    Abstract Many different systems and strategies have been evaluated for drug targeting to tumors over the years. Routinely used systems include liposomes, polymers, micelles, nanoparticles and antibodies, and examples of strategies are passive drug targeting, active drug targeting to cancer cells,

  16. Liver injury from Herbals and Dietary Supplements in the US Drug Induced Liver Injury Network

    Science.gov (United States)

    Navarro, Victor J.; Barnhart, Huiman; Bonkovsky, Herbert L.; Davern, Timothy; Fontana, Robert J.; Grant, Lafaine; Reddy, K. Rajender; Seeff, Leonard B.; Serrano, Jose; Sherker, Averell H.; Stolz, Andrew; Talwalkar, Jayant; Vega, Maricruz; Vuppalanchi, Raj

    2014-01-01

    Background The Drug-Induced Liver Injury Network (DILIN) studies hepatotoxicity due to conventional medications as well as herbals and dietary supplements (HDS). Rationale To characterize hepatotoxicity and its outcomes from HDS versus medications, patients with hepatotoxicity attributed to medications or HDS were enrolled prospectively between 2004 and 2013. The study took place among eight US referral centers that are part of the DILIN. Consecutive patients with liver injury referred to a DILIN center were eligible. The final sample comprised 130 (15.5%) of all subjects enrolled (839) who were judged to have experienced liver injury due to HDS. Hepatotoxicity due to HDS was evaluated by expert opinion. Demographic and clinical characteristics and outcome assessments including death and liver transplantation were ascertained. Cases were stratified and compared according to the type of agent implicated in liver injury; 45 had injury due to bodybuilding HDS, 85 due to non-bodybuilding HDS, and 709 due to medications. Main Results Liver injury due to HDS increased from 7% to 20% (p Bodybuilding HDS caused prolonged jaundice (median 91 days) in young men but did not result in any fatalities or liver transplantation. The remaining HDS cases presented as hepatocellular injury, predominantly in middle-aged women and more frequently led to death or transplantation compared to injury from medications (13% vs. 3%, p bodybuilding HDS is more severe than from bodybuilding HDS or medications, as evidenced by differences in unfavorable outcomes; death and transplantation. PMID:25043597

  17. Liver transplantation for metastatic neuroendocrine tumor: A case report and review of the literature

    Institute of Scientific and Technical Information of China (English)

    Wojciech C Blonski; K Rajender Reddy; Abraham Shaked; Evan Siegelman; David C Metz

    2005-01-01

    Neuroendocrine tumors are divided into gastrointestinal carcinoids and pancreatic neuroendocrine tumors. The WHO has updated the classification of these lesions and has abandoned the term "carcinoid". Both types of tumors are divided into functional and non-functional tumors. They are characterized by slow growth and frequent metastasis to the liver and may be limited to the liver for long periods. The therapeutic approach to hepatic metastases should consider the number and distribution of the liver metastases as well as the severity of symptoms related to hormone production and tumor bulk. Surgery is generally considered as the first line therapy. In patients with unresectable liver metastases,alternative treatments are dependent on the type and the growth rate. Initial treatments consist of long acting somatostatin analogs and/or interferon. Streptozocinbased chemotherapy is usually reserved for symptomatic patients with rapidly advancing disease, but generally the therapy is poorly tolerated and its effects are short-lived.Locoregional therapy directed such as hepatic-artery embolization and chemoembolization, radiofrequency thermal ablation and cryosurgery, is often used instead of systemic therapy, if the disease is limited to the liver.However, liver transplantation should be considered in patients with neuroendocrine metastases to the liver that are not accessible to curative or cytoreductive surgery and if medical or locoregional treatment has failed and if there are life threatening hormonal symptoms. We report a case of liver transplantation for metastatic neuroendocrine tumor of unknown primary source and provide a detailed review of the world literature on this controversial topic.

  18. Diphenhydramine as a Cause of Drug-Induced Liver Injury

    Directory of Open Access Journals (Sweden)

    Yunseok Namn

    2017-01-01

    Full Text Available Drug-induced liver injury (DILI is the most common cause of acute liver failure in the Unites States and accounts for 10% of acute hepatitis cases. We report the only known case of diphenhydramine-induced acute liver injury in the absence of concomitant medications. A 28-year-old man with history of 13/14-chromosomal translocation presented with fevers, vomiting, and jaundice. Aspartate-aminotransferase and alanine-aminotransferase levels peaked above 20,000 IU/L and 5,000 IU/L, respectively. He developed coagulopathy but without altered mental status. Patient reported taking up to 400 mg diphenhydramine nightly, without concomitant acetaminophen, for insomnia. He denied taking other medications, supplements, antibiotics, and herbals. A thorough workup of liver injury ruled out viral hepatitis (including A, B, C, and E, autoimmune, toxic, ischemic, and metabolic etiologies including Wilson’s disease. A liver biopsy was consistent with DILI without evidence of iron or copper deposition. Diphenhydramine was determined to be the likely culprit. This is the first reported case of diphenhydramine-induced liver injury without concomitant use of acetaminophen.

  19. Development of an automated extraction method for liver tumors in three dimensional multiphase multislice CT images

    International Nuclear Information System (INIS)

    Nakagawa, Junya; Shimizu, Akinobu; Kobatake, Hidefumi

    2004-01-01

    This paper proposes a tumor detection method using four phase three dimensional (3D) CT images of livers, i.e. non-contrast, early, portal, and late phase images. The method extracts liver regions from the four phase images and enhances tumors in the livers using a 3D adaptive convergence index filter. Then it detects local maximum points and extracts tumor candidates by a region growing method. Subsequently several features of the candidates are measured and each candidate is classified into true tumor or normal tissue based on Mahalanobis distances. Above processes except liver region extraction are applied to four phase images, independently and four resultant images are integrated into one. We applied the proposed method to 3D abdominal CT images of ten patients obtained with multi-detector row CT scanner and confirmed that tumor detection rate was 100% without false positives, which was quite promising results. (author)

  20. Wavelets in quantification of liver tumors in contrasted computed tomography images

    International Nuclear Information System (INIS)

    Rodrigues, Bruna T.; Alvarez, Matheus; Souza, Rafael T.F.; Miranda, Jose R.A.; Romeiro, Fernando G.; Pina, Diana R. de; Trindade, Andre Petean

    2012-01-01

    This paper presents an original methodology of liver tumors segmentation, based on wavelet transform. A virtual phantom was constructed with the same mean and standard deviation of the intensity of gray presented by the measured liver tissue. The optimized algorithm had a sensitivity ranging from 0.81 to 0.83, with a specificity of 0.95 for differentiation of hepatic tumors from normal tissues. We obtained a 96% agreement between the pixels segmented by an experienced radiologist and the algorithm presented here. According to the results shown in this work, the algorithm is optimal for the beginning of the tests for quantification of liver tumors in retrospective surveys. (author)

  1. Affinity of /sup 167/Tm-citrate for tumor and liver tissue

    Energy Technology Data Exchange (ETDEWEB)

    Ando, A; Ando, I; Hiraki, T; Sakamoto, K; Hisada, K; Takeshita, M

    1983-10-07

    Strong affinity of /sup 167/Tm-citrate for tumor tissue was reconfirmed by using Ehrlich tumor. Excellent tumor imaging was obtained with /sup 167/Tm-citrate because of its strong tumor affinity and because of the suitable physical characteristics of /sup 167/Tm. A large amount of /sup 167/Tm had accumulated in the connective tissue which contained inflammatory tissue, quite large amounts were found in areas containing viable and necrotic tumor tissue, and small amounts were present in viable tumor tissue. /sup 167/Tm was not seen in necrotic tumor tissue. It was concluded that lysosomes did not play a major role in the tumor concentration of /sup 167/Tm, but played an important role in the liver concentration of this nuclide. In the case of hepatoma AH109A, it was presumed that lysosomes played a considerably important role in the tumor concentration of /sup 167/Tm, hepatoma AH109A possessing some residual features of the liver. /sup 167/Tm was bound to acid mucopolysaccharides and transposed by the acid mucopolysaccharides in the tumor tissues and liver. The acid mucopolysaccharides to which /sup 167/Tm were bound in tumor and liver, were heparan sulfate, chondroitin sulfate (or keratosulfate) and heparin (or keratosulfate).

  2. Affinity of 167Tm-citrate for tumor and liver tissue

    International Nuclear Information System (INIS)

    Ando, A.; Ando, I.; Hiraki, T.

    1983-01-01

    Strong affinity of 167 Tm-citrate for tumor tissue was reconfirmed by using Ehrlich tumor. Excellent tumor imaging was obtained with 167 Tm-citrate because of its strong tumor affinity and because of the suitable physical characteristics of 167 Tm. A large amount of 167 Tm had accumulated in the connective tissue which contained inflammatory tissue, quite large amounts were found in areas containing viable and necrotic tumor tissue, and small amounts were present in viable tumor tissue. 167 Tm was not seen in necrotic tumor tissue. It was concluded that lysosomes did not play a major role in the tumor concentration of 167 Tm, but played an important role in the liver concentration of this nuclide. In the case of hepatoma AH109A, it was presumed that lysosomes played a considerably important role in the tumor concentration of 167 Tm, hepatoma AH109A possessing some residual features of the liver. 167 Tm was bound to acid mucopolysaccharides and transposed by the acid mucopolysaccharides in the tumor tissues and liver. The acid mucopolysaccharides to which 167 Tm were bound in tumor and liver, were heparan sulfate, chondroitin sulfate (or keratosulfate) and heparin (or keratosulfate). (orig.)

  3. Polymeric micelles as a drug carrier for tumor targeting

    Directory of Open Access Journals (Sweden)

    Neha M Dand

    2013-01-01

    Full Text Available Polymeric micelle can be targeted to tumor site by passive and active mechanism. Some inherent properties of polymeric micelle such as size in nanorange, stability in plasma, longevity in vivo, and pathological characteristics of tumor make polymeric micelles to be targeted at the tumor site by passive mechanism called enhanced permeability and retention effect. Polymeric micelle formed from the amphiphilic block copolymer is suitable for encapsulation of poorly water soluble, hydrophobic anticancer drugs. Other characteristics of polymeric micelles such as separated functionality at the outer shell are useful for targeting the anticancer drug to tumor by active mechanisms. Polymeric micelles can be conjugated with many ligands such as antibodies fragments, epidermal growth factors, α2 -glycoprotein, transferrine, and folate to target micelles to cancer cells. Application of heat and ultrasound are the alternative methods to enhance drug accumulation in tumoral cells. Targeting using micelles can also be done to tumor angiogenesis which is the potentially promising target for anticancer drugs. This review summarizes about recently available information regarding targeting the anticancer drug to the tumor site using polymeric micelles.

  4. Clinical usefulness of positron emission tomography with fluorine-18-fluorodeoxyglucose in the diagnosis of liver tumors

    Energy Technology Data Exchange (ETDEWEB)

    Iwata, Yoshinori; Shiomi, Susumu; Sasaki, Nobumitsu; Jomura, Hisato; Nishiguchi, Shuhei; Seki, Shuichi; Kawabe, Joji; Ochi, Hironobu [Osaka City Univ. (Japan). Medical School

    2000-04-01

    We studied various liver tumors by positron emission tomography with fluorine-18 fluorodeoxyglucose (FDG-PET) to examine the diagnostic usefulness of this technique. We also examined the relation between findings on FDG-PET and the characteristics of hepatocellular carcinoma. FDG-PET was performed in 78 patients with liver tumors, including 53 with primary liver cancer [48 hepatocellular carcinomas (HCC) and 5 cholangiocellular carcinomas (CCC)], 20 with metastatic liver cancer, 2 with liver hemangioma, and 3 with focal nodular hyperplasia. For quantitative evaluation, a region of interest (ROI) was placed over the entire tumor region, at the level of the maximum diameter of the tumor. A background ROI was then placed over the non-tumor region of the liver. The average activity within each ROI was subsequently corrected for radioactive decay, and the standardized uptake value (SUV) was calculated by dividing the tissue activity by the injected dose of radioactivity per unit body weight. SUV ratio was expressed as the tumor-to-non-tumor ratio of the SUV. The median SUV was significantly lower in HCC than in metastatic live cancer or CCC, and the median SUV ratio was significantly lower in HCC than in metastatic liver cancer or CCC. The median SUV was not higher in multiple HCC than in single HCC, but the median SUV ratio was significantly higher in multiple HCC than in single HCC. The median SUV and the median SUV ratio were significantly higher in the presence of portal vein thrombosis than in the absence of such thrombosis. The Cancer of the Liver Italian Program score and the {alpha}-fetoprotein value correlated significantly with both the SUV and SUV ratio. These results suggest that FDG-PET is clinically useful not only for the differential diagnosis of liver tumors but also for evaluation of the clinical characteristics of HCC. (author)

  5. Drug targeting to tumors: principles, pitfalls and (pre-) clinical progress.

    Science.gov (United States)

    Lammers, Twan; Kiessling, Fabian; Hennink, Wim E; Storm, Gert

    2012-07-20

    Many different systems and strategies have been evaluated for drug targeting to tumors over the years. Routinely used systems include liposomes, polymers, micelles, nanoparticles and antibodies, and examples of strategies are passive drug targeting, active drug targeting to cancer cells, active drug targeting to endothelial cells and triggered drug delivery. Significant progress has been made in this area of research both at the preclinical and at the clinical level, and a number of (primarily passively tumor-targeted) nanomedicine formulations have been approved for clinical use. Significant progress has also been made with regard to better understanding the (patho-) physiological principles of drug targeting to tumors. This has led to the identification of several important pitfalls in tumor-targeted drug delivery, including I) overinterpretation of the EPR effect; II) poor tumor and tissue penetration of nanomedicines; III) misunderstanding of the potential usefulness of active drug targeting; IV) irrational formulation design, based on materials which are too complex and not broadly applicable; V) insufficient incorporation of nanomedicine formulations in clinically relevant combination regimens; VI) negligence of the notion that the highest medical need relates to metastasis, and not to solid tumor treatment; VII) insufficient integration of non-invasive imaging techniques and theranostics, which could be used to personalize nanomedicine-based therapeutic interventions; and VIII) lack of (efficacy analyses in) proper animal models, which are physiologically more relevant and more predictive for the clinical situation. These insights strongly suggest that besides making ever more nanomedicine formulations, future efforts should also address some of the conceptual drawbacks of drug targeting to tumors, and that strategies should be developed to overcome these shortcomings. Copyright © 2011 Elsevier B.V. All rights reserved.

  6. Two Dimensional Drug Diffusion Between Nanoparticles and Fractal Tumors

    Science.gov (United States)

    Samioti, S. E.; Karamanos, K.; Tsiantis, A.; Papathanasiou, A.; Sarris, I.

    2017-11-01

    Drug delivery methods based on nanoparticles are some of the most promising medical applications in nanotechnology to treat cancer. It is observed that drug released by nanoparticles to the cancer tumors may be driven by diffusion. A fractal tumor boundary of triangular Von Koch shape is considered here and the diffusion mechanism is studied for different drug concentrations and increased fractality. A high order Finite Elements method based on the Fenics library is incorporated in fine meshes to fully resolve these irregular boundaries. Drug concentration, its transfer rates and entropy production are calculated in an up to forth order fractal iteration boundaries. We observed that diffusion rate diminishes for successive prefractal generations. Also, the entropy production around the system changes greatly as the order of the fractal curve increases. Results indicate with precision where the active sites are, in which most of the diffusion takes place and thus drug arrives to the tumor.

  7. Drug-induced Liver Disease in Patients with Diabetes Mellitus

    OpenAIRE

    Iryna, Klyarytskaya; Helen, Maksymova; Elena, Stilidi

    2016-01-01

    The study presented here was accomplished to assess the course of drug-induced liver diseases in patient’s rheumatoid arthritis receiving long-term methotrexate therapy. Diabetes mellitus was revealed as the most significant risk factor. The combination of diabetes mellitus with other risk factors (female sex) resulted in increased hepatic fibrosis, degree of hepatic encephalopathy and reduction of hepatic functions. The effectiveness and safety of ursodeoxycholic acid and cytolytic type-with...

  8. Fluorouracil implants caused a diaphragmatic tumor to be misdiagnosed as liver metastasis: a case report

    International Nuclear Information System (INIS)

    Shen, Yang-Yang; Qin, Hong-Wei; Zhang, Jian-Bo; Wang, Zhen-Dan; Li, Pang; Pang, Kai; Zhang, Bo; Li, Sheng; Cui, Kai

    2016-01-01

    Fluorouracil implants are widely used in peritoneal interstitial chemotherapy. Curative effects have been obtained, but implants have also caused some complications. We performed an analysis of a 66-year-old male patient’s case history, as well as conventional pathological analysis and Raman spectroscopic detection of the diaphragmatic tumor. We also analyzed the underlying causes of this condition to prevent complications and reduce misdiagnoses in future cases. The patient had a history of peritoneal fluorouracil implantation. Pathological analysis of the diaphragmatic mass revealed foreign particles, and Raman detection showed that the mass contained fluorouracil. Fluorouracil implants may persist due to the high concentrations of this drug used in peritoneal chemotherapy. This finding should provide guidance and improve the application of peritoneal implants. In clinical trials, and the diagnosis of liver metastasis should be based on pathological results

  9. Local recurrence after microwave thermosphere ablation of malignant liver tumors: results of a surgical series.

    Science.gov (United States)

    Takahashi, Hideo; Kahramangil, Bora; Berber, Eren

    2018-04-01

    Microwave thermosphere ablation is a new treatment modality that creates spherical ablation zones using a single antenna. This study aims to analyze local recurrence associated with this new treatment modality in patients with malignant liver tumors. This is a prospective clinical study of patients who underwent microwave thermosphere ablation of malignant liver tumors between September 2014 and March 2017. Clinical, operative, and oncologic parameters were analyzed using Kaplan-Meier survival and Cox proportional hazards model. One hundred patients underwent 301 ablations. Ablations were performed laparoscopically in 87 and open in 13 patients. Pathology included neuroendocrine liver metastasis (n = 115), colorectal liver metastasis (n = 100), hepatocellular cancer (n = 21), and other tumor types (n = 65). Ninety-day morbidity was 7% with one not procedure-related mortality. Median follow-up was 16 months with 65% of patients completing at least 12 months of follow-up. The rate of local tumor recurrence rate per lesion was 6.6% (20/301). Local tumor, new hepatic, and extrahepatic recurrences were detected in 15%, 40%, and 40% of patients, respectively. Local recurrence rate per pathology was 12% for both colorectal liver metastasis (12/100) and other metastatic tumors (8/65). No local recurrence was observed to date in the neuroendocrine liver metastasis and in the limited number of patients with hepatocellular cancers. Tumor size >3 cm and tumor type were independent predictors of local recurrence. This is the first study to analyze local recurrence after microwave thermosphere ablation of malignant liver tumors. Short-term local tumor control rate compares favorably with that reported for radiofrequency and other microwave technologies in the literature. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Radiation induction of drug resistance in RIF-1 tumors and tumor cells

    International Nuclear Information System (INIS)

    Hopwood, L.E.; Moulder, J.E.

    1989-01-01

    The RIF-1 tumor cell line contains a small number of cells (1-20 per 10(6) cells) that are resistant to various single antineoplastic drugs, including 5-fluorouracil (5FU), methotrexate (MTX), and adriamycin (ADR). For 5FU the frequency of drug resistance is lower for tumor-derived cells than for cells from cell culture; for MTX the reverse is true, and for ADR there is no difference. In vitro irradiation at 5 Gy significantly increased the frequency of drug-resistant cells for 5FU, MTX, and ADR. In vivo irradiation at 3 Gy significantly increased the frequency of drug-resistant cells for 5FU and MTX, but not for ADR. The absolute risk for in vitro induction of MTX, 5FU, and ADR resistance, and for in vivo induction of 5FU resistance, was 1-3 per 10(6) cells per Gy; but the absolute risk for in vivo induction of MTX resistance was 54 per 10(6) cells per Gy. The frequency of drug-resistant cells among individual untreated tumors was highly variable; among individual irradiated tumors the frequency of drug-resistant cells was significantly less variable. These studies provide supporting data for models of the development of tumor drug resistance, and imply that some of the drug resistance seen when chemotherapy follows radiotherapy may be due to radiation-induced drug resistance

  11. A D-D/D-T fusion reaction based neutron generator system for liver tumor BNCT

    International Nuclear Information System (INIS)

    Koivunoro, H.; Lou, T.P.; Leung, K. N.; Reijonen, J.

    2003-01-01

    Boron-neutron capture therapy (BNCT) is an experimental radiation treatment modality used for highly malignant tumor treatments. Prior to irradiation with low energetic neutrons, a 10B compound is located selectively in the tumor cells. The effect of the treatment is based on the high LET radiation released in the 10 B(n,α) 7 Li reaction with thermal neutrons. BNCT has been used experimentally for brain tumor and melanoma treatments. Lately applications of other severe tumor type treatments have been introduced. Results have shown that liver tumors can also be treated by BNCT. At Lawrence Berkeley National Laboratory, various compact neutron generators based on D-D or D-T fusion reactions are being developed. The earlier theoretical studies of the D-D or D-T fusion reaction based neutron generators have shown that the optimal moderator and reflector configuration for brain tumor BNCT can be created. In this work, the applicability of 2.5 MeV neutrons for liver tumor BNCT application was studied. The optimal neutron energy for external liver treatments is not known. Neutron beams of different energies (1eV < E < 100 keV) were simulated and the dose distribution in the liver was calculated with the MCNP simulation code. In order to obtain the optimal neutron energy spectrum with the D-D neutrons, various moderator designs were performed using MCNP simulations. In this article the neutron spectrum and the optimized beam shaping assembly for liver tumor treatments is presented

  12. Oncogenic driver genes and the inflammatory microenvironment dictate liver tumor phenotype

    DEFF Research Database (Denmark)

    Matter, Matthias S; Marquardt, Jens U; Andersen, Jesper B

    2016-01-01

    The majority of hepatocellular carcinoma (HCC) develops in the background of chronic liver inflammation caused by viral hepatitis and alcoholic or non-alcoholic steatohepatitis. However, the impact of different types of chronic inflammatory microenvironments on the phenotypes of tumors generated...... with transcriptome profiles from human HCCs further demonstrated that AKT-CAT tumors generated in the context of chronic liver inflammation showed enrichment of poor prognosis gene sets or decrease of good prognosis gene sets. In contrast, DDC had a more subtle effect on AKT-NRAS(G12V) tumors and primarily enhanced...... by distinct oncogenes is largely unresolved. To address this issue, we generated murine liver tumors by constitutively active AKT-1 (AKT) and β-catenin (CAT) followed by induction of chronic liver inflammation by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) and carbon tetrachloride (CCl4 ). Also...

  13. Mathematical Based Calculation of Drug Penetration Depth in Solid Tumors

    Directory of Open Access Journals (Sweden)

    Hamidreza Namazi

    2016-01-01

    Full Text Available Cancer is a class of diseases characterized by out-of-control cells’ growth which affect cells and make them damaged. Many treatment options for cancer exist. Chemotherapy as an important treatment option is the use of drugs to treat cancer. The anticancer drug travels to the tumor and then diffuses in it through capillaries. The diffusion of drugs in the solid tumor is limited by penetration depth which is different in case of different drugs and cancers. The computation of this depth is important as it helps physicians to investigate about treatment of infected tissue. Although many efforts have been made on studying and measuring drug penetration depth, less works have been done on computing this length from a mathematical point of view. In this paper, first we propose phase lagging model for diffusion of drug in the tumor. Then, using this model on one side and considering the classic diffusion on the other side, we compute the drug penetration depth in the solid tumor. This computed value of drug penetration depth is corroborated by comparison with the values measured by experiments.

  14. Radiological contribution in the treatment of primary and secondary liver tumors

    International Nuclear Information System (INIS)

    Mathias, K.; Hoffmann, G.; Loeffler, T.; Hausamen, T.

    1986-01-01

    The prognosis of patients with primary and secondary liver tumors has been improved recently by more aggressive operative, chemotherapeutic and embolization treatment. In a personal series of 40 patients with liver metastases colorectal cancer, regional intraarterial chemotherapy was superior to systematic intravenous treatment, with a tumor remission rate in 66% in comparison to 48% of the cases. But the benefit of intraarterial chemotherapy is still questionable considering the higher complication rate and the absence of prognostic data of the procedure. (orig.) [de

  15. Incidence of liver tumors in beagles with body burdens of 239Pu or 241Am

    International Nuclear Information System (INIS)

    Taylor, G.N.; Mays, C.W.; Wrenn, M.E.; Shabestari, L.; Lloyd, R.D.

    1986-01-01

    Tetravalent 239 Pu or trivalent 241 Am in a citrate buffer, given via a single intravenous injection to beagles, induced very pronounced liver changes, usually at relatively long postinjection times. The lesions consisted of cell injury or cell necrosis which was followed by nodular hyperplasia and a significant incidence of primary liver tumors. The most frequent neoplasm was the bile duct adenoma, followed by the bile duct carcinoma. A lesser number of sarcomas were also induced, especially fibrosarcomas. The number of hepatic cell tumors was low. An abnormally high incidence of both hyperplastic nodules and primary liver tumors occurred at long postinjection times and at average doses extending down to ∼10 rads. The various nodular lesions and liver tumors frequently occurred as incidental findings in dogs dying from other causes, especially bone cancer. In comparison to bone neoplasia, the liver was a much less important target organ in the high-dose level groups, but in some of the low-dose groups, especially in the 241 Am groups, the risk of radiation-induced liver cancer was approximately equal to or exceeded the risk of skeletal tumors. However, in any projection of the risks observed in this animal model to man, one should be mindful that the beagle skeleton is approximately 25 times more sensitive to radiation-induced bone neoplasia than is the human skeleton (Mays et al., 1976) and that the radiosensitivity difference for the beagle and human liver is unknown. 41 refs., 8 figs., 5 tabs

  16. Human Precision-Cut Liver Slices as an ex Vivo Model to Study Idiosyncratic Drug-Induced Liver Injury

    NARCIS (Netherlands)

    Hadi, Mackenzie; Westra, Inge M.; Starokozhko, Viktoriia; Dragovic, Sanja; Merema, M.T.; Groothuis, Geny M. M.

    Idiosyncratic drug-induced liver injury (IDILI) is a major problem during drug development and has caused drug withdrawal and black-box warnings. Because of the low concordance of the hepatotoxicity of drugs in animals and humans, robust screening methods using human tissue are needed to predict

  17. Human precision-cut liver slices as an ex vivo model to study idiosyncratic drug-induced liver injury

    NARCIS (Netherlands)

    Hadi, Mackenzie; Westra, Inge; Starokozhko, Viktoriia; Dragovic, Sanja; Merema, Maja; Groothuis, Genoveva

    2013-01-01

    Idiosyncratic drug-induced liver injury (IDILI) is a major problem during drug development and has caused drug withdrawal and black-box warnings. Due to the low concordance of the hepatotoxicity of drugs in animals and humans, robust screening methods using human tissue are needed to predict and to

  18. Rb and p53 Liver Functions Are Essential for Xenobiotic Metabolism and Tumor Suppression

    NARCIS (Netherlands)

    Nantasanti, Sathidpak; Toussaint, Mathilda J. M.; Youssef, Sameh A.; Tooten, Peter C. J.; de Bruin, Alain

    2016-01-01

    The tumor suppressors Retinoblastoma (Rb) and p53 are frequently inactivated in liver diseases, such as hepatocellular carcinomas (HCC) or infections with Hepatitis B or C viruses. Here, we discovered a novel role for Rb and p53 in xenobiotic metabolism, which represent a key function of the liver

  19. Nano-Engineered Mesenchymal Stem Cells Increase Therapeutic Efficacy of Anticancer Drug Through True Active Tumor Targeting.

    Science.gov (United States)

    Layek, Buddhadev; Sadhukha, Tanmoy; Panyam, Jayanth; Prabha, Swayam

    2018-06-01

    Tumor-targeted drug delivery has the potential to improve therapeutic efficacy and mitigate non-specific toxicity of anticancer drugs. However, current drug delivery approaches rely on inefficient passive accumulation of the drug carrier in the tumor. We have developed a unique, truly active tumor-targeting strategy that relies on engineering mesenchymal stem cells (MSC) with drug-loaded nanoparticles. Our studies using the A549 orthotopic lung tumor model show that nano-engineered MSCs carrying the anticancer drug paclitaxel (PTX) home to tumors and create cellular drug depots that release the drug payload over several days. Despite significantly lower doses of PTX, nano-engineered MSCs resulted in significant inhibition of tumor growth and superior survival. Anticancer efficacy of nano-engineered MSCs was confirmed in immunocompetent C57BL/6 albino female mice bearing orthotopic Lewis Lung Carcinoma (LL/2-luc) tumors. Furthermore, at doses that resulted in equivalent therapeutic efficacy, nano-engineered MSCs had no effect on white blood cell count, whereas PTX solution and PTX nanoparticle treatments caused leukopenia. Biodistribution studies showed that nano-engineered MSCs resulted in greater than 9-fold higher AUC lung of PTX (1.5 μg.day/g) than PTX solution and nanoparticles (0.2 and 0.1 μg.day/g tissue, respectively) in the target lung tumors. Furthermore, the lung-to-liver and the lung-to-spleen ratios of PTX were several folds higher for nano-engineered MSCs relative to those for PTX solution and nanoparticle groups, suggesting that nano-engineered MSCs demonstrate significantly less off-target deposition. In summary, our results demonstrate that nano-engineered MSCs can serve as an efficient carrier for tumor-specific drug delivery and significantly improved anti-cancer efficacy of conventional chemotherapeutic drugs. Mol Cancer Ther; 17(6); 1196-206. ©2018 AACR . ©2018 American Association for Cancer Research.

  20. Rearrangement of a common cellular DNA domain on chromosome 4 in human primary liver tumors

    International Nuclear Information System (INIS)

    Pasquinelli, C.; Garreau, F.; Bougueleret, L.; Cariani, E.; Thiers, V.; Croissant, O.; Hadchouel, M.; Tiollais, P.; Brechot, C.; Grzeschik, K.H.

    1988-01-01

    Hepatitis B virus (HBV) DNA integration has been shown to occur frequently in human hepatocellular carcinomas. The authors have investigated whether common cellular DNA domains might be rearranged, possibly by HBV integration, in human primary liver tumors. Unique cellular DNA sequences adjacent to an HBV integration site were isolated from a patient with hepatitis B surface antigen-positive hepatocellular carcinoma. These probes detected rearrangement of this cellular region of chromosomal DNA in 3 of 50 additional primary liver tumors studied. Of these three tumor samples, two contained HBV DNA, without an apparent link between the viral DNA and the rearranged allele; HBV DNA sequences were not detected in the third tumor sample. By use of a panel of somatic cell hybrids, these unique cellular DNA sequences were shown to be located on chromosome 4. Therefore, this region of chromosomal DNA might be implicated in the formation of different tumors at one step of liver cell transformation, possible related to HBV integration

  1. Effect of irradiation on microviscosity of the cellular nuclear membrane of tumor and liver of tumor-carriers

    International Nuclear Information System (INIS)

    Mal'tseva, E.L.; Goloshchapov, A.N.; Pal'mina, N.P.; Burlakova, E.B.

    1982-01-01

    Changes of microviscosity of the cellular nuclear membrane of tumor and liver of tumor-carriers with developing Ehrlich ascites tumor (EAT) at various terms after lethal irradiation (650 R) were studied by spin probe method. Two iminoxyl radicals localized mainly in lipid bilayer and near probein layers of membrane lipids were used. The character and the degree of microviscosity changes in different zones of nuclear membranes point to different responses towards effect of radiation of cells of tumor-carrier organ and tumor both in viscosity properties, and in change of lipid-protein relations. The significant contribution of near protein lipid layers into general change of nuclear membrane microviscosity is marked. Microviscosity of nuclear membrane causes different responses of cellular nuclear membranes of liver of tumor-carriers and healthy animals as well as considerable (3 times) dilution of nuclear membrane of EAT cells after irradiation. It is shown that temperature dependence of times of rotatory correlation of both probes is more expressed in EAT cells of irradiated tumor-carriers, than in liver

  2. Assessment of tumor vascularization with functional computed tomography perfusion imaging in patients with cirrhotic liver disease.

    Science.gov (United States)

    Li, Jin-Ping; Zhao, De-Li; Jiang, Hui-Jie; Huang, Ya-Hua; Li, Da-Qing; Wan, Yong; Liu, Xin-Ding; Wang, Jin-E

    2011-02-01

    Hepatocellular carcinoma (HCC) is a common malignant tumor in China, and early diagnosis is critical for patient outcome. In patients with HCC, it is mostly based on liver cirrhosis, developing from benign regenerative nodules and dysplastic nodules to HCC lesions, and a better understanding of its vascular supply and the hemodynamic changes may lead to early tumor detection. Angiogenesis is essential for the growth of primary and metastatic tumors due to changes in vascular perfusion, blood volume and permeability. These hemodynamic and physiological properties can be measured serially using functional computed tomography perfusion (CTP) imaging and can be used to assess the growth of HCC. This study aimed to clarify the physiological characteristics of tumor angiogenesis in cirrhotic liver disease by this fast imaging method. CTP was performed in 30 volunteers without liver disease (control subjects) and 49 patients with liver disease (experimental subjects: 27 with HCC and 22 with cirrhosis). All subjects were also evaluated by physical examination, laboratory screening and Doppler ultrasonography of the liver. The diagnosis of HCC was made according to the EASL criteria. All patients underwent contrast-enhanced ultrasonography, pre- and post-contrast triple-phase CT and CTP study. A mathematical deconvolution model was applied to provide hepatic blood flow (HBF), hepatic blood volume (HBV), mean transit time (MTT), permeability of capillary vessel surface (PS), hepatic arterial index (HAI), hepatic arterial perfusion (HAP) and hepatic portal perfusion (HPP) data. The Mann-Whitney U test was used to determine differences in perfusion parameters between the background cirrhotic liver parenchyma and HCC and between the cirrhotic liver parenchyma with HCC and that without HCC. In normal liver, the HAP/HVP ratio was about 1/4. HCC had significantly higher HAP and HAI and lower HPP than background liver parenchyma adjacent to the HCC. The value of HBF at the tumor

  3. Laparoscopic microwave thermosphere ablation of malignant liver tumors: an initial clinical evaluation.

    Science.gov (United States)

    Berber, Eren

    2016-02-01

    Microwave ablation (MWA) has been recently recognized as a technology to overcome the limitations of radiofrequency ablation. The aim of the current study was to evaluate the safety and efficacy of a new 2.45-GHz thermosphere MWA system in the treatment of malignant liver tumors. This was a prospective IRB-approved study of 18 patients with malignant liver tumors treated with MWA within a 3-month time period. Tumor sizes and response to MWA were obtained from triphasic liver CT scans done before and after MWA. The ablation zones were assessed for complete tumor response and spherical geometry. There were a total of 18 patients with an average of three tumors measuring 1.4 cm (range 0.2-4). Ablations were performed laparoscopically in all, but three patients who underwent combined liver resection. A single ablation was created in 72% and overlapping ablations in 28% of lesions. Total ablation time per patient was 15.6 ± 1.9 min. There was no morbidity or mortality. At 2-week CT scans, there was 100% tumor destruction, with no residual lesions. Roundness indices A, B and transverse were 1.1, 0.9 and 0.9, respectively, confirming the spherical nature of ablation zones. To the best of our knowledge, this is the first report of a new thermosphere MWA technology in the laparoscopic treatment of malignant liver tumors. The results demonstrate the safety of the technology, with satisfactory spherical ablation zones seen on post-procedural CT scans.

  4. Celecoxib and Ibuprofen Restore the ATP Content and the Gluconeogenesis Activity in the Liver of Walker-256 Tumor-Bearing Rats

    Directory of Open Access Journals (Sweden)

    Camila Oliveira de Souza

    2015-07-01

    Full Text Available Background/Aims: The main purpose of this study was to investigate the effects of celecoxib and ibuprofen, both non-steroidal anti-inflammatory drugs (NSAIDs, on the decreased gluconeogenesis observed in liver of Walker-256 tumor-bearing rats. Methods: Celecoxib and ibuprofen (both at 25 mg/Kg were orally administered for 12 days, beginning on the same day when the rats were inoculated with Walker-256 tumor cells. Results: Celecoxib and ibuprofen treatment reversed the reduced production of glucose, pyruvate, lactate and urea from alanine as well as the reduced production of glucose from pyruvate and lactate in perfused liver from tumor-bearing rats. Besides, celecoxib and ibuprofen treatment restored the decreased ATP content, increased triacylglycerol levels and reduced mRNA expression of carnitine palmitoyl transferase 1 (CPT1, while ibuprofen treatment restored the reduced mRNA expression of peroxisome proliferator-activated receptor alpha (PPARα in the liver of tumor-bearing rats. Both treatments tended to decrease TNFα, IL6 and IL10 in the liver of tumor-bearing rats. Finally, the treatment with celecoxib, but not with ibuprofen, reduced the growth of Walker-256 tumor. Conclusion: Celecoxib and ibuprofen restored the decreased gluconeogenesis in the liver of Walker-256 tumor-bearing rats. These effects did not involve changes in tumor growth and probably occurred by anti-inflammatory properties of these NSAIDs, which increased expression of genes associated with fatty acid oxidation (PPARα and CPT1 and consequently the ATP production, normalizing the energy status in the liver of tumor-bearing rats.

  5. Sorafenib metabolism is significantly altered in the liver tumor tissue of hepatocellular carcinoma patient.

    Directory of Open Access Journals (Sweden)

    Ling Ye

    Full Text Available BACKGROUND: Sorafenib, the drug used as first line treatment for hepatocellular carcinoma (HCC, is metabolized by cytochrome P450 (CYP 3A4-mediated oxidation and uridine diphosphate glucuronosyl transferase (UGT 1A9-mediated glucuronidation. Liver diseases are associated with reduced CYP and UGT activities, which can considerably affect drug metabolism, leading to drug toxicity. Thus, understanding the metabolism of therapeutic compounds in patients with liver diseases is necessary. However, the metabolism characteristic of sorafenib has not been systematically determined in HCC patients. METHODS: Sorafenib metabolism was tested in the pooled and individual tumor hepatic microsomes (THLMs and adjacent normal hepatic microsomes (NHLMs of HCC patients (n = 18. Commercial hepatic microsomes (CHLMs were used as a control. In addition, CYP3A4 and UGT1A9 protein expression in different tissues were measured by Western blotting. RESULTS: The mean rates of oxidation and glucuronidation of sorafenib were significantly decreased in the pooled THLMs compared with those in NHLMs and CHLMs. The maximal velocity (Vmax of sorafenib oxidation and glucuronidation were approximately 25-fold and 2-fold decreased in the pooled THLMs, respectively, with unchanged Km values. The oxidation of sorafenib in individual THLMs sample was significantly decreased (ranging from 7 to 67-fold than that in corresponding NHLMs sample. The reduction of glucuronidation in THLMs was observed in 15 out of 18 patients' samples. Additionally, the level of CYP3A4 and UGT1A9 expression were both notably decreased in the pooled THLMs. CONCLUSIONS: Sorafenib metabolism was remarkably decreased in THLMs. This result was associated with the down regulation of the protein expression of CYP3A4 and UGT1A9.

  6. A case of primary neuroendcrine tumor of liver with FDG accumulation by PET/CT

    International Nuclear Information System (INIS)

    Okumura, Yoshihiro; Kishi, Ryotaro; Uka, Mayu; Tsuchihashi, Kazuyo; Hyodo, Takeshi; Takakura, Norihisa; Iguchi, Toshihiro; Kanazawa, Susumu

    2014-01-01

    We report an 80's male with primary hepatic neuroendcrine tumor without clinical symptom. dynamic contrast CT showed a hypervascular tumor at S5 of the liver. EOB-MRI showed high intensity on T2WI, low intensity on T1WI, the hepatic phase and the diffusion weighted image. It showed high FDG accumulation. Pathological examination confirmed neuroendcrine tumor of liver, G2 stage, and owing to the CD56 positive, 12.6% at MIB-1 index, with a little necrosis, no capsule and hemorrhage. (author)

  7. Tumor lysis syndrome following endoscopic radiofrequency interstitial thermal ablation of colorectal liver metastases.

    LENUS (Irish Health Repository)

    Barry, B D

    2012-02-03

    Radiofrequency interstitial thermal ablation (RITA) provides a palliative option for patients suffering from metastatic liver disease. This procedure can be performed using a laparoscopic approach with laparoscopic ultrasound used to position the RITA probe. We describe a case of laparoscopic RITA performed for colorectal liver metastasis that was complicated by tumor lysis syndrome (TLS) following treatment. We consider RITA to be a safe procedure, as supported by the literature, but where intracorporal tumor lysis is the treatment goal we believe that the systemic release of tumor products can overwhelm the excretory capacity; therefore, TLS is an inevitable consequence in some patients.

  8. Electroporation-based treatment planning for deep-seated tumors based on automatic liver segmentation of MRI images.

    Science.gov (United States)

    Pavliha, Denis; Mušič, Maja M; Serša, Gregor; Miklavčič, Damijan

    2013-01-01

    Electroporation is the phenomenon that occurs when a cell is exposed to a high electric field, which causes transient cell membrane permeabilization. A paramount electroporation-based application is electrochemotherapy, which is performed by delivering high-voltage electric pulses that enable the chemotherapeutic drug to more effectively destroy the tumor cells. Electrochemotherapy can be used for treating deep-seated metastases (e.g. in the liver, bone, brain, soft tissue) using variable-geometry long-needle electrodes. To treat deep-seated tumors, patient-specific treatment planning of the electroporation-based treatment is required. Treatment planning is based on generating a 3D model of the organ and target tissue subject to electroporation (i.e. tumor nodules). The generation of the 3D model is done by segmentation algorithms. We implemented and evaluated three automatic liver segmentation algorithms: region growing, adaptive threshold, and active contours (snakes). The algorithms were optimized using a seven-case dataset manually segmented by the radiologist as a training set, and finally validated using an additional four-case dataset that was previously not included in the optimization dataset. The presented results demonstrate that patient's medical images that were not included in the training set can be successfully segmented using our three algorithms. Besides electroporation-based treatments, these algorithms can be used in applications where automatic liver segmentation is required.

  9. Resection of Segments 4, 5 and 8 for a Cystic Liver Tumor Using the Double Liver Hanging Maneuver

    Directory of Open Access Journals (Sweden)

    Atsushi Nanashima

    2008-03-01

    Full Text Available To achieve complete anatomic central hepatectomy for a large tumor compressing surrounding vessels, transection by an anterior approach is preferred but a skillful technique is necessary. We propose the modified technique of Belghiti’s liver hanging maneuver (LHM. The case was a 77-year-old female with a 6-cm liver cystic tumor in the central liver compressing hilar vessels and the right hepatic vein. At the hepatic hilum, the spaces between Glisson’s pedicle and hepatic parenchyma were dissected, which were (1 the space between the right anterior and posterior Glisson pedicles and (2 the space adjacent to the umbilical Glisson pedicle. Two tubes were repositioned in each space and ‘double LHM’ was possible at the two resected planes of segments 4, 5 and 8. Cut planes were easily and adequately obtained and the compressed vessels were secured. Double LHM is a useful surgical technique for hepatectomy for a large tumor located in the central liver.

  10. Reactions of inorganic free radicals with liver protecting drugs

    International Nuclear Information System (INIS)

    Gyoergy, I.; Foeldiak, G.; Blazovics, A.; Feher, J.

    1990-01-01

    Liver protecting drugs, silibinin, a flavonolignane, and the dihydroquinoline derivatives, CH 402 and MTDQ-DA, were shown to inhibit processes in which enzymatically or non-enzymatically generated free radicals were involved. Inorganic free radicals (N 3 , (SCN) 2 - , OH, Trp, CO 2 - , O 2 - ) produced by pulse radiolysis readily react with the compounds, which transform into exceptionally long-lived, unreactive transients. Time evolution of the UV and visible spectra indicate that oxidising radicals form a phenoxyl type radical from silibinin, while OH forms an adduct by attacking, simultaneously, at various sites of the molecule. Superoxide radicals reduce silibinin and oxidise CH 402 and MTDQ-DA. It is concluded that the drugs might exhibit antioxidant behavior in living systems. (author)

  11. The experimental study on liver VX-2 tumor by using MR diffusion-weighted imaging

    International Nuclear Information System (INIS)

    Yuan Youhong; Xiao Enhua; Jin Ke; Yan Ronghua; He Zhong; Shang Quanliang; Hu Weizhou; Yuan Shiwen; Xiang Jun; Tang Keli; Yi Shijian; Yin Qiang

    2005-01-01

    Objective: To study the imaging characteristics of rabbit's liver VX-2 tumor on MR diffusion-weighted imaging. Methods: Of the 35 New Zealand rabbits, 14 were implanted under the skin while 6 were implanted in liver with VX-2 tumor in preparing experiment, and 12 were implanted in liver and 3 as controls in formal experiment. Before and after the implantation, MR diffusion-weighted imaging (DWI), T 1 -weighted and T 2 -weighted images were performed respectively and periodically in 15 tumors including 12 liver tumor implantations in formal experiment. DWI parameters including apparent diffusion coefficient (ADC) value were acquired and statistically analyzed by SPSS 10.0. Results: (1) The successful rate of implantation was 29% (4/14) under the skin and 33% (2/6) in the liver in preparing experiment. And the successful rate of formal experiment was 83% (10/12). (2) DWI signal of VX-2 tumor was high and the signal became lower and lower with b value increased step by step. The signal of VX-2 tumor on ADC map was low. The ADC value of normal group was (2.57 ± 0.26) mm 2 /s (b=100 s/mm 2 ) and (1.73 ± 0.31) mm 2 /s (b=300 s/mm 2 ), and ADC value of VX-2 tumor group was (1.87 ± 0.25) mm 2 /s (b=100 s/mm 2 ) and (1.57 ± 0.23) mm 2 /s (b=300 s/mm 2 ), respectively.The F value of analysis of variance was 43.26 (P<0.001). The distinction of tumor ADC value in different b values was significant (P<0.05), and the distinction of ADC value between VX-2 tumor and normal liver was also significant (P<0.01). (3) VX-2 tumor developed quickly and metastasized early to all parts of the body, especially to the lung, the liver, the lymph nodes of mediastinum and so on. Conclusion: DWI signal of VX-2 tumor has its characteristic and DWI has important value in reflecting the movement of water molecules, discovering the VX-2 tumor, and tracking its progress. (authors)

  12. Intraoperative Detection of Superficial Liver Tumors by Fluorescence Imaging Using Indocyanine Green and 5-aminolevulinic Acid.

    Science.gov (United States)

    Kaibori, Masaki; Matsui, Kosuke; Ishizaki, Morihiko; Iida, Hiroya; Okumura, Tadayoshi; Sakaguchi, Tatsuma; Inoue, Kentaro; Ikeura, Tsukasa; Asano, Hiroaki; Kon, Masanori

    2016-04-01

    Indocyanine green (ICG) and the porphyrin precursor 5-aminolevulinic acid (5-ALA) have been approved as fluorescence imaging agents in the clinical setting. This study evaluated the usefulness of fluorescence imaging with both ICG and 5-ALA for intraoperative identification of latent small liver tumors. There were 48 patients who had main tumors within 5 mm of the liver surface. 5-ALA hydrochloride was orally administered to patients 3 h before surgery. ICG had been intravenously injected within 14 days prior to surgery. Intraoperatively, after visual inspection, manual palpation and ultrasonography fluorescence images of the liver surface were obtained with ICG and 5-ALA prior to resection. With ICG, the sensitivity, specificity and accuracy for detecting the preoperatively identified main tumors were 96%, 50% and 94%, respectively. Twelve latent small tumors were newly detected on the liver surface using ICG, five of which proved to be carcinomas. With 5-ALA, the sensitivity, specificity and accuracy for detecting the main tumors were 57%, 100% and 58%, respectively. Five latent small tumors were newly detected using 5-ALA; all were carcinomas. Overall, five new tumors were detected by both ICG and 5-ALA fluorescence imaging; two were hepatocellular carcinomas (HCCs) and three were metastases of colorectal cancer. The sensitivity and specificity of ICG fluorescence imaging for main tumor detection were relatively high and low, respectively, but the opposite was true of 5-ALA imaging. Fluorescence imaging using 5-ALA may provide greater specificity in the detection of surface-invisible malignant liver tumors than using ICG fluorescence imaging alone. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  13. LP-THAE induced tumor cell apoptosis of rabbit VX2 liver carcinoma

    International Nuclear Information System (INIS)

    Chen Shengli; Quan Yi; Huang Zicheng; Chen Guodong; Zhu Dongliang

    2007-01-01

    Objective: To research tumor cell apoptosis induced by Lp-THAE of rabbit VX2 liver implanted tumor. Methods: 27 New Zealand white rabbits implanted with VX2 tumor at left middle lobe of the liver divided into three groups: Group A(n= 9) Lp-THAE: treated through transhepatic artery catheterization; Group B(n=9) THAI and Group C(n=9) as control. The rabbits were executed at second to fifth day after treatment. HE dye microscopy was taken for counting the typical apoptosis cells and calculating apoptosis index (ApI). FITC-AnnexinV/PI assay was used for measuring apoptosis by flow cytometry. Results: The ApI of tumor central area and marginal area were (17.769±2.417)%, (4.129±1.172)%, P<0.01. The percentages of tumor cell apoptosis and tumor cell necrosis were (16.483±1.404)%, (9.478±0.964)%, P<0.01 and (43.559±5.053)%, (33.460±1.840)%, P=0.093. The total percentages of tumor cell apoptosis and necrosis were (60.042±13.979)%, (42.938±8.979)%, P< 0.01, at tumor center and marginal area in THAE group respectively. The ApI, percentages of tumor cell apoptosis and necrosis in THAE group were significantly higher than those of THAI group (P<0.01). The percentages of tumor cell apoptosis at tumor center area in THAE group were significantly higher than those of tumor marginal area(P<0.01). Conclusion: Induced tumor cell apoptosis and necrosis are two mechanisms of action for Lp-THAE treatment of liver carcinoma. (authors)

  14. Internal radiotherapy of liver cancer with rat hepato-carcinoma-intestine-pancreas gene as a liver tumor-specific promoter

    Energy Technology Data Exchange (ETDEWEB)

    Herve, J.; Cunha, A. Sa; Liu, B.; Valogne, Y.; Longuet, M.; Bregerie, O.; Guettier, C.; Samuel, D.; Brechot, C.; Faivre, J. [Hop Paul Brousse, INSERM, Hepatobiliary Ctr, U785, F-94800 Villejuif (France); Herve, J.; Cunha, A. Sa; Liu, B.; Valogne, Y.; Longuet, M.; Bregerie, O.; Guettier, C.; Samuel, D.; Brechot, C.; Faivre, J. [Univ Paris Sud, Fac Med, F-94800 Villejuif (France); Boisgard, R.; Tavitian, B. [INSERM, U803, F-91400 Orsay (France); Boisgard, R.; Tavitian, B. [CEA, Serv Hosp Frederic Joliot, Lab Imagerie Mol Expt, F-91400 Orsay (France); Roux, J.; Cales, P. [Univ Angers, UPRES EA 3859, Lab Hemodynam Interact Fibrose et Invas Tumorale H, Angers (France); Clerc, J. [Hop Cochin, AP HP, Dept Nucl Med, F-75014 Paris (France)

    2008-07-01

    The hepato-carcinoma-intestine-pancreas (HIP) gene, also called pancreatitis-associated protein-1 (PAP1) or Reg III {alpha}, is activated in most human hepatocellular carcinomas (HCCs) but not in normal liver, which suggests that HIP regulatory sequence could be used as efficient liver tumor-specific promoters to express a therapeutic polynucleotide in liver cancer. The sodium iodide sym-porter (NIS), which has recognized therapeutic and reporter gene properties, is appropriate to evaluate the transcriptional strength and specificity of the HIP promoter in HCC. For this purpose, we constructed a recombinant rat HIP-NIS adeno-viral vector (AdrHIP-NIS), and evaluated its performance as a mediator of selective radio-iodide uptake in tumor hepatocytes. Western blot, immunofluorescence, and iodide uptake assays were performed in AdrHIP-NIS-infected primary hepatocytes and transformed hepatic and non-hepatic cells. Nuclear imaging, tissue counting and immuno-histo-chemistry were performed in normal and HCC-bearing Wistar rats infected with AdrHIP-NIS intra-tumorally or via the hepatic artery. In AdrHIP-NIS-infected transformed hepatic cells, functional NIS was strongly expressed, as in cells infected with a cytomegalovirus-NIS vector. No NIS expression was found in AdrHIP-NIS-infected normal hepatocytes or transformed non-hepatic cells. In rats bearing multi-nodular HCC, AdrHIP-NIS triggered functional NIS expression that was preferential in tumor hepatocytes. Administration of 18 mCi of {sup 131}I resulted in the destruction of AdrHIP-NIS-injected nodules. This study has identified the rHIP regulatory sequence as a potent liver tumor-specific promoter for the transfer of therapeutic genes, and AdrHIP-NIS-mediated. {sup 131}I therapy as a valuable option for the treatment of multi-nodular HCC. (authors)

  15. Internal radiotherapy of liver cancer with rat hepato-carcinoma-intestine-pancreas gene as a liver tumor-specific promoter

    International Nuclear Information System (INIS)

    Herve, J.; Cunha, A. Sa; Liu, B.; Valogne, Y.; Longuet, M.; Bregerie, O.; Guettier, C.; Samuel, D.; Brechot, C.; Faivre, J.; Herve, J.; Cunha, A. Sa; Liu, B.; Valogne, Y.; Longuet, M.; Bregerie, O.; Guettier, C.; Samuel, D.; Brechot, C.; Faivre, J.; Boisgard, R.; Tavitian, B.; Boisgard, R.; Tavitian, B.; Roux, J.; Cales, P.; Clerc, J.

    2008-01-01

    The hepato-carcinoma-intestine-pancreas (HIP) gene, also called pancreatitis-associated protein-1 (PAP1) or Reg III α, is activated in most human hepatocellular carcinomas (HCCs) but not in normal liver, which suggests that HIP regulatory sequence could be used as efficient liver tumor-specific promoters to express a therapeutic polynucleotide in liver cancer. The sodium iodide sym-porter (NIS), which has recognized therapeutic and reporter gene properties, is appropriate to evaluate the transcriptional strength and specificity of the HIP promoter in HCC. For this purpose, we constructed a recombinant rat HIP-NIS adeno-viral vector (AdrHIP-NIS), and evaluated its performance as a mediator of selective radio-iodide uptake in tumor hepatocytes. Western blot, immunofluorescence, and iodide uptake assays were performed in AdrHIP-NIS-infected primary hepatocytes and transformed hepatic and non-hepatic cells. Nuclear imaging, tissue counting and immuno-histo-chemistry were performed in normal and HCC-bearing Wistar rats infected with AdrHIP-NIS intra-tumorally or via the hepatic artery. In AdrHIP-NIS-infected transformed hepatic cells, functional NIS was strongly expressed, as in cells infected with a cytomegalovirus-NIS vector. No NIS expression was found in AdrHIP-NIS-infected normal hepatocytes or transformed non-hepatic cells. In rats bearing multi-nodular HCC, AdrHIP-NIS triggered functional NIS expression that was preferential in tumor hepatocytes. Administration of 18 mCi of 131 I resulted in the destruction of AdrHIP-NIS-injected nodules. This study has identified the rHIP regulatory sequence as a potent liver tumor-specific promoter for the transfer of therapeutic genes, and AdrHIP-NIS-mediated. 131 I therapy as a valuable option for the treatment of multi-nodular HCC. (authors)

  16. Subcellular distribution of 111In and 169Yb in tumor and liver

    International Nuclear Information System (INIS)

    Ando, A.; Ando, I.; Takeshita, M.; Hiraki, T.; Hisada, K.

    1981-01-01

    Subcellular distribution of 111 In and 169 Yb was quantitatively determined to evaluate the role of the lysosome in accumulation of these nuclides in malignant tumor tissue and in the liver using three different tumor models and the host liver. In Yoshida sarcoma and Ehrlich tumor, most of the radioactivity of these nuclides was localized in the supernatant fraction, and only a small amount of radioactivity was localized in the mitochondrial fraction, which contains lysosomes. In the liver, most of the radioactivity was concentrated in the mitochondrial fraction. The radioactivity of this fraction increased with time after the administration of these nuclides and reached approximately 50% of the total radioactivity within 24 h. In the case of hepatoma AH109A, radioactivity of the mitochondrial fraction increased with time after administration, and about 30% of the total radioactivity was concentrated in this fraction after 24 h. It is concluded that the lysosome does not play a major role in the tumor concentration of these nuclides, although it may play an important role in their liver concentration. In the case of hepatoma AH109A, it is pressumed that lysosome plays a considerably important role in the tumor concentration of these nuclides, hepatoma AH109A possessing some residual features of the liver. (orig.)

  17. Subcellular distribution of /sup 111/In and /sup 169/Yb in tumor and liver

    Energy Technology Data Exchange (ETDEWEB)

    Ando, A; Ando, I; Takeshita, M; Hiraki, T; Hisada, K

    1981-05-01

    Subcellular distribution of /sup 111/In and /sup 169/Yb was quantitatively determined to evaluate the role of the lysosome in accumulation of these nuclides in malignant tumor tissue and in the liver using three different tumor models and the host liver. In Yoshida sarcoma and Ehrlich tumor, most of the radioactivity of these nuclides was localized in the supernatant fraction, and only a small amount of radioactivity was localized in the mitochondrial fraction, which contains lysosomes. In the liver, most of the radioactivity was concentrated in the mitochondrial fraction. The radioactivity of this fraction increased with time after the administration of these nuclides and reached approximately 50% of the total radioactivity within 24 h. In the case of hepatoma AH109A, radioactivity of the mitochondrial fraction increased with time after administration, and about 30% of the total radioactivity was concentrated in this fraction after 24 h. It is concluded that the lysosome does not play a major role in the tumor concentration of these nuclides, although it may play an important role in their liver concentration. In the case of hepatoma AH109A, it is pressumed that lysosome plays a considerably important role in the tumor concentration of these nuclides, hepatoma AH109A possessing some residual features of the liver.

  18. Which drug or drug delivery system can change clinical practice for brain tumor therapy?

    OpenAIRE

    Siegal, Tali

    2013-01-01

    The prognosis and treatment outcome for primary brain tumors have remained unchanged despite advances in anticancer drug discovery and development. In clinical trials, the majority of promising experimental agents for brain tumors have had limited impact on survival or time to recurrence. These disappointing results are partially explained by the inadequacy of effective drug delivery to the CNS. The impediments posed by the various specialized physiological barriers and active efflux mechanis...

  19. PREDICTION AND PREVENTION OF LIVER FAILURE AFTER MAJOR LIVER PRIMARY AND METASTATIC TUMORS RESECTION

    Directory of Open Access Journals (Sweden)

    A. D. Kaprin

    2016-01-01

    Full Text Available Abstract Purpose of the study. Improvement of results of treatment in patients with primary and metastatic liver cancer by decreasing the risk of post-resection liver failure on the basis of the evaluation of the functional reserves of the liver.Materials and Methods. The study included two independent samples of patients operated about primary or metastatic lesions of the liver at the Department of abdominal Oncology, P. A. Hertsen MORI. The first group included 53 patients who carried out 13C-breath test metallimovie and dynamic scintigraphy of the liver in the preoperative stage in addition to the standard algorithm of examination. Patients of the 2nd group (n=35 had a standard clinical and laboratory examination, the patients were not performed the preoperative evaluation of the functional reserve of the liver, the incidences of total bilirubin, albumin and prothrombin time did not reveal a reduction of liver function. Post-resection liver failure have been established on the basis of the 50/50 criterion in the evaluation on day 5 after surgery.Results. Analysis of operating characteristics of the functional tests showed the absolute methacin breath test sensitivity (SE≥100%, high specificity (SP≥67% of scintigraphy of the liver and the negative predictive value of outcome (VP≥100% at complex use of two diagnostic methods. The incidence of PROPS in the study group was significantly 2 times higher in the control group –15,1% and 26.8%, respectively (p<0.001.Conclusion. The combination of preoperative dynamic scintigraphy of the liver with carrying out 13C-breath methacin test allows you to conduct a comprehensive evaluation of the liver functional reserve and can significantly improve preoperative evaluation and postoperative results of anatomic resection in patients with primary and metastatic liver lesions.

  20. What effects performance status of patients with hepatocellular carcinoma: stage of tumor versus underlying liver status

    International Nuclear Information System (INIS)

    Sarwar, S.; Tarique, S.

    2015-01-01

    Objective: To identify variables associated with poor performance status of hepatocellular carcinoma (HCC) patients and to compare impact of stage of liver disease and that of hepatoma on functional status of patient. Patients and Methods: We included 254 confirmed cases of liver cancer in a crosssectional analytical study carried out at Doctors Hospital Lahore. Patient's clinical, biochemical and radiological variables were correlated with Karnofsky's performance status (KPS) using pearson correlation. Model for End stage Liver Disease (MELD) and Cancer of Liver Italian Program (CLIP) were evaluated for predicting performance status using Receiver Operating Characteristic (ROC) curve. Results: Mean age of patients was 56.69 (±10.34) and male to female ratio was 2.47: 1 (181/73). On KPS evaluation 84 (33.1%) patients scored between 80-100, 147 (57.9%) had score of 50-70 while in 23 (9.1%) KPS score was between 0-40. Variables associated with poor performance status were bilirubin> 3mg/dl (p value 0.00), albumin< 2.5 g/dl (p value 0.00), creatinine > 1.2mg/dl (p 0.00), prothrombin time> 16seconds (p value 0.00), size of tumor >7cm (p value 0.02), tumor involving > 50% of liver mass (p value 0.00) and vascular invasion (p value 0.00). Both stage of liver disease as determined by MELD and stage of liver cancer as per CLIP scores had strong correlation (p value 0.00) with poor performance status of patient. Area under ROC curve was 0.764 for MELD score and 0.785 for CLIP score. Conclusion: Performance status of liver cancer patients is affected by both stage of liver disease and that of liver tumor. Patients with MELD score above 16 and CLIP score above 4 have poor performance status. (author)

  1. Synergistic gene and drug tumor therapy using a chimeric peptide.

    Science.gov (United States)

    Han, Kai; Chen, Si; Chen, Wei-Hai; Lei, Qi; Liu, Yun; Zhuo, Ren-Xi; Zhang, Xian-Zheng

    2013-06-01

    Co-delivery of gene and drug for synergistic therapy has provided a promising strategy to cure devastating diseases. Here, an amphiphilic chimeric peptide (Fmoc)2KH7-TAT with pH-responsibility for gene and drug delivery was designed and fabricated. As a drug carrier, the micelles self-assembled from the peptide exhibited a much faster doxorubicin (DOX) release rate at pH 5.0 than that at pH 7.4. As a non-viral gene vector, (Fmoc)(2)KH(7)-TAT peptide could satisfactorily mediate transfection of pGL-3 reporter plasmid with or without the existence of serum in both 293T and HeLa cell-lines. Besides, the endosome escape capability of peptide/DNA complexes was investigated by confocal laser scanning microscopy (CLSM). To evaluate the co-delivery efficiency and the synergistic anti-tumor effect of gene and drug, p53 plasmid and DOX were simultaneously loaded in the peptide micelles to form micelleplexes during the self-assembly of the peptide. Cellular uptake and intracellular delivery of gene and drug were studied by CLSM and flow cytometry respectively. And p53 protein expression was determined via Western blot analysis. The in vitro cytotoxicity and in vivo tumor inhibition effect were also studied. Results suggest that the co-delivery of gene and drug from peptide micelles resulted in effective cell growth inhibition in vitro and significant tumor growth restraining in vivo. The chimeric peptide-based gene and drug co-delivery system will find great potential for tumor therapy. Copyright © 2013 Elsevier Ltd. All rights reserved.

  2. Review fantastic medical implications of 3D-printing in liver surgeries, liver regeneration, liver transplantation and drug hepatotoxicity testing: A review.

    Science.gov (United States)

    Wang, Jing-Zhang; Xiong, Nan-Yan; Zhao, Li-Zhen; Hu, Jin-Tian; Kong, De-Cheng; Yuan, Jiang-Yong

    2018-06-07

    The epidemiological trend in liver diseases becomes more serious worldwide. Several recent articles published by International Journal of Surgery in 2018 particularly emphasized the encouraging clinical benefits of hepatectomy, liver regeneration and liver transplantation, however, there are still many technical bottlenecks underlying these therapeutic approaches. Remarkably, a few preliminary studies have shown some clues to the role of three-dimensional (3D) printing in improving traditional therapy for liver diseases. Here, we concisely elucidated the curative applications of 3D-printing (no cells) and 3D Bio-printing (with hepatic cells), such as 3D-printed patient-specific liver models and devices for medical education, surgical simulation, hepatectomy and liver transplantation, 3D Bio-printed hepatic constructs for liver regeneration and artificial liver, 3D-printed liver tissues for evaluating drug's hepatotoxicity, and so on. Briefly, 3D-printed liver models and bioactive tissues may facilitate a lot of key steps to cure liver disorders, predictably bringing promising clinical benefits. This work further provides novel insights into facilitating treatment of hepatic carcinoma, promoting liver regeneration both in vivo and in vitro, expanding transplantable liver resources, maximizing therapeutic efficacy as well as minimizing surgical complications, medical hepatotoxicity, operational time, economic costs, etc. Copyright © 2018. Published by Elsevier Ltd.

  3. Proteomic profiling in incubation medium of mouse, rat and human precision-cut liver slices for biomarker detection regarding acute drug-induced liver injury

    NARCIS (Netherlands)

    van Swelm, Rachel P L; Hadi, Mackenzie; Laarakkers, Coby M M; Masereeuw, R.|info:eu-repo/dai/nl/155644033; Groothuis, Geny M M; Russel, Frans G M

    Drug-induced liver injury is one of the leading causes of drug withdrawal from the market. In this study, we investigated the applicability of protein profiling of the incubation medium of human, mouse and rat precision-cut liver slices (PCLS) exposed to liver injury-inducing drugs for biomarker

  4. RUCAM in Drug and Herb Induced Liver Injury: The Update

    Directory of Open Access Journals (Sweden)

    Gaby Danan

    2015-12-01

    Full Text Available RUCAM (Roussel Uclaf Causality Assessment Method or its previous synonym CIOMS (Council for International Organizations of Medical Sciences is a well established tool in common use to quantitatively assess causality in cases of suspected drug induced liver injury (DILI and herb induced liver injury (HILI. Historical background and the original work confirm the use of RUCAM as single term for future cases, dismissing now the term CIOMS for reasons of simplicity and clarity. RUCAM represents a structured, standardized, validated, and hepatotoxicity specific diagnostic approach that attributes scores to individual key items, providing final quantitative gradings of causality for each suspect drug/herb in a case report. Experts from Europe and the United States had previously established in consensus meetings the first criteria of RUCAM to meet the requirements of clinicians and practitioners in care for their patients with suspected DILI and HILI. RUCAM was completed by additional criteria and validated, assisting to establish the timely diagnosis with a high degree of certainty. In many countries and for more than two decades, physicians, regulatory agencies, case report authors, and pharmaceutical companies successfully applied RUCAM for suspected DILI and HILI. Their practical experience, emerging new data on DILI and HILI characteristics, and few ambiguous questions in domains such alcohol use and exclusions of non-drug causes led to the present update of RUCAM. The aim was to reduce interobserver and intraobserver variability, to provide accurately defined, objective core elements, and to simplify the handling of the items. We now present the update of the well accepted original RUCAM scale and recommend its use for clinical, regulatory, publication, and expert purposes to validly establish causality in cases of suspected DILI and HILI, facilitating a straightforward application and an internationally harmonized approach of causality

  5. Antibody-linked drug destroys tumor cells and tumor blood vessels in many types of cancer | Center for Cancer Research

    Science.gov (United States)

    A team led by Brad St. Croix, Ph.D., Senior Associate Scientist, Mouse Cancer Genetics Program, has developed an antibody-drug conjugate (ADC) that destroys both tumor cells and the blood vessels that nourish them. The drug significantly shrank breast tumors, colon tumors and several other types of cancer and prolonged survival. Learn more...  

  6. The Dynamics of Glutathione Species and Ophthalmate Concentrations in Plasma from the VX2 Rabbit Model of Secondary Liver Tumors

    Directory of Open Access Journals (Sweden)

    R. Abbas

    2011-01-01

    Full Text Available Purpose. Available tumor markers have low sensitivity/specificity for the diagnosis of liver tumors. The present study was designed to evaluate the oxidoreductive status of the liver as surrogates of tumor subsistence and growth. Methods. Glutathione species (GSH:GSSG, ophthalmate (OA concentrations, and their turnover were measured in plasma of rabbits (n=6 in their healthy state and in the state of tumor growth after implantation of the VX2 carcinoma in their liver. Tumors were allowed to grow for a period of 14 days when rabbits were sacrificed. Livers were removed and cysteine concentration was measured in liver tissue. Results. Tumor growth was found in 100% of the rabbits. Concentration and labeling of GSH/GSSG were similar in experimental animals before and after tumor implantation and to sham animals. In contrast, OA concentration increased significantly in experimental animals after tumor implantation when compared to same animals prior to tumor implantation and to sham animals (P<.05. The concentration of cysteine, a precursor of GSH, was found to be significantly lower in the liver tissue adjacent to the tumor (P<.05. Conclusion. Disturbances in the oxidoreductive state of livers appear to be a surrogate of early tumor growth.

  7. Quantitative dual energy CT measurements in rabbit VX2 liver tumors: Comparison to perfusion CT measurements and histopathological findings

    International Nuclear Information System (INIS)

    Zhang, Long Jiang; Wu, Shengyong; Wang, Mei; Lu, Li; Chen, Bo; Jin, Lixin; Wang, Jiandong; Larson, Andrew C.; Lu, Guang Ming

    2012-01-01

    Purpose: To evaluate the correlation between quantitative dual energy CT and perfusion CT measurements in rabbit VX2 liver tumors. Materials and methods: This study was approved by the institutional animal care and use committee at our institution. Nine rabbits with VX2 liver tumors underwent contrast-enhanced dual energy CT and perfusion CT. CT attenuation for the tumors and normal liver parenchyma and tumor-to-liver ratio were obtained at the 140 kVp, 80 kVp, average weighted images and dual energy CT iodine maps. Quantitative parameters for the viable tumor and adjacent liver were measured with perfusion CT. The correlation between the enhancement values of the tumor in iodine maps and perfusion CT parameters of each tumor was analyzed. Radiation dose from dual energy CT and perfusion CT was measured. Results: Enhancement values for the tumor were higher than that for normal liver parenchyma at the hepatic arterial phase (P < 0.05). The highest tumor-to-liver ratio was obtained in hepatic arterial phase iodine map. Hepatic blood flow of the tumor was higher than that for adjacent liver (P < 0.05). Enhancement values of hepatic tumors in the iodine maps positively correlated with permeability of capillary vessel surface (r = 0.913, P < 0.001), hepatic blood flow (r = 0.512, P = 0.010), and hepatic blood volume (r = 0.464, P = 0.022) at the hepatic arterial phases. The effective radiation dose from perfusion CT was higher than that from DECT (P < 0.001). Conclusions: The enhancement values for viable tumor tissues measured in iodine maps were well correlated to perfusion CT measurements in rabbit VX2 liver tumors. Compared with perfusion CT, dual energy CT of the liver required a lower radiation dose.

  8. [Recent developments in biopsy diagnosis of early and undefined liver tumors].

    Science.gov (United States)

    Longerich, T; Schirmacher, P

    2009-01-01

    Biopsy diagnosis of early and highly differentiated liver tumors is difficult and complex. Modern pathology has met this challenge by several different means; elaborate morphological algorithms and novel immunohistological markers support the differential diagnosis of highly differentiated HCC and a new, predictive molecular pathological and histological classification of liver cell adenoma was developed. By these new diagnostic tools together with the so-called 'matrix diagnosis' a reliable diagnostic classification is now feasible in the vast majority of these difficult cases.

  9. Circulating Tumor DNA Analysis for Liver Cancers and Its Usefulness as a Liquid BiopsySummary

    Directory of Open Access Journals (Sweden)

    Atsushi Ono

    2015-09-01

    Full Text Available Background & Aims: Circulating tumor DNA (ctDNA carrying tumor-specific sequence alterations has been found in the cell-free fraction of blood. Liver cancer tumor specimens are difficult to obtain, and noninvasive methods are required to assess cancer progression and characterize underlying genomic features. Methods: We analyzed 46 patients with hepatocellular carcinoma who underwent hepatectomy or liver transplantation and for whom whole-genome sequencing data was available. We designed personalized assays targeting somatic rearrangements of each tumor to quantify serum ctDNA. Exome sequencing was performed using cell-free DNA paired primary tumor tissue DNA from a patient with recurrent liver cancer after transcatheter arterial chemoembolization (TACE. Results: We successfully detected ctDNA from 100 μL of serum samples in 7 of the 46 patients before surgery, increasing with disease progression. The cumulative incidence of recurrence and extrahepatic metastasis in the ctDNA-positive group were statistically significantly worse than in the ctDNA-negative group (P = .0102 and .0386, respectively. Multivariate analysis identified ctDNA (OR 6.10; 95% CI, 1.11–33.33, P = .038 as an independent predictor of microscopic vascular invasion of the portal vein (VP. We identified 45 nonsynonymous somatic mutations in cell-free DNA after TACE and 71 nonsynonymous somatic mutations in primary tumor tissue by exome sequencing. We identified 25 common mutations in both samples, and 83% of mutations identified in the primary tumor could be detected in the cell-free DNA. Conclusions: The presence of ctDNA reflects tumor progression, and detection of ctDNA can predict VP and recurrence, especially extrahepatic metastasis within 2 years. Our study demonstrated the usefulness of ctDNA detection and sequencing analysis of cell-free DNA for personalized treatment of liver cancer. Keywords: Circulating Tumor DNA, Exome Sequencing, Hepatocellular

  10. Whole-liver MR perfusion imaging in rabbit liver VX2 tumors: early findings of coagulative necrosis after percutaneous ethanol injection therapy

    International Nuclear Information System (INIS)

    Zhang Wanshi; Wang Dong; Meng Limin; Shi Huiping; Song Yunlong; Wu Bing

    2007-01-01

    Objective: To investigate the value of whole-liver MR perfusion imaging (MRPI) for early detection of coagulative necrosis after percutaneous ethanol injection (PEI) in rabbit liver VX 2 tumors. Methods: VX 2 tumor cell suspension was inoculated into rabbit liver and liver VX 2 tumors [diameter of (2.6 ± 0.6) cm] were induced in 10 male rabbits. MR T 1 WI and T 2 WI were performed to monitor the development of the liver tumor on the 2 nd and 3 rd week after inoculation. Whole-liver MRPI was performed in the 10 rabbits with liver VX 2 tumors before and 6 days after PEI therapy (1.0 ml ethanol was injected into the most enhanced tumor region under CT guiding). Signal intensity (SI) values of untreated tumor parts and treated areas 6 days after PEI were recorded respectively. The steepest slope (SS) and bolus arrival time (T0) of SI-time curves were measured. The t-Student test was used in statistical analysis of the data. Results: There was significant difference in MRPI data between untreated tumor parts [T0: (16.0 ± 1.2) s and SS: 38.9 ± 2.2] and treated areas [T0: (50.8 ± 5.9) s and SS: 6.0 ± 1.2] 6 days after PEI(t was 15.8 and -39.6 respectively, P 1 WI and T 2 WI could not show any differences between untreated tumor parts and treated areas. Conclusion: Whole-liver MRPI could detect coagulative necrosis of rabbit liver VX 2 tumors after PEI early. Disappearance of early enhancement can be a potential marker for efficacy of PEI. (authors)

  11. Safety and efficacy of Y-90 microsphere treatment in patients with primary and metastatic liver cancer: The tumor selectivity of the treatment as a function of tumor to liver flow ratio

    Directory of Open Access Journals (Sweden)

    Dezarn William A

    2007-03-01

    Full Text Available Abstract Background Treatment records and follow-up data on 40 patients with primary and metastatic liver malignancies who underwent a single whole-liver treatment with Y-90 resin microspheres (SIR-Spheres® Sirtex Medical, Lake Forest, IL were retrospectively reviewed. The objective of the study was to evaluate the anatomic and physiologic determinants of radiation dose distribution, and the dose response of tumor and liver toxicity in patients with liver malignancies who underwent hepatic arterial Y-90 resin microsphere treatment. Methods Liver and tumor volume calculations were performed on pre-treatment CT scans. Fractional tumor and liver flow characteristics and lung shunt fractions were determined using hepatic arterial Tc-99m MAA imaging. Absorbed dose calculations were performed using the MIRD equations. Liver toxicity was assessed clinically and by liver function tests. Tumor response to therapy was assessed by CT and/or tumor markers. Results Of the 40 patients, 5 had hepatocellular cancer (HCC, and 35 had metastatic liver tumors (15 colorectal cancer, 10 neuroendocrine tumors, 4 breast cancer, 2 lung cancer, 1 ovarian cancer, 1 endometrial cancer, and 2 unknown primary adenocarcinoma. All patients were treated in a salvage setting with a 3 to 80 week follow-up (mean: 19 weeks. Tumor volumes ranged from 15.0 to 984.2 cc (mean: 294.9 cc and tumor to normal liver uptake ratios ranged from 2.8 to 15.4 (mean: 5.4. Average administered activity was 1.2 GBq (0.4 to 2.4 GBq. Liver absorbed doses ranged from 0.7 to 99.5 Gy (mean: 17.2 Gy. Tumor absorbed doses ranged from 40.1 to 494.8 Gy (mean: 121.5 Gy. None of the patients had clinical venoocclusive disease or therapy-induced liver failure. Seven patients (17.5 % had transient and 7 patients (17.5 % had persistent LFT abnormalities. There were 27 (67.5% responders (complete response, partial response, and stable disease. Tumor response correlated with higher tumor flow ratio as measured by

  12. Massive hematemesis after radiofrequency ablation of metastatic liver tumor with successful hemostasis achieved through transarterial embolization.

    Science.gov (United States)

    Liu, Chien-An; Chiu, Nai-Chi; Chiou, Yi-You

    2018-03-03

    Hemorrhagic complications are the most common major complications that occur after radiofrequency ablation, but hematemesis as a complication after radiofrequency ablation for hepatic tumor has not been mentioned before. A hepatogastric fistula as a delayed complication is also rare. We present the case of a 77-year-old man with severe hematemesis that occurred 2 months after radiofrequency ablation of a liver metastasis of gastric cancer. A ruptured hepatic artery pseudoaneurysm and a hepatogastric fistula were confirmed through serial imaging examinations. The current case is reported in combination with 2 rare major complications after radiofrequency ablation of a liver tumor. Copyright © 2018. Published by Elsevier Inc.

  13. Study of subcellular distribution of /sup 67/Ga in tumor and liver

    Energy Technology Data Exchange (ETDEWEB)

    Ando, A; Takeshita, M; Hiraki, T [Kanazawa Univ. (Japan). School of Paramedicine; Ando, T; Hisada, K

    1977-02-01

    The following animals and transplanted tumors were used: rats implanted with Yoshida sarcoma and hepatoma AH109A, and mice implanted with Ehrlich tumor. /sup 67/Ga-citrate was injected into the rats intravenously and into the mice intraperitoneally. Ten minutes to 48 hours after the administration of /sup 67/Ga-citrate, the animals were sacrificed, and the tumor tissues and liver were excised. Subcellular fractionation of tumor tissues and livers was carried out according to the method of Hogeboom and Schneider. Radioactivity of each fraction was counted with a well type scintillation counter, and the protein of each fraction was measured according to Lowry's method. In Yoshida sarcoma and Ehrlich tumor, most of the radioactivity was localized in the supernatant fraction, and a small amount of radioactivity was localized in the mitochondrial fraction (lysosome contains in this fraction). But in the liver, most of the radioactivity was concentrated in the mitochondrial fraction, and the radioactivity of this fraction was increased with the passage of time after administration. Twenty-four hours later, about 50% of the total radioactivity was accumulated in this fraction. In the case of hepatoma AH109A, radioactivity of the mitochondrial fraction was increased with the passage of time after administration, and about 30% of total activity was concentrated in this fraction at 24 hours after administration. From these results it is concluded that the lysosome does not play an important role in the concentration of /sup 67/Ga in the tumor, but that the lysosome plays an important role in the concentration of /sup 67/Ga in the liver. In the case of hepatoma AH109A, it is presumed that the lysosome plays a very important role in the concentration of /sup 67/Ga in the tumor, hepatoma AH109A having some nature of liver.

  14. US-Cut: interactive algorithm for rapid detection and segmentation of liver tumors in ultrasound acquisitions

    Science.gov (United States)

    Egger, Jan; Voglreiter, Philip; Dokter, Mark; Hofmann, Michael; Chen, Xiaojun; Zoller, Wolfram G.; Schmalstieg, Dieter; Hann, Alexander

    2016-04-01

    Ultrasound (US) is the most commonly used liver imaging modality worldwide. It plays an important role in follow-up of cancer patients with liver metastases. We present an interactive segmentation approach for liver tumors in US acquisitions. Due to the low image quality and the low contrast between the tumors and the surrounding tissue in US images, the segmentation is very challenging. Thus, the clinical practice still relies on manual measurement and outlining of the tumors in the US images. We target this problem by applying an interactive segmentation algorithm to the US data, allowing the user to get real-time feedback of the segmentation results. The algorithm has been developed and tested hand-in-hand by physicians and computer scientists to make sure a future practical usage in a clinical setting is feasible. To cover typical acquisitions from the clinical routine, the approach has been evaluated with dozens of datasets where the tumors are hyperechoic (brighter), hypoechoic (darker) or isoechoic (similar) in comparison to the surrounding liver tissue. Due to the interactive real-time behavior of the approach, it was possible even in difficult cases to find satisfying segmentations of the tumors within seconds and without parameter settings, and the average tumor deviation was only 1.4mm compared with manual measurements. However, the long term goal is to ease the volumetric acquisition of liver tumors in order to evaluate for treatment response. Additional aim is the registration of intraoperative US images via the interactive segmentations to the patient's pre-interventional CT acquisitions.

  15. Solitary Fibrous Tumor in the Round Ligament of the Liver: A Fortunate Intraoperative Discovery

    Directory of Open Access Journals (Sweden)

    Laura Beyer

    2012-04-01

    Full Text Available Solitary fibrous tumors (SFTs are mesenchymal neoplasms of fibroblastic origin, most commonly found in the pleura. Numerous extrathoracic locations have been reported during the last 2 decades. Herein, we report the first case of an SFT in the round ligament of the liver. A 46-year-old Caucasian man presented with a 12-month history of abdominal pain. An ultrasonography-guided microbiopsy first revealed a desmoid tumor. After failure of first- and second-line medical treatments (celecoxib and tamoxifen, then imatinib, histological reexamination was suspicious for a low-grade sarcoma. MRI was also suspicious for a malignant process. Hence, surgery was decided. Laparotomy found a huge and well-limited tumor that, unexpectedly, was appended to the round ligament of the liver and free from any other intra-abdominal contact. The tumor was easily removed. Excision was monobloc and macroscopically complete. Histological analysis diagnosed an SFT arising from the round ligament of the liver. No adjuvant treatment was given. Ten months after surgery, the patient is alive without any signs or symptoms of relapse. This is the first report of SFT arising from the round ligament of the liver. It illustrates the difficulty in diagnosing such tumors. Whilst diagnosis of SFT is rare, it should be kept in mind to allow early diagnosis and complete surgical resection, which provide the best chance for recovery.

  16. Solitary fibrous tumor in the round ligament of the liver: a fortunate intraoperative discovery.

    Science.gov (United States)

    Beyer, Laura; Delpero, Jean-Robert; Chetaille, Bruno; Sarran, Anthony; Perrot, Delphine; Moureau-Zabotto, Laurence; Guiramand, Jérôme; Bertucci, François

    2012-01-01

    Solitary fibrous tumors (SFTs) are mesenchymal neoplasms of fibroblastic origin, most commonly found in the pleura. Numerous extrathoracic locations have been reported during the last 2 decades. Herein, we report the first case of an SFT in the round ligament of the liver. A 46-year-old Caucasian man presented with a 12-month history of abdominal pain. An ultrasonography-guided microbiopsy first revealed a desmoid tumor. After failure of first- and second-line medical treatments (celecoxib and tamoxifen, then imatinib), histological reexamination was suspicious for a low-grade sarcoma. MRI was also suspicious for a malignant process. Hence, surgery was decided. Laparotomy found a huge and well-limited tumor that, unexpectedly, was appended to the round ligament of the liver and free from any other intra-abdominal contact. The tumor was easily removed. Excision was monobloc and macroscopically complete. Histological analysis diagnosed an SFT arising from the round ligament of the liver. No adjuvant treatment was given. Ten months after surgery, the patient is alive without any signs or symptoms of relapse. This is the first report of SFT arising from the round ligament of the liver. It illustrates the difficulty in diagnosing such tumors. Whilst diagnosis of SFT is rare, it should be kept in mind to allow early diagnosis and complete surgical resection, which provide the best chance for recovery.

  17. Surgical treatment of a rare primary renal carcinoid tumor with liver metastasis

    Directory of Open Access Journals (Sweden)

    Rowland Randall G

    2008-04-01

    Full Text Available Abstract Background Carcinoid tumors are characteristically low grade malignant neoplasms with neuroendocrine differentiation that arise in various body sites, most commonly the lung and gastrointestinal tract, but less frequently the kidneys, breasts, ovaries, testes, prostate and other locations. We report a case of a carcinoid of renal origin with synchronous single liver metastases on radiological studies. Case presentation A 45 year-old patient who presented with abdominal pain was found on CT scan to have lesions in the right ovary, right kidney, and left hepatic lobe. CA-125, CEA, and CA 19-9 were within normal limits, as were preoperative liver function tests and renal function. Biopsy of the liver mass demonstrated metastatic neuroendocrine tumor. At laparotomy, the patient underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy, radical right nephrectomy with lymphadenectomy, and left hepatectomy. Pathology evaluation reported a right ovarian borderline serous tumor, well-differentiated neuroendocrine carcinoma of the kidney (carcinoid with 2 positive retroperitoneal lymph nodes, and a single liver metastasis. Immunohistochemistry revealed that this lesion was positive for synaptophysin and CD56, but negative for chromogranin as well as CD10, CD7, and CD20, consistent with a well-differentiated neuroendocrine tumor. She is doing well one year after her initial surgery, with no evidence of tumor recurrence. Conclusion Early surgical intervention, together with careful surveillance and follow-up, can achieve successful long-term outcomes in patients with this rare malignancy.

  18. Induction of rat liver tumor using the Sleeping Beauty transposon and electroporation.

    Science.gov (United States)

    Park, June-Shine; Kim, Bae-Hwan; Park, Sung Goo; Jung, Sun Young; Lee, Do Hee; Son, Woo-Chan

    2013-05-10

    The Sleeping Beauty (SB) transposon system has been receiving much attention as a gene transfer method of choice since it allows permanent gene expression after insertion into the host chromosome. However, low transposition frequency in higher eukaryotes limits its use in commonly-used mammalian species. Researchers have therefore attempted to modify gene delivery and expression to overcome this limitation. In mouse liver, tumor induction using SB introduced by the hydrodynamic method has been successfully accomplished. Liver tumor in rat models using SB could also be of great use; however, dose of DNA, injection volume, rate of injection and achieving back pressure limit the use of the hydrodynamics-based gene delivery. In the present study, we combined the electroporation, a relatively simple and easy gene delivery method, with the SB transposon system and as a result successfully induced tumor in rat liver by directly injecting the c-Myc, HRAS and shp53 genes. The tumor phenotype was determined as a sarcomatoid carcinoma. To our knowledge, this is the first demonstration of induction of tumor in the rat liver using the electroporation-enhanced SB transposon system. Copyright © 2013 Elsevier Inc. All rights reserved.

  19. Antituberculosis Drug-Induced Liver Injury with Autoimmune Features: Facing Diagnostic and Treatment Challenges

    Directory of Open Access Journals (Sweden)

    Maria Adriana Rangel

    2017-01-01

    Full Text Available The authors present a case report of antituberculosis drug-induced liver injury that offered diagnostic challenges (namely, the possibility of drug-induced autoimmune hepatitis and treatment difficulties.

  20. Factors affecting drug-induced liver injury: antithyroid drugs as instances

    Directory of Open Access Journals (Sweden)

    Reza Heidari

    2014-09-01

    Full Text Available Methimazole and propylthiouracil have been used in the management of hyperthyroidism for more than half a century. However, hepatotoxicity is one of the most deleterious side effects associated with these medications. The mechanism(s of hepatic injury induced by antithyroid agents is not fully recognized yet. Furthermore, there are no specific tools for predicting the occurrence of hepatotoxicity induced by these drugs. The purpose of this article is to give an overview on possible susceptibility factors in liver injury induced by antithyroid agents. Age, gender, metabolism characteristics, alcohol consumption, underlying diseases, immunologic mechanisms, and drug interactions are involved in enhancing antithyroid drugs-induced hepatic damage. An outline on the clinically used treatments for antithyroid drugs-induced hepatotoxicity and the potential therapeutic strategies found to be effective against this complication are also discussed.

  1. Tumor Targeting and Drug Delivery by Anthrax Toxin

    Directory of Open Access Journals (Sweden)

    Christopher Bachran

    2016-07-01

    Full Text Available Anthrax toxin is a potent tripartite protein toxin from Bacillus anthracis. It is one of the two virulence factors and causes the disease anthrax. The receptor-binding component of the toxin, protective antigen, needs to be cleaved by furin-like proteases to be activated and to deliver the enzymatic moieties lethal factor and edema factor to the cytosol of cells. Alteration of the protease cleavage site allows the activation of the toxin selectively in response to the presence of tumor-associated proteases. This initial idea of re-targeting anthrax toxin to tumor cells was further elaborated in recent years and resulted in the design of many modifications of anthrax toxin, which resulted in successful tumor therapy in animal models. These modifications include the combination of different toxin variants that require activation by two different tumor-associated proteases for increased specificity of toxin activation. The anthrax toxin system has proved to be a versatile system for drug delivery of several enzymatic moieties into cells. This highly efficient delivery system has recently been further modified by introducing ubiquitin as a cytosolic cleavage site into lethal factor fusion proteins. This review article describes the latest developments in this field of tumor targeting and drug delivery.

  2. Tumor Targeting and Drug Delivery by Anthrax Toxin.

    Science.gov (United States)

    Bachran, Christopher; Leppla, Stephen H

    2016-07-01

    Anthrax toxin is a potent tripartite protein toxin from Bacillus anthracis. It is one of the two virulence factors and causes the disease anthrax. The receptor-binding component of the toxin, protective antigen, needs to be cleaved by furin-like proteases to be activated and to deliver the enzymatic moieties lethal factor and edema factor to the cytosol of cells. Alteration of the protease cleavage site allows the activation of the toxin selectively in response to the presence of tumor-associated proteases. This initial idea of re-targeting anthrax toxin to tumor cells was further elaborated in recent years and resulted in the design of many modifications of anthrax toxin, which resulted in successful tumor therapy in animal models. These modifications include the combination of different toxin variants that require activation by two different tumor-associated proteases for increased specificity of toxin activation. The anthrax toxin system has proved to be a versatile system for drug delivery of several enzymatic moieties into cells. This highly efficient delivery system has recently been further modified by introducing ubiquitin as a cytosolic cleavage site into lethal factor fusion proteins. This review article describes the latest developments in this field of tumor targeting and drug delivery.

  3. Agressive inflammatory myofibroblastic tumor of the liver with underlying schistosomiasis: a case report.

    Science.gov (United States)

    Pannain, Vera Lucia; Passos, Juliana Vial; Rocha Filho, Ariovaldo; Villela-Nogueira, Cristiane; Caroli-Bottino, Adriana

    2010-09-07

    Inflammatory myofibroblastic tumor (IMT) occurs infrequently in the liver. It is controversial whether it represents a low grade mesenchymal neoplasm or a reactive inflammatory lesion. Local recurrence and metastasis are rare and some tumors are associated with infectious agents. We report on a case of a large and partially resected IMT with local recurrence and diaphragm and kidney infiltration detected on routine surveillance two years later. Histologically, the tumor showed spindle cells without atypia, mitosis or necrotic areas in a myxoid and collagenized background with inflammatory cells. In the liver portal tracts, granulomatous lesions with viable eggs of Schistosoma mansoni were identified. Immunohistochemistry demonstrated spindle cells which were smooth-muscle actin and vimentin positive. In conclusion, this case points out that these histological patterns do not predict the aggressive biological behavior of the lesion. A reason for the recurrence and the infiltration may be incomplete tumor resection. Further investigation is necessary in order to better clarify an infectious cause in some IMTs.

  4. Usefulness of superparamagnetic iron oxide particle (AMI-25) enhanced MR imaging for the diagnosis of liver tumors

    International Nuclear Information System (INIS)

    Hirohashi, Shinji; Hirohashi, Rina; Uchida, Hideo; Kachi, Kenji; Ohtomo, Kuni; Uchiyama, Gyou; Niitsu, Mamoru; Itai, Yuji.

    1994-01-01

    The purpose of this study was to clarify the usefulness of SPIO-enhanced MRI in the diagnosis of liver tumors in comparison with contrast enhanced CT. The subjects were forty patients with 154 nodules in the liver. We compared SPIO-enhanced MRI with contrast-enhanced CT in terms of tumor-liver contrast and detectability of liver tumors. In terms of tumor liver contrast, SPIO-enhanced MRI was equal or superior to contrast-enhanced CT in 82% of cases. In the detectability of liver tumor, SPIO-enhanced MRI detected more tumors than contrast-enhanced CT, especially small tumors. Tumors undetected by SPIO-enhanced MRI that were detected by contrast-enhanced CT and/or plain MRI were adenomatous hyperplasia and inflammatory pseudotumor according to fine needle biopsy. There were no severe complications of SPIO-enhanced MRI. In conclusion, SPIO-enhanced MRI will be more useful than contrast-enhanced CT in the diagnosis of liver tumors. SPIO-enhanced MRI may be a promising diagnostic method for the detection of hepatic tumors, especially small ones. (author)

  5. Interaction of Drug or Food with Drug Transporters in Intestine and Liver.

    Science.gov (United States)

    Nakanishi, Takeo; Tamai, Ikumi

    2015-01-01

    Oral bioavailability (F) is determined as fraction of the drug dose absorbed through the gastrointestinal membranes (Fa), the unmetabolized fraction of the absorbed dose that passes through the gut into the portal blood (Fg), and the hepatic first pass availability (Fh), namely F is expressed as the product of Fa, Fg and Fh (F = Fa.Fg.Fh). Current evidence suggests that transporter proteins play a role in intestinal absorption and hepatobiliary clearance of drugs. Among those transporters, this review will focus on PEPT1 and OATP2B1 as influx transporter and p-glycoprotein (P-gp) and BCRP as efflux transporter in intestinal epithelial cells, and on OATP1B1 and 1B3 as influx transporter and MRP2 as efflux transporter in hepatocytes, respectively, because drug-drug (DDI) and -food (DFI) interactions on these transporter are considered to affect bioavailability of their substrate drugs. DDI and DFI may reduce systemic exposure to drug by blocking influx transporters in intestine, but increase it by modulating influx and efflux transporters in liver and efflux transporters in intestines. Namely, drug disposition and efficacy are likely affected by DDI and DFI, resulting in treatment failures or increase in adverse effect. Therefore, it is of significantly importance to understand precise mechanism of DDI and DFI. This review will present information about transporter-based DDI and DFI in the processes of intestinal absorption and hepatic clearance of drugs, and discuss about their clinical implication.

  6. Computer-aided diagnosis of liver tumors on computed tomography images.

    Science.gov (United States)

    Chang, Chin-Chen; Chen, Hong-Hao; Chang, Yeun-Chung; Yang, Ming-Yang; Lo, Chung-Ming; Ko, Wei-Chun; Lee, Yee-Fan; Liu, Kao-Lang; Chang, Ruey-Feng

    2017-07-01

    Liver cancer is the tenth most common cancer in the USA, and its incidence has been increasing for several decades. Early detection, diagnosis, and treatment of the disease are very important. Computed tomography (CT) is one of the most common and robust imaging techniques for the detection of liver cancer. CT scanners can provide multiple-phase sequential scans of the whole liver. In this study, we proposed a computer-aided diagnosis (CAD) system to diagnose liver cancer using the features of tumors obtained from multiphase CT images. A total of 71 histologically-proven liver tumors including 49 benign and 22 malignant lesions were evaluated with the proposed CAD system to evaluate its performance. Tumors were identified by the user and then segmented using a region growing algorithm. After tumor segmentation, three kinds of features were obtained for each tumor, including texture, shape, and kinetic curve. The texture was quantified using 3 dimensional (3-D) texture data of the tumor based on the grey level co-occurrence matrix (GLCM). Compactness, margin, and an elliptic model were used to describe the 3-D shape of the tumor. The kinetic curve was established from each phase of tumor and represented as variations in density between each phase. Backward elimination was used to select the best combination of features, and binary logistic regression analysis was used to classify the tumors with leave-one-out cross validation. The accuracy and sensitivity for the texture were 71.82% and 68.18%, respectively, which were better than for the shape and kinetic curve under closed specificity. Combining all of the features achieved the highest accuracy (58/71, 81.69%), sensitivity (18/22, 81.82%), and specificity (40/49, 81.63%). The Az value of combining all features was 0.8713. Combining texture, shape, and kinetic curve features may be able to differentiate benign from malignant tumors in the liver using our proposed CAD system. Copyright © 2017 Elsevier B.V. All

  7. Image-Based Monitoring of Magnetic Resonance-Guided Thermoablative Therapies for Liver Tumors

    Energy Technology Data Exchange (ETDEWEB)

    Rempp, Hansjoerg, E-mail: hansjoerg.rempp@med.uni-tuebingen.de; Clasen, Stephan [Eberhard Karls University of Tuebingen, Department of Diagnostic and Interventional Radiology (Germany); Pereira, Philippe L. [SLK-Kliniken, Clinic for Radiology, Nuclear Medicine, and Minimal Invasive Therapies (Germany)

    2012-12-15

    Minimally invasive treatment options for liver tumor therapy have been increasingly used during the last decade because their benefit has been proven for primary and inoperable secondary liver tumors. Among these, radiofrequency ablation has gained widespread consideration. Optimal image-guidance offers precise anatomical information, helps to position interventional devices, and allows for differentiation between already-treated and remaining tumor tissue. Patient safety and complete ablation of the entire tumor are the overriding objectives of tumor ablation. These may be achieved most elegantly with magnetic resonance (MR)-guided therapy, where monitoring can be performed based on precise soft-tissue imaging and additional components, such as diffusion-weighted imaging and temperature mapping. New MR scanner types and newly developed sequence techniques have enabled MR-guided intervention to move beyond the experimental phase. This article reviews the current role of MR imaging in guiding radiofrequency ablation. Signal characteristics of primary and secondary liver tumors are identified, and signal alteration during therapy is described. Diffusion-weighted imaging (DWI) and temperature mapping as special components of MR therapy monitoring are introduced. Practical information concerning coils, sequence selection, and parameters, as well as sequence gating, is given. In addition, sources of artifacts are identified and techniques to decrease them are introduced, and the characteristic signs of residual tumor in T1-, T2-, and DWI are described. We hope to enable the reader to choose MR sequences that allow optimal therapy monitoring depending on the initial signal characteristics of the tumor as well as its size and location in the liver.

  8. Image-Based Monitoring of Magnetic Resonance-Guided Thermoablative Therapies for Liver Tumors

    International Nuclear Information System (INIS)

    Rempp, Hansjörg; Clasen, Stephan; Pereira, Philippe L.

    2012-01-01

    Minimally invasive treatment options for liver tumor therapy have been increasingly used during the last decade because their benefit has been proven for primary and inoperable secondary liver tumors. Among these, radiofrequency ablation has gained widespread consideration. Optimal image-guidance offers precise anatomical information, helps to position interventional devices, and allows for differentiation between already-treated and remaining tumor tissue. Patient safety and complete ablation of the entire tumor are the overriding objectives of tumor ablation. These may be achieved most elegantly with magnetic resonance (MR)-guided therapy, where monitoring can be performed based on precise soft-tissue imaging and additional components, such as diffusion-weighted imaging and temperature mapping. New MR scanner types and newly developed sequence techniques have enabled MR-guided intervention to move beyond the experimental phase. This article reviews the current role of MR imaging in guiding radiofrequency ablation. Signal characteristics of primary and secondary liver tumors are identified, and signal alteration during therapy is described. Diffusion-weighted imaging (DWI) and temperature mapping as special components of MR therapy monitoring are introduced. Practical information concerning coils, sequence selection, and parameters, as well as sequence gating, is given. In addition, sources of artifacts are identified and techniques to decrease them are introduced, and the characteristic signs of residual tumor in T1-, T2-, and DWI are described. We hope to enable the reader to choose MR sequences that allow optimal therapy monitoring depending on the initial signal characteristics of the tumor as well as its size and location in the liver.

  9. Poly(γ-glutamic acid)-coated lipoplexes loaded with Doxorubicin for enhancing the antitumor activity against liver tumors

    Science.gov (United States)

    Qi, Na; Tang, Bo; Liu, Guang; Liang, Xingsi

    2017-05-01

    The study was to develop poly-γ-glutamic acid (γ-PGA)-coated Doxorubicin (Dox) lipoplexes that enhance the antitumor activity against liver tumors. γ-PGA-coated lipoplexes were performed by electrostatistically attracting to the surface of cationic charge liposomes with anionic γ-PGA. With the increasing of γ-PGA concentration, the particle size of γ-PGA-coated Dox lipoplexes slightly increased, the zeta potential from positive shifted to negative, and the entrapment efficiency (EE) were no significant change. The release rate of γ-PGA-coated Dox lipoplexes slightly increased at acidic pH, the accelerated Dox release might be attributed to greater drug delivery to tumor cells, resulting in a higher antitumor activity. Especially, γ-PGA-coated Dox lipoplexes exhibited higher cellular uptake, significant in vitro cytotoxicity in HepG2 cells, and improved in vivo antitumor efficacy toward HepG2 hepatoma-xenografted nude models in comparison with Dox liposomes and free Dox solution. In addition, the analysis results via flow cytometry showed that γ-PGA-coated Dox lipoplexes induce S phase cell cycle arrest and significantly increased apoptosis rate of HepG2 cells. In conclusion, the presence of γ-PGA on the surface of Dox lipoplexes enhanced antitumor effects of liver tumors.

  10. Pharmacokinetics and Histopathological Findings of Chemoembolization Using Cisplatin Powder Mixed with Degradable Starch Microspheres in a Rabbit Liver Tumor Model

    Energy Technology Data Exchange (ETDEWEB)

    Sato, Takeshi; Tanaka, Toshihiro, E-mail: toshihir@bf6.so-net.ne.jp; Nishiofuku, Hideyuki; Fukuoka, Yasushi [IVR CenterNara Medical University, Department of Radiology (Japan); Sakaguchi, Hiroshi [South Nara General Medical Center, Department of Radiology (Japan); Masada, Tetsuya; Tatsumoto, Shota [IVR CenterNara Medical University, Department of Radiology (Japan); Marugami, Nagaaki [Diagnostic Imaging Center, Department of Radiology (Japan); Takano, Masato [Nara Medical University, Department of Diagnostic Pathology (Japan); Yamato, Ichiro; Sho, Masayuki [Nara Medical University, Department of Surgery (Japan); Ohbayashi, Chiho [Nara Medical University, Department of Diagnostic Pathology (Japan); Hirai, Toshiko [Diagnostic Imaging Center, Department of Radiology (Japan); Kichikawa, Kimihiko [IVR CenterNara Medical University, Department of Radiology (Japan)

    2017-03-15

    PurposeThe purpose of this study is to evaluate the pharmacokinetics and histopathological findings of transarterial chemoembolization (TACE) using cisplatin powder mixed with degradable starch microspheres (DSM) (Cis/DSM-TACE) compared with cisplatin arterial infusion (Cis-AI).Materials and MethodsEighteen rabbits with VX2 liver tumors were divided into two groups: Cis/DSM-TACE (n = 9) and Cis-AI (n = 9) groups. In the Cis/DSM-TACE group, a mixture of cisplatin powder and DSM was injected until stasis of hepatic arterial flow was achieved. In the Cis-AI group, cisplatin solution was infused.ResultsThe platinum concentrations in VX2 tumors in the Cis/DSM-TACE group at 24 and 72 h were significantly elevated compared with those in the Cis-AI group (P = .016 and .019, respectively). There were no significant differences in the platinum concentrations in plasma. Histopathological examination revealed the presence of several microspheres inside the tumors at 1 h, which completely disappeared at 24 h. Tumor cell apoptosis at 1 h in the Cis/DSM-TACE group was more frequently observed compared with that in the Cis-AI group (P = .006).ConclusionsTACE using cisplatin powder mixed with DSM provides a higher drug concentration in tumors, thereby achieving stronger antitumor effects compared with arterial infusion of cisplatin solution.

  11. Pharmacokinetics and Histopathological Findings of Chemoembolization Using Cisplatin Powder Mixed with Degradable Starch Microspheres in a Rabbit Liver Tumor Model

    International Nuclear Information System (INIS)

    Sato, Takeshi; Tanaka, Toshihiro; Nishiofuku, Hideyuki; Fukuoka, Yasushi; Sakaguchi, Hiroshi; Masada, Tetsuya; Tatsumoto, Shota; Marugami, Nagaaki; Takano, Masato; Yamato, Ichiro; Sho, Masayuki; Ohbayashi, Chiho; Hirai, Toshiko; Kichikawa, Kimihiko

    2017-01-01

    PurposeThe purpose of this study is to evaluate the pharmacokinetics and histopathological findings of transarterial chemoembolization (TACE) using cisplatin powder mixed with degradable starch microspheres (DSM) (Cis/DSM-TACE) compared with cisplatin arterial infusion (Cis-AI).Materials and MethodsEighteen rabbits with VX2 liver tumors were divided into two groups: Cis/DSM-TACE (n = 9) and Cis-AI (n = 9) groups. In the Cis/DSM-TACE group, a mixture of cisplatin powder and DSM was injected until stasis of hepatic arterial flow was achieved. In the Cis-AI group, cisplatin solution was infused.ResultsThe platinum concentrations in VX2 tumors in the Cis/DSM-TACE group at 24 and 72 h were significantly elevated compared with those in the Cis-AI group (P = .016 and .019, respectively). There were no significant differences in the platinum concentrations in plasma. Histopathological examination revealed the presence of several microspheres inside the tumors at 1 h, which completely disappeared at 24 h. Tumor cell apoptosis at 1 h in the Cis/DSM-TACE group was more frequently observed compared with that in the Cis-AI group (P = .006).ConclusionsTACE using cisplatin powder mixed with DSM provides a higher drug concentration in tumors, thereby achieving stronger antitumor effects compared with arterial infusion of cisplatin solution.

  12. New approach for high-throughput screening of drug activity on Plasmodium liver stages.

    NARCIS (Netherlands)

    Gego, A.; Silvie, O.; Franetich, J.F.; Farhati, K.; Hannoun, L.; Luty, A.J.F.; Sauerwein, R.W.; Boucheix, C.; Rubinstein, E.; Mazier, D.

    2006-01-01

    Plasmodium liver stages represent potential targets for antimalarial prophylactic drugs. Nevertheless, there is a lack of molecules active on these stages. We have now developed a new approach for the high-throughput screening of drug activity on Plasmodium liver stages in vitro, based on an

  13. Study of subcellular distribution of /sup 169/Yb and /sup 111/In in tumor and liver

    Energy Technology Data Exchange (ETDEWEB)

    Ando, A; Takeshita, M; Hiraki, T [Kanazawa Univ. (Japan). School of Paramedicine; Ando, Itsuko; Hisada, Kinichi

    1977-03-01

    Rats were implanted with Yoshida sarcoma and hepatoma AH109A; and mice were implanted with Ehrlich tumor. /sup 169/Yb-citrate and /sup 111/In-citrate were injected into the rats intravenously and into the mice intraperitoneally. Ten minutes to 48 hours after the administration of /sup 169/Yb-citrate and /sup 111/In-citrate, the animals were sacrificed and the tumor tissues and liver were excised. Subcellular fractionation of tumor tissues and liver was carried out according to the method of Hogeboom and Schneider. The /sup 169/Yb and /sup 111/In of each fraction were counted by a well type scintillation counter, and the protein of each fraction was measured according to Lowry's method. In Yoshida sarcoma and Ehrlich tumor, most of the radioactivity was localized in the supernatant fraction, and a small amount of radioactivity was accumulated in the mitochondrial fraction (lysosome is contained in this fraction). But, in the liver, most of the radioactivity was concentrated in the mitochondrial fraction, and the radioactivity of this fraction was increased with the passage of time after administration. Twenty-four hours later, about 50% of the total radioactivity was accumulated in this fraction. In the case of hepatoma AH109A, radioactivity of the mitochondrial fraction was increased with time after administration, and about 30% of total radioactivity was concentrated in this fraction 24 hours after administration. From these results it is concluded that the lysosome does not play an important role in the concentration of /sup 169/Yb and /sup 111/In in the tumor, and that the lysosome plays an important role in the concentration of /sup 169/Yb and /sup 111/In in the liver. In the case of hepatoma AH109A it is presumed that the lysosome plays a very important role in the concentration of /sup 169/Yb and /sup 111/In, in the tumor as hepatoma AH109A retains some nature of liver.

  14. Withaferin A Suppresses Liver Tumor Growth in a Nude Mouse ...

    African Journals Online (AJOL)

    tumor cell invasiveness in colon cancer [7] and is related to angiogenesis in ... Hsp90, phosphorylated STAT3 and annexin II. [18,20-24]. ..... Herbstritt CJ, Ruiz A, Zhang L, Hanson AD, Conner. BP, Rougas J, Pribluda VS. Withaferin A is a ...

  15. Stereotactic body radiotherapy for liver tumors. Principles and practical guidelines of the DEGRO Working Group on Stereotactic Radiotherapy

    International Nuclear Information System (INIS)

    Sterzing, Florian; Brunner, Thomas B.; Ernst, Iris; Greve, Burkhard; Baus, Wolfgang W.; Herfarth, Klaus; Guckenberger, Matthias

    2014-01-01

    This report of the Working Group on Stereotactic Radiotherapy of the German Society of Radiation Oncology (DEGRO) aims to provide a practical guideline for safe and effective stereotactic body radiotherapy (SBRT) of liver tumors. The literature on the clinical evidence of SBRT for both primary liver tumors and liver metastases was reviewed and analyzed focusing on both physical requirements and special biological characteristics. Recommendations were developed for patient selection, imaging, planning, treatment delivery, motion management, dose reporting, and follow-up. Radiation dose constraints to critical organs at risk are provided. SBRT is a well-established treatment option for primary and secondary liver tumors associated with low morbidity. (orig.) [de

  16. HPMA Copolymer-Drug Conjugates with Controlled Tumor-Specific Drug Release.

    Science.gov (United States)

    Chytil, Petr; Koziolová, Eva; Etrych, Tomáš; Ulbrich, Karel

    2018-01-01

    Over the past few decades, numerous polymer drug carrier systems are designed and synthesized, and their properties are evaluated. Many of these systems are based on water-soluble polymer carriers of low-molecular-weight drugs and compounds, e.g., cytostatic agents, anti-inflammatory drugs, or multidrug resistance inhibitors, all covalently bound to a carrier by a biodegradable spacer that enables controlled release of the active molecule to achieve the desired pharmacological effect. Among others, the synthetic polymer carriers based on N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers are some of the most promising carriers for this purpose. This review focuses on advances in the development of HPMA copolymer carriers and their conjugates with anticancer drugs, with triggered drug activation in tumor tissue and especially in tumor cells. Specifically, this review highlights the improvements in polymer drug carrier design with respect to the structure of a spacer to influence controlled drug release and activation, and its impact on the drug pharmacokinetics, enhanced tumor uptake, cellular trafficking, and in vivo antitumor activity. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  17. Extended diagnosis of liver tumor with gadolinium DTPA supplementary to routine procedure in nuclear medicine

    International Nuclear Information System (INIS)

    Ehrenheim, C.; Heintz, P.; Schwarzrock, R.; Schober, O.; Hundeshagen, H.

    1988-01-01

    Several imaging methods and especially their combined application are proven to be useful in the diagnosis and differentiation of liver tumors: Ultrasound, roentgen computed tomography, sequential hepatobiliary scintigraphy (HBSS), blood pool scintigraphy and magnetic resonance imaging. 38 patients with liver tumors (hemangioma, hepatocellular carcinoma, focal nodular hyperplasia) underwent MRI of the liver before and after i.v. injection of 0.2 mmol/kg Gadolinium-DTPA in addition to other imaging methods. Written informed consent we achieved in all cases. The normal and pathological findings in MRI were documented in T1- and T2-weighted images, proton density image, calculated T1- and T2-images and a T1-weighted image after application of the contrast agent. The application of Gadolinium-DTPA as contrast agent improves the delimitation of the most intrahepatic lesions. Concerning the hemangiomas of the liver the improved contrast behaviour induced by Gadolinium-DTPA does not reach the contrast and sensitivity of a native T2-weighted SE image. The demarcation of focal nodular hyperplasia is not improved by use of the contrast agent. This finding supports the assumption that the FNH is not basically different from normal liver tissue. Gadolinium-DTPA provides additional information concerning the delineation of internal tumor details in hepatocellular carcinoma (hyperperfused areas, necroses, fibrous capsular structures). (orig.)

  18. p53-Dependent Nestin Regulation Links Tumor Suppression to Cellular Plasticity in Liver Cancer

    DEFF Research Database (Denmark)

    Tschaharganeh, Darjus F; Xue, Wen; Calvisi, Diego F

    2014-01-01

    The p53 tumor suppressor coordinates a series of antiproliferative responses that restrict the expansion of malignant cells, and as a consequence, p53 is lost or mutated in the majority of human cancers. Here, we show that p53 restricts expression of the stem and progenitor-cell-associated protei...... by p53 restricts cellular plasticity and tumorigenesis in liver cancer....

  19. A high content screening assay to predict human drug-induced liver injury during drug discovery.

    Science.gov (United States)

    Persson, Mikael; Løye, Anni F; Mow, Tomas; Hornberg, Jorrit J

    2013-01-01

    Adverse drug reactions are a major cause for failures of drug development programs, drug withdrawals and use restrictions. Early hazard identification and diligent risk avoidance strategies are therefore essential. For drug-induced liver injury (DILI), this is difficult using conventional safety testing. To reduce the risk for DILI, drug candidates with a high risk need to be identified and deselected. And, to produce drug candidates without that risk associated, risk factors need to be assessed early during drug discovery, such that lead series can be optimized on safety parameters. This requires methods that allow for medium-to-high throughput compound profiling and that generate quantitative results suitable to establish structure-activity-relationships during lead optimization programs. We present the validation of such a method, a novel high content screening assay based on six parameters (nuclei counts, nuclear area, plasma membrane integrity, lysosomal activity, mitochondrial membrane potential (MMP), and mitochondrial area) using ~100 drugs of which the clinical hepatotoxicity profile is known. We find that a 100-fold TI between the lowest toxic concentration and the therapeutic Cmax is optimal to classify compounds as hepatotoxic or non-hepatotoxic, based on the individual parameters. Most parameters have ~50% sensitivity and ~90% specificity. Drugs hitting ≥2 parameters at a concentration below 100-fold their Cmax are typically hepatotoxic, whereas non-hepatotoxic drugs typically hit based on nuclei count, MMP and human Cmax, we identified an area without a single false positive, while maintaining 45% sensitivity. Hierarchical clustering using the multi-parametric dataset roughly separates toxic from non-toxic compounds. We employ the assay in discovery projects to prioritize novel compound series during hit-to-lead, to steer away from a DILI risk during lead optimization, for risk assessment towards candidate selection and to provide guidance of safe

  20. Role of Interleukin-6 in the Radiation Response of Liver Tumors

    International Nuclear Information System (INIS)

    Chen, Miao-Fen; Hsieh, Ching-Chuan; Chen, Wen-Cheng; Lai, Chia-Hsuan

    2012-01-01

    Purpose: To investigate the role of interleukin (IL)-6 in biological sequelae and tumor regrowth after irradiation for hepatic malignancy, which are critical for the clinical radiation response of liver tumors. Methods and Materials: The Hepa 1-6 murine hepatocellular cancer cell line was used to examine the radiation response by clonogenic assays and tumor growth delay in vivo. After irradiation in a single dose of 6 Gy in vitro or 15 Gy in vivo, biological changes including cell death and tumor regrowth were examined by experimental manipulation of IL-6 signaling. The effects of blocking IL-6 were assessed by cells preincubated in the presence of IL-6–neutralizing antibody for 24 hours or stably transfected with IL-6–silencing vectors. The correlations among tumor responses, IL-6 levels, and myeloid-derived suppressor cells (MDSC) recruitment were examined using animal experiments. Results: Interleukin-6 expression was positively linked to irradiation and radiation resistance, as demonstrated by in vitro and in vivo experiments. Interleukin-6–silencing vectors induced more tumor inhibition and DNA damage after irradiation. When subjects were irradiated with a sublethal dose, the regrowth of irradiated tumors significantly correlated with IL-6 levels and MDSC recruitment in vivo. Furthermore, blocking of IL-6 could overcome irradiation-induced MDSC recruitment and tumor regrowth after treatment. Conclusion: These data demonstrate that IL-6 is important in determining the radiation response of liver tumor cells. Irradiation-induced IL-6 and the subsequent recruitment of MDSC could be responsible for tumor regrowth. Therefore, treatment with concurrent IL-6 inhibition could be a potential therapeutic strategy for increasing the radiation response of tumors.

  1. Small heterodimer partner overexpression partially protects against liver tumor development in farnesoid X receptor knockout mice

    International Nuclear Information System (INIS)

    Li, Guodong; Kong, Bo; Zhu, Yan; Zhan, Le; Williams, Jessica A.; Tawfik, Ossama; Kassel, Karen M.; Luyendyk, James P.; Wang, Li; Guo, Grace L.

    2013-01-01

    Farnesoid X receptor (FXR, Nr1h4) and small heterodimer partner (SHP, Nr0b2) are nuclear receptors that are critical to liver homeostasis. Induction of SHP serves as a major mechanism of FXR in suppressing gene expression. Both FXR −/− and SHP −/− mice develop spontaneous hepatocellular carcinoma (HCC). SHP is one of the most strongly induced genes by FXR in the liver and is a tumor suppressor, therefore, we hypothesized that deficiency of SHP contributes to HCC development in the livers of FXR −/− mice and therefore, increased SHP expression in FXR −/− mice reduces liver tumorigenesis. To test this hypothesis, we generated FXR −/− mice with overexpression of SHP in hepatocytes (FXR −/− /SHP Tg ) and determined the contribution of SHP in HCC development in FXR −/− mice. Hepatocyte-specific SHP overexpression did not affect liver tumor incidence or size in FXR −/− mice. However, SHP overexpression led to a lower grade of dysplasia, reduced indicator cell proliferation and increased apoptosis. All tumor-bearing mice had increased serum bile acid levels and IL-6 levels, which was associated with activation of hepatic STAT3. In conclusion, SHP partially protects FXR −/− mice from HCC formation by reducing tumor malignancy. However, disrupted bile acid homeostasis by FXR deficiency leads to inflammation and injury, which ultimately results in uncontrolled cell proliferation and tumorigenesis in the liver. - Highlights: • SHP does not prevent HCC incidence nor size in FXR KO mice but reduces malignancy. • Increased SHP promotes apoptosis. • Bile acids and inflammation maybe critical for HCC formation with FXR deficiency

  2. MiRNA-21 Expression Decreases from Primary Tumors to Liver Metastases in Colorectal Carcinoma.

    Directory of Open Access Journals (Sweden)

    Fabian Feiersinger

    Full Text Available Metastasis is the major cause of death in colorectal cancer patients. Expression of certain miRNAs in the primary tumors has been shown to be associated with progression of colorectal cancer and the initiation of metastasis. In this study, we compared miRNA expression in primary colorectal cancer and corresponding liver metastases in order to get an idea of the oncogenic importance of the miRNAs in established metastases.We analyzed the expression of miRNA-21, miRNA-31 and miRNA-373 in corresponding formalin-fixed paraffin-embedded (FFPE tissue samples of primary colorectal cancer, liver metastasis and healthy tissues of 29 patients by quantitative real-time PCR.All three miRNAs were significantly up-regulated in the primary tumor tissues as compared to healthy colon mucosa of the respective patients (p < 0.01. MiRNA-21 and miRNA-31 were also higher expressed in liver metastases as compared to healthy liver tissues (p < 0.01. No significant difference of expression of miRNA-31 and miRNA-373 was observed between primary tumors and metastases. Of note, miRNA-21 expression was significantly reduced in liver metastases as compared to the primary colorectal tumors (p < 0.01.In the context of previous studies demonstrating increased miRNA-21 expression in metastatic primary tumors, our findings raise the question whether miRNA-21 might be involved in the initiation but not in the perpetuation and growth of metastases.

  3. Wavelets in quantification of liver tumors in contrasted computed tomography images; Wavelets na quantificacao de tumores de figado em exames contrastados de tomografia computadorizada

    Energy Technology Data Exchange (ETDEWEB)

    Rodrigues, Bruna T.; Alvarez, Matheus; Souza, Rafael T.F.; Miranda, Jose R.A., E-mail: matheus@ibb.unesp.br [Universidade Estadual Paulista Julio de Mesquita Filho (UNESP), Botucatu, SP (Brazil). Instituto de Biociencias. Departamento de Fisica e Biofisica; Romeiro, Fernando G. [Universidade Estadual Paulista Julio de Mesquita Filho (UNESP), Botucatu, SP (Brazil). Fac de Mediciana. Departamento de Clinica Medica; Pina, Diana R. de; Trindade, Andre Petean [Universidade Estadual Paulista Julio de Mesquita Filho (UNESP), Botucatu, SP (Brazil). Fac. de Medicina. Departamento de Doencas Tropicais e Diagnostico por Imagem

    2012-12-15

    This paper presents an original methodology of liver tumors segmentation, based on wavelet transform. A virtual phantom was constructed with the same mean and standard deviation of the intensity of gray presented by the measured liver tissue. The optimized algorithm had a sensitivity ranging from 0.81 to 0.83, with a specificity of 0.95 for differentiation of hepatic tumors from normal tissues. We obtained a 96% agreement between the pixels segmented by an experienced radiologist and the algorithm presented here. According to the results shown in this work, the algorithm is optimal for the beginning of the tests for quantification of liver tumors in retrospective surveys. (author)

  4. Essentials in clinical application of p53 for tumors intervention-example of liver cancer

    International Nuclear Information System (INIS)

    Guan Yongsong; He Qing

    2008-01-01

    Recombinant human adenovirus p53 (Ad-p53)injection has been used for treating tumors in combination with several local therapeutic methods. Taking liver cancer as an example, this article introduces the combination of Ad-p53 in procedures of interventional therapy. Mechanisms of their effects are emphasized to pursue an optimal synergism in killing tumors. Intratumoral injection is suggested as the first choice of Ad- p53 administration with the least recommended dosage for a single tumor. The optimal time for intervention of liver cancer is supposed to be 2 to 5 days after the administration of Ad-p53. There are several theories on the therapeutic method taking p53 as a target, some of them are contradictional; therefore one has to select either activating or inhibiting the p53 pathway beforehand. For advanced malignancies, the selection should be cautious for appropriater cases from the proper candidates. (authors)

  5. Comparison of fundamental and wideband harmonic contrast imaging of liver tumors.

    Science.gov (United States)

    Forsberg, F; Liu, J B; Chiou, H J; Rawool, N M; Parker, L; Goldberg, B B

    2000-03-01

    Wideband harmonic imaging (with phase inversion for improved tissue suppression) was compared to fundamental imaging in vivo. Four woodchucks with naturally occurring liver tumors were injected with Imagent (Alliance Pharmaceutical Corp., San Diego, CA). Randomized combinations of dose (0.05, 0.2 and 0.4 ml/kg) and acoustic output power (AO; 5, 25 and 63% or MI Siemens Medical Systems, Issaquah, WA). Tumor vascularity, conspicuity and contrast enhancement were rated by three independent observers. Imagent produced marked tumor enhancement and improved depiction of neovascularity at all dosages and AO settings in both modes. Tumor vascularity and enhancement correlated with mode, dose and AO (P < 0.002). Fundamental imaging produced more enhancement (P < 0.05), but tumor vascularity and conspicuity were best appreciated in harmonic mode (P < 0.05). Under the conditions studied here, the best approach was wideband harmonic imaging with 0.2 ml/kg of Imagent at an AO of 25%.

  6. Mechanism of tumor and liver concentration of /sup 111/In and /sup 169/Yb: /sup 111/In and /sup 169/Yb binding substances in tumor tissues and liver

    Energy Technology Data Exchange (ETDEWEB)

    Ando, A; Ando, I; Hiraki, T; Takeshita, M; Hisada, K

    1982-07-01

    Tumor-bearing animals were injected with /sup 111/In- and /sup 169/Yb-citrate. Tumor homogenates, from which the nuclear fraction was removed, and the mitochondrial fractions of the host livers were digested with pronase P. After digestion, the supernatants of the reaction mixtures were applied to Sephadex G-100 columns. The resultant eluates were analyzed for radioactivity, protein, uronic acid, and sialic acids. Three peaks of radioactivity were obtained by gel filtration. The first peak, eluted the void volume, contained a species whose molecular weight exceeded 40000. The second peak consisted of substances with molecular weights of 9400-40000. Radioactivity in the third peak was liberated /sup 111/In and /sup 169/Yb. These two nuclides in the second peak were bound to acid mucopolysaccharide and/or the sulfated carbohydrate chain of sulfated glycorprotein. It was thought that the nuclides in the first peak might be bound to some acid mucopolysaccharides. The second peak nuclides seemed to be bound to acid mucopolysaccharide that contained no uronic acids, and/or to the sulfated carbohydrate chain of sulfated glycoprotein. It was concluded that they were bound to the acid mucopolysaccharides and/or the sulfated carbohydrate chain of sulfated glycoprotein in tumor tissues and liver lysosomes.

  7. Availability of perfluoroctylbromide (PFOB) emulsion used as agent in the liver tumor imaging of computed tomography (CT)

    International Nuclear Information System (INIS)

    Ozawa, Takachika

    1986-01-01

    We carried out a fundamental study on the availability of perfluoroctylbromide (PFOB) emulsion used as an agent in the liver tumor imaging of computed tomography (CT). For this study, we used emulsified yolk phospolipid as a surfactant for PFOB emulsion because it is generally considered to have higher safety relative to the administration to the humans. In the rabbits' liver tumor model in which VX 2 tumor cell was implanted into their livers, we observed increases in the CT values of the livers when 5 to 10 ml/kg of PFOB emulsion (20 % w/v) was administered into the vein, and also ringlike enhancement and increases in the CT values on the tumor rim when 20 ml/kg of PFOB emulsion was administered. In addition, in the chemical analysis of a gas chromatography, we also observed significant increases in the PFOB concentration on the tumor rim, compared with those of normal liver parenchyma, when 20 ml/kg of PFOB emulsion was given. In the finding of CT values in the human liver tumor by means of organ perfusion system, we recognized increases in the CT values (induced by the accumulation of PFOB emulsion) on the rim of the metastatic tumor of colon cancer. These results suggest that PFOB emulsion has certain availability as an agent for the liver tumor imaging of computed tomography (CT). (author)

  8. C-arm CT for chemo-embolization of liver tumors

    International Nuclear Information System (INIS)

    Huppert, P.E.; Firlbeck, G.; Meissner, O.A.; Wietholtz, H.

    2009-01-01

    Local efficacy of transarterial chemo-embolization (TACE) is enhanced if selective treatment is performed. Selectivity of TACE mainly depends on vascular anatomy but also on the identification and catheterization of tumor feeding arteries. Correlation of vascular territories and target tumor volume in angiographic projection images is more difficult if tumors are not hypervascularized and contrast of liver parenchyma is inhomogeneous. C-arm CT offers the option of selective perfusion imaging via tumor-feeding arteries. This allows the comparison of perfusion images and baseline cross-sectional imaging to evaluate if tumors are covered completely by local treatment and to change the catheter position if necessary. Furthermore the uptake of embolization material, such as lipiodol can be checked by C-arm CT. In a prospective study of 75 TACE of liver tumors and liver metastases we evaluated the appropriateness of 85 catheter positions ready for delivery by perfusion C-arm CT and compared the diagnostic confidence of angiography and perfusion C-arm CT in terms of judgment of correct catheter position for the planned treatment. Diagnostic confidence was improved by perfusion C-arm CT in 55% of cases and in 11 cases (13%) catheter positions were inappropriate and had to be corrected. The reasons for catheter repositioning were incomplete coverage of the target tumor by perfusion volume (mismatch) in 6 cases, inappropriate perfusion of adjacent liver parenchyma in 2 cases and non-selective tumor perfusion via collateral arteries in 3 cases. C-arm CT allowed sufficient visualization of uptake of lipiodol in all cases evaluated. The diagnostic benefit of C-arm CT increases if tumors are treated more selectively, are not strongly hypervascular, are located centrally and if the enhancement of liver parenchyma is inhomogeneous. C-arm CT causes additional working time and contrast load, which is relatively low compared to angiography. Radiation exposure of 151 μGy per C

  9. Ultrasonic enhancement of drug penetration in solid tumors

    Directory of Open Access Journals (Sweden)

    Chun-yen eLai

    2013-08-01

    Full Text Available Increasing the penetration of drugs within solid tumors can be accomplished through multiple ultrasound-mediated mechanisms. The application of ultrasound can directly change the structure or physiology of tissues or can induce changes in a drug or vehicle in order to enhance delivery and efficacy. With each ultrasonic pulse, a fraction of the energy in the propagating wave is absorbed by tissue and results in local heating. When ultrasound is applied to achieve mild hyperthermia, the thermal effects are associated with an increase in perfusion or the release of a drug from a temperature-sensitive vehicle. Higher ultrasound intensities locally ablate tissue and result in increased drug accumulation surrounding the ablated region of interest. Further, the mechanical displacement induced by the ultrasound pulse can result in the nucleation, growth and collapse of gas bubbles. As a result of such cavitation, the permeability of a vessel wall or cell membrane can be increased. Finally, the radiation pressure of the propagating pulse can translate particles or tissues. In this perspective, we will review recent progress in ultrasound-mediated tumor delivery and the opportunities for clinical translation.

  10. Acceptable Toxicity After Stereotactic Body Radiation Therapy for Liver Tumors Adjacent to the Central Biliary System

    Energy Technology Data Exchange (ETDEWEB)

    Eriguchi, Takahisa; Takeda, Atsuya; Sanuki, Naoko; Oku, Yohei; Aoki, Yousuke [Radiation Oncology Center, Ofuna Chuo Hospital, Kanagawa (Japan); Shigematsu, Naoyuki [Department of Radiology, Keio University School of Medicine, Tokyo (Japan); Kunieda, Etsuo, E-mail: kunieda-mi@umin.ac.jp [Department of Radiation Oncology, Tokai University, Kanagawa (Japan)

    2013-03-15

    Purpose: To evaluate biliary toxicity after stereotactic body radiation therapy (SBRT) for liver tumors. Methods and Materials: Among 297 consecutive patients with liver tumors treated with SBRT of 35 to 50 Gy in 5 fractions, patients who were irradiated with >20 Gy to the central biliary system (CBS), including the gallbladder, and had follow-up times >6 months were retrospectively analyzed. Toxicity profiles, such as clinical symptoms and laboratory and radiologic data especially for obstructive jaundice and biliary infection, were investigated in relation to the dose volume and length relationship for each biliary organ. Results: Fifty patients with 55 tumors were irradiated with >20 Gy to the CBS. The median follow-up period was 18.2 months (range, 6.0-80.5 months). In the dose length analysis, 39, 34, 14, and 2 patients were irradiated with >20 Gy, >30 Gy, >40 Gy, and >50 Gy, respectively, to >1 cm of the biliary tract. Seven patients were irradiated with >20 Gy to >20% of the gallbladder. Only 2 patients experienced asymptomatic bile duct stenosis. One patient, metachronously treated twice with SBRT for tumors adjacent to each other, had a transient increase in hepatic and biliary enzymes 12 months after the second treatment. The high-dose area >80 Gy corresponded to the biliary stenosis region. The other patient experienced biliary stenosis 5 months after SBRT and had no laboratory changes. The biliary tract irradiated with >20 Gy was 7 mm and did not correspond to the bile duct stenosis region. No obstructive jaundice or biliary infection was found in any patient. Conclusions: SBRT for liver tumors adjacent to the CBS was feasible with minimal biliary toxicity. Only 1 patient had exceptional radiation-induced bile duct stenosis. For liver tumors adjacent to the CBS without other effective treatment options, SBRT at a dose of 40 Gy in 5 fractions is a safe treatment with regard to biliary toxicity.

  11. Doxorubicin-loaded QuadraSphere microspheres: plasma pharmacokinetics and intratumoral drug concentration in an animal model of liver cancer.

    Science.gov (United States)

    Lee, Kwang-Hun; Liapi, Eleni A; Cornell, Curt; Reb, Philippe; Buijs, Manon; Vossen, Josephina A; Ventura, Veronica Prieto; Geschwind, Jean-Francois H

    2010-06-01

    The purpose of this study was to evaluate, in vitro and in vivo, doxorubicin-loaded poly (vinyl alcohol-sodium acrylate) copolymer microspheres [QuadraSphere microspheres (QSMs)] for transcatheter arterial delivery in an animal model of liver cancer. Doxorubicin loading efficiency and release profile were first tested in vitro. In vivo, 15 rabbits, implanted with a Vx-2 tumor in the liver, were divided into three groups of five rabbits each, based on the time of euthanasia. Twenty-five milligrams of QSMs was diluted in 10 ml of a 10 mg/ml doxorubicin solution and 10 ml of nonionic contrast medium for a total volume of 20 ml. One milliliter of a drug-loaded QSM solution containing 5 mg of doxorubicin was injected into the tumor feeding artery. Plasma doxorubicin and doxorubicinol concentrations, and intratumoral and peritumoral doxorubicin tissue concentrations, were measured. Tumor specimens were pathologically evaluated to record tumor necrosis. As a control, one animal was blandly embolized with plain QSMs in each group. In vitro testing of QSM doxorubicin loadability and release over time showed 82-94% doxorubicin loadability within 2 h and 6% release within the first 6 h after loading, followed by a slow release pattern. In vivo, the doxorubicin plasma concentration declined at 40 min. The peak doxorubicin intratumoral concentration was observed at 3 days and remained detectable till the study's end point (7 days). Mean percentage tumor cell death in the doxorubicin QSM group was 90% at 7 days and 60% in the bland QSM embolization group. In conclusion, QSMs can be efficiently loaded with doxorubicin. Initial experiments with doxorubicin-loaded QSMs show a safe pharmacokinetic profile and effective tumor killing in an animal model of liver cancer.

  12. Doxorubicin-Loaded QuadraSphere Microspheres: Plasma Pharmacokinetics and Intratumoral Drug Concentration in an Animal Model of Liver Cancer

    International Nuclear Information System (INIS)

    Lee, Kwang-Hun; Liapi, Eleni A.; Cornell, Curt; Reb, Philippe; Buijs, Manon; Vossen, Josephina A.; Ventura, Veronica Prieto; Geschwind, Jean-Francois H.

    2010-01-01

    The purpose of this study was to evaluate, in vitro and in vivo, doxorubicin-loaded poly (vinyl alcohol-sodium acrylate) copolymer microspheres [QuadraSphere microspheres (QSMs)] for transcatheter arterial delivery in an animal model of liver cancer. Doxorubicin loading efficiency and release profile were first tested in vitro. In vivo, 15 rabbits, implanted with a Vx-2 tumor in the liver, were divided into three groups of five rabbits each, based on the time of euthanasia. Twenty-five milligrams of QSMs was diluted in 10 ml of a 10 mg/ml doxorubicin solution and 10 ml of nonionic contrast medium for a total volume of 20 ml. One milliliter of a drug-loaded QSM solution containing 5 mg of doxorubicin was injected into the tumor feeding artery. Plasma doxorubicin and doxorubicinol concentrations, and intratumoral and peritumoral doxorubicin tissue concentrations, were measured. Tumor specimens were pathologically evaluated to record tumor necrosis. As a control, one animal was blandly embolized with plain QSMs in each group. In vitro testing of QSM doxorubicin loadability and release over time showed 82-94% doxorubicin loadability within 2 h and 6% release within the first 6 h after loading, followed by a slow release pattern. In vivo, the doxorubicin plasma concentration declined at 40 min. The peak doxorubicin intratumoral concentration was observed at 3 days and remained detectable till the study's end point (7 days). Mean percentage tumor cell death in the doxorubicin QSM group was 90% at 7 days and 60% in the bland QSM embolization group. In conclusion, QSMs can be efficiently loaded with doxorubicin. Initial experiments with doxorubicin-loaded QSMs show a safe pharmacokinetic profile and effective tumor killing in an animal model of liver cancer.

  13. Ultrasound-based tumor movement compensation during navigated laparoscopic liver interventions.

    Science.gov (United States)

    Shahin, Osama; Beširević, Armin; Kleemann, Markus; Schlaefer, Alexander

    2014-05-01

    Image-guided navigation aims to provide better orientation and accuracy in laparoscopic interventions. However, the ability of the navigation system to reflect anatomical changes and maintain high accuracy during the procedure is crucial. This is particularly challenging in soft organs such as the liver, where surgical manipulation causes significant tumor movements. We propose a fast approach to obtain an accurate estimation of the tumor position throughout the procedure. Initially, a three-dimensional (3D) ultrasound image is reconstructed and the tumor is segmented. During surgery, the position of the tumor is updated based on newly acquired tracked ultrasound images. The initial segmentation of the tumor is used to automatically detect the tumor and update its position in the navigation system. Two experiments were conducted. First, a controlled phantom motion using a robot was performed to validate the tracking accuracy. Second, a needle navigation scenario based on pseudotumors injected into ex vivo porcine liver was studied. In the robot-based evaluation, the approach estimated the target location with an accuracy of 0.4 ± 0.3 mm. The mean navigation error in the needle experiment was 1.2 ± 0.6 mm, and the algorithm compensated for tumor shifts up to 38 mm in an average time of 1 s. We demonstrated a navigation approach based on tracked laparoscopic ultrasound (LUS), and focused on the neighborhood of the tumor. Our experimental results indicate that this approach can be used to quickly and accurately compensate for tumor movements caused by surgical manipulation during laparoscopic interventions. The proposed approach has the advantage of being based on the routinely used LUS; however, it upgrades its functionality to estimate the tumor position in 3D. Hence, the approach is repeatable throughout surgery, and enables high navigation accuracy to be maintained.

  14. Laparoscopic Navigated Liver Resection: Technical Aspects and Clinical Practice in Benign Liver Tumors

    Directory of Open Access Journals (Sweden)

    Markus Kleemann

    2012-01-01

    Full Text Available Laparoscopic liver resection has been performed mostly in centers with an extended expertise in both hepatobiliary and laparoscopic surgery and only in highly selected patients. In order to overcome the obstacles of this technique through improved intraoperative visualization we developed a laparoscopic navigation system (LapAssistent to register pre-operatively reconstructed three-dimensional CT or MRI scans within the intra-operative field. After experimental development of the navigation system, we commenced with the clinical use of navigation-assisted laparoscopic liver surgery in January 2010. In this paper we report the technical aspects of the navigation system and the clinical use in one patient with a large benign adenoma. Preoperative planning data were calculated by Fraunhofer MeVis Bremen, Germany. After calibration of the system including camera, laparoscopic instruments, and the intraoperative ultrasound scanner we registered the surface of the liver. Applying the navigated ultrasound the preoperatively planned resection plane was then overlain with the patient's liver. The laparoscopic navigation system could be used under sterile conditions and it was possible to register and visualize the preoperatively planned resection plane. These first results now have to be validated and certified in a larger patient collective. A nationwide prospective multicenter study (ProNavic I has been conducted and launched.

  15. A Dual-Mode Microwave Applicator for Liver Tumor Thermotherapy

    Science.gov (United States)

    Reimann, Carolin; Schüßler, Martin; Jakoby, Rolf; Bazrafshan, Babak; Hübner, Frank; Vogl, Thomas

    2018-03-01

    The concept of a novel dual-mode microwave applicator for diagnosis and thermal ablation treatment of tumorous tissue is presented in this paper. This approach is realized by integrating a planar resonator array to, firstly, detect abnormalities by a relative dielectric analysis, and secondly, perform a highly localized thermal ablation. A further essential advantage is addressed by designing the applicator to be MRI compatible to provide a multimodal imaging procedure. Investigations for an appropriate frequency range lead to the use of much higher operating frequencies between 5 GHz and 10 GHz, providing a significantly lower power consumption for microwave ablation of only 20 W compared to commercial available applicators.

  16. Fatty liver and drugs: the two sides of the same coin.

    Science.gov (United States)

    Miele, L; Liguori, A; Marrone, G; Biolato, M; Araneo, C; Vaccaro, F G; Gasbarrini, A; Grieco, A

    2017-03-01

    Drug-induced liver injury (DILI) is a common and underestimated cause of liver disease. Several drugs and other xenobiotics can be the cause of different clinicopathologic patterns of liver disease. Steatosis and steatohepatitis are rare but well-documented types of DILI. Over the past decades commonly used drugs like amiodarone, tamoxifen, irinotecan, methotrexate, valproic acid and glucocorticoids have been recognized to be associated with steatosis. Even though the pathophysiological pathways are still only partially understood, inhibition of mitochondrial beta-oxidation, reduced very low-density lipoprotein secretion, insulin resistance induction and increased de novo synthesis or increased liver uptake of fatty acids are considered the main pathogenic mechanisms through which drugs can lead to hepatic steatosis. On the other hand, fatty liver itself is a very common clinical condition, and there is a growing awareness of the potential risk factors for DILI due to the underlying metabolic condition itself.

  17. Targeted hyperthermia after selective embolization with ferromagnetic nanoparticles in a VX2 rabbit liver tumor model

    Directory of Open Access Journals (Sweden)

    Sun HL

    2013-10-01

    Full Text Available Hongliang Sun,1 Linfeng Xu,1 Tianyuan Fan,2 Hongzhi Zhan,3 Xiaodong Wang,3 Yanfei Zhou,2 Ren-jie Yang3 1Department of Interventional Therapy, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, 2Pharmacy School of Beijing University, Beijing, 3Department of Interventional Therapy, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Beijing, People's Republic of China Background: The purpose of this study was to observe the effect and feasibility of hyperthermia and the influence of heat on surrounding organs in a VX2 rabbit liver model exposed to an alternating magnetic field after embolization with ferromagnetic nanoparticles. Methods: Forty rabbits containing implanted hepatic VX2 carcinomas were divided into four groups, each containing ten rabbits. Fourteen days after tumor transplantation, we opened the abdomen to observe the size and shape of the tumor. A transfemoral retrograde approach was then used for hepatic arterial catheterization in groups B, C, and D to perform angiography and embolization. The next day, three rabbits in group B and all rabbits in group D were exposed to an alternating magnetic field, and the temperature was recorded simultaneously in the center of the tumor, at the edge of the tumor, and in the normal liver parenchyma. On day 28, all animals was euthanized to observe changes in the implanted liver tumor and the condition of the abdomen. A pathologic examination was also done. Results: Before surgery, there was no significant difference in tumor volume between the four groups. Three different temperature points (center of the tumor, edge of the tumor, and in the normal liver parenchyma of group B under an alternating magnetic field were 37.2°C ± 1.1°C, 36.8°C ± 1.2°C, and 36.9°C ± 2.1°C, none of which were significantly different from pretreatment values. Three points basal temperature in group D showed no significant difference (F = 1.038, P = 0.413. Seven to 26

  18. Plasmonic Nanobubbles Rapidly Detect and Destroy Drug-Resistant Tumors

    Science.gov (United States)

    Lukianova-Hleb, Ekaterina Y.; Ren, Xiaoyang; Townley, Debra; Wu, Xiangwei; Kupferman, Michael E.; Lapotko, Dmitri O.

    2012-01-01

    The resistance of residual cancer cells after oncological resection to adjuvant chemoradiotherapies results in both high recurrence rates and high non-specific tissue toxicity, thus preventing the successful treatment of such cancers as head and neck squamous cell carcinoma (HNSCC). The patients' survival rate and quality of life therefore depend upon the efficacy, selectivity and low non-specific toxicity of the adjuvant treatment. We report a novel, theranostic in vivo technology that unites both the acoustic diagnostics and guided intracellular delivery of anti-tumor drug (liposome-encapsulated doxorubicin, Doxil) in one rapid process, namely a pulsed laser-activated plasmonic nanobubble (PNB). HNSCC-bearing mice were treated with gold nanoparticle conjugates, Doxil, and single near-infrared laser pulses of low energy. Tumor-specific clusters of gold nanoparticles (solid gold spheres) converted the optical pulses into localized PNBs. The acoustic signals of the PNB detected the tumor with high specificity and sensitivity. The mechanical impact of the PNB, co-localized with Doxil liposomes, selectively ejected the drug into the cytoplasm of cancer cells. Cancer cell-specific generation of PNBs and their intracellular co-localization with Doxil improved the in vivo therapeutic efficacy from 5-7% for administration of only Doxil or PNBs alone to 90% thus demonstrating the synergistic therapeutic effect of the PNB-based intracellular drug release. This mechanism also reduced the non-specific toxicity of Doxil below a detectable level and the treatment time to less than one minute. Thus PNBs combine highly sensitive diagnosis, overcome drug resistance and minimize non-specific toxicity in a single rapid theranostic procedure for intra-operative treatment. PMID:23139725

  19. WE-G-18C-06: Is Diaphragm Motion a Good Surrogate for Liver Tumor Motion?

    Energy Technology Data Exchange (ETDEWEB)

    Yang, J [Department of Radiation Oncology, Duke University Medical Center, Durham, NC (United States); School of Information Science and Engineering, Shandong University, Jinan, Shandong (China); Cai, J; Zheng, C; Czito, B; Palta, M; Yin, F [Department of Radiation Oncology, Duke University Medical Center, Durham, NC (United States); Wang, H [School of Information Science and Engineering, Shandong University, Jinan, Shandong (China); Bashir, M [Department of Radiology, Duke University Medical Center, Durham, NC (United States)

    2014-06-15

    Purpose: To investigate whether diaphragm motion is a good surrogate for liver tumor motion by comparing their motion trajectories obtained from cine-MRI. Methods: Fourteen patients with hepatocellular carcinoma (10/14) or liver metastases (4/14) undergoing radiation therapy were included in this study. All patients underwent single-slice 2D cine-MRI simulations across the center of the tumor in three orthogonal planes. Tumor and diaphragm motion trajectories in the superior-inferior (SI), anteriorposterior (AP), and medial-lateral (ML) directions were obtained using the normalized cross-correlation based tracking technique. Agreement between tumor and diaphragm motions was assessed by calculating the phase difference percentage (PDP), intra-class correlation coefficient (ICC), Bland-Altman analysis (Diffs) and paired t-test. The distance (D) between tumor and tracked diaphragm area was analyzed to understand its impact on the correlation between tumor and diaphragm motions. Results: Of all patients, the means (±standard deviations) of PDP were 7.1 (±1.1)%, 4.5 (±0.5)% and 17.5 (±4.5)% in the SI, AP and ML directions, respectively. The means of ICC were 0.98 (±0.02), 0.97 (±0.02), and 0.08 (±0.06) in the SI, AP and ML directions, respectively. The Diffs were 2.8 (±1.4) mm, 2.4 (±1.1) mm, and 2.2 (±0.5) mm in the SI, AP and ML directions, respectively. The p-values derived from the paired t-test were < 0.02 in SI and AP directions, whereas were > 0.58 in ML direction primarily due to the small motion in ML direction. Tumor and diaphragmatic motion had high concordance when the distance between the tumor and tracked diaphragm areas was small. Conclusion: Preliminary results showed that liver tumor motion had good correlations with diaphragm motion in the SI and AP directions, indicating diaphragm motion in the SI and AP directions could potentially be a reliable surrogate for liver tumor motion. NIH (1R21CA165384-01A1), Golfers Against Cancer (GAC

  20. Histological assessment of the efficacy of drug-eluting beads in portal tumor thrombosis of hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Yusuke Imai, MD

    2017-03-01

    Full Text Available A 58-year-old man was diagnosed with advanced hepatocellular carcinoma with portal vein tumor thrombosis (PVTT. The tumors were multiple and existed in both lobes. Drug-eluting beads transcatheter arterial chemoembolization (DEB-TACE was performed for the tumors in the left lobe. Embosphere and Hepasphere were selected for embolization of the arterioportal shunt, followed by loaded epirubicin infusion into the left hepatic artery. Computed tomography showed reduction of PVTT. However, liver failure progressed, and the patient died 67 days after DEB-TACE. Autopsy showed that the beads reached the tumor thrombosis in the portal vein. The prognosis of hepatocellular carcinoma with PVTT is poor. Although there are no established treatments for unresectable PVTT, DEB-TACE might be a useful option for such cases.

  1. Detection of Secondary Liver Tumors in Patients with Colorectal Carcinoma by Using Tumor Markers

    Czech Academy of Sciences Publication Activity Database

    Holubec jr., L.; Topolčan, O.; Třeška, V.; Holubec sen., L.; Pecen, Ladislav; Pikner, R.; Finek, J.; Visokai, V.; Lipská, L.

    2002-01-01

    Roč. 17, č. 3 (2002), s. 134-135 ISSN 0886-3849. [International Conference on Human Tumor Markers /19./. 25.08.2002-29.08.2002, Velje] Institutional research plan: AV0Z1030915 Keywords : tumor markers * colorectal CA Subject RIV: BA - General Mathematics

  2. Tumor Penetrating Theranostic Nanoparticles for Enhancement of Targeted and Image-guided Drug Delivery into Peritoneal Tumors following Intraperitoneal Delivery.

    Science.gov (United States)

    Gao, Ning; Bozeman, Erica N; Qian, Weiping; Wang, Liya; Chen, Hongyu; Lipowska, Malgorzata; Staley, Charles A; Wang, Y Andrew; Mao, Hui; Yang, Lily

    2017-01-01

    The major obstacles in intraperitoneal (i.p.) chemotherapy of peritoneal tumors are fast absorption of drugs into the blood circulation, local and systemic toxicities, inadequate drug penetration into large tumors, and drug resistance. Targeted theranostic nanoparticles offer an opportunity to enhance the efficacy of i.p. therapy by increasing intratumoral drug delivery to overcome resistance, mediating image-guided drug delivery, and reducing systemic toxicity. Herein we report that i.p. delivery of urokinase plasminogen activator receptor (uPAR) targeted magnetic iron oxide nanoparticles (IONPs) led to intratumoral accumulation of 17% of total injected nanoparticles in an orthotopic mouse pancreatic cancer model, which was three-fold higher compared with intravenous delivery. Targeted delivery of near infrared dye labeled IONPs into orthotopic tumors could be detected by non-invasive optical and magnetic resonance imaging. Histological analysis revealed that a high level of uPAR targeted, PEGylated IONPs efficiently penetrated into both the peripheral and central tumor areas in the primary tumor as well as peritoneal metastatic tumor. Improved theranostic IONP delivery into the tumor center was not mediated by nonspecific macrophage uptake and was independent from tumor blood vessel locations. Importantly, i.p. delivery of uPAR targeted theranostic IONPs carrying chemotherapeutics, cisplatin or doxorubicin, significantly inhibited the growth of pancreatic tumors without apparent systemic toxicity. The levels of proliferating tumor cells and tumor vessels in tumors treated with the above theranostic IONPs were also markedly decreased. The detection of strong optical signals in residual tumors following i.p. therapy suggested the feasibility of image-guided surgery to remove drug-resistant tumors. Therefore, our results support the translational development of i.p. delivery of uPAR-targeted theranostic IONPs for image-guided treatment of peritoneal tumors.

  3. Scoring system predictive of survival for patients undergoing stereotactic body radiation therapy for liver tumors

    Directory of Open Access Journals (Sweden)

    Kress Marie-Adele S

    2012-09-01

    Full Text Available Abstract Background Stereotactic body radiation therapy (SBRT is an emerging treatment option for liver tumors. This study evaluated outcomes after SBRT to identify prognostic variables and to develop a novel scoring system predictive of survival. Methods The medical records of 52 patients with a total of 85 liver lesions treated with SBRT from 2003 to 2010 were retrospectively reviewed. Twenty-four patients had 1 lesion; 27 had 2 or more. Thirteen lesions were primary tumors; 72 were metastases. Fiducials were placed in all patients prior to SBRT. The median prescribed dose was 30 Gy (range, 16 – 50 Gy in a median of 3 fractions (range, 1–5. Results With median follow-up of 11.3 months, median overall survival (OS was 12.5 months, and 1 year OS was 50.8%. In 42 patients with radiographic follow up, 1 year local control was 74.8%. On univariate analysis, number of lesions (p = 0.0243 and active extralesional disease (p  Conclusions SBRT offers a safe and feasible treatment option for liver tumors. A prognostic scoring system based on the number of liver lesions, activity of extralesional disease, and KPS predicts survival following SBRT and can be used as a guide for prospective validation and ultimately for treatment decision-making.

  4. Percutaneous fiducial marker placement prior to stereotactic body radiotherapy for malignant liver tumors: an initial experience

    International Nuclear Information System (INIS)

    Ohta, Kengo; Shimohira, Masashi; Murai, Taro; Nishimura, Junichi; Iwata, Hiromitsu; Ogino, Hiroyuki; Hashizume, Takuya; Shibamoto, Yuta

    2016-01-01

    The aim of this study was to describe our initial experience with a gold flexible linear fiducial marker and to evaluate the safety and technical and clinical efficacy of stereotactic body radiotherapy using this marker for malignant liver tumors. Between July 2012 and February 2015, 18 patients underwent percutaneous fiducial marker placement before stereotactic body radiotherapy for malignant liver tumors. We evaluated the technical and clinical success rates of the procedure and the associated complications. Technical success was defined as successful placement of the fiducial marker at the target site, and clinical success was defined as the completion of stereotactic body radiotherapy without the marker dropping out of position. All 18 fiducial markers were placed successfully, so the technical success rate was 100% (18/18). All 18 patients were able to undergo stereotactic body radiotherapy without marker migration. Thus, the clinical success rate was 100% (18/18). Slight pneumothorax occurred as a minor complication in one case. No major complications such as coil migration or bleeding were observed. The examined percutaneous fiducial marker was safely placed in the liver and appeared to be useful for stereotactic body radiotherapy for malignant liver tumors

  5. Effects of Arsenic Trioxide on Radiofrequency Ablation of VX2 Liver Tumor: Intraarterial versus Intravenous Administration

    International Nuclear Information System (INIS)

    Seong, Nak Jong; Yoon, Chang Jin; Kang, Sung Gwon; Chung, Jin Wook; Kim, Hyo Cheol; Park, Jae Hyung

    2012-01-01

    Arsenic trioxide (As 2 O 3 ) can be used as a possible pharmaceutical alternative that augments radiofrequency (RF) ablation by reducing tumor blood flow. The aim of this study was to assess the effect of intraarterial and intravenous administration of As 2 O 3 on RF-induced ablation in an experimentally induced liver tumor. VX2 carcinoma was grown in the livers of 30 rabbits. As 2 O 3 (1 mg/kg) was administered through the hepatic artery (n = 10, group A) or ear vein (n = 10, group B), 30 minutes before RF ablation (125 mA ± 35; 90 ± 5 degrees Celsius). As a control group, 10 rabbits were treated with RF ablation alone (group C). RF was intentionally applied to the peripheral margin of the tumor so that ablation can cover the tumor and adjacent hepatic parenchyma. Ablation areas of the tumor and adjacent parenchymal changes among three groups were compared by the Kruskal-Wallis and Mann-Whitney U test. The overall ablation areas were 156 ± 28.9 mm 2 (group A), 119 ± 31.7 (group B), and 92 ± 17.4 (group C, p 2 ) than both group B (50 ± 19.4, p = 0.02) and group C (28 ± 2.2, p 2 O 3 . The intraarterial administration of As 2 O 3 seems to be helpful for the selective ablation of the tumor.

  6. Drugs of abuse and addiction: A slippery slope toward liver injury.

    Science.gov (United States)

    Roy, Dijendra Nath; Goswami, Ritobrata

    2016-08-05

    Substances of abuse induce alteration in neurobehavioral symptoms, which can lead to simultaneous exacerbation of liver injury. The biochemical changes of liver are significantly observed in the abused group of people using illicit drugs or drugs that are abused. A huge amount of work has been carried out by scientists for validation experiments using animal models to assess hepatotoxicity in cases of drugs of abuse. The risk of hepatotoxicity from these psychostimulants has been determined by different research groups. Hepatotoxicity of these drugs has been recently highlighted and isolated case reports always have been documented in relation to misuse of the drugs. These drugs induce liver toxicity on acute or chronic dose dependent process, which ultimately lead to liver damage, acute fatty infiltration, cholestatic jaundice, liver granulomas, hepatitis, liver cirrhosis etc. Considering the importance of drug-induced hepatotoxicity as a major cause of liver damage, this review emphasizes on various drugs of abuse and addiction which induce hepatotoxicity along with their mechanism of liver damage in clinical aspect as well as in vitro and in vivo approach. However, the mechanisms of drug-induced hepatotoxicity is dependent on reactive metabolite formation via metabolism, modification of covalent bonding between cellular components with drug and its metabolites, reactive oxygen species generation inside and outside of hepatocytes, activation of signal transduction pathways that alter cell death or survival mechanism, and cellular mitochondrial damage, which leads to alteration in ATP generation have been notified here. Moreover, how the cytokines are modulated by these drugs has been mentioned here. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  7. Splenomegaly and tumor marker response following selective internal radiation therapy for non-resectable liver metastases from neuroendocrine tumor

    International Nuclear Information System (INIS)

    Shehata, M.; Yan, K.; Itoh, Seiji; King, J.; Glenn, D.; Quinn, R.; Morris, D.L.

    2009-01-01

    The aim of this study was to investigate changes in spleen size, the level of chromogranin A as a tumor marker, and the relationship between these two parameters before and 3 months after selective internal radiation therapy (SIRT) for non-resectable liver metastases from neuroendocrine tumor (NET). Our first serious adverse event with this relatively new treatment is also discussed. A retrospective review of a prospective database identified patients with non-resectable liver metastases from NET who underwent SIRT between 2003 and 2007. Patients who underwent CT scans before and 3 months after treatment were included. The patients were divided into two groups: those with and without a 20% or more increase in splenic volume on the CT scans. The percentages of patients showing a tumor marker response in the two groups were then compared. Fourteen patients were included in the present analysis. A tumor marker response was seen in 6 of 7 patients (85.7%) who showed an increase in splenic volume of >20%, and in 3 of 7 patients (42.9%) without an increase in splenic volume (p=0.266). There was one death as a result of oesophageal variceal bleeding due to portal hypertension at 9 months after treatment. Splenic enlargement after SIRT may be associated with tumor marker response, although this could not be confirmed statistically in this study due to the small number of patients. Long-term splenomegaly and portal hypertension may be important complications of SIRT. This issue needs to be investigated further using a larger number of patients and longer follow-up. (author)

  8. Cyberknife Stereotactic Body Radiation Therapy for Nonresectable Tumors of the Liver: Preliminary Results

    Directory of Open Access Journals (Sweden)

    K. Goyal

    2010-01-01

    Full Text Available Purpose. Stereotactic body radiation therapy (SBRT has emerged as a treatment option for local tumor control of primary and secondary malignancies of the liver. We report on our updated experience with SBRT in patients with non-resectable tumors of the liver. Methods. Our first 17 consecutive patients (mean age 58.1 years receiving SBRT for HCC (=6, IHC (=3, and LM (=8 are presented. Mean radiation dose was 34Gy delivered over 1–3 fractions. Results. Treated patients had a mean decrease in maximum pretreatment tumor diameter from 6.9±4.6 cm to 5.0±2.1 cm at three months after treatment (<.05. The mean total tumor volume reduction was 44% at six months (<.05. 82% of all patients (14/17 achieved local control with a median follow-up of 8 months. 100% of patients with HCC (=6 achieved local control. Patients with surgically placed fiducial markers had no complications related to marker placement. Conclusion. Our preliminary results showed that SBRT is a safe and effective local treatment modality in selected patients with liver malignancies with minimal adverse events. Further studies are needed to define its role in the management of these malignancies.

  9. Flow mode analysis by Imatron C100 of 44 focal liver tumors

    International Nuclear Information System (INIS)

    Simon-Karneff, J.; Hernigou, A.; Grataloup, C.; Charpentier, A.; Bouillot, J.L.; Plainfosse, M.C.

    1994-01-01

    We studied 44 patients with focal benign (n = 13) or malignant (n = 31) liver tumors proved by histology or follow-up. The flow mode was acquired by electron beam CT (EBCT) after injection (35 cc at 6 ml/sec): 20 slices with a 400 ms exposure time. We looked for abnormal vessels and density curves inside the tumor, liver and aorta. We describe arterial vascularization in most cases (type 1) and particularly in all the hepatocarcinomas (n = 15) associated with abnormal vessels, and also in rare tumors (n = 4). For benign lesions like angiomas (n = 9) we showed surrounding the mass arterial vascularization in add to the typical aspect (type 3); for nodular hyperplasia (n = 3) arterial blush was associated with the last part of the tumoral curve at the same level as liver. Most often metastasis (n = 13) had no central vascularization and a slight peripheral density increased (type 2). Flow mode by EBCT allows a good density curves analysis particularly at arterial time. (authors). 20 refs., 12 figs

  10. Tumor target amplification: Implications for nano drug delivery systems.

    Science.gov (United States)

    Seidi, Khaled; Neubauer, Heidi A; Moriggl, Richard; Jahanban-Esfahlan, Rana; Javaheri, Tahereh

    2018-04-10

    Tumor cells overexpress surface markers which are absent from normal cells. These tumor-restricted antigenic signatures are a fundamental basis for distinguishing on-target from off-target cells for ligand-directed targeting of cancer cells. Unfortunately, tumor heterogeneity impedes the establishment of a solid expression pattern for a given target marker, leading to drastic changes in quality (availability) and quantity (number) of the target. Consequently, a subset of cancer cells remains untargeted during the course of treatment, which subsequently promotes drug-resistance and cancer relapse. Since target inefficiency is only problematic for cancer treatment and not for treatment of other pathological conditions such as viral/bacterial infections, target amplification or the generation of novel targets is key to providing eligible antigenic markers for effective targeted therapy. This review summarizes the limitations of current ligand-directed targeting strategies and provides a comprehensive overview of tumor target amplification strategies, including self-amplifying systems, dual targeting, artificial markers and peptide modification. We also discuss the therapeutic and diagnostic potential of these approaches, the underlying mechanism(s) and established methodologies, mostly in the context of different nanodelivery systems, to facilitate more effective ligand-directed cancer cell monitoring and targeting. Copyright © 2018 Elsevier B.V. All rights reserved.

  11. Expression of phosphatase of regenerating liver-3 is associated with prognosis of Wilms’ tumor

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    Sun F

    2017-01-01

    Full Text Available Fengyin Sun,1 Wenyi Li,2,3 Lie Wang,2 Changfeng Jiao3 1Department of Pediatric Surgery, Qilu Hospital, Shandong University, Jinan, Shandong Province, 2Department of General Surgery, Fuzhou General Hospital of Nanjing Command, PLA, Fuzhou, Fujian Province, 3Department of Vascular Surgery, Xinzhou City People’s Hospital, Xinzhou, Shanxi Province, People’s Republic of China Objective: The current study was undertaken to explore the clinical and prognostic value of phosphatase of regenerating liver-3 (PRL-3 expression in Wilms’ tumor. Methods: Seventy-six patients with Wilms’ tumor in Qilu Hospital from January 2003 to July 2009 were enrolled in the study. Protein expression level of PRL-3 was examined by immunohistochemical staining, and the correlation between PRL-3 expression and histopathological parameters, clinical variables, and outcome of patients with Wilms’ tumor were analyzed. Results: We found that 19% of patients with unfavorable histology had tumor recurrence and 16% of patients died following the operation. PRL-3 was expressed in 15 out of 76 tumors (19% and expressed highly in unfavorable histology Wilms’ tumor (P=0.04. PRL-3 protein expression level was correlated to 2.5-fold increase in recurrence rate of Wilms’ tumor (P=0.06 without any statistically significant difference. However, in favorable histology Wilms’ tumor, PRL-3 expression was correlated to an increase of 3.4-fold in recurrence rate (P=0.03. Conclusion: The expression of PRL-3 protein was correlated with an increased recurrence rate of favorable histology Wilms’ tumor. PRL-3 may serve as a promising biomarker for predicting patients with high risk of Wilms’ tumor. Further investigations are warranted to investigate the clinical function of PRL-3 in Wilms’ tumor. Keywords: Wilms’ tumor, prognosis, tumorigenesis, recurrence

  12. Overview of Methods Able to Overcome Impediments to tumor Drug Delivery with Special Attention to Tumor Interstitial Fluid.

    Directory of Open Access Journals (Sweden)

    Gianfranco eBaronzio

    2015-07-01

    Full Text Available Every drug used to treat cancer (chemotherapeutics, immunologic, monoclonal antibodies, nanoparticles, radionuclides must reach the targeted cells through the tumor environment at adequate concentrations, in order to exert their cell-killing effects. For any of these agents to reach the goal cells they must overcome a number of impediments created by the tumor microenvironment, beginning with tumor interstitial fluid pressure (TIFP and a multifactorial increase in composition of the extracellular matrix (ECM. A primary modifier of tumor microenvironment is hypoxia, which increases the production of growth factors such as vascular endothelial growth factor (VEGF and platelet-derived growth factor (PDGF. These growth factors released by both tumor cells and bone marrow recruited myeloid cells (MDS, form abnormal vasculature characterized by vessels that are tortuous and more permeable. Increased leakiness combined with increased inflammatory byproducts accumulates fluid within the tumor mass [tumor interstitial fluid (TIF], ultimately creating an increased pressure (TIFP. Fibroblasts are also up-regulated by the tumor microenvironment, and deposit fibers that further augment the density of the extracellular matrix (ECM, thus, further worsening the TIFP. Increased TIFP with the ECM are the major obstacles to adequate drug delivery. By decreasing TIFP and decreasing ECM density, we can expect an associated rise in drug concentration within the tumor itself. In this overview we will describe all the methods (drugs, nutraceuticals, physical methods of treatment able to lower TIFP and to modify ECM that can be used for increasing drug concentration within the tumor tissue.

  13. Effect of intravenous drug administration mode on drug distribution in a tumor slab: a finite Fourier transform analysis.

    Science.gov (United States)

    Subramaniam, B; Claudius, J S

    1990-03-08

    Cancer therapy using chemotherapeutic drugs frequently involves injection of the drug into the body through some intravenous mode of administration, viz, continuous (drip) infusion or single/multiple bolus injection(s). An understanding of the effect of the various modes of administration upon tumor penetration of drug is essential to rational design of drug therapy. This paper investigates drug penetration into a model tumor of slab geometry (between two capillaries) in which the overall transport rate of drug is limited by intra-tumor transport characterized by an effective diffusion coefficient. Employing the method of Finite Fourier Transforms (FFT), analytical solutions have been obtained for transient drug distribution in both the plasma and the tumor following three modes of administration, viz, continuous infusion, single bolus injection and equally-spaced equal-dose multiple bolus injections, of a given amount of drug. The qualitative trends exhibited by the plasma drug distribution profiles are consistent with reported experimental studies. Two concepts, viz, the dimensionless decay constant and the plasma/tumor drug concentration trajectories, are found to be particularly useful in the rational design of drug therapy. The dimensionless decay constant provides a measure of the rate of drug decay in the plasma relative to the rate of drug diffusion into the tumor and is thus characteristic of the tumor/drug system. The magnitude of this parameter dictates the choice of drug administration mode for minimizing drug decay in the plasma while simultaneously maximizing drug transport into the tumor. The concentration trajectories provide a measure of the plasma drug concentration relative to the tumor drug concentration at various times following injection. When the tumor drug concentration exceeds the plasma drug concentration, the drug will begin to diffuse out of the tumor. Knowledge of the time at which this diffusion reversal occurs is especially useful

  14. Metabolism of 64Cu and transfer of 125I-MT in the bearing liver ascites tumor (H22) mice

    International Nuclear Information System (INIS)

    Huai Qing; Fang Xingwang; Wang Wenqing

    1998-01-01

    The metabolism of 64 Cu in some tissues of the bearing liver ascites tumor mice has been studied. The liver in normal and tumor bearing mice preferentially accumulates intravenous injection copper, however, the liver in the later mice accumulates much less copper than that of the former. It suggests that in the bearing ascites tumor mice, ascites tumor influences the metabolism of copper. It is found that the content of 64 Cu in the tumor cell is more than 85% in ascites tumor. Gel filtration profile of mice liver homogenate on Sephadex G-75 shows that injected 64 Cu is mainly bound with metallothionein. The tissues uptake of 125 I-labelled (Cd, Zn)-MT which is given in abdominal cavity are also reported. Of the tissues studied, the ascites tumor and kidney accumulate the highest concentration of given 125 I-MT, since over 20% of entire dose accumulated in them. After 125 I-MT is given, it soon goes into ascites tumor, and reaches the maximum in ascites as well as in tumor cell. Therefore, 125 I-MT can go through the membrane of tumor cell and reaches in the tumor cell

  15. Transarterial Fiducial Marker Placement for Image-guided Proton Therapy for Malignant Liver Tumors

    International Nuclear Information System (INIS)

    Ohta, Kengo; Shimohira, Masashi; Sasaki, Shigeru; Iwata, Hiromitsu; Nishikawa, Hiroko; Ogino, Hiroyuki; Hara, Masaki; Hashizume, Takuya; Shibamoto, Yuta

    2015-01-01

    PurposeThe aim of this study is to analyze the technical and clinical success rates and safety of transarterial fiducial marker placement for image-guided proton therapy for malignant liver tumors.Methods and MaterialsFifty-five patients underwent this procedure as an interventional treatment. Five patients had 2 tumors, and 4 tumors required 2 markers each, so the total number of procedures was 64. The 60 tumors consisted of 46 hepatocellular carcinomas and 14 liver metastases. Five-mm-long straight microcoils of 0.018 inches in diameter were used as fiducial markers and placed in appropriate positions for each tumor. We assessed the technical and clinical success rates of transarterial fiducial marker placement, as well as the complications associated with it. Technical success was defined as the successful delivery and placement of the fiducial coil, and clinical success was defined as the completion of proton therapy.ResultsAll 64 fiducial coils were successfully installed, so the technical success rate was 100 % (64/64). Fifty-four patients underwent proton therapy without coil migration. In one patient, proton therapy was not performed because of obstructive jaundice due to bile duct invasion by hepatocellular carcinoma. Thus, the clinical success rate was 98 % (54/55). Slight bleeding was observed in one case, but it was stopped immediately and then observed. None of the patients developed hepatic infarctions due to fiducial marker migration.ConclusionTransarterial fiducial marker placement appears to be a useful and safe procedure for proton therapy for malignant liver tumors

  16. Transarterial Fiducial Marker Placement for Image-guided Proton Therapy for Malignant Liver Tumors

    Energy Technology Data Exchange (ETDEWEB)

    Ohta, Kengo, E-mail: yesterday.is.yesterday@gmail.com; Shimohira, Masashi, E-mail: mshimohira@gmail.com [Nagoya City University Graduate School of Medical Sciences, Department of Radiology (Japan); Sasaki, Shigeru, E-mail: ssasaki916@yahoo.co.jp; Iwata, Hiromitsu, E-mail: h-iwa-ncu@nifty.com; Nishikawa, Hiroko, E-mail: piroko1018@gmail.com; Ogino, Hiroyuki, E-mail: oginogio@gmail.com; Hara, Masaki, E-mail: mhara@med.nagoya-cu.ac.jp [Nagoya City West Medical Center, Department of Radiation Oncology, Nagoya Proton Therapy Center (Japan); Hashizume, Takuya, E-mail: tky300@gmail.com; Shibamoto, Yuta, E-mail: yshiba@med.nagoya-cu.ac.jp [Nagoya City University Graduate School of Medical Sciences, Department of Radiology (Japan)

    2015-10-15

    PurposeThe aim of this study is to analyze the technical and clinical success rates and safety of transarterial fiducial marker placement for image-guided proton therapy for malignant liver tumors.Methods and MaterialsFifty-five patients underwent this procedure as an interventional treatment. Five patients had 2 tumors, and 4 tumors required 2 markers each, so the total number of procedures was 64. The 60 tumors consisted of 46 hepatocellular carcinomas and 14 liver metastases. Five-mm-long straight microcoils of 0.018 inches in diameter were used as fiducial markers and placed in appropriate positions for each tumor. We assessed the technical and clinical success rates of transarterial fiducial marker placement, as well as the complications associated with it. Technical success was defined as the successful delivery and placement of the fiducial coil, and clinical success was defined as the completion of proton therapy.ResultsAll 64 fiducial coils were successfully installed, so the technical success rate was 100 % (64/64). Fifty-four patients underwent proton therapy without coil migration. In one patient, proton therapy was not performed because of obstructive jaundice due to bile duct invasion by hepatocellular carcinoma. Thus, the clinical success rate was 98 % (54/55). Slight bleeding was observed in one case, but it was stopped immediately and then observed. None of the patients developed hepatic infarctions due to fiducial marker migration.ConclusionTransarterial fiducial marker placement appears to be a useful and safe procedure for proton therapy for malignant liver tumors.

  17. Antibody Drug Conjugates Differentiate Uptake and DNA Alkylation of Pyrrolobenzodiazepines in Tumors from Organs of Xenograft Mice.

    Science.gov (United States)

    Ma, Yong; Khojasteh, S Cyrus; Hop, Cornelis E C A; Erickson, Hans K; Polson, Andrew; Pillow, Thomas H; Yu, Shang-Fan; Wang, Hong; Dragovich, Peter S; Zhang, Donglu

    2016-12-01

    Pyrrolobenzodiazepine (PBD)-dimer is a DNA minor groove alkylator, and its CD22 THIOMAB antibody drug conjugate (ADC) demonstrated, through a disulfide linker, an efficacy in tumor reduction for more than 7 weeks with minimal body weight loss in xenograft mice after a single 0.5-1 mg/kg i.v. dose. The DNA alkylation was investigated here in tumors and healthy organs of mice to understand the sustained efficacy and tolerability. The experimental procedures included the collection of tumors and organ tissues of xenograft mice treated with the ADC followed by DNA isolation/hydrolysis/quantitation and payload recovery from reversible DNA alkylation. PBD-dimer formed a considerable amount of adducts with tissue DNA, representing approximately 98% (at 24 hours), and 99% (at 96 hours) of the total PBD-dimer in tumors, and 78-89% in liver and lung tissues, suggesting highly efficient covalent binding of the released PBD-dimer to tissue DNA. The amount of PBD-DNA adducts in tumor tissues was approximately 24-fold (at 24 hours) and 70-fold (at 96 hours) greater than the corresponding amount of adducts in liver and lung tissues. In addition, the DNA alkylation levels increased 3-fold to 4-fold from 24 to 96 hours in tumors [41/10 6 base pairs (bp) at 96 hours] but remained at the same level (1/10 6 bp) in livers and lungs. These results support the typical target-mediated cumulative uptake of ADC into tumors and payload release that offers an explanation for its sustained antitumor efficacy. In addition, the low level of DNA alkylation in normal tissues is consistent with the tolerability observed in mice. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

  18. Radiofrequency ablation of liver tumors by using monopolar perfusion electrode:an analysis of therapeutic results

    International Nuclear Information System (INIS)

    Luo Rongguang; Gu Yangkui; Gao Fei; Zhang Liang; Zhao Ming; Fan Weijun; Wu Peihong; Huang Jinhua

    2010-01-01

    Objective: To investigate the clinical value of CT-guided radiofrequency ablation by using monopolar perfusion electrode in treating liver tumors. Methods: From January 2008 to December 2008, 24 patients with 37 lesions of liver tumors were treated with radiofrequency ablation by using monopolar perfusion electrode (RITA UniBlate). Of the 24 patients,solitary lesion was seen in 14, two lesions in 7 and three lesions in 3. Among 37 lesions,the maximum diameter of the lesion ≤ 3 cm, 3.1∼5 cm and > 5 cm was determined in 24, 8 and 5, respectively. The changes of the tumor size and the AFP level were observed. A follow-up lasting for 12 months was conducted. Results: After radiofrequency ablation twenty-two lesions (22/37, 59.5%) were completely ablated, of which nineteen tumors (19/24, 79.2%) were smaller than 3 cm in diameter, two tumors (2 / 8, 25%) had a diameter between 3.1 cm and 5 cm, one tumor (1 / 5, 20%) was larger than 5 cm. Fifteen tumors (15 / 37, 40.5%) were not completely ablated. During the follow-up period of 12 months, fifteen patients (15 / 24, 62.5%) remained alive and nine patients died, of whom the survival time was less than 6 months in six and was 6 -12 months in 4. After radiofrequency ablation, the AFP level decreased to normal level in 5 patients (5 / 10, 50%), and mild decrease of AFP, but still higher than normal,was seen in 3 patients (3 / 10, 30%). Of 10 patients who had a positive AFP test, 2 (2 / 10, 10%) showed a continuous rise in the AFP level. After radiofrequency ablation, one patient developed a minor hepatic subcapsular bleeding,and all patients complained of different degrees of fever and upper abdominal pain. Conclusion: CT-guided radiofrequency ablation by using monopolar perfusion electrode is a minimally-invasive technique with reliable short-term results and fewer complications. Therefore, it is a safe and effective local treatment for liver cancer. For tumors smaller than 3 cm in diameter complete ablation can be

  19. Liver injury from herbals and dietary supplements in the U.S. Drug-Induced Liver Injury Network.

    Science.gov (United States)

    Navarro, Victor J; Barnhart, Huiman; Bonkovsky, Herbert L; Davern, Timothy; Fontana, Robert J; Grant, Lafaine; Reddy, K Rajender; Seeff, Leonard B; Serrano, Jose; Sherker, Averell H; Stolz, Andrew; Talwalkar, Jayant; Vega, Maricruz; Vuppalanchi, Raj

    2014-10-01

    The Drug-Induced Liver Injury Network (DILIN) studies hepatotoxicity caused by conventional medications as well as herbals and dietary supplements (HDS). To characterize hepatotoxicity and its outcomes from HDS versus medications, patients with hepatotoxicity attributed to medications or HDS were enrolled prospectively between 2004 and 2013. The study took place among eight U.S. referral centers that are part of the DILIN. Consecutive patients with liver injury referred to a DILIN center were eligible. The final sample comprised 130 (15.5%) of all subjects enrolled (839) who were judged to have experienced liver injury caused by HDS. Hepatotoxicity caused by HDS was evaluated by expert opinion. Demographic and clinical characteristics and outcome assessments, including death and liver transplantation (LT), were ascertained. Cases were stratified and compared according to the type of agent implicated in liver injury; 45 had injury caused by bodybuilding HDS, 85 by nonbodybuilding HDS, and 709 by medications. Liver injury caused by HDS increased from 7% to 20% (P Bodybuilding HDS caused prolonged jaundice (median, 91 days) in young men, but did not result in any fatalities or LT. The remaining HDS cases presented as hepatocellular injury, predominantly in middle-aged women, and, more frequently, led to death or transplantation, compared to injury from medications (13% vs. 3%; P bodybuilding HDS or medications, as evidenced by differences in unfavorable outcomes (death and transplantation). (Hepatology 2014;60:1399-1408). © 2014 by the American Association for the Study of Liver Diseases.

  20. Associations of Drug Lipophilicity and Extent of Metabolism with Drug-Induced Liver Injury.

    Science.gov (United States)

    McEuen, Kristin; Borlak, Jürgen; Tong, Weida; Chen, Minjun

    2017-06-22

    Drug-induced liver injury (DILI), although rare, is a frequent cause of adverse drug reactions resulting in warnings and withdrawals of numerous medications. Despite the research community's best efforts, current testing strategies aimed at identifying hepatotoxic drugs prior to human trials are not sufficiently powered to predict the complex mechanisms leading to DILI. In our previous studies, we demonstrated lipophilicity and dose to be associated with increased DILI risk and, and in our latest work, we factored reactive metabolites into the algorithm to predict DILI. Given the inconsistency in determining the potential for drugs to cause DILI, the present study comprehensively assesses the relationship between DILI risk and lipophilicity and the extent of metabolism using a large published dataset of 1036 Food and Drug Administration (FDA)-approved drugs by considering five independent DILI annotations. We found that lipophilicity and the extent of metabolism alone were associated with increased risk for DILI. Moreover, when analyzed in combination with high daily dose (≥100 mg), lipophilicity was statistically significantly associated with the risk of DILI across all datasets ( p < 0.05). Similarly, the combination of extensive hepatic metabolism (≥50%) and high daily dose (≥100 mg) was also strongly associated with an increased risk of DILI among all datasets analyzed ( p < 0.05). Our results suggest that both lipophilicity and the extent of hepatic metabolism can be considered important risk factors for DILI in humans, and that this relationship to DILI risk is much stronger when considered in combination with dose. The proposed paradigm allows the convergence of different published annotations to a more uniform assessment.

  1. Stereotactic body radiation therapy for liver oligo-recurrence and oligo-progression from various tumors

    Energy Technology Data Exchange (ETDEWEB)

    Cha, Yu Jin; Kim, Mi Sook; Jang, Won Il; Seo, Young Seok; Cho, Chul Koo; Yoo, Hyung Jun; Paik, Eun Kyung [Dept. of Radiation Oncology, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)

    2017-06-15

    To evaluate the outcomes of stereotactic body radiation therapy (SBRT) for patients with liver oligo-recurrence and oligo-progression from various primary tumors. Between 2002 and 2013, 72 patients with liver oligo-recurrence (oligo-metastasis with a controlled primary tumor) and oligo-progression (contradictory progression of a few sites of disease despite an overall tumor burden response to therapy) underwent SBRT. Of these, 9 and 8 patients with uncontrollable distant metastases and patients immediate loss to follow-up, respectively, were excluded. The total planning target volume was used to select the SBRT dose (median, 48 Gy; range, 30 to 60 Gy, 3–4 fractions). Toxicity was evaluated using the Common Toxicity Criteria for Adverse Events v4.0. We evaluated 55 patients (77 lesions) treated with SBRT for liver metastases. All patients had controlled primary lesions, and 28 patients had stable lesions at another site (oligo-progression). The most common primary site was the colon (36 patients), followed by the stomach (6 patients) and other sites (13 patients). The 2-year local control and progression-free survival rates were 68% and 22%, respectively. The 2- and 5-year overall survival rates were 56% and 20%, respectively. The most common adverse events were grade 1–2 fatigue, nausea, and vomiting; no grade ≥3 toxicities were observed. Univariate analysis revealed that oligo-progression associated with poor survival. SBRT for liver oligo-recurrence and oligo-progression appears safe, with similar local control rates. For liver oligo-progression, criteria are needed to select patients in whom improved overall survival can be expected through SBRT.

  2. CT-guided percutaneous intratumoral chemotherapy with a novel cisplatin/epinephrine injectable gel for the treatment of unresectable malignant liver tumors

    International Nuclear Information System (INIS)

    Engelmann, K.; Mack, M.G.; Straub, R.; Eichler, K.; Zangos, S.; Vogl, T.J.

    2000-01-01

    Purpose: To evaluate prospectively the volumetric changes of tumor and necrosis in unresectable malignant liver tumors and the clinical aspects after CT-guided direct intratumoral administration of a novel cisplatin/epinephrine injectable gel in a clinical phase II study. Patients and methods: 8 patients with 17 colorectal liver metastases with a mean volume of 42 ml were treated with a mean of 5.1 injections and 8 patients with 11 HCC nodules (mean volume of 22.1 ml) with a mean of 3.25 treatments with CT-guided local administration of a novel cisplatin/epinephrine gel. This method of administration provides a higher local and lower systemic drug concentration. Volumes of tumor and necrosis prior to and after treatment were measured by computer-generated volumetric analysis. Results: Contrast-enhanced studies verified pretherapeutic tumor necrosis with a value of 12.6% in the metastases and 0.6% in the HCC nodules. Intratumoral drug administration resulted in a necrotic volume of 110% in metastases and 128% in HCC versus the mean initial tumor volume, at least 4 treatments resulted in 122% necrosis in metastases and 130% in HCC. Local therapy control rate for the follow-up to 6 months was 38% and 83.3% for the group of metastases and HCC, respectively. Conclusions: Direct intratumoral injection of a novel cisplatin/epinephrine injectable gel results in an induction of a relevant necrosis in malignant liver tumors, with a substantially higher local therapy control rate for HCC compared to colorectal metastases. (orig.) [de

  3. Liver scanning in the diagnosis of metastases from malignant tumors of the gastrointestinal tract

    International Nuclear Information System (INIS)

    Fleites, G.; Gomez, E.; Bell, L.; Peralta, R.; Suarez, J.C.; Cassola, J.R.; Fraga, A.

    1989-01-01

    The National Institute of Oncology and Radiobiology (INOR) established a line of clinical investigation in January, 1974, which was later added to clinical care. This line consisted of trying to arrive at a preoperative diagnosis - by means of liver scanning - of the potential liver metastases of primitive tumors in the gastrointestinal tract. Metastable 113 Indium was used. A review of the results obtained in the 50 patients included in the investigation program is made. The results of preoperative scanning were compared with operative findings. Twelve liver metastases (24%) were found. In 40 patients there was agreement (80%) between preoperative scanning and operatory findings. At present, ultrasound is a necessary supplement to scans, which supplements it but does not exclude it. The tracer element used now is technetium-99 M coloidal sulphide

  4. Avaliação dos tumores hepáticos ao Doppler Doppler evaluation of liver tumors

    Directory of Open Access Journals (Sweden)

    Márcio Martins Machado

    2004-10-01

    Full Text Available Os avanços recentes na ultra-sonografia têm ampliado a possibilidade de detecção de tumores hepáticos. Isto tem auxiliado na perspectiva de melhora do prognóstico destes pacientes, à medida que novas técnicas terapêuticas têm surgido. Neste artigo os autores relatam achados ao Doppler que podem auxiliar na identificação e caracterização dos tumores hepáticos, avaliando dados do Doppler colorido, pulsado e do Doppler de amplitude ("power Doppler". Fazem, também, referência a novas modalidades de imagem, como o uso da harmônica.Recent advances in ultrasound have optimized the detection of liver tumors and helped to improve the prognosis of patients with this condition as newly developed and improved therapeutic modalities have been established. The authors review important Doppler findings which may help in the identification and characterization of some hepatic tumors through the evaluation of color Doppler, pulsed Doppler and power Doppler features. New imaging methods such as the use of harmonics imaging are also reviewed.

  5. Multi-slice CT three dimensional volume measurement of tumors and livers in hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Yu Yuanlong; Li Liangcai; Tang Binghang; Hu Zemin

    2004-01-01

    Objective: To examine the accuracy of multi-slice CT (MSCT) three dimensional (3D) volume measurement of tumors and livers in hepatocellular carcinoma cases by using immersion method as the standard. Methods: (1) The volume of 25 porkling livers was measured using immersion method in experiment group in vitro. Then the models were built according to Matsumoto's method and CT scanning and special software were used to measure the volume of the livers. (2) The volume of the tumors in 25 cases of hepatocellular carcinoma was measured using diameter measurement method and special volume measurement software (tissue measurements). Two tumors of them were measured respectively using MSCT 3D measurement, diameter measurement before the operation and immersion method after the operation. The data of the two groups were examined using pairing t test. Results: (1) The volume range of 25 porkling livers was 68.50-1150.10 ml using immersion method and 69.78-1069.97 ml using MSCT 3D measurement. There was no significant difference of the data in these two groups using t-test (t=1.427, P>0.05). (2) The volume range of 25 hepatocellular tumors was 395.16-2747.7 ml using diameter measurement and 203.10-1463.19 ml using MSCT 3D measurement before the operation. There was significant difference of the data in these two groups using t-test (t=7.689, P<0.001). In 2 ablated tumors, 1 case's volume was (21.75±0.60) ml using MSCT 3D measurement and 33.73 ml using diameter measurement before the operation and 21.50 ml using immersion measurement after the operation. The other case's volume was (696.13±5.30) ml using MSCT 3D measurement and 1323.51 ml using diameter measurement before the operation and 685.50 ml using immersion measurement after the operation. Conclusion: MSCT 3D volume measurement can accurately measure the volume of tumor and liver and has important clinical application value. There is no significant difference between MSCT 3D volume measurement and immersion method

  6. Diagnosis of portal vein thrombosis discontinued with liver tumors in patients with liver cirrhosis and tumors by contrast-enhanced US: A pilot study

    Energy Technology Data Exchange (ETDEWEB)

    Song Zezhou; Huang Min [Department of Ultrasound, First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, Zhejiang Province (China); Jiang Tianan, E-mail: tiananjiang@hzcnc.co [Department of Ultrasound, First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, Zhejiang Province (China); Zhao Qiyu [Department of Hepatobiliary Pancreatic Surgery, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou (China); Yao Lei; Mou Yun; Zhao Junkang; Ao Jianyang [Department of Ultrasound, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, Zhejiang Province (China); Chen Fen [Department of Hepatobiliary Pancreatic Surgery, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou (China); Chen Yan [Department of Ultrasound, First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, Zhejiang Province (China)

    2010-08-15

    Aims: We assessed the role of contrast-enhanced ultrasound (CEUS) in the differential diagnosis between benign and malignant portal vein thrombosis (PVT) in patients who had liver tumors. Methods: Seventeen consecutive patients who had cirrhosis, liver tumors, and PVT were prospectively studied with CEUS. CEUS was performed at low mechanical index after intravenous administration of a second-generation contrast agent (SonoVue, Bracco, Milan, Italy). Presence or absence of thrombus enhancement on CEUS were considered diagnostic for malignant or benign PVT. Five patients also underwent percutaneous portal vein fine-needle biopsy under US guidance. All patients were followed-up. Shrinkage of the thrombus and/or recanalization of the vessels on CDUS during follow-up were considered definitive evidence of the benign nature of the thrombosis, whereas the enlargement of the thrombus, disruption of the vessel wall, and parenchymal infiltration over follow-up were considered consistent with malignancy. Results: Follow-up showed signs of malignant thrombosis in 14 of 17 patients. CEUS showed early arterial enhancement of the PVT in 14 patients of 14 malignant PVT, 1 patient of 3 benign PVT and the absence of thrombus enhancement in 2 patients of 3 benign PVT. FNB confirmed the results for malignant PVT in four of five patients, for benign granulomatous inflammation PVT in one of five patients in which CEUS showed early arterial enhancement of the PVT. The sensitivity, specificity and accuracy is 100%, 66.7% and 93.3% at diagnosis of malignant PVT using CEUS. In one patient with intrahepatic bile duct stone, CEUS were positive for malignant PVT, whereas FNB was negative (benign granulomatous inflammation PVT); follow-up examination confirmed benign PVT. Conclusion: CEUS seems to be the pretty sensitive and specific test for diagnosing malignant portal vein thrombosis in patients with cirrhosis and tumors.

  7. Inhibition of tumor necrosis factor alpha reduces the outgrowth of hepatic micrometastasis of colorectal tumors in a mouse model of liver ischemia-reperfusion injury.

    Science.gov (United States)

    Jiao, Shu-Fan; Sun, Kai; Chen, Xiao-Jing; Zhao, Xue; Cai, Ning; Liu, Yan-Jun; Xu, Long-Mei; Kong, Xian-Ming; Wei, Li-Xin

    2014-01-08

    Patients with colorectal cancer (CRC) often develop liver metastases, in which case surgery is considered the only potentially curative treatment option. However, liver surgery is associated with a risk of ischemia-reperfusion (IR) injury, which is thought to promote the growth of colorectal liver metastases. The influence of IR-induced tumor necrosis factor alpha (TNF-α) elevation in the process still is unknown. To investigate the role of TNF-α in the growth of pre-existing micrometastases in the liver following IR, we used a mouse model of colorectal liver metastases. In this model, mice received IR treatment seven days after intrasplenic injections of colorectal CT26 cells. Prior to IR treatment, either TNF-α blocker Enbrel or low-dose TNF-α, which could inhibit IR-induced TNF-α elevation, was administered by intraperitoneal injection. Hepatic IR treatment significantly promoted CT26 tumor growth in the liver, but either Enbrel or low-dose TNF-α pretreatment reversed this trend. Further studies showed that the CT26 + IR group prominently increased the levels of ALT and AST, liver necrosis, inflammatory infiltration and the expressions of hepatic IL-6, MMP9 and E-selectin compared to those of CT26 group. Inhibition of TNF-α elevation remarkably attenuated the increases of these liver inflammatory damage indicators and tumor-promoting factors. These findings suggested that inhibition of TNF-α elevation delayed the IR-enhanced outgrowth of colorectal liver metastases by reducing IR-induced inflammatory damage and the formation of tumor-promoting microenvironments. Both Enbrel and low-dose TNF-α represented the potential therapeutic approaches for the protection of colorectal liver metastatic patients against IR injury-induced growth of liver micrometastases foci.

  8. Strategies to tackle the challenges of external beam radiotherapy for liver tumors.

    Science.gov (United States)

    Lock, Michael I; Klein, Jonathan; Chung, Hans T; Herman, Joseph M; Kim, Edward Y; Small, William; Mayr, Nina A; Lo, Simon S

    2017-05-18

    Primary and metastatic liver cancer is an increasingly common and difficult to control disease entity. Radiation offers a non-invasive treatment alternative for these patients who often have few options and a poor prognosis. However, the anatomy and aggressiveness of liver cancer poses significant challenges such as accurate localization at simulation and treatment, management of motion and appropriate selection of dose regimen. This article aims to review the options available and provide information for the practical implementation and/or improvement of liver cancer radiation programs within the context of stereotactic body radiotherapy and image-guided radiotherapy guidelines. Specific patient inclusion and exclusion criteria are presented given the significant toxicity found in certain sub-populations treated with radiation. Indeed, certain sub-populations, such as those with tumor thrombosis or those with larger lesions treated with transarterial chemoembolization, have been shown to have significant improvements in outcome with the addition of radiation and merit special consideration. Implementing a liver radiation program requires three primary challenges to be addressed: (1) immobilization and motion management; (2) localization; and (3) dose regimen and constraint selection. Strategies to deal with motion include simple internal target volume (ITV) expansions, non-gated ITV reduction strategies, breath hold methods, and surrogate marker methods to enable gating or tracking. Localization of the tumor and organs-at-risk are addressed using contrast infusion techniques to take advantage of different normal liver and cancer vascular anatomy, imaging modalities, and margin management. Finally, a dose response has been demonstrated and dose regimens appear to be converging. A more uniform approach to treatment in terms of technique, dose selection and patient selection will allow us to study liver radiation in larger and, hopefully, multicenter randomized

  9. Composite Configuration Interventional Therapy Robot for the Microwave Ablation of Liver Tumors

    Science.gov (United States)

    Cao, Ying-Yu; Xue, Long; Qi, Bo-Jin; Jiang, Li-Pei; Deng, Shuang-Cheng; Liang, Ping; Liu, Jia

    2017-11-01

    The existing interventional therapy robots for the microwave ablation of liver tumors have a poor clinical applicability with a large volume, low positioning speed and complex automatic navigation control. To solve above problems, a composite configuration interventional therapy robot with passive and active joints is developed. The design of composite configuration reduces the size of the robot under the premise of a wide range of movement, and the robot with composite configuration can realizes rapid positioning with operation safety. The cumulative error of positioning is eliminated and the control complexity is reduced by decoupling active parts. The navigation algorithms for the robot are proposed based on solution of the inverse kinematics and geometric analysis. A simulation clinical test method is designed for the robot, and the functions of the robot and the navigation algorithms are verified by the test method. The mean error of navigation is 1.488 mm and the maximum error is 2.056 mm, and the positioning time for the ablation needle is in 10 s. The experimental results show that the designed robot can meet the clinical requirements for the microwave ablation of liver tumors. The composite configuration is proposed in development of the interventional therapy robot for the microwave ablation of liver tumors, which provides a new idea for the structural design of medical robots.

  10. Quantitative characterization of liver tumor radiodensity in CT images: a phantom study between two scanners

    Science.gov (United States)

    Berman, Benjamin Paul; Li, Qin; McKenney, Sarah; Fricke, Stanley Thomas; Fang, Yuan; Gavrielides, Marios A.; Petrick, Nicholas

    2018-02-01

    Quantitative assessment of tumor radiodensity is important for the clinical evaluation of contrast enhancement and treatment response, as well as for the extraction of texture-related features for image analysis or radiomics. Radiodensity estimation, Hounsfield Units (HU) in CT images, can be affected by patient factors such as tumor size, and by system factors such as acquisition and reconstruction protocols. In this project, we quantified the measurability of liver tumor HU using a 3D-printed phantom, imaged with two CT systems: Siemens Somatom Force and GE Lightspeed VCT. The phantom was printed by dithering two materials to create spherical tumors (10, 14 mm) with uniform densities (90, 95, 100, 105 HU). Image datasets were acquired at 120 kVp including 15 repeats using two matching exposures across the CT systems, and reconstructed using comparable algorithms. The radiodensity of each tumor was measured using an automated matched-filter method. We assessed the performance of each protocol using the area under the ROC curve (AUC) as the metric for distinguishing between tumors with different radiodensities. The AUC ranged from 0.8 to 1.0 and was affected by tumor size, radiodensity, and scanner; the lowest AUC values corresponded to low dose measurements of 10 mm tumors with less than 5 HU difference. The two scanners exhibited similar performance >0.9 AUC for large lesions with contrast above 7 HU, though differences were observed for the smallest and lowest contrast tumors. These results show that HU estimation should be carefully examined, considering that uncertainty in the tumor radiodensity may propagate to quantification of other characteristics, such as size and texture.

  11. The c-Met Inhibitor MSC2156119J Effectively Inhibits Tumor Growth in Liver Cancer Models

    Energy Technology Data Exchange (ETDEWEB)

    Bladt, Friedhelm, E-mail: Friedhelm.Bladt@merckgroup.com; Friese-Hamim, Manja; Ihling, Christian; Wilm, Claudia; Blaukat, Andree [EMD Serono, and Merck Serono Research and Development, Merck KGaA, Darmstadt 64293 (Germany)

    2014-08-19

    The mesenchymal-epithelial transition factor (c-Met) is a receptor tyrosine kinase with hepatocyte growth factor (HGF) as its only high-affinity ligand. Aberrant activation of c-Met is associated with many human malignancies, including hepatocellular carcinoma (HCC). We investigated the in vivo antitumor and antimetastatic efficacy of the c-Met inhibitor MSC2156119J (EMD 1214063) in patient-derived tumor explants. BALB/c nude mice were inoculated with MHCC97H cells or with tumor fragments of 10 patient-derived primary liver cancer explants selected according to c-Met/HGF expression levels. MSC2156119J (10, 30, and 100 mg/kg) and sorafenib (50 mg/kg) were administered orally as single-agent treatment or in combination, with vehicle as control. Tumor response, metastases formation, and alpha fetoprotein (AFP) levels were measured. MSC2156119J inhibited tumor growth and induced complete regression in mice bearing subcutaneous and orthotopic MHCC97H tumors. AFP levels were undetectable after 5 weeks of MSC2156119J treatment, and the number of metastatic lung foci was reduced. Primary liver explant models with strong c-Met/HGF activation showed increased responsiveness to MSC2156119J, with MSC2156119J showing similar or superior activity to sorafenib. Tumors characterized by low c-Met expression were less sensitive to MSC2156119J. MSC2156119J was better tolerated than sorafenib, and combination therapy did not improve efficacy. These findings indicate that selective c-Met/HGF inhibition with MSC2156119J is associated with marked regression of c-Met high-expressing tumors, supporting its clinical development as an antitumor treatment for HCC patients with active c-Met signaling.

  12. Tumor-Like Liver Abscess Mimicking Malignancy With Lung Metastases in a Patient With Acute Renal Failure: A Case Report.

    Science.gov (United States)

    Wang, Chih Hsin; Sun, Cheuk-Kay; Jiang, Jiunn-Song; Tsai, Ming Hsien

    2016-03-01

    The worldwide incidence of Klebsiella pneumoniae liver abscess (KLA) is increasing. It is important to accurately diagnose this life-threatening disease to provide timely and appropriate treatment. Here we report the case of a 38-year-old man with acute renal failure and a tumor-like liver abscess and septic pulmonary embolism. Initially, his clinical symptoms, laboratory tests, and radiological findings presented equivocal results of malignancy with metastases. Fine needle aspiration of liver tumor was performed, which showed purulent material with a culture positive for K pneumoniae. KLA symptoms are atypical, and radiological findings may mimic a malignancy with tumor necrosis. In some circumstances, liver aspiration biopsy may be necessary to confirm the real etiology, leading to prompt and timely treatment. Moreover, we should be alert for the impression of KLA when facing a diabetic patient with liver mass lesion and acute renal failure.

  13. Development and validation of a microRNA based diagnostic assay for primary tumor site classification of liver core biopsies

    DEFF Research Database (Denmark)

    Perell, Katharina; Vincent, Martin; Vainer, Ben

    2015-01-01

    for normal liver tissue contamination. Performance was estimated by cross-validation, followed by independent validation on 55 liver core biopsies with a tumor content as low as 10%. A microRNA classifier developed, using the statistical contamination model, showed an overall classification accuracy of 74...... on classification. MicroRNA profiling was performed using quantitative Real-Time PCR on formalin-fixed paraffin-embedded samples. 278 primary tumors and liver metastases, representing nine primary tumor classes, as well as normal liver samples were used as a training set. A statistical model was applied to adjust.......5% upon independent validation. Two-thirds of the samples were classified with high-confidence, with an accuracy of 92% on high-confidence predictions. A classifier trained without adjusting for liver tissue contamination, showed a classification accuracy of 38.2%. Our results indicate that surrounding...

  14. Extracellular vesicles as shuttles of tumor biomarkers and anti-tumor drugs.

    Science.gov (United States)

    Zocco, Davide; Ferruzzi, Pietro; Cappello, Francesco; Kuo, Winston Patrick; Fais, Stefano

    2014-01-01

    Extracellular vesicles (EV) include vesicles released by either normal or tumor cells. EV may exceed the nanometric scale (microvesicles), or to be within the nanoscale, also called exosomes. Thus, it appears that only exosomes and larger vesicles may have the size for potential applications in nanomedicine, in either disease diagnosis or therapy. This is of particular interest for research in cancer, also because the vast majority of existing data on EV are coming from pre-clinical and clinical oncology. We know that the microenvironmental features of cancer may favor cell-to-cell paracrine communication through EV, but EV have been purified, characterized, and quantified from plasma of tumor patients as well, thus suggesting that EV may have a role in promoting and maintaining cancer dissemination and progression. These observations are prompting research efforts to evaluate the use of nanovesicles as tumor biomarkers. Moreover, EVs are emerging as natural delivery systems and in particular, exosomes may represent the ideal natural nanoshuttles for new and old anti-tumor drugs. However, much is yet to be understood about the role of EV in oncology and this article aims to discuss the future of EV in cancer on the basis of current knowledge.

  15. Test systems in drug discovery for hazard identification and risk assessment of human drug-induced liver injury.

    Science.gov (United States)

    Weaver, Richard J; Betts, Catherine; Blomme, Eric A G; Gerets, Helga H J; Gjervig Jensen, Klaus; Hewitt, Philip G; Juhila, Satu; Labbe, Gilles; Liguori, Michael J; Mesens, Natalie; Ogese, Monday O; Persson, Mikael; Snoeys, Jan; Stevens, James L; Walker, Tracy; Park, B Kevin

    2017-07-01

    The liver is an important target for drug-induced toxicities. Early detection of hepatotoxic drugs requires use of well-characterized test systems, yet current knowledge, gaps and limitations of tests employed remains an important issue for drug development. Areas Covered: The current state of the science, understanding and application of test systems in use for the detection of drug-induced cytotoxicity, mitochondrial toxicity, cholestasis and inflammation is summarized. The test systems highlighted herein cover mostly in vitro and some in vivo models and endpoint measurements used in the assessment of small molecule toxic liabilities. Opportunities for research efforts in areas necessitating the development of specific tests and improved mechanistic understanding are highlighted. Expert Opinion: Use of in vitro test systems for safety optimization will remain a core activity in drug discovery. Substantial inroads have been made with a number of assays established for human Drug-induced Liver Injury. There nevertheless remain significant gaps with a need for improved in vitro tools and novel tests to address specific mechanisms of human Drug-Induced Liver Injury. Progress in these areas will necessitate not only models fit for application, but also mechanistic understanding of how chemical insult on the liver occurs in order to identify translational and quantifiable readouts for decision-making.

  16. A quantitative systems pharmacology approach, incorporating a novel liver model, for predicting pharmacokinetic drug-drug interactions.

    Science.gov (United States)

    Cherkaoui-Rbati, Mohammed H; Paine, Stuart W; Littlewood, Peter; Rauch, Cyril

    2017-01-01

    All pharmaceutical companies are required to assess pharmacokinetic drug-drug interactions (DDIs) of new chemical entities (NCEs) and mathematical prediction helps to select the best NCE candidate with regard to adverse effects resulting from a DDI before any costly clinical studies. Most current models assume that the liver is a homogeneous organ where the majority of the metabolism occurs. However, the circulatory system of the liver has a complex hierarchical geometry which distributes xenobiotics throughout the organ. Nevertheless, the lobule (liver unit), located at the end of each branch, is composed of many sinusoids where the blood flow can vary and therefore creates heterogeneity (e.g. drug concentration, enzyme level). A liver model was constructed by describing the geometry of a lobule, where the blood velocity increases toward the central vein, and by modeling the exchange mechanisms between the blood and hepatocytes. Moreover, the three major DDI mechanisms of metabolic enzymes; competitive inhibition, mechanism based inhibition and induction, were accounted for with an undefined number of drugs and/or enzymes. The liver model was incorporated into a physiological-based pharmacokinetic (PBPK) model and simulations produced, that in turn were compared to ten clinical results. The liver model generated a hierarchy of 5 sinusoidal levels and estimated a blood volume of 283 mL and a cell density of 193 × 106 cells/g in the liver. The overall PBPK model predicted the pharmacokinetics of midazolam and the magnitude of the clinical DDI with perpetrator drug(s) including spatial and temporal enzyme levels changes. The model presented herein may reduce costs and the use of laboratory animals and give the opportunity to explore different clinical scenarios, which reduce the risk of adverse events, prior to costly human clinical studies.

  17. A quantitative systems pharmacology approach, incorporating a novel liver model, for predicting pharmacokinetic drug-drug interactions.

    Directory of Open Access Journals (Sweden)

    Mohammed H Cherkaoui-Rbati

    Full Text Available All pharmaceutical companies are required to assess pharmacokinetic drug-drug interactions (DDIs of new chemical entities (NCEs and mathematical prediction helps to select the best NCE candidate with regard to adverse effects resulting from a DDI before any costly clinical studies. Most current models assume that the liver is a homogeneous organ where the majority of the metabolism occurs. However, the circulatory system of the liver has a complex hierarchical geometry which distributes xenobiotics throughout the organ. Nevertheless, the lobule (liver unit, located at the end of each branch, is composed of many sinusoids where the blood flow can vary and therefore creates heterogeneity (e.g. drug concentration, enzyme level. A liver model was constructed by describing the geometry of a lobule, where the blood velocity increases toward the central vein, and by modeling the exchange mechanisms between the blood and hepatocytes. Moreover, the three major DDI mechanisms of metabolic enzymes; competitive inhibition, mechanism based inhibition and induction, were accounted for with an undefined number of drugs and/or enzymes. The liver model was incorporated into a physiological-based pharmacokinetic (PBPK model and simulations produced, that in turn were compared to ten clinical results. The liver model generated a hierarchy of 5 sinusoidal levels and estimated a blood volume of 283 mL and a cell density of 193 × 106 cells/g in the liver. The overall PBPK model predicted the pharmacokinetics of midazolam and the magnitude of the clinical DDI with perpetrator drug(s including spatial and temporal enzyme levels changes. The model presented herein may reduce costs and the use of laboratory animals and give the opportunity to explore different clinical scenarios, which reduce the risk of adverse events, prior to costly human clinical studies.

  18. An Overview on the Proposed Mechanisms of Antithyroid Drugs-Induced Liver Injury

    Directory of Open Access Journals (Sweden)

    Reza Heidari

    2015-03-01

    Full Text Available Drug-induced liver injury (DILI is a major problem for pharmaceutical industry and drug development. Mechanisms of DILI are many and varied. Elucidating the mechanisms of DILI will allow clinicians to prevent liver failure, need for liver transplantation, and death induced by drugs. Methimazole and propylthiouracil (PTU are two convenient antithyroid agents which their administration is accompanied by hepatotoxicity as a deleterious side effect. Although several cases of antithyroid drugs-induced liver injury are reported, there is no clear idea about the mechanism(s of hepatotoxicity induced by these medications. Different mechanisms such as reactive metabolites formation, oxidative stress induction, intracellular targets dysfunction, and immune-mediated toxicity are postulated to be involved in antithyroid agents-induced hepatic damage. Due to the idiosyncratic nature of antithyroid drugs-induced hepatotoxicity, it is impossible to draw a specific conclusion about the mechanisms of liver injury. However, it seems that reactive metabolite formation and immune-mediated toxicity have a great role in antithyroids liver toxicity, especially those caused by methimazole. This review attempted to discuss different mechanisms proposed to be involved in the hepatic injury induced by antithyroid drugs.

  19. Tumors with intrahepatic bile duct differentiation in cirrhosis: implications on outcomes after liver transplantation.

    Science.gov (United States)

    Facciuto, Marcelo E; Singh, Manoj K; Lubezky, Nir; Selim, Motaz A; Robinson, Dorothy; Kim-Schluger, Leona; Florman, Sander; Ward, Stephen C; Thung, Swan N; Fiel, MariaIsabel; Schiano, Thomas D

    2015-01-01

    The role of liver transplantation (LT) in the management of cirrhotic patients with tumors exhibiting intrahepatic bile duct differentiation remains controversial. The objective of this study was to characterize the spectrum of these tumors and analyze post-LT outcomes. Retrospective pathology database search of explant histology analysis of liver transplants between April 1993 and November 2013. Thirty-two patients were analyzed, 75% were men with a mean age of 60 years. Seven patients had nodules demonstrating intrahepatic cholangiocarcinoma (I-CCA), nine had I-CCA nodules occurring concomitantly with hepatocellular carcinoma (HCC), and 16 had mixed HCC-CCA nodules. The median number of tumors was 1 and size was 2.5 cm. Overall patient survival post-LT at 1 and 5 years was 71% and 57%, respectively. Patients within Milan criteria, especially with I-CCA features, showed a 5-year tumor recurrence rate (10%) and 5-year survival rate (78%) comparable with other patients having HCC within Milan criteria. This series showed that patients with CCA within Milan criteria may be able to achieve acceptable long-term post-LT survival.

  20. Clinical experience with RF thermotherapy for nonresectable primary and secondary liver tumors

    International Nuclear Information System (INIS)

    Yonemura, Yutaka; Fujimura, Takashi; Takegawa, Shigeru; Miyata, Ryuwa; Kamata, Toru; Miyazaki, Itsuo; Nakajima, Kazuyoshi; Hisazumi, Haruo; Saito, Yasuo

    1987-01-01

    Twenty two patients with primary or secondary liver tumors were treated by radiofrequency hyperthermia (8 MHz) combined with radiation or chemotherapy. Hyperthermia was administered twice a week for 40 - 60 minutes per session up to a total of 5 - 48 sessions. Five fractions per week of irradiation (10 MV X ray) at 180 - 200 cGy or intraarterial chemotherapy using mitomycin C, cis-diamminedichroloplatinum or adriamycine were carried out. Intratumor temperature over 42.5 deg C were obtained in 9 of 17 patients. Of the 22 patients treated, 2 (9 %) showed complete response, 8 (36 %) partial response, 3 (14 %) minor response, 7 (32 %) no change and 2 (9 %) progressive disease. 7 out of 14 tumors, heated over 42.5 deg C showed complete or partial response but only 1 out of 5 tumors, heated under 42.5 deg C was responder. Complication observed were thrombocytopenia and leukopenia in 30 % of cases. These results showed that combined treatment of hyperthermia radiation and chemotherapy appear to be useful from of therapy for the patients with liver tumor. (author)

  1. [Imaging manifestations and pathologic basis for hepatic capsular retraction syndrome caused by benign and malignant liver tumors].

    Science.gov (United States)

    Ou, Youkuan; Xiao, Enhua; Shang, Quanliang; Chen, Juan

    2015-10-01

    To investigate the imaging manifestations of CT, MRI and pathological basis for hepatic capsular retraction syndrome caused by benign and malignant liver tumors.
 CT or MRI images and pathological features for hepatic capsular retraction syndrome were retrospectively analyzed in 50 patients with benign and malignant liver tumors. Picture archive and communication system (PACS) was used to observe and compare the morphology, size, width, depth, edge of the capsular retraction and the status of liquid under the liver capsule. The structure, differentiation and proliferation of the tumor were analyzed under the microscope.
 There were malignant liver tumors in 44 patients and benign tumor in 6 patients. The smooth or rough for the edge of capsular retraction was significant difference between the benign tumors and the malignant tumors with three differentiated grades (all PBenign and malignant hepatic tumors may appear capsule retraction syndrome, but there are morphological differences between them. The differences are closely related with the lesion size, differentiated degree of tumor and fibrous tissue proliferation.

  2. Analysis of factors affecting local tumor progression of colorectal cancer liver metastasis after radiofrequency ablation

    Energy Technology Data Exchange (ETDEWEB)

    Jeon, Seong Hee; Cho, Yun Ku; Choi, Seung A; Kim, Mi Young; Lee, Ho Suk [Veterans Health Service Medical Center, Seoul (Korea, Republic of)

    2017-03-15

    The purpose of this study was to evaluate the independent predictive factors for local tumor progression (LTP) of colorectal liver metastasis (CRLM) after radiofrequency ablation (RFA). Patients with CRLM were included in the analysis if nodules were up to five in number, each nodule was ≤ 5 cm, and RFA was performed in our center from January 2006 to December 2015. Univariate and multivariate analyses to identify the predictors of LTP were performed by using a Cox proportional hazard model. Overall, 58 tumors from 38 patients were included in this study. LTP occurred in 14 tumors from 9 patients. The overall 1- and 3-year LTP rates were 23.5% and 29.4%, respectively. Multivariate analysis showed that tumor size > 2 cm and insufficient ablative margin were two independently significant adverse prognostic factors for LTP (p = 0.045 and 0.022, respectively). The 3-year LTP rates for 33 and 25 tumors with and without sufficient ablative margin were 4.5% and 61.2%, respectively. The difference was statistically significant (p < 0.001). The difference in the 3-year LTP rates according to the tumor size was not statistically significant (p = 0.791). Insufficient ablative margin seems to be the most potent predictor of LTP after RFA of CRLM.

  3. Ultrasound-guided percutaneous radiofrequency ablation of liver tumors: How we do it safety and completely

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Jin Woong; Shin, Sang Soo; Heo, Suk Hee; Hong, Jun Hyung; Lim, Hyo Soon; Seon, Hyun Ju; Hur, Young Hoe; Park, Chang Hwan; Jeong, Yong Yeon; Kang, Heoung Keun [Chonnam National University Medical School, Gwangju (Korea, Republic of)

    2015-12-15

    Ultrasound-guided percutaneous radiofrequency (RF) ablation has become one of the most promising local cancer therapies for both resectable and nonresectable hepatic tumors. Although RF ablation is a safe and effective technique for the treatment of liver tumors, the outcome of treatment can be closely related to the location and shape of the tumors. There may be difficulties with RF ablation of tumors that are adjacent to large vessels or extrahepatic heat-vulnerable organs and tumors in the caudate lobe, possibly resulting in major complications or treatment failure. Thus, a number of strategies have been developed to overcome these challenges, which include artificial ascites, needle track ablation, fusion imaging guidance, parallel targeting, bypass targeting, etc. Operators need to use the right strategy in the right situation to avoid the possibility of complications and incomplete thermal tissue destruction; with the right strategy, RF ablation can be performed successfully, even for hepatic tumors in high-risk locations. This article offers technical strategies that can be used to effectively perform RF ablation as well as to minimize possible complications related to the procedure with representative cases and schematic illustrations.

  4. Laparoscopic microwave thermosphere ablation of malignant liver tumors: An analysis of 53 cases.

    Science.gov (United States)

    Zaidi, Nisar; Okoh, Alexis; Yigitbas, Hakan; Yazici, Pinar; Ali, Noaman; Berber, Eren

    2016-02-01

    Microwave thermosphere ablation (MTA) is a new technology that is designed to create spherical zones of ablation using a single antenna. The aim of this study is to assess the results of MTA in a large series of patients. This was a prospective study assessing the use of MTA in patients with malignant liver tumors. The procedures were done mostly laparoscopically and ablation zones created were assessed for completeness of tumor response, spherical geometry and recurrence on tri-phasic CT scans done on follow-up. There were a total of 53 patients with an average of 3 tumors measuring 1.5 cm. Ablations were performed laparoscopically in all but eight patients. Morbidity was 11.3% (n = 6), and mortality zero. On postoperative scans, there was 99.3% tumor destruction. Roundness indices A, B, and transverse were 1.1, 1.0, and 0.9, respectively. At a median follow-up of 4.5 months, incomplete ablation was seen in 1 of 149 lesions treated (0.7%) and local tumor recurrence in 1 lesion (0.7%). The results of this series confirm the safety and feasibility of MTA technology. The 99.3% rate of complete tumor ablation and low rate of local recurrence at short-term follow up are promising. © 2015 Wiley Periodicals, Inc.

  5. Peripheral hepatojejunostomy as palliative treatment for irresectable malignant tumors of the liver hilum.

    Science.gov (United States)

    Schlitt, H J; Weimann, A; Klempnauer, J; Oldhafer, K J; Nashan, B; Raab, R; Pichlmayr, R

    1999-02-01

    To evaluate the concept of surgical decompression of the biliary tree by peripheral hepatojejunostomy for palliative treatment of jaundice in patients with irresectable malignant tumors of the liver hilum. Jaundice, pruritus, and recurrent cholangitis are major clinical complications in patients with obstructive cholestasis resulting from malignant tumors of the liver hilum. Methods for palliative treatment include endoscopic stenting, percutaneous transhepatic drainage, and surgical decompression. The palliative treatment of choice should be safe, effective, and comfortable for the patient. In a retrospective study, surgical technique, perioperative complications, and efficacy of treatment were analyzed for 56 patients who had received a peripheral hepatojejunostomy between 1982 and 1997. Laparotomy in all of these patients had been performed as an attempt for curative resection. Hepatojejunostomy was exclusively palliative in 50 patients and was used for bridging to resection or transplantation in 7. Anastomosis was bilateral in 36 patients and unilateral in 20. The 1-month mortality in the study group was 9%; median survival was 6 months. In patients surviving >1 month, a marked and persistent decrease in cholestasis was achieved in 87%, although complete return to normal was rare. Among the patients with a marked decrease in cholestasis, 72% had no or only mild clinical symptoms such as fever or jaundice. Peripheral hepatojejunostomy is a feasible and reasonably effective palliative treatment for patients with irresectable tumors of the liver hilum. In patients undergoing exploratory laparotomy for attempted curative resection, this procedure frequently leads to persistent-although rarely complete-decompression of the biliary tree. In a few cases it may also be used for bridging to transplantation or liver resection after relief of cholestasis.

  6. Ectopic adrenocorticotropic hormone syndrome in a case of duodenal neuroendocrine tumor presenting with liver metastasis

    Directory of Open Access Journals (Sweden)

    J Khare

    2018-01-01

    Full Text Available Ectopic adrenocorticotropic hormone (ACTH syndrome is an uncommon disorder and comprises about 15% of all patients with Cushing's syndrome (CS. Duodenal carcinoids are rare, indolent tumors usually associated with a benign progression. We hereby report a rare case of CS resulting from ectopic ACTH secretion from a duodenal neuroendocrine tumor (NET presenting with liver metastasis. A 37-year-old female presented with abdominal discomfort and dyspepsia of 1-month duration. Ultrasound abdomen suggested a well-defined hypoechoic lesion in the left lobe of the liver, suggestive of neoplasia. On clinical examination, she had Cushingoid features and persistent hypokalemia. Midnight ACTH and cortisol levels were grossly elevated at 1027 pg/ml (n < 46 pg/ml and 87.56 μg/dl (n < 7.5 μg/ml, respectively. Both overnight and high-dose dexamethasone suppression test confirmed nonsuppressed cortisol levels - 86.04 and 84.42 μg/dl (n < 1.8 μg/ml, respectively. Magnetic resonance imaging brain showed a structurally normal pituitary gland. Computed tomography scan of the abdomen revealed hepatic lesion with bilateral adrenal enlargement. A diagnosis of ectopic ACTH-dependent CS was made. Intraoperatively, a duodenal lesion of 0.5 cm × 0.5 cm was identified alongside an 8 cm × 6 cm exophytic lesion in segment IV of the liver. Frozen section of the duodenal lesion was positive for NET. She underwent a Whipple's surgery, cholecystectomy, and left hepatic lobectomy. Postoperatively, she showed clinical and biochemical remission. Herewith, we report the third case of duodenal carcinoid tumor presenting as ectopic ACTH syndrome and the first with liver metastasis.

  7. Biodegradable Drug-Loaded Hydroxyapatite Nanotherapeutic Agent for Targeted Drug Release in Tumors.

    Science.gov (United States)

    Sun, Wen; Fan, Jiangli; Wang, Suzhen; Kang, Yao; Du, Jianjun; Peng, Xiaojun

    2018-03-07

    Tumor-targeted drug delivery systems have been increasingly used to improve the therapeutic efficiency of anticancer drugs and reduce their toxic side effects in vivo. Focused on this point, doxorubicin (DOX)-loaded hydroxyapatite (HAP) nanorods consisting of folic acid (FA) modification (DOX@HAP-FA) were developed for efficient antitumor treatment. The DOX-loaded nanorods were synthesized through in situ coprecipitation and hydrothermal method with a DOX template, demonstrating a new procedure for drug loading in HAP materials. DOX could be efficiently released from DOX@HAP-FA within 24 h in weakly acidic buffer solution (pH = 6.0) because of the degradation of HAP nanorods. With endocytosis under the mediation of folate receptors, the nanorods exhibited enhanced cellular uptake and further degraded, and consequently, the proliferation of targeted cells was inhibited. More importantly, in a tumor-bearing mouse model, DOX@HAP-FA treatment demonstrated excellent tumor growth inhibition. In addition, no apparent side effects were observed during the treatment. These results suggested that DOX@HAP-FA may be a promising nanotherapeutic agent for effective cancer treatment in vivo.

  8. The Hepatoprotection Provided by Taurine and Glycine against Antineoplastic Drugs Induced Liver Injury in an Ex Vivo Model of Normothermic Recirculating Isolated Perfused Rat Liver

    Directory of Open Access Journals (Sweden)

    Reza Heidari

    2016-03-01

    Full Text Available Taurine (2-aminoethane sulfonic acid is a non-protein amino acid found in high concentration in different tissues. Glycine (Amino acetic acid is the simplest amino acid incorporated in the structure of proteins. Several investigations indicate the hepatoprotective properties of these amino acids. On the other hand, antineoplastic agents-induced serum transaminase elevation and liver injury is a clinical complication. The current investigation was designed to screen the possible hepatoprotective properties of taurine and glycine against antineoplastic drugs-induced hepatic injury in an ex vivo model of isolated perfused rat liver. Rat liver was perfused with different concentration (10 μM, 100 μM and 1000 μM of antineoplastic drugs (Mitoxantrone, Cyclophosphamide, Cisplatin, 5 Fluorouracil, Doxorubicin and Dacarbazine via portal vein. Taurine and glycine were administered to drug-treated livers and liver perfusate samples were collected for biochemical measurements (ALT, LDH, AST, and K+. Markers of oxidative stress (reactive oxygen species formation, lipid peroxidation, total antioxidant capacity and glutathione were also assessed in liver tissue. Antineoplastic drugs caused significant pathological changes in perfusate biochemistry. Furthermore, markers of oxidative stress were significantly elevated in drug treated livers. It was found that taurine (5 and 10 mM and glycine (5 and 10 mM administration significantly mitigated the biomarkers of liver injury and attenuated drug induced oxidative stress. Our data indicate that taurine and glycine supplementation might help as potential therapeutic options to encounter anticancer drugs-induced liver injury.

  9. Suitability of semi-automated tumor response assessment of liver metastases using a dedicated software package

    International Nuclear Information System (INIS)

    Kalkmann, Janine; Ladd, S.C.; Greiff, A. de; Forsting, M.; Stattaus, J.

    2010-01-01

    Purpose: to evaluate the suitability of semi-automated compared to manual tumor response assessment (TRA) of liver metastases. Materials and methods: in total, 32 patients with colorectal cancer and liver metastases were followed by an average of 2.8 contrast-enhanced CT scans. Two observers (O1, O2) measured the longest diameter (LD) of 269 liver metastases manually and semi-automatically using software installed as thin-client on a PACS workstation (LMS-Liver, MEDIAN Technologies). LD and TRA (''progressive'', ''stable'', ''partial remission'') were performed according to RECIST (Response Evaluation Criteria in Solid Tumors) and analyzed for between-method, interobserver and intraobserver variability. The time needed for evaluation was compared for both methods. Results: all measurements correlated excellently (r ≥ 0.96). Intraobserver (semi-automated), interobserver (manual) and between-method differences (by O1) in LD of 1.4 ± 2.6 mm, 1.9 ± 1.9 mm and 2.1 ± 2.0 mm, respectively, were not significant. Interobserver (semi-automated) and between-method (by O2) differences in LD of 3.0 ± 3.0 mm and 2.6 ± 2.0 mm, respectively, reflected a significant variability (p < 0.01). The interobserver agreement in manual and semi-automated TRA was 91.4%. The intraobserver agreement in semi-automated TRA was 84.5%. Between both methods a TRA agreement of 86.2% was obtained. Semi-automated evaluation (2.7 min) took slightly more time than manual evaluation (2.3 min). Conclusion: semi-automated and manual evaluation of liver metastases yield comparable results in response assessments and require comparable effort. (orig.)

  10. Inflammatory cascades driven by tumor necrosis factor-alpha play a major role in the progression of acute liver failure and its neurological complications.

    Directory of Open Access Journals (Sweden)

    Anne Chastre

    Full Text Available Acute liver failure (ALF due to ischemic or toxic liver injury is a clinical condition that results from massive loss of hepatocytes and may lead to hepatic encephalopathy (HE, a serious neuropsychiatric complication. Although increased expression of tumor necrosis factor-alpha (TNF-α in liver, plasma and brain has been observed, conflicting results exist concerning its roles in drug-induced liver injury and on the progression of HE. The present study aimed to investigate the therapeutic value of etanercept, a TNF-α neutralizing molecule, on the progression of liver injury and HE in mice with ALF resulting from azoxymethane (AOM hepatotoxicity.Mice were administered saline or etanercept (10 mg/kg; i.p. 30 minutes prior to, or up to 6 h after AOM. Etanercept-treated ALF mice were sacrificed in parallel with vehicle-treated comatose ALF mice and controls. AOM induced severe hepatic necrosis, leading to HE, and etanercept administered prior or up to 3 h after AOM significantly delayed the onset of coma stages of HE. Etanercept pretreatment attenuated AOM-induced liver injury, as assessed by histological examination, plasma ammonia and transaminase levels, and by hepatic glutathione content. Peripheral inflammation was significantly reduced by etanercept as shown by decreased plasma IL-6 (4.1-fold; p<0.001 and CD40L levels (3.7-fold; p<0.001 compared to saline-treated ALF mice. Etanercept also decreased IL-6 levels in brain (1.2-fold; p<0.05, attenuated microglial activation (assessed by OX-42 immunoreactivity, and increased brain glutathione concentrations.These results indicate that systemic sequestration of TNF-α attenuates both peripheral and cerebral inflammation leading to delayed progression of liver disease and HE in mice with ALF due to toxic liver injury. These results suggest that etanercept may provide a novel therapeutic approach for the management of ALF patients awaiting liver transplantation.

  11. Drug-induced liver toxicity and prevention by herbal antioxidants: an overview

    Directory of Open Access Journals (Sweden)

    Divya eSingh

    2016-01-01

    Full Text Available The liver is the center for drug and xenobiotic metabolism, which is influenced most with medication/xenobiotic-mediated toxic activity. Drug-induced hepatotoxicity is common and its actual frequency is hard to determine due to underreporting, difficulties in detection or diagnosis, and incomplete observation of exposure. The death rate is high, up to about 10% for medication instigated liver danger. Endorsed medications (counting acetaminophen represented >50% of instances of intense liver failure in a study from the Acute Liver Failure Study Group (ALFSG of the patients admitted in 17 US healing facilities. Albeit different studies are accessible uncovering the mechanistic aspects of medication prompted hepatotoxicity, we are in the dilemma about the virtual story. The expanding prevalence and effectiveness of Ayurveda and herbal products in the treatment of various disorders led the investigators to look into their potential in countering drug-induced liver toxicity. Several plant products have been reported to date to mitigate the drug-induced toxicity. The dietary nature and less side reactions of the herbs provide them an extra edge over other candidates of supplementary medication. In this paper, we have discussed on the mechanism involved in drug-induced liver toxicity and the potential of herbal antioxidants as supplementary medication.

  12. Mouse precision-cut liver slices as an ex vivo model to study idiosyncratic drug-induced liver injury.

    Science.gov (United States)

    Hadi, Mackenzie; Chen, Yixi; Starokozhko, Viktoriia; Merema, Marjolijn T; Groothuis, Geny M M

    2012-09-17

    Idiosyncratic drug-induced liver injury (IDILI) has been the top reason for withdrawing drugs from the market or for black box warnings. IDILI may arise from the interaction of a drug's reactive metabolite with a mild inflammation that renders the liver more sensitive to injury resulting in increased toxicity (inflammatory stress hypothesis). Aiming to develop a robust ex vivo screening method to study inflammatory stress-related IDILI mechanisms and to find biomarkers that can detect or predict IDILI, mouse precision-cut liver slices (mPCLS) were coincubated for 24 h with IDILI-related drugs and lipopolysaccharide. Lipopolysaccharide exacerbated ketoconazole (15 μM) and clozapine (45 μM) toxicity but not their non-IDILI-related comparators, voriconazole (1500 μM) and olanzapine (45 μM). However, the other IDILI-related drugs tested [diclofenac (200 μM), carbamazepine (400 μM), and troglitazone (30 μM)] did not cause synergistic toxicity with lipopolysaccharide after 24 h of incubation. Lipopolysaccharide further decreased the reduced glutathione levels caused by ketoconazole or clozapine in mPCLS after 24 h of incubation, which was not the case for the other drugs. Lipopolysaccharide significantly increased nitric oxide (NO), cytokine, and chemokine release into the mPCLS media, while the treatment with the drugs alone did not cause any substantial change. All seven drugs drastically reduced lipopolysaccharide-induced NO production. Interestingly, only ketoconazole and clozapine increased the lipopolysaccharide-induced granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) release. Pilot experiments showed that diclofenac and troglitazone, but not carbamazepine, demonstrated synergistic toxicity with lipopolysaccharide after a longer incubation of 48 h in mPCLS. In conclusion, we have developed an ex vivo model to detect inflammatory stress-related liver toxicity and identified ketoconazole, clozapine

  13. Cyclophilin A enhances cell proliferation and tumor growth of liver fluke-associated cholangiocarcinoma

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    Sawanyawisuth Kanlayanee

    2011-08-01

    Full Text Available Abstract Background Cyclophilin A (CypA expression is associated with malignant phenotypes in many cancers. However, the role and mechanisms of CypA in liver fluke-associated cholangiocarcinoma (CCA are not presently known. In this study, we investigated the expression of CypA in CCA tumor tissues and CCA cell lines as well as regulation mechanisms of CypA in tumor growth using CCA cell lines. Methods CypA expression was determined by real time RT-PCR, Western blot or immunohistochemistry. CypA silence or overexpression in CCA cells was achieved using gene delivery techniques. Cell proliferation was assessed using MTS assay or Ki-67 staining. The effect of silencing CypA on CCA tumor growth was determined in nude mice. The effect of CypA knockdown on ERK1/2 activation was assessed by Western blot. Results CypA was upregulated in 68% of CCA tumor tissues. Silencing CypA significantly suppressed cell proliferation in several CCA cell lines. Likewise, inhibition of CypA peptidyl-prolyl cis-trans isomerase (PPIase activity using cyclosporin A (CsA decreased cell proliferation. In contrast, overexpression of CypA resulted in 30% to 35% increases in proliferation of CCA cell lines. Interestingly, neither silence nor overexpression of CypA affected cell proliferation of a non-tumor human cholangiocyte cell line, MMNK1. Suppression of CypA expression attenuated ERK1/2 activity in CCA M139 cells by using both transient and stable knockdown methods. In the in vivo study, there was a 43% reduction in weight of tumors derived from CypA-silenced CCA cell lines compared with control vector CCA tumors in mice; these tumors with stable CypA silencing showed a reduced cell proliferation. Conclusions CypA is upregulated in majority of CCA patients' tissues and confers a significant growth advantage in CCA cells. Suppression of CypA expression decreases proliferation of CCA cell lines in vitro and reduces tumor growth in the nude mouse model. Inhibition of Cyp

  14. Role of nonalcoholic fatty liver disease as risk factor for drug-induced hepatotoxicity

    Science.gov (United States)

    Massart, Julie; Begriche, Karima; Moreau, Caroline; Fromenty, Bernard

    2017-01-01

    Background Obesity is often associated with nonalcoholic fatty liver disease (NAFLD), which refers to a large spectrum of hepatic lesions including fatty liver, nonalcoholic steatohepatitis (NASH) and cirrhosis. Different investigations showed or suggested that obesity and NAFLD are able to increase the risk of hepatotoxicity of different drugs. Some of these drugs could induce more frequently an acute hepatitis in obese individuals whereas others could worsen pre-existing NAFLD. Aim The main objective of the present review was to collect the available information regarding the role of NAFLD as risk factor for drug-induced hepatotoxicity. For this purpose, we performed a data-mining analysis using different queries including drug-induced liver injury (or DILI), drug-induced hepatotoxicity, fatty liver, nonalcoholic fatty liver disease (or NAFLD), steatosis and obesity. The main data from the collected articles are reported in this review and when available, some pathophysiological hypotheses are put forward. Relevance for patients Drugs that could pose a potential risk in obese patients include compounds belonging to different pharmacological classes such as acetaminophen, halothane, methotrexate, rosiglitazone, stavudine and tamoxifen. For some of these drugs, experimental investigations in obese rodents confirmed the clinical observations and unveiled different pathophysiological mechanisms which could explain why these pharmaceuticals are particularly hepatotoxic in obesity and NAFLD. Other drugs such as pentoxifylline, phenobarbital and omeprazole might also pose a risk but more investigations are required to determine whether this risk is significant or not. Because obese people often take several drugs for the treatment of different obesity-related diseases such as type 2 diabetes, hyperlipidemia and coronary heart disease, it is urgent to identify the main pharmaceuticals that can cause acute hepatitis on a fatty liver background or induce NAFLD worsening

  15. A Glycyrrhetinic Acid-Modified Curcumin Supramolecular Hydrogel for liver tumor targeting therapy

    Science.gov (United States)

    Chen, Guoqin; Li, Jinliang; Cai, Yanbin; Zhan, Jie; Gao, Jie; Song, Mingcai; Shi, Yang; Yang, Zhimou

    2017-03-01

    Curcumin (Cur), a phenolic anti-oxidant compound obtained from Curcuma longa plant, possesses a variety of therapeutic properties. However, it is suffered from its low water solubility and low bioavailability property, which seriously restricts its clinical application. In this study, we developed a glycyrrhetinic acid (GA) modified curcumin supramolecular pro-gelator (GA-Cur) and a control compound Nap-Cur by replacing GA with the naphthylacetic acid (Nap). Both compounds showed good water solubility and could form supramolecular gels by disulfide bond reduction triggered by glutathione (GSH) in vitro. Both formed gels could sustainedly release Cur in buffer solutions. We also investigated the cytotoxicity of pro-gelators to HepG2 cells by a MTT assay and determined the cellular uptake behaviours of them by fluorescence microscopy and LC-MS. Due to the over expression of GA receptor in liver cancer cells, our pro-gelator of GA-Cur showed an enhanced cellular uptake and better inhibition capacity to liver tumor cells than Nap-Cur. Therefore, the GA-Cur could significantly inhibit HepG2 cell growth. Our study provides a novel nanomaterial for liver tumor chemotherapy.

  16. The effect of antifibrotic drugs in rat precision-cut fibrotic liver slices

    NARCIS (Netherlands)

    Westra, Inge M; Oosterhuis, Dorenda; Groothuis, Geny M M; Olinga, Peter

    2014-01-01

    Two important signaling pathways in liver fibrosis are the PDGF-and TGF beta pathway and compounds inhibiting these pathways are currently developed as antifibrotic drugs. Testing antifibrotic drugs requires large numbers of animal experiments with high discomfort. Therefore, a method to study these

  17. Assessment of intratumor hypoxia by integrated 18F-FDG PET / perfusion CT in a liver tumor model.

    Directory of Open Access Journals (Sweden)

    Yong Wang

    Full Text Available Hypoxia in solid tumors occurs when metabolic demands in tumor cells surpass the delivery of oxygenated blood. We hypothesize that the 18F-fluorodeoxyglucose (18F-FDG metabolism and tumor blood flow mismatch would correlate with tumor hypoxia.Liver perfusion computed tomography (CT and 18F-FDG positron emission tomography (PET imaging were performed in twelve rabbit livers implanted with VX2 carcinoma. Under CT guidance, a fiber optic probe was inserted into the tumor to measure the partial pressure of oxygen (pO2. Tumor blood flow (BF and standardized uptake value (SUV were measured to calculate flow-metabolism ratio (FMR. Tumor hypoxia was further identified using pimonidazole immunohistochemical staining. Pearson correlation analysis was performed to determine the correlation between the imaging parameters and pO2 and pimonidazole staining.Weak correlations were found between blood volume (BV and pO2 level (r = 0.425, P = 0.004, SUV and pO2 (r = -0.394, P = 0.007, FMR and pimonidazole staining score (r = -0.388, P = 0.031. However, there was stronger correlation between tumor FMR and pO2 level (r = 0.557, P < 0.001.FMR correlated with tumor oxygenation and pimonidazole staining suggesting it may be a potential hypoxic imaging marker in liver tumor.

  18. SU-D-201-04: Study On the Impact of Tumor Shape and Size On Drug Delivery to Pancreatic Tumors

    International Nuclear Information System (INIS)

    Soltani, M; Bazmara, H; Sefidgar, M; Subramaniam, R; Rahmim, A

    2015-01-01

    Purpose: Drug delivery to solid tumors can be expressed physically using transport phenomena such as convection and diffusion for the drug of interest within extracellular matrices. We aimed to carefully model these phenomena, and to investigate the effect of tumor shape and size on drug delivery to solid tumors in the pancreas. Methods: In this study, multiple tumor geometries as obtained from clinical PET/CT images were considered. An advanced numerical method was used to simultaneously solve fluid flow and solute transport equations. Data from n=45 pancreatic cancer patients with non-resectable locoregional disease were analyzed, and geometrical information from the tumors including size, shape, and aspect ratios were classified. To investigate effect of tumor shape, tumors with similar size but different shapes were selected and analyzed. Moreover, to investigate effect of tumor size, tumors with similar shapes but different sizes, ranging from 1 to 77 cm 3 , were selected and analyzed. A hypothetical tumor similar to one of the analyzed tumors, but scaled to reduce its size below 0.2 cm 3 , was also analyzed. Results: The results showed relatively similar average drug concentration profiles in tumors with different sizes. Generally, smaller tumors had higher absolute drug concentration. In the hypothetical tumor, with volume less than 0.2 cm 3 , the average drug concentration was 20% higher in comparison to its counterparts. For the various real tumor geometries, however, the maximum difference between average drug concentrations was 10% for the smallest and largest tumors. Moreover, the results demonstrated that for pancreatic tumors the shape is not significant. The negligible difference of drug concentration in different tumor shapes was due to the minimum effect of convection in pancreatic tumors. Conclusion: In tumors with different sizes, smaller tumors have higher drug delivery; however, the impact of tumor shape in the case of pancreatic tumors is not

  19. SU-D-201-04: Study On the Impact of Tumor Shape and Size On Drug Delivery to Pancreatic Tumors

    Energy Technology Data Exchange (ETDEWEB)

    Soltani, M [ohns Hopkins University School of Medicine, Baltimore, Maryland, and KNT university, Tehran (Iran, Islamic Republic of); Bazmara, H [KNT university, Tehran (Iran, Islamic Republic of); Sefidgar, M [IKI University, Qazvin (Iran, Islamic Republic of); Subramaniam, R; Rahmim, A [Johns Hopkins University School of Medicine, Baltimore, MD (United States)

    2015-06-15

    Purpose: Drug delivery to solid tumors can be expressed physically using transport phenomena such as convection and diffusion for the drug of interest within extracellular matrices. We aimed to carefully model these phenomena, and to investigate the effect of tumor shape and size on drug delivery to solid tumors in the pancreas. Methods: In this study, multiple tumor geometries as obtained from clinical PET/CT images were considered. An advanced numerical method was used to simultaneously solve fluid flow and solute transport equations. Data from n=45 pancreatic cancer patients with non-resectable locoregional disease were analyzed, and geometrical information from the tumors including size, shape, and aspect ratios were classified. To investigate effect of tumor shape, tumors with similar size but different shapes were selected and analyzed. Moreover, to investigate effect of tumor size, tumors with similar shapes but different sizes, ranging from 1 to 77 cm{sup 3}, were selected and analyzed. A hypothetical tumor similar to one of the analyzed tumors, but scaled to reduce its size below 0.2 cm{sup 3}, was also analyzed. Results: The results showed relatively similar average drug concentration profiles in tumors with different sizes. Generally, smaller tumors had higher absolute drug concentration. In the hypothetical tumor, with volume less than 0.2 cm{sup 3}, the average drug concentration was 20% higher in comparison to its counterparts. For the various real tumor geometries, however, the maximum difference between average drug concentrations was 10% for the smallest and largest tumors. Moreover, the results demonstrated that for pancreatic tumors the shape is not significant. The negligible difference of drug concentration in different tumor shapes was due to the minimum effect of convection in pancreatic tumors. Conclusion: In tumors with different sizes, smaller tumors have higher drug delivery; however, the impact of tumor shape in the case of pancreatic

  20. Classification of malignant and benign liver tumors using a radiomics approach

    Science.gov (United States)

    Starmans, Martijn P. A.; Miclea, Razvan L.; van der Voort, Sebastian R.; Niessen, Wiro J.; Thomeer, Maarten G.; Klein, Stefan

    2018-03-01

    Correct diagnosis of the liver tumor phenotype is crucial for treatment planning, especially the distinction between malignant and benign lesions. Clinical practice includes manual scoring of the tumors on Magnetic Resonance (MR) images by a radiologist. As this is challenging and subjective, it is often followed by a biopsy. In this study, we propose a radiomics approach as an objective and non-invasive alternative for distinguishing between malignant and benign phenotypes. T2-weighted (T2w) MR sequences of 119 patients from multiple centers were collected. We developed an efficient semi-automatic segmentation method, which was used by a radiologist to delineate the tumors. Within these regions, features quantifying tumor shape, intensity, texture, heterogeneity and orientation were extracted. Patient characteristics and semantic features were added for a total of 424 features. Classification was performed using Support Vector Machines (SVMs). The performance was evaluated using internal random-split cross-validation. On the training set within each iteration, feature selection and hyperparameter optimization were performed. To this end, another cross validation was performed by splitting the training sets in training and validation parts. The optimal settings were evaluated on the independent test sets. Manual scoring by a radiologist was also performed. The radiomics approach resulted in 95% confidence intervals of the AUC of [0.75, 0.92], specificity [0.76, 0.96] and sensitivity [0.52, 0.82]. These approach the performance of the radiologist, which were an AUC of 0.93, specificity 0.70 and sensitivity 0.93. Hence, radiomics has the potential to predict the liver tumor benignity in an objective and non-invasive manner.

  1. Precision-cut mouse liver slices as an ex vivo model to study the mechanism of inflammatory stress-related idiosyncratic drug-induced liver injury

    NARCIS (Netherlands)

    Hadi, Mackenzie; Chen, Y.; Starokozhko, Viktoriia; Merema, Maja; Groothuis, Genoveva

    2012-01-01

    Idiosyncratic drug reactions (IDRs) can be defined as adverse drug reactions that occur in a small minority of the patients taking clinically-relevant doses and do not involve the known pharmacological effects of the drug. IDR related to hepatotoxicity or idiosyncratic drug-induced liver injury

  2. Target coverage in image-guided stereotactic body radiotherapy of liver tumors.

    Science.gov (United States)

    Wunderink, Wouter; Méndez Romero, Alejandra; Vásquez Osorio, Eliana M; de Boer, Hans C J; Brandwijk, René P; Levendag, Peter C; Heijmen, Ben J M

    2007-05-01

    To determine the effect of image-guided procedures (with computed tomography [CT] and electronic portal images before each treatment fraction) on target coverage in stereotactic body radiotherapy for liver patients using a stereotactic body frame (SBF) and abdominal compression. CT guidance was used to correct for day-to-day variations in the tumor's mean position in the SBF. By retrospectively evaluating 57 treatment sessions, tumor coverage, as obtained with the clinically applied CT-guided protocol, was compared with that of alternative procedures. The internal target volume-plus (ITV(+)) was introduced to explicitly include uncertainties in tumor delineations resulting from CT-imaging artifacts caused by residual respiratory motion. Tumor coverage was defined as the volume overlap of the ITV(+), derived from a tumor delineated in a treatment CT scan, and the planning target volume. Patient stability in the SBF, after acquisition of the treatment CT scan, was evaluated by measuring the displacement of the bony anatomy in the electronic portal images relative to CT. Application of our clinical protocol (with setup corrections following from manual measurements of the distances between the contours of the planning target volume and the daily clinical target volume in three orthogonal planes, multiple two-dimensional) increased the frequency of nearly full (> or = 99%) ITV(+) coverage to 77% compared with 63% without setup correction. An automated three-dimensional method further improved the frequency to 96%. Patient displacements in the SBF were generally small (design, patient stability in the SBF should be verified with portal imaging.

  3. Combined cytotoxic effects of tumor necrosis factor-alpha with various cytotoxic agents in tumor cell lines that are drug resistant due to mutated p53

    NARCIS (Netherlands)

    Sleijfer, S; Le, T. K. P.; de Jong, S.; Timmer-Bosscha, H; Withoff, S; Mulder, NH

    Several studies suggest that tumor necrosis factor-alpha (TNF) is able to overcome drug resistance in tumors. Whether TNF is able to do so in tumor cell lines that are drug resistant due to a mutation in the tumor suppressor gene p53 is unclear. Therefore, we studied the in vitro cytotoxic effects

  4. Adverse effects of the antimalaria drug, mefloquine: due to primary liver damage with secondary thyroid involvement?

    Directory of Open Access Journals (Sweden)

    Herxheimer Andrew

    2002-03-01

    Full Text Available Abstract Background Mefloquine is a clinically important antimalaria drug, which is often not well tolerated. We critically reviewed 516 published case reports of mefloquine adverse effects, to clarify the phenomenology of the harms associated with mefloquine, and to make recommendations for safer prescribing. Presentation We postulate that many of the adverse effects of mefloquine are a post-hepatic syndrome caused by primary liver damage. In some users we believe that symptomatic thyroid disturbance occurs, either independently or as a secondary consequence of the hepatocellular injury. The mefloquine syndrome presents in a variety of ways including headache, gastrointestinal disturbances, nervousness, fatigue, disorders of sleep, mood, memory and concentration, and occasionally frank psychosis. Previous liver or thyroid disease, and concurrent insults to the liver (such as from alcohol, dehydration, an oral contraceptive pill, recreational drugs, and other liver-damaging drugs may be related to the development of severe or prolonged adverse reactions to mefloquine. Implications We believe that people with active liver or thyroid disease should not take mefloquine, whereas those with fully resolved neuropsychiatric illness may do so safely. Mefloquine users should avoid alcohol, recreational drugs, hormonal contraception and co-medications known to cause liver damage or thyroid damage. With these caveats, we believe that mefloquine may be safely prescribed in pregnancy, and also to occupational groups who carry out safety-critical tasks. Testing Mefloquine's adverse effects need to be investigated through a multicentre cohort study, with small controlled studies testing specific elements of the hypothesis.

  5. An image-guided system for optimized volumetric treatment planning and execution for radiofrequency ablation of liver tumors

    Energy Technology Data Exchange (ETDEWEB)

    Banovac, F.; Popa, T.; Cheng, P.; Cleary, K. [Computer Aided Interventions and Medical Robotics (CAIMR), Imaging Science and Information Systems (ISIS) Center, Georgetown Univ. Medical Center, Washington, DC (United States); Abeledo, H.; Campos-Nanez, E. [Dept. of Engineering Management and System Engineering, George Washington Univ., Washington, DC (United States); Wood, B.J. [Diagnostic Radiology Dept., NIH Clinical Center, Bethesda, MD (United States)

    2007-06-15

    Radiofrequency ablation of liver tumors is becoming an increasingly popular option for the treatment of cancer. However, the procedure has several technical challenges, mostly associated with precision targeting of the tumor and ensuring complete ablation coverage. In this paper we describe an image-guided system that we are developing for improved visualization and probe placement during these procedures. The system will include a pre-procedure optimization module and an intra-procedure guidance component. The system concept is explained and some preliminary results are given. While this system is designed for radiofrequency ablation of liver tumors, the methods are applicable to other organs and treatment methods. (orig.)

  6. Effects of Arsenic Trioxide on Radiofrequency Ablation of VX2 Liver Tumor: Intraarterial versus Intravenous Administration

    Energy Technology Data Exchange (ETDEWEB)

    Seong, Nak Jong; Yoon, Chang Jin; Kang, Sung Gwon [Seoul National University Bundang Hospital, Seongnam (Korea, Republic of); Chung, Jin Wook; Kim, Hyo Cheol; Park, Jae Hyung [Seoul National University Hospital, Seoul (Korea, Republic of)

    2012-03-15

    Arsenic trioxide (As{sub 2}O{sub 3}) can be used as a possible pharmaceutical alternative that augments radiofrequency (RF) ablation by reducing tumor blood flow. The aim of this study was to assess the effect of intraarterial and intravenous administration of As{sub 2}O{sub 3} on RF-induced ablation in an experimentally induced liver tumor. VX2 carcinoma was grown in the livers of 30 rabbits. As{sub 2}O{sub 3} (1 mg/kg) was administered through the hepatic artery (n = 10, group A) or ear vein (n = 10, group B), 30 minutes before RF ablation (125 mA {+-} 35; 90 {+-} 5 degrees Celsius). As a control group, 10 rabbits were treated with RF ablation alone (group C). RF was intentionally applied to the peripheral margin of the tumor so that ablation can cover the tumor and adjacent hepatic parenchyma. Ablation areas of the tumor and adjacent parenchymal changes among three groups were compared by the Kruskal-Wallis and Mann-Whitney U test. The overall ablation areas were 156 {+-} 28.9 mm{sup 2} (group A), 119 {+-} 31.7 (group B), and 92 {+-} 17.4 (group C, p < 0.04). The ablation area of the tumor was significantly larger in group A (73 {+-} 19.7 mm{sup 2}) than both group B (50 {+-} 19.4, p = 0.02) and group C (28 {+-} 2.2, p < 0.01). The ratios of the tumoral ablation area to the overall ablation area were larger in group A (47 {+-} 10.5%) than that of the other groups (42 {+-} 7.3% in group B and 32 {+-} 5.6% in group C) (p < 0.03). Radiofrequency-induced ablation area can be increased with intraarterial or intravenous administration of As{sub 2}O{sub 3}. The intraarterial administration of As{sub 2}O{sub 3} seems to be helpful for the selective ablation of the tumor.

  7. Comprehensive preclinical evaluation of a multi-physics model of liver tumor radiofrequency ablation.

    Science.gov (United States)

    Audigier, Chloé; Mansi, Tommaso; Delingette, Hervé; Rapaka, Saikiran; Passerini, Tiziano; Mihalef, Viorel; Jolly, Marie-Pierre; Pop, Raoul; Diana, Michele; Soler, Luc; Kamen, Ali; Comaniciu, Dorin; Ayache, Nicholas

    2017-09-01

    We aim at developing a framework for the validation of a subject-specific multi-physics model of liver tumor radiofrequency ablation (RFA). The RFA computation becomes subject specific after several levels of personalization: geometrical and biophysical (hemodynamics, heat transfer and an extended cellular necrosis model). We present a comprehensive experimental setup combining multimodal, pre- and postoperative anatomical and functional images, as well as the interventional monitoring of intra-operative signals: the temperature and delivered power. To exploit this dataset, an efficient processing pipeline is introduced, which copes with image noise, variable resolution and anisotropy. The validation study includes twelve ablations from five healthy pig livers: a mean point-to-mesh error between predicted and actual ablation extent of 5.3 ± 3.6 mm is achieved. This enables an end-to-end preclinical validation framework that considers the available dataset.

  8. RGD-modified lipid disks as drug carriers for tumor targeted drug delivery

    Science.gov (United States)

    Gao, Jie; Xie, Cao; Zhang, Mingfei; Wei, Xiaoli; Yan, Zhiqiang; Ren, Yachao; Ying, Man; Lu, Weiyue

    2016-03-01

    Melittin, the major component of the European bee venom, is a potential anticancer candidate due to its lytic properties. However, in vivo applications of melittin are limited due to its main side effect, hemolysis, especially when applied through intravenous administration. The polyethylene glycol-stabilized lipid disk is a novel type of nanocarrier, and the rim of lipid disks has a high affinity to amphiphilic peptides. In our study, a c(RGDyK) modified lipid disk was developed as a tumor targeted drug delivery system for melittin. Cryo-TEM was used to confirm the shape and size of lipid disks with or without c(RGDyK) modification. In vitro and in vivo hemolysis analyses revealed that the hemolysis effect significantly decreased after melittin associated with lipid disks. Importantly, the results of our in vivo biodistribution and tumor growth inhibitory experiments showed that c(RGDyK) modification increased the distribution of lipid disks in the tumor and the anticancer efficacy of melittin loaded lipid disks. Thus, we successfully achieved a targeted drug delivery system for melittin and other amphiphilic peptides with a good therapeutic effect and low side effects.

  9. Assessment of the image quality and tumor detectability of breath-hold T2-weighted imaging of liver tumors using a fast gradient MR system

    International Nuclear Information System (INIS)

    Yoshida, Kotaro; Suto, Yuji; Sugihara, Shuji; Tokuda, Yukiko

    1996-01-01

    Fourteen patients with various types of focal liver tumors were imaged with turbo spin-echo (TSE), breath-hold TSE (BH-TSE) and half-Fourier single-shot TSE (HASTE) pulse sequences using a fast gradient magnetic resonance imaging (MRI) system. We compared the T2-weighted images of the liver with the TSE, BH-TSE, HASTE and conventional spin-echo (SE) pulse sequences in order to determine whether those fast T2-weighted images, including fat suppressed images, could replace SE images. In quantitative and qualitative analysis, the fast T2-weighted images were slightly superior to the SE images, but they were inferior in the conspicuousness of liver tumor to the SE images. These findings suggest that the fast T2-weighted images can shorten the examination time of the liver MRI, but cannot replace the T2-weighted SE images because of the low conspicuousness. (author)

  10. Ursodeoxycholic Acid Can Improve Liver Transaminase Quantities in Children with Anticonvulsant Drugs Hepatotoxicity: a Pilot Study.

    Directory of Open Access Journals (Sweden)

    Masoumeh Asgarshirazi

    2015-06-01

    Full Text Available The present study has been directed to investigate Ursodeoxycholic Acid (UDCA effect in children, to reduce the high Liver transaminases induced by Anticonvulsant drugs (drug induced hepatitis. This idea has been driven from Cytoprotective and antioxidant properties of UDCA to be used in drug induced inflammation in Liver. Twenty two epileptic patients aged between 4 mo - 3 yr whom were under anticonvulsant therapy with drugs such as valperoic acid, primidone, levetiracetam, Phenobarbital or any combination of them and had shown Liver transaminases rise , after rule out of Viral-Autoimmune, Metabolic and Anatomic causes, have been prescribed UDCA in dose of 10-15 mg/kg/day, at least for 6 months. Any patient who have shown confusing factors such as genetic disorders with liver involvement or spontaneous decline in enzymes or had not treatment compliance has been excluded from the study. Transaminases range changes as well as Probable side effects of the drug have been monitored. The results indicated that UDCA is effective and well tolerable in the children with drug induced hyper transaminasemia. No side effect has been seen and recorded in this study. Based on this study and its results, we recommend UDCA as a safe and effective choice in drug induced hepatotoxicities.

  11. Is percutaneous microwave ablation of liver tumor safe for patients with renal dysfunction

    International Nuclear Information System (INIS)

    Liu Cun; Wang Yang; Yu Xiaoling; Dong Baowei; Zhou Pei; Ren He; Liang Ping

    2011-01-01

    Purpose: To determine the safety of percutaneous microwave ablation of primary and metastatic liver tumor for patients with renal dysfunction. Materials and methods: Fifty primary and metastatic liver tumors in 23 patients with renal dysfunction were retrospectively reviewed at our institution. Renal function was determined by measuring serum creatinine and serum urea before MWA as baseline, within 1 week and at last follow-up. The mean creatinine was 1.69 ± 0.32 mg/dL, 1.71 ± 0.33 mg/dL, and 1.71 ± 0.26 mg/dL respectively, there was not a statistically significant difference between baseline and at last follow-up (P = 0.26). The mean serum urea was 52.52 ± 6.48 mg/dL, 56.55 ± 14.72 mg/dL, and 57.90 ± 16.39 mg/dL respectively, there was not a statistically significant difference between baseline and within 1 week (P = 0.119), between within baseline and at last follow-up (P = 0.090). At the last follow-up examination, all patients had adequately functioning kidneys and did not require any form of renal replacement therapy. This is a small retrospectively study including highly selected patients treated. Therefore, further study should to determine the safety of percutaneous MWA for patients with renal dysfunction in the future. Conclusions: Percutaneous microwave ablation of primary and metastatic liver tumor is no adverse influence on renal function for patients with renal dysfunction in this preliminary series, which can be a minimally invasive alternative therapy.

  12. Tumors of the liver; a ten year study in Children Medical Center

    Directory of Open Access Journals (Sweden)

    Farahmand F

    2007-06-01

    Full Text Available Background: The aim of this study was to review the frequency, histopathology and outcome in children with tumors of the liver. Methods: Included in this retrospective/descriptive study were 30 children treated for liver tumors from 1375-1384 (ca. 1996-2005, at Children’s Hospital Medical Center, Tehran, Iran. We included the clinical, radiologic, and pathologic data of our patients, focusing on the frequency, etiology and outcome. Results: Patient ages ranged from three months to 12 years (median 3.8 years, with 18 males (60% and 12 females (40%. Of these, 17 patients had hepatoblastoma (55.66%, including 13 males and four females, with an age range of six months to five years. Four cases (13.33% had neuroblastoma. Hepatocellular carcinoma (HCC was found in three cases (10%, all of whom were carriers of hepatitis B. Two cases (6.66% were diagnosed with mesenchymal hamartoma, two cases (6.66% with hemangioendothelioma and two cases (6.66% with rhabdomyosarcoma and leiomyosarcoma of the biliary tract. Abdominal swelling and hepatomegaly were seen in all of patients. Jaundice was observed in two cases. Serum alpha-fetoprotein levels greater than 500 ng/ml were seen in 17 cases (56.66%. All patients were receiving specific treatment. The three-year survival rate was 65% for hepatoblastoma and 2% for HCC Conclusion: With the introduction of specific treatment, the survival rate for children with tumors of the liver has significantly increased. Further improvement can be achieved using diagnostic biopsy for hepatoblastoma, although it may result in complications, and preoperative chemotherapy followed by complete surgical excision (per International Society of Pediatric Oncology guidelines, yielding an outstanding survival rate of 80%.

  13. Multitriggered Tumor-Responsive Drug Delivery Vehicles Based on Protein and Polypeptide Coassembly for Enhanced Photodynamic Tumor Ablation.

    Science.gov (United States)

    Zhang, Ning; Zhao, Fenfang; Zou, Qianli; Li, Yongxin; Ma, Guanghui; Yan, Xuehai

    2016-11-01

    Tumor-responsive nanocarriers are highly valuable and demanded for smart drug delivery particularly in the field of photodynamic therapy (PDT), where a quick release of photosensitizers in tumors is preferred. Herein, it is demonstrated that protein-based nanospheres, prepared by the electrostatic assembly of proteins and polypeptides with intermolecular disulfide cross-linking and surface polyethylene glycol coupling, can be used as versatile tumor-responsive drug delivery vehicles for effective PDT. These nanospheres are capable of encapsulation of various photosensitizers including Chlorin e6 (Ce6), protoporphyrin IX, and verteporfin. The Chlorin e6-encapsulated nanospheres (Ce6-Ns) are responsive to changes in pH, redox potential, and proteinase concentration, resulting in multitriggered rapid release of Ce6 in an environment mimicking tumor tissues. In vivo fluorescence imaging results indicate that Ce6-Ns selectively accumulate near tumors and the quick release of Ce6 from Ce6-Ns can be triggered by tumors. In tumors the fluorescence of released Ce6 from Ce6-Ns is observed at 0.5 h postinjection, while in normal tissues the fluorescence appeared at 12 h postinjection. Tumor ablation is demonstrated by in vivo PDT using Ce6-Ns and the biocompatibility of Ce6-Ns is evident from the histopathology imaging, confirming the enhanced in vivo PDT efficacy and the biocompatibility of the assembled drug delivery vehicles. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  14. Impact of associating liver partition and portal vein occlusion for staged hepatectomy on tumor growth in a mouse model of liver metastasis.

    Science.gov (United States)

    Kikuchi, Yutaro; Hiroshima, Yukihiko; Matsuo, Kenichi; Murakami, Takashi; Kawaguchi, Daisuke; Kasahara, Kohei; Tanaka, Kuniya

    2018-01-01

    The impact of associating liver partition and portal vein occlusion for staged hepatectomy (ALPPS) on tumor growth activity was investigated. A BALB/c mouse model (male, 8-10 weeks old) of liver metastasis labeled by red fluorescent protein was established. Changes in future liver remnant (FLR) volumes, tumor growth activity, and levels of cytokines and growth factors in liver tissues during the treatment period were compared among the models involving ALPPS, portal vein ligation (PVL), or sham operation. The ratio of the FLR volume to body weight at 24 h after the procedure was greater for ALPPS (4.45 ± 0.12 × 10 -2 ) than for PVL (3.79 ± 0.12 × 10 -2 ; P = 0.003) and sham operation (3.18 ± 0.16 × 10 -2 ; P < 0.001). No differences in tumor progression in the FLR were observed at any time point after the procedures. Within the deportalized liver (DL), although tumor progression was observed during a later period after ALPPS (9 days postoperative) and PVL (12 days postoperative), no acceleration of tumor growth after ALPPS was observed in an early period similar to PVL. ALPPS induces a rapid increase in FLR volume and avoids remnant tumor progression during the early postoperative period. Copyright © 2017 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

  15. Evaluating the influence of setup uncertainties on treatment planning for focal liver tumors

    International Nuclear Information System (INIS)

    Balter, J.M.; Brock, K.K.; Lam, K.L.; Dawson, L.A.; McShan, D.L.; Ten Haken, R.K.

    2001-01-01

    Purpose: A mechanism has been developed to evaluate the influence of systematic and random setup variations on dose during treatment planning. The information available for studying these factors shifts from population-based models towards patient-specific data as treatment progresses and setup measurements for an individual patient become available. This study evaluates the influence of population as well as patient-specific setup distributions on treatment plans for focal liver tumors. Materials and Methods: 8 patients with focal liver tumors were treated on a protocol that involved online setup measurement and adjustment, as well as ventilatory immobilization. Summary statistics from these treatments yielded individual and population distributions of position at initial setup for each fraction as well as after setup adjustment. A convolution model for evaluation of the influence of random setup variation on calculated dose distributions has been previously described and investigated for application to focal liver radiotherapy by our department. Individual patient doses based on initial setup positions were calculated by applying the measured systematic offset to the initial treatment plan, and then convolving the calculated dose distribution with an anisotropic probability distribution function representing the individual patient's random variations. A separate calculation with no offset and convolution using population averaged random variations was performed. Individual beam apertures were then adjusted to provide plans that ensured proper dose to the clinical target volume (CTV) following convolution with population distributions prior to and following setup adjustment. Results: Input distributions comprised 262 position measurements. Individual patient setup distributions for the course of treatment had systematic offsets ranging from (σ) 1.1 to 4.1 mm (LR), -2.0 to 1.4 mm (AP), and 5.6 to 1.7 mm (IS). Individual random setup variations ranged from 2.5 to 5

  16. Drug-induced liver injury due to antimicrobials, central nervous system agents, and nonsteroidal anti-inflammatory drugs.

    Science.gov (United States)

    Devarbhavi, Harshad; Andrade, Raúl J

    2014-05-01

    Antimicrobial agents including antituberculosis (anti-TB) agents are the most common cause of idiosyncratic drug-induced liver injury (DILI) and drug-induced liver failure across the world. Better molecular and genetic biomarkers are acutely needed to help identify those at risk of liver injury particularly for those needing antituberculosis therapy. Some antibiotics such as amoxicillin-clavulanate and isoniazid consistently top the lists of agents in retrospective and prospective DILI databases. Central nervous system agents, particularly antiepileptics, account for the second most common class of agents implicated in DILI registries. Hepatotoxicity from older antiepileptics such as carbamazepine, phenytoin, and phenobarbital are often associated with hypersensitivity features, whereas newer antiepileptic drugs have a more favorable safety profile. Antidepressants and nonsteroidal anti-inflammatory drugs carry very low risk of significant liver injury, but their prolific use make them important causes of DILI. Early diagnosis and withdrawal of the offending agent remain the mainstays of minimizing hepatotoxicity. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  17. Inositol pyrophosphates promote tumor growth and metastasis by antagonizing liver kinase B1

    Science.gov (United States)

    Rao, Feng; Xu, Jing; Fu, Chenglai; Cha, Jiyoung Y.; Gadalla, Moataz M.; Xu, Risheng; Barrow, James C.; Snyder, Solomon H.

    2015-01-01

    The inositol pyrophosphates, molecular messengers containing an energetic pyrophosphate bond, impact a wide range of biologic processes. They are generated primarily by a family of three inositol hexakisphosphate kinases (IP6Ks), the principal product of which is diphosphoinositol pentakisphosphate (IP7). We report that IP6K2, via IP7 synthesis, is a major mediator of cancer cell migration and tumor metastasis in cell culture and in intact mice. IP6K2 acts by enhancing cell-matrix adhesion and decreasing cell–cell adhesion. This action is mediated by IP7-elicited nuclear sequestration and inactivation of the tumor suppressor liver kinase B1 (LKB1). Accordingly, inhibitors of IP6K2 offer promise in cancer therapy. PMID:25617365

  18. Cationized gelatin-HVJ envelope with sodium borocaptate improved the BNCT efficacy for liver tumors in vivo

    Directory of Open Access Journals (Sweden)

    Ono Koji

    2011-01-01

    Full Text Available Abstract Background Boron neutron capture therapy (BNCT is a cell-selective radiation therapy that uses the alpha particles and lithium nuclei produced by the boron neutron capture reaction. BNCT is a relatively safe tool for treating multiple or diffuse malignant tumors with little injury to normal tissue. The success or failure of BNCT depends upon the 10B compound accumulation within tumor cells and the proximity of the tumor cells to the body surface. To extend the therapeutic use of BNCT from surface tumors to visceral tumors will require 10B compounds that accumulate strongly in tumor cells without significant accumulation in normal cells, and an appropriate delivery method for deeper tissues. Hemagglutinating Virus of Japan Envelope (HVJ-E is used as a vehicle for gene delivery because of its high ability to fuse with cells. However, its strong hemagglutination activity makes HVJ-E unsuitable for systemic administration. In this study, we developed a novel vector for 10B (sodium borocaptate: BSH delivery using HVJ-E and cationized gelatin for treating multiple liver tumors with BNCT without severe adverse events. Methods We developed cationized gelatin conjugate HVJ-E combined with BSH (CG-HVJ-E-BSH, and evaluated its characteristics (toxicity, affinity for tumor cells, accumulation and retention in tumor cells, boron-carrying capacity to multiple liver tumors in vivo, and bio-distribution and effectiveness in BNCT therapy in a murine model of multiple liver tumors. Results CG-HVJ-E reduced hemagglutination activity by half and was significantly less toxic in mice than HVJ-E. Higher 10B concentrations in murine osteosarcoma cells (LM8G5 were achieved with CG-HVJ-E-BSH than with BSH. When administered into mice bearing multiple LM8G5 liver tumors, the tumor/normal liver ratios of CG-HVJ-E-BSH were significantly higher than those of BSH for the first 48 hours (p . In suppressing the spread of tumor cells in mice, BNCT treatment was as

  19. Cationized gelatin-HVJ envelope with sodium borocaptate improved the BNCT efficacy for liver tumors in vivo

    International Nuclear Information System (INIS)

    Fujii, Hitoshi; Tabata, Yasuhiko; Kaneda, Yasufumi; Sawa, Yoshiki; Lee, Chun Man; Matsuyama, Akifumi; Komoda, Hiroshi; Sasai, Masao; Suzuki, Minoru; Asano, Tomoyuki; Doki, Yuichiro; Kirihata, Mitsunori; Ono, Koji

    2011-01-01

    Boron neutron capture therapy (BNCT) is a cell-selective radiation therapy that uses the alpha particles and lithium nuclei produced by the boron neutron capture reaction. BNCT is a relatively safe tool for treating multiple or diffuse malignant tumors with little injury to normal tissue. The success or failure of BNCT depends upon the 10 B compound accumulation within tumor cells and the proximity of the tumor cells to the body surface. To extend the therapeutic use of BNCT from surface tumors to visceral tumors will require 10 B compounds that accumulate strongly in tumor cells without significant accumulation in normal cells, and an appropriate delivery method for deeper tissues. Hemagglutinating Virus of Japan Envelope (HVJ-E) is used as a vehicle for gene delivery because of its high ability to fuse with cells. However, its strong hemagglutination activity makes HVJ-E unsuitable for systemic administration. In this study, we developed a novel vector for 10 B (sodium borocaptate: BSH) delivery using HVJ-E and cationized gelatin for treating multiple liver tumors with BNCT without severe adverse events. We developed cationized gelatin conjugate HVJ-E combined with BSH (CG-HVJ-E-BSH), and evaluated its characteristics (toxicity, affinity for tumor cells, accumulation and retention in tumor cells, boron-carrying capacity to multiple liver tumors in vivo, and bio-distribution) and effectiveness in BNCT therapy in a murine model of multiple liver tumors. CG-HVJ-E reduced hemagglutination activity by half and was significantly less toxic in mice than HVJ-E. Higher 10 B concentrations in murine osteosarcoma cells (LM8G5) were achieved with CG-HVJ-E-BSH than with BSH. When administered into mice bearing multiple LM8G5 liver tumors, the tumor/normal liver ratios of CG-HVJ-E-BSH were significantly higher than those of BSH for the first 48 hours (p < 0.05). In suppressing the spread of tumor cells in mice, BNCT treatment was as effective with CG-HVJ-E-BSH as with BSH

  20. Multicenter results of stereotactic body radiotherapy (SBRT) for non-resectable primary liver tumors

    Energy Technology Data Exchange (ETDEWEB)

    Ibarra, Rafael A.; Rojas, Daniel; Sanabria, Juan R. [Dept. of Surgery, Univ. Hospitals-Case Medical Center, Cleveland, OH (United States)], email: juan.sanabria@uhhospitals.org [and others

    2012-05-15

    Background. An excess of 100 000 individuals are diagnosed with primary liver tumors every year in USA but less than 20% of those patients are amenable to definitive surgical management due to advanced local disease or comorbidities. Local therapies to arrest tumor growth have limited response and have shown no improvement on patient survival. Stereotactic body radiotherapy (SBRT) has emerged as an alternative local ablative therapy. The purpose of this study was to evaluate the tumor response to SBRT in a combined multicenter database. Study design. Patients with advanced hepatocellular carcinoma (HCC, n = 21) or intrahepatic cholangiocarcinoma (ICC, n = 11) treated with SBRT from four Academic Medical Centers were entered into a common database. Statistical analyses were performed for freedom from local progression (FFLP) and patient survival. Results. The overall FFLP for advanced HCC was 63% at a median follow-up of 12.9 months. Median tumor volume decreased from 334.2 to 135 cm{sup 3} (p < 0.004). The median time to local progression was 6.3 months. The 1- and 2-years overall survival rates were 87% and 55%, respectively. Patients with ICC had an overall FFLP of 55.5% at a median follow-up of 7.8 months. The median time to local progression was 4.2 months and the six-month and one-year overall survival rates were 75% and 45%, respectively. The incidence of grade 1-2 toxicities, mostly nausea and fatigue, was 39.5%. Grade 3 and 4 toxicities were present in two and one patients, respectively. Conclusion. Higher rates of FFLP were achieved by SBRT in the treatment of primary liver malignancies with low toxicity.

  1. Drug-Induced Liver Injury Associated with Complementary and Alternative Medicines

    Science.gov (United States)

    Takahashi, Koji; Kanda, Tatsuo; Yasui, Shin; Haga, Yuki; Kumagai, Junichiro; Sasaki, Reina; Wu, Shuang; Nakamoto, Shingo; Nakamura, Masato; Arai, Makoto; Yokosuka, Osamu

    2016-01-01

    A 24-year-old man was admitted due to acute hepatitis with unknown etiology. After his condition and laboratory data gradually improved with conservative therapy, he was discharged 1 month later. Two months after his discharge, however, liver dysfunction reappeared. After his mother accidentally revealed that he took complementary and alternative medicine, discontinuation of the therapy caused his condition to improve. Finally, he was diagnosed with a recurrent drug-induced liver injury associated with Japanese complementary and alternative medicine. It is important to take the medical history in detail and consider complementary and alternative medicine as a cause of liver disease. PMID:28100990

  2. Target Coverage in Image-Guided Stereotactic Body Radiotherapy of Liver Tumors

    International Nuclear Information System (INIS)

    Wunderink, Wouter; Romero, Alejandra Mendez; Osorio, Eliana M. Vasquez; Boer, Hans C.J. de; Brandwijk, Rene P.; Levendag, Peter C.; Heijmen, Ben

    2007-01-01

    Purpose: To determine the effect of image-guided procedures (with computed tomography [CT] and electronic portal images before each treatment fraction) on target coverage in stereotactic body radiotherapy for liver patients using a stereotactic body frame (SBF) and abdominal compression. CT guidance was used to correct for day-to-day variations in the tumor's mean position in the SBF. Methods and Materials: By retrospectively evaluating 57 treatment sessions, tumor coverage, as obtained with the clinically applied CT-guided protocol, was compared with that of alternative procedures. The internal target volume-plus (ITV + ) was introduced to explicitly include uncertainties in tumor delineations resulting from CT-imaging artifacts caused by residual respiratory motion. Tumor coverage was defined as the volume overlap of the ITV + , derived from a tumor delineated in a treatment CT scan, and the planning target volume. Patient stability in the SBF, after acquisition of the treatment CT scan, was evaluated by measuring the displacement of the bony anatomy in the electronic portal images relative to CT. Results: Application of our clinical protocol (with setup corrections following from manual measurements of the distances between the contours of the planning target volume and the daily clinical target volume in three orthogonal planes, multiple two-dimensional) increased the frequency of nearly full (≥99%) ITV + coverage to 77% compared with 63% without setup correction. An automated three-dimensional method further improved the frequency to 96%. Patient displacements in the SBF were generally small (≤2 mm, 1 standard deviation), but large craniocaudal displacements (maximal 7.2 mm) were occasionally observed. Conclusion: Daily, CT-assisted patient setup may substantially improve tumor coverage, especially with the automated three-dimensional procedure. In the present treatment design, patient stability in the SBF should be verified with portal imaging

  3. Using a 3-d model system to screen for drugs effective on solid tumors

    OpenAIRE

    Fayad, Walid

    2011-01-01

    There is a large medical need for the development of effective anticancer agents with minimal side effects. The present thesis represents an attempt to identify potent drugs for treatment of solid tumors. We used a strategy where 3-D multicellular tumor spheroids (cancer cells grown in three dimensional culture) were utilized as in vitro models for solid tumors. Drug libraries were screened using spheroids as targets and using apoptosis induction and loss of cell viability as endpoints. The h...

  4. Arming drug carriers to disable the Hepatic Stellate Cell : the targeted delivery of apoptosis-inducing drugs to the fibrotic liver

    NARCIS (Netherlands)

    Hagens, Werner Ivo

    2006-01-01

    Chronic liver damage of various origins (e.g. viral hepatitis; chronic intoxication by alcohol, chemicals or drugs; Wilson’s disease) can eventually lead to liver cirrhosis, the end stage of liver fibrosis. This process is characterized by the accumulation of excessive amounts of scar tissue within

  5. Peptide-Mediated Liposomal Drug Delivery System Targeting Tumor Blood Vessels in Anticancer Therapy

    Directory of Open Access Journals (Sweden)

    Han-Chung Wu

    2010-01-01

    Full Text Available Solid tumors are known to recruit new blood vessels to support their growth. Therefore, unique molecules expressed on tumor endothelial cells can function as targets for the antiangiogenic therapy of cancer. Current efforts are focusing on developing therapeutic agents capable of specifically targeting cancer cells and tumor-associated microenvironments including tumor blood vessels. These therapies hold the promise of high efficacy and low toxicity. One recognized strategy for improving the therapeutic effectiveness of conventional chemotherapeutics is to encapsulate anticancer drugs into targeting liposomes that bind to the cell surface receptors expressed on tumor-associated endothelial cells. These anti-angiogenic drug delivery systems could be used to target both tumor blood vessels as well as the tumor cells, themselves. This article reviews the mechanisms and advantages of various present and potential methods using peptide-conjugated liposomes to specifically destroy tumor blood vessels in anticancer therapy.

  6. Nanodrug-enhanced radiofrequency tumor ablation: effect of micellar or liposomal carrier on drug delivery and treatment efficacy.

    Directory of Open Access Journals (Sweden)

    Marwan Moussa

    Full Text Available To determine the effect of different drug-loaded nanocarriers (micelles and liposomes on delivery and treatment efficacy for radiofrequency ablation (RFA combined with nanodrugs.Fischer 344 rats were used (n = 196. First, single subcutaneous R3230 tumors or normal liver underwent RFA followed by immediate administration of i.v. fluorescent beads (20, 100, and 500 nm, with fluorescent intensity measured at 4-24 hr. Next, to study carrier type on drug efficiency, RFA was combined with micellar (20 nm or liposomal (100 nm preparations of doxorubicin (Dox; targeting HIF-1α or quercetin (Qu; targeting HSP70. Animals received RFA alone, RFA with Lipo-Dox or Mic-Dox (1 mg i.v., 15 min post-RFA, and RFA with Lipo-Qu or Mic-Qu given 24 hr pre- or 15 min post-RFA (0.3 mg i.v.. Tumor coagulation and HIF-1α or HSP70 expression were assessed 24 hr post-RFA. Third, the effect of RFA combined with i.v. Lipo-Dox, Mic-Dox, Lipo-Qu, or Mic-Qu (15 min post-RFA compared to RFA alone on tumor growth and animal endpoint survival was evaluated. Finally, drug uptake was compared between RFA/Lipo-Dox and RFA/Mic-Dox at 4-72 hr.Smaller 20 nm beads had greater deposition and deeper tissue penetration in both tumor (100 nm/500 nm and liver (100 nm (p<0.05. Mic-Dox and Mic-Qu suppressed periablational HIF-1α or HSP70 rim thickness more than liposomal preparations (p<0.05. RFA/Mic-Dox had greater early (4 hr intratumoral doxorubicin, but RFA/Lipo-Dox had progressively higher intratumoral doxorubicin at 24-72 hr post-RFA (p<0.04. No difference in tumor growth and survival was seen between RFA/Lipo-Qu and RFA/Mic-Qu. Yet, RFA/Lipo-Dox led to greater animal endpoint survival compared to RFA/Mic-Dox (p<0.03.With RF ablation, smaller particle micelles have superior penetration and more effective local molecular modulation. However, larger long-circulating liposomal carriers can result in greater intratumoral drug accumulation over time and reduced tumor growth. Accordingly

  7. Nanoparticle-mediated combination chemotherapy and photodynamic therapy overcomes tumor drug resistance.

    Science.gov (United States)

    Khdair, Ayman; Chen, Di; Patil, Yogesh; Ma, Linan; Dou, Q Ping; Shekhar, Malathy P V; Panyam, Jayanth

    2010-01-25

    Tumor drug resistance significantly limits the success of chemotherapy in the clinic. Tumor cells utilize multiple mechanisms to prevent the accumulation of anticancer drugs at their intracellular site of action. In this study, we investigated the anticancer efficacy of doxorubicin in combination with photodynamic therapy using methylene blue in a drug-resistant mouse tumor model. Surfactant-polymer hybrid nanoparticles formulated using an anionic surfactant, Aerosol-OT (AOT), and a naturally occurring polysaccharide polymer, sodium alginate, were used for synchronized delivery of the two drugs. Balb/c mice bearing syngeneic JC tumors (mammary adenocarcinoma) were used as a drug-resistant tumor model. Nanoparticle-mediated combination therapy significantly inhibited tumor growth and improved animal survival. Nanoparticle-mediated combination treatment resulted in enhanced tumor accumulation of both doxorubicin and methylene blue, significant inhibition of tumor cell proliferation, and increased induction of apoptosis. These data suggest that nanoparticle-mediated combination chemotherapy and photodynamic therapy using doxorubicin and methylene blue has significant therapeutic potential against drug-resistant tumors. Copyright 2009 Elsevier B.V. All rights reserved.

  8. Radiation induction of drug resistance in RIF-1: Correlation of tumor and cell culture results

    International Nuclear Information System (INIS)

    Moulder, J.E.; Hopwood, L.E.; Volk, D.M.; Davies, B.M.

    1991-01-01

    The RIF-1 tumor line contains cells that are resistant to various anti-neoplastic drugs, including 5-fluorouracil (5FU), methotrexate (MTX), adriamycin (ADR), and etoposide (VP16). The frequency of these drug-resistant cells is increased after irradiation. The frequency of drug-resistant cells and the magnitude of radiation-induced drug resistance are different in cell culture than in tumors. The dose-response and expression time relationships for radiation induction of drug resistance observed in RIF-1 tumors are unusual.We hypothesize that at high radiation doses in vivo, we are selecting for cells that are both drug resistant and radiation resistant due to microenvironmental factors, whereas at low radiation doses in vivo and all radiation doses in vitro, we are observing true mutants. These studies indicate that there can be significant differences in drug-resistance frequencies between tumors and their cell lines of origin, and that radiation induction of drug resistance depends significantly on whether the induction is done in tumors or in cell culture. These results imply that theories about the induction of drug resistance that are based on cell culture studies may be inapplicable to the induction of drug resistance in tumors

  9. Advanced 3D image processing techniques for liver and hepatic tumor location and volumetry

    Science.gov (United States)

    Chemouny, Stephane; Joyeux, Henri; Masson, Bruno; Borne, Frederic; Jaeger, Marc; Monga, Olivier

    1999-05-01

    To assist radiologists and physicians in diagnosing, and in treatment planning and evaluating in liver oncology, we have developed a fast and accurate segmentation of the liver and its lesions within CT-scan exams. The first step of our method is to reduce spatial resolution of CT images. This will have two effects: obtain near isotropic 3D data space and drastically decrease computational time for further processing. On a second step a 3D non-linear `edge- preserving' smoothing filtering is performed throughout the entire exam. On a third step the 3D regions coming out from the second step are homogeneous enough to allow a quite simple segmentation process, based on morphological operations, under supervisor control, ending up with accurate 3D regions of interest (ROI) of the liver and all the hepatic tumors. On a fourth step the ROIs are eventually set back into the original images, features like volume and location are immediately computed and displayed. The segmentation we get is as precise as a manual one but is much faster.

  10. Dynamic-thresholding level set: a novel computer-aided volumetry method for liver tumors in hepatic CT images

    Science.gov (United States)

    Cai, Wenli; Yoshida, Hiroyuki; Harris, Gordon J.

    2007-03-01

    Measurement of the volume of focal liver tumors, called liver tumor volumetry, is indispensable for assessing the growth of tumors and for monitoring the response of tumors to oncology treatments. Traditional edge models, such as the maximum gradient and zero-crossing methods, often fail to detect the accurate boundary of a fuzzy object such as a liver tumor. As a result, the computerized volumetry based on these edge models tends to differ from manual segmentation results performed by physicians. In this study, we developed a novel computerized volumetry method for fuzzy objects, called dynamic-thresholding level set (DT level set). An optimal threshold value computed from a histogram tends to shift, relative to the theoretical threshold value obtained from a normal distribution model, toward a smaller region in the histogram. We thus designed a mobile shell structure, called a propagating shell, which is a thick region encompassing the level set front. The optimal threshold calculated from the histogram of the shell drives the level set front toward the boundary of a liver tumor. When the volume ratio between the object and the background in the shell approaches one, the optimal threshold value best fits the theoretical threshold value and the shell stops propagating. Application of the DT level set to 26 hepatic CT cases with 63 biopsy-confirmed hepatocellular carcinomas (HCCs) and metastases showed that the computer measured volumes were highly correlated with those of tumors measured manually by physicians. Our preliminary results showed that DT level set was effective and accurate in estimating the volumes of liver tumors detected in hepatic CT images.

  11. Assessment of [18F]-fluoroacetate PET/CT as a tumor-imaging modality. Preclinical study in healthy volunteers and clinical evaluation in patients with liver tumor

    International Nuclear Information System (INIS)

    Takemoto, Kenji; Hatano, Etsuro; Nishii, Ryuichi

    2014-01-01

    Although [ 18 F]-FDG is a useful oncologic PET tracer, FDG uptake is known to be low in a certain type of hepatocellular carcinoma (HCC). [ 18 F]-fluoroacetate ( 18 F-FACE) is an [ 18 F] fluorinated acetate, which is known to be converted into fatty acids, incorporated in membrane and is expected to be a promising oncologic PET tracer. The aim of this study was to evaluate the usefulness of 18 F-FACE as an oncologic PET tracer in preclinical study in healthy volunteers and in patients with liver tumors. Twenty-four healthy volunteers (age 48.2 ± 12.9 years old; 15 male and 9 female) and ten patients with liver tumor (age 72.1 ± 7.0 years old; 6 male and 4 female) were included. We performed whole-body static PET/CT scan using 18 F-FACE (n=34) and 18 F-FDG (n=5 for volunteers, n=8 for patients) on each day, respectively. Qualitative analysis and quantitative analysis of tumors (5 HCCs, 1 cholangiocellular carcinoma, 4 metastatic tumors from colon cancer and P-NET) were performed using SUVmax and tumor-to-normal liver ratio (TNR). In healthy volunteers, 18 F-FACE was metabolically stable in vivo and its biodistribution was almost similar to blood pool, basically uniformly independent of age and gender during PET scan time (up to 3 h). Normal physiological uptake of 18 F-FACE at each organ including liver (SUVmean 1.8 ± 0.2) was lower than that of blood pool (SUVmean 2.3 ± 0.3) at 1 h after injection. Chronic inflammatory uptake around femur of post-operative state of femoral osteotomy and faint uptake of benign hemangioma were observed in a case of healthy volunteer. 18 F-FACE (SUVmax 2.7 ± 0.6, TNR 1.5 ± 0.4) of liver tumors was significantly lower than those of 18 F-FDG uptake (6.5 ± 4.2, 2.6 ± 1.7, respectively). In qualitative analysis, 18 F-FDG was positive in 4 tumors (3 HCCs, 1 CCC) and negative in the other 6 tumors, while 18 F-FACE was also positive in 4 tumors which were the same tumors with positive 18 F-FDG uptake. Biodistribution of 18 F-FACE was

  12. Quality of Life After Stereotactic Body Radiation Therapy for Primary and Metastatic Liver Tumors

    International Nuclear Information System (INIS)

    Mendez Romero, Alejandra; Wunderink, Wouter; Os, Rob M. van; Nowak, Peter J.C.M.; Heijmen, Ben J.M.; Nuyttens, Joost J.; Brandwijk, Rene P.; Verhoef, Cornelis; IJzermans, Jan N.M.; Levendag, Peter C.

    2008-01-01

    Purpose: Stereotactic body radiation therapy (SBRT) provides a high local control rate for primary and metastatic liver tumors. The aim of this study is to assess the impact of this treatment on the patient's quality of life. This is the first report of quality of life associated with liver SBRT. Methods and Materials: From October 2002 to March 2007, a total of 28 patients not suitable for other local treatments and with Karnofsky performance status of at least 80% were entered in a Phase I-II study of SBRT for liver tumors. Quality of life was a secondary end point. Two generic quality of life instruments were investigated, EuroQol-5D (EQ-5D) and EuroQoL-Visual Analogue Scale (EQ-5D VAS), in addition to a disease-specific questionnaire, the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ C-30). Points of measurement were directly before and 1, 3, and 6 months after treatment. Mean scores and SDs were calculated. Statistical analysis was performed using paired-samples t-test and Student t-test. Results: The calculated EQ-5D index, EQ-5D VAS and QLQ C-30 global health status showed that mean quality of life of the patient group was not significantly influenced by treatment with SBRT; if anything, a tendency toward improvement was found. Conclusions: Stereotactic body radiation therapy combines a high local control rate, by delivering a high dose per fraction, with no significant change in quality of life. Multicenter studies including larger numbers of patients are recommended and under development

  13. Anionic clay as the drug delivery vehicle: tumor targeting function of layered double hydroxide-methotrexate nanohybrid in C33A orthotopic cervical cancer model.

    Science.gov (United States)

    Choi, Goeun; Piao, Huiyan; Alothman, Zeid A; Vinu, Ajayan; Yun, Chae-Ok; Choy, Jin-Ho

    2016-01-01

    Methotrexate (MTX), an anticancer agent, was successfully intercalated into the anionic clay, layered double hydroxides to form a new nanohybrid drug. The coprecipitation and subsequent hydrothermal method were used to prepare chemically, structurally, and morphologically well-defined two-dimensional drug-clay nanohybrid. The resulting two-dimensional drug-clay nanohybrid showed excellent colloidal stability not only in deionized water but also in an electrolyte solution of Dulbecco's Modified Eagle's Medium with 10% fetal bovine serum, in which the average particle size in colloid and the polydispersity index were determined to be around 100 and 0.250 nm, respectively. The targeting property of the nanohybrid drug was confirmed by evaluating the tumor-to-blood and tumor-to-liver ratios of the MTX with anionic clay carrier, and these ratios were compared to those of free MTX in the C33A orthotopic cervical cancer model. The biodistribution studies indicated that the mice treated with the former showed 3.5-fold higher tumor-to-liver ratio and fivefold higher tumor-to-blood ratio of MTX than those treated with the latter at 30 minutes postinjection.

  14. Targeting the ECM to Enhance Drug Delivery in Nf1-Associated Nerve Sheath Tumors

    Science.gov (United States)

    2016-10-01

    development of the principal discipline(s) of the project? • We have learned that the drug PEGPH20, which degrades a component of connective tissue called...AWARD NUMBER: W81XWH-15-1-0114 TITLE: Targeting the ECM to Enhance Drug Delivery in Nf1-Associated Nerve Sheath Tumors PRINCIPAL INVESTIGATOR...14 Sep 2016 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER NF140089 Targeting the ECM to Enhance Drug Delivery in Nf1-Associated Nerve Sheath Tumors 5b

  15. Intrabiliary growth of recurrent tumor after percutaneous RF ablation for treating liver metastasis from colon cancer: a case report

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Youn Kyung; Kim, Seung Kwon; Hong, Hyun Pyo [Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of)

    2007-12-15

    A 64-year-old man who underwent right hemicolectomy 3.5 years ago for ascending colon cancer and then RF ablation for two metastatic nodules in the liver was admitted to our hospital with a new metastatic nodule in the S6/7 segment of the liver. The CT scan showed a low attenuating metastatic nodule 2.2 cm in diameter in the S6/7 segment of the liver, and the liver showed peripheral bile duct dilatation. This nodule was treated with percutaneous RF ablation. A follow-up CT seven months after RF ablation showed the presence of a viable tumor in the RF ablation zone, with tumor extension along the dilated bile duct. These findings were confirmed on the resected specimen.

  16. Scaffold-free 3D bio-printed human liver tissue stably maintains metabolic functions useful for drug discovery.

    Science.gov (United States)

    Kizawa, Hideki; Nagao, Eri; Shimamura, Mitsuru; Zhang, Guangyuan; Torii, Hitoshi

    2017-07-01

    The liver plays a central role in metabolism. Although many studies have described in vitro liver models for drug discovery, to date, no model has been described that can stably maintain liver function. Here, we used a unique, scaffold-free 3D bio-printing technology to construct a small portion of liver tissue that could stably maintain drug, glucose, and lipid metabolism, in addition to bile acid secretion. This bio-printed normal human liver tissue maintained expression of several kinds of hepatic drug transporters and metabolic enzymes that functioned for several weeks. The bio-printed liver tissue displayed glucose production via cAMP/protein kinase A signaling, which could be suppressed with insulin. Bile acid secretion was also observed from the printed liver tissue, and it accumulated in the culture medium over time. We observed both bile duct and sinusoid-like structures in the bio-printed liver tissue, which suggested that bile acid secretion occurred via a sinusoid-hepatocyte-bile duct route. These results demonstrated that our bio-printed liver tissue was unique, because it exerted diverse liver metabolic functions for several weeks. In future, we expect our bio-printed liver tissue to be applied to developing new models that can be used to improve preclinical predictions of long-term toxicity in humans, generate novel targets for metabolic liver disease, and evaluate biliary excretion in drug development.

  17. Improved Tumor-Specific Drug Accumulation by Polymer Therapeutics with pH-Sensitive Drug Release Overcomes Chemotherapy Resistance.

    Science.gov (United States)

    Heinrich, Anne-Kathrin; Lucas, Henrike; Schindler, Lucie; Chytil, Petr; Etrych, Tomáš; Mäder, Karsten; Mueller, Thomas

    2016-05-01

    The success of chemotherapy is limited by poor selectivity of active drugs combined with occurrence of tumor resistance. New star-like structured N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-based drug delivery systems containing doxorubicin attached via a pH-sensitive hydrazone bond were designed and investigated for their ability to overcome chemotherapy resistance. These conjugates combine two strategies to achieve a high drug concentration selectively at the tumor site: (I) high accumulation by passive tumor targeting based on enhanced permeability and retention effect and (II) pH-sensitive site-specific drug release due to an acidic tumor microenvironment. Mice bearing doxorubicin-resistant xenograft tumors were treated with doxorubicin, PBS, poly HPMA (pHPMA) precursor or pHPMA-doxorubicin conjugate at different equivalent doses of 5 mg/kg bodyweight doxorubicin up to a 7-fold total dose using different treatment schedules. Intratumoral drug accumulation was analyzed by fluorescence imaging utilizing intrinsic fluorescence of doxorubicin. Free doxorubicin induced significant toxicity but hardly any tumor-inhibiting effects. Administering at least a 3-fold dose of pHPMA-doxorubicin conjugate was necessary to induce a transient response, whereas doses of about 5- to 6-fold induced strong regressions. Tumors completely disappeared in some cases. The onset of response was differential delayed depending on the tumor model, which could be ascribed to distinct characteristics of the microenvironment. Further fluorescence imaging-based analyses regarding underlying mechanisms of the delayed response revealed a related switch to a more supporting intratumoral microenvironment for effective drug release. In conclusion, the current study demonstrates that the concept of tumor site-restricted high-dose chemotherapy is able to overcome therapy resistance. Mol Cancer Ther; 15(5); 998-1007. ©2016 AACR. ©2016 American Association for Cancer Research.

  18. Comparative study of rabbit VX2 hepatic implantation tumor and normal liver tissue on magnetic resonance perfusion weighted imaging

    International Nuclear Information System (INIS)

    Jiao Zimei; Wang Xizhen; Wang Bin; Liu Feng; Li Haiqing; Sun Yequan; Dong Peng

    2012-01-01

    Objective: To investigate the value of magnetic resonance (MR) perfusion weighted imaging (PWI) in evaluating the blood perfusion of tumor by analyzing the features and indexes of PWI on rabbit VX2 hepatic implantation tumor and normal liver tissue. Methods: Twenty-four New Zealand White rabbits with VX2 carcinoma were established under direct surgical vision embedding tumor tissue. MR examination was performed at 21 days after the tumor implantation. The signal intensity -time curve of hepatic tumor and normal liver tissue were obtained. Mean time to enhance (MTE), negative enhancement integral (NEI), time to minimum (TM), maximum slope of decrease (MSD) and maximum slope of increase (MSI) were measured. Results: MTE, NEI, TM, MSD, and MSI of the normal liver tissue were 208.341±2.226 ms, 78.334±8.152, 24.059±1.927 ms, 38.221±2.443, and 15.389±2.526, respectively. MTE, NEI, TM, MSD, and MSI of the tumor tissue were 175.437±4.182 ms, 123.203±19.455, 17.061±1.834 ms, 125.740±4.842, and 67.832±2.882, respectively. The MTE and TM of tumor were shorter than those of normal hepatic tissue (P<0.05). NEI, MSD, and MSI of tumor were higher than those of normal hepatic tissue (P<0.05). Conclusion: PWI can distinguish the normal liver tissue from the tumor tissue, which is helpful in evaluating blood perfusion of different hepatic tissues. (authors)

  19. [Study on liver targeted drug delivery system of the effective anticancer component from Bolbstemma paniculatum].

    Science.gov (United States)

    Sun, Yi-Yi; Ll, Tong-Hui; Tang, Chen-Kang; Zhu, Zi-Ping; Chi, Qun; Hou, Shi-Xiang

    2005-06-01

    To study the liver targeted drug delivery system of TBMS--the effective anticancer component from Bolbstemma paniculatum, and to discuss the system's function of decreasing toxicity. BCA was used as carrier material. The preparation through overall feedback dynamic techniques. The properties of preparation and toxicology were also technology of nanoparticles was optimized studied. Thenanoparticles' targeting in mice vivo was observed with transmission electron microscopy. The function of decreasing toxicity was researched by the XXTX-2000 automatic quantitative analysis management system. D50 was 0.68 microm. Drug-loading rate and entrapment rate were 37.3% and 88.6% respectively. The release in vitro accorded with Weibull equation. The reaching release balance time and the t 1/2 extended 26 times and 19 times respectively comparing with injection. Nanoparticles mainly distributed in liver tissue. Their toxicity to lung and liver was evidently lower than injection. Nanoparticles' LD50 exceeded injection's by 13.5% and their stimulus was much lower than injection. The TBMS can be targeted to liver by liver targeted drug delivery system. At the same time, the problem about the toxicity hindering clinical application could be solved, which lays the foundation for the further studies on TBMS.

  20. Case Characterization, Clinical Features and Risk Factors in Drug-Induced Liver Injury

    Directory of Open Access Journals (Sweden)

    Aida Ortega-Alonso

    2016-05-01

    Full Text Available Idiosyncratic drug-induced liver injury (DILI caused by xenobiotics (drugs, herbals and dietary supplements presents with a range of both phenotypes and severity, from acute hepatitis indistinguishable of viral hepatitis to autoimmune syndromes, steatosis or rare chronic vascular syndromes, and from asymptomatic liver test abnormalities to acute liver failure. DILI pathogenesis is complex, depending on the interaction of drug physicochemical properties and host factors. The awareness of risk factors for DILI is arising from the analysis of large databases of DILI cases included in Registries and Consortia networks around the world. These networks are also enabling in-depth phenotyping with the identification of predictors for severe outcome, including acute liver failure and mortality/liver transplantation. Genome wide association studies taking advantage of these large cohorts have identified several alleles from the major histocompatibility complex system indicating a fundamental role of the adaptive immune system in DILI pathogenesis. Correct case definition and characterization is crucial for appropriate phenotyping, which in turn will strengthen sample collection for genotypic and future biomarkers studies.

  1. Local recurrence after laparoscopic radiofrequency ablation of malignant liver tumors: Results of a contemporary series.

    Science.gov (United States)

    Takahashi, Hideo; Akyuz, Muhammet; Aksoy, Erol; Karabulut, Koray; Berber, Eren

    2017-06-01

    The aims of this study were to determine the incidence of Local recurrence (LR) in patients at long-term follow-up after laparoscopic RFA (LRFA) and also to determine the risk factors for LR from a contemporary series. Patients undergoing LRFA between 2005 and 2014 by a single surgeon were reviewed. Demographic and perioperative data were analyzed from a prospective database. LRFA was performed on 316 patients with 901 lesions. Median follow-up was 25 months, with 76% of whom completed at least one year of follow-up. The LR rate was 18.4%. The LR in patients followed for less than 12 months was 13.8%, 20.3% for 12 months, and 19.7% for 18 months (P = 0.02). One-fourth of the LRs developed after the 1st year. Morbidity was 8.9% and mortality 0.3%. Tumor type, size, ablation margin, and surgeon experience affected LR, with tumor type, size, and ablation margin being independent. This study shows that 14% of malignant liver tumors will develop LR within a year after LRFA. Additional 4% of the lesions will demonstrate recurrence within 1 cm of the ablation zone, mostly as part of a multifocal recurrence. Ablation margin is the only parameter that the surgeon can manipulate to decrease LR. © 2017 Wiley Periodicals, Inc.

  2. Minimum datasets to establish a CAR-mediated mode of action for rodent liver tumors.

    Science.gov (United States)

    Peffer, Richard C; LeBaron, Matthew J; Battalora, Michael; Bomann, Werner H; Werner, Christoph; Aggarwal, Manoj; Rowe, Rocky R; Tinwell, Helen

    2018-07-01

    Methods for investigating the Mode of Action (MoA) for rodent liver tumors via constitutive androstane receptor (CAR) activation are outlined here, based on current scientific knowledge about CAR and feedback from regulatory agencies globally. The key events (i.e., CAR activation, altered gene expression, cell proliferation, altered foci and increased adenomas/carcinomas) can be demonstrated by measuring a combination of key events and associative events that are markers for the key events. For crop protection products, a primary dataset typically should include a short-term study in the species/strain that showed the tumor response at dose levels that bracket the tumorigenic and non-tumorigenic dose levels. The dataset may vary depending on the species and the test compound. As examples, Case Studies with nitrapyrin (in mice) and metofluthrin (in rats) are described. Based on qualitative differences between the species, the key events leading to tumors in mice or rats by this MoA are not operative in humans. In the future, newer approaches such as a CAR biomarker signature approach and/or in vitro CAR3 reporter assays for mouse, rat and human CAR may eventually be used to demonstrate a CAR MoA is operative, without the need for extensive additional studies in laboratory animals. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

  3. Transient mTOR inhibition facilitates continuous growth of liver tumors by modulating the maintenance of CD133+ cell populations.

    Directory of Open Access Journals (Sweden)

    Zhaojuan Yang

    Full Text Available The mammalian target of the rapamycin (mTOR pathway, which drives cell proliferation, is frequently hyperactivated in a variety of malignancies. Therefore, the inhibition of the mTOR pathway has been considered as an appropriate approach for cancer therapy. In this study, we examined the roles of mTOR in the maintenance and differentiation of cancer stem-like cells (CSCs, the conversion of conventional cancer cells to CSCs and continuous tumor growth in vivo. In H-Ras-transformed mouse liver tumor cells, we found that pharmacological inhibition of mTOR with rapamycin greatly increased not only the CD133+ populations both in vitro and in vivo but also the expression of stem cell-like genes. Enhancing mTOR activity by over-expressing Rheb significantly decreased CD133 expression, whereas knockdown of the mTOR yielded an opposite effect. In addition, mTOR inhibition severely blocked the differentiation of CD133+ to CD133- liver tumor cells. Strikingly, single-cell culture experiments revealed that CD133- liver tumor cells were capable of converting to CD133+ cells and the inhibition of mTOR signaling substantially promoted this conversion. In serial implantation of tumor xenografts in nude BALB/c mice, the residual tumor cells that were exposed to rapamycin in vivo displayed higher CD133 expression and had increased secondary tumorigenicity compared with the control group. Moreover, rapamycin treatment also enhanced the level of stem cell-associated genes and CD133 expression in certain human liver tumor cell lines, such as Huh7, PLC/PRC/7 and Hep3B. The mTOR pathway is significantly involved in the generation and the differentiation of tumorigenic liver CSCs. These results may be valuable for the design of more rational strategies to control clinical malignant HCC using mTOR inhibitors.

  4. Physico-Chemical Strategies to Enhance Stability and Drug Retention of Polymeric Micelles for Tumor-Targeted Drug Delivery

    NARCIS (Netherlands)

    Shi, Y.; Lammers, Twan Gerardus Gertudis Maria; Storm, Gerrit; Hennink, W.E.

    2017-01-01

    Polymeric micelles (PM) have been extensively used for tumor-targeted delivery of hydrophobic anti-cancer drugs. The lipophilic core of PM is naturally suitable for loading hydrophobic drugs and the hydrophilic shell endows them with colloidal stability and stealth properties. Decades of research on

  5. Liver Tumor Segmentation from MR Images Using 3D Fast Marching Algorithm and Single Hidden Layer Feedforward Neural Network

    Directory of Open Access Journals (Sweden)

    Trong-Ngoc Le

    2016-01-01

    Full Text Available Objective. Our objective is to develop a computerized scheme for liver tumor segmentation in MR images. Materials and Methods. Our proposed scheme consists of four main stages. Firstly, the region of interest (ROI image which contains the liver tumor region in the T1-weighted MR image series was extracted by using seed points. The noise in this ROI image was reduced and the boundaries were enhanced. A 3D fast marching algorithm was applied to generate the initial labeled regions which are considered as teacher regions. A single hidden layer feedforward neural network (SLFN, which was trained by a noniterative algorithm, was employed to classify the unlabeled voxels. Finally, the postprocessing stage was applied to extract and refine the liver tumor boundaries. The liver tumors determined by our scheme were compared with those manually traced by a radiologist, used as the “ground truth.” Results. The study was evaluated on two datasets of 25 tumors from 16 patients. The proposed scheme obtained the mean volumetric overlap error of 27.43% and the mean percentage volume error of 15.73%. The mean of the average surface distance, the root mean square surface distance, and the maximal surface distance were 0.58 mm, 1.20 mm, and 6.29 mm, respectively.

  6. Chronic liver injury in mice promotes impairment of skin barrier function via tumor necrosis factor-alpha.

    Science.gov (United States)

    Yokoyama, Satoshi; Hiramoto, Keiichi; Koyama, Mayu; Ooi, Kazuya

    2016-09-01

    Alcohol is frequently used to induce chronic liver injury in laboratory animals. Alcohol causes oxidative stress in the liver and increases the expression of inflammatory mediators that cause hepatocellular damage. However, during chronic liver injury, it is unclear if/how these liver-derived factors affect distal tissues, such as the skin. The purpose of this study was to evaluate skin barrier function during chronic liver injury. Hairless mice were administered 5% or 10% ethanol for 8 weeks, and damages to the liver and skin were assessed using histological and protein-analysis methods, as well as by detecting inflammatory mediators in the plasma. After alcohol administration, the plasma concentration of the aspartate and alanine aminotransferases increased, while albumin levels decreased. In mice with alcohol-induced liver injury, transepidermal water loss was significantly increased, and skin hydration decreased concurrent with ceramide and type I collagen degradation. The plasma concentrations of [Formula: see text]/[Formula: see text] and tumor necrosis factor-alpha (TNF-α) were significantly increased in mice with induced liver injury. TNF receptor (TNFR) 2 expression was upregulated in the skin of alcohol-administered mice, while TNFR1 levels remained constant. Interestingly, the impairment of skin barrier function in mice administered with 10% ethanol was ameliorated by administering an anti-TNF-α antibody. We propose a novel mechanism whereby plasma TNF-α, via TNFR2 alone or with TNFR1, plays an important role in skin barrier function during chronic liver disease in these mouse models.

  7. [A Case of Transverse Colon Cancer with Liver Metastasis and Tumor Thrombosis of Portal Vein Effectively Treated with Chemotherapy].

    Science.gov (United States)

    Aida, Toshiaki; Shiobara, Masayuki; Wakatsuki, Kazuo; Arai, Shuka; Suda, Kosuke; Miyazawa, Kotaro; Miyoshi, Tetsutaro; Takahashi, Yoshihisa; Yoshioka, Shigeru

    2018-02-01

    The patient was a 70-year-old man. He was diagnosed with advanced transverse colon cancer. A computed tomography (CT)revealed liver metastasis and tumor thrombosis of portal vein. We started combination chemotherapy with capecita- bine/oxaliplatin(CapeOX). Perforation of the tumor was observed 5 days after CapeOX therapy was started. Treatment with abscess drainage and ileostmy, infection was controlled and general condition was improved. After 9 courses of CapeOX, we changed chemotherapy regimen to irinotecan/tegafur-gimeracil-oteracilpotassium (IRIS)due to strong side effects. In CT and FDG-PET examination after 8 courses of IRIS, the tumor of transverse colon, liver metastasis, and the tumor thrombosis of portalvein became unclear. A year and 6 months have passed since chemotherapy was started, recurrence was not observed. For the patients with unresectable colorectal cancer, it is necessary to consider multidisciplinary treatments including chemotherapy while considering the general condition of them.

  8. The impact of surgical resection of the primary tumor on the development of synchronous colorectal liver metastasis: a systematic review.

    Science.gov (United States)

    Pinson, H; Cosyns, S; Ceelen, Wim P

    2018-05-22

    In recent years different therapeutic strategies for synchronously liver metastasized colorectal cancer were described. Apart from the classical staged surgical approach, simultaneous and liver-first strategies are now commonly used. One theoretical drawback of the classical approach is, however, the stimulatory effect on liver metastases growth that may result from resection of the primary tumour. This systematic review, therefore, aims to investigate the current insights on the stimulatory effects of colorectal surgery on the growth of synchronous colorectal liver metastases in humans. The systematic review was conducted according to the PRISMA statement. A literature search was performed using PubMed and Embase. Articles investigating the effects of colorectal surgery on synchronous colorectal liver metastases were included. Primary endpoints were metastatic tumor volume, metabolic and proliferative activity and tumour vascularization. Four articles meeting the selection criteria were found involving 200 patients. These studies investigate the effects of resection of the primary tumour on synchronous liver metastases using histological and radiological techniques. These papers support a possible stimulatory effect of resection of the primary tumor. Some limited evidence supports the hypothesis that colorectal surgery might stimulate the growth and development of synchronous colorectal liver metastases.

  9. Physiologic Effect of Stent Therapy for Inferior Vena Cava Obstruction Due to Malignant Liver Tumor

    International Nuclear Information System (INIS)

    Kishi, Kazushi; Sonomura, Tetsuo; Fujimoto, Hisashi; Kimura, Masashi; Yamada, Katsuya; Sato, Morio; Juri, Masanobu

    2006-01-01

    Purpose. To understand systemic the influence of stent therapy for inferior vena cava (IVC) obstruction due to advanced liver tumor. Methods. Seven patients with symptomatic IVC obstruction due to advanced primary (n 4) or secondary (n = 3) liver tumor were subjected to stent therapy. Enrollment criteria included high IVC pressure over 15 mmHg and the presence of edema and ascites. Z-stents were deployed using coaxial sheath technique via femoral venous puncture. Physiologic and hematobiochemical parameters were analyzed. Results. All procedures were successful, and the stents remained patent until patient death. Promptly after stent placement, the IVC flow recovered, and the venous blood pressure in the IVC below the obstruction level showed a significant decrease from 20.8 ± 1.2 mmHg (mean ± SE) to 10.7 ± 0.7 mmHg (p 0.6) with the urine volume increase, and with the decreased volume of edema and ascites. The urine volume increase correlated well with the decrement of edema, but not with that of ascites. Improvements for various durations in the levels of blood urea nitrogen, serum creatinine, lactate dehydrogenase, fibrinogen, and platelet count were found (p < 0.05). These hematobiochemical changes were well correlated with each other and with the decrement of ascites. Two patients showed a low blood sodium level of 128.5 mEq/l after intensive natriuresis, and one of them died on day 21 with hepatic failure, which was interpreted as maladaptation aggravation. The mean survival time was 94.1 ± 34.1 days (mean ± SD), ranging from 21 to 140 days after stent treatment. Conclusion. The stent therapy for IVC obstruction due to malignant liver tumors was followed by a series of physiologic and hematobiochemical consequences, most of them favorable but some possibly unfavorable. Rational interpretations and predictions of sequelae based on physiologic science including cardiology, hepatology, and nephrology would facilitate the best management of stent therapy for

  10. Clinical, biochemical, serological, histological and ultrastructural features of liver disease in drug abusers.

    Science.gov (United States)

    Weller, I V; Cohn, D; Sierralta, A; Mitcheson, M; Ross, M G; Montano, L; Scheuer, P; Thomas, H C

    1984-01-01

    Heroin abusers are frequently found to have abnormal liver function tests and hepatic histology. Hepatitis viruses A, B, and NANB, other drugs or drug contaminants and excessive alcohol consumption are factors thought to contribute. One hundred and sixteen heroin abusers attending a London treatment centre were studied. Sixty two (53%) had a raised aspartate transaminase. This was not explained by current infection with hepatitis A and B, cytomegalo or Epstein-Barr viruses, excessive alcohol consumption (greater than 80 g/day) or concomitant drug taking. Abnormal liver function tests were as frequent in those with markers of current or past HBV infection as those without and there was evidence that both HBV infection and the cause of the abnormal liver function tests were acquired in the first few years of intravenous drug abuse. Liver biopsies from eight patients showed chronic hepatitis with a mild lobular and portal inflammatory infiltrate, fatty change and prominent sinusoidal cells. Electron microscopy showed cytoplasmic trilaminar tubular structures and dense fused membranes in dilated endoplasmic reticulum. These clinical, biochemical, serological, and histological features would suggest a major role for NANB virus infection in the aetiology of hepatitis in heroin abusers. Images Fig. 2 Fig. 3 Fig. 4 PMID:6423458

  11. Tumor vessel normalization by the PI3K inhibitor HS-173 enhances drug delivery.

    Science.gov (United States)

    Kim, Soo Jung; Jung, Kyung Hee; Son, Mi Kwon; Park, Jung Hee; Yan, Hong Hua; Fang, Zhenghuan; Kang, Yeo Wool; Han, Boreum; Lim, Joo Han; Hong, Soon-Sun

    2017-09-10

    Tumor vessels are leaky and immature, which causes poor oxygen and nutrient supply to tumor vessels and results in cancer cell metastasis to distant organs. This instability of tumor blood vessels also makes it difficult for anticancer drugs to penetrate and reach tumors. Numerous tumor vessel normalization approaches have been investigated for improving drug delivery into tumors. In this study, we investigated whether phosphoinositide 3-kinase (PI3K) inhibitors are able to improve vascular structure and function over the prolonged period necessary to achieve effective vessel normalization. The PI3K inhibitors, HS-173 and BEZ235 potently suppressed tumor growth and hypoxia, and increased tumor apoptosis in animal models. PI3K inhibitors also induced a regular, flat monolayer of endothelial cells (ECs) in vessels, improving stability of vessel structure, and normalized tumor vessels by increasing vascular maturity, pericyte coverage, basement membrane thickness, and tight-junctions. These effects resulted in a decrease in tumor vessel tortuosity and vessel thinning, and improved vessel function and blood flow. The tumor vessel stabilization effect of the PI3K inhibitor HS-173 also decreased the number of metastatic lung nodules in vivo metastasis model. Furthermore, HS-173 improved the delivery of doxorubicin into the tumor region, enhancing its anticancer effects. Mechanistic studies suggested that PI3K inhibitor HS-173-induced vessel normalization reflected changes in endothelial Notch signaling. Taken together, our findings indicate that vessel normalization by PI3K inhibitors restrained tumor growth and metastasis while improving chemotherapy by enhancing drug delivery into the tumor, suggesting that HS-173 may have a therapeutic value as an enhancer or an anticancer drug. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Addressing challenges of heterogeneous tumor treatment through bispecific protein-mediated pretargeted drug delivery.

    Science.gov (United States)

    Yang, Qi; Parker, Christina L; McCallen, Justin D; Lai, Samuel K

    2015-12-28

    Tumors are frequently characterized by genomically and phenotypically distinct cancer cell subpopulations within the same tumor or between tumor lesions, a phenomenon termed tumor heterogeneity. These diverse cancer cell populations pose a major challenge to targeted delivery of diagnostic and/or therapeutic agents, as the conventional approach of conjugating individual ligands to nanoparticles is often unable to facilitate intracellular delivery to the full spectrum of cancer cells present in a given tumor lesion or patient. As a result, many cancers are only partially suppressed, leading to eventual tumor regrowth and/or the development of drug-resistant tumors. Pretargeting (multistep targeting) approaches involving the administration of 1) a cocktail of bispecific proteins that can collectively bind to the entirety of a mixed tumor population followed by 2) nanoparticles containing therapeutic and/or diagnostic agents that can bind to the bispecific proteins accumulated on the surface of target cells offer the potential to overcome many of the challenges associated with drug delivery to heterogeneous tumors. Despite its considerable success in improving the efficacy of radioimmunotherapy, the pretargeting strategy remains underexplored for a majority of nanoparticle therapeutic applications, especially for targeted delivery to heterogeneous tumors. In this review, we will present concepts in tumor heterogeneity, the shortcomings of conventional targeted systems, lessons learned from pretargeted radioimmunotherapy, and important considerations for harnessing the pretargeting strategy to improve nanoparticle delivery to heterogeneous tumors. Copyright © 2015 Elsevier B.V. All rights reserved.

  13. Tumor deposit is a poor prognostic indicator in patients who underwent simultaneous resection for synchronous colorectal liver metastases

    Directory of Open Access Journals (Sweden)

    Lin Q

    2015-01-01

    Full Text Available Qi Lin,# Ye Wei,# Li Ren,# Yunshi Zhong,# Chunzhi Qin, Peng Zheng, Pingping Xu, Dexiang Zhu, Meiling Ji, Jianmin XuDepartment of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China#These authors contributed equally to this workBackground: Tumor deposits are one of the important influencing factors among the different editions of Tumor, Node, Metastasis classification. Incidence and prognosis of tumor deposits in stage I, II, and III colorectal cancer patients has been explored. The aim of this study was to determine the prognostic value of tumor deposits in stage IV colorectal cancer patients who underwent simultaneous resection for synchronous colorectal liver metastases (SCRLM.Methods: Clinicopathological and outcome data of 146 consecutive SCRLM patients who underwent simultaneous R0 resection between July 2003 and July 2013 were collected from our prospectively established SCRLM database. The prognostic value of tumor deposits was evaluated by Kaplan–Meier and Cox regression analysis.Results: Tumor deposits were detected in 41.8% (61/146 of these SCRLM patients. Tumor deposits were significantly correlated with lymph node metastasis and nerve invasion of the primary tumors (P=0.002, P=0.041; respectively. The Kaplan–Meier survival analysis revealed that the overall survival (OS and disease-free survival (DFS of SCRLM patients with tumor deposits were significantly poorer than those with no tumor deposits (P=0.039, P=0.001; respectively. And with multivariate analysis, we found that positive tumor deposits were significantly associated with shorter DFS independent of lymph node status (P=0.002. Subgroup analysis found that of the 57 SCRLM patients with negative lymph node status, the OS and DFS of patients with positive tumor deposits were significantly shorter than those with negative tumor deposits (P=0.002 and P=0.031, respectively. Of the 89 patients with positive lymph node status, the OS of

  14. Drug resistance following irradiation of RIF-1 tumors: Influence of the interval between irradiation and drug treatment

    International Nuclear Information System (INIS)

    Hopwood, L.E.; Davies, B.M.; Moulder, J.E.

    1990-01-01

    RIF-1 tumors contain a small number of cells (1 to 100 per 10(6) cells) that are resistant to 5-fluorouracil, methotrexate, or adriamycin. The frequency of drug-resistant cells among individual untreated tumors is highly variable. Radiation, delivered in vivo at doses of 3 to 12 Gy, increases the frequency of methotrexate- and 5-fluorouracil-resistant cells, but not the frequency of adriamycin-resistant cells. The magnitude of induction of 5-fluorouracil and methotrexate resistance shows a complex dependence on the radiation dose and on the interval between irradiation and assessment of drug resistance. For a dose of 3 Gy, induced 5-fluorouracil and methotrexate resistance is seen only after an interval of 5 to 7 days, whereas for a dose of 12 Gy, high levels of induced resistance are observed 1 to 3 days after irradiation. The maximum absolute risk for induction of resistance is 4 per 10(4) cells per Gy for methotrexate, and 3 per 10(6) cells per Gy for 5-fluorouracil. These results indicate that tumor hypoxia may play a role in the increased levels of drug resistance seen after irradiation, and that both genetic and environmental factors may influence radiation-induction of drug resistance. These studies provide essential data for models of the development of tumor drug resistance, and imply that some of the drug resistance seen when chemotherapy follows radiotherapy may be caused by radiation-induced drug resistance

  15. [Advances of tumor targeting peptides drug delivery system with pH-sensitive activities].

    Science.gov (United States)

    Ma, Yin-yun; Li, Li; Huang, Hai-feng; Gou, San-hu; Ni, Jing-man

    2016-05-01

    The pH-sensitive peptides drug delivery systems, which target to acidic extracellular environment of tumor tissue, have many advantages in drug delivery. They exhibit a high specificity to tumor and low cytotoxicity, which significantly increase the efficacy of traditional anti-cancer drugs. In recent years the systems have received a great attention. The pH-sensitive peptides drug delivery systems can be divided into five types according to the difference in pH-responsive mechanism,type of peptides and carrier materials. This paper summarizes the recent progresses in the field with a focus on the five types of pH-sensitive peptides in drug delivery systems. This may provide a guideline to design and application of tumor targeting drugs.

  16. Pancreatic endocrine tumor with neoplastic venous thrombus and bilobar liver metastasis. A case report.

    Science.gov (United States)

    Barbier, L; Turrini, O; Sarran, A; Delpero, J-R

    2010-02-01

    We report the case of an asymptomatic 56-year-old woman with a metastatic pancreatic endocrine tumor, fortuitously discovered by abdominal imaging. A CT-scan showed a large mass in the pancreatic tail invading the spleen and stomach; in addition, there was neoplastic thrombus within the spleno-mesentericoportal venous confluence and bilobar liver metastases. Surgical resection was performed in two stages. The first procedure was an extended left pancreatectomy with venous thrombectomy and "clearance" of the left hepatic lobe. During the interval, embolization of the right portal vein was carried out. Right hepatectomy and radiofrequency destruction of residual metastases was then performed. On the basis of completeness of the resection and the histopathological data, the patient did not undergo any adjuvant therapy, in accordance with French guidelines. At 1 year of follow-up, there was no evidence of recurrence. (c) 2010 Elsevier Masson SAS. All rights reserved.

  17. The impact of share wave elastography in differentiation of hepatic hemangioma from malignant liver tumors in pediatric population

    International Nuclear Information System (INIS)

    Özmen, Evrim; Adaletli, İbrahim; Kayadibi, Yasemin; Emre, Şenol; Kılıç, Fahrettin; Dervişoğlu, Sergülen; Kuruğoğlu, Sebuh; Şenyüz, Osman Faruk

    2014-01-01

    Highlights: • We evaluated the impact of share wave elastography technique in differentiation hepatic hemangiomas from malignant liver tumors in pediatric population. • Share wave technique can increase the diagnostic capability of conventional ultrasonography in the differential diagnosis of liver tumors in children. • Share wave elastography is a potential adjunctive diagnostic technique for pediatric liver tumors. - Abstract: Objective: In children it is crucial to differentiate malignant liver tumors from the most common benign tumor, hepatic hemangiomas since the treatment strategies are quite different. We aimed to evaluate the efficiency of shear wave elastography (SWE) technique in differentiation of malignant hepatic tumors and hepatic hemangiomas. Methods: Twenty patients with hepatic tumor were included in our study. Two radiologists performed SWE for 13 patients with malignant hepatic tumors including hepatoblastoma (n = 7), hepatocellular carcinoma (n = 3), metastasis (n = 2), embryonal sarcoma (n = 1) and 7 patients with hepatic hemangioma. All of our patients were between the age of 1 and 192 months (mean age: 56.88 months). Receiver operating characteristic analysis was achieved to evaluate the diagnostic accuracy of SWE and to determine the optimal cut-off value in differentiation hepatic hemangioma from malignant hepatic tumors. Results: The mean SWE values (in kPa) for the first observer were 46.94 (13.8–145) and 22.38 (6.6–49.6) and those for the second observer were 57.91 (11–237) and 23.87 (6.4–57.5), respectively for malignant hepatic tumors and hepatic hemangiomas. The SWE values of malignant hepatic tumors were significantly higher than those of hepatic hemangioma (p = 0.02). The inter-observer agreement was almost perfect (0.81). The area under the receiver operating characteristic curve of SWE for differentiating the hepatic hemangioma from malignant hepatic tumors was 0.77 with a sensitivity of 72.7% and a specificity of 66

  18. Liver stem/progenitor cells in the canals of Hering: cellular origin of hepatocellular carcinoma with bile duct tumor thrombi?

    Science.gov (United States)

    Peng, Ningfu; Li, Lequn; Cai, Xiang; Tan, Shaozao; Wu, Ting

    2010-12-01

    It is generally believed that the invasion of hepatocellular carcinoma (HCC) into the biliary tree ultimately leads to the formation of bile duct tumor thrombi (BDTT). However, recent studies revealed that primary tumor might be small, even undetectable, and there was no histopathologic evidence of direct tumor invasion into bile duct wall in some patients. During the last decade, efforts on stem cell biology may shed light on the pathogenesis of BDTT. Presently, accumulating evidence supports the following notions: (1) the canals of Hering (CoH) are the most likely origin of liver stem/progenitor cells (LSPCs) in adult livers; (2) similar signalling pathways may regulate self-renewal in LSPCs and liver cancer cells, and a substantial proportion of liver tumors may often originate from the transformation of LSPCs; and (3) liver cancer contains rare cells with stem cell-like properties, which could derive from malignant transformation of LSPCs. Herein, we propose that HCC with BDTT, especially with small or undetectable primary lesion and/or no histopathologic evidence for bile duct invasion, might arise from LSPCs residing in the CoH and, possibly, some primary lesions are formed firstly within the intrahepatic biliary tree. When "tumor thrombi" extends mainly along bile duct, there might be "BDTT" alone; when it invades into surrounding parenchyma, there might often be small "primary tumor" with "BDTT". If this holds true, the putative type may be a particular subset of HCC, and most importantly it would facilitate our understanding of stem-cell origin of HCC.

  19. Differential control of the cholesterol biosynthetic pathway in tumor versus liver: evidence for decontrolled tumor cholesterogenesis in a cell-free system

    International Nuclear Information System (INIS)

    Azrolan, N.

    1987-01-01

    Cholesterol biosynthesis was characterized in cell-free post-mitochondrial supernatant (PMS) systems prepared from both normal rat liver and Morris hepatoma 3924A. Per cell, the rate of cholesterol synthesis from either 14 C-citrate of 14 -acetate in the hepatoma system was 9-fold greater than that observed in the liver system. Furthermore, the ratio of sterol-to-fatty acid synthesis rates from 14 C-citrate was more than 3-fold greater in the tumor than in the normal liver system. Incubations using radiolabeled acetate and mevalonate have demonstrated the loss of a normally rate-limiting control site within the early portion of the cholesterol biosynthetic pathway in the tumor system. Upon analysis of the steady-state levels of early lipogenic intermediates, the specific site of decontrol in the tumor was identified as the 3-hydroxy-3-methylglutaryl-CoA → mevalonate site of this pathway. In contrast, this reaction appeared to retain its rate-limiting properties in the cell-free system from normal liver

  20. MicroRNAs as Signaling Mediators and Biomarkers of Drug- and Chemical-Induced Liver Injury

    Directory of Open Access Journals (Sweden)

    Mitchell R. McGill

    2015-05-01

    Full Text Available Drug-induced liver injury (DILI is major problem for both the drug industry and for clinicians. There are two basic categories of DILI: intrinsic and idiosyncratic. The former is the chief cause of acute liver failure in several developed countries, while the latter is the most common reason for post-marketing drug withdrawal and a major reason for failure to approve new drugs in the U.S. Although considerably more progress has been made in the study of intrinsic DILI, our understanding of both forms of drug hepatotoxicity remains incomplete. Recent work involving microRNAs (miRNAs has advanced our knowledge of DILI in two ways: (1 possible roles of miRNAs in the pathophysiological mechanisms of DILI have been identified, and (2 circulating miRNA profiles have shown promise for the detection and diagnosis of DILI in clinical settings. The purpose of this review is to summarize major findings in these two areas of research. Taken together, exciting progress has been made in the study of miRNAs in DILI. Possible mechanisms through which miRNA species contribute to the basic mechanisms of DILI are beginning to emerge, and new miRNA-based biomarkers have the potential to greatly improve diagnosis of liver injury and prediction of patient outcomes.

  1. Nanodiamond-Manganese dual mode MRI contrast agents for enhanced liver tumor detection.

    Science.gov (United States)

    Hou, Weixin; Toh, Tan Boon; Abdullah, Lissa Nurrul; Yvonne, Tay Wei Zheng; Lee, Kuan J; Guenther, Ilonka; Chow, Edward Kai-Hua

    2017-04-01

    Contrast agent-enhanced magnetic resonance (MR) imaging is critical for the diagnosis and monitoring of a number of diseases, including cancer. Certain clinical applications, including the detection of liver tumors, rely on both T1 and T2-weighted images even though contrast agent-enhanced MR imaging is not always reliable. Thus, there is a need for improved dual mode contrast agents with enhanced sensitivity. We report the development of a nanodiamond-manganese dual mode contrast agent that enhanced both T1 and T2-weighted MR imaging. Conjugation of manganese to nanodiamonds resulted in improved longitudinal and transverse relaxivity efficacy over unmodified MnCl 2 as well as clinical contrast agents. Following intravenous administration, nanodiamond-manganese complexes outperformed current clinical contrast agents in an orthotopic liver cancer mouse model while also reducing blood serum concentration of toxic free Mn 2+ ions. Thus, nanodiamond-manganese complexes may serve as more effective dual mode MRI contrast agent, particularly in cancer. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Maximum Diameter and Number of Tumors as a New Prognostic Indicator of Colorectal Liver Metastases.

    Science.gov (United States)

    Yoshimoto, Toshiaki; Morine, Yuji; Imura, Satoru; Ikemoto, Tetsuya; Iwahashi, Syuichi; Saito, Y U; Yamada, Sinichiro; Ishikawa, Daichi; Teraoku, Hiroki; Yoshikawa, Masato; Higashijima, Jun; Takasu, Chie; Shimada, Mitsuo

    2017-01-01

    Surgical resection is currently considered the only potentially curative option as a treatment strategy of colorectal liver metastases (CRLM). However, the criteria for selection of resectable CRLM are not clear. The aim of this study was to confirm a new prognostic indicator of CRLM after hepatic resection. One hundred thirty nine patients who underwent initial surgical resection from 1994 to 2015 were investigated retrospectively. Prognostic factors of overall survival including the product of maximum diameter and number of metastases (MDN) were analyzed. Primary tumor differentiation, vessel invasion, lymph node (LN) metastasis, non-optimally resectable metastases, H score, grade of liver metastases, resection with non-curative intent and MDN were found to be prognostic factors of overall survival (OS). In multivariate analyses of clinicopathological features associated with OS, MDN and non-curative intent were independent prognostic factors. Patients with MDN ≥30 had shown significantly poorer prognosis than patients with MDN <30 in OS and relapse-free survival (RFS). MDN ≥30 is an independent prognostic factor of survival in patients with CRLM and optimal surgical criterion of hepatectomy for CRLM. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  3. Evaluation of potential internal target volume of liver tumors using cine-MRI.

    Science.gov (United States)

    Akino, Yuichi; Oh, Ryoong-Jin; Masai, Norihisa; Shiomi, Hiroya; Inoue, Toshihiko

    2014-11-01

    Four-dimensional computed tomography (4DCT) is widely used for evaluating moving tumors, including lung and liver cancers. For patients with unstable respiration, however, the 4DCT may not visualize tumor motion properly. High-speed magnetic resonance imaging (MRI) sequences (cine-MRI) permit direct visualization of respiratory motion of liver tumors without considering radiation dose exposure to patients. Here, the authors demonstrated a technique for evaluating internal target volume (ITV) with consideration of respiratory variation using cine-MRI. The authors retrospectively evaluated six patients who received stereotactic body radiotherapy (SBRT) to hepatocellular carcinoma. Before acquiring planning CT, sagittal and coronal cine-MRI images were acquired for 30 s with a frame rate of 2 frames/s. The patient immobilization was conducted under the same condition as SBRT. Planning CT images were then acquired within 15 min from cine-MRI image acquisitions, followed by a 4DCT scan. To calculate tumor motion, the motion vectors between two continuous frames of cine-MRI images were calculated for each frame using the pyramidal Lucas-Kanade method. The target contour was delineated on one frame, and each vertex of the contour was shifted and copied onto the following frame using neighboring motion vectors. 3D trajectory data were generated with the centroid of the contours on sagittal and coronal images. To evaluate the accuracy of the tracking method, the motion of clearly visible blood vessel was analyzed with the motion tracking and manual detection techniques. The target volume delineated on the 50% (end-exhale) phase of 4DCT was translated with the trajectory data, and the distribution of the occupancy probability of target volume was calculated as potential ITV (ITV Potential). The concordance between ITV Potential and ITV estimated with 4DCT (ITV 4DCT) was evaluated using the Dice's similarity coefficient (DSC). The distance between blood vessel positions

  4. Evaluation of potential internal target volume of liver tumors using cine-MRI

    Energy Technology Data Exchange (ETDEWEB)

    Akino, Yuichi, E-mail: akino@radonc.med.osaka-u.ac.jp [Department of Radiation Oncology, Osaka University Graduate School of Medicine, Suita, Osaka 5650871, Japan and Miyakojima IGRT Clinic, Miyakojima-ku, Osaka 5340021 (Japan); Oh, Ryoong-Jin; Masai, Norihisa; Shiomi, Hiroya; Inoue, Toshihiko [Miyakojima IGRT Clinic, Miyakojima-ku, Osaka 5340021 (Japan)

    2014-11-01

    Purpose: Four-dimensional computed tomography (4DCT) is widely used for evaluating moving tumors, including lung and liver cancers. For patients with unstable respiration, however, the 4DCT may not visualize tumor motion properly. High-speed magnetic resonance imaging (MRI) sequences (cine-MRI) permit direct visualization of respiratory motion of liver tumors without considering radiation dose exposure to patients. Here, the authors demonstrated a technique for evaluating internal target volume (ITV) with consideration of respiratory variation using cine-MRI. Methods: The authors retrospectively evaluated six patients who received stereotactic body radiotherapy (SBRT) to hepatocellular carcinoma. Before acquiring planning CT, sagittal and coronal cine-MRI images were acquired for 30 s with a frame rate of 2 frames/s. The patient immobilization was conducted under the same condition as SBRT. Planning CT images were then acquired within 15 min from cine-MRI image acquisitions, followed by a 4DCT scan. To calculate tumor motion, the motion vectors between two continuous frames of cine-MRI images were calculated for each frame using the pyramidal Lucas–Kanade method. The target contour was delineated on one frame, and each vertex of the contour was shifted and copied onto the following frame using neighboring motion vectors. 3D trajectory data were generated with the centroid of the contours on sagittal and coronal images. To evaluate the accuracy of the tracking method, the motion of clearly visible blood vessel was analyzed with the motion tracking and manual detection techniques. The target volume delineated on the 50% (end-exhale) phase of 4DCT was translated with the trajectory data, and the distribution of the occupancy probability of target volume was calculated as potential ITV (ITV {sub Potential}). The concordance between ITV {sub Potential} and ITV estimated with 4DCT (ITV {sub 4DCT}) was evaluated using the Dice’s similarity coefficient (DSC). Results

  5. A clinical trial comparing the responses of animal tumors receiving heat sensitizing drugs prior to whole body hyperthermia

    International Nuclear Information System (INIS)

    Klein, M.K.; Forsyth, K.; Dewhirst, M.W.; Fuller, D.J.M.

    1984-01-01

    Whole body hyperthermia (WBH) has rarely been found effective in inducing complete tumor responses. Recent in vitro studies showing that heat sensitizion is possible have renewed interest in this field. In this protocol, WBH is induced via a commercially available inductive device and maintained at 42 0 C for thirty minutes. The heat sensitizing drugs, difluoromethylornithine (DFMO) methylglyoxal bis (guanylhydrazone) (MGBG) are administered 48 hours before, in accordance with in vitro studies. Goals of the study include evaluation of normal tissue toxicity and tumor response. Two normal dogs were treated to study acute toxicities before inception of the clinical trial. The gastrointestinal and hematopoietic systems were used to monitor toxicities using systems review and serial bloodwork. These studies and preliminary clinical results of observed tumor regression in dogs with lymphomas are discussed. Consistent changes in all patients included elevations in liver enzymes, creatine phosphokinase (CPK), and white blood cell counts, as well as, decreases in platelet counts. All changes were transient and clinical signs were not associated with them. Tumor volume reductions from 25% to 74% have been documented

  6. DNA alkylation and tumor induction in regenerating rat liver after cell cycle-related continuous N-nitrosodimethylamine infusion

    Energy Technology Data Exchange (ETDEWEB)

    Rabes, H.M.; Kerler, R.; Wilhelm, R.

    1983-01-01

    Synchronized regenerating rat liver after partial hepatectomy was used to study cell cycle-related DNA base alkylation and liver carcinogenesis. A continuous iv infusion of (/sup 14/C)N-nitrosodimethylamine (DMN) at a dose of 0.5 mg/kg/hour was given to inbred male Wistar Af/Han rats over a period of 8 hours either during the G1 phase, hydroxyurea-synchronized DNA synthesis, or the G2+M-phase of regenerating liver or to untreated rats (G0-phase liver--carcinogen dose, 1.5 mg/kg/hour). Two hours after the end of the infusion, the amount of 7-methylguanine was highest in the G0-phase liver, with a decrease in the G1 phase, the S-phase, and the G2+M-phase. After continuous DMN exposure, the O/sub 6/-methylguanine:7-methylguanine ratio was lower in the S-phase and G2+M-phase livers than in the G0-phase and G1-phase livers, indicating an increased O/sub 6/-methylguanine repair during DNA synthesis and the G2+M-phase. Liver tumors in rats treated by continuous DMN infusion either during the G0 phase or the S-phase developed only after carcinogen exposure during DNA synthesis.

  7. Circumvention of the tumor membrane barrier to WR-2721 absorption by reduction of drug hydrophilicity

    International Nuclear Information System (INIS)

    Yuhas, J.M.; Davis, M.E.; Glover, D.; Brown, D.Q.; Ritter, M.

    1982-01-01

    In attempting to account for the ability of most solid tumors to restrict the absorption of WR-2721, aminopropyl-aminoethylphosphorothioate, we examined a number of drug characteristics which might allow for this restriction, and observed that drug hypdrophilicity was a major contributing factor. When the highly hydrophilic WR-2721 was dephosphorylated, the drug became less hydrophilic and could readily cross tumor cell membranes. In addition, conventional radioprotectants, such as cysteine and mercaptoethylamine, were shown to be less hydrophilic than WR-2721 and also to cross tumor membranes readily. Therefore, drug hydrophilicity would appear to be the factor underlying the ability of WR-2721 to selectively protect normal tissues while most other protectors alter the radiation resistance of normal and tumor tissue alike. A red blood cell model for studying this problem in greater detail is described

  8. Assessing Concordance of Drug-Induced Transcriptional Response in Rodent Liver and Cultured Hepatocytes.

    Directory of Open Access Journals (Sweden)

    Jeffrey J Sutherland

    2016-03-01

    Full Text Available The effect of drugs, disease and other perturbations on mRNA levels are studied using gene expression microarrays or RNA-seq, with the goal of understanding molecular effects arising from the perturbation. Previous comparisons of reproducibility across laboratories have been limited in scale and focused on a single model. The use of model systems, such as cultured primary cells or cancer cell lines, assumes that mechanistic insights derived from the models would have been observed via in vivo studies. We examined the concordance of compound-induced transcriptional changes using data from several sources: rat liver and rat primary hepatocytes (RPH from Drug Matrix (DM and open TG-GATEs (TG, human primary hepatocytes (HPH from TG, and mouse liver/HepG2 results from the Gene Expression Omnibus (GEO repository. Gene expression changes for treatments were normalized to controls and analyzed with three methods: 1 gene level for 9071 high expression genes in rat liver, 2 gene set analysis (GSA using canonical pathways and gene ontology sets, 3 weighted gene co-expression network analysis (WGCNA. Co-expression networks performed better than genes or GSA when comparing treatment effects within rat liver and rat vs. mouse liver. Genes and modules performed similarly at Connectivity Map-style analyses, where success at identifying similar treatments among a collection of reference profiles is the goal. Comparisons between rat liver and RPH, and those between RPH, HPH and HepG2 cells reveal lower concordance for all methods. We observe that the baseline state of untreated cultured cells relative to untreated rat liver shows striking similarity with toxicant-exposed cells in vivo, indicating that gross systems level perturbation in the underlying networks in culture may contribute to the low concordance.

  9. Long-term survival after liver transplant for recurrent hepatocellular carcinoma with bile duct tumor thrombus: case report.

    Science.gov (United States)

    Liu, Chao; Wang, Jie

    2012-12-01

    Hepatocellular carcinoma with bile duct tumor thrombus is considered an aggressive malignancy, and the prognosis of liver transplant for it remains obscure. A 42-year-old man with recurrent hepatocellular carcinoma and a history of surgical resection was admitted to our hospital with a 10-day history of yellowish urine and itchy skin. There were 3 lesions in the right lobe with the diameter of 2 cm each. A mass was found in the upper part of common bile duct, and the intrahepatic bile duct was dilated. His serum alpha-fetoprotein level was 2476 μg/L, total bilirubin level was 327 μmol/L, direct bilirubin level was 261 μmol/L, and alanine aminotransferase was 714 U/L. There was no main portal vein thrombus or extrahepatic metastases. Because of his poor liver function, he was listed for a liver transplant. During the wait (30 d), he underwent 9 episodes of plasmapheresis to decrease the serum level of bilirubin. He had an orthotopic liver transplant with the graft from a deceased donor. After the liver transplant, he received 5 cycles of chemotherapy with the regimen of oxaliplatin and 5-fluorouracil. This patient has survived without recurrence of hepatocellular carcinoma for more than 82 months and remains in good condition. Liver transplant may have a favorable result for hepatocellular carcinoma patient with a bile duct tumor thrombus, within the Milan criteria.

  10. Anesthetic drugs accelerate the progression of postoperative metastases of mouse tumors.

    OpenAIRE

    Shapiro, J; Jersky, J; Katzav, S; Feldman, M; Segal, S

    1981-01-01

    Experiments were made to investigate the effect of four anesthetic drugs that are commonly used in surgical practice on the postoperative growth of mouse tumors in syngeneic recipients. These experiments revealed that some of the anesthetics when applied for surgical excision of the local tumor, strongly accelerated postoperative progression of spontaneous lung metastases produced by the 3LL Lewis lung carcinoma and by the B16 melanoma. Some of the drugs caused the appearance of metastases in...

  11. Tumor and liver determinants of prognosis in unresectable hepatocellular carcinoma: a large case cohort study.

    Science.gov (United States)

    Carr, Brian I; Pancoska, Petr; Branch, Robert A

    2009-12-24

    967 patients with unresectable and untransplantable, biopsy-proven hepatocellular carcinoma (HCC) were prospectively evaluated at baseline and followed up till death. Survival was the end point. We found that male gender, ascites, cirrhosis, portal vein thrombosis (PVT), elevated AFP or bilirubin, or alkaline phosphatase, were each statistically significant adverse prognostic factors. Patients with normal AFP survived longer than those with elevated AFP, even in the presence of PVT, large or bilobar tumors or cirrhosis. We used a bivariate analysis to separate patient sub groups based on liver function and tumor characteristics and found clear discrimination in survival between subsets; in addition both cirrhosis and presence of PVT were significant factors. We also used a purely mathematical approach to derive subgroups and a prognostic model for individual patients. Interestingly, the two approaches gave similar predictive information, which opens the possibility of a more detailed mathematical analysis in the future. The results of this large dataset show that amongst non-surgical HCC patients, there are clear subsets with longer survival. The data supports the concept of heterogeneity of HCC. The three factors, bilirubin, AFP, and PVT predominate in prognosis.

  12. Tumor and liver determinants of prognosis in unresectable hepatocellular carcinoma: a case cohort study.

    Science.gov (United States)

    Carr, Brian I; Buch, Shama C; Kondragunta, Venkateswarlu; Pancoska, Petr; Branch, Robert A

    2008-08-01

    A total of 967 patients with unresectable and untransplantable, biopsy-proven hepatocellular carcinoma (HCC) were prospectively evaluated at baseline and followed up till death. Survival was the end-point for all analyses. We found in our overall analysis, that male gender, ascites, cirrhosis, portal vein thrombosis (PVT), elevated alpha-fetoprotein (AFP) or bilirubin or alkaline phosphatases were each statistically significant adverse prognostic factors. Patients with normal AFP survived longer than those with elevated AFP, in the presence of PVT, large or bilobar tumors or cirrhosis. We used a bivariate analysis to separate patient subgroups based on poor liver function and aggressive tumor characteristics. In subgroup analysis based on these subsets, there was clear discrimination in survival between subsets; in addition both cirrhosis and presence of PVT were significant, independent but modest risk factors. The results of this large dataset show that amongst nonsurgical HCC patients, there are clear subsets with longer survival than other subsets. This data also supports the concept of heterogeneity of HCC.

  13. Approaches to drug resistance in solid tumors : with emphasis on lung cancer

    NARCIS (Netherlands)

    Bakker, Marleen

    2005-01-01

    De novo or acquired resistance of tumor cells to anticancer agents remains a major problem for the therapeutic efficacy of chemotherapeutic drugs. Most solid tumors are intrinsically insensitive or acquire resistance after initial response to chemotherapy. Different mechanisms seem to play a role in

  14. Evaluation of factors affecting tumor response and survival in patients with primary and metastatic liver cancer treated with microspheres.

    Science.gov (United States)

    Demirelli, Serkan; Erkilic, Metin; Oner, Ali Ozan; Budak, Evrim Surer; Gunduz, Seyda; Ozgur, Ozhan; Bozcuk, Hakan; Sindel, Hakki Timur; Boz, Adil

    2015-04-01

    Radioembolization with the yttrium-90 (Y-90) microspheres is being used increasingly more often in the treatment of patients with primary or metastatic liver cancer. Although technetium-99m macroaggregated albumin (Tc-99m MAA) scintigraphy performed following diagnostic angiography has an important role in predicting the effectiveness of treatment and in dose estimation, the number of studies using quantitative assessment of Tc-99m MAA scintigraphy is limited in this field. In the present study, the aim was to assess whether a tumor dose is required to obtain objective tumor response and to check whether this threshold value is predictive in terms of tumor response, survival, and liver toxicity by using Tc-99m MAA single-photon emission computed tomography (SPECT) images. Overall, 54 patients (20 women and 34 men; median age: 60 years) who underwent Y-90 Resin (SIR-Spheres) and Glass (TheraSphere) microsphere treatment with a diagnosis of unresectable liver cancer between August 2010 and April 2013 were included in the study. The mean doses to normal liver and tumor were estimated for each patient using Tc-99m MAA SPECT images and the medical internal radiation dosimetry method. The responses were assessed according to Response Evaluation Criteria In Solid Tumors (RECIST) and European Organisation for Research and Treatment of Cancer (EORTC) criteria. Kaplan-Meier survival curves and univariate Cox regression analysis were used in survival analysis. The relationship between treatment response and other parameters included was assessed using logistic regression analysis. The variables with a P value less than 0.01 in univariate analysis were assessed with multivariate analysis. Fifty-four Y-90 microsphere treatments (eight by using a Y-90 glass microsphere and 46 by using a Y-90 resin microsphere) were performed. In the multivariate analysis, the only parameter related to response was tumor dose (P<0.01). With a tumor dose of 280 Gy or higher, objective tumor

  15. Reference intervals for putative biomarkers of drug-induced liver injury and liver regeneration in healthy human volunteers.

    Science.gov (United States)

    Francis, Ben; Clarke, Joanna I; Walker, Lauren E; Brillant, Nathalie; Jorgensen, Andrea L; Park, B Kevin; Pirmohamed, Munir; Antoine, Daniel J

    2018-05-02

    The potential of mechanistic biomarkers to improve the prediction of drug-induced liver injury (DILI) and hepatic regeneration is widely acknowledged. We sought to determine reference intervals for new biomarkers of DILI and regeneration as well as to characterize their natural variability and impact of diurnal variation. Serum samples from 200 healthy volunteers were recruited as part of a cross sectional study; of these, 50 subjects had weekly serial sampling over 3 weeks, while 24 had intensive blood sampling over a 24h period. Alanine aminotransferase (ALT), MicroRNA-122 (miR-122), high mobility group box-1 (HMGB1), total keratin-18 (FL-K18), caspase cleaved keratin-18 (cc-K18), glutamate dehydrogenase (GLDH) and colony stimulating factor-1 (CSF-1) were assessed by validated assays. Reference intervals were established for each biomarker based on the 97.5% quantile (90% CI) following the assessment of fixed effects in univariate and multivariable models (ALT 50 (41-50) U/l, miR-122 3548 (2912-4321) copies/µl, HMGB1 2.3 (2.2-2.4) ng/ml, FL-K18 475 (456-488) U/l, cc-K18 272 (256-291) U/l, GLDH 27 (26-30) U/l and CSF-1 2.4 (2.3-2.9) ng/ml). There was a small but significant intra-individual time random effect detected but no significant impact of diurnal variation was observed, with the exception of GLDH. Reference intervals for novel DILI biomarkers have been described for the first time. An upper limit of a reference range might represent the most appropriate method to utilize these data. Regulatory authorities have published letters of support encouraging further qualification of leading candidate biomarkers. These data can now be used to interpret data from exploratory clinical DILI studies and to assist their further qualification. Drug-induced liver injury (DILI) has a big impact on patient health and the development of new medicines. Unfortunately, currently used blood-based tests to assess liver injury and recovery suffer from insufficiencies. Newer blood

  16. Automatic Multiple-Needle Surgical Planning of Robotic-Assisted Microwave Coagulation in Large Liver Tumor Therapy.

    Directory of Open Access Journals (Sweden)

    Shaoli Liu

    Full Text Available The "robotic-assisted liver tumor coagulation therapy" (RALTCT system is a promising candidate for large liver tumor treatment in terms of accuracy and speed. A prerequisite for effective therapy is accurate surgical planning. However, it is difficult for the surgeon to perform surgical planning manually due to the difficulties associated with robot-assisted large liver tumor therapy. These main difficulties include the following aspects: (1 multiple needles are needed to destroy the entire tumor, (2 the insertion trajectories of the needles should avoid the ribs, blood vessels, and other tissues and organs in the abdominal cavity, (3 the placement of multiple needles should avoid interference with each other, (4 an inserted needle will cause some deformation of liver, which will result in changes in subsequently inserted needles' operating environment, and (5 the multiple needle-insertion trajectories should be consistent with the needle-driven robot's movement characteristics. Thus, an effective multiple-needle surgical planning procedure is needed. To overcome these problems, we present an automatic multiple-needle surgical planning of optimal insertion trajectories to the targets, based on a mathematical description of all relevant structure surfaces. The method determines the analytical expression of boundaries of every needle "collision-free reachable workspace" (CFRW, which are the feasible insertion zones based on several constraints. Then, the optimal needle insertion trajectory within the optimization criteria will be chosen in the needle CFRW automatically. Also, the results can be visualized with our navigation system. In the simulation experiment, three needle-insertion trajectories were obtained successfully. In the in vitro experiment, the robot successfully achieved insertion of multiple needles. The proposed automatic multiple-needle surgical planning can improve the efficiency and safety of robot-assisted large liver tumor

  17. Automatic Multiple-Needle Surgical Planning of Robotic-Assisted Microwave Coagulation in Large Liver Tumor Therapy.

    Science.gov (United States)

    Liu, Shaoli; Xia, Zeyang; Liu, Jianhua; Xu, Jing; Ren, He; Lu, Tong; Yang, Xiangdong

    2016-01-01

    The "robotic-assisted liver tumor coagulation therapy" (RALTCT) system is a promising candidate for large liver tumor treatment in terms of accuracy and speed. A prerequisite for effective therapy is accurate surgical planning. However, it is difficult for the surgeon to perform surgical planning manually due to the difficulties associated with robot-assisted large liver tumor therapy. These main difficulties include the following aspects: (1) multiple needles are needed to destroy the entire tumor, (2) the insertion trajectories of the needles should avoid the ribs, blood vessels, and other tissues and organs in the abdominal cavity, (3) the placement of multiple needles should avoid interference with each other, (4) an inserted needle will cause some deformation of liver, which will result in changes in subsequently inserted needles' operating environment, and (5) the multiple needle-insertion trajectories should be consistent with the needle-driven robot's movement characteristics. Thus, an effective multiple-needle surgical planning procedure is needed. To overcome these problems, we present an automatic multiple-needle surgical planning of optimal insertion trajectories to the targets, based on a mathematical description of all relevant structure surfaces. The method determines the analytical expression of boundaries of every needle "collision-free reachable workspace" (CFRW), which are the feasible insertion zones based on several constraints. Then, the optimal needle insertion trajectory within the optimization criteria will be chosen in the needle CFRW automatically. Also, the results can be visualized with our navigation system. In the simulation experiment, three needle-insertion trajectories were obtained successfully. In the in vitro experiment, the robot successfully achieved insertion of multiple needles. The proposed automatic multiple-needle surgical planning can improve the efficiency and safety of robot-assisted large liver tumor therapy

  18. Amenorrhea as a rare drug-related adverse event associated with everolimus for pancreatic neuroendocrine tumors.

    Science.gov (United States)

    Kawaguchi, Yoshiaki; Maruno, Atsuko; Kawashima, Yohei; Ito, Hiroyuki; Ogawa, Masami; Mine, Tetsuya

    2014-11-14

    The patient was an asymptomatic 43-year-old woman. Abdominal ultrasonography and enhanced computed tomography showed a tumor lesion accompanied by multiple cystic changes in the liver and the pancreatic tail. Endoscopic ultrasound-fine needle aspiration was performed on the pancreatic tumor lesion and revealed pancreatic neuroendocrine tumor (PNET). As it was unresectable due to multiple liver metastases, the decision was made to initiate treatment with everolimus and transcatheter arterial chemoembolization. The patient ceased menstruating after the start of everolimus administration. When the administration was discontinued due to interstitial lung disease, menstruation resumed, but then again stopped with everolimus resumption. An association between everolimus and amenorrhea was highly suspected. Amenorrhea occurred as a rare adverse event of everolimus. As the younger women might be included in PNETs patients, we should put this adverse event into consideration.

  19. Drug delivery to solid tumors: the predictive value of the multicellular tumor spheroid model for nanomedicine screening

    Directory of Open Access Journals (Sweden)

    Millard M

    2017-10-01

    Full Text Available Marie Millard,1,2 Ilya Yakavets,1–3 Vladimir Zorin,3,4 Aigul Kulmukhamedova,1,2,5 Sophie Marchal,1,2 Lina Bezdetnaya1,2 1Centre de Recherche en Automatique de Nancy, Centre National de la Recherche Scientifique UMR 7039, Université de Lorraine, 2Research Department, Institut de Cancérologie de Lorraine, Vandœuvre-lès-Nancy, France; 3Laboratory of Biophysics and Biotechnology, 4International Sakharov Environmental Institute, Belarusian State University, Minsk, Belarus; 5Department of Radiology, Medical Company Sunkar, Almaty, Kazakhstan Abstract: The increasing number of publications on the subject shows that nanomedicine is an attractive field for investigations aiming to considerably improve anticancer chemotherapy. Based on selective tumor targeting while sparing healthy tissue, carrier-mediated drug delivery has been expected to provide significant benefits to patients. However, despite reduced systemic toxicity, most nanodrugs approved for clinical use have been less effective than previously anticipated. The gap between experimental results and clinical outcomes demonstrates the necessity to perform comprehensive drug screening by using powerful preclinical models. In this context, in vitro three-dimensional models can provide key information on drug behavior inside the tumor tissue. The multicellular tumor spheroid (MCTS model closely mimics a small avascular tumor with the presence of proliferative cells surrounding quiescent cells and a necrotic core. Oxygen, pH and nutrient gradients are similar to those of solid tumor. Furthermore, extracellular matrix (ECM components and stromal cells can be embedded in the most sophisticated spheroid design. All these elements together with the physicochemical properties of nanoparticles (NPs play a key role in drug transport, and therefore, the MCTS model is appropriate to assess the ability of NP to penetrate the tumor tissue. This review presents recent developments in MCTS models for a

  20. Application of chimeric mice with humanized liver for study of human-specific drug metabolism.

    Science.gov (United States)

    Bateman, Thomas J; Reddy, Vijay G B; Kakuni, Masakazu; Morikawa, Yoshio; Kumar, Sanjeev

    2014-06-01

    Human-specific or disproportionately abundant human metabolites of drug candidates that are not adequately formed and qualified in preclinical safety assessment species pose an important drug development challenge. Furthermore, the overall metabolic profile of drug candidates in humans is an important determinant of their drug-drug interaction susceptibility. These risks can be effectively assessed and/or mitigated if human metabolic profile of the drug candidate could reliably be determined in early development. However, currently available in vitro human models (e.g., liver microsomes, hepatocytes) are often inadequate in this regard. Furthermore, the conduct of definitive radiolabeled human ADME studies is an expensive and time-consuming endeavor that is more suited for later in development when the risk of failure has been reduced. We evaluated a recently developed chimeric mouse model with humanized liver on uPA/SCID background for its ability to predict human disposition of four model drugs (lamotrigine, diclofenac, MRK-A, and propafenone) that are known to exhibit human-specific metabolism. The results from these studies demonstrate that chimeric mice were able to reproduce the human-specific metabolite profile for lamotrigine, diclofenac, and MRK-A. In the case of propafenone, however, the human-specific metabolism was not detected as a predominant pathway, and the metabolite profiles in native and humanized mice were similar; this was attributed to the presence of residual highly active propafenone-metabolizing mouse enzymes in chimeric mice. Overall, the data indicate that the chimeric mice with humanized liver have the potential to be a useful tool for the prediction of human-specific metabolism of xenobiotics and warrant further investigation.

  1. Trabectedin and Plitidepsin: Drugs from the Sea that Strike the Tumor Microenvironment

    Directory of Open Access Journals (Sweden)

    Carlos M. Galmarini

    2014-01-01

    Full Text Available The prevailing paradigm states that cancer cells acquire multiple genetic mutations in oncogenes or tumor suppressor genes whose respective activation/up-regulation or loss of function serve to impart aberrant properties, such as hyperproliferation or inhibition of cell death. However, a tumor is now considered as an organ-like structure, a complex system composed of multiple cell types (e.g., tumor cells, inflammatory cells, endothelial cells, fibroblasts, etc. all embedded in an inflammatory stroma. All these components influence each other in a complex and dynamic cross-talk, leading to tumor cell survival and progression. As the microenvironment has such a crucial role in tumor pathophysiology, it represents an attractive target for cancer therapy. In this review, we describe the mechanism of action of trabectedin and plitidepsin as an example of how these specific drugs of marine origin elicit their antitumor activity not only by targeting tumor cells but also the tumor microenvironment.

  2. Addressing brain tumors with targeted gold nanoparticles: a new gold standard for hydrophobic drug delivery?

    Science.gov (United States)

    Cheng, Yu; Meyers, Joseph D; Agnes, Richard S; Doane, Tennyson L; Kenney, Malcolm E; Broome, Ann-Marie; Burda, Clemens; Basilion, James P

    2011-08-22

    EGF-modified Au NP-Pc 4 conjugates showed 10-fold improved selectivity to the brain tumor compared to untargeted conjugates. The hydrophobic photodynamic therapy drug Pc 4 can be delivered efficiently into glioma brain tumors by EGF peptide-targeted Au NPs. Compared to the untargeted conjugates, EGF-Au NP-Pc 4 conjugates showed 10-fold improved selectivity to the brain tumor. This delivery system holds promise for future delivery of a wider range of hydrophobic therapeutic drugs for the treatment of hard-to-reach cancers. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  3. Green tea, red wine and lemon extracts reduce experimental tumor growth and cancer drug toxicity.

    Science.gov (United States)

    Zaletok, S P; Gulua, L; Wicker, L; Shlyakhovenko, V A; Gogol, S; Orlovsky, O; Karnaushenko, O V; Verbinenko, A; Milinevska, V; Samoylenko, O; Todor, I; Turmanidze, T

    2015-12-01

    To evaluate antitumor effect of plant polyphenol extracts from green tea, red wine lees and/or lemon peel alone and in combination with antitumor drugs on the growth of different transplanted tumors in experimental animals. Green tea extract (GTE) was prepared from green tea infusion. GTE-based composites of red wine (GTRW), lemon peel (GTRWL) and/or NanoGTE as well as corresponding nanocomposites were prepared. The total polyphenolics of the different GTE-based extracts ranged from 18.0% to 21.3%. The effects of GTE-based extracts were studied in sarcoma 180, Ehrlich carcinoma, B16 melanoma, Ca755 mammary carcinoma, P388 leukemia, L1210 leukemia, and Guerin carcinoma (original, cisplatin-resistant and doxorubicin-resistant variants). The extracts were administered as 0.1% solution in drinking water (0.6-1.0 mg by total polyphenolics per mouse per day and 4.0-6.3 mg per rat per day). Tumor growth inhibition (TGI) in mice treated with NanoGTE, cisplatin or cisplatin + NanoGTE was 27%, 55% and 78%, respectively, in Sarcoma 180%, 21%, 45% and 59%, respectively, in Ehrlich carcinoma; and 8%, 13% and 38%, respectively in B16 melanoma. Composites of NanoGTE, red wine, and lemon peel (NanoGTRWL) enhanced the antitumor effects of cyclophosphamide in mice with Ca755 mammary carcinoma. The treatment with combination of NanoGTE and inhibitors of polyamines (PA) synthesis (DFMO + MGBG) resulted in significant TGI of P388 leukemia (up to 71%) and L1210 leukemia. In rats transplanted with Guerin carcinoma (parental strain), treatment with GTRW or GTE alone resulted in 25-28% TGI vs. 55-68% TGI in cisplatin-treated animals. The inhibition observed in the case of combination of GTE or GTRW with cisplatin was additive giving 81-88% TGI. Similar effects were observed when combinations of the cytostatics with GTE (or NanoGTE) were tested against cisplatin- or doxorubicin-resistant Guerin carcinoma. Moreover, the plant extracts lowered side toxicity of the drugs. Treatment with GTE

  4. hTe exciting potential of nanotherapy in brain-tumor targeted drug delivery approaches

    Institute of Scientific and Technical Information of China (English)

    Vivek Agrahari

    2017-01-01

    Delivering therapeutics to the central nervous system (CNS) and brain-tumor has been a major challenge. hTe current standard treatment approaches for the brain-tumor comprise of surgical resection followed by immunotherapy, radiotherapy, and chemotherapy. However, the current treatments are limited in provid-ing signiifcant beneifts to the patients and despite recent technological advancements; brain-tumor is still challenging to treat. Brain-tumor therapy is limited by the lack of effective and targeted strategies to deliver chemotherapeutic agents across the blood-brain barrier (BBB). hTe BBB is the main obstacle that must be overcome to allow compounds to reach their targets in the brain. Recent advances have boosted the nan-otherapeutic approaches in providing an attractive strategy in improving the drug delivery across the BBB and into the CNS. Compared to conventional formulations, nanoformulations offer signiifcant ad vantages in CNS drug delivery approaches. Considering the above facts, in this review, the physiological/anatomical features of the brain-tumor and the BBB are brielfy discussed. hTe drug transport mechanisms at the BBB are outlined. hTe approaches to deliver chemotherapeutic drugs across the CNS into the brain-tumor using nanocarriers are summarized. In addition, the challenges that need to be addressed in nanotherapeutic ap-proaches for their enhanced clinical application in brain-tumor therapy are discussed.

  5. The exciting potential of nanotherapy in brain-tumor targeted drug delivery approaches

    Directory of Open Access Journals (Sweden)

    Vivek Agrahari

    2017-01-01

    Full Text Available Delivering therapeutics to the central nervous system (CNS and brain-tumor has been a major challenge. The current standard treatment approaches for the brain-tumor comprise of surgical resection followed by immunotherapy, radiotherapy, and chemotherapy. However, the current treatments are limited in providing significant benefits to the patients and despite recent technological advancements; brain-tumor is still challenging to treat. Brain-tumor therapy is limited by the lack of effective and targeted strategies to deliver chemotherapeutic agents across the blood-brain barrier (BBB. The BBB is the main obstacle that must be overcome to allow compounds to reach their targets in the brain. Recent advances have boosted the nanotherapeutic approaches in providing an attractive strategy in improving the drug delivery across the BBB and into the CNS. Compared to conventional formulations, nanoformulations offer significant advantages in CNS drug delivery approaches. Considering the above facts, in this review, the physiological/anatomical features of the brain-tumor and the BBB are briefly discussed. The drug transport mechanisms at the BBB are outlined. The approaches to deliver chemotherapeutic drugs across the CNS into the brain-tumor using nanocarriers are summarized. In addition, the challenges that need to be addressed in nanotherapeutic approaches for their enhanced clinical application in brain-tumor therapy are discussed.

  6. In vivo imaging of passively tumor targeted polymer carrier and the enzymatically cleavable drug model

    Czech Academy of Sciences Publication Activity Database

    Pola, Robert; Heinrich, A. K.; Mueller, T.; Kostka, Libor; Mäder, K.; Pechar, Michal; Etrych, Tomáš

    2017-01-01

    Roč. 6, 4 (Suppl) (2017), s. 90 ISSN 2325-9604. [International Conference and Exhibition on Nanomedicine and Drug Delivery. 29.05.2017-31.05.2017, Osaka] R&D Projects: GA MZd(CZ) NV16-28594A Institutional support: RVO:61389013 Keywords : polymer drug carrier * tumor targeting * enzymatic release Subject RIV: FD - Oncology ; Hematology

  7. Tumor Architecture and Notch Signaling Modulate Drug Response in Basal Cell Carcinoma.

    Science.gov (United States)

    Eberl, Markus; Mangelberger, Doris; Swanson, Jacob B; Verhaegen, Monique E; Harms, Paul W; Frohm, Marcus L; Dlugosz, Andrzej A; Wong, Sunny Y

    2018-02-12

    Hedgehog (Hh) pathway inhibitors such as vismodegib are highly effective for treating basal cell carcinoma (BCC); however, residual tumor cells frequently persist and regenerate the primary tumor upon drug discontinuation. Here, we show that BCCs are organized into two molecularly and functionally distinct compartments. Whereas interior Hh + /Notch + suprabasal cells undergo apoptosis in response to vismodegib, peripheral Hh +++ /Notch - basal cells survive throughout treatment. Inhibiting Notch specifically promotes tumor persistence without causing drug resistance, while activating Notch is sufficient to regress already established lesions. Altogether, these findings suggest that the three-dimensional architecture of BCCs establishes a natural hierarchy of drug response in the tumor and that this hierarchy can be overcome, for better or worse, by modulating Notch. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Drug-Induced Liver Injury Network Causality Assessment: Criteria and Experience in the United States

    Directory of Open Access Journals (Sweden)

    Paul H. Hayashi

    2016-02-01

    Full Text Available Hepatotoxicity due to drugs, herbal or dietary supplements remains largely a clinical diagnosis based on meticulous history taking and exclusion of other causes of liver injury. In 2004, the U.S. Drug-Induced Liver Injury Network (DILIN was created under the auspices of the U.S. National Institute of Diabetes and Digestive and Kidney Diseases with the aims of establishing a large registry of cases for clinical, epidemiological and mechanistic study. From inception, the DILIN has used an expert opinion process that incorporates consensus amongst three different DILIN hepatologists assigned to each case. It is the most well-established, well-described and vigorous expert opinion process for DILI to date, and yet it is an imperfect standard. This review will discuss the DILIN expert opinion process, its strengths and weaknesses, psychometric performance and future.

  9. Stereotactic body radiotherapy for liver tumors. Principles and practical guidelines of the DEGRO Working Group on Stereotactic Radiotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Sterzing, Florian [Deutsches Krebsforschungszentrum (DKFZ), Klinische Kooperationseinheit Strahlentherapie, Heidelberg (Germany); Radiologische Universitaetsklinik, Abteilung fuer Radioonkologie und Strahlentherapie, Heidelberg (Germany); Brunner, Thomas B. [Universitaetsklinikum Freiburg, Klinik fuer Strahlenheilkunde, Radiologische Klinik, Freiburg (Germany); Ernst, Iris; Greve, Burkhard [Universitaetsklinikum Muenster, Klinik fuer Strahlentherapie - Radioonkologie, Muenster (Germany); Baus, Wolfgang W. [Universitaetsklinikum Koeln, Klinik und Poliklinik fuer Strahlentherapie, Koeln (Germany); Herfarth, Klaus [Radiologische Universitaetsklinik, Abteilung fuer Radioonkologie und Strahlentherapie, Heidelberg (Germany); Guckenberger, Matthias [UniversitaetsSpital Zuerich, Klinik fuer Radio-Onkologie, Zuerich (Switzerland)

    2014-10-15

    This report of the Working Group on Stereotactic Radiotherapy of the German Society of Radiation Oncology (DEGRO) aims to provide a practical guideline for safe and effective stereotactic body radiotherapy (SBRT) of liver tumors. The literature on the clinical evidence of SBRT for both primary liver tumors and liver metastases was reviewed and analyzed focusing on both physical requirements and special biological characteristics. Recommendations were developed for patient selection, imaging, planning, treatment delivery, motion management, dose reporting, and follow-up. Radiation dose constraints to critical organs at risk are provided. SBRT is a well-established treatment option for primary and secondary liver tumors associated with low morbidity. (orig.) [German] Die Arbeitsgruppe Stereotaxie der Deutschen Gesellschaft fuer Radioonkologie (DEGRO) legt hier eine Empfehlung zur sicheren und effektiven Durchfuehrung der SBRT von Lebertumoren vor. Eine Literaturrecherche zur Untersuchung der Evidenz der SBRT sowohl fuer primaere Lebertumore als auch fuer Lebermetastasen wurde durchgefuehrt. Auf dieser Basis werden Empfehlungen fuer technisch-physikalische Voraussetzungen wie auch fuer die taegliche Praxis der Leber-SBRT gegeben. Weiterhin werden radiobiologische Besonderheiten dieses Verfahrens dargestellt. Praktische Vorgaben werden fuer Patientenselektion, Bildgebung, Planung, Applikation, Bewegungsmanagement, Dosisdokumentation und Follow-up gegeben. Dosisempfehlungen fuer die kritischen Risikoorgane werden dargestellt. Die SBRT stellt eine etablierte Behandlungsmethode fuer primaere und sekundaere Lebertumore dar und ist mit niedriger Morbiditaet assoziiert. (orig.)

  10. 131I-MIBG scintigraphy in carcinoid tumor with liver metastases (case report)

    International Nuclear Information System (INIS)

    Eftekhari, M.; Olamaei, R.; Fard, A.; Beiki, D.; Saghari, M.

    2003-01-01

    A 65 year old male presented with abdominal pain (R.U.Q) and constipation, associated with weight loss and anorexia since 40 days prior to admission. Serum biochemical tests were normal. Colonoscopy showed hemorrhagic polyploid lesion in the cecum Barium enema revealed filling defect in the cecum. Sonography revealed a target-shaped lesion(3cm X 2.5 cm)in upper segment of the right hepatic lobe. CT scan confirmed the same finding as a hypodense lesion. Following segmental resection of the cecum, pathology indicated the presence of the carcinoid tumor. For the better evaluation, 131 I-MIBG scintigraphy was carried out, demonstrating tracer avid metastatic lesions in the right and left hepatic lobes. A review of the series reported in the literature, shows that approximately 50-60% of carcinoids are able to concentrate radiolabeled MIBG. MIBG uptake apparently correlated with the urinary excretion of 5-HIAA, although this is not a universal finding. The most frequently occurring midgut carcinoids probably concentrate the radiolabeled MIBG more readily than those in the hind gut and fore gut. Primary and residual tumors are sometimes visualized , but the most striking imaging is that of carcinoids metastases in the peritoneum and liver(provided that SPECT images with 123 I-MIBG or alternatively 131 I-MIBG delayed scans are performed). Lymph node involvement, bone deposits and ovarian metastases have been reported as well. When radioiodinated MIBG and somatostatin scintigraphy results are compared, somatostatin scintigraphy shows a better sensitivity (>80%) in detecting both primary and metastatic lesions. These radiopharmaceuticals play complementary roles in that each give unique information concerning possible treatment either with octreotide or 131 I-MIBG, or both. MIBG imaging can not generally relied upon either to detect a carcinoid, or to rule out the disease.When a tumor is strongly suspected of being carcinoid however, the test can be worthwhile for the

  11. Angled cool-tip electrode for radiofrequency ablation of small superficial subcapsular tumors in the liver: A feasibility study

    Energy Technology Data Exchange (ETDEWEB)

    Park, Sung Il; Shin, Min Woo; Shin, Won Seon [Severance Hospital, Yonsei University College of Medicine, Seoul (Korea, Republic of); and others

    2016-09-15

    To evaluate the feasibility of angled cool-tip electrode for radiofrequency ablation of small superficial subcapsular liver tumors abutting abdominal wall, in order to traverse normal liver parenchyma, and thereby, obtain favorable configuration of ablation margin. In this study, we retrospectively analyzed 15 small superficial subcapsular liver tumors abutting abdominal wall in 15 patients, treated with radiofrequency ablation from March 2013 to June 2015 using a cool-tip electrode manually modified to create 25–35° angle at the junction between exposed and insulated segments. The tumors were hepatocellular carcinoma (n = 13) and metastases (n = 2: cholangiocellular carcinoma and rectosigmoid cancer), with maximum diameter of 10–26 mm (mean, 15.68 ± 5.29 mm). Under ultrasonographic guidance, the electrode tip was advanced to the depth of the tumors' epicenter about 1 cm from the margin. The tip was re-directed to penetrate the tumor for radiofrequency ablation. Minimal ablation margin was measured at immediate post-treatment CT. Radiological images and medical records were evaluated for success rate, length of minimal ablation margin and complications. Technical success rate of obtaining complete necrosis of the tumors was 100%, with no procedure-related complication. Minimal ablation margin ranged from 3–12 mm (mean, 7.07 ± 2.23 mm). CT/MRI follow-up at 21–1022 days (mean, 519.47 ± 304.51 days) revealed no local recurrence, but distant recurrence in 9 patients. Using an angled cool-tip electrode for radiofrequency ablation of small superficial subcapsular tumors abutting abdominal wall may be a feasible technique for obtaining adequate ablation margin and lower complication rate.

  12. Angled Cool-Tip Electrode for Radiofrequency Ablation of Small Superficial Subcapsular Tumors in the Liver: A Feasibility Study

    Energy Technology Data Exchange (ETDEWEB)

    Park, Sung Il [Department of Radiology, Research Institute of Radiological Science, Severance Hospital, Yonsei University College of Medicine, Seoul 03722 (Korea, Republic of); Kim, Il Jung [Department of Radiology, Bucheon St. Mary' s Hospital, College of Medicine, The Catholic University of Korea, Bucheon 14647 (Korea, Republic of); Lee, Shin Jae [Department of Radiology, CHA Bundang Medical Center, CHA University, Seongnam 13496 (Korea, Republic of); Shin, Min Woo; Shin, Won Sun; Chung, Yong Eun; Kim, Gyoung Min; Kim, Man Deuk; Won, Jong Yun; Lee, Do Yun [Department of Radiology, Research Institute of Radiological Science, Severance Hospital, Yonsei University College of Medicine, Seoul 03722 (Korea, Republic of); Choi, Jin Sub [Department of Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul 03722 (Korea, Republic of); Han, Kwang-Hyub [Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul 03722 (Korea, Republic of)

    2016-11-01

    To evaluate the feasibility of angled cool-tip electrode for radiofrequency ablation of small superficial subcapsular liver tumors abutting abdominal wall, in order to traverse normal liver parenchyma, and thereby, obtain favorable configuration of ablation margin. In this study, we retrospectively analyzed 15 small superficial subcapsular liver tumors abutting abdominal wall in 15 patients, treated with radiofrequency ablation from March 2013 to June 2015 using a cool-tip electrode manually modified to create 25–35° angle at the junction between exposed and insulated segments. The tumors were hepatocellular carcinoma (n = 13) and metastases (n = 2: cholangiocellular carcinoma and rectosigmoid cancer), with maximum diameter of 10–26 mm (mean, 15.68 ± 5.29 mm). Under ultrasonographic guidance, the electrode tip was advanced to the depth of the tumors' epicenter about 1 cm from the margin. The tip was re-directed to penetrate the tumor for radiofrequency ablation. Minimal ablation margin was measured at immediate post-treatment CT. Radiological images and medical records were evaluated for success rate, length of minimal ablation margin and complications. Technical success rate of obtaining complete necrosis of the tumors was 100%, with no procedure-related complication. Minimal ablation margin ranged from 3–12 mm (mean, 7.07 ± 2.23 mm). CT/MRI follow-up at 21–1022 days (mean, 519.47 ± 304.51 days) revealed no local recurrence, but distant recurrence in 9 patients. Using an angled cool-tip electrode for radiofrequency ablation of small superficial subcapsular tumors abutting abdominal wall may be a feasible technique for obtaining adequate ablation margin and lower complication rate.

  13. Angled cool-tip electrode for radiofrequency ablation of small superficial subcapsular tumors in the liver: A feasibility study

    International Nuclear Information System (INIS)

    Park, Sung Il; Shin, Min Woo; Shin, Won Seon

    2016-01-01

    To evaluate the feasibility of angled cool-tip electrode for radiofrequency ablation of small superficial subcapsular liver tumors abutting abdominal wall, in order to traverse normal liver parenchyma, and thereby, obtain favorable configuration of ablation margin. In this study, we retrospectively analyzed 15 small superficial subcapsular liver tumors abutting abdominal wall in 15 patients, treated with radiofrequency ablation from March 2013 to June 2015 using a cool-tip electrode manually modified to create 25–35° angle at the junction between exposed and insulated segments. The tumors were hepatocellular carcinoma (n = 13) and metastases (n = 2: cholangiocellular carcinoma and rectosigmoid cancer), with maximum diameter of 10–26 mm (mean, 15.68 ± 5.29 mm). Under ultrasonographic guidance, the electrode tip was advanced to the depth of the tumors' epicenter about 1 cm from the margin. The tip was re-directed to penetrate the tumor for radiofrequency ablation. Minimal ablation margin was measured at immediate post-treatment CT. Radiological images and medical records were evaluated for success rate, length of minimal ablation margin and complications. Technical success rate of obtaining complete necrosis of the tumors was 100%, with no procedure-related complication. Minimal ablation margin ranged from 3–12 mm (mean, 7.07 ± 2.23 mm). CT/MRI follow-up at 21–1022 days (mean, 519.47 ± 304.51 days) revealed no local recurrence, but distant recurrence in 9 patients. Using an angled cool-tip electrode for radiofrequency ablation of small superficial subcapsular tumors abutting abdominal wall may be a feasible technique for obtaining adequate ablation margin and lower complication rate

  14. Angled Cool-Tip Electrode for Radiofrequency Ablation of Small Superficial Subcapsular Tumors in the Liver: A Feasibility Study

    International Nuclear Information System (INIS)

    Park, Sung Il; Kim, Il Jung; Lee, Shin Jae; Shin, Min Woo; Shin, Won Sun; Chung, Yong Eun; Kim, Gyoung Min; Kim, Man Deuk; Won, Jong Yun; Lee, Do Yun; Choi, Jin Sub; Han, Kwang-Hyub

    2016-01-01

    To evaluate the feasibility of angled cool-tip electrode for radiofrequency ablation of small superficial subcapsular liver tumors abutting abdominal wall, in order to traverse normal liver parenchyma, and thereby, obtain favorable configuration of ablation margin. In this study, we retrospectively analyzed 15 small superficial subcapsular liver tumors abutting abdominal wall in 15 patients, treated with radiofrequency ablation from March 2013 to June 2015 using a cool-tip electrode manually modified to create 25–35° angle at the junction between exposed and insulated segments. The tumors were hepatocellular carcinoma (n = 13) and metastases (n = 2: cholangiocellular carcinoma and rectosigmoid cancer), with maximum diameter of 10–26 mm (mean, 15.68 ± 5.29 mm). Under ultrasonographic guidance, the electrode tip was advanced to the depth of the tumors' epicenter about 1 cm from the margin. The tip was re-directed to penetrate the tumor for radiofrequency ablation. Minimal ablation margin was measured at immediate post-treatment CT. Radiological images and medical records were evaluated for success rate, length of minimal ablation margin and complications. Technical success rate of obtaining complete necrosis of the tumors was 100%, with no procedure-related complication. Minimal ablation margin ranged from 3–12 mm (mean, 7.07 ± 2.23 mm). CT/MRI follow-up at 21–1022 days (mean, 519.47 ± 304.51 days) revealed no local recurrence, but distant recurrence in 9 patients. Using an angled cool-tip electrode for radiofrequency ablation of small superficial subcapsular tumors abutting abdominal wall may be a feasible technique for obtaining adequate ablation margin and lower complication rate

  15. Levosimendan: a cardiovascular drug to prevent liver ischemia-reperfusion injury?

    Directory of Open Access Journals (Sweden)

    Peter Onody

    Full Text Available INTRODUCTION: Temporary occlusion of the hepatoduodenal ligament leads to an ischemic-reperfusion (IR injury in the liver. Levosimendan is a new positive inotropic drug, which induces preconditioning-like adaptive mechanisms due to opening of mitochondrial KATP channels. The aim of this study was to examine possible protective effects of levosimendan in a rat model of hepatic IR injury. MATERIAL AND METHODS: Levosimendan was administered to male Wistar rats 1 hour (early pretreatment or 24 hours (late pretreatment before induction of 60-minute segmental liver ischemia. Microcirculation of the liver was monitored by laser Doppler flowmeter. After 24 hours of reperfusion, liver and blood samples were taken for histology, immuno- and enzyme-histochemistry (TUNEL; PARP; NADH-TR as well as for laboratory tests. Furthermore, liver antioxidant status was assessed and HSP72 expression was measured. RESULTS: In both groups pretreated with levosimendan, significantly better hepatic microcirculation was observed compared to respective IR control groups. Similarly, histological damage was also reduced after levosimendan administration. This observation was supported by significantly lower activities of serum ALT (p early = 0.02; p late = 0.005, AST (p early = 0.02; p late = 0.004 and less DNA damage by TUNEL test (p early = 0.05; p late = 0.034 and PAR positivity (p early = 0.02; p late = 0.04. Levosimendan pretreatment resulted in significant improvement of liver redox homeostasis. Further, significantly better mitochondrial function was detected in animals receiving late pretreatment. Finally, HSP72 expression was increased by IR injury, but it was not affected by levosimendan pretreatment. CONCLUSION: Levosimendan pretreatment can be hepatoprotective and it could be useful before extensive liver resection.

  16. Drug-Induced Liver Injury: Cascade of Events Leading to Cell Death, Apoptosis or Necrosis

    Directory of Open Access Journals (Sweden)

    Andrea Iorga

    2017-05-01

    Full Text Available Drug-induced liver injury (DILI can broadly be divided into predictable and dose dependent such as acetaminophen (APAP and unpredictable or idiosyncratic DILI (IDILI. Liver injury from drug hepatotoxicity (whether idiosyncratic or predictable results in hepatocyte cell death and inflammation. The cascade of events leading to DILI and the cell death subroutine (apoptosis or necrosis of the cell depend largely on the culprit drug. Direct toxins to hepatocytes likely induce oxidative organelle stress (such as endoplasmic reticulum (ER and mitochondrial stress leading to necrosis or apoptosis, while cell death in idiosyncratic DILI (IDILI is usually the result of engagement of the innate and adaptive immune system (likely apoptotic, involving death receptors (DR. Here, we review the hepatocyte cell death pathways both in direct hepatotoxicity such as in APAP DILI as well as in IDILI. We examine the known signaling pathways in APAP toxicity, a model of necrotic liver cell death. We also explore what is known about the genetic basis of IDILI and the molecular pathways leading to immune activation and how these events can trigger hepatotoxicity and cell death.

  17. Chemotherapeutic drug delivery by tumoral extracellular matrix targeting

    NARCIS (Netherlands)

    Raavé , R.; Kuppevelt, T.H. van; Daamen, W.F.

    2018-01-01

    Systemic chemotherapy is a primary strategy in the treatment of cancer, but comes with a number of limitations such as toxicity and unfavorable biodistribution. To overcome these issues, numerous targeting systems for specific delivery of chemotherapeutics to tumor cells have been designed and

  18. Computer optimization of noncoplanar beam setups improves stereotactic treatment of liver tumors

    International Nuclear Information System (INIS)

    Pooter, Jacco A. de; Mendez Romero, Alejandra; Jansen, Wim; Storchi, Pascal; Woudstra, Evert; Levendag, Peter C.; Heijmen, Ben

    2006-01-01

    Purpose: To investigate whether computer-optimized fully noncoplanar beam setups may improve treatment plans for the stereotactic treatment of liver tumors. Methods: An algorithm for automated beam orientation and weight selection (Cycle) was extended for noncoplanar stereotactic treatments. For 8 liver patients previously treated in our clinic using a prescription isodose of 65%, Cycle was used to generate noncoplanar and coplanar plans with the highest achievable minimum planning target volume (PTV) dose for the clinically delivered isocenter and mean liver doses, while not violating the clinically applied hard planning constraints. The clinical and the optimized coplanar and noncoplanar plans were compared, with respect to D PTV,99% , the dose received by 99% of the PTV, the PTV generalized equivalent uniform dose (gEUD), and the compliance with the clinical constraints. Results: For each patient, the ratio between D PTV,99% and D isoc , and the gEUD -5 and gEUD -2 values of the optimized noncoplanar plan were higher than for the clinical plan with an average increase of respectively 18.8% (range, 7.8-24.0%), 6.4 Gy (range, 3.4-11.8 Gy), and 10.3 Gy (range, 6.7-12.5). D PTV,99% /D isoc , gEUD -5 , and gEUD -2 of the optimized noncoplanar plan was always higher than for the optimized coplanar plan with an average increase of, respectively, 4.5% (range, 0.2-9.7%), 2.7 Gy (range, 0.6-9.7 Gy), and 3.4 Gy (range, 0.6-9.9 Gy). All plans were within the imposed hard constraints. On average, the organs at risk were better spared with the optimized noncoplanar plan than with the optimized coplanar plan and the clinical plan. Conclusions: The use of automatically generated, fully noncoplanar beam setups results in plans that are favorable compared with coplanar techniques. Because of the automation, we found that the planning workload can be decreased from 1 to 2 days to 1 to 2 h

  19. 1H magnetic resonance spectroscopy (MRS) of the liver and hepatic malignant tumors at 3.0 Tesla

    International Nuclear Information System (INIS)

    Fischbach, F.; Thormann, M.; Ricke, J.

    2004-01-01

    Use of whole-body MRI beyond 1.5 Tesla (T) has initiated a renaissance in spectroscopic procedures (MRS). The superior signal-to-noise ratio of clinical 3T tomographs allows reliable acquisition of MR spectra not only in fixed organs but also in targets moved by breathing such as the liver. The following contribution describes the principles of 1 H MRS and our own initial experiences with spectroscopy of the liver and hepatic malignant tumors with 3T whole-body MRI. (orig.) [de

  20. Ultrasound-guided cytology of spleen and liver: a prognostic tool in canine cutaneous mast cell tumor.

    Science.gov (United States)

    Stefanello, D; Valenti, P; Faverzani, S; Bronzo, V; Fiorbianco, V; Pinto da Cunha, N; Romussi, S; Cantatore, M; Caniatti, M

    2009-01-01

    In the clinical staging of cutaneous mast cell tumors (cMCT), the diagnosis of metastasis is controversial based on cytological examination of lymph nodes, spleen, liver, bone marrow, and blood. To define the prognostic role of ultrasound-guided cytology of spleen and liver in cMCT. The results of cytological evaluation were compared in relation with survival time. Fifty-two client-owned dogs with a diagnosis of cMCT. Selection of cases was based on cytological evaluation of liver and spleen to detect infiltration at distant sites. The Kaplan Meier method was used to compare survival in dogs with and without infiltration of spleen and liver (log-rank test P dogs with cMCT had mast cell infiltration of spleen, liver, or both and 4 of these dogs had involvement of the regional lymph nodes. The majority of dogs had 2 or more ultrasonographically abnormal findings simultaneously in spleen and liver. Nine dogs had grade II cMCT, and 1 had grade III cMCT. Dogs with positive evidence of mast cell infiltration to spleen, liver, or both had shorter survival times (34 versus 733 days) compared with dogs negative for mast cell infiltration at distant sites. Dogs with evidence of mast cell infiltration at distant sites have a shorter survival times than dogs without evidence of infiltration at distant sites. This study suggests that cytology of spleen and liver is indicated either for ultrasonographically normal or for ultrasonographically abnormal spleen and liver in dogs with cMCT.

  1. Tumor treatment by sustained intratumoral release of cisplatin: effects of drug alone and combined with radiation

    International Nuclear Information System (INIS)

    Yapp, Donald T.T.; Lloyd, David K.; Zhu, Julian; Lehnert, Shirley M.

    1997-01-01

    Purpose: The effect of intratumoral delivery of cisplatin to a mouse tumor model (RIF-1) by means of a biodegradable polymer implant with and without radiation was studied. Methods and Materials: The polymer bis(p-carboxyphenoxy)propane-sebacic acid (CPP:SA; 80:20) and its degradation products have been characterized. Polymer rods (8 x 0.5 mm) containing 17% cisplatin by weight were prepared by extrusion, and the in vitro degradation rate measured. The implants were placed into mouse tumors and their effect (with and without radiation) on tumor growth delay studied. The levels of Pt in the mouse kidney, tumor, and blood plasma at selected intervals after implant were also determined. These results were compared with those obtained when cisplatin was delivered systematically. Results: When cisplatin was delivered by the polymer implants, higher levels were present in the tumor for longer time periods (cf. systemic delivery of the drug). For both nonirradiated and irradiated tumors, those treated with the polymer implants had significantly longer tumor growth delays compared to nonimplanted controls and to systematically treated tumors. Conclusions: The results show that intratumoral delivery of cisplatin is more efficient than systemic delivery. Using the biodegradable polymer implant, higher doses of cisplatin can be tolerated by the animal as the drug is localized within the tumor, and the high levels of the drug in the tumor can be maintained for an extended period of time. When radiation is given in conjunction with cisplatin, the tumor response is supraadditive for all modes of cisplatin administration but is potentiated to a greater extent when cisplatin is delivered through the polymer implant. The greatest effect is seen for treatment with cisplatin delivered by polymer implant combined with fractionated radiation

  2. Combined Stimulation with the Tumor Necrosis Factor α and the Epidermal Growth Factor Promotes the Proliferation of Hepatocytes in Rat Liver Cultured Slices

    Directory of Open Access Journals (Sweden)

    Francis Finot

    2012-01-01

    Full Text Available The culture liver slices are mainly used to investigate drug metabolism and xenobiotic-mediated liver injuries while apoptosis and proliferation remain unexplored in this culture model. Here, we show a transient increase in LDH release and caspase activities indicating an ischemic injury during the slicing procedure. Then, caspase activities decrease and remain low in cultured slices demonstrating a low level of apoptosis. The slicing procedure is also associated with the G0/G1 transition of hepatocytes demonstrated by the activation of stress and proliferation signalling pathways including the ERK1/2 and JNK1/2/3 MAPKinases and the transient upregulation of c-fos. The cells further progress up to mid-G1 phase as indicated by the sequential induction of c-myc and p53 mRNA levels after the slicing procedure and at 24 h of culture, respectively. The stimulation by epidermal growth factor induces the ERK1/2 phosphorylation but fails to activate expression of late G1 and S phase markers such as cyclin D1 and Cdk1 indicating that hepatocytes are arrested in mid-G1 phase of the cell cycle. However, we found that combined stimulation by the proinflammatory cytokine tumor necrosis factor α and the epidermal growth factor promotes the commitment to DNA replication as observed in vivo during the liver regeneration.

  3. Cone-Beam CT Angiography for Determination of Tumor-Feeding Vessels During Chemoembolization of Liver Tumors: Comparison of Conventional and Dedicated-Software Analysis.

    Science.gov (United States)

    Ronot, Maxime; Abdel-Rehim, Mohamed; Hakimé, Antoine; Kuoch, Viseth; Roux, Marion; Chiaradia, Mélanie; Vilgrain, Valérie; de Baere, Thierry; Deschamps, Frédéric

    2016-01-01

    To compare the ability of dedicated software and conventional cone-beam computed tomography (CT) analysis to identify tumor-feeding vessels in hypervascular liver tumors treated with chemoembolization. Between January 2012 and January 2013, 45 patients (32 men, mean age of 61 y; range, 27-85 y) were enrolled, and 66 tumors were treated (mean, 32 mm ± 18; range, 10-81 mm) with conventional chemoembolization with arterial cone-beam CT. Data were independently analyzed by six interventional radiologists with standard postprocessing software, a computer-aided analysis with FlightPlan for liver (FPFL; ie, "raw FPFL"), and a review of this computer-aided FPFL analysis ("reviewed FPFL"). Analyses were compared with a reference reading established by two study supervisors in consensus who had access to all imaging data. Sensitivities, positive predictive values (PPVs), and false-positive (FP) ratios were compared by McNemar, χ(2), and Fisher exact tests. Analysis durations were compared by Mann-Whitney test, and interreader agreement was assessed. Reference reading identified 179 feeder vessels. The sensitivity of raw FPFL was significantly higher than those of reviewed FPFL and conventional analyses (90.9% vs 83.2% and 82.1%; P software enabled a fast, accurate, and sensitive detection of tumor feeder vessels. Copyright © 2016 SIR. Published by Elsevier Inc. All rights reserved.

  4. Cancer in silico drug discovery: a systems biology tool for identifying candidate drugs to target specific molecular tumor subtypes.

    Science.gov (United States)

    San Lucas, F Anthony; Fowler, Jerry; Chang, Kyle; Kopetz, Scott; Vilar, Eduardo; Scheet, Paul

    2014-12-01

    Large-scale cancer datasets such as The Cancer Genome Atlas (TCGA) allow researchers to profile tumors based on a wide range of clinical and molecular characteristics. Subsequently, TCGA-derived gene expression profiles can be analyzed with the Connectivity Map (CMap) to find candidate drugs to target tumors with specific clinical phenotypes or molecular characteristics. This represents a powerful computational approach for candidate drug identification, but due to the complexity of TCGA and technology differences between CMap and TCGA experiments, such analyses are challenging to conduct and reproduce. We present Cancer in silico Drug Discovery (CiDD; scheet.org/software), a computational drug discovery platform that addresses these challenges. CiDD integrates data from TCGA, CMap, and Cancer Cell Line Encyclopedia (CCLE) to perform computational drug discovery experiments, generating hypotheses for the following three general problems: (i) determining whether specific clinical phenotypes or molecular characteristics are associated with unique gene expression signatures; (ii) finding candidate drugs to repress these expression signatures; and (iii) identifying cell lines that resemble the tumors being studied for subsequent in vitro experiments. The primary input to CiDD is a clinical or molecular characteristic. The output is a biologically annotated list of candidate drugs and a list of cell lines for in vitro experimentation. We applied CiDD to identify candidate drugs to treat colorectal cancers harboring mutations in BRAF. CiDD identified EGFR and proteasome inhibitors, while proposing five cell lines for in vitro testing. CiDD facilitates phenotype-driven, systematic drug discovery based on clinical and molecular data from TCGA. ©2014 American Association for Cancer Research.

  5. Tumor control induced by Boron Neutron Capture Therapy (BNCT) as a function of dose in an experimental model of liver metastases at 5 weeks follow-up

    International Nuclear Information System (INIS)

    Pozzi, E C C; Trivillin, V A; Colombo, L L; Monti Hughes, A; Thorp, S; Cardoso, J E; Garabalino, M A; Molinari, A J; Heber, E M; Curotto, Paula; Miller, M; Itoiz, M E; Aromando, R F; Nigg, D W; Schwint, A E

    2012-01-01

    BNCT has been proposed for the treatment of multifocal, non-resectable, bilobar colorectal liver metastases that do not respond to chemotherapy. We recently reported that BNCT mediated by boronophenylalanine (BPA) induced significant remission of experimental colorectal tumor nodules in rat liver at 3 weeks follow-up with no contributory liver toxicity (Pozzi et al.,2012). The aim of the present study was to evaluate tumor control and potential liver toxicity of BPA-BNCT at 5 weeks follow-up. Prescribed dose was retrospectively evaluated based on blood boron values, allowing for assessment of response over a range of delivered dose values (author)

  6. Tumor vascular-targeted co-delivery of anti-angiogenesis and chemotherapeutic agents by mesoporous silica nanoparticle-based drug delivery system for synergetic therapy of tumor

    Directory of Open Access Journals (Sweden)

    Li X

    2015-12-01

    Full Text Available Xiaoyu Li, Meiying Wu, Limin Pan, Jianlin Shi State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai, People’s Republic of China Abstract: To overcome the drawback of drug non-selectivity in traditional chemotherapy, the construction of multifunctional targeting drug delivery systems is one of the most effective and prevailing approaches. The intratumoral anti-angiogenesis and the tumor cell-killing are two basic approaches in fighting tumors. Herein we report a novel tumor vascular-targeting multidrug delivery system using mesoporous silica nanoparticles as carrier to co-load an antiangiogenic agent (combretastatin A4 and a chemotherapeutic drug (doxorubicin and conjugate with targeting molecules (iRGD peptide for combined anti-angiogenesis and chemotherapy. Such a dual-loaded drug delivery system is capable of delivering the two agents at tumor vasculature and then within tumors through a differentiated drug release strategy, which consequently results in greatly improved antitumor efficacy at a very low doxorubicin dose of 1.5 mg/kg. The fast release of the antiangiogenic agent at tumor vasculatures led to the disruption of vascular structure and had a synergetic effect with the chemotherapeutic drug slowly released in the following delivery of chemotherapeutic drug into tumors. Keywords: mesoporous silica nanoparticles, drug delivery, tumor vasculatures targeting, antiangiogenic agent

  7. A cellular model to study drug-induced liver injury in nonalcoholic fatty liver disease: Application to acetaminophen

    Energy Technology Data Exchange (ETDEWEB)

    Michaut, Anaïs; Le Guillou, Dounia [INSERM, U991, Université de Rennes 1, Rennes (France); Moreau, Caroline [INSERM, U991, Université de Rennes 1, Rennes (France); Service de Biochimie et Toxicologie, CHU Pontchaillou, Rennes (France); Bucher, Simon [INSERM, U991, Université de Rennes 1, Rennes (France); McGill, Mitchell R. [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States); Martinais, Sophie [INSERM, U991, Université de Rennes 1, Rennes (France); Gicquel, Thomas; Morel, Isabelle [INSERM, U991, Université de Rennes 1, Rennes (France); Service de Biochimie et Toxicologie, CHU Pontchaillou, Rennes (France); Robin, Marie-Anne [INSERM, U991, Université de Rennes 1, Rennes (France); Jaeschke, Hartmut [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States); Fromenty, Bernard, E-mail: bernard.fromenty@inserm.fr [INSERM, U991, Université de Rennes 1, Rennes (France)

    2016-02-01

    Obesity and nonalcoholic fatty liver disease (NAFLD) can increase susceptibility to hepatotoxicity induced by some xenobiotics including drugs, but the involved mechanisms are poorly understood. For acetaminophen (APAP), a role of hepatic cytochrome P450 2E1 (CYP2E1) is suspected since the activity of this enzyme is consistently enhanced during NAFLD. The first aim of our study was to set up a cellular model of NAFLD characterized not only by triglyceride accumulation but also by higher CYP2E1 activity. To this end, human HepaRG cells were incubated for one week with stearic acid or oleic acid, in the presence of different concentrations of insulin. Although cellular triglycerides and the expression of lipid-responsive genes were similar with both fatty acids, CYP2E1 activity was significantly increased only by stearic acid. CYP2E1 activity was reduced by insulin and this effect was reproduced in cultured primary human hepatocytes. Next, APAP cytotoxicity was assessed in HepaRG cells with or without lipid accretion and CYP2E1 induction. Experiments with a large range of APAP concentrations showed that the loss of ATP and glutathione was almost always greater in the presence of stearic acid. In cells pretreated with the CYP2E1 inhibitor chlormethiazole, recovery of ATP was significantly higher in the presence of stearate with low (2.5 mM) or high (20 mM) concentrations of APAP. Levels of APAP-glucuronide were significantly enhanced by insulin. Hence, HepaRG cells can be used as a valuable model of NAFLD to unveil important metabolic and hormonal factors which can increase susceptibility to drug-induced hepatotoxicity. - Highlights: • Nonalcoholic fatty liver disease (NAFLD) is frequent in obese individuals. • NAFLD can favor hepatotoxicity induced by some drugs including acetaminophen (APAP). • A model of NAFLD was set up by using HepaRG cells incubated with stearate or oleate. • Stearate-loaded HepaRG cells presented higher cytochrome P450 2E1 (CYP2E1

  8. Comparative assessment of liver tumor motion using cine-magnetic resonance imaging versus 4-dimensional computed tomography.

    Science.gov (United States)

    Fernandes, Annemarie T; Apisarnthanarax, Smith; Yin, Lingshu; Zou, Wei; Rosen, Mark; Plastaras, John P; Ben-Josef, Edgar; Metz, James M; Teo, Boon-Keng

    2015-04-01

    To compare the extent of tumor motion between 4-dimensional CT (4DCT) and cine-MRI in patients with hepatic tumors treated with radiation therapy. Patients with liver tumors who underwent 4DCT and 2-dimensional biplanar cine-MRI scans during simulation were retrospectively reviewed to determine the extent of target motion in the superior-inferior, anterior-posterior, and lateral directions. Cine-MRI was performed over 5 minutes. Tumor motion from MRI was determined by tracking the centroid of the gross tumor volume using deformable image registration. Motion estimates from 4DCT were performed by evaluation of the fiducial, residual contrast (or liver contour) positions in each CT phase. Sixteen patients with hepatocellular carcinoma (n=11), cholangiocarcinoma (n=3), and liver metastasis (n=2) were reviewed. Cine-MRI motion was larger than 4DCT for the superior-inferior direction in 50% of patients by a median of 3.0 mm (range, 1.5-7 mm), the anterior-posterior direction in 44% of patients by a median of 2.5 mm (range, 1-5.5 mm), and laterally in 63% of patients by a median of 1.1 mm (range, 0.2-4.5 mm). Cine-MRI frequently detects larger differences in hepatic intrafraction tumor motion when compared with 4DCT most notably in the superior-inferior direction, and may be useful when assessing the need for or treating without respiratory management, particularly in patients with unreliable 4DCT imaging. Margins wider than the internal target volume as defined by 4DCT were required to encompass nearly all the motion detected by cine-MRI for some of the patients in this study. Copyright © 2015 Elsevier Inc. All rights reserved.

  9. FOXM1: A novel drug target in gastroenteropancreatic neuroendocrine tumors

    Science.gov (United States)

    Briest, Franziska; Berg, Erika; Grass, Irina; Freitag, Helma; Kaemmerer, Daniel; Lewens, Florentine; Christen, Friederike; Arsenic, Ruza; Altendorf-Hofmann, Annelore; Kunze, Almut; Sänger, Jörg; Knösel, Thomas; Siegmund, Britta; Hummel, Michael; Grabowski, Patricia

    2015-01-01

    Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are heterogeneous tumors that need to be molecularly defined to obtain novel therapeutic options. Forkheadbox protein M1 (FOXM1) is a crucial transcription factor in neoplastic cells and has been associated with differentiation and proliferation. We found that FOXM1 is strongly associated with tumor differentiation and occurrence of metastases in gastrointestinal NENs. In vitro inhibition by the FOXM1 inhibitor siomycin A led to down-regulation of mitotic proteins and resulted in a strong inhibitory effect. Siomycin A decreased mitosis rate, induced apoptosis in GEP-NEN cell lines and exerts synergistic effects with chemotherapy. FOXM1 is associated with clinical outcome and FOXM1 inhibition impairs survival in vitro. We therefore propose FOXM1 as novel therapeutic target in GEP-NENs. PMID:25797272

  10. Interstitial fluid flow and drug delivery in vascularized tumors: a computational model.

    Directory of Open Access Journals (Sweden)

    Michael Welter

    Full Text Available Interstitial fluid is a solution that bathes and surrounds the human cells and provides them with nutrients and a way of waste removal. It is generally believed that elevated tumor interstitial fluid pressure (IFP is partly responsible for the poor penetration and distribution of therapeutic agents in solid tumors, but the complex interplay of extravasation, permeabilities, vascular heterogeneities and diffusive and convective drug transport remains poorly understood. Here we consider-with the help of a theoretical model-the tumor IFP, interstitial fluid flow (IFF and its impact upon drug delivery within tumor depending on biophysical determinants such as vessel network morphology, permeabilities and diffusive vs. convective transport. We developed a vascular tumor growth model, including vessel co-option, regression, and angiogenesis, that we extend here by the interstitium (represented by a porous medium obeying Darcy's law and sources (vessels and sinks (lymphatics for IFF. With it we compute the spatial variation of the IFP and IFF and determine its correlation with the vascular network morphology and physiological parameters like vessel wall permeability, tissue conductivity, distribution of lymphatics etc. We find that an increased vascular wall conductivity together with a reduction of lymph function leads to increased tumor IFP, but also that the latter does not necessarily imply a decreased extravasation rate: Generally the IF flow rate is positively correlated with the various conductivities in the system. The IFF field is then used to determine the drug distribution after an injection via a convection diffusion reaction equation for intra- and extracellular concentrations with parameters guided by experimental data for the drug Doxorubicin. We observe that the interplay of convective and diffusive drug transport can lead to quite unexpected effects in the presence of a heterogeneous, compartmentalized vasculature. Finally we discuss

  11. Interstitial fluid flow and drug delivery in vascularized tumors: a computational model.

    Science.gov (United States)

    Welter, Michael; Rieger, Heiko

    2013-01-01

    Interstitial fluid is a solution that bathes and surrounds the human cells and provides them with nutrients and a way of waste removal. It is generally believed that elevated tumor interstitial fluid pressure (IFP) is partly responsible for the poor penetration and distribution of therapeutic agents in solid tumors, but the complex interplay of extravasation, permeabilities, vascular heterogeneities and diffusive and convective drug transport remains poorly understood. Here we consider-with the help of a theoretical model-the tumor IFP, interstitial fluid flow (IFF) and its impact upon drug delivery within tumor depending on biophysical determinants such as vessel network morphology, permeabilities and diffusive vs. convective transport. We developed a vascular tumor growth model, including vessel co-option, regression, and angiogenesis, that we extend here by the interstitium (represented by a porous medium obeying Darcy's law) and sources (vessels) and sinks (lymphatics) for IFF. With it we compute the spatial variation of the IFP and IFF and determine its correlation with the vascular network morphology and physiological parameters like vessel wall permeability, tissue conductivity, distribution of lymphatics etc. We find that an increased vascular wall conductivity together with a reduction of lymph function leads to increased tumor IFP, but also that the latter does not necessarily imply a decreased extravasation rate: Generally the IF flow rate is positively correlated with the various conductivities in the system. The IFF field is then used to determine the drug distribution after an injection via a convection diffusion reaction equation for intra- and extracellular concentrations with parameters guided by experimental data for the drug Doxorubicin. We observe that the interplay of convective and diffusive drug transport can lead to quite unexpected effects in the presence of a heterogeneous, compartmentalized vasculature. Finally we discuss various

  12. RFA Guardian: Comprehensive Simulation of Radiofrequency Ablation Treatment of Liver Tumors.

    Science.gov (United States)

    Voglreiter, Philip; Mariappan, Panchatcharam; Pollari, Mika; Flanagan, Ronan; Blanco Sequeiros, Roberto; Portugaller, Rupert Horst; Fütterer, Jurgen; Schmalstieg, Dieter; Kolesnik, Marina; Moche, Michael

    2018-01-15

    The RFA Guardian is a comprehensive application for high-performance patient-specific simulation of radiofrequency ablation of liver tumors. We address a wide range of usage scenarios. These include pre-interventional planning, sampling of the parameter space for uncertainty estimation, treatment evaluation and, in the worst case, failure analysis. The RFA Guardian is the first of its kind that exhibits sufficient performance for simulating treatment outcomes during the intervention. We achieve this by combining a large number of high-performance image processing, biomechanical simulation and visualization techniques into a generalized technical workflow. Further, we wrap the feature set into a single, integrated application, which exploits all available resources of standard consumer hardware, including massively parallel computing on graphics processing units. This allows us to predict or reproduce treatment outcomes on a single personal computer with high computational performance and high accuracy. The resulting low demand for infrastructure enables easy and cost-efficient integration into the clinical routine. We present a number of evaluation cases from the clinical practice where users performed the whole technical workflow from patient-specific modeling to final validation and highlight the opportunities arising from our fast, accurate prediction techniques.

  13. Liposomal Tumor Targeting in Drug Delivery Utilizing MMP-2- and MMP-9-Binding Ligands

    Directory of Open Access Journals (Sweden)

    Oula Penate Medina

    2011-01-01

    Full Text Available Nanotechnology offers an alternative to conventional treatment options by enabling different drug delivery and controlled-release delivery strategies. Liposomes being especially biodegradable and in most cases essentially nontoxic offer a versatile platform for several different delivery approaches that can potentially enhance the delivery and targeting of therapies to tumors. Liposomes penetrate tumors spontaneously as a result of fenestrated blood vessels within tumors, leading to known enhanced permeability and subsequent drug retention effects. In addition, liposomes can be used to carry radioactive moieties, such as radiotracers, which can be bound at multiple locations within liposomes, making them attractive carriers for molecular imaging applications. Phage display is a technique that can deliver various high-affinity and selectivity peptides to different targets. In this study, gelatinase-binding peptides, found by phage display, were attached to liposomes by covalent peptide-PEG-PE anchor creating a targeted drug delivery vehicle. Gelatinases as extracellular targets for tumor targeting offer a viable alternative for tumor targeting. Our findings show that targeted drug delivery is more efficient than non-targeted drug delivery.

  14. Model-Based Radiation Dose Correction for Yttrium-90 Microsphere Treatment of Liver Tumors With Central Necrosis

    International Nuclear Information System (INIS)

    Liu, Ching-Sheng; Lin, Ko-Han; Lee, Rheun-Chuan; Tseng, Hsiou-Shan; Wang, Ling-Wei; Huang, Pin-I; Chao, Liung-Sheau; Chang, Cheng-Yen; Yen, Sang-Hue; Tung, Chuan-Jong; Wang, Syh-Jen; Oliver Wong, Ching-yee; Liu, Ren-Shyan

    2011-01-01

    Purpose: The objectives of this study were to model and calculate the absorbed fraction φ of energy emitted from yttrium-90 ( 90 Y) microsphere treatment of necrotic liver tumors. Methods and Materials: The tumor necrosis model was proposed for the calculation of φ over the spherical shell region. Two approaches, the semianalytic method and the probabilistic method, were adopted. In the former method, the range--energy relationship and the sampling of electron paths were applied to calculate the energy deposition within the target region, using the straight-ahead and continuous-slowing-down approximation (CSDA) method. In the latter method, the Monte Carlo PENELOPE code was used to verify results from the first method. Results: The fraction of energy, φ, absorbed from 90 Y by 1-cm thickness of tumor shell from microsphere distribution by CSDA with complete beta spectrum was 0.832 ± 0.001 and 0.833 ± 0.001 for smaller (r T = 5 cm) and larger (r T = 10 cm) tumors (where r is the radii of the tumor [T] and necrosis [N]). The fraction absorbed depended mainly on the thickness of the tumor necrosis configuration, rather than on tumor necrosis size. The maximal absorbed fraction φ that occurred in tumors without central necrosis for each size of tumor was different: 0.950 ± 0.000, and 0.975 ± 0.000 for smaller (r T = 5 cm) and larger (r T = 10 cm) tumors, respectively (p 90 Y microsphere treatment of hepatic tumors with central necrosis. With this model, important information is provided regarding the absorbed fraction applicable to clinical 90 Y microsphere treatment.

  15. MRI after magnetic drug targeting in patients with advanced solid malignant tumors

    International Nuclear Information System (INIS)

    Lemke, A.-J.; Senfft von Pilsach, M.-I.; Felix, R.; Luebbe, A.; Bergemann, C.; Riess, H.

    2004-01-01

    The purpose of this study was to evaluate the ability of MRI to detect magnetic particle uptake into advanced solid malignant tumors and to document the extension of these tumors, carried out in the context of magnetic drug targeting. In a prospective phase I trial, 11 patients were examined with MRI before and after magnetic drug targeting. The sequence protocol included T1-WI and T2-WI in several planes, followed by quantitative and qualitative evaluation of the signal intensities and tumor extensions. In nine patients, a signal decrease was observed in the early follow-up (2-7 days after therapy) on the T2-weighted images; two patients did not show a signal change. The signal changes in T1-WI were less distinct. In late follow-up (4-6 weeks after therapy), signal within nine tumors reached their initially normal level on both T1-WI and T2-WI; two tumors showed a slight signal decrease on T2-WI and a slight signal increase on T1-WI. Within the surveillance period, tumor remission in 3 out of 11 patients was observed, and in 5 patients tumor growth had stopped. The remaining three patients showed significant tumor growth. There was no statistically significant correlation between signal change and response. MRI is a suitable method to detect magnetite particles, deposited at the tumor site via magnetic drug targeting. MRI is therefore eligible to control the success of MDT and to assess the tumor size after the end of therapy. (orig.)

  16. A novel multi-drug metronomic chemotherapy significantly delays tumor growth in mice.

    Science.gov (United States)

    Tagliamonte, Maria; Petrizzo, Annacarmen; Napolitano, Maria; Luciano, Antonio; Rea, Domenica; Barbieri, Antonio; Arra, Claudio; Maiolino, Piera; Tornesello, Marialina; Ciliberto, Gennaro; Buonaguro, Franco M; Buonaguro, Luigi

    2016-02-24

    The tumor immunosuppressive microenvironment represents a major obstacle to an effective tumor-specific cellular immune response. In the present study, the counterbalance effect of a novel metronomic chemotherapy protocol on such an immunosuppressive microenvironment was evaluated in a mouse model upon sub-cutaneous ectopic implantation of B16 melanoma cells. The chemotherapy consisted of a novel multi-drug cocktail including taxanes and alkylating agents, administered in a daily metronomic fashion. The newly designed strategy was shown to be safe, well tolerated and significantly efficacious. Treated animals showed a remarkable delay in tumor growth and prolonged survival as compared to control group. Such an effect was directly correlated with CD4(+) T cell reduction and CD8(+) T cell increase. Furthermore, a significant reduction in the percentage of both CD25(+)FoxP3(+) and CD25(+)CD127(low) regulatory T cell population was found both in the spleens and in the tumor lesions. Finally, the metronomic chemotherapy induced an intrinsic CD8(+) T cell response specific to B16 naturally expressed Trp2 TAA. The novel multi-drug daily metronomic chemotherapy evaluated in the present study was very effective in counterbalancing the immunosuppressive tumor microenvironment. Consequently, the intrinsic anti-tumor T cell immunity could exert its function, targeting specific TAA and significantly containing tumor growth. Overall, the results show that this represents a promising adjuvant approach to significantly enhance efficacy of intrinsic or vaccine-elicited tumor-specific cellular immunity.

  17. Clinical evaluation of synthetic aperture sequential beamforming ultrasound in patients with liver tumors

    DEFF Research Database (Denmark)

    Hansen, Peter Møller; Hemmsen, Martin Christian; Brandt, Andreas Hjelm

    2014-01-01

    Medical ultrasound imaging using synthetic aperture sequential beamforming (SASB) has for the first time been used for clinical patient scanning. Nineteen patients with cancer of the liver (hepatocellular carcinoma or colorectal liver metastases) were scanned simultaneously with conventional...

  18. Laparoscopic liver resection for hepatocellular carcinoma in cirrhotic patients. Feasibility of nonanatomic resection in difficult tumor locations

    Directory of Open Access Journals (Sweden)

    Marco Casaccia

    2011-01-01

    Full Text Available Background: Surgical resection for hepatocellular carcinoma (HCC in cirrhotic patients remains controversial because of high morbidity and recurrence rates. Laparoscopic resection of liver tumors has recently been developed and could reduce morbidity. The aim of this study was to evaluate retrospectively our results for laparoscopic liver resection (LLR for HCC including lesions in the posterosuperior segments of the liver in terms of feasibility, outcome, recurrence and survival. Materials and Methods: Between June 2005 and February 2009, we performed 20 LLR for HCC. Median age of the patients was 66 years. The underlying cirrhosis was staged as Child A in 17 cases and Child B in 3. Results: LLR included anatomic resection in six cases and nonanatomic resection in 14. Eleven procedures were associated in nine (45% patients. Median tumor size and surgical margins were 3.1 cm and 15 mm, respectively. A conversion to laparotomy occurred in one (5% patient for hemorrhage. Mortality and morbidity rates were 0% and 15% (3/20. Median hospital stay was 8 days (range: 5-16 days. Over a mean follow-up period of 26 months (range: 19-62 months, 10 (50% patients presented recurrence, mainly at distance from the surgical site. Treatment of recurrence was possible in all the patients, including orthotopic liver transplantation in three cases. Conclusions: LLR for HCC in selected patients is a safe procedure with good short-term results. It can also be proposed in tumor locations with a difficult surgical access maintaining a low morbidity rate and good oncological adequacy. This approach could have an impact on the therapeutic strategy of HCC complicating cirrhosis as a treatment with curative intent or as a bridge to liver transplantation.

  19. Current advances in mathematical modeling of anti-cancer drug penetration into tumor tissues.

    Science.gov (United States)

    Kim, Munju; Gillies, Robert J; Rejniak, Katarzyna A

    2013-11-18

    Delivery of anti-cancer drugs to tumor tissues, including their interstitial transport and cellular uptake, is a complex process involving various biochemical, mechanical, and biophysical factors. Mathematical modeling provides a means through which to understand this complexity better, as well as to examine interactions between contributing components in a systematic way via computational simulations and quantitative analyses. In this review, we present the current state of mathematical modeling approaches that address phenomena related to drug delivery. We describe how various types of models were used to predict spatio-temporal distributions of drugs within the tumor tissue, to simulate different ways to overcome barriers to drug transport, or to optimize treatment schedules. Finally, we discuss how integration of mathematical modeling with experimental or clinical data can provide better tools to understand the drug delivery process, in particular to examine the specific tissue- or compound-related factors that limit drug penetration through tumors. Such tools will be important in designing new chemotherapy targets and optimal treatment strategies, as well as in developing non-invasive diagnosis to monitor treatment response and detect tumor recurrence.

  20. Liver

    International Nuclear Information System (INIS)

    Bernardino, M.E.; Sones, P.J. Jr.; Barton Price, R.; Berkman, W.A.

    1984-01-01

    Evaluation of the liver for focal lesions is extremely important because the liver is one of the most common sites for metastatic disease. Most patients with metastatic deposits to the liver have a survival rate of about 6 months. Thus, metastatic disease to the liver has an extremely grave prognosis. In the past patients with hepatic lesions had no therapeutic recourse. However, with recent aggressive surgical advances (such as partial hepatectomies) and hepatic artery embolization, survival of patients with hepatic metastases has increased. Thus it is important for noninvasive imaging not only to detect lesions early in their course, but also to give their true hepatic involvement and the extent of the neoplastic process elsewhere in the body. Recent advances in imaging have been rapidly changing over the past 5 years. These changes have been more rapid in computed tomography (CT) and ultrasound than in radionuclide imaging. Thus, the question addressed in this chapter is: What is the relationship of hepatic ultrasound to the other current diagnostic modalities in detecting metastatic liver disease and other focal liver lesions? Also, what is its possible future relationship to nuclear magnetic resonance?

  1. Biodistribution of 10B in a rat liver tumor model following intra-arterial administration of sodium borocaptate (BSH)/degradable starch microspheres (DSM) emulsion

    International Nuclear Information System (INIS)

    Suzuki, Minoru; Nagata, Kenji; Masunaga, Shinichiro; Kinashi, Yuko; Sakurai, Yoshinori; Maruhashi, Akira; Ono, Koji

    2004-01-01

    We reported that intra-arterial administration of borocaptate sodium (BSH)/lipiodol emulsion provided selectively high 10 B concentrations (approximately 200 ppm 6 h after administration) in experimental liver tumors. In the present study, we investigated the pharmacokinetics of BSH following intra-arterial administration of BSH with other embolizing agent, degradable starch microspheres (DSM). The 10 B concentration in the tumor at 1 h after administration of BSH with DSM was 231 ppm. At 6 h, the 10 B concentration in the tumor in BSH with DSM group was 81.5 ppm. The 10 B concentration in the liver at 1 h after administration of BSH with DSM was 184 ppm. At 6 h, the 10 B concentration in the liver in BSH with DSM group was 78 ppm. The tumor/liver 10 B concentration ratios (T/L ratio) in the 'BSH+DSM' group were significantly smaller than those in the 'BSH+lipiodol' group at 1 h (1.4 vs. 3.6) and 6 h (1.1 vs. 14.9). BSH/DSM-boron neutron capture therapy (BNCT) was not suitable for treatment of multiple liver tumors due to the low T/L 10 B concentration ratio. However, the high 10 B accumulation in the liver tumors following intra-arterial administration of BSH/DSM emulsion suggests that BSH/DSM-BNCT has the potential for application to malignant tumors in other sites

  2. Tumor Targeting and Drug Delivery by Anthrax Toxin

    OpenAIRE

    Bachran, Christopher; Leppla, Stephen H.

    2016-01-01

    Anthrax toxin is a potent tripartite protein toxin from Bacillus anthracis. It is one of the two virulence factors and causes the disease anthrax. The receptor-binding component of the toxin, protective antigen, needs to be cleaved by furin-like proteases to be activated and to deliver the enzymatic moieties lethal factor and edema factor to the cytosol of cells. Alteration of the protease cleavage site allows the activation of the toxin selectively in response to the presence of tumor-associ...

  3. Anionic clay as the drug delivery vehicle: tumor targeting function of layered double hydroxide-methotrexate nanohybrid in C33A orthotopic cervical cancer model

    Directory of Open Access Journals (Sweden)

    Choi G

    2016-01-01

    Full Text Available Goeun Choi,1 Huiyan Piao,1 Zeid A Alothman,2 Ajayan Vinu,3 Chae-Ok Yun,4 Jin-Ho Choy1 1Center for Intelligent Nano-Bio Materials, Department of Chemistry and Nano Science, Ewha Womans University, Seoul, Korea; 2Advanced Materials Research Chair, Chemistry Department, College of Science, King Saud University, Riyadh, Saudi Arabia; 3Future Industries Institute, University of South Australia, Mawson Lakes, SA, Australia; 4Department of Bioengineering, College of Engineering, Hanyang University, Seoul, Korea Abstract: Methotrexate (MTX, an anticancer agent, was successfully intercalated into the anionic clay, layered double hydroxides to form a new nanohybrid drug. The coprecipitation and subsequent hydrothermal method were used to prepare chemically, structurally, and morphologically well-defined two-dimensional drug-clay nanohybrid. The resulting two-dimensional drug-clay nanohybrid showed excellent colloidal stability not only in deionized water but also in an electrolyte solution of Dulbecco’s Modified Eagle’s Medium with 10% fetal bovine serum, in which the average particle size in colloid and the polydispersity index were determined to be around 100 and 0.250 nm, respectively. The targeting property of the nanohybrid drug was confirmed by evaluating the tumor-to-blood and tumor-to-liver ratios of the MTX with anionic clay carrier, and these ratios were compared to those of free MTX in the C33A orthotopic cervical cancer model. The biodistribution studies indicated that the mice treated with the former showed 3.5-fold higher tumor-to-liver ratio and fivefold higher tumor-to-blood ratio of MTX than those treated with the latter at 30 minutes postinjection. Keywords: anionic clay, biodistribution, cervical cancer, colloidal stability, layered double hydroxide, methotrexate 

  4. Imatinib mesylate induces responses in patients with liver metastases from gastrointestinal stromal tumor failing intra-arterial hepatic chemotherapy

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    Fiorentini Giammaria

    2006-01-01

    Full Text Available Background: Imatinib mesylate represents a real major paradigm shift in cancer therapy, targeting the specific molecular abnormalities, crucial in the etiology of tumor. Intra-arterial hepatic chemotherapy (IAHC followed by embolization, has been considered an interesting palliative option for patients with liver metastases from gastrointestinal stromal tumor (GIST, due to the typically hypervascular pattern of the tumor. Aims: We report our experience with IAHC followed by Imatinib mesylate, in order to show the superiority of the specific molecular approach in liver metastases from GIST. Materials and Methods: Three patients (pts with pretreated massive liver metastases from GIST, received IAHC with Epirubicin 50 mg/mq, every 3 weeks for 6 cycles. At the evidence of progression, they received Imatinib mesylate. Results: We observed progressive diseases in all cases. In 1998, one patient underwent Thalidomide at 150 mg orally, every day for 4 months, with evidence of stable disease and clinical improvement. In 2001, two patients received Imatinib mesylate at 400 mg orally, every day, with evidence of partial response lasting 18+ months and 16 months. One of them had grade 3 neutropenia, with suspension of therapy for 3 weeks. Conclusion: No patient treated with IAHC, reported objective responses, but two of them obtained partial response after the assumption of Imatinib mesylate and one showed temporary stabilization with thalidomide. Imatinib mesylate represents a new opportunity in GIST therapy, targeting the specific molecular alteration. It seems to be superior to conventional intra arterial hepatic chemotherapy.

  5. Protective Effect of Prosopis cineraria Against N-Nitrosodiethylamine Induced Liver Tumor by Modulating Membrane Bound Enzymes and Glycoproteins

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    Naina Mohamed Pakkir Maideen

    2012-06-01

    Full Text Available Purpose: The objective of the present study was to evaluate the protective effect of methanol extract of Prosopis cineraria (MPC against N-nitrosodiethylamine (DEN, 200mg/kg induced Phenobarbital promoted experimental liver tumors in male Wistar rats. Methods: The rats were divided into four groups, each group consisting of six animals. Group 1 served as control animals. Liver tumor was induced in group 2, 3, and 4 and Group 3 animals received MPC 200mg/kg and Group 4 animals received MPC 400mg/kg. Results: Administration of DEN has brought down the levels of membrane bound enzymes like Na+/ K+ ATPase, Mg2+ ATPase and Ca2+ATPase which were later found to be increased by the administration of Prosopis cineraria (200 and 400mg/kg in dose dependent manner. The MPC extract also suppressed the levels of glycoproteins like Hexose, Hexosamine and Sialic acid when compared to liver tumor bearing animals. Conclusions: Our study suggests that MPC may extend its protective role by modulating the levels of membrane bound enzymes and suppressing glycoprotein levels.

  6. Supporting Data for Multifunctional all-in-one drug delivery systems for tumor targeting and sequential release of three different anti-tumor drugs

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    Guowei Wu

    2016-06-01

    Full Text Available Although nanoparticulate drug delivery systems (NDDSs can preferentially accumulate in tumors, active targeting by targeting ligands (e.g. monoclonal antibody is necessary for increasing its targeting efficacy in vivo. We conjugated mAb198.3 on the SiO2@AuNP system surface to make it obtain active targeting efficacy. The FAT1 targeting capability of SiO2@AuNP system is the first issue to be solved. Thus, flow cytometry analysis was attempted to demonstrate that the SiO2@AuNP system could bind to native FAT1 molecules on the surface of Colo205 cells. Also, together with the drug release behavior study of self-decomposable SiO2 NPs, the continuous morphological evolution needed to be clarified. Therefore, to characterize the morphological evolution in vitro, we analyzed the morphology of inner self-decomposable NPs in different time intervals using transmission electron microscopy (TEM. A more comprehensive analysis of this data may be obtained from the article “Multifunctional all-in-one drug delivery systems for tumor targeting and sequential release of three different anti-tumor drugs” in Biomaterials.

  7. In Silico Identification of Proteins Associated with Drug-induced Liver Injury Based on the Prediction of Drug-target Interactions.

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    Ivanov, Sergey; Semin, Maxim; Lagunin, Alexey; Filimonov, Dmitry; Poroikov, Vladimir

    2017-07-01

    Drug-induced liver injury (DILI) is the leading cause of acute liver failure as well as one of the major reasons for drug withdrawal from clinical trials and the market. Elucidation of molecular interactions associated with DILI may help to detect potentially hazardous pharmacological agents at the early stages of drug development. The purpose of our study is to investigate which interactions with specific human protein targets may cause DILI. Prediction of interactions with 1534 human proteins was performed for the dataset with information about 699 drugs, which were divided into three categories of DILI: severe (178 drugs), moderate (310 drugs) and without DILI (211 drugs). Based on the comparison of drug-target interactions predicted for different drugs' categories and interpretation of those results using clustering, Gene Ontology, pathway and gene expression analysis, we identified 61 protein targets associated with DILI. Most of the revealed proteins were linked with hepatocytes' death caused by disruption of vital cellular processes, as well as the emergence of inflammation in the liver. It was found that interaction of a drug with the identified targets is the essential molecular mechanism of the severe DILI for the most of the considered pharmaceuticals. Thus, pharmaceutical agents interacting with many of the identified targets may be considered as candidates for filtering out at the early stages of drug research. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  8. Precision-cut liver slices as a model for the early onset of liver fibrosis to test antifibrotic drugs

    Energy Technology Data Exchange (ETDEWEB)

    Westra, Inge M. [Division of Pharmacokinetics, Toxicology and Targeting, Department of Pharmacy, University of Groningen (Netherlands); Oosterhuis, Dorenda [Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen (Netherlands); Groothuis, Geny M.M. [Division of Pharmacokinetics, Toxicology and Targeting, Department of Pharmacy, University of Groningen (Netherlands); Olinga, Peter, E-mail: p.olinga@rug.nl [Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen (Netherlands)

    2014-01-15

    Induction of fibrosis during prolonged culture of precision-cut liver slices (PCLS) was reported. In this study, the use of rat PCLS was investigated to further characterize the mechanism of early onset of fibrosis in this model and the effects of antifibrotic compounds. Rat PCLS were incubated for 48 h, viability was assessed by ATP and gene expression of PDGF-B and TGF-β1 and the fibrosis markers Hsp47, αSma and Pcol1A1 and collagen1 protein expressions were determined. The effects of the antifibrotic drugs imatinib, sorafenib and sunitinib, PDGF-pathway inhibitors, and perindopril, valproic acid, rosmarinic acid, tetrandrine and pirfenidone, TGFβ-pathway inhibitors, were determined. After 48 h of incubation, viability of the PCLS was maintained and gene expression of PDGF-B was increased while TGF-β1 was not changed. Hsp47, αSma and Pcol1A1 gene expressions were significantly elevated in PCLS after 48 h, which was further increased by PDGF-BB and TGF-β1. The increased gene expression of fibrosis markers was inhibited by all three PDGF-inhibitors, while TGFβ-inhibitors showed marginal effects. The protein expression of collagen 1 was inhibited by imatinib, perindopril, tetrandrine and pirfenidone. In conclusion, the increased gene expression of PDGF-B and the down-regulation of fibrosis markers by PDGF-pathway inhibitors, together with the absence of elevated TGF-β1 gene expression and the limited effect of the TGFβ-pathway inhibitors, indicated the predominance of the PDGF pathway in the early onset of fibrosis in PCLS. PCLS appear a useful model for research of the early onset of fibrosis and for testing of antifibrotic drugs acting on the PDGF pathway. - Highlights: • During culture, fibrosis markers increased in precision-cut liver slices (PCLS). • Gene expression of PDGF-β was increased, while TGFβ was not changed in rat PCLS. • PDGF-pathway inhibitors down-regulated this increase of fibrosis markers. • TGFβ-pathway inhibitors had only

  9. Effect of interventional treatment with p53 on the invasion and metastasis of VX2 liver tumor in experimental rabbits

    International Nuclear Information System (INIS)

    Li Caixia; Feng Yan; Gu Tao; Li Chunmei

    2010-01-01

    Objective: To investigate the effect of interventional treatment with p53 on the invasion and metastasis of VX2 liver tumor in experimental rabbits. Methods: VX2 carcinoma cells were surgically implanted into the left hepatic lobe in 48 New Zealand white rabbits, and the rabbit hepatic carcinoma models were thus established. The rabbits were randomly divided into 4 groups with 12 rabbits in each group. After hepatic arterial catheterization was completed physiological saline (control group), Lipiodol (Group A), Ad-p53 (Group B) and Lipiodol+Ad-p53 (Group C) were respectively infused into the rabbits of four groups via common hepatic artery. One week after the procedure the rabbits were sacrificed and the livers were removed for the determination of matrix metalloprotein-2 (MMP-2), proliferating cell nuclear antigen (PCNA) and vascular endothelial growth factor (VEGF) of the tumor with immunohistochemistry technique. Results: The tumor growth in study groups (group A, B and C) was markedly suppressed, which was significantly different in comparison with that in control group (P 0.05). The positive rates of MMP-2, PCNA and VEGF in group B and C were significantly lower than those in control group (P < 0.05). The positive rates of MMP-2, PCNA and VEGF of the rabbits with metastasis were markedly higher than those without metastasis(P < 0.05). MMP-2 bore a certain relationship with VEGF and PCNA (P < 0.05). Conclusion: The increase of the positive rates of MMP-2, PCNA and VEGF indicates that the tumor possesses higher possibility for developing metastasis, proliferation and vascular formation. The interventional treatment with Adp53 or Lipiodol+Ad-p53 can inhibit the growth, metastasis and vascular formation of VX2 liver tumor in experimental rabbits. (J Intervent Radiol, 2010, 19 : 800-804) (authors)

  10. Minimally invasive liver resection to obtain tumor-infiltrating lymphocytes for adoptive cell therapy in patients with metastatic melanoma

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    Alvarez-Downing Melissa M

    2012-06-01

    Full Text Available Abstract Background Adoptive cell therapy (ACT with tumor-infiltrating lymphocytes (TIL in patients with metastatic melanoma has been reported to have a 56% overall response rate with 20% complete responders. To increase the availability of this promising therapy in patients with advanced melanoma, a minimally invasive approach to procure tumor for TIL generation is warranted. Methods A feasibility study was performed to determine the safety and efficacy of laparoscopic liver resection to generate TIL for ACT. Retrospective review of a prospectively maintained database identified 22 patients with advanced melanoma and visceral metastasis (AJCC Stage M1c who underwent laparoscopic liver resection between 1 October 2005 and 31 July 2011. The indication for resection in all patients was to receive postoperative ACT with TIL. Results Twenty patients (91% underwent resection utilizing a closed laparoscopic technique, one required hand-assistance and another required conversion to open resection. Median intraoperative blood loss was 100 mL with most cases performed without a Pringle maneuver. Median hospital stay was 3 days. Three (14% patients experienced a complication from resection with no mortality. TIL were generated from 18 of 22 (82% patients. Twelve of 15 (80% TIL tested were found to have in vitro tumor reactivity. Eleven patients (50% received the intended ACT. Two patients were rendered no evidence of disease after surgical resection, with one undergoing delayed ACT with generated TIL after relapse. Objective tumor response was seen in 5 of 11 patients (45% who received TIL, with one patient experiencing an ongoing complete response (32+ months. Conclusions Laparoscopic liver resection can be performed with minimal morbidity and serve as an effective means to procure tumor to generate therapeutic TIL for ACT to patients with metastatic melanoma.

  11. Current status of prediction of drug disposition and toxicity in humans using chimeric mice with humanized liver.

    Science.gov (United States)

    Kitamura, Shigeyuki; Sugihara, Kazumi

    2014-01-01

    1. Human-chimeric mice with humanized liver have been constructed by transplantation of human hepatocytes into several types of mice having genetic modifications that injure endogenous liver cells. Here, we focus on liver urokinase-type plasminogen activator-transgenic severe combined immunodeficiency (uPA/SCID) mice, which are the most widely used human-chimeric mice. Studies so far indicate that drug metabolism, drug transport, pharmacological effects and toxicological action in these mice are broadly similar to those in humans. 2. Expression of various drug-metabolizing enzymes is known to be different between humans and rodents. However, the expression pattern of cytochrome P450, aldehyde oxidase and phase II enzymes in the liver of human-chimeric mice resembles that in humans, not that in the host mice. 3. Metabolism of various drugs, including S-warfarin, zaleplon, ibuprofen, naproxen, coumarin, troglitazone and midazolam, in human-chimeric mice is mediated by human drug-metabolizing enzymes, not by host mouse enzymes, and thus resembles that in humans. 4. Pharmacological and toxicological effects of various drugs in human-chimeric mice are also similar to those in humans. 5. The current consensus is that chimeric mice with humanized liver are useful to predict drug metabolism catalyzed by cytochrome P450, aldehyde oxidase and phase II enzymes in humans in vivo and in vitro. Some remaining issues are discussed in this review.

  12. Nanoparticle tumor localization, disruption of autophagosomal trafficking, and prolonged drug delivery improve survival in peritoneal mesothelioma.

    Science.gov (United States)

    Liu, Rong; Colby, Aaron H; Gilmore, Denis; Schulz, Morgan; Zeng, Jialiu; Padera, Robert F; Shirihai, Orian; Grinstaff, Mark W; Colson, Yolonda L

    2016-09-01

    The treatment outcomes for malignant peritoneal mesothelioma are poor and associated with high co-morbidities due to suboptimal drug delivery. Thus, there is an unmet need for new approaches that concentrate drug at the tumor for a prolonged period of time yielding enhanced antitumor efficacy and improved metrics of treatment success. A paclitaxel-loaded pH-responsive expansile nanoparticle (PTX-eNP) system is described that addresses two unique challenges to improve the outcomes for peritoneal mesothelioma. First, following intraperitoneal administration, eNPs rapidly and specifically localize to tumors. The rate of eNP uptake by tumors is an order of magnitude faster than the rate of uptake in non-malignant cells; and, subsequent accumulation in autophagosomes and disruption of autophagosomal trafficking leads to prolonged intracellular retention of eNPs. The net effect of these combined mechanisms manifests as rapid localization to intraperitoneal tumors within 4 h of injection and persistent intratumoral retention for >14 days. Second, the high tumor-specificity of PTX-eNPs leads to delivery of greater than 100 times higher concentrations of drug in tumors compared to PTX alone and this is maintained for at least seven days following administration. As a result, overall survival of animals with established mesothelioma more than doubled when animals were treated with multiple doses of PTX-eNPs compared to equivalent dosing with PTX or non-responsive PTX-loaded nanoparticles. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. A mesenchymal-like phenotype and expression of CD44 predict lack of apoptotic response to sorafenib in liver tumor cells.

    Science.gov (United States)

    Fernando, Joan; Malfettone, Andrea; Cepeda, Edgar B; Vilarrasa-Blasi, Roser; Bertran, Esther; Raimondi, Giulia; Fabra, Àngels; Alvarez-Barrientos, Alberto; Fernández-Salguero, Pedro; Fernández-Rodríguez, Conrado M; Giannelli, Gianluigi; Sancho, Patricia; Fabregat, Isabel

    2015-02-15

    The multikinase inhibitor sorafenib is the only effective drug in advanced cases of hepatocellular carcinoma (HCC). However, response differs among patients and effectiveness only implies a delay. We have recently described that sorafenib sensitizes HCC cells to apoptosis. In this work, we have explored the response to this drug of six different liver tumor cell lines to define a phenotypic signature that may predict lack of response in HCC patients. Results have indicated that liver tumor cells that show a mesenchymal-like phenotype, resistance to the suppressor effects of transforming growth factor beta (TGF-β) and high expression of the stem cell marker CD44 were refractory to sorafenib-induced cell death in in vitro studies, which correlated with lack of response to sorafenib in nude mice xenograft models of human HCC. In contrast, epithelial-like cells expressing the stem-related proteins EpCAM or CD133 were sensitive to sorafenib-induced apoptosis both in vitro and in vivo. A cross-talk between the TGF-β pathway and the acquisition of a mesenchymal-like phenotype with up-regulation of CD44 expression was found in the HCC cell lines. Targeted CD44 knock-down in the mesenchymal-like cells indicated that CD44 plays an active role in protecting HCC cells from sorafenib-induced apoptosis. However, CD44 effect requires a TGF-β-induced mesenchymal background, since the only overexpression of CD44 in epithelial-like HCC cells is not sufficient to impair sorafenib-induced cell death. In conclusion, a mesenchymal profile and expression of CD44, linked to activation of the TGF-β pathway, may predict lack of response to sorafenib in HCC patients. © 2014 UICC.

  14. Premature drug release of polymeric micelles and its effects on tumor targeting.

    Science.gov (United States)

    Miller, Tobias; Breyer, Sandra; van Colen, Gwenaelle; Mier, Walter; Haberkorn, Uwe; Geissler, Simon; Voss, Senta; Weigandt, Markus; Goepferich, Achim

    2013-03-10

    Based on the enhanced permeability and retention (EPR) effect, nanoparticles are believed to accumulate in tumors. In this conjunction, the stability of drug encapsulation is assumed to be sufficient. For clarification purposes, PEGylated poly-(D,L-lactic acid) (PEG-PDLLA) micelles which incorporated the hydrophobic model drug dechloro-4-iodo-fenofibrate (IFF) were investigated. H2N-PEG-PDLLA was synthesized, coupled to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and labeled with 111-indium. From this polymeric species, mixed micelles with H3CO-PEG-PDLLA were prepared which encapsulated the 125-iodine or 131-iodine labeled drug IFF. Bioimaging and biodistribution experiments in healthy and AR42J-tumor bearing mice were carried out to quantify the uptake of the drug and its carrier in single organs. As a result, upon injection of this system, a rapid dissociation of the polymeric carrier and the incorporated drug (system allowed for successful solubilization of the hydrophobic drug by physical incorporation into micelles whereas the tumor targeting properties of the drug delivery system could not be sufficiently shown. Copyright © 2013 Elsevier B.V. All rights reserved.

  15. Pathogen infection distribution and drug resistance analysis of patients with severe liver disease

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    Xi CHEN

    2018-04-01

    Full Text Available Objective To explore the infection distribution and drug resistance of pathogens in patients with severe liver disease, and provide reference for clinical medication. Methods Retrospective analysis of the microbiological specimens from patients with severe liver disease in Department of Infection of our hospital from August 2014 to November 2016 and the drug susceptibility testing were carried out by means of K-B disc diffusion method after bacterial culturing, and the distribution and drug resistance of pathogens were analyzed. Results Totally 17 of 73 patients with severe liver disease developed hospital infection (23.3%. 104 strains of bacteria were isolated and 78 strains out of them were multidrug-resistant bacteria (75.0%. Among them, 28(26.9% strains were gram-positive coccus, mainly consisting of Staphylococcus aureus and Staphylococcus epidermidis, and 58(55.8% were gram-negative coccus, mainly composed of Escherichia coli, Klebsiella pneumonia and Acinetobacter baumannii, and 18(17.3% strains fungi. S.aureus and enterococci were resistant to penicillin, erythromycin and levofloxacin, the resistance rates were above 80.0%, but had low resistance rates to vancomycin, teicoplanin and tigecycline. The resistance rates of E.coli and K.pneumoniae to piperacillin, cefazolin and cefuroxime sodium were above 85.0%, but they had lower resistance rates to tigecycline and amikacin. Acinetobacter baumannii was 100% resistant to piperacillin and tazobactam, ceftazidime, imipenem and amikacin, but had low resistance to tigecycline and minocycline. Conclusions Multi-drug resistant bacteria are the main bacterial pathogens in patients with severe liver disease and have a high resistance rate to commonly used antibiotics, empirical treatment in the population at high risk of multidrug-resistant bacteria infections requires the use of broad-spectrum or high-grade antibiotics (e.g. carbapenems or tigecycline and drugs against specific pathogenic

  16. A drug development perspective on targeting tumor-associated myeloid cells.

    Science.gov (United States)

    Majety, Meher; Runza, Valeria; Lehmann, Christian; Hoves, Sabine; Ries, Carola H

    2018-02-01

    Despite decades of research, cancer remains a devastating disease and new treatment options are needed. Today cancer is acknowledged as a multifactorial disease not only comprising of aberrant tumor cells but also the associated stroma including tumor vasculature, fibrotic plaques, and immune cells that interact in a complex heterotypic interplay. Myeloid cells represent one of the most abundant immune cell population within the tumor stroma and are equipped with a broad functional repertoire that promotes tumor growth by suppressing cytotoxic T cell activity, stimulating neoangiogenesis and tissue remodeling. Therefore, myeloid cells have become an attractive target for pharmacological intervention. In this review, we summarize the pharmacological approaches to therapeutically target tumor-associated myeloid cells with a focus on advanced programs that are clinically evaluated. In addition, for each therapeutic strategy, the preclinical rationale as well as advantages and challenges from a drug development perspective are discussed. © 2017 Federation of European Biochemical Societies.

  17. New in vitro system to predict chemotherapeutic efficacy of drug combinations in fresh tumor samples

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    Frank Christian Kischkel

    2017-03-01

    Full Text Available Background To find the best individual chemotherapy for cancer patients, the efficacy of different chemotherapeutic drugs can be predicted by pretesting tumor samples in vitro via the chemotherapy-resistance (CTR-Test®. Although drug combinations are widely used among cancer therapy, so far only single drugs are tested by this and other tests. However, several first line chemotherapies are combining two or more chemotherapeutics, leading to the necessity of drug combination testing methods. Methods We established a system to measure and predict the efficacy of chemotherapeutic drug combinations with the help of the Loewe additivity concept in combination with the CTR-test. A combination is measured by using half of the monotherapy’s concentration of both drugs simultaneously. With this method, the efficacy of a combination can also be calculated based on single drug measurements. Results The established system was tested on a data set of ovarian carcinoma samples using the combination carboplatin and paclitaxel and confirmed by using other tumor species and chemotherapeutics. Comparing the measured and the calculated values of the combination testings revealed a high correlation. Additionally, in 70% of the cases the measured and the calculated values lead to the same chemotherapeutic resistance category of the tumor. Conclusion Our data suggest that the best drug combination consists of the most efficient single drugs and the worst drug combination of the least efficient single drugs. Our results showed that single measurements are sufficient to predict combinations in specific cases but there are exceptions in which it is necessary to measure combinations, which is possible with the presented system.

  18. Digesting a Path Forward: The Utility of Collagenase Tumor Treatment for Improved Drug Delivery.

    Science.gov (United States)

    Dolor, Aaron; Szoka, Francis C

    2018-06-04

    Collagen and hyaluronan are the most abundant components of the extracellular matrix (ECM) and their overexpression in tumors is linked to increased tumor growth and metastasis. These ECM components contribute to a protective tumor microenvironment by supporting a high interstitial fluid pressure and creating a tortuous setting for the convection and diffusion of chemotherapeutic small molecules, antibodies, and nanoparticles in the tumor interstitial space. This review focuses on the research efforts to deplete extracellular collagen with collagenases to normalize the tumor microenvironment. Although collagen synthesis inhibitors are in clinical development, the use of collagenases is contentious and clinically untested in cancer patients. Pretreatment of murine tumors with collagenases increased drug uptake and diffusion 2-10-fold. This modest improvement resulted in decreased tumor growth, but the benefits of collagenase treatment are confounded by risks of toxicity from collagen breakdown in healthy tissues. In this review, we evaluate the published in vitro and in vivo benefits and limitations of collagenase treatment to improve drug delivery.

  19. Systemic agonistic anti-CD40 treatment of tumor bearing mice modulates hepatic myeloid suppressive cells and causes immune-mediated liver damage

    Science.gov (United States)

    Medina-Echeverz, José; Ma, Chi; Duffy, Austin; Eggert, Tobias; Hawk, Nga; Kleiner, David E.; Korangy, Firouzeh; Greten, Tim F.

    2015-01-01

    Immune stimulatory monoclonal antibodies are currently evaluated as anti tumor agents. Although overall toxicity appears to be moderate, liver toxicities have been reported and are not completely understood. We studied the effect of systemic CD40 antibody treatment on myeloid cells in spleen and liver. Naïve and tumor-bearing mice were treated systemically with agonistic anti-CD40 antibody. Immune cell subsets in liver and spleen, serum transaminases and liver histologies were analyzed after antibody administration. Nox2−/−, Cd40−/− as well as bone marrow chimeric mice were used to study the mechanism by which agonistic anti-CD40 mediates its effects in vivo. Suppressor function of murine and human tumor-induced myeloid derived suppressive cells was studied upon CD40 ligation. Agonistic CD40 antibody caused liver damage within 24 hours after injection in two unrelated tumor models and mice strains. Using bone marrow chimeras we demonstrated that CD40 antibody-induced hepatitis in tumor-bearing mice was dependent on the presence of CD40-expressing hematopoietic cells. Agonistic CD40 ligation-dependent liver damage was induced by the generation of reactive oxygen species. Furthermore, agonistic CD40 antibody resulted in increased CD80 and CD40 positive liver CD11b+Gr-1+ immature myeloid cells. CD40 ligation on tumor-induced murine and human CD14+HLA-DRlow PBMC from cancer patients reduced their immune suppressor function. Collectively, agonistic CD40 antibody treatment activated tumor-induced, myeloid cells, caused myeloid dependent hepatotoxicity and ameliorated the suppressor function of murine and human MDSC. Collectively, our data suggests that CD40 may mature immunosuppressive myeloid cells and thereby cause liver damage in mice with an accumulation of tumor-induced hepatic MDSC. PMID:25637366

  20. Computed tomography of liver tumors, 2. Differential diagnosis between hepatocellular carcinoma and metastatic hepatic tumor by dynamic CT scanning

    Energy Technology Data Exchange (ETDEWEB)

    Naito, Akira; Fukuoka, Haruhito; Kashiwado, Kouzou; Ichiki, Toshio; Makidono, Yoko [Hiroshima Red Cross Hospital (Japan)

    1984-02-01

    Differential diagnosis between hepatocellular carcinoma and metastatic hepatic tumor was attempted using dynamic CT scanning. Homogeneous and patchy types were peculiar to hepatocellular carcinoma, and ring-like type to metastatic hepatic tumor. However, with no enhancement, hepatocellular carcinoma could not be denied. Hepatocellular carcinoma was characterized by the enhancement shown on the early stage of dynamic CT. Ring enhancement was not visualized on dynamic CT but visualized on conventional contrast enhanced CT in hepatocellular carcinomas; it was visualized on conventional contrast enhanced CT and on dynamic CT in metastatic hepatic tumors.

  1. Transcriptional changes associated with reduced spontaneous liver tumor incidence in mice chronically exposed to high dose arsenic

    International Nuclear Information System (INIS)

    Nelson, Gail M.; Ahlborn, Gene J.; Allen, James W.; Ren, Hongzu; Corton, J. Christopher; Waalkes, Michael P.; Kitchin, Kirk T.; Diwan, Bhalchandra A.; Knapp, Geremy; Delker, Don A.

    2009-01-01

    Exposure of male C3H mice in utero (from gestational days 8-18) to 85 ppm sodium arsenite via the dams' drinking water has previously been shown to increase liver tumor incidence by 2 years of age. However, in our companion study (Ahlborn et al., 2009), continuous exposure to 85 ppm sodium arsenic (from gestational day 8 to postnatal day 365) did not result in increased tumor incidence, but rather in a significant reduction (0% tumor incidence). The purpose of the present study was to examine the gene expression responses that may lead to the apparent protective effect of continuous arsenic exposure. Genes in many functional categories including cellular growth and proliferation, gene expression, cell death, oxidative stress, protein ubiquitination, and mitochondrial dysfunction were altered by continuous arsenic treatment. Many of these genes are known to be involved in liver cancer. One such gene associated with rodent hepatocarcinogenesis, Scd1, encodes stearoyl-CoA desaturase and was down-regulated by continuous arsenic treatment. An overlap between the genes in our study affected by continuous arsenic exposure and those from the literature affected by long-term caloric restriction suggests that reduction in the spontaneous tumor incidence under both conditions may involve similar gene pathways such as fatty acid metabolism, apoptosis, and stress response.

  2. Correlation of ultrasound findings, liver and spleen cytology, and prognosis in the clinical staging of high metastatic risk canine mast cell tumors.

    Science.gov (United States)

    Book, Alison P; Fidel, Janean; Wills, Tamara; Bryan, Jeffrey; Sellon, Rance; Mattoon, John

    2011-01-01

    Cytologic sampling of the ultrasonographically normal spleen and liver is not implemented routinely in the clinical staging of canine cutaneous mast cell tumors and normal ultrasound findings are often accepted as sufficient evidence for ruling out splenic or liver metastasis. Our objective was to define the specificity and sensitivity of ultrasound findings for diagnosis of mast cell infiltration when verified with cytologic evaluation, and to define the prognostic role of cytologic evaluation of liver and splenic aspirates. Dogs with a diagnosis of clinically aggressive grade II, or grade III mast cell tumor treated with a combination vinblastine/CCNU chemotherapy protocol, were selected retrospectively based on availability of cytologic evaluation of spleen plus or minus liver for staging. Out of 19 dogs, 10 dogs had a grade II tumor and nine a grade III tumor. Seven dogs had mast cell infiltration of the spleen, liver, or both. The sensitivity of ultrasound for detecting mast cell infiltration was 43% for the spleen and 0% for the liver. Dogs with positive cytologic evidence of mast cell infiltration to spleen, liver, or both had significantly shorter survival (100 vs. 291 days) than dogs without evidence of mast cell infiltration (Pdogs with a clinically aggressive mast cell tumor. © 2011 Veterinary Radiology & Ultrasound.

  3. Lipid conjugated prodrugs for enzyme-triggered liposomal drug delivery to tumors

    DEFF Research Database (Denmark)

    Clausen, Mads Hartvig

    2011-01-01

    For some time we have been developing novel enzyme-triggered prodrugs for drug delivery targeting cancer. The liposomal prodrugs take advantage of the EPR effect to localize to tumors and of the local over-expression of secretory phospholipase A2 in tumors. Compared to conventional liposomal drug...... delivery systems, our prodrug-lipid conjugates have two main advantages: 1) the drugs are covalently linked to the lipids and thus leakage is circumvented and 2) the lipophilic bilayer of the formulated liposomes effectively shields the drugs from the aqueous environment in vivo. Consequently, the strategy...... targeting nuclear receptors and structural proteins. The presentation will highlight various strategies and recent progress towards improved systems, including chemical synthesis, enzyme activity and cytotoxicity....

  4. Novel 3D Culture Systems for Studies of Human Liver Function and Assessments of the Hepatotoxicity of Drugs and Drug Candidates.

    Science.gov (United States)

    Lauschke, Volker M; Hendriks, Delilah F G; Bell, Catherine C; Andersson, Tommy B; Ingelman-Sundberg, Magnus

    2016-12-19

    The liver is an organ with critical importance for drug treatment as the disposition and response to a given drug is often determined by its hepatic metabolism. Patient-specific factors can entail increased susceptibility to drug-induced liver injury, which constitutes a major risk for drug development programs causing attrition of promising drug candidates or costly withdrawals in postmarketing stages. Hitherto, mainly animal studies and 2D hepatocyte systems have been used for the examination of human drug metabolism and toxicity. Yet, these models are far from satisfactory due to extensive species differences and because hepatocytes in 2D cultures rapidly dedifferentiate resulting in the loss of their hepatic phenotype and functionality. With the increasing comprehension that 3D cell culture systems more accurately reflect in vivo physiology, in the recent decade more and more research has focused on the development and optimization of various 3D culture strategies in an attempt to preserve liver properties in vitro. In this contribution, we critically review these developments, which have resulted in an arsenal of different static and perfused 3D models. These systems include sandwich-cultured hepatocytes, spheroid culture platforms, and various microfluidic liver or multiorgan biochips. Importantly, in many of these models hepatocytes maintain their phenotype for prolonged times, which allows probing the potential of newly developed chemical entities to cause chronic hepatotoxicity. Moreover, some platforms permit the investigation of drug action in specific genetic backgrounds or diseased hepatocytes, thereby significantly expanding the repertoire of tools to detect drug-induced liver injuries. It is concluded that the development of 3D liver models has hitherto been fruitful and that systems are now at hand whose sensitivity and specificity in detecting hepatotoxicity are superior to those of classical 2D culture systems. For the future, we highlight the

  5. Subtoxic Alterations in Hepatocyte-Derived Exosomes: An Early Step in Drug-Induced Liver Injury?

    Science.gov (United States)

    Holman, Natalie S; Mosedale, Merrie; Wolf, Kristina K; LeCluyse, Edward L; Watkins, Paul B

    2016-06-01

    Drug-induced liver injury (DILI) is a significant clinical and economic problem in the United States, yet the mechanisms that underlie DILI remain poorly understood. Recent evidence suggests that signaling molecules released by stressed hepatocytes can trigger immune responses that may be common across DILI mechanisms. Extracellular vesicles released by hepatocytes, principally hepatocyte-derived exosomes (HDEs), may constitute one such signal. To examine HDE alterations as a function of drug-induced stress, this work utilized prototypical hepatotoxicant acetaminophen (APAP) in male Sprague-Dawley (SD) rats, SD rat hepatocytes, and primary human hepatocytes. HDE were isolated using ExoQuick precipitation reagent and analyzed by quantification of the liver-specific RNAs albumin and microRNA-122 (miR-122). In vivo, significant elevations in circulating exosomal albumin mRNA were observed at subtoxic APAP exposures. Significant increases in exosomal albumin mRNA were also observed in primary rat hepatocytes at subtoxic APAP concentrations. In primary human hepatocytes, APAP elicited increases in both exosomal albumin mRNA and exosomal miR-122 without overt cytotoxicity. However, the number of HDE produced in vitro in response to APAP did not increase with exosomal RNA quantity. We conclude that significant drug-induced alterations in the liver-specific RNA content of HDE occur at subtoxic APAP exposures in vivo and in vitro, and that these changes appear to reflect selective packaging rather than changes in exosome number. The current findings demonstrate that translationally relevant HDE alterations occur in the absence of overt hepatocellular toxicity, and support the hypothesis that HDE released by stressed hepatocytes may mediate early immune responses in DILI. © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  6. Bradycardia Associated With Drug-Eluting Beads Loaded With Irinotecan (DEBIRI) Infusion for Colorectal Liver Metastases

    International Nuclear Information System (INIS)

    Pua, Uei

    2013-01-01

    Intra-arterial injection of drug-eluting beads loaded with irinotecan (DEBIRI) is a new treatment option being investigated, with encouraging results, for unresectable colorectal liver metastases that are refractory to systemic chemotherapy (Martin et al., Ann Surg Oncol 18:192–198, 2011). Toxicity related to DEBIRI has also been described (Martin et al., Cardiovasc Intervent Radiol 33:960–966, 2010). Nevertheless, experience and literature related to DEBIRI remain limited, and experience with this treatment is expected to increase. The purpose of this article is to describe bradycardia occurring during DEBIRI administration, which has not been reported thus far.

  7. Bradycardia Associated With Drug-Eluting Beads Loaded With Irinotecan (DEBIRI) Infusion for Colorectal Liver Metastases

    Energy Technology Data Exchange (ETDEWEB)

    Pua, Uei, E-mail: druei@yahoo.com [Tan Tock Seng Hospital, Department of Diagnostic Radiology (Singapore)

    2013-06-15

    Intra-arterial injection of drug-eluting beads loaded with irinotecan (DEBIRI) is a new treatment option being investigated, with encouraging results, for unresectable colorectal liver metastases that are refractory to systemic chemotherapy (Martin et al., Ann Surg Oncol 18:192-198, 2011). Toxicity related to DEBIRI has also been described (Martin et al., Cardiovasc Intervent Radiol 33:960-966, 2010). Nevertheless, experience and literature related to DEBIRI remain limited, and experience with this treatment is expected to increase. The purpose of this article is to describe bradycardia occurring during DEBIRI administration, which has not been reported thus far.

  8. Harnessing high density lipoproteins to block transforming growth factor beta and to inhibit the growth of liver tumor metastases.

    Directory of Open Access Journals (Sweden)

    José Medina-Echeverz

    Full Text Available Transforming growth factor β (TGF-β is a powerful promoter of cancer progression and a key target for antitumor therapy. As cancer cells exhibit active cholesterol metabolism, high density lipoproteins (HDLs appear as an attractive delivery system for anticancer TGFβ-inhibitory molecules. We constructed a plasmid encoding a potent TGF-β-blocking peptide (P144 linked to apolipoprotein A-I (ApoA-I through a flexible linker (pApoLinkerP144. The ApoLinkerP144 sequence was then incorporated into a hepatotropic adeno-associated vector (AAVApoLinkerP144. The aim was to induce hepatocytes to produce HDLs containing a modified ApoA-I capable of blocking TGF-β. We observed that transduction of the murine liver with pApoLinkerP144 led to the appearance of a fraction of circulating HDL containing the fusion protein. These HDLs were able to attenuate TGF-β signaling in the liver and to enhance IL-12 -mediated IFN-γ production. Treatment of liver metastasis of MC38 colorectal cancer with AAVApoLinkerP144 resulted in a significant reduction of tumor growth and enhanced expression of IFN-γ and GM-CSF in cancerous tissue. ApoLinkerP144 also delayed MC38 liver metastasis in Rag2-/-IL2rγ-/- immunodeficient mice. This effect was associated with downregulation of TGF-β target genes essential for metastatic niche conditioning. Finally, in a subset of ret transgenic mice, a model of aggressive spontaneous metastatic melanoma, AAVApoLinkerP144 delayed tumor growth in association with increased CD8+ T cell numbers in regional lymph nodes. In conclusion, modification of HDLs to transport TGF-β-blocking molecules is a novel and promising approach to inhibit the growth of liver metastases by immunological and non-immunological mechanisms.

  9. Particle radiotherapy, a novel external radiation therapy, versus liver resection for hepatocellular carcinoma accompanied with inferior vena cava tumor thrombus: A matched-pair analysis.

    Science.gov (United States)

    Komatsu, Shohei; Kido, Masahiro; Asari, Sadaki; Toyama, Hirochika; Ajiki, Tetsuo; Demizu, Yusuke; Terashima, Kazuki; Okimoto, Tomoaki; Sasaki, Ryohei; Fukumoto, Takumi

    2017-12-01

    Hepatocellular carcinoma accompanied with inferior vena cava tumor thrombus carries a dismal prognosis, and the feasibility of local treatment has remained controversial. The present study aimed to compare the outcomes of particle radiotherapy and liver resection in patients with hepatocellular carcinoma with inferior vena cava tumor thrombus. Thirty-one and 19 patients, respectively, underwent particle radiotherapy and liver resection for hepatocellular carcinoma with inferior vena cava tumor thrombus. A matched-pair analysis was undertaken to compare the short- and long-term outcomes according to tumor stage determined using the tumor-node-metastasis classification. Both stages IIIB and IV (IVA and IVB) patients were well-matched for 12 factors, including treatment policy and patient and tumor characteristics. The median survival time of matched patients with stage IIIB tumors in the particle radiotherapy group was greater than that in the liver resection group (748 vs 272 days, P = .029), whereas no significant difference was observed in the median survival times of patients with stage IV tumors (239 vs 311 days, respectively). There were significantly fewer treatment-related complications of grade 3 or greater in the particle radiotherapy group (0%) than in the liver resection group (26%). Particle radiotherapy is potentially preferable in hepatocellular carcinoma patients with stage IIIB inferior vena cava tumor thrombus and at least equal in efficiency to liver resection in those with stage IV disease, while causing significantly fewer complications. Considering the relatively high survival and low invasiveness of particle radiotherapy when compared to liver resection, this approach may represent a novel treatment modality for hepatocellular carcinoma with inferior vena cava tumor thrombus. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. A Challenge for Diagnosing Acute Liver Injury with Concomitant/Sequential Exposure to Multiple Drugs: Can Causality Assessment Scales Be Utilized to Identify the Offending Drug?

    Directory of Open Access Journals (Sweden)

    Roxanne Lim

    2014-01-01

    Full Text Available Drug-induced hepatotoxicity most commonly manifests as an acute hepatitis syndrome and remains the leading cause of drug-induced death/mortality and the primary reason for withdrawal of drugs from the pharmaceutical market. We report a case of acute liver injury in a 12-year-old Hispanic boy, who received a series of five antibiotics (amoxicillin, ceftriaxone, vancomycin, ampicillin/sulbactam, and clindamycin for cervical lymphadenitis/retropharyngeal cellulitis. Histopathology of the liver biopsy specimen revealed acute cholestatic hepatitis. All known causes of acute liver injury were appropriately excluded and (only drug-induced liver injury was left as a cause of his cholestasis. Liver-specific causality assessment scales such as Council for the International Organization of Medical Sciences/Roussel Uclaf Causality Assessment Method scoring system (CIOMS/RUCAM, Maria and Victorino scale, and Digestive Disease Week-Japan were applied to seek the most likely offending drug. Although clindamycin is the most likely cause by clinical diagnosis, none of causality assessment scales aid in the diagnosis.

  11. Differential diagnosis between metastatic tumors and nonsolid benign lesions of the liver using ferucarbotran-enhanced MR imaging

    Energy Technology Data Exchange (ETDEWEB)

    Higashihara, Hiroki [Department of Radiology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 5650871 (Japan)], E-mail: h-higashihara@radiol.med.osaka-u.ac.jp; Murakami, Takamichi [Department of Radiology, Kinki University School of Medicine 377-2 Oonohigashi, Osakasayama, Osaka 5898511 (Japan); Kim, Tonsok; Hori, Masatoshi; Onishi, Hiromitsu [Department of Radiology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 5650871 (Japan); Nakata, Saki [Department of Radiology, Toyonaka Municipal Hospital, 4-14-1 Shibahara Chou, Toyonaka, Osaka 5608565 (Japan); Osuga, Keigo; Tomoda, Kaname; Nakamura, Hironobu [Department of Radiology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 5650871 (Japan)

    2010-01-15

    Purpose: To evaluate ability of ferucarbotran-enhanced MR imaging (MRI) in differentiating metastases from nonsolid benign lesions of the liver according to signal-intensity characteristics. Materials and methods: Sixty-six consecutive patients, who had 138 focal hepatic lesions (26 cysts, 11 hemangiomas, and 101 metastases), underwent ferucarbotran-enhanced MRI. The signal-intensity pattern of each kind of lesion relative to the liver parenchyma on ferucarbotran-enhanced T2* and heavily T1-weighted gradient-echo images were assessed and categorized into the following three categories: high-intensity and iso-intensity, respectively (category A), high and low (category B), and iso- and low-intensity (category C). For category B, lesions were subdivided into two groups based on single-shot half-Fourier RARE images: category B1 (not significantly high-intensity) and category B2 (significantly high-intensity). Results: Category A had 11 hemangiomas and 2 metastatic tumors, category B1 had 97 metastatic tumors, category B2 had 2 metastatic tumors and 9 cysts, and category C had 17 cysts. When a tumor with a signal intensity of category A was considered to be hemangioma, category B1 metastasis, and category B2 and C cyst, the diagnostic accuracy for differentiating these lesions was 97% (134/138). Conclusion: The combination of signal-intensity pattern on ferucarbotran-enhanced T2*- and heavily T1-weighted gradient-echo MRI has ability to differentiate liver metastases from nonsolid benign lesions. However, T2-weighted single-shot half-Fourier RARE imaging should also be employed to achieve better performance.

  12. Effective experimental tumor therapy with targeted polymer drug delivery systems based on HPMA copolymers.

    Czech Academy of Sciences Publication Activity Database

    Šírová, Milada; Horková, Veronika; Sivák, Ladislav; Etrych, Tomáš; Říhová, Blanka; Studenovský, Martin

    SI (2016), s. 24-24 ISSN 0014-2980. [3rd Meeting of Middle – European Societies for Immunology and Allergology. 01.12.2016-03.12.2016, Budapest ] R&D Projects: GA ČR(CZ) GA14-12742S Institutional support: RVO:61388971 ; RVO:61389013 Keywords : Tumor therapy * polymer drug * HPMA copolymers Subject RIV: EE - Microbiology, Virology

  13. Tumor regression achieved by encapsulating a moderately soluble drug into a polymeric thermogel

    Science.gov (United States)

    Ci, Tianyuan; Chen, Liang; Yu, Lin; Ding, Jiandong

    2014-07-01

    For cancer chemotherapy, a tumor regression without any surgical resection and severe side effects is greatly preferred to merely slowing down the growth of tumors. Here, we report a formulation composed of irinotecan (IRN) and poly(D,L-lactide-co-glycolide)-b-poly(ethylene glycol)-b-poly(D,L-lactide-co-glycolide) (PLGA-PEG-PLGA). IRN is a clinically used antitumor drug with active and inactive chemical forms in equilibrium, and the major form at physiological conditions is inactive but still has side effects. The aqueous solution of the PLGA-PEG-PLGA is a sol at room temperature and physically gels at body temperature, forming a thermogel. We successfully mixed this moderately soluble drug into the amphiphilic copolymer aqueous solution for the first time. The mixture was subcutaneously injected into nude mice with xenografted SW620 human colon tumors. Excellent in vivo antitumor efficacy was observed in the group that received the IRN-loaded thermogel. The tumor was significantly regressed after being treated with the IRN/thermogel, and the side effects (blood toxicity and body weight decrease) were very mild. These results might be attributed to the ideal sustained release profile and period of release of the drug from the thermogel and to the significant enhancement of the fraction of the active form of the drug by the thermogel.

  14. Monitoring early tumor response to drug therapy with diffuse optical tomography

    Science.gov (United States)

    Flexman, Molly L.; Vlachos, Fotios; Kim, Hyun Keol; Sirsi, Shashank R.; Huang, Jianzhong; Hernandez, Sonia L.; Johung, Tessa B.; Gander, Jeffrey W.; Reichstein, Ari R.; Lampl, Brooke S.; Wang, Antai; Borden, Mark A.; Yamashiro, Darrell J.; Kandel, Jessica J.; Hielscher, Andreas H.

    2012-01-01

    Although anti-angiogenic agents have shown promise as cancer therapeutics, their efficacy varies between tumor types and individual patients. Providing patient-specific metrics through rapid noninvasive imaging can help tailor drug treatment by optimizing dosages, timing of drug cycles, and duration of therapy--thereby reducing toxicity and cost and improving patient outcome. Diffuse optical tomography (DOT) is a noninvasive three-dimensional imaging modality that has been shown to capture physiologic changes in tumors through visualization of oxygenated, deoxygenated, and total hemoglobin concentrations, using non-ionizing radiation with near-infrared light. We employed a small animal model to ascertain if tumor response to bevacizumab (BV), an anti-angiogenic agent that targets vascular endothelial growth factor (VEGF), could be detected at early time points using DOT. We detected a significant decrease in total hemoglobin levels as soon as one day after BV treatment in responder xenograft tumors (SK-NEP-1), but not in SK-NEP-1 control tumors or in non-responder control or BV-treated NGP tumors. These results are confirmed by magnetic resonance imaging T2 relaxometry and lectin perfusion studies. Noninvasive DOT imaging may allow for earlier and more effective control of anti-angiogenic therapy.

  15. Nanoparticle-mediated combination chemotherapy and photodynamic therapy overcomes tumor drug resistance in vitro.

    Science.gov (United States)

    Khdair, Ayman; Handa, Hitesh; Mao, Guangzhao; Panyam, Jayanth

    2009-02-01

    Drug resistance limits the success of many anticancer drugs. Reduced accumulation of the drug at its intracellular site of action because of overexpression of efflux transporters such as P-glycoprotein (P-gp) is a major mechanism of drug resistance. In this study, we investigated whether photodynamic therapy (PDT) using methylene blue, also a P-gp inhibitor, can be used to enhance doxorubicin-induced cytotoxicity in drug-resistant tumor cells. Aerosol OT (AOT)-alginate nanoparticles were used as a carrier for the simultaneous cellular delivery of doxorubicin and methylene blue. Methylene blue was photoactivated using light of 665 nm wavelength. Induction of apoptosis and necrosis following treatment with combination chemotherapy and PDT was investigated in drug-resistant NCI/ADR-RES cells using flow cytometry and fluorescence microscopy. Effect of encapsulation in nanoparticles on the intracellular accumulation of doxorubicin and methylene blue was investigated qualitatively using fluorescence microscopy and was quantitated using HPLC. Encapsulation in AOT-alginate nanoparticles significantly enhanced the cytotoxicity of combination therapy in resistant tumor cells. Nanoparticle-mediated combination therapy resulted in a significant induction of both apoptosis and necrosis. Improvement in cytotoxicity could be correlated with enhanced intracellular and nuclear delivery of the two drugs. Further, nanoparticle-mediated combination therapy resulted in significantly elevated reactive oxygen species (ROS) production compared to single drug treatment. In conclusion, nanoparticle-mediated combination chemotherapy and PDT using doxorubicin and methylene blue was able to overcome resistance mechanisms and resulted in improved cytotoxicity in drug-resistant tumor cells.

  16. Dosimetry and prescription in liver radioembolization with 90Y microspheres: 3D calculation of tumor-to-liver ratio from global 99mTc-MAA SPECT information

    Science.gov (United States)

    Mañeru, Fernando; Abós, Dolores; Bragado, Laura; Fuentemilla, Naiara; Caudepón, Fernando; Pellejero, Santiago; Miquelez, Santiago; Rubio, Anastasio; Goñi, Elena; Hernández-Vitoria, Araceli

    2017-12-01

    Dosimetry in liver radioembolization with 90Y microspheres is a fundamental tool, both for the optimization of each treatment and for improving knowledge of the treatment effects in the tissues. Different options are available for estimating the administered activity and the tumor/organ dose, among them the so-called partition method. The key factor in the partition method is the tumor/normal tissue activity uptake ratio (T/N), which is obtained by a single-photon emission computed tomography (SPECT) scan during a pre-treatment simulation. The less clear the distinction between healthy and tumor parenchyma within the liver, the more difficult it becomes to estimate the T/N ratio; therefore the use of the method is limited. This study presents a methodology to calculate the T/N ratio using global information from the SPECT. The T/N ratio is estimated by establishing uptake thresholds consistent with previously performed volumetry. This dose calculation method was validated against 3D voxel dosimetry, and was also compared with the standard partition method based on freehand regions of interest (ROI) outlining on SPECT slices. Both comparisons were done on a sample of 20 actual cases of hepatocellular carcinoma treated with resin microspheres. The proposed method and the voxel dosimetry method yield similar results, while the ROI-based method tends to over-estimate the dose to normal tissues. In addition, the variability associated with the ROI-based method is more extreme than the other methods. The proposed method is simpler than either the ROI or voxel dosimetry approaches and avoids the subjectivity associated with the manual selection of regions.

  17. Detection of tumor-specific cytotoxic drug activity in vitro using the fluorometric microculture cytotoxicity assay and primary cultures of tumor cells from patients.

    Science.gov (United States)

    Nygren, P; Fridborg, H; Csoka, K; Sundström, C; de la Torre, M; Kristensen, J; Bergh, J; Hagberg, H; Glimelius, B; Rastad, J

    1994-03-01

    The semi-automated fluorometric microculture cytotoxicity assay (FMCA), based on the measurement of fluorescence generated from cellular hydrolysis of fluorescein diacetate (FDA) by viable cells, was employed for cytotoxic drug sensitivity testing of tumor cells from patients with hematological or solid tumors. In total, 390 samples from 20 diagnoses were tested with up to 12 standard cytotoxic drugs. The technical success rate for different tumor types ranged from 67 to 95%. Fluorescence was linearly related to cell number but variably steep depending on tumor type. Samples from most solid tumors thus showed higher signal-to-noise ratios than hematological samples. A wide spectrum of in vitro drug activity was obtained, with acute leukemias and non-Hodgkin's lymphomas being sensitive to almost all tested drugs, whereas renal and adrenocortical carcinomas were essentially totally resistant. Between these extremes were samples of breast and ovarian carcinomas and sarcomas. When in vitro response was compared with known clinical response patterns, a good correspondence was observed. The results indicate that the FMCA is a rapid and efficient method for in vitro measurement of tumor-specific drug activity both in hematological and in solid tumors. The assay may be suitable for new drug development and direction of phase-2 trials to suitable patients.

  18. Targeting of VX2 Rabbit Liver Tumor by Selective Delivery of 3-Bromopyruvate: A Biodistribution and Survival Study

    Science.gov (United States)

    Vali, Mustafa; Vossen, Josephina A.; Buijs, Manon; Engles, James M.; Liapi, Eleni; Ventura, Veronica Prieto; Khwaja, Afsheen; Acha-Ngwodo, Obele; Shanmugasundaram, Ganapathy; Syed, Labiq; Wahl, Richard L.; Geschwind, Jean-Francois H.

    2009-01-01

    The aim of this study was to determine the biodistribution and tumor targeting ability of 14C-labeled 3-bromopyruvate ([14C]3-BrPA) after i.a. and i.v. delivery in the VX2 rabbit model. In addition, we evaluated the effects of [14C]3-BrPA on tumor and healthy tissue glucose metabolism by determining 18F-deoxyglucose (FDG) uptake. Last, we determined the survival benefit of i.a. administered 3-BrPA. In total, 60 rabbits with VX2 liver tumor received either 1.75 mM [14C]3-BrPA i.a., 1.75 mM [14C]3-BrPA i.v., 20 mM [14C]3-BrPA i.v., or 25 ml of phosphate-buffered saline (PBS). All rabbits (with the exception of the 20 mM i.v. group) received FDG 1 h before sacrifice. Next, we compared survival of animals treated with i.a. administered 1.75 mM [14C]3-BrPA in 25 ml of PBS (n = 22) with controls (n = 10). After i.a. infusion, tumor uptake of [14C]3-BrPA was 1.8 ± 0.2% percentage of injected dose per gram of tissue (%ID/g), whereas other tissues showed minimal uptake. After i.v. infusion (1.75 mM), tumor uptake of [14C]3-BrPA was 0.03 ± 0.01% ID/g. After i.a. administration of [14C]3-BrPA, tumor uptake of FDG was 26 times lower than in controls. After i.v. administration of [14C]3-BrPA, there was no significant difference in tumor FDG uptake. Survival analysis showed that rabbits treated with 1.75 mM 3-BrPA survived longer (55 days) than controls (18.6 days). Intra-arterially delivered 3-BrPA has a favorable biodistribution profile, combining a high tumor uptake resulting in blockage of FDG uptake with no effects on healthy tissue. The local control of the liver tumor by 3-BrPA resulted in a significant survival benefit. PMID:18591216

  19. Percutaneous radiofrequency ablation for a recurrent metastasis after resection of liver metastases from an ileal clear-cell sarcoma: Long-term local tumor control.

    Science.gov (United States)

    Seo, Jung Wook

    2017-12-01

    Clear-cell sarcomas (CCSs) in the gastrointestinal tract are extremely rare and aggressive tumors. We present the first case of a CCS arising in the ileum and metastasizing to the liver; our patient was a 60-year-old man. After the resection of the CCS and the liver metastases, a new liver metastasis developed, which was treated via percutaneous radiofrequency ablation only. At the 5-year follow-up, the ablated region was stable without local tumor progression. Percutaneous radiofrequency ablation is a viable local treatment option for recurrent metastases from an ileal CCS if they are detected when small and at an early stage in follow-up studies.

  20. Docetaxel (DTX)-loaded polydopamine-modified TPGS-PLA nanoparticles as a targeted drug delivery system for the treatment of liver cancer.

    Science.gov (United States)

    Zhu, Dunwan; Tao, Wei; Zhang, Hongling; Liu, Gan; Wang, Teng; Zhang, Linhua; Zeng, Xiaowei; Mei, Lin

    2016-01-01

    Polydopamine-based surface modification is a simple way to functionalize polymeric nanoparticle (NP) surfaces with ligands and/or additional polymeric layers. In this work, we developed DTX-loaded formulations using polydopamine-modified NPs synthesized using D-α-tocopherol polyethylene glycol 1000 succinate-poly(lactide) (pD-TPGS-PLA/NPs). To target liver cancer cells, galactosamine was conjugated on the prepared NPs (Gal-pD-TPGS-PLA/NPs) to enhance the delivery of DTX via ligand-mediated endocytosis. The size and morphology of pD-TPGS-PLA/NPs and Gal-pD-TPGS-PLA/NPs changed obviously compared with TPGS-PLA/NPs. In vitro studies showed that TPGS-PLA/NPs, pD-TPGS-PLA/NPs and Gal-pD-TPGS-PLA/NPs had similar release profiles of DTX. Both confocal laser scanning microscopy and flow cytometric results showed that coumarin 6-loaded Gal-pD-TPGS-PLA/NPs had the highest cellular uptake efficiency in liver cancer cell line HepG2. Moreover, DTX-loaded Gal-pD-TPGS-PLA/NPs inhibited the growth of HepG2 cells more potently than TPGS-PLA/NPs, pD-TPGS-PLA/NPs, and a clinically available DTX formulation (Taxotere®). The in vivo biodistribution experiments show that the Gal-pD-TPGS-PLA/NPs are specifically targeted to the tumor. Furthermore, the in vivo anti-tumor effects study showed that injecting DTX-loaded Gal-pD-TPGS-PLA/NPs reduced the tumor size most significantly on hepatoma-bearing nude mice. These results suggest that Gal-pD-TPGS-PLA/NPs prepared in the study specifically interacted with the hepatocellular carcinoma cells through ligand-receptor recognition and they may be used as a potentially eligible drug delivery system targeting liver cancers. Polydopamine-based surface modification is a simple way to functionalize polymeric nanoparticle surfaces with ligands and/or additional polymeric layers. In this work, we developed docetaxel (DTX)-loaded formulations using polydopamine-modified NPs synthesized from D-α-tocopherol polyethylene glycol 1000 succinate

  1. Unhealthy alcohol use, HIV infection and risk of liver fibrosis in drug users with hepatitis C.

    Directory of Open Access Journals (Sweden)

    Roberto Muga

    Full Text Available AIM: To analyze alcohol use, clinical data and laboratory parameters that may affect FIB-4, an index for measuring liver fibrosis, in HCV-monoinfected and HCV/HIV-coinfected drug users. PATIENTS AND METHODS: Patients admitted for substance abuse treatment between 1994 and 2006 were studied. Socio-demographic data, alcohol and drug use characteristics and clinical variables were obtained through hospital records. Blood samples for biochemistry, liver function tests, CD4 cell count, and serology of HIV and HCV infection were collected at admission. Multivariate linear regression was used to analyze the predictors of FIB-4 increase. RESULTS: A total of 472 (83% M, 17% F patients were eligible. The median age at admission was 31 years (Interquartile range (IQR 27-35 years, and the median duration of drug use was 10 years (IQR 5.5-15 years. Unhealthy drinking (>50 grams/day was reported in 32% of the patients. The FIB-4 scores were significantly greater in the HCV/HIV-coinfected patients (1.14, IQR 0.76-1.87 than in the HCV-monoinfected patients (0.75, IQR 0.56-1.11 (p<0.001. In the multivariate analysis, unhealthy drinking (p = 0.034, lower total cholesterol (p = 0.042, serum albumin (p<0.001, higher GGT (p<0.001 and a longer duration of addiction (p = 0.005 were independently associated with higher FIB-4 scores in the HCV-monoinfected drug users. The effect of unhealthy drinking on FIB-4 scores disappeared in the HCV/HIV-coinfected patients, whereas lower serum albumin (p<0.001, a lower CD4 cell count (p = 0.006, higher total bilirubin (p<0.001 and a longer drug addiction duration (p<0.001 were significantly associated with higher FIB-4 values. CONCLUSIONS: Unhealthy alcohol use in the HCV-monoinfected patients and HIV-related immunodeficiency in the HCV/HIV-coinfected patients are important risk factors associated with liver fibrosis in the respective populations.

  2. Cushing syndrome as presenting symptom of calcifying nested stromal-epithelial tumor of the liver in an adolescent boy: a case report

    NARCIS (Netherlands)

    Weeda, V. B.; de Reuver, Ph R.; Bras, H.; Zsíros, J.; Lamers, W. H.; Aronson, D. C.

    2016-01-01

    Ectopic adrenocorticotropic hormone-producing primary liver tumors are rare, especially in children. We report the case of an adolescent boy of mixed Dutch and Moroccan descent with an adrenocorticotropic hormone-producing calcifying nested stromal-epithelial tumor with long-term follow-up. Thus

  3. Resveratrol-loaded glycyrrhizic acid-conjugated human serum albumin nanoparticles wrapping resveratrol nanoparticles: Preparation, characterization, and targeting effect on liver tumors.

    Science.gov (United States)

    Wu, Mingfang; Lian, Bolin; Deng, Yiping; Feng, Ziqi; Zhong, Chen; Wu, Weiwei; Huang, Yannian; Wang, Lingling; Zu, Chang; Zhao, Xiuhua

    2017-08-01

    In this study, glycyrrhizic acid-conjugated human serum albumin nanoparticles wrapping resveratrol nanoparticles were prepared to establish a tumor targeting nano-sized drug delivery system. Glycyrrhizic acid was coupled to human serum albumin, and resveratrol was encapsulated in glycyrrhizic acid-conjugated human serum albumin by high-pressure homogenization emulsification. The average particle size of sample nanoparticles prepared under the optimal conditions was 108.1 ± 5.3 nm with a polydispersity index (PDI) of 0.001, and the amount of glycyrrhizic acid coupled with human serum albumin was 112.56 µg/mg. The drug encapsulation efficiency and drug loading efficiency were 83.6 and 11.5%, respectively. The glycyrrhizic acid-conjugated human serum albumin nanoparticles wrapping resveratrol nanoparticles were characterized through laser light scattering, scanning electron microscopy, Fourier-transform infrared spectroscopy, X-ray diffraction, differential scanning calorimetry, thermogravimetric analyses, and gas chromatography. The characterization results showed that resveratrol in glycyrrhizic acid-conjugated human serum albumin nanoparticles wrapping resveratrol nanoparticles existed in amorphous state and the residual amounts of chloroform and methanol in nanoparticles were separately less than the international conference on harmonization (ICH) limit. The in vitro drug-release study showed that the nanoparticles released the drug slowly and continuously. The inhibitory rate of glycyrrhizic acid-conjugated human serum albumin nanoparticles wrapping resveratrol nanoparticles was measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2 H-tetrazolium bromide method. The IC50 values of glycyrrhizic acid-conjugated human serum albumin nanoparticles wrapping resveratrol nanoparticles and resveratrol were 62.5 and 95.5 µg/ml, respectively. The target ability of glycyrrhizic acid-conjugated human serum albumin nanoparticles wrapping resveratrol nanoparticles

  4. Leveraging Hypoxia-Activated Prodrugs to Prevent Drug Resistance in Solid Tumors.

    Directory of Open Access Journals (Sweden)

    Danika Lindsay

    2016-08-01

    Full Text Available Experimental studies have shown that one key factor in driving the emergence of drug resistance in solid tumors is tumor hypoxia, which leads to the formation of localized environmental niches where drug-resistant cell populations can evolve and survive. Hypoxia-activated prodrugs (HAPs are compounds designed to penetrate to hypoxic regions of a tumor and release cytotoxic or cytostatic agents; several of these HAPs are currently in clinical trial. However, preliminary results have not shown a survival benefit in several of these trials. We hypothesize that the efficacy of treatments involving these prodrugs depends heavily on identifying the correct treatment schedule, and that mathematical modeling can be used to help design potential therapeutic strategies combining HAPs with standard therapies to achieve long-term tumor control or eradication. We develop this framework in the specific context of EGFR-driven non-small cell lung cancer, which is commonly treated with the tyrosine kinase inhibitor erlotinib. We develop a stochastic mathematical model, parametrized using clinical and experimental data, to explore a spectrum of treatment regimens combining a HAP, evofosfamide, with erlotinib. We design combination toxicity constraint models and optimize treatment strategies over the space of tolerated schedules to identify specific combination schedules that lead to optimal tumor control. We find that (i combining these therapies delays resistance longer than any monotherapy schedule with either evofosfamide or erlotinib alone, (ii sequentially alternating single doses of each drug leads to minimal tumor burden and maximal reduction in probability of developing resistance, and (iii strategies minimizing the length of time after an evofosfamide dose and before erlotinib confer further benefits in reduction of tumor burden. These results provide insights into how hypoxia-activated prodrugs may be used to enhance therapeutic effectiveness in the

  5. In vitro microfluidic models of tumor microenvironment to screen transport of drugs and nanoparticles.

    Science.gov (United States)

    Ozcelikkale, Altug; Moon, Hye-Ran; Linnes, Michael; Han, Bumsoo

    2017-09-01

    Advances in nanotechnology have enabled numerous types of nanoparticles (NPs) to improve drug delivery to tumors. While many NP systems have been proposed, their clinical translation has been less than anticipated primarily due to failure of current preclinical evaluation techniques to adequately model the complex interactions between the NP and physiological barriers of tumor microenvironment. This review focuses on microfluidic tumor models for characterization of delivery efficacy and toxicity of cancer nanomedicine. Microfluidics offer significant advantages over traditional macroscale cell cultures by enabling recapitulation of tumor microenvironment through precise control of physiological cues such as hydrostatic pressure, shear stress, oxygen, and nutrient gradients. Microfluidic systems have recently started to be adapted for screening of drugs and NPs under physiologically relevant settings. So far the two primary application areas of microfluidics in this area have been high-throughput screening using traditional culture settings such as single cells or multicellular tumor spheroids, and mimicry of tumor microenvironment for study of cancer-related cell-cell and cell-matrix interactions. These microfluidic technologies are also useful in modeling specific steps in NP delivery to tumor and characterize NP transport properties and outcomes by systematic variation of physiological conditions. Ultimately, it will be possible to design drug-screening platforms uniquely tailored for individual patient physiology using microfluidics. These in vitro models can contribute to development of precision medicine by enabling rapid and patient-specific evaluation of cancer nanomedicine. WIREs Nanomed Nanobiotechnol 2017, 9:e1460. doi: 10.1002/wnan.1460 For further resources related to this article, please visit the WIREs website. © 2017 Wiley Periodicals, Inc.

  6. [111In-DTPA]octreotide tumor uptake in GEPNET liver metastases after intra-arterial administration: An overview of preclinical and clinical observations and implications for tumor radiation dose after peptide radionuclide therapy

    NARCIS (Netherlands)

    S.E. Pool (Stefan); B.L. Kam (Boen); G.A. Koning (Gerben); M. Konijnenberg (Mark); T.L.M. ten Hagen (Timo); W.A.P. Breeman (Woulter); E.P. Krenning (Eric); M. de Jong (Marcel); C.H.J. van Eijck (Casper)

    2014-01-01

    textabstractAims: With the aim to improve peptide receptor radionuclide therapy effects in patients with gastroenteropancreatic neuroendocrine tumor (GEPNET) liver metastases we explored the effect of intra-arterial (IA) administration of [111In-DTPA]octreotide (111In-DTPAOC) on tumor uptake in an

  7. Liver tumor formation by a mutant retinoblastoma protein in the transgenic mice is caused by an upregulation of c-Myc target genes

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Bo; Hikosaka, Keisuke; Sultana, Nishat; Sharkar, Mohammad Tofael Kabir [Department of Biochemistry, Hamamatsu University School of Medicine, 1-20-1 Handa-yama, Higashi-ku, Hamamatsu 431-3192 (Japan); Noritake, Hidenao [Department of Biochemistry, Hamamatsu University School of Medicine, 1-20-1 Handa-yama, Higashi-ku, Hamamatsu 431-3192 (Japan); Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handa-yama, Higashi-ku, Hamamatsu 431-3192 (Japan); Kimura, Wataru; Wu, Yi-Xin [Department of Biochemistry, Hamamatsu University School of Medicine, 1-20-1 Handa-yama, Higashi-ku, Hamamatsu 431-3192 (Japan); Kobayashi, Yoshimasa [Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handa-yama, Higashi-ku, Hamamatsu 431-3192 (Japan); Uezato, Tadayoshi [Department of Biochemistry, Hamamatsu University School of Medicine, 1-20-1 Handa-yama, Higashi-ku, Hamamatsu 431-3192 (Japan); Miura, Naoyuki, E-mail: nmiura@hama-med.ac.jp [Department of Biochemistry, Hamamatsu University School of Medicine, 1-20-1 Handa-yama, Higashi-ku, Hamamatsu 431-3192 (Japan)

    2012-01-06

    Highlights: Black-Right-Pointing-Pointer Fifty percent of the mutant Rb transgenic mice produced liver tumors. Black-Right-Pointing-Pointer In the tumor, Foxm1, Skp2, Bmi1 and AP-1 mRNAs were up-regulated. Black-Right-Pointing-Pointer No increase in expression of the Myc-target genes was observed in the non-tumorous liver. Black-Right-Pointing-Pointer Tumor formation depends on up-regulation of the Myc-target genes. -- Abstract: The retinoblastoma (Rb) tumor suppressor encodes a nuclear phosphoprotein that regulates cellular proliferation, apoptosis and differentiation. In order to adapt itself to these biological functions, Rb is subjected to modification cycle, phosphorylation and dephosphorylation. To directly determine the effect of phosphorylation-resistant Rb on liver development and function, we generated transgenic mice expressing phosphorylation-resistant human mutant Rb (mt-Rb) under the control of the rat hepatocyte nuclear factor-1 gene promoter/enhancer. Expression of mt-Rb in the liver resulted in macroscopic neoplastic nodules (adenomas) with {approx}50% incidence within 15 months old. Interestingly, quantitative reverse transcriptase-PCR analysis showed that c-Myc was up-regulated in the liver of mt-Rb transgenic mice irrespective of having tumor tissues or no tumor. In tumor tissues, several c-Myc target genes, Foxm1, c-Jun, c-Fos, Bmi1 and Skp2, were also up-regulated dramatically. We determined whether mt-Rb activated the Myc promoter in the HTP9 cells and demonstrated that mt-Rb acted as an inhibitor of wild-type Rb-induced repression on the Myc promoter. Our results suggest that continued upregulation of c-Myc target genes promotes the liver tumor formation after about 1 year of age.

  8. Delay equations modeling the effects of phase-specific drugs and immunotherapy on proliferating tumor cells.

    Science.gov (United States)

    Barbarossa, Maria Vittoria; Kuttler, Christina; Zinsl, Jonathan

    2012-04-01

    In this work we present a mathematical model for tumor growth based on the biology of the cell cycle. For an appropriate description of the effects of phase-specific drugs, it is necessary to look at the cell cycle and its phases. Our model reproduces the dynamics of three different tumor cell populations: quiescent cells, cells during the interphase and mitotic cells. Starting from a partial differential equations (PDEs) setting, a delay differential equations (DDE) model is derived for an easier and more realistic approach. Our equations also include interactions of tumor cells with immune system effectors. We investigate the model both from the analytical and the numerical point of view, give conditions for positivity of solutions and focus on the stability of the cancer-free equilibrium. Different immunotherapeutic strategies and their effects on the tumor growth are considered, as well.

  9. Non-alcoholic fatty liver disease (NAFLD) models in drug discovery.

    Science.gov (United States)

    Cole, Banumathi K; Feaver, Ryan E; Wamhoff, Brian R; Dash, Ajit

    2018-02-01

    The progressive disease spectrum of non-alcoholic fatty liver disease (NAFLD), which includes non-alcoholic steatohepatitis (NASH), is a rapidly emerging public health crisis with no approved therapy. The diversity of various therapies under development highlights the lack of consensus around the most effective target, underscoring the need for better translatable preclinical models to study the complex progressive disease and effective therapies. Areas covered: This article reviews published literature of various mouse models of NASH used in preclinical studies, as well as complex organotypic in vitro and ex vivo liver models being developed. It discusses translational challenges associa