Cardiotoxicity Associated with Trastuzumab Therapy in Taiwan: A Single Medical Center's 5-Year Experience

Directory of Open Access Journals (Sweden)

Che-Ming Chang

2015-06-01

Conclusions: Trastuzumab led to measurable decreases in LVEF (but only 2.7% was symptomatic heart failure and new mitral regurgitation. Therefore, regular follow-up with echocardiography is essential for early detection and prevention of trastuzumab-induced cardiomyopathy.

Trastuzumab-binding peptide display by Tobacco mosaic virus

International Nuclear Information System (INIS)

Frolova, Olga Y.; Petrunia, Igor V.; Komarova, Tatiana V.; Kosorukov, Vyacheslav S.; Sheval, Eugene V.; Gleba, Yuri Y.; Dorokhov, Yuri L.

2010-01-01

Human epidermal growth factor receptor-2 (HER2/neu) is a target for the humanized monoclonal antibody trastuzumab. Recently, trastuzumab-binding peptides (TBP) of HER2/neu that inhibit proliferation of breast cancer cells were identified. We have now studied conditions of efficient assembly in vivo of Tobacco mosaic virus (TMV)-based particles displaying TBP on its surface. The system is based on an Agrobacterium-mediated co-delivery of binary vectors encoding TMV RNA and coat protein (CP) with TBP in its C-terminal extension into plant leaves. We show how the fusion of amino acid substituted TBP (sTBP) to CP via a flexible peptide linker can improve the manufacturability of recombinant TMV (rTMV). We also reveal that rTMV particles with exposed sTBP retained trastuzumab-binding capacity but lost an anti-HER2/neu immunogenic scaffold function. Mouse antibodies against rTMV did not recognize HER2/neu on surface of human SK-BR-3 cells.

Cardiotoxicity and Cardiac Monitoring During Adjuvant Trastuzumab in Daily Dutch Practice: A Study of the Southeast Netherlands Breast Cancer Consortium

NARCIS (Netherlands)

Seferina, S.C.; Boer, M. de; Derksen, M.W.J.; Berkmortel, F. van den; Kampen, R.J. van; Wouw, A.J. van de; Joore, M.; Peer, P.G.M.; Voogd, A.C.; Tjan-Heijnen, V.C.

2016-01-01

INTRODUCTION: We assessed the incidence and timing of first cardiac events, impact on trastuzumab prescription, and role of left ventricular ejection fraction (LVEF) monitoring in daily practice of trastuzumab-treated patients with human epidermal growth receptor 2 (HER2)-positive early breast

Trastuzumab has preferential activity against breast cancers driven by HER2 homodimers

Science.gov (United States)

Ghosh, Ritwik; Narasanna, Archana; Wang, Shizhen Emily; Liu, Shuying; Chakrabarty, Anindita; Balko, Justin M.; González-Angulo, Ana María; Mills, Gordon B.; Penuel, Elicia; Winslow, John; Sperinde, Jeff; Dua, Rajiv; Pidaparthi, Sailaja; Mukherjee, Ali; Leitzel, Kim; Kostler, Wolfgang J.; Lipton, Allan; Bates, Michael; Arteaga, Carlos L.

2011-01-01

In breast cancer cells with HER2 gene amplification, HER2 receptors exist on the cell surface as monomers, homodimers and heterodimers with EGFR/HER3. The therapeutic antibody trastuzumab, an approved therapy for HER2+ breast cancer, cannot block ligand-induced HER2 heterodimers, suggesting it cannot effectively inhibit HER2 signaling. Hence, HER2 oligomeric states may predict the odds of a clinical response to trastuzumab in HER2-driven tumors. To test this hypothesis, we generated non-transformed human MCF10A mammary epithelial cells stably expressing a chimeric HER2-FKBP molecule that could be conditionally induced to homodimerize by adding the FKBP ligand AP1510, or instead induced to heterodimerize with EGFR or HER3 by adding the heterodimer ligands EGF/TGFα or heregulin. AP1510, EGF, and heregulin each induced growth of MCF10A cells expressing HER2-FKBP. As expected, trastuzumab inhibited homodimer-mediated but not heterodimer-mediated cell growth. In contrast, the HER2 antibody pertuzumab, which blocks HER2 heterodimerization, inhibited growth induced by heregulin but not AP1510. Lastly, HER2/EGFR tyrosine kinase inhibitor lapatinib blocked both homodimer- and heterodimer-induced growth. AP1510 triggered phosphorylation of Erk1/2 but not AKT, whereas trastuzumab inhibited AP1510-induced Erk1/2 phosphorylation and Shc-HER2 homodimer binding, but not TGFα-induced AKT phosphorylation. Consistent with these observations, high levels of HER2 homodimers correlated with longer time to progression following trastuzumab therapy in a cohort of HER2-overexpressing patients. Together, our findings corroborate the hypothesis that HER2 oligomeric states regulate HER2 signaling, also arguing that trastuzumab sensitivity of homodimers reflects an inability to activate the PI3K/AKT pathway. One of the most important clinical implications of our results is that high levels of HER2 homodimers may predict a positive response to trastuzumab. PMID:21324925

Trastuzumab emtansine: first global approval.

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Ballantyne, Anita; Dhillon, Sohita

2013-05-01

Genentech and ImmunoGen are collaborating on the development of trastuzumab emtansine, a HER2 antibody-drug conjugate that comprises Genentech's trastuzumab antibody linked to ImmunoGen's anti-mitotic agent, mertansine (a maytansine derivative; also known as DM1). The conjugate combines two strategies: the anti-HER2 activity of trastuzumab, and the targeted intracellular delivery of mertansine, a tubulin polymerisation inhibitor which interferes with mitosis and promotes apoptosis. The linker in trastuzumab emtansine is a non-reducible thioether linker, N-succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC, designated MCC after conjugation). Trastuzumab emtansine (Kadcyla™) has been launched in the USA as second-line monotherapy for HER2-positive metastatic breast cancer, and has been filed for approval in the EU and Japan in this indication. Trastuzumab emtansine is in phase III development as first-line combination therapy or monotherapy for metastatic HER2-positive breast cancer, and as third-line monotherapy for metastatic HER2-positive breast cancer. Phase II development is underway for early-stage breast cancer and phase II/III development is underway in patients with HER2-positive gastric cancer. This article summarizes the milestones in the development of trastuzumab emtansine leading to this first approval for the treatment of patients with HER2-positive, metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination.

In-111-Trastuzumab Scintigraphy in HER2-Positive Metastatic Breast Cancer Patients Remains Feasible during Trastuzumab Treatment

NARCIS (Netherlands)

Gaykema, Sietske B. M.; de Jong, Johan R.; Perik, Patrick J.; Brouwers, Adrienne H.; Schroder, Carolien P.; Oude Munnink, Thijs H.; Bongaerts, Alphons H. H.; de Vries, Elisabeth G. E.; Lub-de Hooge, Marjolijn N.

Human epidermal growth factor receptor (HER)2 imaging with radiolabeled trastuzumab might support HER2-targeted therapy. It is, however, frequently questioned whether HER2 imaging is also possible during trastuzumab treatment as the receptor might be saturated. We studied the effect of trastuzumab

Trastuzumab Mediated T-Cell Response against HER-2/Neu Overexpressing Esophageal Adenocarcinoma Depends on Intact Antigen Processing Machinery

NARCIS (Netherlands)

Milano, F.; Guarriera, M.; Rygiel, A.M.; Krishnadath, K.K.

2010-01-01

BACKGROUND: Esophageal adenocarcinoma (EAC) is a highly aggressive disease with poor prognosis, which frequently exhibits HER-2 gene amplification. Trastuzumab, the humanized antibody against HER-2, has potent growth inhibitory effects on HER-2 overexpressing cancers. One effect of trastuzumab is

Cardiac dysfunction in the trastuzumab clinical trials experience.

Science.gov (United States)

Seidman, Andrew; Hudis, Clifford; Pierri, Mary Kathryn; Shak, Steven; Paton, Virginia; Ashby, Mark; Murphy, Maureen; Stewart, Stanford J; Keefe, Deborah

2002-03-01

This study sought to estimate cardiac dysfunction (CD) risk for patients receiving trastuzumab; to characterize observed CD by severity, treatment, and clinical outcome; to assess effects of baseline clinical risk factors on CD; and to assess effects of cumulative doses of anthracyclines and trastuzumab on CD. A retrospective review of records for patients enrolled onto any of seven phase II and III trastuzumab clinical trials was performed. Predefined criteria were used for the diagnosis, and the New York Heart Association functional classification system was used to document CD severity. Product-limit estimates were used to summarize the cumulative anthracycline and trastuzumab doses at the time of CD onset. Patients treated with trastuzumab were found to be at an increased risk for CD. The incidence was greatest in patients receiving concomitant trastuzumab and anthracycline plus cyclophosphamide (27%). The risk was substantially lower in patients receiving paclitaxel and trastuzumab (13%) or trastuzumab alone (3% to 7%); however, most of these patients had received prior anthracycline therapy. CD was noted in 8% of patients receiving anthracycline plus cyclophosphamide and 1% receiving paclitaxel alone. Most trastuzumab-treated patients developing CD were symptomatic (75%), and most improved with standard treatment for congestive heart failure (79%). Trastuzumab is associated with an increased risk of CD, which is greatest in patients receiving concurrent anthracyclines. In most patients with metastatic breast cancer, the risk of CD can be justified given the improvement in overall survival previously reported with trastuzumab.

Trastuzumab in early stage breast cancer: a cost-effectiveness analysis for Belgium.

Science.gov (United States)

Neyt, Mattias; Huybrechts, Michel; Hulstaert, Frank; Vrijens, France; Ramaekers, Dirk

2008-08-01

Although trastuzumab is traditionally used in metastatic breast cancer treatment, studies reported on the efficacy and safety of trastuzumab in adjuvant setting for the treatment of early stage breast cancer in HER2+ tumors. We estimated the cost-effectiveness and budget impact of reimbursing trastuzumab in this indication from a payer's perspective. We constructed a health economic model. Long-term consequences of preventing patients to progress to metastatic breast cancer and side effects such as congestive heart failure were taken into account. Uncertainty was handled applying probabilistic modeling and through probabilistic sensitivity analyses. In the HERA scenario, applying an arbitrary threshold of euro30000 per life-year gained, early stage breast cancer treatment with trastuzumab is cost-effective for 9 out of 15 analyzed subgroups (according to age and stage). In contrast, treatment according to the FinHer scenario is cost-effective in 14 subgroups. Furthermore, the FinHer regimen is most of the times cost saving with an average incremental cost of euro668, euro-1045, and euro-6869 for respectively stages I, II and III breast cancer patients whereas the HERA regimen is never cost saving due to the higher initial treatment costs. The model shows better cost-effectiveness for the 9-week initial treatment (FinHer) compared to no trastuzumab treatment than for the 1-year post-chemotherapy treatment (HERA). Both from a medical and an economic point of view, the 9-week initial treatment regimen with trastuzumab shows promising results and justifies the initiation of a large comparative trial with a 1-year regimen.

Trastuzumab Benefits Women with Locally Advanced or Inflammatory

Science.gov (United States)

Women treated with trastuzumab (Herceptin) and chemotherapy before surgery and trastuzumab again after surgery had a reduced risk of the disease recurring or progressing compared with women who received pre-surgical chemotherapy but no trastuzumab, accord

Trastuzumab re-treatment following adjuvant trastuzumab and the importance of distant disease-free interval: the HERA trial experience.

Science.gov (United States)

Metzger-Filho, Otto; de Azambuja, Evandro; Procter, Marion; Krieguer, Magalie; Smith, Ian; Baselga, Jose; Cameron, David; Untch, Michael; Jackisch, Christian; Bell, Richard; Gianni, Luca; Goldhirsch, Aron; Piccart, Martine; Gelber, Richard D

2016-01-01

This retrospective analysis conducted using data from patients enrolled onto the Herceptin Adjuvant has two objectives: The first is to evaluate the impact of the time interval between the end of adjuvant trastuzumab and distant recurrence (TDRI) upon overall survival (OS). The second is to describe the duration of trastuzumab-based regimens in the metastatic setting for patients previously treated with adjuvant trastuzumab. The first objective included 187 patients treated with adjuvant trastuzumab and diagnosed with distant recurrence at 4-year median follow-up. The second objective included data from questionnaires sent to investigators retreating patients with trastuzumab upon distant recurrence: 144 of 156 questionnaires were returned (93 %), and 90 patients were selected based on available clinical information and consent for subsequent studies. There was no statistically significant relationship between TDRI following 1 year of adjuvant trastuzumab and OS from distant recurrence: hazard ratio 0.991, p = 0.46. The median OS from distant recurrence was numerically longer among patients with a TDRI of ≥12 months (n = 103) than information beyond disease progression should be included in future clinical studies.

Switching between intravenous and subcutaneous trastuzumab

DEFF Research Database (Denmark)

Gligorov, Joseph; Curigliano, Giuseppe; Müller, Volkmar

2017-01-01

AIM: To assess the safety and tolerability of switching between subcutaneous (SC) and intravenous (IV) trastuzumab in the PrefHer study (NCT01401166). PATIENTS AND METHODS: Patients with HER2-positive early breast cancer completed (neo)adjuvant chemotherapy and were randomised to receive four...... cycles of SC trastuzumab, via single-use injection device (SID; Cohort 1) or hand-held syringe (Cohort 2), followed by four cycles of IV, or vice versa (the crossover period presented here) as part of their 18 standard cycles of adjuvant trastuzumab treatment. Adverse events (AEs) were reported using....... Rates of clinically important events, including grade ≥3 AEs, serious AEs, AEs leading to study drug discontinuation and cardiac AEs, were low and similar between treatment arms (trastuzumab were observed. CONCLUSIONS: PrefHer revealed...

Biodistribution of 212Pb Conjugated Trastuzumab in Mice

International Nuclear Information System (INIS)

Schneider, N.; Lobaugh, M.; Sandwall, P.; Glover, S.; Murry, M.; Dong, Z.; Spitz, H.

2014-01-01

Clinical use of radiolabeled monoclonal antibodies in therapeutic treatment of cancer is increasing. This study demonstrates an increased uptake rate in the tumor over a 72 hr period of observation following a single intravenous injection of 212Pb-trastuzumab in mice. Whereas 212Pb-trastuzumab appeared not to cause systemic toxicity4, there may be concomitant uptake in other organs that should be considered in evaluating the risk of radiation toxicity associated with therapy. Additional laboratory and clinical study with 212Pb-trastuzumab should be conducted to define an optimized therapeutic strategy and determine the radiation doses delivered to non-targeted organs and tissues using microdosimetry methods. Results of this biodistribution study support further investigation of radiolabeled 212Pb-TCMC-trastuzumab, radiobiological organ microdosimetry, and optimal dosing regimens for 212Pb-trastuzumab as a therapeutic agent

Trastuzumab: designer drug or fashionable fad?

Science.gov (United States)

Freebairn, A J; Last, A J; Illidg, T M

2001-01-01

Trastuzumab (Herceptin) is the first monoclonal antibody to be approved for the treatment of a solid tumour and is directed against the c-erb-B2 receptor. c-erb-B2 is a member of the epidermal growth factor family and approximately 25% of breast cancers express such receptors, which appear to confer a poorer prognosis and may be an indicator of resistance to cytotoxic chemotherapy. This review assesses the mechanisms of action of trastuzumab, discusses the measurement of the HER-2/neu gene and its products, and describes the preclinical and clinical studies that have been instrumental to date in the emergence of trastuzumab in clinical practice.

Integrating molecular mechanisms and clinical evidence in the management of trastuzumab resistant or refractory HER-2⁺ metastatic breast cancer.

Science.gov (United States)

Wong, Hilda; Leung, Roland; Kwong, Ava; Chiu, Joanne; Liang, Raymond; Swanton, Charles; Yau, Thomas

2011-01-01

Human epidermal growth factor receptor (HER)-2(+) breast cancer is a distinct molecular and clinical entity, the prognosis of which is improved by trastuzumab. However, primary resistance to trastuzumab is observed in >50% of patients with HER-2(+) advanced breast cancer, and the majority of patients who initially respond to treatment eventually develop disease progression. To facilitate crosstrial comparisons and the understanding of resistance mechanisms, we propose a unifying definition of trastuzumab resistance as progression at first radiological reassessment at 8-12 weeks or within 3 months after first-line trastuzumab in the metastatic setting or new recurrences diagnosed during or within 12 months after adjuvant trastuzumab. In contrast, we define trastuzumab-refractory breast cancer as disease progression after two or more lines of trastuzumab-containing regimens that initially achieved disease response or stabilization at first radiological assessment. We review mechanisms of trastuzumab resistance mediated by p95HER-2 overexpression, phosphoinositide 3-kinase pathway activation, and signaling pathway activation driven by HER-3, epidermal growth factor receptor, and insulin-like growth factor 1 receptor. We distinguish in vitro from in vivo evidence, highlighting that most data describing trastuzumab resistance are derived from preclinical studies or small retrospective patient cohorts, and discuss targeted therapeutic approaches to overcome resistance. Prospective analysis through clinical trials with robust tissue collection procedures, prior to and following acquisition of resistance, integrated with next-generation tumor genome sequencing technologies, is identified as a priority area for development. The identification of predictive biomarkers is of paramount importance to optimize health economic costs and enhance stratification of anti-HER-2 targeted therapies.

Preclinical characterisation of In-111-DTPA-trastuzumab

NARCIS (Netherlands)

Lub-de Hooge, MN; Kosterink, JGW; Perik, PJ; Nijnuis, H; Tran, L; Bart, J; Suurmeijer, AJH; de Jong, S; Jager, PL; de Vries, EGE

Trastuzumab (Herceptin(R)) is a recombinant humanised IgG1 monoclonal antibody against the human epidermal growth factor receptor 2 (HER2), used for metastatic breast cancer treatment. Radiolabelled trastuzumab may have several future applications for diagnostic use. The aim of the present study was

Radiation recall dermatitis induced by trastuzumab

Directory of Open Access Journals (Sweden)

Emre Kaynak

2014-12-01

Full Text Available Radiation recall phenomenon is an acute, egzematous reaction that develops throughout a previously irradiated area, precipitated by the administration of docetaxel, doxorubicin, gemcitabine and paclitaxel. We report a 52-year-old woman with breast cancer who received locoregional radiotherapy followed by trastuzumab monotherapy. Three day after the first cycle of trastuzumab monotherapy, dermatitis developed in the previously irradiated skin.

Trastuzumab-induced pulmonaryfibrosis: A case report and review of literature

OpenAIRE

Tamojit Chaudhuri; Saurabh Karmakar

2012-01-01

Optimal treatment for human epidermal growth factor receptor 2 (HER2)/neu-positive, node-positive early breast cancer should include the monoclonal antibody trastuzumab. This relatively new targeted agent has shown very limited pulmonary toxicity. We report a case of Trastuzumab-induced pulmonary fibrosis in a 41-year-old female that occurred 4 months after starting adjuvant trastuzumab. To the best of our knowledge, this is the first ever report of trastuzumab-induced pulmonary fibrosis in t...

Associations between the uptake of {sup 111}In-DTPA-trastuzumab, HER2 density and response to trastuzumab (Herceptin) in athymic mice bearing subcutaneous human tumour xenografts

Energy Technology Data Exchange (ETDEWEB)

McLarty, Kristin; Cornelissen, Bart; Scollard, Deborah A. [University of Toronto, Department of Pharmaceutical Sciences, Toronto, ON (Canada); Done, Susan J. [University of Toronto, Department of Medical Biophysics, Toronto, ON (Canada)]|[University of Toronto, Department of Laboratory Medicine and Pathobiology, Toronto, ON (Canada)]|[University Health Network, Department of Pathology, Toronto, ON (Canada); Chun, Kathy [North York General Hospital, Genetics Program, Toronto, ON (Canada); Reilly, Raymond M. [University of Toronto, Department of Pharmaceutical Sciences, Toronto, ON (Canada)]|[University of Toronto, Department of Medical Imaging, Toronto, ON (Canada)]|[University Health Network, Toronto General Research Institute, Toronto, ON (Canada)]|[University of Toronto, Leslie Dan Faculty of Pharmacy, Toronto, ON (Canada)

2009-01-15

The purpose of the study was to investigate the associations between uptake of {sup 111}In-DTPA-trastuzumab, tumour HER2 density and response to trastuzumab (Herceptin) of human breast cancer (BC) xenografts in athymic mice. The tumour uptake of {sup 111}In-DTPA-trastuzumab in athymic mice bearing BC xenografts with increasing HER2 density (0 to 3+) was evaluated. Specific uptake ratios were established in biodistribution (SUR) and imaging studies (ROI-SUR) using {sup 111}In-labeled mouse IgG ({sup 111}In-DTPA-mIgG). Further corrections were made for circulating radioactivity using tumour-to-blood ratios defined as a localization index (LI) and region-of-interest localization index (ROI-LI), respectively. Mice were treated with trastuzumab (Herceptin). A tumour growth inhibition index (TGI) was calculated and relative TGIs calculated by dividing the TGI of control by that of trastuzumab-treated mice. Strong, nonlinear associations with HER2 density were obtained if the uptake of {sup 111}In-DTPA-trastuzumab was corrected for nonspecific IgG localization (i.e., SUR; r{sup 2}=0.99) and circulating radioactivity (i.e., LI; r{sup 2} =0.87), but without these corrections, the association between HER2 density and tumour uptake was poor (r{sup 2}=0.22). There was a strong association between ROI-SUR and ROI-LI values and HER2 expression (r{sup 2}=0.90 and r{sup 2}=0.95), respectively. All tumours were imaged. Relative TGI values were associated with increasing uncorrected tumour uptake of {sup 111}In-DTPA-trastuzumab but not always with HER2 density (i.e., MCF-HER2-18 cells with trastuzumab-resistance). HER2 expression (0 to 3+) can be differentiated using {sup 111}In-DTPA-trastuzumab, but requires correction of tumour uptake for nonspecific IgG localization and circulating radioactivity. The uncorrected uptake of {sup 111}In-DTPA-trastuzumab was associated with tumour response to trastuzumab. (orig.)

TNFα-Induced Mucin 4 Expression Elicits Trastuzumab Resistance in HER2-Positive Breast Cancer.

Science.gov (United States)

Mercogliano, María F; De Martino, Mara; Venturutti, Leandro; Rivas, Martín A; Proietti, Cecilia J; Inurrigarro, Gloria; Frahm, Isabel; Allemand, Daniel H; Deza, Ernesto Gil; Ares, Sandra; Gercovich, Felipe G; Guzmán, Pablo; Roa, Juan C; Elizalde, Patricia V; Schillaci, Roxana

2017-02-01

Although trastuzumab administration improved the outcome of HER2-positive breast cancer patients, resistance events hamper its clinical benefits. We demonstrated that TNFα stimulation in vitro induces trastuzumab resistance in HER2-positive breast cancer cell lines. Here, we explored the mechanism of TNFα-induced trastuzumab resistance and the therapeutic strategies to overcome it. Trastuzumab-sensitive breast cancer cells, genetically engineered to stably overexpress TNFα, and de novo trastuzumab-resistant tumors, were used to evaluate trastuzumab response and TNFα-blocking antibodies effectiveness respectively. Immunohistochemistry and antibody-dependent cell cytotoxicity (ADCC), together with siRNA strategy, were used to explore TNFα influence on the expression and function of its downstream target, mucin 4 (MUC4). The clinical relevance of MUC4 expression was studied in a cohort of 78 HER2-positive breast cancer patients treated with adjuvant trastuzumab. TNFα overexpression turned trastuzumab-sensitive cells and tumors into resistant ones. Histopathologic findings revealed mucin foci in TNFα-producing tumors. TNFα induced upregulation of MUC4 that reduced trastuzumab binding to its epitope and impaired ADCC. Silencing MUC4 enhanced trastuzumab binding, increased ADCC, and overcame trastuzumab and trastuzumab-emtansine antiproliferative effects in TNFα-overexpressing cells. Accordingly, administration of TNFα-blocking antibodies downregulated MUC4 and sensitized de novo trastuzumab-resistant breast cancer cells and tumors to trastuzumab. In HER2-positive breast cancer samples, MUC4 expression was found to be an independent predictor of poor disease-free survival (P = 0.008). We identified TNFα-induced MUC4 expression as a novel trastuzumab resistance mechanism. We propose MUC4 expression as a predictive biomarker of trastuzumab efficacy and a guide to combination therapy of TNFα-blocking antibodies with trastuzumab. Clin Cancer Res; 23(3); 636-48. �

ABP 980: promising trastuzumab biosimilar for HER2-positive breast cancer.

Science.gov (United States)

Paplomata, Elisavet; Nahta, Rita

2018-03-01

Approval of the HER2-targeted antibody trastuzumab dramatically improved outcomes for patients with HER2-positive breast cancer. Multiple trastuzumab biosimilars, including ABP 980, are in clinical development. Biosimilars are not identical to the reference biologic, but exhibit equivalence and safety in analytical and clinical studies. Areas covered: A brief introduction to trastuzumab, overview of trastuzumab biosimilars, and detailed review of ABP 980 preclinical and clinical studies are included. We searched PubMed and 2016-2017 ASCO and ESMO conference proceedings for 'ABP 980' or 'trastuzumab biosimilar'. 'ABP 980 and breast cancer' or 'trastuzumab biosimilar and breast cancer' were used to search clinicaltrials.gov for phase III trials. Analytical studies of ABP 980 pharmacokinetics (PK) or pharmacodynamics (PD), phase I studies of ABP 980 safety and PK/PD, and phase III studies of clinical efficacy vs trastuzumab are included. Expert opinion: Questions remain regarding long-term impact of biosimilars on overall healthcare costs, insurance coverage of multiple approved biosimilars, and extensive clinical safety and efficacy follow-up. By producing a competitive market, trastuzumab biosimilars are anticipated to improve access to standard of care therapies, although real-world evidence remains to be obtained. Increased global access to HER2-targeted therapy may eventually alter the landscape of breast cancer and survival rates.

IGF-1R and ErbB3/HER3 contribute to enhanced proliferation and carcinogenesis in trastuzumab-resistant ovarian cancer model

International Nuclear Information System (INIS)

Jia, Yanhan; Zhang, Yan; Qiao, Chunxia; Liu, Guijun; Zhao, Qing; Zhou, Tingting; Chen, Guojiang; Li, Yali; Feng, Jiannan; Li, Yan; Zhang, Qiuping; Peng, Hui

2013-01-01

Highlights: •We established trastuzumab-resistant cell line SKOV3/T. •SKOV3/T enhances proliferation and in vivo carcinogenesis. •IGF-1R and HER3 genes were up-regulated in SKOV3/T based on microarray analysis. •Targeting IGF-1R and/or HER3 inhibited the proliferation of SKOV3/T. •Therapies targeting IGF-1R and HER3 might be effective in ovarian cancer. -- Abstract: Trastuzumab (Herceptin®) has demonstrated clinical potential in several types of HER2-overexpressing human cancers. However, primary and acquired resistance occurs in many HER2-positive patients with regimens. To investigate the possible mechanism of acquired therapeutic resistance to trastuzumab, we have developed a preclinical model of human ovarian cancer cells, SKOV3/T, with the distinctive feature of stronger carcinogenesis. The differences in gene expression between parental and the resistant cells were explored by microarray analysis, of which IGF-1R and HER3 were detected to be key molecules in action. Their correctness was validated by follow-up experiments of RT-PCR, shRNA-mediated knockdown, downstream signal activation, cell cycle distribution and survival. These results suggest that IGF-1R and HER3 differentially regulate trastuzumab resistance and could be promising targets for trastuzumab therapy in ovarian cancer

IGF-1R and ErbB3/HER3 contribute to enhanced proliferation and carcinogenesis in trastuzumab-resistant ovarian cancer model

Energy Technology Data Exchange (ETDEWEB)

Jia, Yanhan [Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei 430071 (China); Department of Immunology, Institute of Basic Medical Sciences, Beijing 100850 (China); Zhang, Yan [Department of Gynaecology and Obstetrics, PLA General Hospital, Beijing 100853 (China); Qiao, Chunxia; Liu, Guijun [Department of Immunology, Institute of Basic Medical Sciences, Beijing 100850 (China); Zhao, Qing [Department of Immunology, Institute of Basic Medical Sciences, Beijing 100850 (China); Department of Gynaecology and Obstetrics, PLA General Hospital, Beijing 100853 (China); Zhou, Tingting; Chen, Guojiang [Department of Immunology, Institute of Basic Medical Sciences, Beijing 100850 (China); Li, Yali [Department of Gynaecology and Obstetrics, PLA General Hospital, Beijing 100853 (China); Feng, Jiannan; Li, Yan [Department of Immunology, Institute of Basic Medical Sciences, Beijing 100850 (China); Zhang, Qiuping, E-mail: qpzhang@whu.edu.cn [Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei 430071 (China); Peng, Hui, E-mail: p_h2002@hotmail.com [Department of Immunology, Institute of Basic Medical Sciences, Beijing 100850 (China); Cardiovascular Drug Research Center, Institute of Health and Environmental Medicine, Beijing 100850 (China)

2013-07-12

Highlights: •We established trastuzumab-resistant cell line SKOV3/T. •SKOV3/T enhances proliferation and in vivo carcinogenesis. •IGF-1R and HER3 genes were up-regulated in SKOV3/T based on microarray analysis. •Targeting IGF-1R and/or HER3 inhibited the proliferation of SKOV3/T. •Therapies targeting IGF-1R and HER3 might be effective in ovarian cancer. -- Abstract: Trastuzumab (Herceptin®) has demonstrated clinical potential in several types of HER2-overexpressing human cancers. However, primary and acquired resistance occurs in many HER2-positive patients with regimens. To investigate the possible mechanism of acquired therapeutic resistance to trastuzumab, we have developed a preclinical model of human ovarian cancer cells, SKOV3/T, with the distinctive feature of stronger carcinogenesis. The differences in gene expression between parental and the resistant cells were explored by microarray analysis, of which IGF-1R and HER3 were detected to be key molecules in action. Their correctness was validated by follow-up experiments of RT-PCR, shRNA-mediated knockdown, downstream signal activation, cell cycle distribution and survival. These results suggest that IGF-1R and HER3 differentially regulate trastuzumab resistance and could be promising targets for trastuzumab therapy in ovarian cancer.

Gene expression profiling upon 212Pb-TCMC-trastuzumab treatment in the LS-174T i.p. xenograft model

International Nuclear Information System (INIS)

Yong, Kwon J; Milenic, Diane E; Baidoo, Kwamena E; Kim, Young-Seung; Brechbiel, Martin W

2013-01-01

Recent studies have demonstrated that therapy with 212 Pb-TCMC-trastuzumab resulted in (1) induction of apoptosis, (2) G2/M arrest, and (3) blockage of double-strand DNA damage repair in LS-174T i.p. (intraperitoneal) xenografts. To further understand the molecular basis of the cell killing efficacy of 212 Pb-TCMC-trastuzumab, gene expression profiling was performed with LS-174T xenografts 24 h after exposure to 212 Pb-TCMC-trastuzumab. DNA damage response genes (84) were screened using a quantitative real-time polymerase chain reaction array (qRT-PCR array). Differentially regulated genes were identified following exposure to 212 Pb-TCMC-trastuzumab. These included genes involved in apoptosis (ABL, GADD45α, GADD45γ, PCBP4, and p73), cell cycle (ATM, DDIT3, GADD45α, GTSE1, MKK6, PCBP4, and SESN1), and damaged DNA binding (DDB) and repair (ATM and BTG2). The stressful growth arrest conditions provoked by 212 Pb-TCMC-trastuzumab were found to induce genes involved in apoptosis and cell cycle arrest in the G2/M phase. The expression of genes involved in DDB and single-strand DNA breaks was also enhanced by 212 Pb-TCMC-trastuzumab while no modulation of genes involved in double-strand break repair was apparent. Furthermore, the p73/GADD45 signaling pathway mediated by p38 kinase signaling may be involved in the cellular response, as evidenced by the enhanced expression of genes and proteins of this pathway. These results further support the previously described cell killing mechanism by 212 Pb-TCMC-trastuzumab in the same LS-174T i.p. xenograft. Insight into these mechanisms could lead to improved strategies for rational application of radioimmunotherapy using α-particle emitters. The apoptotic response and associated gene modulations have not been clearly defined following exposure of cells to α-particle radioimmunotherapy (RIT). Gene expression profiling was performed with LS-174T i.p. (intraperitoneal) xenografts after exposure to 212 Pb-TCMC-trastuzumab

The short-term safety of adjuvant paclitaxel plus trastuzumab - A single centre experience.

Science.gov (United States)

Ates, Ozturk; Sunar, Veli; Aslan, Alma; Karatas, Fatih; Sahin, Suleyman; Altundag, Kadri

2017-01-01

HER2-amplified breast cancer (BC) has a poor prognosis. The combination of trastuzumab with chemotherapy in the adjuvant setting decreases recurrence and improves overall survival in HER2-positive BC. However, the role of adjuvant treatment in patients with HER2-amplified small BC without lymph node involvement is still under debate. The purpose of this study was to investigate the safety of adjuvant paclitaxel and trastuzumab (APT) in this group of patients. A total of 87 operated early BC patients without lymph node involvement (N0) were treated with APT for 12 weeks followed by trastuzumab alone for a total of 9 months. Clinicopathological features and adverse events were analyzed. The median patient age was 50 years (range 28- 82), and 51% of them were postmenopausal. The median tumor diameter was 2.4 cm (range 0.5-6), with 51% of the patients having tumor size between 2 and 3 cm. Eighty-one percent of patients had invasive ductal carcinoma (IDC), and 64% had grade 3 tumors. Adjuvant hormone therapy and adjuvant radiotherapy were administered to 65 and 54% of patients, respectively. At a median follow up of 13 months (range 6-38), one patient (1.1%, 95% CI 0-3.4) experienced an asymptomatic decrease in left ventricular ejection fraction (LVEF) and 3 patients (3.4%, 95% CI 0-6.9) experienced grade 3 neuropathy. APT appears to be a safe combination in early-stage, HER2-amplified and node-negative BC.

Trastuzumab and survival of patients with metastatic breast cancer.

Science.gov (United States)

Kast, Karin; Schoffer, Olaf; Link, Theresa; Forberger, Almuth; Petzold, Andrea; Niedostatek, Antje; Werner, Carmen; Klug, Stefanie J; Werner, Andreas; Gatzweiler, Axel; Richter, Barbara; Baretton, Gustavo; Wimberger, Pauline

2017-08-01

Prognosis of Her2-positive breast cancer has changed since the introduction of trastuzumab for treatment in metastatic and early breast cancer. It was described to be even better compared to prognosis of Her2-negative metastatic breast cancer. The purpose of this study was to evaluate the effect of trastuzumab in our cohort. Besides the effect of adjuvant pretreatment with trastuzumab on survival of patients with metastatic Her2-positive breast cancer was analyzed. All patients with primary breast cancer of the Regional Breast Cancer Center Dresden diagnosed during the years 2001-2013 were analyzed for treatment with or without trastuzumab in the adjuvant and in the metastatic treatment setting using Kaplan-Meier survival estimation and Cox regression. Age and tumor stage at time of first diagnosis of breast cancer as well as hormone receptor status, grading, time, and site of metastasis at first diagnosis of distant metastatic disease were analyzed. Of 4.481 female patients with primary breast cancer, 643 presented with metastatic disease. Her2-positive status was documented in 465 patients, including 116 patients with primary or secondary metastases. Median survival of patients with Her2-positive primary metastatic disease was 3.0 years (95% CI 2.3-4.0). After adjustment for other factors, survival was better in patients with Her2-positive breast cancer with trastuzumab therapy compared to Her2-negative metastatic disease (HR 2.10; 95% CI 1.58-2.79). Analysis of influence of adjuvant therapy with and without trastuzumab by Kaplan-Meier showed a trend for better survival in not pretreated patients. Median survival was highest in hormone receptor-positive Her2-positive (triple-positive) primary metastatic breast cancer patients with 3.3 years (95% CI 2.3-4.6). Prognosis of patients with Her2-positive metastatic breast cancer after trastuzumab treatment is more favorable than for Her2-negative breast cancer. The role of adjuvant chemotherapy with or without

Neratinib overcomes trastuzumab resistance in HER2 amplified breast cancer.

OpenAIRE

Canonici, A; Gijsen, M; Mullooly, M; Bennett, R; Bouguern, N; Pedersen, K; O'Brien, NA; Roxanis, I; Li, J-L; Bridge, E; Finn, R; Siamon, D; McGowan, P; Duffy, MJ; O'Donovan, N

2013-01-01

Trastuzumab has been shown to improve the survival outcomes of HER2 positive breast cancer patients. However, a significant proportion of HER2-positive patients are either inherently resistant or develop resistance to trastuzumab. We assessed the effects of neratinib, an irreversible panHER inhibitor, in a panel of 36 breast cancer cell lines. We further assessed its effects with or without trastuzumab in several sensitive and resistant breast cancer cells as well as a BT474 xenograft model. ...

Incidence and identification of risk factors for trastuzumab-induced cardiotoxicity in breast cancer patients: an audit of a single "real-world" setting.

Science.gov (United States)

Tang, Grace H; Acuna, Sergio A; Sevick, Laura; Yan, Andrew T; Brezden-Masley, Christine

2017-09-01

Management of human epidermal growth factor receptor-2-positive (HER2+) breast cancer patients includes the combination of adjuvant chemotherapy and trastuzumab. A meta-analysis reported that risk factors associated with TIC among less selected patients. A retrospective cohort study was carried out in 160 HER2+ breast cancer patients who received adjuvant chemotherapy with trastuzumab from January 2006 to June 2014 at St. Michael's Hospital, Toronto, Canada. Patient demographics, cardiovascular history, and TIC were recorded. TIC was defined as symptomatic (heart failure) or asymptomatic [decline in left ventricular ejection fraction (LVEF) by ≥10% or LVEF ≤ 50%]. Of the 160 patients [median age 52 (IQR 45-60), 48.1% on anthracycline-based chemotherapy], 34 patients (21.3%) experienced TIC (median follow-up 55.4 months). The median time to development of TIC was 28.5 weeks during trastuzumab therapy. Those with TIC were more likely to have undergone a mastectomy (52.9 vs. 33.3%, p = 0.04). However, after adjusting for anthracycline-based chemotherapy, and radiotherapy, mastectomy was not independently associated with TIC (HR 2.02; 95% CI 0.88-4.63). The incidence of TIC is higher in our "real-world" population compared to clinical trial data. The median time to development of TIC was 28 weeks after trastuzumab initiation, approximately the 10th treatment of trastuzumab. Timely identification and management of patients is important to avoid irreversible cardiac toxicity and improve breast cancer survival.

Mediation designs for tobacco prevention research

Science.gov (United States)

MacKinnon, David P.; Taborga, Marcia P.; Morgan-Lopez, Antonio A.

2010-01-01

This paper describes research designs and statistical analyses to investigate how tobacco prevention programs achieve their effects on tobacco use. A theoretical approach to program development and evaluation useful for any prevention program guides the analysis. The theoretical approach focuses on action theory for how the program affects mediating variables and on conceptual theory for how mediating variables are related to tobacco use. Information on the mediating mechanisms by which tobacco prevention programs achieve effects is useful for the development of efficient programs and provides a test of the theoretical basis of prevention efforts. Examples of these potential mediating mechanisms are described including mediated effects through attitudes, social norms, beliefs about positive consequences, and accessibility to tobacco. Prior research provides evidence that changes in social norms are a critical mediating mechanism for successful tobacco prevention. Analysis of mediating variables in single group designs with multiple mediators are described as well as multiple group randomized designs which are the most likely to accurately uncover important mediating mechanisms. More complicated dismantling and constructive designs are described and illustrated based on current findings from tobacco research. Mediation analysis for categorical outcomes and more complicated statistical methods are outlined. PMID:12324176

First line chemotherapy plus trastuzumab in metastatic breast cancer ...

African Journals Online (AJOL)

First line chemotherapy plus trastuzumab in metastatic breast cancer HER2 positive - Observational institutional study. ... The progression free survival was estimated by the Kaplan-Meier method, from the date of first cycle to the date of progression or at the last consultation, and the median was 12.8 months. Trastuzumab ...

Synthesis and Preliminary Biological Evaluations of Fluorescent or 149Promethium Labeled Trastuzumab-Polyethylenimine

Directory of Open Access Journals (Sweden)

Jonathan Fitzsimmons

2015-12-01

Full Text Available Background: Radioimmunotherapy utilize a targeting antibody coupled to a therapeutic isotope to target and treat a tumor or disease. In this study we examine the synthesis and cell binding of a polymer scaffold containing a radiotherapeutic isotope and a targeting antibody. Methods: The multistep synthesis of a fluorescent or 149Promethium-labeled Trastuzumab-polyethyleneimine (PEI, Trastuzumab, or PEI is described. In vitro uptake, internalization and/or the binding affinity to the Her2/neu expressing human breast adenocarcinoma SKBr3 cells was investigated with the labeled compounds. Results: Fluorescent-labeled Trastuzumab-PEI was internalized more into cells at 2 and 18 h than fluorescent-labeled Trastuzumab or PEI. The fluorescent-labeled Trastuzumab was concentrated on the cell surface at 2 and 18 h and the labeled PEI had minimal uptake. DOTA-PEI was prepared and contained an average of 16 chelates per PEI; the compound was radio-labeled with 149Promethium and conjugated to Trastuzumab. The purified 149Pm-DOTA-PEI-Trastuzumab had a radiochemical purity of 96.7% and a specific activity of 0.118 TBq/g. The compound demonstrated a dissociation constant for the Her2/neu receptor of 20.30 ± 6.91 nM. Conclusion: The results indicate the DOTA-PEI-Trastuzumab compound has potential as a targeted therapeutic carrier, and future in vivo studies should be performed.

SAFE trial: an ongoing randomized clinical study to assess the role of cardiotoxicity prevention in breast cancer patients treated with anthracyclines with or without trastuzumab.

Science.gov (United States)

Meattini, Icro; Curigliano, Giuseppe; Terziani, Francesca; Becherini, Carlotta; Airoldi, Mario; Allegrini, Giacomo; Amoroso, Domenico; Barni, Sandro; Bengala, Carmelo; Guarneri, Valentina; Marchetti, Paolo; Martella, Francesca; Piovano, Pierluigi; Vannini, Agnese; Desideri, Isacco; Tarquini, Roberto; Galanti, Giorgio; Barletta, Giuseppe; Livi, Lorenzo

2017-05-01

Over the years, thanks to the addition of new generation systemic agents, as well as the use of more advanced and precise radiotherapy techniques, it was able to obtain a high curability rate for breast cancer. Anthracyclines play a key role in the treatment of breast disease, with a well-known benefit on disease-free survival of patients with positive nodal status. Trastuzumab have shown a significant outcome advantage after 1-year administration in case of HER2-positive disease. Unfortunately, significant increase in cardiotoxicity has been observed after anthracyclines and trastuzumab therapies. Even though the cardiology and oncology community strongly recommend a cardiotoxicity prevention strategy for this subset of patients, there is still no consensus on the optimal patient's approach. We aimed to review the published and ongoing researches on cardioprevention strategies and to present the SAFE trial (CT registry ID: NCT2236806; EudraCT number: 2015-000914-23). It is a randomized phase 3, four-arm, single-blind, placebo-controlled study that aims to evaluate the effect of bisoprolol, ramipril or both drugs, compared to placebo, on subclinical heart damage evaluated by speckle tracking cardiac ultrasound in non-metastatic breast cancer patients.

In vivo monitoring of intranuclear p27{sup kip1} protein expression in breast cancer cells during trastuzumab (Herceptin) therapy

Energy Technology Data Exchange (ETDEWEB)

Cornelissen, Bart [Division of Nuclear Medicine, University Health Network, Toronto, ON, Canada M5S 3E2 (Canada); Department of Pharmaceutical Sciences, University of Toronto, Toronto, ON, M5S 3M2 (Canada); MRC/CRUK Gray Institute for Radiation Oncology and Biology, Oxford University, OX3 7LJ Oxford (United Kingdom)], E-mail: bart.cornelissen@rob.ox.ac.uk; Kersemans, Veerle; McLarty, Kristin [Division of Nuclear Medicine, University Health Network, Toronto, ON, M5S 3E2 (Canada); Department of Pharmaceutical Sciences, University of Toronto, Toronto, ON, M5S 3M2 (Canada); Tran, Lara [Department of Pharmaceutical Sciences, University of Toronto, Toronto, ON, M5S 3M2 (Canada); Vallis, Katherine A. [MRC/CRUK Gray Institute for Radiation Oncology and Biology, Oxford University, OX3 7LJ Oxford (United Kingdom); Reilly, Raymond M. [Division of Nuclear Medicine, University Health Network, Toronto, ON, M5S 3E2 (Canada); Department of Medical Imaging, University of Toronto, Toronto, ON, M5S 3E2 (Canada); Department of Pharmaceutical Sciences, University of Toronto, Toronto, ON, M5S 3M2 (Canada)

2009-10-15

Introduction: Trastuzumab, a humanized antibody directed against the Her2 receptor, induces the expression of p27{sup kip1}, an intranuclear cyclin-dependent kinase inhibitor in some breast cancer cells. The aim of this study was to develop a radioimmunoconjugate (RIC) to monitor trastuzumab-induced p27{sup kip1} protein up-regulation in vivo. Materials and Methods: Anti-p27{sup kip1} IgG was purified, and conjugated to diethylenetriaminopentaacetate, to allow radiolabeling with {sup 111}In for in vivo detection. Then tat peptide (GRKKRRQRRRPPQGYG), containing a nuclear localization sequence (underlined), was conjugated to the Fc-domain of IgG, using NaIO{sub 4} oxidation of carbohydrates and the resulting Schiff base stabilized with NaCNBH{sub 3}. The conjugate was radiolabeled with {sup 111}In, yielding [{sup 111}In]-anti-p27{sup kip1}-tat. {sup 111}In labeling efficiency, purity and p27{sup kip1} binding were measured. Trastuzumab-induced p27{sup kip1} up-regulation was assessed in a panel of breast cancer cell lines by Western blot analysis. Uptake and retention of [{sup 111}In]-anti-p27{sup kip1}-tat were measured in MDA-MB-361 and SKBr3 cells after exposure to trastuzumab. Uptake of [{sup 111}In]-anti-p27{sup kip1}-tat was determined at 72 h postintravenous injection in MDA-MB-361 xenografts in athymic mice treated with trastuzumab or saline. Results: [{sup 111}In]-anti-p27{sup kip1}-tat was synthesized to 97% purity. The RIC was able to bind to p27{sup kip1} protein and internalized in the cells and was transported to the nuclei of MDA-MB-361 cells. The level of p27{sup kip1} protein in MDA-MB-361 cells was increased after exposure to clinically relevant doses of trastuzumab for 3 days. Trastuzumab-mediated induction of p27{sup kip1} was not associated with increased cellular uptake or nuclear localization of [{sup 111}In]-anti-p27{sup kip1}-tat (6.53{+-}0.61% vs. 6.98{+-}1.36% internalized into trastuzumab-treated vs. control cells, respectively). However

Budget Impact Analysis of Biosimilar Trastuzumab for the Treatment of Breast Cancer in Croatia.

Science.gov (United States)

Cesarec, August; Likić, Robert

2017-04-01

Breast cancer is the most common cancer in women and has considerable impact on healthcare budgets and patients' quality of life. Trastuzumab (Herceptin ® ) is a monoclonal antibody directed against the human epidermal growth factor receptor (HER2) for the treatment of breast cancer. Several trastuzumab biosimilars are currently in development. In 2015, trastuzumab was the drug with the highest financial consumption among all drugs in Croatia. This model estimates the 1-year budget impact of the introduction of biosimilar trastuzumab in Croatia. A budget impact model, based on approvals for trastuzumab treatment in 2015, was developed for the introduction of biosimilars. Two biosimilar scenarios were developed: biosimilar scenario 1, based on all approvals in 2015, and biosimilar scenario 2, based on approvals after February 2015 and the reimbursement of the subcutaneous formulation of trastuzumab in Croatia. Only trastuzumab-naïve patients and drug-acquisition costs were used in the model. Uptake of biosimilar was assumed at 50 %. Scenarios were calculated with price discounts of 15, 25 and 35 %. The robustness of the model was tested by extensive sensitivity analyses. The projected drug cost savings from the introduction of biosimilar trastuzumab range from €0.26 million (scenario 2, 15 % price discount) to €0.69 million (scenario 1, 35 % price discount). If budget savings were reinvested to treat additional patients with trastuzumab, 14 (scenario 2, 15 % price discount) to 47 (scenario 1, 35 % price discount) additional patients could be treated. Sensitivity analyses showed that the incidence of breast cancer had the highest impact on the model, with a 10 % decrease in incidence leading to an 11.3 % decrease in projected savings. The introduction of biosimilar trastuzumab could lead to significant drug cost savings in Croatia.

Maintenance Therapy with Trastuzumab in Her2 Positive Metastatic Parotid Ductal Adenocarcinoma

Directory of Open Access Journals (Sweden)

Muhammad Shahid Iqbal

2014-01-01

Full Text Available Salivary ductal carcinomas (SDCs are extremely rare and aggressive malignancies, accounting for approximately 6% of all salivary gland malignancies. One distinct feature is their resemblance to ductal carcinomas of breast. A significant percentage of SDCs overexpress Her2 and the use of targeted therapy with trastuzumab can be considered in these patients. We report a rare case of long term disease control with trastuzumab in Her2 positive metastatic parotid ductal carcinoma. Our case also highlights that isolated brain metastasis should be managed aggressively to allow optimal local control when systemic disease is under remission with trastuzumab. We have also reviewed the published literature on the use of trastuzumab in SDCs.

Tumor delivery of antisense oligomer using trastuzumab within a streptavidin nanoparticle

Energy Technology Data Exchange (ETDEWEB)

Wang, Yi [University of Massachusetts Medical School, Division of Nuclear Medicine, Department of Radiology, Worcester, MA (United States); Yale University, Yale PET Center, Department of Diagnostic Radiology, New Haven, CT (United States); Liu, Xinrong; Chen, Ling; Cheng, Dengfeng; Rusckowski, Mary [University of Massachusetts Medical School, Division of Nuclear Medicine, Department of Radiology, Worcester, MA (United States); Hnatowich, Donald J. [University of Massachusetts Medical School, Division of Nuclear Medicine, Department of Radiology, Worcester, MA (United States); Umass Medical School, Department of Radiology, Worcester, MA (United States)

2009-12-15

Trastuzumab (Herceptin trademark) is often internalized following binding to Her2+ tumor cells. The objective of this study was to investigate whether trastuzumab can be used as a specific carrier to deliver antisense oligomers into Her2+ tumor cells both in vitro and in vivo. A biotinylated MORF oligomer antisense to RhoC mRNA and its biotinylated sense control were labeled with either lissamine for fluorescence detection or {sup 99m}Tc for radioactivity detection and were linked to biotinylated trastuzumab via streptavidin. The nanoparticles were studied in SUM190 (RhoC+, Her2+) study and SUM149 (RhoC+, Her2-) control cells in culture and as xenografts in mice. As evidence of unimpaired Her2+ binding of trastuzumab within the nanoparticle, accumulations were clearly higher in SUM190 compared to SUM149 cells and, by whole-body imaging, targeting of SUM190 tumor was similar to that expected for a radiolabeled trastuzumab. As evidence of internalization, fluorescence microscopy images of cells grown in culture and obtained from xenografts showed uniform cytoplasm distribution of the lissamine-MORF. An invasion assay showed decreased RhoC expression in SUM190 cells when incubated with the antisense MORF nanoparticles at only 100 nM. Both in cell culture and in animals, the nanoparticle with trastuzumab as specific carrier greatly improved tumor delivery of the antisense oligomer against RhoC mRNA into tumor cells overexpressing Her2 and may be of general utility. (orig.)

Development of a Mass Spectrometric Method for Pharmacokinetic Study of Trastuzumab

Energy Technology Data Exchange (ETDEWEB)

Hong, Nam Young; Choi, Jin Nyoung; Kang, Jeong Won; Choi, Do Young; Kim, Kwang Pyo [Kyung Hee Univ., Yongin (Korea, Republic of); Park, Gyutae [CKD Research Institute, Yongin (Korea, Republic of)

2014-06-15

The HPLC-MS/MS method described here is a simple, rapid and specific method for determining the concentration of biologics in mouse serum. This method was validated for the quantification trastuzumab in ICR mice serum. Although the ELISA method is available for the pharmacokinetics study for trastuzumab, but these methods require development of the target specific antibodies. Generally, the development of the target specific antibodies for quantification is time consuming and expensive. In contrast, MRM-based method does not need antibodies for quantification. The therapeutic monoclonal antibody drug Trastuzumab (INN; trade name Herceptin) is widely used for treating metastatic breast cancer patients with overexpression of HER2 on the tumor. Trastuzumab is a representative target therapeutics as a monoclonal antibody that selectively binds with high affinity to the extracellular domain of the human epidermal growth factor receptor 2 protein, HER2. HER2 is amplified or over-expressed in about 20% to 30% of patients with breast cancer and is associated with aggressive disease. Trastuzumab has an inhibitory effect on the overexpression of HER2 receptor, thereby it has been used in treating breast cancer, and also gastric cancer.

64Cu-DOTA-trastuzumab PET imaging in patients with HER2-positive breast cancer.

Science.gov (United States)

Tamura, Kenji; Kurihara, Hiroaki; Yonemori, Kan; Tsuda, Hitoshi; Suzuki, Junko; Kono, Yuzuru; Honda, Natsuki; Kodaira, Makoto; Yamamoto, Harukaze; Yunokawa, Mayu; Shimizu, Chikako; Hasegawa, Koki; Kanayama, Yousuke; Nozaki, Satoshi; Kinoshita, Takayuki; Wada, Yasuhiro; Tazawa, Shusaku; Takahashi, Kazuhiro; Watanabe, Yasuyoshi; Fujiwara, Yasuhiro

2013-11-01

The purpose of this study was to determine the safety, distribution, internal dosimetry, and initial human epidermal growth factor receptor 2 (HER2)-positive tumor images of (64)Cu-DOTA-trastuzumab in humans. PET was performed on 6 patients with primary or metastatic HER2-positive breast cancer at 1, 24, and 48 h after injection of approximately 130 MBq of the probe (64)Cu-DOTA-trastuzumab. Radioactivity data were collected from the blood, urine, and normal-tissue samples of these 6 patients, and the multiorgan biodistribution and internal dosimetry of the probe were evaluated. Safety data were collected for all the patients after the administration of (64)Cu-DOTA-trastuzumab and during the 1-wk follow-up period. According to our results, the best timing for the assessment of (64)Cu-DOTA-trastuzumab uptake by the tumor was 48 h after injection. Radiation exposure during (64)Cu-DOTA-trastuzumab PET was equivalent to that during conventional (18)F-FDG PET. The radioactivity in the blood was high, but uptake of (64)Cu-DOTA-trastuzumab in normal tissues was low. In 2 patients, (64)Cu-DOTA-trastuzumab PET showed brain metastases, indicative of blood-brain barrier disruptions. In 3 patients, (64)Cu-DOTA-trastuzumab PET imaging also revealed primary breast tumors at the lesion sites initially identified by CT. The findings of this study indicated that (64)Cu-DOTA-trastuzumab PET is feasible for the identification of HER2-positive lesions in patients with primary and metastatic breast cancer. The dosimetry and pharmacologic safety results were acceptable at the dose required for adequate PET imaging.

2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA)

DEFF Research Database (Denmark)

Goldhirsch, Aron; Gelber, Richard D; Piccart-Gebhart, Martine J

2013-01-01

Trastuzumab has established efficacy against breast cancer with overexpression or amplification of the HER2 oncogene. The standard of care is 1 year of adjuvant trastuzumab, but the optimum duration of treatment is unknown. We compared 2 years of treatment with trastuzumab with 1 year of treatment......, and updated the comparison of 1 year of trastuzumab versus observation at a median follow-up of 8 years, for patients enrolled in the HERceptin Adjuvant (HERA) trial....

Adjuvant trastuzumab with chemotherapy is effective in women with small, node-negative, HER2-positive breast cancer.

Science.gov (United States)

McArthur, Heather L; Mahoney, Kathleen M; Morris, Patrick G; Patil, Sujata; Jacks, Lindsay M; Howard, Jane; Norton, Larry; Hudis, Clifford A

2011-12-15

Several large, randomized trials established the benefits of adjuvant trastuzumab with chemotherapy. However, the benefit for women with small, node-negative HER2-positive (HER2+) disease is unknown, as these patients were largely excluded from these trials. Therefore, a retrospective, single-institution, sequential cohort study of women with small, node-negative, HER2+ breast cancer who did or did not receive adjuvant trastuzumab was conducted. Women with ≤ 2 cm, node-negative, HER2+ (immunohistochemistry 3+ or fluorescence in situ hybridization ≥ 2) breast cancer were identified through an institutional database. A "no-trastuzumab" cohort of 106 trastuzumab-untreated women diagnosed between January 1, 2002 and May 14, 2004 and a "trastuzumab" cohort of 155 trastuzumab-treated women diagnosed between May 16, 2005 and December 31, 2008 were described. Survival and recurrence outcomes were estimated by Kaplan-Meier methods. The cohorts were similar in age, median tumor size, histology, hormone receptor status, hormone therapy, and locoregional therapy. Chemotherapy was administered in 66% and 100% of the "no trastuzumab" and "trastuzumab" cohorts, respectively. The median recurrence-free and survival follow-up was: 6.5 years (0.7-8.5) and 6.8 years (0.7-8.5), respectively, for the "no trastuzumab" cohort and 3.0 years (0.5-5.2) and 3.0 years (0.6-5.2), respectively, for the "trastuzumab" cohort. The 3-year locoregional invasive recurrence-free, distant recurrence-free, invasive disease-free, and overall survival were 92% versus 98% (P = .0137), 95% versus 100% (P = .0072), 82% versus 97% (P < .0001), and 97% versus 99% (P = .18) for the "no trastuzumab" and "trastuzumab" cohorts, respectively. Women with small, node-negative, HER2+ primary breast cancers likely derive significant benefit from adjuvant trastuzumab with chemotherapy. Copyright © 2011 American Cancer Society.

Evaluating the potential of {sup 188}Re-SOCTA-trastuzumab as a new radioimmunoagent for breast cancer treatment

Energy Technology Data Exchange (ETDEWEB)

Luo, T.-Y. [Isotope Application Division, Institute of Nuclear Energy Research, P.O. Box 3-27, Longtan, Taoyuan 325, Taiwan (China)], E-mail: tylo@iner.gov.tw; Tang, I-C.; Wu, Y.-L.; Hsu, K.-L. [Isotope Application Division, Institute of Nuclear Energy Research, P.O. Box 3-27, Longtan, Taoyuan 325, Taiwan (China); Liu, S.-W. [Chemistry Division, Institute of Nuclear Energy Research, Taoyuan 325, Taiwan (China); Kung, H.-C. [Department of Electrical Engineering, Tung Nan University, Taipei 222, Taiwan (China); Lai, P.-S. [Department of Chemistry, National Chung Hsing University, Taichung 402, Taiwan (China); Lin, W.-J. [Isotope Application Division, Institute of Nuclear Energy Research, P.O. Box 3-27, Longtan, Taoyuan 325, Taiwan (China)

2009-01-15

Introduction: Radioimmunotherapy, which utilizes monoclonal antibodies and therapeutic radioisotopes against antigen-expressing tumor tissues, is an attractive therapeutic approach for cancer therapy. Trastuzumab (Herceptin) is a humanized anti-HER-2/neu monoclonal antibody for breast cancer treatment. In this paper, we introduce a new radioimmunoagent, {sup 188}Re-trastuzumab, via a bifunctional ligand, succinimidyl 3,6-diaza-5-oxo-3-[2-((triphenylmethyl)thio)ethyl] -8-[(triphenylmethyl)thio]octanoate (SOCTA), and evaluate its potential to be a therapeutic radiopharmaceutical for breast cancer treatment. Methods: Equimolar amounts of SOCTA and trastuzumab were selected to react, and the conjugation ratio of SOCTA-trastuzumab was evaluated by the MALDI-TOF method. The immunoreactivity of SOCTA-trastuzumab was compared with nonconjugated trastuzumab in HER-2/neu overexpressing human breast cancer cell BT-474. Biodistribution experiment and microSPECT/CT images of {sup 188}Re-SOCTA-trastuzumab being administered intravenously to SCID mice bearing xenografted BT-474 breast cancer were investigated to evaluate the tumor-targeting capability. Results: The covalent attachment of SOCTA to trastuzumab (at 1:1 molar ratio) resulted in the averaged conjugation ratio of 0.27{+-}0.06 (n=3). The complex could easily be labeled with {sup 188}Re and achieve 95% radiochemical purity (RCP) after 1 h of reaction at room temperature. The in vitro stability study also revealed that the RCP of {sup 188}Re-SOCTA-trastuzumab was at a value of more than 85% after 48 h of incubation with human serum. The immunoreactivity evaluation showed that SOCTA-trastuzumab and nonconjugated trastuzumab had similar binding capacity (B{sub max}) to HER-2/neu receptor in BT-474 cells. The animal experiments showed that {sup 188}Re-SOCTA-trastuzumab accumulated more intensively in the tumor site as compared to normal tissue. Conclusion: We suggest that {sup 188}Re-SOCTA-trastuzumab could be a potential

Sunitinib in combination with trastuzumab for the treatment of advanced breast cancer: activity and safety results from a phase II study

International Nuclear Information System (INIS)

Bachelot, Thomas; Wang, Zhixiao; Cesari, Rossano; Tassell, Vanessa; Kern, Kenneth A; Blay, Jean-Yves; Lluch, Ana; Garcia-Saenz, Jose A; Verma, Sunil; Gutierrez, Maya; Pivot, Xavier; Kozloff, Mark F; Prady, Catherine; Huang, Xin; Khosravan, Reza

2014-01-01

This phase II study evaluated the efficacy and safety/tolerability of sunitinib plus trastuzumab in patients with HER2-positive advanced breast cancer (ABC). Eligible patients received sunitinib 37.5 mg/day and trastuzumab administered either weekly (loading, 4 mg/kg; then weekly 2 mg/kg) or 3-weekly (loading, 8 mg/kg; then 3-weekly 6 mg/kg). Prior trastuzumab and/or lapatinib treatment were permitted. The primary endpoint was objective response rate (ORR). Sixty patients were enrolled and evaluable for safety; 57 were evaluable for efficacy. The majority of patients (58%) had received no prior chemotherapy in the metastatic setting. The ORR was 37%; the clinical benefit rate (CBR; percent objective response plus stable disease ≥ 24 weeks) was 56%. Among patients who were treatment-naïve or had received only adjuvant therapy, the ORR was 44% and the CBR was 59%. Overall, median overall survival had not been reached and the 1-year survival rate was 91%. The majority of adverse events (AEs) were mild to moderate in severity. Forty percent of patients experienced AEs related to measured left ventricular ejection fraction (LVEF) declines, which occurred more frequently in patients who had received prior anthracycline treatment. Ten percent of patients exhibited symptoms related to LVEF declines. One patient died on study from cardiogenic shock. Antitumor response and several safety parameters appeared to correlate with sunitinib exposure. Sunitinib plus trastuzumab demonstrated antitumor activity in patients with HER2-positive ABC, particularly those who were treatment-naïve or had only received prior adjuvant treatment. Sunitinib plus trastuzumab had acceptable safety and tolerability in patients with HER2-positive ABC who had not received prior anthracycline therapy. clinicaltrials.gov/ct2/show/NCT00243503

Intrathecal trastuzumab in the management of HER2+ breast leptomeningeal disease: a single institution experience.

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Figura, Nicholas B; Long, Wendy; Yu, Michael; Robinson, Timothy J; Mokhtari, Sepideh; Etame, Arnold B; Tran, Nam D; Diaz, Roberto; Soliman, Hatem; Han, Heather S; Sahebjam, Solmaz; Forsyth, Peter A; Ahmed, Kamran A

2018-06-01

Leptomeningeal disease is a rare and devastating presentation of advanced stage metastatic breast cancer with historically poor overall survival. We assessed the safety and feasibility of intrathecal (IT) trastuzumab in HER2+ leptomeningeal disease. A total of 13 patients were treated at our institution with IT trastuzumab beginning November 2012 and followed until November 2017. Outcomes including craniospinal progression as well as overall survival (OS) following initiation of IT trastuzumab were assessed from review of the clinical chart and radiologic examinations. The median age of patients was 48 (range 29-75). Median time from breast cancer diagnosis to development of brain metastases was 87.7 months with a median of 4.6 months from brain metastases diagnosis to the development of leptomeningeal disease. Previous whole brain radiotherapy was received by the majority of patients (92%) and prior surgery for brain metastases was performed in 23%. Median duration of IT trastuzumab treatment was 6.4 months. Median time from IT trastuzumab start to craniospinal progression was 5.7 months with 6- and 12-month Kaplan-Meier rates of 41 and 21%, respectively. Sustained responses > 6 months were achieved in 4 patients. Median survival from the start of IT trastuzumab was 10.6 months with 6- and 12-month OS rates of 68 and 47%, respectively. IT trastuzumab was well tolerated with one patient developing ventriculitis, which resolved with IV antibiotics. IT trastuzumab was well tolerated with prolongation of OS over historical controls. IT trastuzumab should be considered for management of HER2+ leptomeningeal disease patients.

Tumor Uptake of 64Cu-DOTA-Trastuzumab in Patients with Metastatic Breast Cancer.

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Mortimer, Joanne E; Bading, James R; Park, Jinha M; Frankel, Paul H; Carroll, Mary I; Tran, Tri T; Poku, Erasmus K; Rockne, Russell C; Raubitschek, Andrew A; Shively, John E; Colcher, David M

2018-01-01

The goal of this study was to characterize the relationship between tumor uptake of 64 Cu-DOTA-trastuzumab as measured by PET/CT and standard, immunohistochemistry (IHC)-based, histopathologic classification of human epidermal growth factor receptor 2 (HER2) status in women with metastatic breast cancer (MBC). Methods: Women with biopsy-confirmed MBC and not given trastuzumab for 2 mo or more underwent complete staging, including 18 F-FDG PET/CT. Patients were classified as HER2-positive (HER2+) or -negative (HER2-) based on fluorescence in situ hybridization (FISH)-supplemented immunohistochemistry of biopsied tumor tissue. Eighteen patients underwent 64 Cu-DOTA-trastuzumab injection, preceded in 16 cases by trastuzumab infusion (45 mg). PET/CT was performed 21-25 (day 1) and 47-49 (day 2) h after 64 Cu-DOTA-trastuzumab injection. Radiolabel uptake in prominent lesions was measured as SUV max Average intrapatient SUV max ( pt ) was compared between HER2+ and HER2- patients. Results: Eleven women were HER2+ (8 immunohistochemistry 3+; 3 immunohistochemistry 2+/FISH amplified), whereas 7 were HER2- (3 immunohistochemistry 2+/FISH nonamplified; 4 immunohistochemistry 1+). Median pt for day 1 and day 2 was 6.6 and 6.8 g/mL for HER 2+ and 3.7 and 4.3 g/mL for HER2- patients ( P pt overlapped between the 2 groups, and interpatient variability was greater for HER2+ than HER2- disease ( P DOTA-trastuzumab in MBC is strongly associated with patient HER2 status and is indicative of binding to HER2. The variability within and among HER2+ patients, as well as the overlap between the HER2+ and HER2- groups, suggests a role for 64 Cu-DOTA-trastuzumab PET/CT in optimizing treatments that include trastuzumab. © 2018 by the Society of Nuclear Medicine and Molecular Imaging.

Vinorelbine plus 3-weekly trastuzumab in metastatic breast cancer: a single-centre phase 2 trial

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Staiano Maria

2007-03-01

Full Text Available Abstract Background After two studies reporting response rates higher than 70% in HER2-positive metastatic breast cancer with weekly trastuzumab and vinorelbine, we planned a phase 2 study to test activity of the same combination, with trastuzumab given every 3 weeks. Methods Patients with HER2-positive metastatic breast cancer (3+ at immunohistochemistry or positive at fluorescence in situ hybridization, PS ≤2, normal left-ventricular ejection fraction (LVEF and no more than one chemotherapy line for metastatic disease were eligible. Vinorelbine (30 mg/m2 was given on days 1&8 every 21 and trastuzumab (8 mg/kg day 1, then 6 mg/kg every 21 days. A single-stage phase 2 design, with p0 = 0.45, p1 = 0.65, type I and II error = 0.10, was applied; 22 objective responses were required in 39 patients. Results From Nov 2002 to May 2005, 50 patients were enrolled, with a median age of 54 years (range 31–81. Among 40 patients eligible for response assessment, there were 7 complete and 13 partial responses (overall response rate 50%; 95% exact CI 33.8–66.2; 11 patients had disease stabilization, lasting more than 6 months in 10 cases. Response rate did not vary according to patients and tumor characteristics, type and amount of previous chemotherapy. Within the whole series, median progression-free survival was 9.6 months (95% CI 7.3–12.3, median overall survival 22.7 months (95% CI 19.5-NA. Fifteen patients (30% developed brain metastases at a median time of 12 months (range 1–25. There was one toxic death due to renal failure in a patient receiving concomitant pamidronate. Twenty-three patients (46% had grade 3–4 neutropenia, 2 (4% grade 3 anemia, 4 (8% febrile neutropenia. Two patients stopped treatment because of grade 2 decline of LVEF and one patient because of grade 2 liver toxicity concomitant with a grade 1 decline of LVEF. One patient stopped trastuzumab after 50 cycles because of grade 1 decline of LVEF. Conclusion Although lower

mRNA profiling reveals determinants of trastuzumab efficiency in HER2-positive breast cancer.

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Silvia von der Heyde

Full Text Available Intrinsic and acquired resistance to the monoclonal antibody drug trastuzumab is a major problem in the treatment of HER2-positive breast cancer. A deeper understanding of the underlying mechanisms could help to develop new agents. Our intention was to detect genes and single nucleotide polymorphisms (SNPs affecting trastuzumab efficiency in cell culture. Three HER2-positive breast cancer cell lines with different resistance phenotypes were analyzed. We chose BT474 as model of trastuzumab sensitivity, HCC1954 as model of intrinsic resistance, and BTR50, derived from BT474, as model of acquired resistance. Based on RNA-Seq data, we performed differential expression analyses on these cell lines with and without trastuzumab treatment. Differentially expressed genes between the resistant cell lines and BT474 are expected to contribute to resistance. Differentially expressed genes between untreated and trastuzumab treated BT474 are expected to contribute to drug efficacy. To exclude false positives from the candidate gene set, we removed genes that were also differentially expressed between untreated and trastuzumab treated BTR50. We further searched for SNPs in the untreated cell lines which could contribute to trastuzumab resistance. The analysis resulted in 54 differentially expressed candidate genes that might be connected to trastuzumab efficiency. 90% of 40 selected candidates were validated by RT-qPCR. ALPP, CALCOCO1, CAV1, CYP1A2 and IGFBP3 were significantly higher expressed in the trastuzumab treated than in the untreated BT474 cell line. GDF15, IL8, LCN2, PTGS2 and 20 other genes were significantly higher expressed in HCC1954 than in BT474, while NCAM2, COLEC12, AFF3, TFF3, NRCAM, GREB1 and TFF1 were significantly lower expressed. Additionally, we inferred SNPs in HCC1954 for CAV1, PTGS2, IL8 and IGFBP3. The latter also had a variation in BTR50. 20% of the validated subset have already been mentioned in literature. For half of them we

[(64) Cu]-labelled trastuzumab: optimisation of labelling by DOTA and NODAGA conjugation and initial evaluation in mice.

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Schjoeth-Eskesen, Christina; Nielsen, Carsten Haagen; Heissel, Søren; Højrup, Peter; Hansen, Paul Robert; Gillings, Nic; Kjaer, Andreas

2015-05-30

The human epidermal growth factor receptor-2 (HER2) is overexpressed in 20-30% of all breast cancer cases, leading to increased cell proliferation, growth and migration. The monoclonal antibody, trastuzumab, binds to HER2 and is used for treatment of HER2-positive breast cancer. Trastuzumab has previously been labelled with copper-64 by conjugation of a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelator. The aim of this study was to optimise the (64) Cu-labelling of DOTA-trastuzumab and as the first to produce and compare with its 1,4,7-triazacyclononane, 1-glutaric acid-5,7 acetic acid (NODAGA) analogue in a preliminary HER2 tumour mouse model. The chelators were conjugated to trastuzumab using the activated esters DOTA mono-N-hydroxysuccinimide (NHS) and NODAGA-NHS. (64) Cu-labelling of DOTA-trastuzumab was studied by varying the amount of DOTA-trastuzumab used, reaction temperature and time. Full (64) Cu incorporation could be achieved using a minimum of 10-µg DOTA-trastuzumab, but the fastest labelling was obtained after 15 min at room temperature using 25 µg of DOTA-trastuzumab. In comparison, 80% incorporation was achieved for (64) Cu-labelling of NODAGA-trastuzumab. Both [(64) Cu]DOTA-trastuzumab and [(64) Cu]NODAGA-trastuzumab were produced after purification with radiochemical purities of >97%. The tracers were injected into mice with HER2 expressing tumours. The mice were imaged by positron emission tomography and showed high tumour uptake of 3-9% ID/g for both tracers. © 2015 The Authors Journal of Labelled Compounds and Radiopharmaceuticals published by John Wiley & Sons Ltd.

Complete response in HER2+ leptomeningeal carcinomatosis from breast cancer with intrathecal trastuzumab.

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Oliveira, Mafalda; Braga, Sofia; Passos-Coelho, José Luís; Fonseca, Ricardo; Oliveira, João

2011-06-01

Trastuzumab, a monoclonal antibody against the HER2 receptor, is a major breakthrough in the treatment of HER2+ breast cancer. However, its high molecular weight precludes it from crossing the intact blood-brain barrier, making the central nervous system a sanctuary to HER2+ breast cancer metastases. We prospectively assessed functional outcome and toxicity of administering trastuzumab directly into the cerebrospinal fluid of a patient with leptomeningeal carcinomatosis (LC) and brain metastases from HER2+ breast cancer that had already been treated with other intrathecal chemotherapy, with no benefit. Upon signed informed consent, weekly lumbar puncture with administration of trastuzumab 25 mg was begun to a 44 year-old women with metastatic breast cancer (lymph node, bone, lung, and liver involvement) previously treated with tamoxifen, letrozole, anthracyclines, taxanes, capecitabine, intravenous trastuzumab, and lapatinib. She received 67 weekly administrations of intrathecal trastuzumab with marked clinical improvement and no adverse events. She survived 27 months after LC diagnosis. A complete leptomeningeal response, with no evidence of leptomeningeal metastasis at necropsy, was achieved. We believe that intrathecal trastuzumab administration should be prospectively evaluated to confirm clinical activity and optimize dose, schedule, and duration of treatment.

Autophagy Protects from Trastuzumab-Induced Cytotoxicity in HER2 Overexpressing Breast Tumor Spheroids.

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Cristina E Rodríguez

Full Text Available Multicellular tumor spheroids represent a 3D in vitro model that mimics solid tumor essential properties including assembly and development of extracellular matrix and nutrient, oxygen and proliferation gradients. In the present study, we analyze the impact of 3D spatial organization of HER2-overexpressing breast cancer cells on the response to Trastuzumab. We cultured human mammary adenocarcinoma cell lines as spheroids with the hanging drop method and we observed a gradient of proliferating, quiescent, hypoxic, apoptotic and autophagic cells towards the inner core. This 3D organization decreased Trastuzumab sensitivity of HER2 over-expressing cells compared to monolayer cell cultures. We did not observe apoptosis induced by Trastuzumab but found cell arrest in G0/G1 phase. Moreover, the treatment downregulated the basal apoptosis only found in tumor spheroids, by eliciting protective autophagy. We were able to increase sensitivity to Trastuzumab by autophagy inhibition, thus exposing the interaction between apoptosis and autophagy. We confirmed this result by developing a resistant cell line that was more sensitive to autophagy inhibition than the parental BT474 cells. In summary, the development of Trastuzumab resistance relies on the balance between death and survival mechanisms, characteristic of 3D cell organization. We propose the use of spheroids to further improve the understanding of Trastuzumab antitumor activity and overcome resistance.

Predicting for activity of second-line trastuzumab-based therapy in her2-positive advanced breast cancer

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Rottenfusser Andrea

2009-10-01

Full Text Available Abstract Background In Her2-positive advanced breast cancer, the upfront use of trastuzumab is well established. Upon progression on first-line therapy, patients may be switched to lapatinib. Others however remain candidates for continued antibody treatment (treatment beyond progression. Here, we aimed to identify factors predicting for activity of second-line trastuzumab-based therapy. Methods Ninety-seven patients treated with > 1 line of trastuzumab-containing therapy were available for this analysis. Her2-status was determined by immunohistochemistry and re-analyzed by FISH if a score of 2+ was gained. Time to progression (TTP on second-line therapy was defined as primary study endpoint. TTP and overall survival (OS were estimated using the Kaplan-Meier product limit method. Multivariate analyses (Cox proportional hazards model, multinomial logistic regression were applied in order to identify factors associated with TTP, response, OS, and incidence of brain metastases. p values Results Median TTP on second-line trastuzumab-based therapy was 7 months (95% CI 5.74-8.26, and 8 months (95% CI 6.25-9.74 on first-line, respectively (n.s.. In the multivariate models, none of the clinical or histopthological features could reliably predict for activity of second-line trastuzumab-based treatment. OS was 43 months suggesting improved survival in patients treated with trastuzumab in multiple-lines. A significant deterioration of cardiac function was observed in three patients; 40.2% developed brain metastases while on second-line trastuzumab or thereafter. Conclusion Trastuzumab beyond progression showed considerable activity. None of the variables investigated correlated with activity of second-line therapy. In order to predict for activity of second-line trastuzumab, it appears necessary to evaluate factors known to confer trastuzumab-resistance.

Pregnancy occurring during or following adjuvant trastuzumab in patients enrolled in the HERA trial (BIG 01-01).

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Azim, Hatem A; Metzger-Filho, Otto; de Azambuja, Evandro; Loibl, Sibylle; Focant, Florine; Gresko, Ekaterina; Arfi, Mounir; Piccart-Gebhart, Martine

2012-05-01

Only few case reports describe the pregnancy course and outcome of breast cancer patients, who were under treatment with trastuzumab at the time of conception or who have completed trastuzumab therapy before becoming pregnant. The HERA trial is a large phase III randomized clinical trial in which patients with early HER2-positive breast cancer were randomized to receive 1 or 2 years of trastuzumab or observation following completion of primary chemotherapy. To examine the effect of trastuzumab on pregnancy outcome, we report all pregnancy events that occurred until March 2010 in patients enrolled in the study. For the sake of this analysis, patients were assigned to three groups: (1) pregnancy occurring during and up to 3 months after trastuzumab exposure (group 1); (2) pregnancy occurring >3 months of last trastuzumab dose (group 2); and (3) pregnancy occurring in patients without prior exposure to trastuzumab (group 3). Sixteen, 45 and 9 pregnancies took place in groups 1, 2, and 3, respectively. 25 and 16% of patients in groups 1 and 2 experienced spontaneous abortion, the former being higher than figures reported in the general population. However, short-term fetal outcome appeared normal across the three groups. Only 2 congenital anomalies were reported, one in group 2 and one in group 3. No congenital anomalies were reported in those exposed to trastuzumab in utero. This is the first report from a large randomized trial assessing the effect of trastuzumab on pregnancy course and outcome. Based on our results, trastuzumab does not appear to affect fetal outcome in patients who manage to complete their pregnancy. We are currently initiating a collaboration to collect similar data from the other large adjuvant trastuzumab trials to confirm these findings.

Functional Imaging of HER2-Positive Metastatic Breast Cancer Using 64Cu-DOTA-Trastuzumab Positron Emission Tomography

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Mortimer, Joanne E.; Bading, James R.; Colcher, David M.; Conti, Peter S.; Frankel, Paul H.; Carroll, Mary I.; Tong, Shan; Poku, Erasmus; Miles, Joshua K.; Shively, John E.; Raubitschek, Andrew A.

2014-01-01

Women with human epidermal growth factor receptor 2 (HER2)-positive breast cancer are candidates for treatment with the anti-HER2 antibody trastuzumab. Assessment of HER2 status in recurrent disease is usually made by core needle biopsy of a single lesion which may not be representative of the larger tumor mass or other sites of disease. Our long-range goal is to develop positron emission tomography (PET) of radiolabeled trastuzumab for systemically assessing tumor HER2 expression and identifying appropriate use of anti-HER2 therapies. The purpose of this study was to evaluate PET-CT of 64Cu-DOTA-trastuzumab for detecting and measuring tumor uptake of trastuzumab in patients with HER2-positive metastatic breast cancer. Methods Eight women with biopsy-confirmed HER2-positive metastatic breast cancer and no anti-HER2 therapy for ≥ 4 mo underwent complete staging, including 18F-fluorodeoxyglucose (FDG)/PET-CT. For 6 of the 8 patients, 64Cu-DOTA-trastuzumab injection (364-512 MBq, 5 mg trastuzumab) was preceded by trastuzumab infusion (45 mg). PET-CT (PET scan duration 1 h) was performed 21-25 (“Day 1”) and 47-49 (“Day 2”) h after 64Cu-DOTA-trastuzumab injection. Scan fields of view were chosen based on 18F-FDG/PET-CT. Lesions visualized relative to adjacent tissue on PET were considered PET-positive; analysis was limited to lesions identifiable on CT. Radiolabel uptake in prominent lesions was measured as maximum single-voxel standardized uptake value (SUVmax). Results Liver uptake of 64Cu was reduced approximately 75% with the 45 mg trastuzumab pre-dose, without significant effect on tumor uptake. The study included 89 CT-positive lesions; detection sensitivity was 77, 89 and 93% for Day 1, Day 2 and 18F-FDG, respectively. On average, tumor uptake was similar for 64Cu-DOTA-trastuzumab and 18F-FDG [SUVmax (mean, range): Day 1 (8.1, 3.0-22.5, n=48); Day 2 (8.9, 0.9-28.9, n=38); 18F-FDG (9.7, 3.3-25.4, n=56)], but the extent of same-lesion uptake was not

Direct {sup 99m}Tc labeling of Herceptin (trastuzumab) by {sup 99m}Tc(I) tricarbonyl ion

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Chen, W.-J.; Yen, C.-L.; Lo, S.-T.; Chen, K.-T. [Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu 30013, Taiwan (China); Lo, J.-M. [Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu 30013, Taiwan (China)], E-mail: jmlo@mx.nthu.edu.tw

2008-03-15

By simply incubating Herceptin (trastuzumab) with [{sup 99m}Tc(CO){sub 3}(OH{sub 2}){sub 3}]{sup +} ion in saline, a significant yield of {sup 99m}Tc-labeled trastuzumab was found to be achievable. The effective labeling may be based on that trastuzumab is inherent with endogenous histidine group to which {sup 99m}Tc(I) tricarbonyl ion can be strongly bound. For practical {sup 99m}Tc labeling processing, trastuzumab was purified beforehand from the commercial product, Herceptin (Genentech) via size exclusion chromatography to remove the excipient, {alpha}-histidine and a high-labeled yield could be obtained by incubating the purified trastuzumab with [{sup 99m}Tc(CO){sub 3}(OH{sub 2}){sub 3}]{sup +}. Retention of bioactivity of the {sup 99m}Tc(I)-labeled trastuzumab was validated using a cell binding test.

HER2 in Breast Cancer Stemness: A Negative Feedback Loop towards Trastuzumab Resistance

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Babak Nami

2017-04-01

Full Text Available HER2 receptor tyrosine kinase that is overexpressed in approximately 20% of all breast cancers (BCs is a poor prognosis factor and a precious target for BC therapy. Trastuzumab is approved by FDA to specifically target HER2 for treating HER2+ BC. However, about 60% of patients with HER2+ breast tumor develop de novo resistance to trastuzumab, partially due to the loss of expression of HER2 extracellular domain on their tumor cells. This is due to shedding/cleavage of HER2 by metalloproteinases (ADAMs and MMPs. HER2 shedding results in the accumulation of intracellular carboxyl-terminal HER2 (p95HER2, which is a common phenomenon in trastuzumab-resistant tumors and is suggested as a predictive marker for trastuzumab resistance. Up-regulation of the metalloproteinases is a poor prognosis factor and is commonly seen in mesenchymal-like cancer stem cells that are risen during epithelial to mesenchymal transition (EMT of tumor cells. HER2 cleavage during EMT can explain why secondary metastatic tumors with high percentage of mesenchymal-like cancer stem cells are mostly resistant to trastuzumab but still sensitive to lapatinib. Importantly, many studies report HER2 interaction with oncogenic/stemness signaling pathways including TGF-β/Smad, Wnt/β-catenin, Notch, JAK/STAT and Hedgehog. HER2 overexpression promotes EMT and the emergence of cancer stem cell properties in BC. Increased expression and activation of metalloproteinases during EMT leads to proteolytic cleavage and shedding of HER2 receptor, which downregulates HER2 extracellular domain and eventually increases trastuzumab resistance. Here, we review the hypothesis that a negative feedback loop between HER2 and stemness signaling drives resistance of BC to trastuzumab.

Budget impact analysis of trastuzumab in early breast cancer: a hospital district perspective.

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Purmonen, Timo T; Auvinen, Päivi K; Martikainen, Janne A

2010-04-01

Adjuvant trastuzumab is widely used in HER2-positive (HER2+) early breast cancer, and despite its cost-effectiveness, it causes substantial costs for health care. The purpose of the study was to develop a tool for estimating the budget impact of new cancer treatments. With this tool, we were able to estimate the budget impact of adjuvant trastuzumab, as well as the probability of staying within a given budget constraint. The created model-based evaluation tool was used to explore the budget impact of trastuzumab in early breast cancer in a single Finnish hospital district with 250,000 inhabitants. The used model took into account the number of patients, HER2+ prevalence, length and cost of treatment, and the effectiveness of the therapy. Probabilistic sensitivity analysis and alternative case scenarios were performed to ensure the robustness of the results. Introduction of adjuvant trastuzumab caused substantial costs for a relatively small hospital district. In base-case analysis the 4-year net budget impact was 1.3 million euro. The trastuzumab acquisition costs were partially offset by the reduction in costs associated with the treatment of cancer recurrence and metastatic disease. Budget impact analyses provide important information about the overall economic impact of new treatments, and thus offer complementary information to cost-effectiveness analyses. Inclusion of treatment outcomes and probabilistic sensitivity analysis provides more realistic estimates of the net budget impact. The length of trastuzumab treatment has a strong effect on the budget impact.

Drifts in ADCC-related quality attributes of Herceptin®: Impact on development of a trastuzumab biosimilar.

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Kim, Seokkyun; Song, Jinsu; Park, Seungkyu; Ham, Sunyoung; Paek, Kyungyeol; Kang, Minjung; Chae, Yunjung; Seo, Heewon; Kim, Hyung-Chan; Flores, Michael

A biosimilar product needs to demonstrate biosimilarity to the originator reference product, and the quality profile of the latter should be monitored throughout the period of the biosimilar's development to match the quality attributes of the 2 products that relate to efficacy and safety. For the development of a biosimilar version of trastuzumab, the reference product, Herceptin®, was extensively characterized for the main physicochemical and biologic properties by standard or state-of-the-art analytical methods, using multiple lots expiring between March 2015 and December 2019. For lots with expiry dates up to July 2018, a high degree of consistency was observed for all the tested properties. However, among the lots expiring in August 2018 or later, a downward drift was observed in %afucose (G0+G1+G2). Furthermore, the upward drift of %high mannose (M5+M6) was observed in the lots with expiry dates from June 2019 to December 2019. As a result, the combination of %afucose and %high mannose showed 2 marked drifts in the lots with expiry dates from August 2018 to December 2019, which was supported by the similar trend of biologic data, such as FcγRIIIa binding and antibody-dependent cell-mediated cytotoxicity (ADCC) activity. Considering that ADCC is one of the clinically relevant mechanisms of action for trastuzumab, the levels of %afucose and %high mannose should be tightly monitored as critical quality attributes for biosimilar development of trastuzumab.

Toxicity of trastuzumab labeled {sup 177}Lu on MCF7 and SKBr3 cell lines

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Rasaneh, Samira [Department of Medical Physics, Faculty of Medical Sciences, Tarbiat Modares University, P.O. Box 14115-331, Tehran (Iran, Islamic Republic of); Rajabi, Hossein, E-mail: hrajabi@modares.ac.i [Department of Medical Physics, Faculty of Medical Sciences, Tarbiat Modares University, P.O. Box 14115-331, Tehran (Iran, Islamic Republic of); Hossein Babaei, Mohammad; Johari Daha, Fariba [Department of Radioisotope, Nuclear Science and Technology Research Institute, Tehran (Iran, Islamic Republic of)

2010-10-15

In this study, we labeled trastuzumab with {sup 177}Lu to synthesize a new radiopharmaceutical for therapy of breast cancer and at the first stage investigated its therapeutic effects on SKBr3 and MCF7 breast cancer cell lines. Trastuzumab-{sup 177}Lu showed very good in-vitro characteristics such as high radiochemical purity (91{+-}0.9%), good stability in PBS buffer (86{+-}2.3%) and blood serum (81{+-}2.7%) up to 96 h, appropriate immunoreactivity (85.4{+-}1.1%) and high cytotoxicity in HER2 expression cells. 5 fold increase in toxicity of trastuzumab-{sup 177}Lu was observed when compared with unlabeled trastuzumab on SKBr3 cells.

Dramatic Clinical Response of Relapsed Metastatic Extramammary Paget’s Disease to Trastuzumab Monotherapy

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S. Wakabayashi

2012-01-01

Full Text Available We report the first case of 68-year-old Japanese woman with metastatic HER2-positive extramammary Paget’s disease that showed the validity of trastuzumab monotherapy. We administered trastuzumab at a loading dose of 8 mg/kg i.v., followed by a 6 mg/kg maintenance dose every three weeks according to a protocol for HER2-positive metastatic breast cancers and a near-complete response was achieved after the tenth infusion. The patient experienced a moderate headache and flushing during the first infusion, but had no advanced effects during subsequent infusions with ibuprofen and d-chlorpheniramine maleate. Given the dramatic response, the patient has had 17 infusions of trastuzumab with no disease progression. Thus, trastuzumab has few side effects and is well tolerated for elderly patients. It may become a new choice of the adjubant therapy of this disease.

Functional imaging of human epidermal growth factor receptor 2-positive metastatic breast cancer using (64)Cu-DOTA-trastuzumab PET.

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Mortimer, Joanne E; Bading, James R; Colcher, David M; Conti, Peter S; Frankel, Paul H; Carroll, Mary I; Tong, Shan; Poku, Erasmus; Miles, Joshua K; Shively, John E; Raubitschek, Andrew A

2014-01-01

Women with human epidermal growth factor receptor 2 (HER2)-positive breast cancer are candidates for treatment with the anti-HER2 antibody trastuzumab. Assessment of HER2 status in recurrent disease is usually made by core needle biopsy of a single lesion, which may not represent the larger tumor mass or other sites of disease. Our long-range goal is to develop PET of radiolabeled trastuzumab for systemically assessing tumor HER2 expression and identifying appropriate use of anti-HER2 therapies. The purpose of this study was to evaluate PET/CT of (64)Cu-DOTA-trastuzumab for detecting and measuring tumor uptake of trastuzumab in patients with HER2-positive metastatic breast cancer. Eight women with biopsy-confirmed HER2-positive metastatic breast cancer and no anti-HER2 therapy for 4 mo or longer underwent complete staging, including (18)F-FDG PET/CT. For 6 of the 8 patients, (64)Cu-DOTA-trastuzumab injection (364-512 MBq, 5 mg of trastuzumab) was preceded by trastuzumab infusion (45 mg). PET/CT (PET scan duration 1 h) was performed 21-25 (day 1) and 47-49 (day 2) h after (64)Cu-DOTA-trastuzumab injection. Scan fields of view were chosen on the basis of (18)F-FDG PET/CT. Tumor detection sensitivity and uptake analyses were limited to lesions identifiable on CT; lesions visualized relative to adjacent tissue on PET were considered PET-positive. Radiolabel uptake in prominent lesions was measured as maximum single-voxel standardized uptake value (SUVmax). Liver uptake of (64)Cu was reduced approximately 75% with the 45-mg trastuzumab predose, without significant effect on tumor uptake. The study included 89 CT-positive lesions. Detection sensitivity was 77%, 89%, and 93% for day 1, day 2, and (18)F-FDG, respectively. On average, tumor uptake was similar for (64)Cu-DOTA-trastuzumab and (18)F-FDG (SUVmax and range, 8.1 and 3.0-22.5 for day 1 [n = 48]; 8.9 and 0.9-28.9 for day 2 [n = 38]; 9.7 and 3.3-25.4 for (18)F-FDG [n = 56]), but same-lesion SUVmax was not correlated

CD147 knockdown improves the antitumor efficacy of trastuzumab in HER2-positive breast cancer cells.

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Xiong, Lijuan; Ding, Li; Ning, Haoyong; Wu, Chenglin; Fu, Kaifei; Wang, Yuxiao; Zhang, Yan; Liu, Yan; Zhou, Lijun

2016-09-06

Trastuzumab is widely used in the clinical treatment of human epidermal growth factor receptor-2 (HER2)-positive breast cancer, but the patient response rate is low. CD147 stimulates cancer cell proliferation, migration, metastasis and differentiation and is involved in chemoresistance in many types of cancer cells. Whether CD147 alters the effect of trastuzumab on HER2-positive breast cancer cells has not been previously reported. Our study confirmed that CD147 suppression enhances the effects of trastuzumab both in vitro and in vivo. CD147 suppression increased the inhibitory rate of trastuzumab and cell apoptosis in SKBR3, BT474, HCC1954 and MDA-MB453 cells compared with the controls. Furthermore, CD147 knockdown increased expression of cleaved Caspase-3/9 and poly (ADP-ribose) polymerase (PARP) and decreased both mitogen-activated protein kinase (MAPK) and Akt phosphorylation in the four cell lines. In an HCC1954 xenograft model, trastuzumab achieved greater suppression of tumor growth in the CD147-knockdown group than in the shRNA negative control (NC) group. These data indicated that enhancement of the effect of trastuzumab on HER2-positive cells following CD147 knockdown might be attributed to increased apoptosis and decreased phosphorylation of signaling proteins. CD147 may be a key protein for enhancing the clinical efficacy of trastuzumab.

A randomized, single-blind, single-dose study evaluating the pharmacokinetic equivalence of proposed biosimilar ABP 980 and trastuzumab in healthy male subjects.

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Hanes, Vladimir; Chow, Vincent; Zhang, Nan; Markus, Richard

2017-05-01

This study compared the pharmacokinetic (PK) profiles of the proposed biosimilar ABP 980 and trastuzumab in healthy males. In this single-blind study, 157 healthy males were randomized 1:1:1 to a single 6 mg/kg intravenous infusion of ABP 980, FDA-licensed trastuzumab [trastuzumab (US)], or EU-authorized trastuzumab [trastuzumab (EU)]. Primary endpoints were area under the serum concentration-time curve from time 0 to infinity (AUC inf ) and maximum observed serum concentration (C max ). To establish equivalence, the geometric mean ratio (GMR) and 90% confidence interval (CI) for C max and AUC inf had to be within the equivalence criteria of 0.80-1.25. The GMRs and 90% CIs for C max and AUC inf , respectively, were: 1.04 (0.99-1.08) and 1.06 (1.00-1.12) for ABP 980 versus trastuzumab (US); 0.99 (0.95-1.03) and 1.00 (0.95-1.06) for ABP 980 versus trastuzumab (EU); and 0.96 (0.92-1.00) and 0.95 (0.90-1.01) for trastuzumab (US) versus trastuzumab (EU). All comparisons were within the equivalence criteria of 0.80-1.25. Treatment-emergent adverse events (TEAEs) were reported in 84.0, 75.0, and 78.2 of subjects in the ABP 980, trastuzumab (US), and trastuzumab (EU) groups, respectively. There were no deaths or TEAEs leading to study discontinuation and no binding or neutralizing anti-drug anti-bodies were detected. This study demonstrated the PK similarity of ABP 980 to both trastuzumab (US) and trastuzumab (EU), and of trastuzumab (US) to trastuzumab (EU). No differences in safety and tolerability between treatments were noted; no subject tested positive for binding anti-bodies.

Efficacy and Safety of Pertuzumab and Trastuzumab Administered in a Single Infusion Bag, Followed by Vinorelbine

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Andersson, Michael; López-Vega, José M; Petit, Thierry

2017-01-01

BACKGROUND: VELVET Cohort 1 demonstrated the applicability of pertuzumab, trastuzumab, and vinorelbine as an alternative first-line treatment regimen for patients with HER2-positive locally advanced or metastatic breast cancer (MBC) who cannot receive docetaxel. Co-infusion of pertuzumab and tras......BACKGROUND: VELVET Cohort 1 demonstrated the applicability of pertuzumab, trastuzumab, and vinorelbine as an alternative first-line treatment regimen for patients with HER2-positive locally advanced or metastatic breast cancer (MBC) who cannot receive docetaxel. Co-infusion of pertuzumab...... and trastuzumab may reduce clinic time and medical resource utilization. We report results from Cohort 2, in which pertuzumab and trastuzumab were co-infused, followed by vinorelbine. PATIENTS AND METHODS: During cycle 1, patients with HER2-positive locally advanced or MBC received loading doses of pertuzumab...... (840 mg) and trastuzumab (8 mg/kg) on consecutive days, followed by vinorelbine (25 mg/m(2)) on days two and nine. From cycle 2 onwards, patients received a co-infusion of pertuzumab (420 mg) and trastuzumab (6 mg/kg) on day one, followed by vinorelbine (30-35 mg/m(2)) on days one and eight (or days...

Elevation in inflammatory serum biomarkers predicts response to trastuzumab-containing therapy.

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Ahmed A Alkhateeb

Full Text Available Approximately half of all HER2/neu-overexpressing breast cancer patients do not respond to trastuzumab-containing therapy. Therefore, there remains an urgent and unmet clinical need for the development of predictive biomarkers for trastuzumab response. Recently, several lines of evidence have demonstrated that the inflammatory tumor microenvironment is a major contributor to therapy resistance in breast cancer. In order to explore the predictive value of inflammation in breast cancer patients, we measured the inflammatory biomarkers serum ferritin and C-reactive protein (CRP in 66 patients immediately before undergoing trastuzumab-containing therapy and evaluated their progression-free and overall survival. The elevation in pre-treatment serum ferritin (>250 ng/ml or CRP (>7.25 mg/l was a significant predictor of reduced progression-free survival and shorter overall survival. When patients were stratified based on their serum ferritin and CRP levels, patients with elevation in both inflammatory biomarkers had a markedly poorer response to trastuzumab-containing therapy. Therefore, the elevation in inflammatory serum biomarkers may reflect a pathological state that decreases the clinical efficacy of this therapy. Anti-inflammatory drugs and life-style changes to decrease inflammation in cancer patients should be explored as possible strategies to sensitize patients to anti-cancer therapeutics.

Trastuzumab anti-tumor efficacy in patient-derived esophageal squamous cell carcinoma xenograft (PDECX mouse models

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Wu Xianhua

2012-08-01

Full Text Available Abstract Background Trastuzumab is currently approved for the clinical treatment of breast and gastric cancer patients with HER-2 positive tumors, but not yet for the treatment of esophageal carcinoma patients, whose tumors typically show 5 ~ 35% HER-2 gene amplification and 0 ~ 56% HER-2 protein expression. This study aimed to investigate the therapeutic efficacy of Trastuzumab in patient-derived esophageal squamous cell carcinoma xenograft (PDECX mouse models. Methods PDECX models were established by implanting patient esophageal squamous cell carcinoma (ESCC tissues into immunodeficient (SCID/nude mice. HER-2 gene copy number (GCN and protein expression were determined in xenograft tissues and corresponding patient EC samples by FISH and IHC analysis. Trastuzumab anti-tumor efficacy was evaluated within these PDECX models (n = 8 animals/group. Furthermore, hotspot mutations of EGFR, K-ras, B-raf and PIK3CA genes were screened for in the PDECX models and their corresponding patient’s ESCC tissues. Similarity between the PDECX models and their corresponding patient’s ESCC tissue was confirmed by histology, morphology, HER-2 GCN and mutation. Results None of the PDECX models (or their corresponding patient’s ESCC tissues harbored HER-2 gene amplification. IHC staining showed HER-2 positivity (IHC 2+ in 2 PDECX models and negativity in 3 PDECX models. Significant tumor regression was observed in the Trastuzumab-treated EC044 HER-2 positive model (IHC 2+. A second HER-2 positive (IHC 2+ model, EC039, harbored a known PIK3CA mutation and showed strong activation of the AKT signaling pathway and was insensitive to Trastuzumab treatment, but could be resensitised using a combination of Trastuzumab and AKT inhibitor AZD5363. In summary, we established 5 PDECX mouse models and demonstrated tumor regression in response to Trastuzumab treatment in a HER-2 IHC 2+ model, but resistance in a HER-2 IHC 2+/PIK3CA mutated model. Conclusions

Percutaneous left atrial appendage closure for stroke prevention

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De Backer, Ole; Loupis, Anastasia M; Ihlemann, Nikolaj

2014-01-01

INTRODUCTION: In atrial fibrillation (AF) patients with an increased stroke risk, oral anticoagulation (OAC) is the standard treatment for stroke prevention. However, this therapy carries a high risk of major bleeding. Percutaneous closure of the left atrial appendage (LAA) is suggested as an alt...

Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer

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von Minckwitz, Gunter; Procter, Marion; de Azambuja, Evandro

2017-01-01

BACKGROUND: Pertuzumab increases the rate of pathological complete response in the preoperative context and increases overall survival among patients with metastatic disease when it is added to trastuzumab and chemotherapy for the treatment of human epidermal growth factor receptor 2 (HER2......)-positive breast cancer. In this trial, we investigated whether pertuzumab, when added to adjuvant trastuzumab and chemotherapy, improves outcomes among patients with HER2-positive early breast cancer. METHODS: We randomly assigned patients with node-positive or high-risk node-negative HER2-positive......, operable breast cancer to receive either pertuzumab or placebo added to standard adjuvant chemotherapy plus 1 year of treatment with trastuzumab. We assumed a 3-year invasive-disease-free survival rate of 91.8% with pertuzumab and 89.2% with placebo. RESULTS: In the trial population, 63% of the patients...

HSP90 inhibition is effective in breast cancer: a phase II trial of tanespimycin (17-AAG) plus trastuzumab in patients with HER2-positive metastatic breast cancer progressing on trastuzumab.

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Modi, Shanu; Stopeck, Alison; Linden, Hannah; Solit, David; Chandarlapaty, Sarat; Rosen, Neal; D'Andrea, Gabriella; Dickler, Maura; Moynahan, Mary E; Sugarman, Steven; Ma, Weining; Patil, Sujata; Norton, Larry; Hannah, Alison L; Hudis, Clifford

2011-08-01

HSP90 is a chaperone protein required for the stability of a variety of client proteins. 17-Demethoxygeldanamycin (17-AAG) is a natural product that binds to HSP90 and inhibits its activity, thereby inducing the degradation of these clients. In preclinical studies, HER2 is one of the most sensitive known client proteins of 17-AAG. On the basis of these data and activity in a phase I study, we conducted a phase II study of 17-AAG (tanespimycin) with trastuzumab in advanced trastuzumab-refractory HER2-positive breast cancer. We enrolled patients with metastatic HER2(+) breast cancer whose disease had previously progressed on trastuzumab. All patients received weekly treatment with tanespimycin at 450 mg/m(2) intravenously and trastuzumab at a conventional dose. Therapy was continued until disease progression. The primary endpoint was response rate by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Thirty-one patients were enrolled with a median age of 53 years and a median Karnofsky performance status (KPS) of 90%. The most common toxicities, largely grade 1, were diarrhea, fatigue, nausea, and headache. The overall response rate was 22%, the clinical benefit rate [complete response + partial response + stable disease] was 59%, the median progression-free survival was 6 months (95% CI: 4-9), and the median overall survival was 17 months (95% CI: 16-28). This is the first phase II study to definitively show RECIST-defined responses for 17-AAG in solid tumors. Tanespimycin plus trastuzumab has significant anticancer activity in patients with HER2-positive, metastatic breast cancer previously progressing on trastuzumab. Further research exploring this therapeutic interaction and the activity of HSP90 inhibitors is clearly warranted. ©2011 AACR.

Trastuzumab for metastatic breast cancer: Real world outcomes from an Australian whole-of-population cohort (2001-2016).

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Daniels, Benjamin; Kiely, Belinda E; Lord, Sarah J; Houssami, Nehmat; Lu, Christine Y; Ward, Robyn L; Pearson, Sallie-Anne

2018-04-01

Outcomes for patients treated in clinical trials may not reflect the experience in routine clinical care. We aim to describe the real-world treatment patterns and overall survival (OS) for women receiving trastuzumab for metastatic breast cancer (MBC). Retrospective, whole-of-population cohort study using demographic, dispensing, and medical services data for women in the Herceptin Program for HER2+MBC. We estimated time on trastuzumab and OS from first dispensing of trastuzumab for MBC and rates of cardiac monitoring prior to and during treatment. We stratified outcomes by two groups based on year of initiation: 2001-2008 and 2009-2015. We benchmarked outcomes to two key trastuzumab clinical trials: H0648g (median OS 25 months) and CLEOPATRA (control group median OS 41 months). Median age of the 5899 women at first trastuzumab dispensing was 57 years (interquartile range [IQR]: 48-66). Median time on trastuzumab increased from 15 months (7-33) in Group One to 18 months (8-42) in Group Two. Median OS increased from 27 months (12-57) in Group One to 38 months (16-83) in Group Two. Rates of cardiac monitoring increased at baseline (52%-76%), and on-treatment (47%-67%), in Group One and Two, respectively. OS, duration of trastuzumab, and frequency of cardiac monitoring increased over the study period. Outcomes for trastuzumab in this heterogeneous real world population were reassuringly comparable to those from clinical trials, with the median OS > 3 years in Group Two and 25% of patients living 7 years or longer. Copyright © 2017 Elsevier Ltd. All rights reserved.

Seven-Year Follow-Up Assessment of Cardiac Function in NSABP B-31, a Randomized Trial Comparing Doxorubicin and Cyclophosphamide Followed by Paclitaxel (ACP) With ACP Plus Trastuzumab As Adjuvant Therapy for Patients With Node-Positive, Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer

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Romond, Edward H.; Jeong, Jong-Hyeon; Rastogi, Priya; Swain, Sandra M.; Geyer, Charles E.; Ewer, Michael S.; Rathi, Vikas; Fehrenbacher, Louis; Brufsky, Adam; Azar, Catherine A.; Flynn, Patrick J.; Zapas, John L.; Polikoff, Jonathan; Gross, Howard M.; Biggs, David D.; Atkins, James N.; Tan-Chiu, Elizabeth; Zheng, Ping; Yothers, Greg; Mamounas, Eleftherios P.; Wolmark, Norman

2012-01-01

Purpose Cardiac dysfunction (CD) is a recognized risk associated with the addition of trastuzumab to adjuvant chemotherapy for human epidermal growth factor receptor 2–positive breast cancer, especially when the treatment regimen includes anthracyclines. Given the demonstrated efficacy of trastuzumab, ongoing assessment of cardiac safety and identification of risk factors for CD are important for optimal patient care. Patients and Methods In National Surgical Adjuvant Breast and Bowel Project B-31, a phase III adjuvant trial, 1,830 patients who met eligibility criteria for initiation of trastuzumab were evaluated for CD. Recovery from CD was also assessed. A statistical model was developed to estimate the risk of severe congestive heart failure (CHF). Baseline patient characteristics associated with anthracycline-related decline in cardiac function were also identified. Results At 7-year follow-up, 37 (4.0%) of 944 patients who received trastuzumab experienced a cardiac event (CE) versus 10 (1.3%) of 743 patients in the control arm. One cardiac-related death has occurred in each arm of the protocol. A Cardiac Risk Score, calculated using patient age and baseline left ventricular ejection fraction (LVEF) by multiple-gated acquisition scan, statistically correlates with the risk of a CE. After stopping trastuzumab, the majority of patients who experienced CD recovered LVEF in the normal range, although some decline from baseline often persists. Only two CEs occurred more than 2 years after initiation of trastuzumab. Conclusion The late development of CHF after the addition of trastuzumab to paclitaxel after doxorubicin/ cyclophosphamide chemotherapy is uncommon. The risk versus benefit of trastuzumab as given in this regimen remains strongly in favor of trastuzumab. PMID:22987084

Serum HER-2 predicts response and resistance to trastuzumab treatment in breast cancer

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Petersen, Eva Rabing Brix; Sørensen, Patricia Diana; Jakobsen, Erik Hugger

2013-01-01

Serum HER2 (S-HER2) was approved in 2003 by the US Food and Drug Administration (FDA) for monitoring trastuzumab treatment in tissue HER2 positive breast cancer patients. Information of the value of S-HER2 is scarce. We hypothesised that S-HER2 would reflect the clinical effect of trastuzumab....

[64Cu]-Labelled Trastuzumab: Optimisation of Labelling by DOTA and NODAGA Conjugation and Initial Evaluation in Mice

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Schjøth-Eskesen, Christina; Nielsen, Carsten Haagen; Heissel, Søren

2015-01-01

The human epidermal growth factor receptor-2 (HER2) is overexpressed in 20-30% of all breast cancer cases, leading to increased cell proliferation, growth and migration. The monoclonal antibody, trastuzumab, binds to HER2 and is used for treatment of HER2-positive breast cancer. Trastuzumab has...... [(64) Cu]DOTA-trastuzumab and [(64) Cu]NODAGA-trastuzumab were produced after purification with radiochemical purities of >97%. The tracers were injected into mice with HER2 expressing tumours. The mice were imaged by positron emission tomography and showed high tumour uptake of 3-9% ID/g for both...

Chemotherapy-related amenorrhea after adjuvant paclitaxel-trastuzumab (APT trial).

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Ruddy, Kathryn J; Guo, Hao; Barry, William; Dang, Chau T; Yardley, Denise A; Moy, Beverly; Marcom, P Kelly; Albain, Kathy S; Rugo, Hope S; Ellis, Matthew J; Shapira, Iuliana; Wolff, Antonio C; Carey, Lisa A; Overmoyer, Beth A; Hudis, Clifford; Krop, Ian E; Burstein, Harold J; Winer, Eric P; Partridge, Ann H; Tolaney, Sara M

2015-06-01

Chemotherapy-related amenorrhea (CRA) is associated with infertility and menopausal symptoms. Learning how frequently paclitaxel and trastuzumab cause amenorrhea is important. Most other adjuvant breast cancer therapies induce CRA in approximately 50 % of all premenopausal recipients [1]. 410 patients enrolled on the APT Trial, a single-arm phase 2 adjuvant study of 12 weeks of paclitaxel and trastuzumab followed by nine months of trastuzumab monotherapy. Eligible patients had ≤3 cm node-negative HER2 + breast cancers. Premenopausal enrollees were asked to complete menstrual surveys every 3-12 months for 72 months. Women who responded to at least one survey at least 15 months after chemotherapy initiation (and who did not undergo hysterectomy and/or bilateral oophorectomy or receive ovarian suppressing medications prior to 15 months) were included in this analysis. A participant was defined as having amenorrhea in follow-up if her self-reported last menstrual period at last follow-up was greater than 12 months prior to the survey. Among the 64 women in the evaluable population (median age at study entry 44 years, range 27-52 years), the median time between chemotherapy initiation and last menstrual survey was 51 months (range 16-79). 18 of 64 women (28 %, 95 % CI 18-41 %) were amenorrheic at that time point. Amenorrhea rates among premenopausal women treated with adjuvant paclitaxel and trastuzumab for early stage breast cancer appear lower than those seen historically with standard alkylator-based breast cancer regimens. Future studies are needed to understand the impact of this regimen on related issues of fertility and menopausal symptoms.

Preference for subcutaneous or intravenous administration of trastuzumab in patients with HER2-positive early breast cancer (PrefHer)

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Pivot, Xavier; Gligorov, Joseph; Müller, Volkmar

2013-01-01

Subcutaneous trastuzumab has shown non-inferior efficacy and a similar pharmacokinetic and safety profile when compared with intravenous trastuzumab in patients with HER2-positive early breast cancer. We assessed patient preference for either subcutaneous or intravenous trastuzumab...

Alteration of gene expression in MDA-MB-453 breast cancer cell line in response to continuous exposure to Trastuzumab.

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Sharieh, Elham Abu; Awidi, Abdulla S; Ahram, Mamoun; Zihlif, Malek A

2016-01-10

Development of resistance against cancer therapeutic agents is a common problem in cancer management. Trastuzumab resistance is one of the challenges in management of HER-2-positive breast cancer patients resulting in breast cancer progression, metastasis, and patient poor outcome. The aim of this study is to determine the alteration in gene expression in response to Trastuzumab resistance after long-term exposure to Trastuzumab. The Trastuzumab-resistant MDA-MB-453 (MDA-MB-453/TR) cell line was developed by exposing cells to 10 μM Trastuzumab continuously for 6 months. Sensitivity toward Trastuzumab was tested using cell viability assays. The acquisition of an epithelial-to mesenchymal transition (EMT) phenotype was also observed in parallel with the development of resistance. Based on the real-time-based PCR array technology, several genes were altered affecting multiple networks. The most up-regulated genes were TGF-β1 and EGF, and IGFBP-3. These genes are known to have a critical role in Trastuzumab resistance in breast cancer cell lines and/or in the acquisition of EMT. They are also recognized for their role in cancer progression and metastasis. These alterations indicate that the development of Trastuzumab resistance is multifactorial and involves a development of a mesenchymal like phenotype. Copyright © 2015 Elsevier B.V. All rights reserved.

Clinical effects of prior trastuzumab on combination eribulin mesylate plus trastuzumab as first-line treatment for human epidermal growth factor receptor 2 positive locally recurrent or metastatic breast cancer: results from a Phase II, single-arm, multicenter study

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Puhalla S

2016-12-01

Full Text Available Shannon Puhalla,1 Sharon Wilks,2 Adam M Brufsky,1 Joyce O’Shaughnessy,3 Lee S Schwartzberg,4 Erhan Berrak,5 James Song,5 Linda Vahdat6 1Department of Hematology and Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA, 2Department of Hematology Oncology, US Oncology-Cancer Care Centers of South Texas, San Antonio, TX, 3Department of Medical Oncology, Texas Oncology-Baylor Charles A. Sammons Cancer Center US Oncology, Dallas, TX, 4Department of Hematology/Oncology, West Cancer Center, University of Tennessee Health Science Center, Memphis, TN, 5Department of Medical Affairs, Formerly of Eisai Inc., Woodcliff Lake, NJ, 6Department of Medicine, Weill Cornell Medical College, New York, NY, USA Abstract: Eribulin mesylate, a novel nontaxane microtubule dynamics inhibitor in the halichondrin class of antineoplastic drugs, is indicated for the treatment of patients with metastatic breast cancer who previously received ≥2 chemotherapy regimens in the metastatic setting. Primary data from a Phase II trial for the first-line combination of ­eribulin plus trastuzumab in human epidermal growth factor receptor 2 positive patients showed a 71% objective response rate and tolerability consistent with the known profile of these agents. Here, we present prespecified analyses of efficacy of this combination based on prior trastuzumab use. Patients received eribulin mesylate 1.4 mg/m2 (equivalent to 1.23 mg/m2 eribulin [expressed as free base] intravenously on days 1 and 8 plus trastuzumab (8 mg/kg intravenously/cycle 1, then 6 mg/kg on day 1 of each 21-day cycle. Objective response rates, progression-free survival, and tolerability were assessed in patients who had and had not received prior adjuvant or neoadjuvant (neo/adjuvant trastuzumab treatment. Fifty-two patients (median age: 59.5 years received eribulin/trastuzumab for a median treatment duration of ~31 weeks; 40.4% (n=21 had been previously treated with neo/adjuvant trastuzumab prior to

Is there any advantage to combined trastuzumab and chemotherapy in perioperative setting her 2neu positive localized gastric adenocarcinoma?

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Albouzidi Abderrahmane

2011-09-01

Full Text Available Abstract We report here a 44-year-old Moroccan man with resectable gastric adenocarcinoma with overexpression of human epidermal growth factor receptor 2 (HER2 by immunohistochemistry who was treated with trastuzumab in combination with chemotherapy in perioperative setting. He received 3 cycles of neoadjuvant chemotherapy consisting of trastuzumab, oxaliplatin, and capecitabine. Afterwards, he received total gastrectomy with extended D2 lymphadenectomy without spleno-pancreatectomy. A pathologic complete response was obtained with a combination of trastuzumab and oxaliplatin and capecitabine. He received 3 more cycles of trastuzumab containing regimen postoperatively. We conclude that resectable gastric carcinoma with overexpression of the c-erbB-2 protein should ideally be managed with perioperative combination of trastuzumab with chemotherapy. Further research to evaluate trastuzumab in combination with chemotherapy regimens in the perioperative and adjuvant setting is urgently needed.

Radiotherapy and HER2: point on the association of ionizing radiation and trastuzumab; Radiotherapie et HER2: point sur l'association de radiations ionisantes et de trastuzumab

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Liem, X.; Lartigau, E. [Centre Oscar-Lambret, 59 - Lille (France)

2009-10-15

The addition of the two treatments (trastuzumab and radiotherapy) poses the problem of their toxicity addition, particularly at the cardiac level. The data speak in favour of trastuzumab continuation during radiotherapy, taken into account the benefits. Because of the technical advances in radiotherapy ( respiratory automatic control, intensity modulated radiotherapy, I.M.R.T.) it will be possible to avoid the mediastinum structures improving then the tolerance. (N.C.)

Cellular uptake of radioiodine delivered by trastuzumab can be modified by the addition of epidermal growth factor

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Nordberg, Erika; Steffen, Ann-Charlott; Sundberg, Aasa L.; Carlsson, Joergen [Uppsala University, Division of Biomedical Radiation Sciences, Department of Oncology, Radiology and Clinical Immunology, Rudbeck Laboratory, Uppsala (Sweden); Persson, Mikael [Uppsala University, Division of Biomedical Radiation Sciences, Department of Oncology, Radiology and Clinical Immunology, Rudbeck Laboratory, Uppsala (Sweden); Uppsala University, Division of Experimental Urology, Department of Surgical Sciences, Rudbeck Laboratory, Uppsala (Sweden); Glimelius, Bengt [Uppsala University, Division of Oncology, Department of Oncology, Radiology and Clinical Immunology, Rudbeck Laboratory, Uppsala (Sweden)

2005-07-01

The purpose of this study was to analyse whether non-radiolabelled epidermal growth factor (EGF) can modify the cellular uptake of {sup 125}I when delivered as [{sup 125}I]trastuzumab. {sup 125}I was used as a marker for the diagnostically and therapeutically more interesting isotopes {sup 123}I (SPECT), {sup 124}I (PET) and {sup 131}I (therapy). The cell-associated radioactivity was measured in squamous carcinoma A431 cells following addition of [{sup 125}I]trastuzumab. Different concentrations of [{sup 125}I]trastuzumab and unlabelled EGF were used, and the total, membrane-bound and internalised radioactivity was measured. We also analysed how EGF and trastuzumab affected the cell growth. It was generally found that the cellular {sup 125}I uptake was decreased by the addition of EGF when [{sup 125}I]trastuzumab was added for short incubation times. However, if the incubation times were longer, EGF increased the {sup 125}I uptake. This shift came earlier when higher [{sup 125}I]trastuzumab concentrations were applied. The addition of EGF also influenced cell proliferation, and concentrations above 10 ng/ml reduced cell growth by approximately 20% after 24 h of incubation. By adding unlabelled EGF, it was possible to modify the cellular uptake of [{sup 125}I]trastuzumab. This points towards new approaches for the modification of radionuclide uptake in EGFR- and HER2-positive tumours. (orig.)

Adjuvant Chemotherapy and Trastuzumab Is Safe and Effective in Older Women With Small, Node-Negative, HER2-Positive Early-Stage Breast Cancer.

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Cadoo, Karen A; Morris, Patrick G; Cowell, Elizabeth P; Patil, Sujata; Hudis, Clifford A; McArthur, Heather L

2016-12-01

The benefit of adjuvant trastuzumab with chemotherapy is well established for women with higher risk human epidermal growth factor receptor 2-positive (HER2 + ) breast cancer. However, its role in older patients with smaller, node-negative tumors is less clear. We conducted a retrospective, sequential cohort study of this population to describe the impact of trastuzumab on breast cancer outcomes and cardiac safety. Women ≥ 55 years with ≤ 2 cm, node-negative, HER2 + breast cancer were identified and electronic medical records reviewed. A no-trastuzumab cohort of 116 women diagnosed between January 1, 1999 and May 14, 2004 and a trastuzumab cohort of 128 women diagnosed between May 16, 2006 and December 31, 2010 were identified. Overall survival and distant relapse-free survival were estimated by Kaplan-Meier methods. The median ages of the trastuzumab and no-trastuzumab cohorts were 62 and 64 years, respectively. More patients in the trastuzumab cohort had grade III (P = .001), lymphovascular invasion (P = .001), or estrogen receptor-negative (P cancers. The majority of the trastuzumab cohort received chemotherapy versus one-half of the no-trastuzumab cohort (98% vs. 53%; P women in the trastuzumab cohort and 1 in the no-trastuzumab cohort developed symptomatic heart failure. There were no cardiac-related deaths in either arm. Following adjuvant trastuzumab with chemotherapy, selected older women with small, node-negative, HER2 + breast cancers have excellent disease control. The rate of cardiac events is low. Copyright © 2016 Elsevier Inc. All rights reserved.

Trastuzumab produces therapeutic actions by upregulating miR-26a and miR-30b in breast cancer cells.

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Takehiro Ichikawa

Full Text Available OBJECTIVE: Trastuzumab has been used for the treatment of HER2-positive breast cancer (BC. However, a subset of BC patients exhibited resistance to trastuzumab therapy. Thus, clarifying the molecular mechanism of trastuzumab treatment will be beneficial to improve the treatment of HER2-positive BC patients. In this study, we identified trastuzumab-responsive microRNAs that are involved in the therapeutic effects of trastuzumab. METHODS AND RESULTS: RNA samples were obtained from HER2-positive (SKBR3 and BT474 and HER2-negetive (MCF7 and MDA-MB-231 cells with and without trastuzumab treatment for 6 days. Next, we conducted a microRNA profiling analysis using these samples to screen those microRNAs that were up- or down-regulated only in HER2-positive cells. This analysis identified miR-26a and miR-30b as trastuzumab-inducible microRNAs. Transfecting miR-26a and miR-30b induced cell growth suppression in the BC cells by 40% and 32%, respectively. A cell cycle analysis showed that these microRNAs induced G1 arrest in HER2-positive BC cells as trastuzumab did. An Annexin-V assay revealed that miR-26a but not miR-30b induced apoptosis in HER2-positive BC cells. Using the prediction algorithms for microRNA targets, we identified cyclin E2 (CCNE2 as a target gene of miR-30b. A luciferase-based reporter assay demonstrated that miR-30b post-transcriptionally reduced 27% (p = 0.005 of the gene expression by interacting with two binding sites in the 3'-UTR of CCNE2. CONCLUSION: In BC cells, trastuzumab modulated the expression of a subset of microRNAs, including miR-26a and miR-30b. The upregulation of miR-30b by trastuzumab may play a biological role in trastuzumab-induced cell growth inhibition by targeting CCNE2.

Treatment of HER2-positive breast carcinomatous meningitis with intrathecal administration of {alpha}-particle-emitting {sup 211}At-labeled trastuzumab

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Boskovitz, Abraham; McLendon, Roger E.; Okamura, Tatsunori [Department of Pathology, Duke University Medical Center, Durham, NC 27710 (United States); Sampson, John H. [Department of Surgery, Duke University Medical Center, Durham, NC 27710 (United States); Bigner, Darell D. [Department of Pathology, Duke University Medical Center, Durham, NC 27710 (United States); Zalutsky, Michael R. [Department of Radiology, Duke University Medical Center, Durham, NC 27710 (United States)], E-mail: zalut001@mc.duke.edu

2009-08-15

Introduction: Carcinomatous meningitis (CM) is a devastating disease characterized by the dissemination of malignant tumor cells into the subarachnoid space along the brain and spine. Systemic treatment with monoclonal antibody (mAb) trastuzumab can be effective against HER2-positive systemic breast carcinoma but, like other therapies, is ineffective against CM. The goal of this study was to evaluate the therapeutic effect of {alpha}-particle emitting {sup 211}At-labeled trastuzumab following intrathecal administration in a rat model of breast carcinoma CM. Methods: Athymic rats were injected intrathecally with MCF-7/HER2-18 breast carcinoma cells through a surgically implanted indwelling intrathecal catheter. In Experiment 1, animals received 33 or 66 {mu}Ci {sup 211}At-labeled trastuzumab, cold trastuzumab or saline. In Experiment 2, animals were inoculated with a lower tumor burden and received 46 or 92 {mu}Ci {sup 211}At-labeled trastuzumab or saline. In Experiment 3, animals received 28 {mu}Ci {sup 211}At-labeled trastuzumab, 30 {mu}Ci {sup 211}At-labeled TPS3.2 control mAb or saline. Histopathological analysis of the neuroaxis was performed at the end of the study. Results: In Experiment 1, median survival increased from 21 days for the saline and cold trastuzumab groups to 45 and 48 days for 33 and 66 {mu}Ci {sup 211}At-labeled trastuzumab, respectively. In Experiment 2, median survival increased from 23 days for saline controls to 68 and 92 days for 46 and 92 {mu}Ci {sup 211}At-labeled trastuzumab, respectively. In Experiment 3, median survival increased from 20 days to 29 and 36 days for animals treated with {sup 211}At-labeled TPS3.2 and {sup 211}At-labeled trastuzumab, respectively. Long-term survivors were observed exclusively in the {sup 211}At-trastuzumab-treated groups. Conclusion: Intrathecal {sup 211}At-labeled trastuzumab shows promise as a treatment for patients with HER2-positive breast CM.

In vivo examination of {sup 188}Re(I)-tricarbonyl-labeled trastuzumab to target HER2-overexpressing breast cancer

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Chen, K.-T. [Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu 30013, Taiwan (China); Lee, T.-W. [Institute of Nuclear Energy Research, Longtan 32546, Taiwan (China); Lo, Jem-Mau [Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu 30013, Taiwan (China); Institute of Nuclear Engineering and Science, National Tsing Hua University, Hsinchu 30013, Taiwan (China)], E-mail: jmlo@mx.nthu.edu.tw

2009-05-15

Introduction: Trastuzumab (Herceptin), a humanized IgG1 monoclonal antibody directed against the extracellular domain of the HER2 protein, acts as an immunotherapeutic agent for HER2-overexpressing human breast cancers. Radiolabeled trastuzumab with {beta}- or {alpha} emitters can be used as radioimmunotherapeutic agent for the similar purpose but with additional radiation effect. Methods: In this study, trastuzumab was labeled with {sup 188}Re for radioimmunotherapy of HER2/neu-positive breast cancer. {sup 188}Re(I)-tricarbonyl ion, [{sup 188}Re(OH{sub 2}){sub 3}(CO){sub 3}]{sup +}, was employed as a precursor for directly labeling the monoclonal antibody with {sup 188}Re. The immunoreactivity of {sup 188}Re(I)-trastuzumab was estimated by competition receptor-binding assay using HER2/neu-overexpressive BT-474 human breast cancer cells. The localization properties of {sup 188}Re(I)-trastuzumab within both tumor and normal tissues of athymic mice bearing BT-474 human breast cancer xenografts (HER2/neu-overexpressive) and similar mice bearing MCF-7 human breast cancer xenografts (HER2/neu-low expressive) were investigated. Results: When incubated with human serum albumin and histidine at 25{sup o}C, {sup 188}Re(I)-trastuzumab was found to be stable within 24 h. The IC{sub 50} of {sup 188}Re(I)-trastuzumab was found to be 22.63{+-}4.57 nM. {sup 188}Re(I)-trastuzumab was shown to accumulate specifically in BT-474 tumor tissue in in vivo biodistribution studies. By microSPECT/CT, the image of {sup 188}Re localized BT-474 tumor was clearly visualized within 24 h. In contrast, {sup 188}Re(I)-trastuzumab uptake in HER2-low-expressing MCF-7 tumor was minimal, and the {sup 188}Re image at the localization of the tumor was dim. Conclusion: These results reveal that {sup 188}Re(I)-trastuzumab could be an appropriate radioimmunotherapeutic agent for the treatment of HER2/neu-overexpressing cancers.

Potential risk and benefit of the combination of trastuzumab to chemotherapy and radiation therapy in non-metastatic breast cancer; Benefice et risques potentiels de l'association du trastuzumab a la chimiotherapie et a la radiotherapie dans le cancer du sein non metastatique

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Belkacemi, Y. [CLCC Oscar-Lambret, Universite de Lille-2, Dept. d' Oncologie-Radiotherapie, 59 - Lille (France); Laharie-Mineur, H. [CLCC, institut Bergonie, 33 - Bordeaux (France); Gligorov, J. [APHP, Hopital Tenon, Cancer-Est, 75 - Paris (France); Azria, D. [CLCC Val d' Aurelle-Paul-Lamarque, Inserm, EMI 0227, 34 - Montpellier (France)

2007-09-15

Trastuzumab (Herceptin) is the first humanized monoclonal antibody targeting the HER2 antigen in breast cancer. HER2 receptor has been individualised 20 years ago. During the past 10 years, trastuzumab administration has radically modified the prognosis of the patients that are treated for HER2 positive breast cancer. Its efficacy has been demonstrated in the metastatic and adjuvant settings. While, trastuzumab based-regimens became the standard of care in the treatment of HER2/neu positive breast cancer, the optimal combination (concurrently or sequentially) to chemotherapy and radiation therapy is still unknown. Indeed, while the concurrent administration of trastuzumab and anthracyclines is not recommended because of a high risk of cardiac toxicity, there is no published data on the best sequence of trastuzumab and radiation therapy administration, particularly when internal mammary chain is involved. The benefit/risk ratio of the concurrent and sequential administration of trastuzumab with chemotherapy and radiation therapy will be discussed in this review. (authors)

Phase III randomized study comparing docetaxel plus trastuzumab with vinorelbine plus trastuzumab as first-line therapy of metastatic or locally advanced human epidermal growth factor receptor 2-positive breast cancer: the HERNATA study

DEFF Research Database (Denmark)

Andersson, Michael; Lidbrink, Elisabeth; Bjerre, Karsten

2011-01-01

To evaluate docetaxel or vinorelbine, both with trastuzumab, as first-line therapy of human epidermal growth factor receptor 2-positive advanced breast cancer.......To evaluate docetaxel or vinorelbine, both with trastuzumab, as first-line therapy of human epidermal growth factor receptor 2-positive advanced breast cancer....

Novel approaches to target HER2-positive breast cancer: trastuzumab emtansine

International Nuclear Information System (INIS)

Recondo, Gonzalo Jr; Vega, Maximo de la; Galanternik, Fernando; Díaz-Cantón, Enrique; Leone, Bernardo Amadeo; Leone, José Pablo

2016-01-01

The human epidermal growth factor receptor 2 (HER2) is overexpressed in 20% of breast carcinomas. Prior to the development of targeted therapies, HER2-positive breast cancer was associated with more aggressive disease and poor prognosis. Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that results from the combination of trastuzumab and DM1, a derivative of the antimicrotubule agent maytansine. This molecule has the ability to enhance cytotoxic drug delivery to specifically targeted cells that overexpress HER2, therefore, maximizing efficacy while sparing toxicity. In recent years, T-DM1 has shown to improve outcomes in metastatic HER2-positive breast cancer that is resistant to trastuzumab. In addition, T-DM1 is currently being tested in the neoadjuvant and adjuvant settings to identify patients who may benefit from this therapy. This review focuses on the mechanism of action, early and late-phase clinical trials, and ongoing studies of T-DM1 in HER2-positive breast cancer

Potential risk and benefit of the combination of trastuzumab to chemotherapy and radiation therapy in non-metastatic breast cancer

International Nuclear Information System (INIS)

Belkacemi, Y.; Laharie-Mineur, H.; Gligorov, J.; Azria, D.

2007-01-01

Trastuzumab (Herceptin) is the first humanized monoclonal antibody targeting the HER2 antigen in breast cancer. HER2 receptor has been individualised 20 years ago. During the past 10 years, trastuzumab administration has radically modified the prognosis of the patients that are treated for HER2 positive breast cancer. Its efficacy has been demonstrated in the metastatic and adjuvant settings. While, trastuzumab based-regimens became the standard of care in the treatment of HER2/neu positive breast cancer, the optimal combination (concurrently or sequentially) to chemotherapy and radiation therapy is still unknown. Indeed, while the concurrent administration of trastuzumab and anthracyclines is not recommended because of a high risk of cardiac toxicity, there is no published data on the best sequence of trastuzumab and radiation therapy administration, particularly when internal mammary chain is involved. The benefit/risk ratio of the concurrent and sequential administration of trastuzumab with chemotherapy and radiation therapy will be discussed in this review. (authors)

Cost-effectiveness analysis of trastuzumab in the adjuvant setting for treatment of HER2-positive breast cancer.

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Garrison, Louis P; Lubeck, Deborah; Lalla, Deepa; Paton, Virginia; Dueck, Amylou; Perez, Edith A

2007-08-01

Adding trastuzumab to adjuvant chemotherapy provides significant clinical benefit in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. A cost-effectiveness analysis was performed to assess clinical and economic implications of adding trastuzumab to adjuvant chemotherapy, based upon joint analysis of NSABP B-31 and NCCTG N9831 trials. A Markov model with 4 health states was used to estimate the cost utility for a 50-year-old woman on the basis of trial results through 4 years and estimates of long-term recurrence and death based on a meta-analysis of trials. From 6 years onward, rates of recurrence and death were assumed to be the same in both trastuzumab and chemotherapy-only arms. Incremental costs were estimated for diagnostic and treatment-related costs. Analyses were from payer and societal perspectives, and these analyses were projected to lifetime and 20-year horizons. Over a lifetime, the projected cost of trastuzumab per quality-adjusted life year (QALY; discount rate 3%) gained was 26,417 dollars (range 9,104 dollars-69,340 dollars under multiway sensitivity analysis). Discounted incremental lifetime cost was 44,923 dollars, and projected life expectancy was 3 years longer for patients who received trastuzumab (19.4 years vs 16.4 years). During a 20-year horizon, the projected cost of adding trastuzumab to chemotherapy was 34,201 dollars per QALY gained. Key cost-effectiveness drivers were discount rate, trastuzumab price, and probability of metastasis. The cost-effectiveness result was robust to sensitivity analysis. Trastuzumab for adjuvant treatment of early stage breast cancer was projected to be cost effective over a lifetime horizon, achieving a cost-effectiveness ratio below that of many widely accepted oncology treatments. (c) 2007 American Cancer Society.

Brain metastases in patients who receive trastuzumab-containing chemotherapy for HER2-overexpressing metastatic breast cancer

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Ono, Makiko; Ando, Masashi; Yunokawa, Mayu

2009-01-01

Recently, a high rate of brain metastases has been reported among patients with human epidermal growth factor receptor (HER2)-overexpressing metastatic breast cancer who were treated with trastuzumab. The present study examined risk factors for the development of brain metastasis in patients with HER2-overexpressing breast cancer who were treated with trastuzumab. We retrospectively reviewed 204 patients with HER-2-overexpressing breast cancer who were treated with a trastuzumab-containing regimen between 1999 and 2006. Patients with clinical symptoms were diagnosed as having brain metastases when brain magnetic resonance imaging (MRI) or a computed tomography (CT) scan revealed positive findings for brain metastases. The median follow-up time of this cohort was 53.6 months. Among the patients who received a trastuzumab-containing regimen, 74 patients (36.3%) developed brain metastases. The median survival from the diagnosis of brain metastases was 13.5 months (95% confidence interval [CI], 12.2-14.7 months). The median time interval between the beginning of trastuzumab treatment and the diagnosis of brain metastases was 13.6 months (range, 0.0-45.8 months). Among patients with brain metastases, the median overall survival period was 39 months. A multivariate logistic regression analysis showed that age (≤50 years), recurrent breast cancer, and liver metastases were significant risk factors for the development of brain metastases. Patients with HER2-overexpressing breast cancer treated with trastuzumab had a high incidence of brain metastases (36.3%). Routine screening for brain metastases 1 year after the start of trastuzumab treatment, may be warranted in younger patients (≤50 years) who had recurrent breast cancer with liver metastases. (author)

Cardiotoxicity of the adjuvant trastuzumab in a Saudi population: clinical experience of a single institution

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Hamed Rasha Hamdy

2016-06-01

Full Text Available Adjuvant trastuzumab is currently an internationally standard for the treatment of localised breast cancer that over express HER2 with the most adverse effect being cardiotoxicity. We conducted this study to evaluate the cardiac safety of trastuzumab in clinical practice.

Sanctuary site leptomeningeal metastases in HER-2 positive breast cancer: A review in the era of trastuzumab.

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Kordbacheh, T; Law, W Y; Smith, I E

2016-04-01

The development of trastuzumab and other targeted systemic therapies has transformed the management of HER-2 positive breast cancers. However, as patients live longer and systemic therapies may not cross the blood brain barrier a rising number of patients are developing leptomeningeal metastases and brain metastases as a sanctuary site of disease. Intrathecal trastuzumab has been reported to treat these. We describe a breast cancer patient with HER-2 positive leptomeningeal disease in the spinal cord successfully treated with intrathecal trastuzumab and methotrexate, alongside systemic anti-HER-2 therapy and radiotherapy. We also review the literature to date on the efficacy and safety of intrathecal trastuzumab, and recent evidence suggesting that intrathecal trastuzumab passes via the blood brain barrier into the serum to achieve intravenous concentrations similar to that seen with systemic therapy alone. Overall, intrathecal trastuzumab appears to be a safe and often effective treatment for leptomeningeal metastases in HER-2 positive breast cancer. Ongoing phase I and II studies are required to determine optimum dosing schedules, validate CSF and CSF-to-serum pharmacokinetics, determine efficacy, and to assess the added benefits or disadvantages of prior radiotherapy and concomitant systemic therapy. Copyright © 2016 Elsevier Ltd. All rights reserved.

The Effect of Adjuvant Trastuzumab on Locoregional Recurrence of Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer Treated with Mastectomy.

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Lanning, Ryan M; Morrow, Monica; Riaz, Nadeem; McArthur, Heather L; Dang, Chau; Moo, Tracy-Ann; El-Tamer, Mahmoud; Krause, Kate; Siu, Chun; Hsu, Meier; Zhang, Zhigang; Pei, Xin; McCormick, Beryl; Powell, Simon N; Ho, Alice

2015-08-01

Human epidermal growth factor receptor 2 (HER2) overexpression was associated with locoregional recurrence (LRR) in the preadjuvant trastuzumab era. This study aimed to examine the effect of trastuzumab on LRR in mastectomy patients and whether it varied with postmastectomy radiation (PMRT). From the authors' institutional database, 501 women with stages I-III HER2-positive breast cancer who underwent mastectomy from 1998 to 2007 were identified. A landmark analysis was performed to compare two cohorts: 170 women who received trastuzumab and 281 who did not. Kaplan-Meier methods were used to estimate locoregional recurrence-free survival (LRRFS). A propensity score analysis was used to balance the treatment groups with respect to multiple covariates. Analogous methods were used to study the effect of PMRT. The women in the trastuzumab group were more likely to be node positive and to receive systemic therapy or PMRT (p < 0.01). The 5-year LRRFS was 98 % in the trastuzumab troup versus 94 % in the no trastuzumab group [hazard ratio (HR) 0.31; 95 % confidence interval (CI) 0.09-1.09; p = 0.07]. After adjustment for multiple covariates, including receipt of chemotherapy and PMRT, trastuzumab decreased LRR rates (HR 0.21; 95 % CI 0.04-0.94; p = 0.04). Among the women who received PMRT, trastuzumab reduced the 5-year LRR rate (0 vs 5 %; p = 0.06). Among those who did not receive PMRT, trastuzumab did not significantly decrease LRR (3 vs 6 %; p = 0.26). High rates of locoregional control (5-year rate, 98 %) were observed among patients who received trastuzumab and mastectomy ± PMRT. Trastuzumab decreased LRR in HER2-positive women who received mastectomy and PMRT, suggesting that the largest benefit is seen in a higher-risk subset of patients.

(64)Cu-DOTA-trastuzumab PET imaging and HER2 specificity of brain metastases in HER2-positive breast cancer patients.

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Kurihara, Hiroaki; Hamada, Akinobu; Yoshida, Masayuki; Shimma, Schuichi; Hashimoto, Jun; Yonemori, Kan; Tani, Hitomi; Miyakita, Yasuji; Kanayama, Yousuke; Wada, Yasuhiro; Kodaira, Makoto; Yunokawa, Mayu; Yamamoto, Harukaze; Shimizu, Chikako; Takahashi, Kazuhiro; Watanabe, Yasuyoshi; Fujiwara, Yasuhiro; Tamura, Kenji

2015-01-01

The purpose of this study was to determine whether brain metastases from HER2-positive breast cancer could be detected noninvasively using positron emission tomography (PET) with (64)Cu-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-trastuzumab. PET was performed on five patients with brain metastases from HER2-positive breast cancer, at 24 or 48 h after the injection of approximately 130 MBq of the probe (64)Cu-DOTA-trastuzumab. Radioactivity in metastatic brain tumors was evaluated based on PET images in five patients. Autoradiography, immunohistochemistry (IHC), and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis were performed in one surgical case to confirm HER2 specificity of (64)Cu-DOTA-trastuzumab. Metastatic brain lesions could be visualized by (64)Cu-DOTA-trastuzumab PET in all of five cases, which might indicated that trastuzumab passes through the blood-brain barrier (BBB). The HER2 specificity of (64)Cu-DOTA-trastuzumab was demonstrated in one patient by autoradiography, immunohistochemistry, and LC-MS/MS. Cu-DOTA-trastuzumab PET could be a potential noninvasive procedure for serial identification of metastatic brain lesions in patients with HER2-positive breast cancer. UMIN000004170.

Trastuzumab in the adjuvant treatment of HER2-positive early breast cancer patients: a meta-analysis of published randomized controlled trials.

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Wenjin Yin

Full Text Available BACKGROUND: Adjuvant trastuzumab therapy has yielded conflicting results for overall survival, concerns about central nervous system (CNS metastasis, and questions about optimal schedule. Therefore, we carried out a meta-analysis to assess the benefits of concurrent or sequential trastuzumab with adjuvant chemotherapy for early breast cancer patients with HER2-positive tumors. METHODS: Computerized and manual searches were performed to identify randomized clinical trials comparing adjuvant chemotherapy with or without trastuzumab in HER2-positive early breast cancer patients. Odds ratios were used to estimate the association between the addition of trastuzumab to adjuvant chemotherapy and various survival outcomes. The fixed-effects or random-effects model was used to combine data. FINDINGS: With six eligible studies identified, this analysis demonstrated that patients with HER2-positive breast cancer derived benefit in disease-free survival, overall survival, locoregional recurrence and distant recurrence (all P<0.001 from the addition of trastuzumab to adjuvant chemotherapy, whereas trastuzumab did worse in CNS recurrence as compared to the control group (P = 0.018. Furthermore, concomitant use of trastuzumab significantly lowered the hazard of death (P<0.001 but bore a higher incidence of CNS recurrence (P = 0.010, while statistical significance failed to be discerned for either overall survival (P = 0.069 or CNS metastasis (P = 0.374 between the sequential and observation arms. CONCLUSION: This analysis verifies the efficacy of trastuzumab in the adjuvant setting. Additionally, our findings indirectly corroborate the superiority of concurrent trastuzumab to sequential use and also illuminate that prolonged survival is the possible reason for the higher incidence of CNS with trastuzumab versus observation.

Terapia combinada con Trastuzumab en el tratamiento del Cáncer de mama: eficacia y efectos adversos

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Hernández Martín, María Sol

2015-01-01

Introducción: El cáncer de mama es el más frecuente entre la población femenina. Entre un 25-30% de los cánceres de mama son HER2-positivo. Este tipo de cáncer, se ha relacionado con una mayor agresividad clínica e histológica, mayor riesgo de recurrencia y muerte asociada al cáncer de mama. Trastuzumab, es un anticuerpo monoclonal humanizado contra este receptor. Actualmente se dispone de cuatro agentes anti-HER2 autorizados: Trastuzumab, Pertuzumab, Lapatinib y Trastuzumab...

Radiotherapy and HER2: point on the association of ionizing radiation and trastuzumab

International Nuclear Information System (INIS)

Liem, X.; Lartigau, E.

2009-01-01

The addition of the two treatments (trastuzumab and radiotherapy) poses the problem of their toxicity addition, particularly at the cardiac level. The data speak in favour of trastuzumab continuation during radiotherapy, taken into account the benefits. Because of the technical advances in radiotherapy ( respiratory automatic control, intensity modulated radiotherapy, I.M.R.T.) it will be possible to avoid the mediastinum structures improving then the tolerance. (N.C.)

SU-C-201-05: Imaging 212Pb-TCMC-Trastuzumab for Alpha Radioimmunotherapy for Ovarian Cancer

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Shen, S; Meredith, R; Azure, M; Yoder, D [University of Alabama, Birmingham, AL (United States); Torgue, J; Banaga, E [AREVA Med LLC, Bethesda, MD (United States)

2015-06-15

Purpose: To support the phase I trial for toxicity, biodistribution and pharmacokinetics of intra-peritoneal (IP) 212Pb-TCMC-trastuzumab in patients with HER-2 expressing malignancy. A whole body gamma camera imaging method was developed for estimating amount of 212Pb-TCMC-trastuzumab left in the peritoneal cavity. Methods: {sup 212}Pb decays to {sup 212}Bi via beta emission. {sup 212}Bi emits an alpha particle at an average of 6.1 MeV. The 238.6 keV gamma ray with a 43.6% yield can be exploited for imaging. Initial phantom was made of saline bags with 212Pb. Images were collected for 238.6 keV with a medium energy general purpose collimator. There are other high energy gamma emissions (e.g. 511keV, 8%; 583 keV, 31%) that penetrate the septae of the collimator and contribute scatter into 238.6 keV. An upper scatter window was used for scatter correction for these high energy gammas. Results: A small source containing 212Pb can be easily visualized. Scatter correction on images of a small 212Pb source resulted in a ∼50% reduction in the full width at tenth maximum (FWTM), while change in full width at half maximum (FWHM) was <10%. For photopeak images, substantial scatter around phantom source extended to > 5 cm outside; scatter correction improved image contrast by removing this scatter around the sources. Patient imaging, in the 1st cohort (n=3) showed little redistribution of 212Pb-TCMC-trastuzumab out of the peritoneal cavity. Compared to the early post-treatment images, the 18-hour post-injection images illustrated the shift to more uniform anterior/posterior abdominal distribution and the loss of intensity due to radioactive decay. Conclusion: Use of medium energy collimator, 15% width of 238.6 keV photopeak, and a 7.5% upper scatter window is adequate for quantification of 212Pb radioactivity inside peritoneal cavity for alpha radioimmunotherapy of ovarian cancer. Research Support: AREVA Med, NIH 1UL1RR025777-01.

Modeling ERBB receptor-regulated G1/S transition to find novel targets for de novo trastuzumab resistance

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Thieffry Denis

2009-01-01

Full Text Available Abstract Background In breast cancer, overexpression of the transmembrane tyrosine kinase ERBB2 is an adverse prognostic marker, and occurs in almost 30% of the patients. For therapeutic intervention, ERBB2 is targeted by monoclonal antibody trastuzumab in adjuvant settings; however, de novo resistance to this antibody is still a serious issue, requiring the identification of additional targets to overcome resistance. In this study, we have combined computational simulations, experimental testing of simulation results, and finally reverse engineering of a protein interaction network to define potential therapeutic strategies for de novo trastuzumab resistant breast cancer. Results First, we employed Boolean logic to model regulatory interactions and simulated single and multiple protein loss-of-functions. Then, our simulation results were tested experimentally by producing single and double knockdowns of the network components and measuring their effects on G1/S transition during cell cycle progression. Combinatorial targeting of ERBB2 and EGFR did not affect the response to trastuzumab in de novo resistant cells, which might be due to decoupling of receptor activation and cell cycle progression. Furthermore, examination of c-MYC in resistant as well as in sensitive cell lines, using a specific chemical inhibitor of c-MYC (alone or in combination with trastuzumab, demonstrated that both trastuzumab sensitive and resistant cells responded to c-MYC perturbation. Conclusion In this study, we connected ERBB signaling with G1/S transition of the cell cycle via two major cell signaling pathways and two key transcription factors, to model an interaction network that allows for the identification of novel targets in the treatment of trastuzumab resistant breast cancer. Applying this new strategy, we found that, in contrast to trastuzumab sensitive breast cancer cells, combinatorial targeting of ERBB receptors or of key signaling intermediates does not

Imaging and biodistribution of Her2/neu expression in non-small cell lung cancer xenografts with 64Cu-labeled trastuzumab PET

International Nuclear Information System (INIS)

Paudyal, P.; Paudyal, B.; Hanaoka, Hirofumi

2010-01-01

Non-small cell lung carcinomas (NSCLC) overexpress the Her2/neu gene in approximately 59% of cases. Trastuzumab, a humanized monoclonal antibody, interferes with Her2 signaling and is approved for the treatment of Her2/neu overexpressing breast cancer. However, its therapeutic use in Her2/neu overexpressing NSCLC remains obscure. The present study aimed to determine the role of 64 Cu-labeled trastuzumab positron emission tomography (PET) for non-invasive imaging of Her2/neu expression in NSCLC. Trastuzumab was conjugated with the bifunctional chelator 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid (DOTA) and radiolabeled with 64 Cu. The molecular specificity of DOTA-trastuzumab was determined in NSCLC cell lines with Her2/neu overexpression (NCI-H2170) and negative expression (NCI-H520). Imaging of Her2/neu expression was performed in NCI-H2170 tumor-bearing mice with 64 Cu-DOTA-trastuzumab PET and 64 Cu-DOTA-immunoglobulin G (IgG). In vitro studies revealed specific binding of DOTA-trastuzumab in the Her2/neu positive NCI-H2170 cells, while no binding was seen in the Her2/neu negative NCI-H520 cell line. Biodistribution and PET studies revealed a significantly high accumulation of 64 Cu-DOTA-trastuzumab in the Her2/neu overexpressing NCI-H2170 tumor at 24 and 48 h post-injection (21.4±1.4% and 23.2±5.1% injection dose/gram (% ID/g), respectively). PET imaging of Her2/neu negative NCI-H520 tumors showed much less uptake of 64 Cu-DOTA-trastuzumab (4.0% ID/g). The NCI-H2170 tumor uptake of 64 Cu-DOTA-trastuzumab was significantly higher than that of 64 Cu-DOTA-IgG (P 64 Cu-DOTA-trastuzumab showed a very clear image of a Her2/neu positive tumor and appeared to be effective as a PET tracer for imaging of Her2/neu gene expression in NSCLC, suggesting its potential clinical use for identifying patients that might benefit from trastuzumab-based therapy. (author)

Efficacy and safety of short course adjuvant trastuzumab combination chemotherapy in breast cancer

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Sachin S Hingmire

2017-01-01

Full Text Available Background: The adjuvant short course 9-week trastuzumab combination therapy for human epidermal receptor 2 positive breast cancer patients may often be considered as a cost-effective and safe option and has important implications for the Indian subcontinent as well as other developing countries. However, such regimens of shorter duration trastuzumab therapy like FinHer, offered in view of economic constraints, may not be able to achieve globally comparable cure rates in early breast cancer especially with high-risk women with more than 3 lymph node positive. Methods and Material: Outcome of 21 patients with HER2 positive breast cancer was treated with short course trastuzumab combination chemotherapy in the adjuvant setting was studied. Results: Out of 21 patients 15 are alive and disease free with a follow up of up to 73 months (median follow up 42 months.

Medical resource utilization for administration of trastuzumab in a New Zealand oncology outpatient setting: a time and motion study

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North RT

2015-07-01

Full Text Available Richard T North,1 Vernon J Harvey,2 Levonne C Cox,2 Stuart N Ryan3 1Cancer and Haematology Service, Tauranga Hospital, Tauranga, 2Regional Cancer and Blood Centre, Auckland City Hospital, Auckland, 3Medical Affairs, Roche Products (New Zealand Ltd, Auckland, New Zealand Background: In New Zealand, trastuzumab is standard therapy for human epidermal growth factor receptor-2 (HER2-positive early and metastatic breast cancer. Given the requirement for ongoing adjuvant or maintenance treatment and intravenous (IV delivery, such a regimen consumes considerable health care resources. The development of a subcutaneous (SC trastuzumab formulation with a short administration time offers the potential to reduce hospital expenditure. The aim of this study was to determine medical resource utilization associated with administration of trastuzumab SC injection via handheld syringe vs trastuzumab IV infusion in patients with HER2-positive breast cancer in New Zealand. Methods: This noninterventional, descriptive study was conducted at the outpatient oncology centers at Auckland City and Tauranga Hospitals. Trained observers recorded times associated with health care professional (HCP tasks and consumables use associated with preparation and administration of trastuzumab IV or SC in women with early or metastatic breast cancer. The cost for each formulation was calculated as the mean cost of HCP time (based on Pharmaceutical Management Agency hourly rates plus the mean cost of consumables used. Results: Use of trastuzumab SC vs IV reduced mean chair time by 36.95 minutes and total nurse time by 6.12 minutes; there was a 20.45-minute reduction in pharmacist time when the SC formulation was used. After adding consumable costs, the overall estimated saving with trastuzumab SC vs IV was $76.94 (New Zealand dollars per patient per cycle. Conclusions: Compared with trastuzumab IV infusion, administration of trastuzumab via SC injection reduced time spent in the

Targeted delivery of doxorubicin-utilizing chitosan nanoparticles surface-functionalized with anti-Her2 trastuzumab

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Yousefpour P

2011-09-01

Full Text Available Parisa Yousefpour1, Fatemeh Atyabi2, Ebrahim Vasheghani-Farahani3, Ali-Akbar Mousavi Movahedi1, Rassoul Dinarvand21Department of Biotechnology, Faculty of Science, University of Tehran, 2Nanotechnology Research Centre, Faculty of Pharmacy, Tehran University of Medical Sciences, 3Biotechnology Group, Department of Chemical Engineering, Faculty of Engineering, Tarbiat Modares University, Tehran, IranBackground: Targeting drugs to their sites of action to overcome the systemic side effects associated with most antineoplastic agents is still a major challenge in pharmaceutical research. In this study, the monoclonal antibody, trastuzumab, was used as a targeting agent in nanoparticles carrying the antitumor drug, doxorubicin, specifically to its site of action.Methods: Chitosan-doxorubicin conjugation was carried out using succinic anhydride as a crosslinker. Trastuzumab was conjugated to self-assembled chitosan-doxorubin conjugate (CS-DOX nanoparticles (particle size, 200 nm via thiolation of lysine residues and subsequent linking of the resulted thiols to chitosan. Conjugation was confirmed by gel permeation chromatography, differential scanning calorimetry, Fourier transform infrared spectroscopy, and 1H nuclear magnetic resonance spectroscopy studies. Dynamic light scattering, transmission electron microscopy, and zeta potential determination were used to characterize the nanoparticles.Results: CS-DOX conjugated nanoparticles had a spherical shape and smooth surface with a narrow size distribution and core-shell structure. Increasing the ratio of doxorubicin to chitosan in the conjugation reaction gave rise to a higher doxorubicin content but lower conjugation efficiency. Trastuzumab-decorated nanoparticles (CS-DOX-mAb contained 47 µg/mg doxorubicin and 33.5 µg/mg trastuzumab. Binding of trastuzumab to the nanoparticles was further probed thermodynamically by isothermal titration calorimetry. Fluorescence microscopy demonstrated enhanced and

Long-Term Follow-Up of Cardiac Function and Quality of Life for Patients in NSABP Protocol B-31/NRG Oncology: A Randomized Trial Comparing the Safety and Efficacy of Doxorubicin and Cyclophosphamide (AC) Followed by Paclitaxel With AC Followed by Paclitaxel and Trastuzumab in Patients With Node-Positive Breast Cancer With Tumors Overexpressing Human Epidermal Growth Factor Receptor 2.

Science.gov (United States)

Ganz, Patricia A; Romond, Edward H; Cecchini, Reena S; Rastogi, Priya; Geyer, Charles E; Swain, Sandra M; Jeong, Jong-Hyeon; Fehrenbacher, Louis; Gross, Howard M; Brufsky, Adam M; Flynn, Patrick J; Wahl, Tanya A; Seay, Thomas E; Wade, James L; Biggs, David D; Atkins, James N; Polikoff, Jonathan; Zapas, John L; Mamounas, Eleftherios P; Wolmark, Norman

2017-12-10

Purpose Early cardiac toxicity is a risk associated with adjuvant chemotherapy plus trastuzumab. However, objective measures of cardiac function and health-related quality of life are lacking in long-term follow-up of patients who remain cancer free after completion of adjuvant treatment. Patients and Methods Patients in NSABP Protocol B-31 received anthracycline and taxane chemotherapy with or without trastuzumab for adjuvant treatment of node-positive, human epidermal growth factor receptor 2-positive early-stage breast cancer. A long-term follow-up assessment was undertaken for patients who were alive and disease free, which included measurement of left ventricular ejection fraction by multigated acquisition scan along with patient-reported outcomes using the Duke Activity Status Index (DASI), the Medical Outcomes Study questionnaire, and a review of current medications and comorbid conditions. Results At a median follow-up of 8.8 years among eligible participants, five (4.5%) of 110 in the control group and 10 (3.4%) of 297 in the trastuzumab group had a > 10% decline in left ventricular ejection fraction from baseline to a value < 50%. Lower DASI scores correlated with age and use of medications for hypertension, cardiac conditions, diabetes, and hyperlipidemia, but not with whether patients had received trastuzumab. Conclusion In patients without underlying cardiac disease at baseline, the addition of trastuzumab to adjuvant anthracycline and taxane-based chemotherapy does not result in long-term worsening of cardiac function, cardiac symptoms, or health-related quality of life. The DASI questionnaire may provide a simple and useful tool for monitoring patient-reported changes that reflect cardiac function.

Phase II study of paclitaxel given once per week along with trastuzumab and pertuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer.

Science.gov (United States)

Dang, Chau; Iyengar, Neil; Datko, Farrah; D'Andrea, Gabriella; Theodoulou, Maria; Dickler, Maura; Goldfarb, Shari; Lake, Diana; Fasano, Julie; Fornier, Monica; Gilewski, Theresa; Modi, Shanu; Gajria, Devika; Moynahan, Mary Ellen; Hamilton, Nicola; Patil, Sujata; Jochelson, Maxine; Norton, Larry; Baselga, Jose; Hudis, Clifford

2015-02-10

The CLEOPATRA (Clinical Evaluation of Trastuzumab and Pertuzumab) study demonstrated superior progression-free survival (PFS) and overall survival when pertuzumab was added to trastuzumab and docetaxel. Paclitaxel given once per week is effective and less toxic than docetaxel. We performed a phase II study to evaluate the efficacy and safety of pertuzumab and trastuzumab with paclitaxel given once per week. Patients with metastatic human epidermal growth factor receptor 2-positive breast cancer with zero to one prior therapy were enrolled. Treatment consisted of paclitaxel 80 mg/m(2) once per week plus trastuzumab (8 mg/kg loading dose → 6 mg/kg) once every 3 weeks plus pertuzumab (840 mg loading dose → 420 mg) once every 3 weeks, all given intravenously. The primary end point was 6-month PFS assessed by Kaplan-Meier methods. From January 2011 to December 2013, we enrolled 69 patients: 51 (74%) and 18 (26%) treated in first- and second-line metastatic settings, respectively. At a median follow-up of 21 months (range, 3 to 38 months), 6-month PFS was 86% (95% CI, 75% to 92%). The median PFS was 19.5 months (95% CI, 14 to 26 months) overall. PFS was 24.2 months (95% CI, 14 months to not reached [NR]) and 16.4 months (95% CI, 8.5 months to NR) for those without and with prior treatment, respectively. At 1 year, Kaplan-Meier PFS was 70% (95% CI, 56% to 79%) overall, 71% (95% CI, 55% to 82%) for those without prior therapy, and 66% (95% CI, 40% to 83%) for those with prior therapy. Treatment was well-tolerated; there was no febrile neutropenia or symptomatic left ventricular systolic dysfunction. Paclitaxel given once per week with trastuzumab and pertuzumab is highly active and well tolerated and seems to be an effective alternative to docetaxel-based combination therapy. © 2014 by American Society of Clinical Oncology.

Safety of trastuzumab (Herceptin) during pregnancy: two case reports.

LENUS (Irish Health Repository)

Goodyer, Matthew J

2009-01-01

We report on two cases of women on trastuzumab therapy for breast cancer who became pregnant and delivered healthy live infants. At the time of reporting the children are growing and developing normally (ages 3 and 2).

Brain metastases from breast cancer: prognostic significance of HER-2 overexpression, effect of trastuzumab and cause of death

International Nuclear Information System (INIS)

Le Scodan, Romuald; Jouanneau, Ludivine; Massard, Christophe; Gutierrez, Maya; Kirova, Youlia; Cherel, Pascal; Gachet, Julie; Labib, Alain; Mouret-Fourme, Emmanuelle

2011-01-01

To access the prognostic significance of HER-2 overexpression, the effect of trastuzumab and the cause of death in patients with brain metastases (BM) from breast cancer (BC). We analyzed the outcome of 130 patients with BM from BC who received whole-brain radiotherapy (WBRT) (without surgery or radiosurgery) between January 1998 and April 2006. Demographic data, tumor characteristics, and treatments were prospectively recorded. The impact of HER-2 overexpression and trastuzumab-based therapy on overall survival (OS) and the cause of death were evaluated. The median follow-up for the whole population was 6.25 months (mean: 9.15; range: 0.23-53). The median survival time and 1-year survival rates after BM diagnosis were 7.43 months and 35.8% (95% CI: 28-45.7) respectively. The median survival time for HER-2 negative patients (n = 78), HER-2 positive patients not treated with trastuzumab (n = 20) and HER-2 positive patients treated with trastuzumab (n = 32) were 5.9 months, 5.6 months and 19.53 months, respectively. The 1-year survival rates were 26.1%, 29.2% and 62.6% respectively, (p < 0.004). Among the 18 HER-2 positive patients treated with trastuzumab who died, 11 (61%) apparently succumbed from CNS progression, in the face of stable or responsive non-CNS disease. Trastuzumab-based therapy was associated with a 51% reduction in the risk of death (multiadjusted hazard ratio: 0.49; 95% CI, 0.29-0.83). In our experience, trastuzumab-based therapy for HER-overexpressing tumors was associated with improved survival in BM BC patients. This subgroup of patients may benefit from innovative approaches, in order to obtain better intra cerebral control

Human epidermal growth factor receptor 2-positive breast cancer: which cytotoxic agent best complements trastuzumab's efficacy in vitro?

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Hurrell T

2013-06-01

Full Text Available Tracey Hurrell, Kim OuthoffDepartment of Pharmacology, University of Pretoria, Pretoria, South AfricaIntroduction: Despite trastuzumab having enhanced selectivity for human epidermal growth factor receptor 2 (HER-2 overexpressing breast cancer cells, treatment is hampered by interindividual variation and tumors with high mitogenic potential. The lack of significant clinical benefit in certain patient cohorts suggests that HER-2 expression is ineffective as a sole prognostic indicator of response to therapy. Therefore, optimizing the clinical role of trastuzumab in drug combinations remains critical for clinical success.Aim: To investigate the effects of trastuzumab in combination with either doxorubicin or geldanamycin on in vitro cell viability, cell cycling, apoptosis and relative HER-2 expression in HER-2-positive (SK-BR-3 and estrogen receptor-positive (MCF-7 breast adenocarcinoma models.Results: HER-2-rich SK-BR-3 cells demonstrated a greater sensitivity to the effects of doxorubicin than MCF-7 cells. Concurrent trastuzumab exposure resulted in a further reduction in cell viability. This decreased cell viability induced by doxorubicin was associated with activation of executioner caspases as well as with alterations in cell-cycle kinetics, primarily promoting S-phase accumulation. Doxorubicin had no effect on surface HER-2 density expression. Geldanamycin reduced cell viability significantly greater in SK-BR-3 than MCF-7 cells, and was associated with G2 cell-cycle accumulation. The addition of trastuzumab did not augment these effects. Geldanamycin promoted substantial reductions in relative surface HER-2 density in SK-BR-3 cells.Conclusion: The in vitro data supported the rationale for using doxorubicin in trastuzumab-based therapies. Therefore, despite the incidence of cardiotoxicity, doxorubicin could retain a fundamental role in treating HER-2-positive breast cancer. While geldanamycin is a potent cytotoxic agent, its concurrent use

Switching between intravenous and subcutaneous trastuzumab: safety results from the PrefHer trial

OpenAIRE

Gligorov, Joseph; Curigliano, Giuseppe; Müller, Volkmar; Knoop, Ann; Jenkins, Valerie; Verma, Sunil; Osborne, Stuart; Lauer, Sabine; Machackova, Zuzana; Fallowfield, Lesley; Pivot, Xavier

2017-01-01

Aim: To assess the safety and tolerability of switching between subcutaneous (SC) and intravenous (IV) trastuzumab in the PrefHer study (NCT01401166).\\ud \\ud Patients and methods: Patients with HER2-positive early breast cancer completed (neo)adjuvant chemotherapy and were randomised to receive four cycles of SC trastuzumab, via single-use injection device (SID; Cohort 1) or hand-held syringe (Cohort 2), followed by four cycles of IV, or vice versa (the crossover period presented here) as par...

Circulating HER2 DNA after trastuzumab treatment predicts survival and response in breast cancer

DEFF Research Database (Denmark)

Sorensen, Boe S; Mortensen, Lise S; Andersen, Jørn

2010-01-01

BACKGROUND: Only a subset of breast cancer patients responds to the HER2 inhibitor trastuzumab, and methods to identify responders are needed. PATIENTS AND METHODS: We studied 28 patients with metastatic breast cancer that had amplified human epidermal growth factor receptor 2 (HER2) genes...... in their primary tumour and were treated with a combination of trastuzumab and chemotherapy. Plasma was collected and amplification of the HER2 gene in circulating DNA and the amounts of the extracellular domain (ECD) of HER2 were measured just before first treatment (n=28) and just before second treatment three...... response (p=0.02), and overall survival (p=0.05). HER2 ECD kinetics did not correlate to clinical data. CONCLUSION: We suggest that a decrease in HER2 gene amplification in the plasma predicts a more favourable response to trastuzumab....

A time and motion study of subcutaneous versus intravenous trastuzumab in patients with HER2-positive early breast cancer

DEFF Research Database (Denmark)

De Cock, Erwin; Pivot, Xavier; Hauser, Nik

2016-01-01

Within PrefHer (NCT01401166), patients and healthcare professionals (HCPs) preferred subcutaneous (SC) over intravenous (IV) trastuzumab. We undertook a prospective, observational time and motion study to quantify patients' time in infusion chairs and active HCP time in PrefHer. Patients with HER2......-positive early breast cancer received four adjuvant cycles of SC trastuzumab (600 mg fixed dose via SC single-use injection device [SID, Cohort 1] or SC handheld syringe [HHS, Cohort 2]) then four cycles of standard IV trastuzumab or the reverse sequence. Generic case report forms for IV and SC management...... (range across countries: 4-16; P trastuzumab, delivered via SID or HHS, saved patient chair and active HCP times versus IV infusion, supporting a transition to either SC method....

Phase II Study of Paclitaxel Given Once per Week Along With Trastuzumab and Pertuzumab in Patients With Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer

Science.gov (United States)

Dang, Chau; Iyengar, Neil; Datko, Farrah; D'Andrea, Gabriella; Theodoulou, Maria; Dickler, Maura; Goldfarb, Shari; Lake, Diana; Fasano, Julie; Fornier, Monica; Gilewski, Theresa; Modi, Shanu; Gajria, Devika; Moynahan, Mary Ellen; Hamilton, Nicola; Patil, Sujata; Jochelson, Maxine; Norton, Larry; Baselga, Jose; Hudis, Clifford

2015-01-01

Purpose The CLEOPATRA (Clinical Evaluation of Trastuzumab and Pertuzumab) study demonstrated superior progression-free survival (PFS) and overall survival when pertuzumab was added to trastuzumab and docetaxel. Paclitaxel given once per week is effective and less toxic than docetaxel. We performed a phase II study to evaluate the efficacy and safety of pertuzumab and trastuzumab with paclitaxel given once per week. Patients and Methods Patients with metastatic human epidermal growth factor receptor 2–positive breast cancer with zero to one prior therapy were enrolled. Treatment consisted of paclitaxel 80 mg/m2 once per week plus trastuzumab (8 mg/kg loading dose → 6 mg/kg) once every 3 weeks plus pertuzumab (840 mg loading dose → 420 mg) once every 3 weeks, all given intravenously. The primary end point was 6-month PFS assessed by Kaplan-Meier methods. Results From January 2011 to December 2013, we enrolled 69 patients: 51 (74%) and 18 (26%) treated in first- and second-line metastatic settings, respectively. At a median follow-up of 21 months (range, 3 to 38 months), 6-month PFS was 86% (95% CI, 75% to 92%). The median PFS was 19.5 months (95% CI, 14 to 26 months) overall. PFS was 24.2 months (95% CI, 14 months to not reached [NR]) and 16.4 months (95% CI, 8.5 months to NR) for those without and with prior treatment, respectively. At 1 year, Kaplan-Meier PFS was 70% (95% CI, 56% to 79%) overall, 71% (95% CI, 55% to 82%) for those without prior therapy, and 66% (95% CI, 40% to 83%) for those with prior therapy. Treatment was well-tolerated; there was no febrile neutropenia or symptomatic left ventricular systolic dysfunction. Conclusion Paclitaxel given once per week with trastuzumab and pertuzumab is highly active and well tolerated and seems to be an effective alternative to docetaxel-based combination therapy. PMID:25547504

Radiolabeled Antibody Fragment for Preparation of (177Lu-DOTAm-PAMAM G3.0-F(ab’2 trastuzumab as a Radiopharmaceutical for Cancer Therapy

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R.D. Haryuni

2017-06-01

Full Text Available Several radiolabeled monoclonal antibodies (mAbs have been used as radioimmunotherapy (RIT agents for cancer therapy. The use of mAbs as RIT agents is due to their ability to carry effectors, in the form of radionuclides which emit alpha (α particles, beta (β particles, or auger electrons, and bind specifically to cancer expressed receptor. This paper reports the preparation of radiolabelled trastuzumab in form of (177Lu-DOTAm-PAMAM G3-F(ab'2-trastuzumab, which will be expected as a potential RIT agent for therapy of breast cancer overexpressed human epidermal growth factor receptor 2 (HER2. Due to its reduced molecular weight, the use of F(ab'2-trastuzumab on the aforementioned RIT agent candidate is expected to reach its target much faster compared to the intact trastuzumab. Meanwhile, the role of PAMAM G3 is to increase the specific activity of the radiotherapeutic agent of Lu-177 due to the ability of its 32 –NH2 functional groups that are able to bind many DOTAs (£ 31 which in turn can bind a large number of 177Lu. The preparation was initiated by fragmentation of trastuzumab using pepsin enzyme in 0.02 M acetic acid buffer with a pH of 4.5 to produce F(ab'2-trastuzumab with a purity of 95 % after purification with PD-10 column. The F(ab'2-trastuzumab was then reacted with succinimidyl 4-(N-maleimidomethyl cyclohexane-1-carboxylate (SMCC to produce SMCC-F(ab'2-trastuzumab. The next reaction was to conjugate SMCC-F(ab'2-trastuzumab with DOTA-PAMAM G3.0-SH, which was prepared by reaction NHS-DOTA with PAMAM G3.0 and followed by reacting it with 2-iminothiolane to give (DOTAm-PAMAM G3.0-F(ab'2-trastuzumab. Finally, the (DOTAm-PAMAM G3.0-F(ab'2-trastuzumab was radiolabelled with 177Lu to produce (177Lu-DOTAm-PAMAM G3.0-F(ab'2-trastuzumab, resulting in a radiochemical purity of 98 % after purification with PD-10 column.Received: 31 October 2015; Revised: 30 June 2016; Accepted: 25 September 2016

Assessing the real-world cost-effectiveness of adjuvant trastuzumab in HER-2/neu positive breast cancer.

LENUS (Irish Health Repository)

Hedden, Lindsay

2012-01-01

Among women with surgically removed, high-risk HER-2\\/neu-positive breast cancer, trastuzumab has demonstrated significant improvements in disease-free and overall survival. The objective of this study is to evaluate the cost-effectiveness of the currently recommended 12-month adjuvant protocol of trastuzumab using a Markov modeling approach and real-world cost data.

HERMIONE: a randomized Phase 2 trial of MM-302 plus trastuzumab versus chemotherapy of physician’s choice plus trastuzumab in patients with previously treated, anthracycline-naïve, HER2-positive, locally advanced/metastatic breast cancer

International Nuclear Information System (INIS)

Miller, Kathy; Cortes, Javier; Hurvitz, Sara A.; Krop, Ian E.; Tripathy, Debu; Verma, Sunil; Riahi, Kaveh; Reynolds, Joseph G.; Wickham, Thomas J.; Molnar, Istvan; Yardley, Denise A.

2016-01-01

Human epidermal growth factor receptor 2 (HER2)-positive breast cancer is a particularly aggressive form of the disease, and ultimately progresses in patients with metastases on standard therapies. Anthracyclines, such as doxorubicin, are an effective treatment for HER2-positive breast cancer, particularly when administered in combination with trastuzumab – however, doxorubicin-related cardiotoxicity has limited its use. Many patients are therefore never treated with anthracyclines, even upon disease progression, despite the potential for benefit. MM-302 is a novel, HER2-targeted antibody–liposomal doxorubicin conjugate that specifically targets HER2-overexpressing cells. Preclinical and Phase 1 data suggest that MM-302, as a monotherapy or in combination with trastuzumab, could be effective for managing previously treated, anthracycline-naïve, HER2-positive breast cancer, without the cardiotoxicity observed with free doxorubicin formulations. HERMIONE is an open-label, multicenter, randomized (1:1) Phase 2 trial of MM-302 plus trastuzumab versus chemotherapy of physician’s choice (gemcitabine, capecitabine, or vinorelbine) plus trastuzumab planned to enroll 250 anthracycline-naïve patients with locally advanced/metastatic HER2-positive breast cancer. Key inclusion criteria are: previous treatment with trastuzumab (with or without pertuzumab) in any setting; refractory or intolerant to pertuzumab (refractory to pertuzumab defined as progression in the locally advanced or metastatic setting, or disease recurrence during or within 12 months of completing pertuzumab-containing neoadjuvant and/or adjuvant therapy); and disease progression on, or intolerant to, ado-trastuzumab emtansine for locally advanced or metastatic disease. The trial is currently being conducted at sites in the USA, Canada, and Western Europe. Treatment will be administered in 21-day cycles, and will be continued until disease progression or unacceptable toxicity. The primary endpoint is

Preclinical evaluation of [ 111 In]-DOTA-trastuzumab for clinical trials

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Behrouz Alirezapour

2014-01-01

Full Text Available Context: Herceptin and its fragments have been radiolabeled and used in the imaging of human epidermal growth factor receptor 2 (HER2/neu-positive tumors and development of diagnostic kits is of great importance in radiopharmacy. Aims: In this study, 111 In-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-trastuzumab ( 111 In-DOTA-trastuzumab was successively prepared and evaluated for ultimate use in the HER2 antigen imaging in oncology. Settings and Design: The conjugate was prepared, labeled and evaluated using in vitro (radioimmunoassay [RIA], enzyme-linked immunosorbent assay (ELISA, stability, binding, internalization/in vivo (bio-distribution, single-photon emission computed tomography [SPECT] experiments. Materials and Methods: 111 In-DOTA-trastuzumab was prepared followed by determination of radiochemical purity (RCP, integrity of protein, immunoreactivity of radiolabeled antibody with HER2/neu antigen (by SkBr3 cell line binding and RIA methods were determined followed by stability tests, internalization studies and the tissue bio-distribution determination in wild-type rats as well as SPECT imaging in SkBr3-bearing mice. Statistical Analysis Used: All values were expressed as mean ± standard deviation (mean ± SD and the data were compared using Student′s t-test. Statistical significance was defined as P 95 ± 0.5%, S.A. 5.3 μCi/μg with the average number of chelators per antibody of 6:1 showing significant immune-reactivity retention using ELISA. In vitro stability was >90% in phosphate buffered saline and 80 ± 0.5% in serum over 48 h. Cell binding was significant (>0.79. In vitro internalization reached up to %12-13 in 10 h. Significant tumor uptake was observed. Conclusions: In vitro and in vivo/SPECT imaging in SkBr3-bearing mice demonstrated that 111 In-DOTA-trastuzumab is a potential compound for molecular imaging of SPECT for diagnosis and follow-up of HER2 expression in oncology.

The Efficacy of Trastuzumab in Animal Models of Breast Cancer: A Systematic Review and Meta-Analysis.

Directory of Open Access Journals (Sweden)

Jiarong Chen

Full Text Available Breast cancer is the most frequent cancers and is the second leading cause of cancer death among women. Trastuzumab is an effective treatment, the first monoclonal antibody directed against the human epidermal growth factor receptor 2 (HER2. To inform the development of other effective treatments we report summary estimates of efficacy of trastuzumab on survival and tumour volume in animal models of breast cancer.We searched PubMed and EMBASE systematically to identify publications testing trastuzumab in animal models of breast cancer. Data describing tumour volume, median survival and animal features were extracted and we assessed quality using a 12-item checklist. We analysed the impact of study design and quality and evidence for publication bias.We included data from 83 studies reporting 169 experiments using 2076 mice. Trastuzumab treatment caused a substantial reduction in tumour growth, with tumours in treated animals growing to 32.6% of the volume of tumours in control animals (95%CI 27.8%-38.2%. Median survival was prolonged by a factor of 1.45 (1.30-1.62. Many study design and quality features accounted for between-study heterogeneity and we found evidence suggesting publication bias.We have found trastuzumab to be effective in animal breast cancer models across a range of experimental circumstances. However the presence of publication bias and a low prevalence of measures to reduce bias provide a focus for future improvements in preclinical breast cancer research.

Optimized preparation and preliminary evaluation of [64Cu]-DOTA-trastuzumab for targeting ErbB2/Neu expression

International Nuclear Information System (INIS)

Behrooz Alirezapour; Mohammad Javad Rasaee

2013-01-01

Breast cancer radioimmunoscintigraphy targeting HER2/neu expression is a growing field of work in nuclear medicine research. Trastuzumab is a monoclonal antibody that binds with high affinity to HER2/neu, which is over expressed on breast and other tumors. Developing new tracers for the detection of this cancer is of great interest. In this study, trastuzumab was successively labeled with [ 64 Cu]CuCl 2 after conjugation with DOTA-NHS-ester. The conjugate was purified by molecular filtration, the average number of DOTA conjugated per mAb was calculated and total concentration was determined by spectrophotometric method. DOTA-trastuzumab was labeled with 64 Cu produced by 68 Zn(p,αn) 64 Cu nuclear reaction (30 MeV protons at 180 μA). Radiochemical purity, integrity of protein after radiolabeling and immunoreactivity of radiolabeled mAb trastuzumab with HER2/neu antigen and SkBr3 cell line were performed by RIA. In vitro stability of radiolabeled mAb in human serum was determined by thin layer chromatography. In vitro internalization studies were performed with the SkBr3 cell line and the tissue biodistribution of the 64 Cu-DOTA-trastuzumab was evaluated in wild-type rat (90 ± 5.5 μCi, 2, 6, 12, 24 h p.i.). The radioimmunoconjugate was prepared with a radiochemical purity of higher than 96 ± 0.5 % (ITLC) and specific activity as high as 5.3 μCi/μg. The average number of chelators per antibody for the conjugate used in this study was 5.8/1. The sample was showed to have similar patterns of migration in the gel electrophoresis. The 64 Cu-DOTA-trastuzumab showed high immunoreactivity towards HER2/neu antigen and SkBr3 cell line. In vitro stability of the labeled product was found to be more than 94 % in PBS and 82 ± 0.5 % in human serum over 48 h. In vitro internalization studies of the 64 Cu-DOTA-trastuzumab showed that up to 11.5 % of the radioimmunoconjugate internalized after 10 h. The accumulation of the radiolabeled mAb in liver, skin, intestine, lung

p95HER2 Methionine 611 Carboxy-Terminal Fragment Is Predictive of Trastuzumab Adjuvant Treatment Benefit in the FinHer Trial.

Science.gov (United States)

Sperinde, Jeff; Huang, Weidong; Vehtari, Aki; Chenna, Ahmed; Kellokumpu-Lehtinen, Pirkko-Liisa; Winslow, John; Bono, Petri; Lie, Yolanda S; Petropoulos, Christos J; Weidler, Jodi; Joensuu, Heikki

2018-03-13

Purpose: Expression of p95HER2 (p95), a truncated form of the HER2 receptor, which lacks the trastuzumab binding site but retains kinase activity, has been reported as a prognostic biomarker for poor outcomes in patients with trastuzumab-treated HER2-positive metastatic breast cancer. The impact of p95 expression on trastuzumab treatment efficacy in early HER2-positive breast cancer is less clear. In the current study, p95 was tested as a predictive marker of trastuzumab treatment benefit in the HER2-positive subset of the FinHer adjuvant phase III trial. Experimental Design: In the FinHer trial, 232 patients with HER2-positive early breast cancer were randomized to receive chemotherapy plus 9 weeks of trastuzumab or no trastuzumab treatment. Quantitative p95 protein expression was measured in formalin-fixed paraffin-embedded samples using the p95 VeraTag assay (Monogram Biosciences), specific for the M611 form of p95. Quantitative HER2 protein expression was measured using the HERmark assay (Monogram Biosciences). Distant disease-free survival (DDFS) was used as the primary outcome measure. Results: In the arm receiving chemotherapy only, increasing log 10 (p95) correlated with shorter DDFS (HR, 2.0; P = 0.02). In the arm receiving chemotherapy plus trastuzumab ( N = 95), increasing log 10 (p95) was not correlated with a shorter DDFS. In a combined analysis of both treatment arms, high breast tumor p95 content was significantly correlated with trastuzumab treatment benefit in multivariate models (interaction P = 0.01). Conclusions: A high p95HER2/HER2 ratio identified patients with metastatic breast cancer with poor outcomes on trastuzumab-based therapies. Further investigation of the p95HER2/HER2 ratio as a potential prognostic or predictive biomarker for HER2-targeted therapy is warranted. Clin Cancer Res; 1-7. ©2018 AACR. ©2018 American Association for Cancer Research.

Chemotherapeutic Drugs and Mitochondrial Dysfunction: Focus on Doxorubicin, Trastuzumab, and Sunitinib

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Stefania Gorini

2018-01-01

Full Text Available Many cancer therapies produce toxic side effects whose molecular mechanisms await full elucidation. The most feared and studied side effect of chemotherapeutic drugs is cardiotoxicity. Also, skeletal muscle physiology impairment has been recorded after many chemotherapeutical treatments. However, only doxorubicin has been extensively studied for its side effects on skeletal muscle. Chemotherapeutic-induced adverse side effects are, in many cases, mediated by mitochondrial damage. In particular, trastuzumab and sunitinib toxicity is mainly associated with mitochondria impairment and is mostly reversible. Vice versa, doxorubicin-induced toxicity not only includes mitochondria damage but can also lead to a more robust and extensive cell injury which is often irreversible and lethal. Drugs interfering with mitochondrial functionality determine the depletion of ATP reservoirs and lead to subsequent reversible contractile dysfunction. Mitochondrial damage includes the impairment of the respiratory chain and the loss of mitochondrial membrane potential with subsequent disruption of cellular energetic. In a context of increased stress, AMPK has a key role in maintaining energy homeostasis, and inhibition of the AMPK pathway is one of the proposed mechanisms possibly mediating mitochondrial toxicity due to chemotherapeutics. Therapies targeting and protecting cell metabolism and energy management might be useful tools in protecting muscular tissues against the toxicity induced by chemotherapeutic drugs.

Overview of the trastuzumab (Herceptin) anti-HER2 monoclonal antibody clinical program in HER2-overexpressing metastatic breast cancer. Herceptin Multinational Investigator Study Group.

Science.gov (United States)

Shak, S

1999-08-01

The recombinant humanized anti-HER2 monoclonal antibody trastuzumab (Herceptin; Genentech, San Francisco, CA) was evaluated in human clinical trials for treatment of women with metastatic breast cancer who have tumors that overexpress HER2. The trastuzumab clinical program consisted of a series of phase I, phase II, and phase III clinical trials. Clinical experience with this novel biologic has been obtained in more than 1,000 women with HER2-overexpressing metastatic breast cancer. Two pivotal trials were performed to evaluate trastuzumab efficacy and safety: (1) trastuzumab in combination with chemotherapy as first-line therapy and (2) trastuzumab as a single agent in second- and third-line chemotherapy. Preliminary results of the pivotal clinical trials that have been presented at national meetings are summarized below. The data suggest that trastuzumab will be an important new treatment option for women with HER2-overexpressing metastatic breast cancer.

The distribution of the therapeutic monoclonal antibodies cetuximab and trastuzumab within solid tumors

International Nuclear Information System (INIS)

Lee, Carol M; Tannock, Ian F

2010-01-01

Poor distribution of some anticancer drugs in solid tumors may limit their anti-tumor activity. Here we used immunohistochemistry to quantify the distribution of the therapeutic monoclonal antibodies cetuximab and trastuzumab in relation to blood vessels and to regions of hypoxia in human tumor xenografts. The antibodies were injected into mice implanted with human epidermoid carcinoma A431 or human breast carcinoma MDA-MB-231 transfected with ERBB2 (231-H2N) that express high levels of ErbB1 and ErbB2 respectively, or wild-type MDA-MB-231, which expresses intermediate levels of ErbB1 and low levels of ErbB2. The distribution of cetuximab in A431 xenografts and trastuzumab in 231-H2N xenografts was time and dose dependent. At early intervals after injection of 1 mg cetuximab into A431 xenografts, the concentration of cetuximab decreased with increasing distance from blood vessels, but became more uniformly distributed at later times; there remained however limited distribution and binding in hypoxic regions of tumors. Injection of lower doses of cetuximab led to heterogeneous distributions. Similar results were observed with trastuzumab in 231-H2N xenografts. In MDA-MB-231 xenografts, which express lower levels of ErbB1, homogeneity of distribution of cetuximab was achieved more rapidly. Cetuximab and trastuzumab distribute slowly, but at higher doses achieve a relatively uniform distribution after about 24 hours, most likely due to their long half-lives in the circulation. There remains poor distribution within hypoxic regions of tumors

EGF Prevents the Neuroendocrine Differentiation of LNCaP Cells Induced By Serum Deprivation: The Modulator Role of P13K/Akt

Directory of Open Access Journals (Sweden)

Rosa M. Martín-Orozco

2007-08-01

Full Text Available The primary focus of this investigation was to study the relationship between neuroendocrine (NE differentiation, epidermal growth factor (EGF because both have been implicated in the progression of prostate cancer. For this purpose, we used gefitinib, trastuzumab, which are inhibitors of EGF receptor (EGFR, ErbB2, respectively. EGF prevents NE differentiation induced by androgen depletion. This effect is prevented by gefitinib, which blocks the activation of EGFR, ErbB2, stimulation of mitogen-activated protein kinase (MAPK, cell proliferation induced by EGF. Conversely, trastuzumab does not inhibit the effect of EGF on EGFR phosphorylation, MAPK activity, cell proliferation, NE differentiation, although it reduces ErbB2 levels specifically, suggesting that ErbB2 is not necessary to inhibit NE differentiation. Prevention of NE differentiation by EGF is mediated by a MAPK-dependent mechanism, requires constitutive Akt activation. The abrogation of the PI3K/Akt pathway changes the role of EGF from inhibitor to inductor of NE differentiation. We show that EGFR tyrosine kinase, MAPK, PI3K inhibitors inhibit the cell proliferation stimulated by EGF but induce the acquisition of NE phenotype. Altogether, the present data should be borne in mind when designing new clinical schedules for the treatment of prostate cancer, including the use of ErbB receptors, associated signaling pathway inhibitors.

Efficacy and Safety of Pertuzumab and Trastuzumab Administered in a Single Infusion Bag, Followed by Vinorelbine

DEFF Research Database (Denmark)

Andersson, Michael; López-Vega, José M; Petit, Thierry

2017-01-01

two and nine). The primary endpoint was objective response rate (ORR) in patients with measurable disease. Secondary endpoints included progression-free survival (PFS) and safety. RESULTS: Cohort 2 enrolled 107 patients. The ORR was 63.7% (95% confidence interval [CI] 53.0-73.6) in patients...... suggestive of congestive heart failure. CONCLUSION: These results support the feasibility of pertuzumab and trastuzumab co-infusion from a safety perspective and support Cohort 1 conclusions that vinorelbine offers an alternative chemotherapy companion for pertuzumab and trastuzumab. The Oncologist 2017......;22:1160-1168 IMPLICATIONS FOR PRACTICE: Combined treatment with pertuzumab, trastuzumab, and docetaxel is the standard of care for first-line HER2-positive metastatic breast cancer. However, some patients cannot, or choose not to, receive docetaxel. VELVET Cohort 2 results support the results from Cohort 1 that suggest...

Trastuzumab-associated cardiac adverse effects in the herceptin adjuvant trial

NARCIS (Netherlands)

Suter, Thomas M.; Procter, Marion; van Veldhuisen, Dirk J.; Muscholl, Michael; Bergh, Jonas; Carlomagno, Chiara; Perren, Timothy; Passalacqua, Rodolfo; Bighin, Claudia; Klijn, Jan G. M.; Ageev, Fail T.; Hitre, Erika; Groetz, Juergen; Iwata, Hiroji; Knap, Malgorzata; Gnant, Michael; Muehlbauer, Susanne; Spence, Alison; Gelber, Richard D.; Piccart-Gebhart, Martine J.

2007-01-01

Purpose The purpose of this analysis was to investigate trastuzumab- associated cardiac adverse effects in breast cancer patients after completion of ( neo) adjuvant chemotherapy with or without radiotherapy. Patients and Methods The Herceptin Adjuvant ( HERA) trial is a three- group, multicenter,

Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: a german breast group 26/breast international group 03-05 study

DEFF Research Database (Denmark)

von Minckwitz, Gunter; du Bois, Andreas; Schmidt, Marcus

2009-01-01

PURPOSE: Trastuzumab shows clinical activity in human epidermal growth factor receptor 2 (HER-2)-positive early and advanced breast cancer. In the German Breast Group 26/Breast International Group 03-05 trial, we investigated if trastuzumab treatment should be continued beyond progression. METHODS......: Patients with HER-2-positive breast cancer that progresses during treatment with trastuzumab were randomly assigned to receive capecitabine (2,500 mg/m(2) body-surface area on days 1 through 14 [1,250 mg/m(2) semi-daily]) alone or with continuation of trastuzumab (6 mg/kg body weight) in 3-week cycles....... The primary end point was time to progression. RESULTS: We randomly assigned 78 patients to capecitabine and 78 patients to capecitabine plus trastuzumab. Sixty-five events and 38 deaths in the capecitabine group and 62 events and 33 deaths in the capecitabine-plus-trastuzumab group occurred during 15...

Demands for 'off-licence' access to trastuzumab (Herceptin): content analysis of UK newspaper articles.

Science.gov (United States)

Hind, Daniel; Wailoo, Allan J; Sutcliffe, Paul

2011-03-01

Sensationalized reporting styles and a distorted framing of health-care issues in newspapers may trigger inappropriate commissioning decisions. We evaluated UK press coverage of pre-licensing access to trastuzumab (Herceptin) for early breast cancer as a case study. Content analysis of newspaper articles published between April 2005 and May 2006 were coded by two researchers for interest groups represented, claims made and sensationalized reporting. Disagreements in coding were resolved by a third researcher. One thousand and ninety published articles were identified in the study period and a 20% sample (n = 218) was included in the content analysis. Most articles (76%, 95% CI 71-82) included claims about the clinical benefits of trastuzumab, and this was significantly higher than those expressing the uncertainty surrounding such benefits (6%, 95% CI 3-9) or those that discussed the potential harms (5%, 95% CI 2-8). Articles were significantly more likely to feature claims made by a breast cancer survivor or family member than any other interest group (P articles carried some message to the effect that trastuzumab would make the difference between life and death (47%, 95% CI 40-53). Over a quarter (28%, 95% CI 22-34) suggested that trastuzumab is a 'miracle drug' or similar. The benefits of drugs are highlighted, frequently using sensationalist language, without equal consideration of uncertainty or risks. Health-care purchasers should express decisions in opportunity cost terms; journalists should give fairer coverage to such arguments. © 2010 Blackwell Publishing Ltd.

Analysis of trastuzumab and chemotherapy in advanced breast cancer after the failure of at least one earlier combination: An observational study

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Locker Gottfried J

2006-03-01

Full Text Available Abstract Background Combining trastuzumab and chemotherapy is standard in her2/neu overexpressing advanced breast cancer. It is not established however, whether trastuzumab treatment should continue after the failure of one earlier combination. In this trial, we report our experience with continued treatment beyond disease progression. Methods Fifty-four patients, median age 46 years, range 25–73 years, were included. We analysed for time to tumour progression (TTP for first, second and beyond second line treatment, response rates and overall survival. Results Median time of observation was 24 months, range 7–51. Response rates for first line treatment were 7.4% complete remission (CR, 35.2% partial remissions (PR, 42.6% stable disease > 6 months (SD and 14.8% of patients experienced disease progression despite treatment (PD. Corresponding numbers for second line were 3.7% CR, 22.2% PR, 42.6% SD and 31.5% PD; numbers for treatment beyond second line (60 therapies, 33 pts 3rd line, 18 pts 4th line, 6 pts 5th line, 2 pts 6th line and 1 patient 7th line were 1.7% CR, 28.3% PR, 28.3% SD and 41.6% PD respectively. Median TTP was 6 months (m in the first line setting, and also 6 m for second line and beyond second line. An asymptomatic drop of left ventricular ejection fraction below 50% was observed in one patient. No case of symptomatic congestive heart failure was observed. Conclusion The data presented clearly strengthen evidence that patients do profit from continued trastuzumab treatment. The fact that TTP did not decrease significantly from first line to beyond second line treatment is especially noteworthy. Still, randomized trials are warranted.

Implementation of trastuzumab in conjunction with adjuvant chemotherapy in the treatment of non-metastatic breast cancer in the Netherlands

NARCIS (Netherlands)

de Munck, L.; Schaapveld, M.; Siesling, S.; Wesseling, J.; Voogd, A. C.; Tjan-Heijnen, V. C. G.; Otter, R.; Willemse, P. H. B.

Trastuzumab in conjunction with adjuvant chemotherapy markedly improves outcome. In the Netherlands, a national guideline was released in September 2005 stating that trastuzumab should be given in conjunction with adjuvant chemotherapy in women with HER2-positive breast cancer. Aim of this study was

Development and validation of an enzyme-linked immunosorbent assay for the quantification of trastuzumab in human serum and plasma

NARCIS (Netherlands)

Damen, Carola W. N.; de Groot, Els R.; Heij, Marianne; Boss, David S.; Schellens, Jan H. M.; Rosing, Hilde; Beijnen, Jos H.; Aarden, Lucien A.

2009-01-01

Trastuzumab, a humanized monoclonal antibody, is used for the treatment of breast cancer patients who overexpress the HER2 receptor. To optimize therapy, pharmacokinetic studies are necessary. The aim of this study was to develop an enzyme-linked immunosorbent assay (ELISA) for trastuzumab to

Implementation of trastuzumab in conjunction with adjuvant chemotherapy in the treatment of non-metastatic breast cancer in the Netherlands

NARCIS (Netherlands)

de Munck, L.; Schaapveld, M.; Siesling, Sabine; Wessling, J.; Voogd, A.C.; Tjan-Heijnen, V.C.G.; Otter, R.; Willemse, P.H.B.

2011-01-01

Trastuzumab in conjunction with adjuvant chemotherapy markedly improves outcome. In the Netherlands, a national guideline was released in September 2005 stating that trastuzumab should be given in conjunction with adjuvant chemotherapy in women with HER2-positive breast cancer. Aim of this study was

Pilot study of 68Ga-DOTA-F(ab?)2-trastuzumab in patients with breast cancer

OpenAIRE

Beylergil, Volkan; Morris, Patrick G.; Smith-Jones, Peter M.; Modi, Shanu; Solit, David; Hudis, Clifford A.; Lu, Yang; O?Donoghue, Joseph; Lyashchenko, Serge K.; Carrasquillo, Jorge A.; Larson, Steven M.; Akhurst, Timothy J.

2013-01-01

Objective 68Ga-1,4,7,10-Tetraazacyclododecane-N,N?,N??,N???-tetraacetic acid (DOTA)-F(ab?)2-trastuzumab [68Ga-DOTA-F(ab?)2-trastuzumab] has been developed at our institution as a positron imaging reagent for assessing human epidermal growth factor receptor 2 (HER2) expression status by in-vivo imaging. Initial studies on animals demonstrated promising results in the monitoring of treatment response to heat shock protein 90-targeted drugs that inhibit the client protein HER2. We report here ou...

Hsp90 inhibitor 17-AAG reduces ErbB2 levels and inhibits proliferation of the trastuzumab resistant breast tumor cell line JIMT-1.

Science.gov (United States)

Zsebik, Barbara; Citri, Ami; Isola, Jorma; Yarden, Yosef; Szöllosi, János; Vereb, György

2006-04-15

ErbB2, a member of the EGF receptor family of tyrosine kinases is overexpressed on many tumor cells of epithelial origin and is the molecular target of trastuzumab (Herceptin), the first humanized antibody used in the therapy of solid tumors. Trastuzumab, which is thought to act, at least in part, by downregulating ErbB2 expression is only effective in approximately 30-40% of ErbB2 positive breast tumors. Geldanamycin and its derivative 17-AAG are potential antitumor agents capable of downregulating client proteins of Hsp90, including ErbB2. To investigate the ability of 17-AAG to downregulate ErbB2 in trastuzumab resistant breast cancer cells and the possibility of 17-AAG and trastuzumab potentiating each other's effect, the recently established trastuzumab resistant breast cancer cell line, JIMT-1 was compared to the known trastuzumab sensitive SKBR-3 line. Baseline and stimulus-evoked dimerization and activation levels of ErbB2, and the effects of trastuzumab and 17-AAG alone and in combination on cell proliferation and apoptosis, as well as on ErbB2 expression and phosphorylation have been measured. Baseline activation and amenability to activation and downregulation by trastuzumab was much lower in the resistant line. However, 17-AAG enhanced ErbB2 homodimerization after 5-10 min of treatment in both cell lines, and decreased proliferation with an IC50 of 70 nM for SKBR-3 and 10nM for JIMT-1. Thus, 17-AAG may be a useful drug in trastuzumab resistant ErbB2 overexpressing tumors. The antiproliferative effect of 17-AAG was positively correlated with phosphorylation and downregulation of ErbB2 and was dominated by apoptosis, although, especially at higher doses, necrosis was also present. Interestingly, IC50 values for ErbB2 downregulation and phosphorylation, in the 30-40 nM range, were not significantly different for the two cell lines. This observation and the negative correlation between resting ErbB2 levels and the antiproliferative effect of 17-AAG may

PTEN expression as a predictor for the response to trastuzumab-based therapy in Her-2 overexpressing metastatic breast cancer.

Directory of Open Access Journals (Sweden)

Daphne Gschwantler-Kaulich

Full Text Available Even though trastuzumab is an effective therapy in early stage Her-2+ breast cancer, 40-50% of advanced Her-2+ breast cancer patients develop trastuzumab resistance. A potential resistance mechanism is aberrant downstream signal transmission due to loss of phosphatase and tensin homologue (PTEN. This study investigated the relationship between the expression of PTEN and trastuzumab response in Her-2 overexpressing metastatic breast cancer patients.Between 2000 and 2007, 164 patients with Her-2+ metastatic breast cancer received trastuzumab-based therapy in our institution. We analyzed PTEN status by immunohistochemistry of 115 available tumor tissues and analyzed associations with other histopathological parameters, response rate, progression free survival (PFS and overall survival (OS with a median follow-up of 60 months.Eighty patients were PTEN positive (69.6% and 35 patients PTEN negative (30.4%. We found a significant association of the expression of PTEN and p53 (p = 0.041, while there was no association with grading, hormone receptor status, IGFR or MIB. We found significantly more cases with progressive disease under trastuzumab-based therapy in patients with PTEN positive breast cancers (p = 0.018, while there was no significant correlation with PFS or OS.In Her-2-positive metastatic breast cancers, PTEN positivity was significantly associated with progressive disease, but not with PFS or OS.

Trastuzumab after Chemotherapy Is Effective in HER2-Positive Breast Cancer

Science.gov (United States)

Treatment with trastuzumab for 1 year following standard chemotherapy improved disease-free survival in women with HER2-positive early breast cancer, according to 4-year follow-up results of the Herceptin Adjuvant (HERA) trial reported February 25, 2011,

Synthesis and stability test of radiogadolinium(III-DOTA-PAMAM G3.0-trastuzumab as SPECT-MRI molecular imaging agent for diagnosis of HER-2 positive breast cancer

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Hardiani Rahmania

2015-01-01

Full Text Available Nonivasive diagnosis of cancer can be provided by molecular imaging using hybrid modality to obtain better sensitivity, specificity and depiction localization of the disease. In this study, we developed a new molecular imaging agent, radiogadolinium(III-DOTA-PAMAM G3.0-trastuzumab in the form of 147Gd-DOTA-PAMAM G3.0-trastuzumab, that can be both target-specific radiopharmaceutical in SPECT as well as targeted contrast agent in MRI for the purpose of diagnosis of HER-2 positive breast cancer. 147Gd radionuclide emits γ-rays that can be used in SPECT modality, but because of technical constraint, 147Gd radionuclide was simulated by its radioisotope, 153Gd. Gd-DOTA complex has also been known as good MRI contrast agent. PAMAM G3.0 is useful to concentrate Gd-DOTA compelexes in large quantities, thus minimizing the number of trastuzumab molecules used. Trastuzumab is human monoclonal antibody that can spesifically interact with HER-2. Synthesis of radiogadolinium(III-DOTA-PAMAM G3.0-trastuzumab was initiated by conjugating DOTA NHS ester ligand with PAMAM G3.0 dendrimer. The DOTA-PAMAM G3.0 produced was conjugated to trastuzumab molecule and labeled with 153Gd. Characterization DOTA-PAMAM G3.0-trastuzumab immunoconjugate was performed using HPLC system equipped with SEC. The formation of immunoconjugate was indicated by the shorter retention time (6.82 min compared to that of trastuzumab (7.06 min. Radiochemical purity of radiogadolinium(III-DOTA-PAMAM G3.0-trastuzumab was >99% after purification process by PD-10 desalting column. Radiogadolinium(III-DOTA-PAMAM G3.0-trastuzumab compound was stable at room temperature and at 2–8 0C as indicated by its radiochemical purity 97.6 ± 0.5%–99.1 ± 0.5% after 144 h storage.

Use of trastuzumab for HER2-positive metastatic breast cancer in daily practice : a population-based study focusing on the elderly

NARCIS (Netherlands)

van Rooijen, Johan M.; de Munck, Linda; Teeuwen, Guusje M.; de Graaf, Jacques C.; Jansman, Frank G.; Boers, James E.; Siesling, Sabine

The addition of trastuzumab to chemotherapy in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) prolongs overall survival (OS) in clinical trials. However, treatment patterns and survival in daily practice are unknown. This study aims to compare trastuzumab use

Use of trastuzumab for HER2-positive metastatic breast cancer in daily practice: a population-based study focusing on the elderly

NARCIS (Netherlands)

van Rooijen, Johan M.; de Munck, Linda; Teeuwen, Guusje M.; de Graaf, Jacques C.; Jansman, Frank G.; Boers, James E.; Siesling, Sabine

2016-01-01

The addition of trastuzumab to chemotherapy in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) prolongs overall survival (OS) in clinical trials. However, treatment patterns and survival in daily practice are unknown. This study aims to compare trastuzumab use

HER2 overexpression and amplification is present in a subset of ovarian mucinous carcinomas and can be targeted with trastuzumab therapy

International Nuclear Information System (INIS)

McAlpine, Jessica N; Gilks, C Blake; Miller, Dianne M; Wiegand, Kimberly C; Vang, Russell; Ronnett, Bridgett M; Adamiak, Anna; Köbel, Martin; Kalloger, Steve E; Swenerton, Kenneth D; Huntsman, David G

2009-01-01

The response rate of ovarian mucinous carcinomas to paclitaxel/carboplatin is low, prompting interest in targeted molecular therapies. We investigated HER2 expression and amplification, and the potential for trastuzumab therapy in this histologic subtype of ovarian cancer. HER2 status was tested in 33 mucinous carcinomas and 16 mucinous borderline ovarian tumors (BOT)). Five cases with documented recurrence and with tissue from the recurrence available for testing were analyzed to determine whether HER2 amplification status changed over time. Three prospectively identified recurrent mucinous ovarian carcinomas were assessed for HER2 amplification and patients received trastuzumab therapy with conventional chemotherapy. Amplification of HER2 was observed in 6/33 (18.2%) mucinous carcinomas and 3/16 (18.8%) BOT. HER2 amplification in primary mucinous carcinomas was not associated with an increased likelihood of recurrence. The prospectively identified recurrent mucinous carcinomas showed overexpression and amplification of HER2; one patient's tumor responded dramatically to trastuzumab in combination with conventional chemotherapy, while another patient experienced an isolated central nervous system recurrence after trastuzumab therapy. HER2 amplification is relatively common in ovarian mucinous carcinomas (6/33, 18.2%), although not of prognostic significance. Trastuzumab therapy is a treatment option for patients with mucinous carcinoma when the tumor has HER2 amplification and overexpression

Targeting Cellular Calcium Homeostasis to Prevent Cytokine-Mediated Beta Cell Death.

Science.gov (United States)

Clark, Amy L; Kanekura, Kohsuke; Lavagnino, Zeno; Spears, Larry D; Abreu, Damien; Mahadevan, Jana; Yagi, Takuya; Semenkovich, Clay F; Piston, David W; Urano, Fumihiko

2017-07-17

Pro-inflammatory cytokines are important mediators of islet inflammation, leading to beta cell death in type 1 diabetes. Although alterations in both endoplasmic reticulum (ER) and cytosolic free calcium levels are known to play a role in cytokine-mediated beta cell death, there are currently no treatments targeting cellular calcium homeostasis to combat type 1 diabetes. Here we show that modulation of cellular calcium homeostasis can mitigate cytokine- and ER stress-mediated beta cell death. The calcium modulating compounds, dantrolene and sitagliptin, both prevent cytokine and ER stress-induced activation of the pro-apoptotic calcium-dependent enzyme, calpain, and partly suppress beta cell death in INS1E cells and human primary islets. These agents are also able to restore cytokine-mediated suppression of functional ER calcium release. In addition, sitagliptin preserves function of the ER calcium pump, sarco-endoplasmic reticulum Ca 2+ -ATPase (SERCA), and decreases levels of the pro-apoptotic protein thioredoxin-interacting protein (TXNIP). Supporting the role of TXNIP in cytokine-mediated cell death, knock down of TXNIP in INS1-E cells prevents cytokine-mediated beta cell death. Our findings demonstrate that modulation of dynamic cellular calcium homeostasis and TXNIP suppression present viable pharmacologic targets to prevent cytokine-mediated beta cell loss in diabetes.

Trastuzumab beyond progression: overall survival analysis of the GBG 26/BIG 3-05 phase III study in HER2-positive breast cancer

DEFF Research Database (Denmark)

von Minckwitz, Gunter; Schwedler, Kathrin; Schmidt, Marcus

2011-01-01

Continuation of trastuzumab plus capecitabine (XH) showed a significantly improved overall response rate and time to progression compared with capecitabine (X) alone in women with HER2-positive breast cancer progressing during trastuzumab treatment. Here, we report the final analysis on overall...

Coexistence of Gastric Adenocarcinoma and Choriocarcinoma: Complete Response to Trastuzumab and Chemotherapy

Directory of Open Access Journals (Sweden)

Seyda Gunduz

2012-07-01

Full Text Available Gastric choriocarcinoma is a rare neoplasm and usually accompanies gastric adenocarcinoma. The prognosis is poor due to the aggressive course of the disease. A 57-year-old female patient with weight loss and abdominal pain was examined. The patient was operated following the examination, and pathological analysis revealed the presence of a gastric adenocarcinoma associated with choriocarcinoma. Immunohistochemical analysis showed a positive reaction with antibodies to beta-human chorionic gonadotropin and overexpression of the cErbB2 proto-oncogene. Staging revealed multiple metastases in the liver. A complete response was obtained with a combination of trastuzumab and chemotherapy. The diagnosis of gastric choriocarcinomas without pathological examination is difficult due to their rare occurrence. A complete response can be obtained with trastuzumab in the treatment of cases with overexpression of the cErbB2 protein.

Cigarette smoking habit does not reduce the benefit from first line trastuzumab-based treatment in advanced breast cancer patients.

Science.gov (United States)

Santini, Daniele; Vincenzi, Bruno; Adamo, Vincenzo; Addeo, Raffaele; Fusco, Vittorio; Russo, Antonio; Montemurro, Filippo; Roato, Ilaria; Redana, Stefania; Lanzetta, Gaetano; Satolli, Maria Antonietta; Berruti, Alfredo; Leoni, Valentina; Galluzzo, Sara; Antimi, Mauro; Ferraro, Giuseppa; Rossi, Maura; Del Prete, Salvatore; Valerio, Maria Rosaria; Marra, Monica; Caraglia, Michele; Tonini, Giuseppe

2011-06-01

Many ErbB2-positive cancers may show intrinsic resistance, and the frequent development of acquired resistance to ErbB-targeted agents represents a substantial clinical problem. The constitutive NF-κB activation in some HER-2/neu positive breast cancer may represent a potential cause of resistance to trastuzumab therapy. Preclinical data revealed that 4-(N-Methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), the tobacco-specific nitrosamine is able to enhance NF-κB DNA binding activity and theoretically to increase the resistance to trastuzumab. Two hundred and forty-eight women with pathologically confirmed, uni- or bidimensionally measurable, HER-2-positive metastatic breast cancer (MBC) treated with trastuzumab-based therapy as first line combination for metastatic disease were considered eligible. For all included patients data on smoking habit were detectable from medical records. We retrospectively analysed the smoking habits of 248 MBC patients and correlated these habits with activity and efficacy of trastuzumab-based therapy. No statistically significant difference in terms of response rate (RR), time to progression (TTP) and overall survival (OS) was identified between smokers (former plus active smokers) and never smokers. Moreover, no statistically significant difference in terms of RR, TTP and OS was identified either comparing active smokers and former smokers. Moreover, we did not observed any significant statistical difference in terms of TTP and OS between smokers ≥10 cigarettes/day and smoking habit and both activity and efficacy of trastuzumab-based first line therapy in metastatic HER2/neu positive breast cancer patients.

A combination of Trastuzumab and 17-AAG induces enhanced ubiquitinylation and lysosomal pathway-dependent ErbB2 degradation and cytotoxicity in ErbB2-overexpressing breast cancer cells.

Science.gov (United States)

Raja, Srikumar M; Clubb, Robert J; Bhattacharyya, Mitra; Dimri, Manjari; Cheng, Hao; Pan, Wei; Ortega-Cava, Cesar; Lakku-Reddi, Alagarsamy; Naramura, Mayumi; Band, Vimla; Band, Hamid

2008-10-01

ErbB2 (or Her2/Neu) overexpression in breast cancer signifies poorer prognosis, yet it has provided an avenue for targeted therapy as demonstrated by the success of the humanized monoclonal antibody Trastuzumab (Herceptin). Resistance to Trastuzumab and eventual failure in most cases, however, necessitate alternate ErbB2-targeted therapies. HSP90 inhibitors such as 17-allylaminodemethoxygeldanamycin (17-AAG), potently downregulate the cell surface ErbB2. While the precise mechanisms of Trastuzumab or 17-AAG action remain unclear, ubiquitinylation-dependent proteasomal or lysosomal degradation of ErbB2 appears to play a substantial role. As Trastuzumab and 17-AAG induce the recruitment of distinct E3 ubiquitin ligases, Cbl and CHIP respectively, to ErbB2, we hypothesized that 17-AAG and Trastuzumab combination could induce a higher level of ubiquitinylation and downregulation of ErbB2 as compared to single drug treatments. We present biochemical and cell biological evidence that combined 17-AAG and Trastuzumab treatment of ErbB2-overexpressing breast cancer cell lines leads to enhanced ubiquitinylation, downregulation from the cell surface and lysosomal degradation of ErbB2. Importantly, combined 17-AAG and Trastuzumab treatment induced synergistic growth arrest and cell death specifically in ErbB2-overexpressing but not in ErbB2-low breast cancer cells. Our results suggest the 17-AAG and Trastuzumab combination as a mechanism-based combinatorial targeted therapy for ErbB2-overexpressing breast cancer patients.

Tumor-Targeting Salmonella typhimurium A1-R in Combination with Trastuzumab Eradicates HER-2-Positive Cervical Cancer Cells in Patient-Derived Mouse Models.

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Yukihiko Hiroshima

Full Text Available We have previously developed mouse models of HER-2-positive cervical cancer. Tumors in nude mice had histological structures similar to the original tumor and were stained by anti-HER-2 antibody in the same pattern as the patient's cancer. We have also previously developed tumor-targeting Salmonella typhimurium A1-R and have demonstrated its efficacy against patient-derived tumor mouse models, both alone and in combination. In the current study, we determined the efficacy of S. typhimurium A1-R in combination with trastuzumab on a patient-cancer nude-mouse model of HER-2 positive cervical cancer. Mice were randomized to 5 groups and treated as follows: (1 no treatment; (2 carboplatinum (30 mg/kg, ip, weekly, 5 weeks; (3 trastuzumab (20 mg/kg, ip, weekly, 5 weeks; (4 S. typhimurium A1-R (5 × 107 CFU/body, ip, weekly, 5 weeks; (5 S. typhimurium A1-R (5 × 107 CFU/body, ip, weekly, 5 weeks + trastuzumab (20 mg/kg, ip, weekly, 5 weeks. All regimens had significant efficacy compared to the untreated mice. The relative tumor volume of S. typhimurium A1-R + trastuzumab-treated mice was smaller compared to trastuzumab alone (p = 0.007 and S. typhimurium A1-R alone (p = 0.039. No significant body weight loss was found compared to the no treatment group except for carboplatinum-treated mice (p = 0.021. Upon histological examination, viable tumor cells were not detected, and replaced by stromal cells in the tumors treated with S. typhimurium A1-R + trastuzumab. The results of the present study suggest that S. typhimurium A1-R and trastuzumab in combination are highly effective against HER-2-expressing cervical cancer.

A phase 1 study evaluating the combination of an allosteric AKT inhibitor (MK-2206) and trastuzumab in patients with HER2-positive solid tumors.

Science.gov (United States)

Hudis, Clifford; Swanton, Charles; Janjigian, Yelena Y; Lee, Ray; Sutherland, Stephanie; Lehman, Robert; Chandarlapaty, Sarat; Hamilton, Nicola; Gajria, Devika; Knowles, James; Shah, Jigna; Shannon, Keith; Tetteh, Ernestina; Sullivan, Daniel M; Moreno, Carolina; Yan, Li; Han, Hyo Sook

2013-11-19

Trastuzumab is effective in human epidermal growth factor receptor 2 (HER2)-over-expressing breast and gastric cancers. However, patients may develop resistance through downstream signaling via the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. This phase 1 trial was conducted to determine the safety and tolerability of the investigational AKT inhibitor MK-2206, to prepare for future studies to determine whether the combination with trastuzumab could inhibit compensatory signaling. Patients with HER2+ treatment-refractory breast and gastroesophageal cancer were enrolled. Treatment consisted of standard doses of intravenous trastuzumab and escalating dose levels of oral MK-2206 using either an every-other-day (45 mg and 60 mg QOD) or once-weekly (135 mg and 200 mg QW) schedule. A total of 34 patients with HER2+ disease were enrolled; 31 received study-drug. The maximum tolerated dose (MTD) for MK-2206 in combination with trastuzumab was 60 mg for the QOD schedule and 135 mg for the QW schedule, although a true MTD was not established due to early termination of the trial. The most common treatment-emergent toxicities included fatigue, hyperglycemia, and dermatologic rash, consistent with prior experience; one death unrelated to treatment was reported. There was one complete response in a patient with metastatic breast cancer, one patient achieved a partial response, and 5 patients had stable disease for at least 4 months, despite progression on multiple prior trastuzumab- and lapatinib-based therapies. Results also indicate that trastuzumab does not affect the pharmacokinetics of MK-2206. Results suggest the AKT inhibitor MK-2206 can be safely combined with trastuzumab, and is associated with clinical activity, supporting further investigation. ClinicalTrials.gov; identifier: NCT00963547.

Randomized Phase III Trial of Trastuzumab Plus Capecitabine With or Without Pertuzumab in Patients With Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer Who Experienced Disease Progression During or After Trastuzumab-Based Therapy.

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Urruticoechea, Ander; Rizwanullah, Mohammed; Im, Seock-Ah; Ruiz, Antonio Carlos Sánchez; Láng, István; Tomasello, Gianluca; Douthwaite, Hannah; Badovinac Crnjevic, Tanja; Heeson, Sarah; Eng-Wong, Jennifer; Muñoz, Montserrat

2017-09-10

Purpose To assess the efficacy and safety of trastuzumab plus capecitabine with or without pertuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer who experienced disease progression during or after trastuzumab-based therapy and received a prior taxane. Patients and Methods Patients were randomly assigned to arm A: trastuzumab 8 mg/kg → 6 mg/kg once every 3 weeks plus capecitabine 1,250 mg/m 2 twice a day (2 weeks on, 1 week off, every 3 weeks); or arm B: pertuzumab 840 mg → 420 mg once every 3 weeks plus trastuzumab at the same dose and schedule as arm A plus capecitabine 1,000 mg/m 2 on the same schedule as arm A. The primary end point was independent review facility-assessed progression-free survival (IRF PFS). Secondary end points included overall survival (OS) and safety. Hierarchical testing procedures were used to control type I error for statistical testing of IRF PFS, OS, and objective response rate. Results Randomly assigned (intent-to-treat) populations were 224 and 228 patients in arms A and B, respectively. Median IRF PFS at 28.6 and 25.3 months' median follow-up was 9.0 v 11.1 months (hazard ratio, 0.82; 95% CI, 0.65 to 1.02; P = .0731) and interim OS was 28.1 v 36.1 months (hazard ratio, 0.68; 95% CI, 0.51 to 0.90). The most common adverse events (all grades; incidence of ≥ 10% in either arm and ≥ 5% difference between arms) were hand-foot syndrome, nausea, and neutropenia in arm A, and diarrhea, rash, and nasopharyngitis in arm B. Conclusion The addition of pertuzumab to trastuzumab and capecitabine did not significantly improve IRF PFS. An 8-month increase in median OS to 36.1 months with pertuzumab was observed. Statistical significance for OS cannot be claimed because of the hierarchical testing of OS after the primary PFS end point; however, the magnitude of OS difference is in keeping with prior experience of pertuzumab in metastatic breast cancer. No new safety signals were identified.

Neratinib Plus Paclitaxel vs Trastuzumab Plus Paclitaxel in Previously Untreated Metastatic ERBB2-Positive Breast Cancer: The NEfERT-T Randomized Clinical Trial.

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Awada, Ahmad; Colomer, Ramon; Inoue, Kenichi; Bondarenko, Igor; Badwe, Rajendra A; Demetriou, Georgia; Lee, Soo-Chin; Mehta, Ajay O; Kim, Sung-Bae; Bachelot, Thomas; Goswami, Chanchal; Deo, Suryanarayan; Bose, Ron; Wong, Alvin; Xu, Feng; Yao, Bin; Bryce, Richard; Carey, Lisa A

2016-12-01

Efficacious ERBB2 (formerly HER2 or HER2/neu)-directed treatments, in addition to trastuzumab and lapatinib, are needed. To determine whether neratinib, an irreversible pan-ERBB tyrosine kinase inhibitor, plus paclitaxel improves progression-free survival compared with trastuzumab plus paclitaxel in the first-line treatment of recurrent and/or metastatic ERBB2-positive breast cancer. In the randomized, controlled, open-label NEfERT-T trial conducted from August 2009 to December 2014 at 188 centers in 34 countries in Europe, Asia, Africa, and North America, 479 women with previously untreated recurrent and/or metastatic ERBB2-positive breast cancer were randomized to 1 of 2 treatment arms (neratinib-paclitaxel [n = 242] or trastuzumab-paclitaxel [n = 237]). Women with asymptomatic central nervous system metastases were eligible, and randomization was stratified by prior trastuzumab and lapatinib exposure, hormone-receptor status, and region. Women received neratinib (240 mg/d orally) or trastuzumab (4 mg/kg then 2 mg/kg weekly), each combined with paclitaxel (80 mg/m2 on days 1, 8, and 15 every 28 days). Primary prophylaxis for diarrhea was not mandatory. The primary outcome was progression-free survival. Secondary end points were response rate, clinical benefit rate, duration of response, frequency, and time to symptomatic and/or progressive central nervous system lesions, and safety. The intent-to-treat population comprised 479 women 18 years or older (neratinib-paclitaxel, n = 242; trastuzumab-paclitaxel, n = 237) randomized and stratified in their respective treatment arms by prior trastuzumab and lapatinib exposure, hormone-receptor status, and region. Median progression-free survival was 12.9 months (95% CI, 11.1-14.9) with neratinib-paclitaxel and 12.9 months (95% CI, 11.1-14.8) with trastuzumab-paclitaxel (hazard ratio [HR], 1.02; 95% CI, 0.81-1.27; P =.89). With neratinib-paclitaxel, the incidence of central nervous system recurrences was

Multi-arm Cost-Effectiveness Analysis (CEA comparing different durations of adjuvant trastuzumab in early breast cancer, from the English NHS payer perspective.

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Caroline S Clarke

Full Text Available Trastuzumab improves survival in HER2+ breast cancer patients, with some evidence of adverse cardiac side effects. Current recommendations are to give adjuvant trastuzumab for one year or until recurrence, although trastuzumab treatment for only 9 or 10 weeks has shown similar survival rates to 12-month treatment. We present here a multi-arm joint analysis examining the relative cost-effectiveness of different durations of adjuvant trastuzumab.Network meta-analysis (NMA was used to examine which trials' data to include in the cost-effectiveness analysis (CEA. A network using FinHer (9 weeks vs. zero and BCIRG006 (12 months vs. zero trials offered the only jointly randomisable network so these trials were used in the CEA. The 3-arm CEA compared costs and quality-adjusted life-years (QALYs associated with zero, 9-week and 12-month adjuvant trastuzumab durations in early breast cancer, using a decision tree followed by a Markov model that extrapolated the results to a lifetime time horizon. Pairwise incremental cost-effectiveness ratios (ICERs were also calculated for each pair of regimens and used in budget impact analysis, and the Bucher method was used to check face validity of the findings. Addition of the PHARE trial (6 months vs. 12 months to the network, in order to create a 4-arm CEA including the 6-month regimen, was not possible as late randomisation in this trial resulted in recruitment of a different patient population as evidenced by the NMA findings. The CEA results suggest that 9 weeks' trastuzumab is cost-saving and leads to more QALYs than 12 months', i.e. the former dominates the latter. The cost-effectiveness acceptability frontier (CEAF favours zero trastuzumab at willingness-to-pay levels below £2,500/QALY and treatment for 9 weeks above this threshold. The combination of the NMA and Bucher investigations suggests that the 9-week duration is as efficacious as the 12-month duration for distant-disease-free survival and overall

miR-21 Expression in Cancer Cells may Not Predict Resistance to Adjuvant Trastuzumab in Primary Breast Cancer

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Nielsen, Boye Schnack; Balslev, Eva; Poulsen, Tim Svenstrup

2014-01-01

, predominantly in cancer cells, or in both stromal and cancer cells. There was no obvious difference between the HER2-positive and HER2-negative tumors in terms of the miR-21 expression patterns and intensities. To explore the possibility that miR-21 expression levels and/or cellular localization could predict...... expression patterns and intensities revealed no association between the miR-21 scores in the cancer cell population (p = 0.69) or the stromal cells population (p = 0.13) and recurrent disease after adjuvant trastuzumab. Thus, our findings show that elevated miR-21 expression does not predict resistance......Trastuzumab is established as standard care for patients with HER2-positive breast cancer both in the adjuvant and metastatic setting. However, 50% of the patients do not respond to the trastuzumab therapy, and therefore new predictive biomarkers are highly warranted. MicroRNAs (miRs) constitute...

Neoadjuvant chemotherapy with trastuzumab in HER2-positive breast cancer: pathologic complete response rate, predictive and prognostic factors

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I.P.C. Buzatto

Full Text Available The purpose of this study was to retrospectively review the pathologic complete response (pCR rate from patients (n=86 with stage II and III HER2-positive breast cancer treated with neoadjuvant chemotherapy at our institution from 2008 to 2013 and to determine possible predictive and prognostic factors. Immunohistochemistry for hormone receptors and Ki-67 was carried out. Clinical and pathological features were analyzed as predictive factors of response to therapy. For survival analysis, we used Kaplan-Meier curves to estimate 5-year survival rates and the log-rank test to compare the curves. The addition of trastuzumab to neoadjuvant chemotherapy significantly improved pCR rate from 4.8 to 46.8%, regardless of the number of preoperative trastuzumab cycles (P=0.0012. Stage II patients achieved a higher response rate compared to stage III (P=0.03. The disease-free and overall survivals were not significantly different between the group of patients that received trastuzumab in the neoadjuvant setting (56.3 and 70% at 5 years, respectively and the group that initiated it post-operatively (75.8 and 88.7% at 5 years, respectively. Axillary pCR post neoadjuvant chemotherapy with trastuzumab was associated with reduced risk of recurrence (HR=0.34; P=0.03 and death (HR=0.21; P=0.02. In conclusion, we confirmed that trastuzumab improves pCR rates and verified that this improvement occurs even with less than four cycles of the drug. Hormone receptors and Ki-67 expressions were not predictive of response in this subset of patients. Axillary pCR clearly denotes prognosis after neoadjuvant target therapy and should be considered to be a marker of resistance, providing an opportunity to investigate new strategies for HER2-positive treatment.

A comparison of 111In- or 64Cu-DOTA-trastuzumab Fab fragments for imaging subcutaneous HER2-positive tumor xenografts in athymic mice using microSPECT/CT or microPET/CT

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2011-01-01

Background Our objective was to compare 111In- or 64Cu-DOTA-trastuzumab Fab fragments for imaging small or large s.c. tumor xenografts in athymic mice that display a wide range of human epidermal growth factor receptor-2 (HER2) expression using microSPECT/CT or microPET/CT. Methods Trastuzumab Fab were labeled with 111In or 64Cu by conjugation to 1,4,7,10-tetraazacyclododecane N, N', N'', N'''-tetraacetic acid (DOTA). The purity of 111In- and 64Cu-DOTA-trastuzumab Fab was measured by SDS-PAGE and HPLC. HER2 binding affinity was determined in saturation radioligand binding assays using SKBR-3 cells (1.3 × 106 HER2/cell). MicroSPECT/CT and microPET/CT were performed in athymic mice bearing s.c. BT-20 and MDA-MB-231 xenografts with low (0.5 to 1.6 × 105 receptors/cell), MDA-MB-361 tumors with intermediate (5.1 × 105 receptors/cell) or SKOV-3 xenografts with high HER2 expression (1.2 × 106 receptors/cell) at 24 h p.i. of 70 MBq (10 μg) of 111In-DOTA-trastuzumab Fab or 22 MBq (10 μg) of 64Cu-DOTA-trastuzumab Fab or irrelevant 111In- or 64Cu-DOTA-rituximab Fab. Tumor and normal tissue uptake were quantified in biodistribution studies. Results 111In- and 64Cu-DOTA-trastuzumab were > 98% radiochemically pure and bound HER2 with high affinity (Kd = 20.4 ± 2.5 nM and 40.8 ± 3.5 nM, respectively). MDA-MB-361 and SKOV-3 tumors were most clearly imaged using 111In- and 64Cu-DOTA-trastuzumab Fab. Significantly higher tumor/blood (T/B) ratios were found for 111In-DOTA-trastuzumab Fab than 111In-DOTA-rituximab Fab for BT-20, MDA-MB-231 and MDA-MB-361 xenografts, and there was a direct association between T/B ratios and HER2 expression. In contrast, tumor uptake of 64Cu-DOTA-trastuzumab Fab was significantly higher than 64Cu-DOTA-rituximab Fab in MDA-MB-361 tumors but no direct association with HER2 expression was found. Both 111In- and 64Cu-DOTA-trastuzumab Fab imaged small (5 to 10 mm) or larger (10 to 15 mm) MDA-MB-361 tumors. Higher blood, liver, and spleen

The Influence of "No Child Left Behind" Legislation on Drug Prevention in U.S. Schools

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Cho, Hyunsan; Hallfors, Denise Dion; Iritani, Bonita J.; Hartman, Shane

2009-01-01

This study examines prevention practices and perceptions in U.S. schools since passage of federal No Child Left Behind (NCLB) legislation, using survey data from state education agencies (SEA) and a population-based sample of school districts. Only one third of U.S. public school districts rely on evidence-based prevention curriculum in middle…

Mechanisms of Acquired Resistance to Trastuzumab Emtansine in Breast Cancer Cells.

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Li, Guangmin; Guo, Jun; Shen, Ben-Quan; Bumbaca Yadav, Daniela; Sliwkowski, Mark X; Crocker, Lisa M; Lacap, Jennifer A; Lewis Phillips, Gail D

2018-04-25

The receptor tyrosine kinase HER2 is overexpressed in approximately 20% of breast cancer, and its amplification is associated with reduced survival. Trastuzumab emtansine (Kadcyla®, T-DM1), an antibody-drug conjugate that is comprised of trastuzumab covalently linked to the anti-mitotic agent DM1 through a stable linker, was designed to selectively deliver DM1 to HER2-overexpressing tumor cells. T-DM1 is approved for the treatment of patients with HER2-positive metastatic breast cancer following progression on trastuzumab and a taxane. Despite the improvement in clinical outcome, many patients who initially respond to T-DM1 treatment eventually develop progressive disease. The mechanisms that contribute to T-DM1 resistance are not fully understood. To this end, we developed T-DM1-resistant in vitro models to examine the mechanisms of acquired T-DM1 resistance. We demonstrate that decreased HER2 and up-regulation of MDR1 contribute to T-DM1 resistance in KPL-4 T-DM1 resistant cells. In contrast, both loss of SLC46A3 and PTEN deficiency play a role in conferring resistance in BT-474M1 T-DM1 resistant cells. Our data suggest that these two cell lines acquire resistance through distinct mechanisms. Furthermore, we show that the KPL-4 T-DM1 resistance can be overcome by treatment with an inhibitor of MDR1, whereas a PI3K inhibitor can rescue PTEN loss-induced resistance in T-DM1-resistant BT-474M1 cells. Our results provide a rationale for developing therapeutic strategies to enhance T-DM1 clinical efficacy by combining T-DM1 and other inhibitors that target signaling transduction or resistance pathways. Copyright ©2018, American Association for Cancer Research.

Adjuvant Trastuzumab in HER2-Positive Early Breast Cancer by Age and Hormone Receptor Status: A Cost-Utility Analysis.

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Leung, William; Kvizhinadze, Giorgi; Nair, Nisha; Blakely, Tony

2016-08-01

The anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibody trastuzumab improves outcomes in patients with node-positive HER2+ early breast cancer. Given trastuzumab's high cost, we aimed to estimate its cost-effectiveness by heterogeneity in age and estrogen receptor (ER) and progesterone receptor (PR) status, which has previously been unexplored, to assist prioritisation. A cost-utility analysis was performed using a Markov macro-simulation model, with a lifetime horizon, comparing a 12-mo regimen of trastuzumab with chemotherapy alone using the latest (2014) effectiveness measures from landmark randomised trials. A New Zealand (NZ) health system perspective was adopted, employing high-quality national administrative data. Incremental quality-adjusted life-years for trastuzumab versus chemotherapy alone are two times higher (2.33 times for the age group 50-54 y; 95% CI 2.29-2.37) for the worst prognosis (ER-/PR-) subtype compared to the best prognosis (ER+/PR+) subtype, causing incremental cost-effectiveness ratios (ICERs) for the former to be less than half those of the latter for the age groups from 25-29 to 90-94 y (0.44 times for the age group 50-54 y; 95% CI 0.43-0.45). If we were to strictly apply an arbitrary cost-effectiveness threshold equal to the NZ gross domestic product per capita (2011 purchasing power parity [PPP]-adjusted: US$30,300; €23,700; £21,200), our study suggests that trastuzumab (2011 PPP-adjusted US$45,400/€35,900/£21,900 for 1 y at formulary prices) may not be cost-effective for ER+ (which are 61% of all) node-positive HER2+ early breast cancer patients but cost-effective for ER-/PR- subtypes (37% of all cases) to age 69 y. Market entry of trastuzumab biosimilars will likely reduce the ICER to below this threshold for premenopausal ER+/PR- cancer but not for ER+/PR+ cancer. Sensitivity analysis using the best-case effectiveness measure for ER+ cancer had the same result. A key limitation was a lack of treatment

Adjuvant Trastuzumab in HER2-Positive Early Breast Cancer by Age and Hormone Receptor Status: A Cost-Utility Analysis.

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William Leung

2016-08-01

Full Text Available The anti-human epidermal growth factor receptor 2 (HER2 monoclonal antibody trastuzumab improves outcomes in patients with node-positive HER2+ early breast cancer. Given trastuzumab's high cost, we aimed to estimate its cost-effectiveness by heterogeneity in age and estrogen receptor (ER and progesterone receptor (PR status, which has previously been unexplored, to assist prioritisation.A cost-utility analysis was performed using a Markov macro-simulation model, with a lifetime horizon, comparing a 12-mo regimen of trastuzumab with chemotherapy alone using the latest (2014 effectiveness measures from landmark randomised trials. A New Zealand (NZ health system perspective was adopted, employing high-quality national administrative data. Incremental quality-adjusted life-years for trastuzumab versus chemotherapy alone are two times higher (2.33 times for the age group 50-54 y; 95% CI 2.29-2.37 for the worst prognosis (ER-/PR- subtype compared to the best prognosis (ER+/PR+ subtype, causing incremental cost-effectiveness ratios (ICERs for the former to be less than half those of the latter for the age groups from 25-29 to 90-94 y (0.44 times for the age group 50-54 y; 95% CI 0.43-0.45. If we were to strictly apply an arbitrary cost-effectiveness threshold equal to the NZ gross domestic product per capita (2011 purchasing power parity [PPP]-adjusted: US$30,300; €23,700; £21,200, our study suggests that trastuzumab (2011 PPP-adjusted US$45,400/€35,900/£21,900 for 1 y at formulary prices may not be cost-effective for ER+ (which are 61% of all node-positive HER2+ early breast cancer patients but cost-effective for ER-/PR- subtypes (37% of all cases to age 69 y. Market entry of trastuzumab biosimilars will likely reduce the ICER to below this threshold for premenopausal ER+/PR- cancer but not for ER+/PR+ cancer. Sensitivity analysis using the best-case effectiveness measure for ER+ cancer had the same result. A key limitation was a lack of

Reorienting the Fab domains of trastuzumab results in potent HER2 activators.

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Justin M Scheer

Full Text Available The structure of the Fab region of antibodies is critical to their function. By introducing single cysteine substitutions into various positions of the heavy and light chains of the Fab region of trastuzumab, a potent antagonist of HER2, and using thiol chemistry to link the different Fabs together, we produced a variety of monospecific F(ab'(2-like molecules with activities spanning from activation to inhibition of breast tumor cell growth. These isomers (or bis-Fabs of trastuzumab, with varying relative spatial arrangements between the Fv-regions, were able to either promote or inhibit cell-signaling activities through the PI3K/AKT and MAPK pathways. A quantitative phosphorylation mapping of HER2 indicated that the agonistic isomers produced a distinct phosphorylation pattern associated with activation. This study suggests that antibody geometric isomers, found both in nature and during synthetic antibody development, can have profoundly different biological activities independent of their affinities for their target molecules.

Efficient production of Trastuzumab Fab antibody fragments in Brevibacillus choshinensis expression system.

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Mizukami, Makoto; Onishi, Hiromasa; Hanagata, Hiroshi; Miyauchi, Akira; Ito, Yuji; Tokunaga, Hiroko; Ishibashi, Matsujiro; Arakawa, Tsutomu; Tokunaga, Masao

2018-10-01

The Brevibacillus expression system has been successfully employed for the efficient productions of a variety of recombinant proteins, including enzymes, cytokines, antigens and antibody fragments. Here, we succeeded in secretory expression of Trastuzumab Fab antibody fragments using B. choshinensis/BIC (Brevibacillus in vivocloning) expression system. In the fed-batch high-density cell culture, recombinant Trastuzumab Fab with amino-terminal His-tag (His-BcFab) was secreted at high level, 1.25 g/liter, and Fab without His-tag (BcFab) at ∼145 mg/L of culture supernatant. His-BcFab and BcFab were purified to homogeneity using combination of conventional column chromatographies with a yield of 10-13%. This BcFab preparation exhibited native structure and functions evaluated by enzyme-linked immunosorbent assay, surface plasmon resonance, circular dichroism measurements and size exclusion chromatography. To our knowledge, this is the highest production of Fab antibody fragments in gram-positive bacterial expression/secretion systems. Copyright © 2018 Elsevier Inc. All rights reserved.

Reorienting the Fab Domains of Trastuzumab Results in Potent HER2 Activators

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Scheer, Justin M.; Sandoval, Wendy; Elliott, J. Michael; Shao, Lily; Luis, Elizabeth; Lewin-Koh, Sock-Cheng; Schaefer, Gabriele; Vandlen, Richard

2012-01-01

The structure of the Fab region of antibodies is critical to their function. By introducing single cysteine substitutions into various positions of the heavy and light chains of the Fab region of trastuzumab, a potent antagonist of HER2, and using thiol chemistry to link the different Fabs together, we produced a variety of monospecific F(ab′)2-like molecules with activities spanning from activation to inhibition of breast tumor cell growth. These isomers (or bis-Fabs) of trastuzumab, with varying relative spatial arrangements between the Fv-regions, were able to either promote or inhibit cell-signaling activities through the PI3K/AKT and MAPK pathways. A quantitative phosphorylation mapping of HER2 indicated that the agonistic isomers produced a distinct phosphorylation pattern associated with activation. This study suggests that antibody geometric isomers, found both in nature and during synthetic antibody development, can have profoundly different biological activities independent of their affinities for their target molecules. PMID:23284778

Is Administration of Trastuzumab an Independent Risk Factor for Developing Osteonecrosis of the Jaw Among Metastatic Breast Cancer Patients Under Zoledronic Acid Treatment?

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Pilanci, Kezban Nur; Alco, Gul; Ordu, Cetin; Sarsenov, Dauren; Celebi, Filiz; Erdogan, Zeynep; Agacayak, Filiz; Ilgun, Serkan; Tecimer, Coskun; Demir, Gokhan; Eralp, Yesim; Okkan, Sait; Ozmen, Vahit

2015-01-01

Abstract One of the most important adverse effects of zoledronic acid (ZA) is osteonecrosis of the jaw (ONJ). In previous literature, several risk factors have been identified in the development of ONJ. In this study, we aimed to determine the role of trastuzumab, an antiangiogenic agent, as an independent risk factor for the development of this serious side effect. Our study included 97 patients (mean age: 54 ± 10 years) with breast cancer, recorded in the archives of the Istanbul Florence Nightingale Breast Study Group, who received ZA therapy due to bone metastases between March 2006 and December 2013. We recorded the patients’ ages, weights, duration of treatment with ZA, number of ZA infusions, dental procedures, anticancer treatments (chemotherapy, aromatase inhibitor, trastuzumab), the presence of diabetes mellitus or renal dysfunction, and smoking habits. Thirteen patients (13.40%) had developed ONJ. Among the patients with ONJ, the mean time of exposure to ZA was 41 months (range: 13–82) and the mean number of ZA infusions was 38 (range: 15–56). The duration of treatment with ZA and the use of trastuzumab were observed to be 2 factors that influenced the development of ONJ (P = 0.049 and P = 0.028, respectively). The development of ONJ under ZA treatment may be associated solely with the duration of ZA treatment and the concurrent administration of trastuzumab. These findings show that patients who are administered trastuzumab for metastatic breast cancer while undergoing ZA treatment are prone to developing ONJ. Therefore, we recommend intense clinical observation to avoid this particular condition in patients receiving ZA and trastuzumab. PMID:25950681

Mediation Analysis of an Adolescent HIV/STI/Pregnancy Prevention Intervention

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Glassman, Jill R.; Franks, Heather M.; Baumler, Elizabeth R.; Coyle, Karin K.

2014-01-01

Most interventions designed to prevent HIV/STI/pregnancy risk behaviours in young people have multiple components based on psychosocial theories (e.g. social cognitive theory) dictating sets of mediating variables to influence to achieve desired changes in behaviours. Mediation analysis is a method for investigating the extent to which a variable…

The vitamin E analog, alpha-tocopheryloxyacetic acid enhances the anti-tumor activity of trastuzumab against HER2/neu-expressing breast cancer

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Penichet Manuel L

2011-11-01

Full Text Available Abstract Background HER2/neu is an oncogene that facilitates neoplastic transformation due to its ability to transduce growth signals in a ligand-independent manner, is over-expressed in 20-30% of human breast cancers correlating with aggressive disease and has been successfully targeted with trastuzumab (Herceptin®. Because trastuzumab alone achieves only a 15-30% response rate, it is now commonly combined with conventional chemotherapeutic drugs. While the combination of trastuzumab plus chemotherapy has greatly improved response rates and increased survival, these conventional chemotherapy drugs are frequently associated with gastrointestinal and cardiac toxicity, bone marrow and immune suppression. These drawbacks necessitate the development of new, less toxic drugs that can be combined with trastuzumab. Recently, we reported that orally administered alpha-tocopheryloxyacetic acid (α-TEA, a novel ether derivative of alpha-tocopherol, dramatically suppressed primary tumor growth and reduced the incidence of lung metastases both in a transplanted and a spontaneous mouse model of breast cancer without discernable toxicity. Methods In this study we examined the effect of α-TEA plus HER2/neu-specific antibody treatment on HER2/neu-expressing breast cancer cells in vitro and in a HER2/neu positive human xenograft tumor model in vivo. Results We show in vitro that α-TEA plus anti-HER2/neu antibody has an increased cytotoxic effect against murine mammary tumor cells and human breast cancer cells and that the anti-tumor effect of α-TEA is independent of HER2/neu status. More importantly, in a human breast cancer xenograft model, the combination of α-TEA plus trastuzumab resulted in faster tumor regression and more tumor-free animals than trastuzumab alone. Conclusion Due to the cancer cell selectivity of α-TEA, and because α-TEA kills both HER2/neu positive and HER2/neu negative breast cancer cells, it has the potential to be effective and

Vinorelbine-based salvage therapy in HER2-positive metastatic breast cancer patients progressing during trastuzumab-containing regimens: a retrospective study

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Viale Giuseppe

2008-07-01

Full Text Available Abstract Background The vinka-alkaloyd vinorelbine is a potentially valuable treatment in patients with HER2-positive, trastuzumab-resistant advanced breast cancer. We sought to document the clinical activity of vinorelbine-based salvage treatments in this clinical setting. Methods We analyzed a cohort of 424 consecutive women receiving trastuzumab-based therapy for HER2-positive advanced breast cancer. Of these, 299 were identified as progressing during the initial trastuzumab-based treatment, and 77 received vinorelbine-based therapy as first salvage treatment. Central review of pathological specimens revealed that 70 patients had HER2-amplification detected by FISH. For these patients we determined overall response rate (ORR = complete-CR + partial-PR and clinical benefit (CB = CR+PR+ Stable disease lasting at least 6 months, time to progression (TTP and overall survival (OS from the initiation of vinorelbine-based salvage therapy. Results In 60 patients who were evaluable for tumor response, ORR and CB rates were 28% (95% C.I. 18%-41% and 50% (95% C.I. 38%-62%, respectively. Median follow-up from the initiation of salvage therapy was 15 months (range 1–63 months. Median TTP and OS were 7.1 months (95% C.I. 6.6–7.7 months and 21 months (95% C.I. 14.3–27.7 months, respectively. No differences in clinical outcomes were observed according to whether vinorelbine was administered as a single agent or in combination with other cytostatics, or whether trastuzumab was stopped or continued beyond disease progression. Conclusion our findings suggests that vinorelbine-based combinations are active and should be further evaluated in studies conducted in trastuzumab-resistant patients, including those evaluating newer HER2-targeting agents.

Social Anxiety and Internet Addiction among Rural Left-behind Children: The Mediating Effect of Loneliness.

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Ren, Yujia; Yang, Jiao; Liu, Liqiong

2017-12-01

At present, the mental health of rural left-behind children is a major social problem in China. Internet addiction, social anxiety, and loneliness are common psychological and behavioral problems among rural left-behind children, but the relationships among these issues have not been clearly identified. A total of 432 junior year 1 to senior year 3 students were randomly selected from 2 rural middle schools in Hunan Province of China as the research subjects. The Internet Addiction Disorder Diagnostic Scale, Social Anxiety Subscale of the Self-Consciousness Scale (SASS-CS), and University of California Los Angeles Loneliness Scale were employed to measure the degree of Internet addiction, feelings of social fear, social avoidance behavior, and the level of loneliness among the research subjects. The rate of Internet addiction among rural left-behind middle school students was 18.27%, and was correlated with the length of time their parents spent at home as well as whether one or both parents migrated for work. Positive correlations were found among Internet addiction, social anxiety, and loneliness. Loneliness was found to play a mediating role in the relationship between social anxiety and Internet addiction among rural left-behind middle school students. Social anxiety and loneliness both increase the likelihood of Internet addiction in rural left-behind middle school students and social anxiety can affect Internet addiction through loneliness, implying an urgent need to strengthen care for rural left-behind children, reduce their loneliness, and thereby effectively alleviate the problem of Internet addiction among rural left-behind middle school students.

HER-2-PET imaging with Zr-89-trastuzumab in metastatic breast cancer patients

NARCIS (Netherlands)

Munnink, T. Oude; Dijkers, E.; Hooge, M. Lub-de; Kosterink, J.; Brouwers, A.; de Jong, J. R.; van Dongen, G.; de Vries, E.

2009-01-01

1045 Background: Non-invasive diagnostic tools can optimize and evaluate HER2 directed therapy in HER2 positive breast cancer patients. HER2 imaging with (111)In-trastuzumab SPECT showed promising results (Perik et al, J Clin Oncol. 2006). To further optimize HER2 imaging, we developed

The efficiency and safety of trastuzumab and lapatinib added to neoadjuvant chemotherapy in Her2-positive breast cancer patients: a randomized meta-analysis

Directory of Open Access Journals (Sweden)

Chen ZL

2016-05-01

Full Text Available Zhe-Ling Chen, Yan-Wei Shen, Shu-Ting Li, Chun-Li Li, Ling-Xiao Zhang, Jiao Yang, Meng Lv, Ya-Yun Lin, Xin Wang, Jin Yang Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China Background: The addition of human epidermal growth factor receptor 2 (Her2 therapies to neoadjuvant chemotherapy (NAC during treatment of Her2-positive breast cancer has been proposed as an effective way to improve the prognosis. However, the treatment outcomes of adding trastuzumab, lapatinib, or both to NAC were not unequivocal in randomized clinical trials. Based on these data, a meta-analysis was performed. Objective: The main objective was to evaluate the efficiency and safety of trastuzumab and lapatinib added to NAC for treatment of Her2-positive breast cancer. Methods: ClinicalTrials.gov and PubMed were searched for randomized clinical trials that compared trastuzumab, lapatinib, or both, added to NAC. The main endpoint was a pathologically complete response (pCR rate, in breast only or in breast and lymph nodes. The drug safety and the influence of hormone-receptor status, comparing the clinical response and the rate of breast conservation, were evaluated. Results: A total of eight publications were included in the primary analysis, designed as two or three subgroups. The cumulative cases were 2,349 and the analyses of all the clinical trials showed that the pCR rate was significantly higher in the group receiving trastuzumab than that in the group with lapatinib, either in breast only (P=0.001 or in breast and lymph nodes (P=0.0001. Similar results could be seen in comparisons of the combination versus trastuzumab group. Further studies of subgroups divided into hormone receptor-positive or-negative patients showed that the addition of trastuzumab or dual Her2-targeted therapy significantly improved the pCR rate in patients who were hormone-insensitive. Regarding the toxic

Preventing and De-Escalating Ethical Conflict: A Communication-Training Mediation Model.

Science.gov (United States)

Levin, Tomer T; Parker, Patricia A

2015-01-01

While ethical conflicts in the provision of healthcare are common, the current third-party mediator model is limited by a lack of expert ethical mediators, who are often not on site when conflict escalates. In order to improve clinical outcomes in situations such as conflicts at the end of life, we suggest that clinicians-physicians, nurses and social workers-be trained to prevent and de-escalate emerging conflicts. This can be achieved using a mediation model framed by a communication-training approach. A case example is presented and the model is discussed. The implication of this preventative/early intervention model for improving clinical outcomes, in particular end-of life conflict, is considered. Copyright 2015 The Journal of Clinical Ethics. All rights reserved.

Evaluación económica del trastuzumab como tratamiento adyuvante en cáncer de mama HER2- positivo en Colombia

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Jefferson Antonio Buendía

2013-09-01

Full Text Available Introducción. El trastuzumab es un anticuerpo monoclonal de reconocida efectividad para el tratamiento en mujeres con cáncer de mama positivo para HER2. Sin embargo, la mayoría de estudios de costo-efectividad se han llevado a cabo en países desarrollados. Objetivo. Determinar el costo-efectividad del tratamiento adyuvante con trastuzumab en mujeres concáncer de mama HER2+ en Colombia. Materiales y métodos. Se construyó un modelo de Markov, con ciclos de transición anuales y desde la perspectiva del pagador, para estimar los resultados clínicos y económicos derivados de la administración de trastuzumab en mujeres con HER2 positivo. El modelo incorpora cinco estados de transición: libre de enfermedad, recurrencia local, metástasis, falla cardiaca y muerte. La tasa de eventos y la razón de tazas instantáneas (0,51; IC95% 0,44-0,59; p<0,0001 se derivaron del reporte a cuatro años de los ensayos clínicos controlados N9831 y NSABP B-31. Los costos y las utilidades se estimados a partir de la literatura científica, utilizando una tasa de descuento del 5 % anual. Resultados. El modelo revela que la utilización de trastuzumab como tratamiento adyuvante prolongala expectativa de vida ajustada por calidad en 0,8 años, en comparación con la quimioterapia sin trastuzumab; a una razón de costo efectividad incremental (sic. de US$ 71.491 por año de vida ganado ajustado por calidad de vida. Conclusión. El tratamiento con trastuzumab durante un año no es costo-efectivo en Colombia, utilizando la definición de costo-efectividad de la OMS de menos de dos a tres veces el PIB per cápita por año de vida ganado ajustado por calidad de vida. doi: http://dx.doi.org/10.7705/biomedica.v33i3.832

Translating genetic research into preventive intervention: The baseline target moderated mediator design

Directory of Open Access Journals (Sweden)

George W. Howe

2016-01-01

Full Text Available In this paper we present and discuss a novel research approach, the baseline target moderated mediation (BTMM design, that holds substantial promise for advancing our understanding of how genetic research can inform prevention research. We first discuss how genetically informed research on developmental psychopathology can be used to identify potential intervention targets. We then describe the BTMM design, which employs moderated mediation within a longitudinal study to test whether baseline levels of intervention targets moderate the impact of the intervention on change in that target, and whether change in those targets mediates causal impact of preventive or treatment interventions on distal health outcomes. We next discuss how genetically informed BTMM designs can be applied to both microtrials and full-scale prevention trials. We end with a discussion of some of the advantages and limitations of this approach.

A kit to prepare {sup 111}In-DTPA-trastuzumab (Herceptin) Fab fragments injection under GMP conditions for imaging or radioimmunoguided surgery of HER2-positive breast cancer

Energy Technology Data Exchange (ETDEWEB)

Scollard, Deborah A.; Chan, Conrad [Department of Pharmaceutical Sciences, University of Toronto, Toronto, ON, M5S 3M2 (Canada); Holloway, Claire M.B. [Department of Surgery, Sunnybrook Health Sciences Centre, Toronto, ON, M4N 1H1 (Canada); Reilly, Raymond M., E-mail: raymond.reilly@utoronto.c [Department of Pharmaceutical Sciences, University of Toronto, Toronto, ON, M5S 3M2 (Canada); Department of Medical Imaging, University of Toronto, Toronto, ON, M5S 3E2 (Canada); Toronto General Research Institute, University Health Network, Toronto, ON, M5G 2M9 (Canada)

2011-01-15

Introduction: The human epidermal growth factor receptor-2 (HER2) gene is amplified in 25% of invasive breast cancers, and receptor overexpression has been noted in up to 60% of early stages of the disease [ductal carcinoma in situ (DCIS)]. Preclinical studies have revealed high tumor/blood ratios (>27:1) for {sup 111}In-labeled Fab fragments of the HER2 monoclonal antibody, trastuzumab (Herceptin) ({sup 111}In-DTPA-trastuzumab Fab) at 72 h pi in athymic mice bearing subcutaneous human breast cancer xenografts. Our aim in this study was to formulate a kit for preparation of {sup 111}In-DTPA-trastuzumab Fab injection under good manufacturing practice (GMP) conditions suitable for human administration in a Phase I clinical trial of imaging and radioimmunoguided surgery (RIGS) of HER2-positive breast cancer. Methods: Fab fragments were produced by digestion of trastuzumab IgG (Herceptin) with immobilized papain for 20 h at 37{sup o}C. Fab fragments were purified by ultrafiltration, then reacted with a 10-fold molar excess of diethylenetriaminepentaacetic acid (DTPA) dianhydride. DTPA-Fab fragments were purified, then sterilized by filtration into unit dose glass vials (kits). Kits were tested against specifications for volume (0.9-1.1 ml), protein concentration (0.45-0.55 mg/ml), pH (5.5-6.5), DTPA substitution (0.5-4.0 mol DTPA/mol Fab), appearance (clear, colorless and particle free), labeling efficiency ({>=}85%), and sterility and apyrogenicity (USP XXXII). Immunoreactivity of {sup 111}In-DTPA-trastuzumab Fab towards HER2 was measured by saturation radioligand binding assays using SKBR-3 human breast cancer cells (specifications: K{sub a}=0.6-9.6x10{sup 7} L/mol; B{sub max}=0.6-10.4x10{sup 6} sites/cell). {sup 111}In-DTPA-trastuzumab Fab injection was prepared by adding 80-100 MBq of {sup 111}InCl{sub 3} to a single kit vial and incubating for 30 min at room temperature. {sup 111}In-DTPA-trastuzumab Fab was assayed for the amount of radioactivity and tested for p

The relationship between quantitative human epidermal growth factor receptor 2 gene expression by the 21-gene reverse transcriptase polymerase chain reaction assay and adjuvant trastuzumab benefit in Alliance N9831.

Science.gov (United States)

Perez, Edith A; Baehner, Frederick L; Butler, Steven M; Thompson, E Aubrey; Dueck, Amylou C; Jamshidian, Farid; Cherbavaz, Diana; Yoshizawa, Carl; Shak, Steven; Kaufman, Peter A; Davidson, Nancy E; Gralow, Julie; Asmann, Yan W; Ballman, Karla V

2015-10-01

The N9831 trial demonstrated the efficacy of adjuvant trastuzumab for patients with human epidermal growth factor receptor 2 (HER2) locally positive tumors by protein or gene analysis. We used the 21-gene assay to examine the association of quantitative HER2 messenger RNA (mRNA) gene expression and benefit from trastuzumab. N9831 tested the addition of trastuzumab to chemotherapy in stage I-III HER2-positive breast cancer. For two of the arms of the trial, doxorubicin and cyclophosphamide followed by paclitaxel (AC-T) and doxorubicin and cyclophosphamide followed by paclitaxel and trastuzumab concurrent chemotherapy-trastuzumab (AC-TH), recurrence score (RS) and HER2 mRNA expression were determined by the 21-gene assay (Oncotype DX®) (negative 10 % positive cells = positive), 91 % for RT-PCR versus central fluorescence in situ hybridization (FISH) (≥2.0 = positive) and 94 % for central IHC versus central FISH. In the primary analysis, the association of HER2 expression by 21-gene assay with trastuzumab benefit was marginally nonsignificant (nonlinear p = 0.057). In hormone receptor-positive patients (local IHC) the association was significant (p = 0.002). The association was nonlinear with the greatest estimated benefit at lower and higher HER2 expression levels. Concordance among HER2 assessments by central IHC, FISH, and RT-PCR were similar and high. Association of HER2 mRNA expression with trastuzumab benefit as measured by time to distant recurrence was nonsignificant. A consistent benefit of trastuzumab irrespective of mHER2 levels was observed in patients with either IHC-positive or FISH-positive tumors. Trend for benefit was observed also for the small groups of patients with negative results by any or all of the central assays. Clinicaltrials.gov NCT00005970 . Registered 5 July 2000.

PI3K pathway activation results in low efficacy of both trastuzumab and lapatinib

International Nuclear Information System (INIS)

Wang, Leiping; Hu, Xichun; Zhang, Qunling; Zhang, Jian; Sun, Si; Guo, Haiyi; Jia, Zhen; Wang, Biyun; Shao, Zhimin; Wang, Zhonghua

2011-01-01

Human epidermal growth factor receptor 2 (HER2) is the most crucial ErbB receptor tyrosine kinase (RTK) family member in HER2-positive (refered to HER2-overexpressing) breast cancer which are dependent on or 'addictive' to the Phosphatidylinositol-3-kinase (PI3K) pathway. HER2-related target drugs trastuzumab and lapatinib have been the foundation of treatment of HER2--positive breast cancer. This study was designed to explore the relationship between PI3K pathway activation and the sensitivity to lapatinib in HER2--positive metastatic breast cancer patients pretreated with anthracyclins, taxanes and trastuzumab. Sixty-seven HER2-positive metastatic breast cancer patients were recruited into a global lapatinib Expanded Access Program and 57 patients have primary tumor specimens available for determination of PI3K pathway status. PTEN status was determined by immunohistochemical staining and PIK3CA mutations were detected via PCR sequencing. All patients were treated with lapatinib 1250 mg/day continuously and capecitabine 1000 mg/m 2 twice daily on a 2-week-on and 1-week-off schedule until disease progression, death, withdrawal of informed consent, or intolerable toxicity. PIK3CA mutations and PTEN loss were detected in 12.3% (7/57) and 31.6% (18/57) of the patients, respectively. Twenty-two patients with PI3K pathway activation (defined as PIK3CA mutation and/or PTEN expression loss) had a lower clinical benefit rate (36.4% versus 68.6%, P = 0.017) and a lower overall response rate (9.1% versus 31.4%, P = 0.05), when compared with the 35 patients with no activation. A retrospective analysis of first trastuzumab-containing regimen treatment data showed that PI3K pathway activation correlated with a shorter median progression-free survival (4.5 versus 9.0 months, P = 0.013). PIK3CA mutations occur more frequently in elder patients for HER2-positive breast cancer. PIK3CA mutations and PTEN loss are not mutually exclusive. PI3K pathway activation resulting

Modifications in dynamic contrast-enhanced magnetic resonance imaging parameters after α-particle-emitting ²²⁷Th-trastuzumab therapy of HER2-expressing ovarian cancer xenografts.

Science.gov (United States)

Heyerdahl, Helen; Røe, Kathrine; Brevik, Ellen Mengshoel; Dahle, Jostein

2013-09-01

The purpose of this study was to investigate the effect of α-particle-emitting (227)Th-trastuzumab radioimmunotherapy on tumor vasculature to increase the knowledge about the mechanisms of action of (227)Th-trastuzumab. Human HER2-expressing SKOV-3 ovarian cancer xenografts were grown bilaterally in athymic nude mice. Mice with tumor volumes 253 ± 36 mm(3) (mean ± SEM) were treated with a single injection of either (227)Th-trastuzumab at a dose of 1000 kBq/kg body weight (treated group, n=14 tumors) or 0.9% NaCl (control group, n=10 tumors). Dynamic T1-weighted contrast-enhanced magnetic resonance imaging (DCEMRI) was used to study the effect of (227)Th-trastuzumab on tumor vasculature. DCEMRI was performed before treatment and 1, 2, and 3 weeks after therapy. Tumor contrast-enhancement curves were extracted voxel by voxel and fitted to the Brix pharmacokinetic model. Pharmacokinetic parameters for the tumors that underwent radioimmunotherapy were compared with the corresponding parameters of control tumors. Significant increases of kep, the rate constant of diffusion from the extravascular extracellular space to the plasma (PTh-trastuzumab treatment of HER2-expressing ovarian cancer xenografts. Copyright © 2013 Elsevier Inc. All rights reserved.

Costs of subcutaneous and intravenous administration of trastuzumab for patients with HER2-positive breast cancer

DEFF Research Database (Denmark)

Olsen, Jens; Jensen, Kenneth Forsstrøm; Olesen, Daniel Sloth

2018-01-01

AIM: Trastuzumab is available in an intravenous (iv.) and a subcutaneous (sc.) formulation. The objective of this study was to estimate the costs of administration of iv. and sc. trastuzumab treatment. MATERIALS & METHODS: Via interviews, we identified all the activities associated with iv. and sc....... administration. The outcome was time estimates. To estimate the administration costs, the time estimates were valued by average gross wages. RESULTS: The iv. administration takes longer time as infusion time is longer (25 or 85 min). The iv. administration is associated with higher cost for 17 cycles; €971...... (€1858 vs €887). CONCLUSION: sc. administration is associated with lower administration costs. Switching patients from iv. to sc. would make it possible to treat more patients without increasing the personnel resources....

Translating Genetic Research into Preventive Intervention: The Baseline Target Moderated Mediator Design.

Science.gov (United States)

Howe, George W; Beach, Steven R H; Brody, Gene H; Wyman, Peter A

2015-01-01

In this paper we present and discuss a novel research approach, the baseline target moderated mediation (BTMM) design, that holds substantial promise for advancing our understanding of how genetic research can inform prevention research. We first discuss how genetically informed research on developmental psychopathology can be used to identify potential intervention targets. We then describe the BTMM design, which employs moderated mediation within a longitudinal study to test whether baseline levels of intervention targets moderate the impact of the intervention on change in that target, and whether change in those targets mediates causal impact of preventive or treatment interventions on distal health outcomes. We next discuss how genetically informed BTMM designs can be applied to both microtrials and full-scale prevention trials. We use simulated data to illustrate a BTMM, and end with a discussion of some of the advantages and limitations of this approach.

External influences and priority-setting for anti-cancer agents: a case study of media coverage in adjuvant trastuzumab for breast cancer

Directory of Open Access Journals (Sweden)

Fralick John

2007-06-01

Full Text Available Abstract Background Setting priorities for the funding of new anti-cancer agents is becoming increasingly complex. The funding of adjuvant trastuzumab for breast cancer has brought this dilemma to the fore. In this paper we review external factors that may influence decision-making bodies and present a case study of media response in Ontario, Canada to adjuvant trastuzumab for breast cancer. Methods A comprehensive search of the databases of Canadian national and local newspapers and television was performed. Articles pertaining to trastuzumab in adjuvant breast cancer as well as 17 other anti-cancer drugs and indications were retrieved. The search period was from the date when individual trial results were announced to the date funding was made available in Ontario. Results During the 2.6 months between the release of the trastuzumab results to funding approval in Ontario, we identified 51 episodes of media coverage. For the 17 other drugs/indications (7 breast and 10 non-breast, the median time to funding approval was 31 months (range 14–46. Other recent major advances in oncology such as adjuvant vinorelbine/cisplatin for resected NSCLC and docetaxel for advanced prostate cancer received considerably less media attention (17 media reports for each than trastuzumab. The median number of media reports for breast cancer drugs was 4.5 compared to 2.5 for non-breast cancer drugs (p = 0.56. Conclusion Priority-setting for novel anti-cancer agents is a complex process that tries to ensure fair use of constrained resources to fund therapies with the best evidence of clinical benefit. However, this process is subject to external factors including the influence of media, patient advocates, politicians, and industry. The data in this case study serve to illustrate the significant involvement one (or all of these external factors may play in the debate over priority-setting.

Changes in 2-fluoro-2-deoxy-D-glucose incorporation, hexokinase activity and lactate production by breast cancer cells responding to treatment with the anti-HER-2 antibody trastuzumab

Energy Technology Data Exchange (ETDEWEB)

Cheyne, Richard W. [School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD (United Kingdom); Trembleau, Laurent; McLaughlin, Abbie [School of Natural and Computing Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD (United Kingdom); Smith, Tim A.D., E-mail: t.smith@abdn.ac.u [School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD (United Kingdom)

2011-04-15

Introduction: Changes in 2-[{sup 18}F]-fluoro-2-deoxy-D-glucose (FDG) incorporation by tumors, detected using positron emission tomography, during response to chemotherapy are utilized clinically in patient management. Here, the effect of treatment with growth-inhibitory doses of the anti-human epidermal growth factor receptor-2 antibody trastuzumab (Herceptin) on the incorporation of FDG by breast tumor cells was measured along with hexokinase (HK) and glucose transport to determine the potential of FDG-positron emission tomography in predicting response to these biological anti-cancer therapies and their modulatory effects on the steps involved in FDG incorporation. Methods: The sensitivity to trastuzumab of three breast tumor cell lines, SKBr3, MDA-MB-453 and MDA-MB-468, expressing human epidermal growth factor receptor-2 at high, medium and low levels, respectively, was determined using MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay over a 6-day period, and a clonogenic assay was carried out after 7- and 10-day exposures. FDG incorporation by cells treated with growth-inhibitory doses of trastuzumab was carried out after 4 h and 2, 4 and 6 days of treatment. Glucose transport (rate of uptake of the non-metabolizable analogue [{sup 3}H]O-methyl-D-glucose), HK activity and lactate production were measured on cells treated with inhibitory doses of trastuzumab for 6 days. Results: The IC{sub 50} doses for SKBr3 and MDA-MB-453 and the IC{sub 20} dose for MDA-MB-468 after 6 days of treatment with trastuzumab were 0.25, 1 and 170 {mu}g/ml, respectively. FDG incorporation by SKBr3 and MDA-MB-453 cells was found to be decreased using IC{sub 50} doses of trastuzumab for 6 days. At the IC{sub 50} doses, FDG incorporation was also decreased at 4 days and, in the case of MDA-MB-453, even after 4 h of treatment. Decreased FDG incorporation corresponded with decreased HK activity in these cells. Lactate production, previously suggested to be a

Population-based outcomes after brain radiotherapy in patients with brain metastases from breast cancer in the Pre-Trastuzumab and Trastuzumab eras

International Nuclear Information System (INIS)

Karam, Irene; Hamilton, Sarah; Nichol, Alan; Woods, Ryan; Speers, Caroline; Kennecke, Hagen; Tyldesley, Scott

2013-01-01

To evaluate the survival of patients with human epidermal growth factor receptor 2 (HER2) positive and negative metastatic breast cancer irradiated for brain metastases before and after the availability of trastuzumab (T). Women diagnosed with brain metastasis from breast cancer in two eras between 2000 and 2007 (T-era, n = 441) and 1986 to 1992 (PreT-era, n = 307), treated with whole brain radiotherapy (RT) were identified. In the T-era, HER2 testing was part of routine clinical practice, and in the preT-era 128/307 (42%) cases had HER2 testing performed retrospectively on tissue microarrays. Overall survival (OS) was estimated using the Kaplan-Meier method and comparisons between eras used log-rank tests. In the preT- and T-era cohorts, the rate of HER2 positivity was 40% (176/441) and 26% (33/128) (p < 0.001). The median time from diagnosis to brain RT was longer in the preT-era (3.3 years versus 2.3 years, p < 0.001). Survival after brain RT was improved in the T-era compared to the preT-era (1-year OS 26% versus 12%, p < 0.001). The 1-year OS rate for HER2 negative patients was 20% in both eras (p = 0.97). Among HER2 positive patients, the 1-year OS in the preT-era was 5% compared to 40% in the T-era (p < 0.001). Distinct from patients with HER2 negative disease in whom no difference in survival after brain RT was observed over time, patients with HER2 positive brain metastases experienced significantly improved survival subsequent to the availability of trastuzumab

Efficacy and safety of ABP 980 compared with reference trastuzumab in women with HER2-positive early breast cancer (LILAC study): a randomised, double-blind, phase 3 trial.

Science.gov (United States)

von Minckwitz, Gunter; Colleoni, Marco; Kolberg, Hans-Christian; Morales, Serafin; Santi, Patricia; Tomasevic, Zorica; Zhang, Nan; Hanes, Vladimir

2018-06-04

ABP 980 (Amgen Inc, Thousand Oaks, CA, USA) is a biosimilar of trastuzumab, with analytical, functional, and pharmacokinetic similarities. We compared the clinical safety and efficacy of ABP 980 with that of trastuzumab in women with HER2-positive early breast cancer. We did a randomised, multicentre, double-blind, active-controlled equivalence trial at 97 study centres in 20 countries, mainly in Europe and South America. Eligible women were aged 18 years or older, had histologically confirmed HER2-positive invasive early breast cancer, an Eastern Cooperative Oncology Group performance status score of 0 or 1, and were planning to have surgical resection of the breast tumour with sentinel or axillary lymph node dissection and neoadjuvant chemotherapy. After four cycles of run-in anthracycline-based chemotherapy, patients were assigned 1:1 to receive ABP 980 or trastuzumab with a permuted block design (blocks of four) computer-generated randomisation schedule. Patients received neoadjuvant therapy with a loading dose (8 mg/kg) of ABP 980 or trastuzumab plus paclitaxel 175 mg/m 2 in a 90 min intravenous infusion, followed by three cycles of 6 mg/kg intravenous ABP 980 or trastuzumab plus paclitaxel 175 mg/m 2 every 3 weeks in 30 min intravenous infusions (or 80 mg/m 2 paclitaxel once per week for 12 cycles if that was the local standard of care). Randomisation was stratified by T stage, node status, hormone receptor status, planned paclitaxel dosing schedule, and geographical region. Surgery was completed 3-7 weeks after the last dose of neoadjuvant treatment, after which adjuvant treatment with ABP 980 or trastuzumab was given every 3 weeks for up to 1 year after the first dose in the study. Patients had been randomly assigned at baseline to continue APB 980, continue trastuzumab, or switch from trastuzumab to APB 980 as their adjuvant treatment. The co-primary efficacy endpoints were risk difference and risk ratio (RR) of pathological complete response in breast

Left atrial appendage occlusion for stroke prevention in atrial fibrillation in Europe

DEFF Research Database (Denmark)

Lip, Gregory Y.H.; Dagres, Nikolaos; Proclemer, Alessandro

2013-01-01

The purpose of this EP wire survey was to assess clinical practice in relation to the use of left atrial appendage occlusion (LAAO) devices for stroke prevention in atrial fibrillation (AF) among members of the European Heart Rhythm Association research network. The average number of performed LA...... are most often performed by interventional cardiologists. Experience varied widely, and this was reflected in the wide range of thromboembolic and procedural (tamponade, bleeding) complications reported by the respondents to this EP wire survey....

Health-related quality-of-life assessment in CLEOPATRA, a phase III study combining pertuzumab with trastuzumab and docetaxel in metastatic breast cancer.

Science.gov (United States)

Cortés, J; Baselga, J; Im, Y-H; Im, S-A; Pivot, X; Ross, G; Clark, E; Knott, A; Swain, S M

2013-10-01

The phase III CLEOPATRA study demonstrated that combining pertuzumab with trastuzumab plus docetaxel significantly improves progression-free and overall survival in previously untreated HER2-positive metastatic breast cancer. Here, we report health-related quality-of-life (HRQoL) results from CLEOPATRA. Participants were randomly assigned to pertuzumab or placebo, each given with trastuzumab plus docetaxel every 3 weeks. Pertuzumab and trastuzumab were administered until progression and six or more docetaxel cycles were recommended. Time from randomization to a ≥ 5-point decrease in Trial Outcome Index-Physical/Functional/Breast (TOI-PFB) of the Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaire was analyzed as a prespecified secondary end point. A post hoc exploratory analysis investigated time to ≥ 2-point deterioration in Breast Cancer Subscale (BCS) score. Time to ≥ 5-point decline in TOI-PFB did not differ significantly between the pertuzumab and placebo arms [hazard ratio (HR), 0.97; P = 0.7161]. The median times to TOI-PFB deterioration were 18.4 and 18.3 weeks, respectively (approximately six cycles). The mean TOI-PFB declined slightly until week 18 and recovered thereafter. Pertuzumab increased time until BCS deterioration versus placebo (median 26.7 versus 18.3 weeks; HR, 0.77; P = 0.0061). Combining pertuzumab with trastuzumab and docetaxel had no adverse impact on HRQoL and may prolong time to worsening of breast cancer-specific symptoms.

Radiobromination of humanized anti-HER2 monoclonal antibody trastuzumab using N-succinimidyl 5-bromo-3-pyridinecarboxylate, a potential label for immunoPET

Energy Technology Data Exchange (ETDEWEB)

Mume, Eskender [Organic Chemistry, Department of Chemistry, Uppsala University, S-751 24 Uppsala (Sweden); Orlova, Anna [Affibody AB, S-161 02 Bromma (Sweden); Malmstroem, Per-Uno [Division of Urology, Department of Surgical Sciences, Uppsala University, S-751 85 Uppsala (Sweden); Lundqvist, Hans [Unit of Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala University, S-751 85 Uppsala (Sweden); Sjoeberg, Stefan [Organic Chemistry, Department of Chemistry, Uppsala University, S-751 24 Uppsala (Sweden); Tolmachev, Vladimir [Unit of Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala University, S-751 85 Uppsala (Sweden)]. E-mail: vladimir.tolmachev@bms.uu.se

2005-08-01

Combining the specificity of radioimmunoscintigraphy and the high sensitivity of PET in an in vivo detection technique could improve the quality of nuclear diagnostics. Positron-emitting nuclide {sup 76}Br (T {sub 1/2}=16.2 h) might be a possible candidate for labeling monoclonal antibodies (mAbs) and their fragments, provided that the appropriate labeling chemistry has been established. For internalizing antibodies, such as the humanized anti-HER2 monoclonal antibody, trastuzumab, radiobromine label should be residualizing, i.e., ensuring that radiocatabolites are trapped intracellularly after the proteolytic degradation of antibody. This study evaluated the chemistry of indirect radiobromination of trastuzumab using N-succinimidyl 5-(tributylstannyl)-3-pyridinecarboxylate. Literature data indicated that the use of this method provided residualizing properties for iodine and astatine labels on some antibodies. An optimized 'one-pot' procedure produced an overall labeling efficiency of 45.5{+-}1.2% over 15 min. The bromine label was stable under physiological and denaturing conditions. The labeled trastuzumab retained its capacity to bind specifically to HER2-expressing SKOV-3 ovarian carcinoma cells in vitro (immunoreactivity more than 75%). However, in vitro cell test did not demonstrate that the radiobromination of trastuzumab using N-succinimidyl 5-bromo-3-pyridinecarboxylate improves cellular retention of radioactivity in comparison with the use of N-succinimidyl 4-bromobenzoate.

IMPLICATIONS OF GLOBAL PRICING POLICIES ON ACCESS TO INNOVATIVE DRUGS: THE CASE OF TRASTUZUMAB IN SEVEN LATIN AMERICAN COUNTRIES.

Science.gov (United States)

Pichon-Riviere, Andres; Garay, Osvaldo Ulises; Augustovski, Federico; Vallejos, Carlos; Huayanay, Leandro; Bueno, Maria del Pilar Navia; Rodriguez, Alarico; de Andrade, Carlos José Coelho; Buendía, Jefferson Antonio; Drummond, Michael

2015-01-01

Differential pricing, based on countries' purchasing power, is recommended by the World Health Organization to secure affordable medicines. However, in developing countries innovative drugs often have similar or even higher prices than in high-income countries. We evaluated the potential implications of trastuzumab global pricing policies in terms of cost-effectiveness (CE), coverage, and accessibility for patients with breast cancer in Latin America (LA). A Markov model was designed to estimate life-years (LYs), quality-adjusted life-years (QALYs), and costs from a healthcare perspective. To better fit local cancer prognosis, a base case scenario using transition probabilities from clinical trials was complemented with two alternative scenarios with transition probabilities adjusted to reflect breast cancer epidemiology in each country. Incremental discounted benefits ranged from 0.87 to 1.00 LY and 0.51 to 0.60 QALY and incremental CE ratios from USD 42,104 to USD 110,283 per QALY (2012 U.S. dollars), equivalent to 3.6 gross domestic product per capita (GDPPC) per QALY in Uruguay and to 35.5 GDPPC in Bolivia. Probabilistic sensitivity analysis showed 0 percent probability that trastuzumab is CE if the willingness-to-pay threshold is one GDPPC per QALY, and remained so at three GDPPC threshold except for Chile and Uruguay (4.3 percent and 26.6 percent, respectively). Trastuzumab price would need to decrease between 69.6 percent to 94.9 percent to became CE in LA. Although CE in other settings, trastuzumab was not CE in LA. The use of health technology assessment to prioritize resource allocation and support price negotiations is critical to making innovative drugs available and affordable in developing countries.

Total encephalic radiotherapy and concomitant administering of trastuzumab for brain metastases of a mammary carcinoma with HER2 overexpression: experience of the Curie Institute; Radiotherapie encephalique totale et administration concomitante de trastuzumab pour des metastases cerebrales d'un carcinome mammaire surexprimant HER2: experience de l'institut Curie

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Chargari, C.; Idrissi, H.R.; Pierga, J.Y.; Bollet, M.; Dieras, V.; Campana, F.; Cottu, P.; Fourquet, A.; Kirova, Y. [Institut Curie, 75 - Paris (France)

2010-10-15

The authors report a retrospective study of assessment of the tolerance to and of the activity of the trastuzumab in association with a total encephalic irradiation. The study is based on 31 patients suffering from brain metastases in relationship with a mammary cancer with HER2 expression, and who have been submitted to a total encephalic radiotherapy with a trastuzumab treatment. This medicine appears to be efficient and harmless. A clinic trial should confirm these results. Short communication

The left atrium, atrial fibrillation, and the risk of stroke in hypertensive patients with left ventricular hypertrophy

DEFF Research Database (Denmark)

Wachtell, K.; Devereux, R.B.; Lyle, P.A.

2008-01-01

was superior to atenolol-based treatment for reducing new-onset AF and complications, especially stroke, associated with new-onset or pre-existing AF. Potential mechanisms of AF prevention by angiotensin receptor blockade supported by LIFE results include greater reduction in left atrial size and LV......The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study provided extensive data on predisposing factors, consequences, and prevention of atrial fibrillation (AF) in patients with hypertension and left ventricular (LV) hypertrophy. Randomized losartan-based treatment...... hypertrophy. Differential effects of antihypertensive treatment on the left atrium and left ventricle may help prevent AF and reduce risk of stroke associated with hypertensive heart disease Udgivelsesdato: 2008/12...

Imaging of HER2/neu-positive BT-474 human breast cancer xenografts in athymic mice using 111In-trastuzumab (Herceptin) Fab fragments

International Nuclear Information System (INIS)

Tang Ying; Wang, Judy; Scollard, Deborah A.; Mondal, Hridya; Holloway, Claire; Kahn, Harriette J.; Reilly, Raymond M.

2005-01-01

Trastuzumab (Herceptin) Fab were prepared by digestion of intact IgG with immobilized papain, derivatized with diethylenetriaminepentaacetic acid (DTPA) and radiolabeled with 111 In. The dissociation constant (K d ) for binding of Fab to HER2/neu-positive SK-BR-3 human breast cancer cells was two- to threefold higher than for intact IgG (14-36 vs. 8-14 nM). The binding affinity was not significantly decreased after DTPA derivatization (K d =47 nM). 111 In-trastuzumab Fab localized specifically in HER2/neu-positive BT-474 human breast cancer xenografts in athymic mice with tumor uptake of 7.8±0.7% injected dose (ID)/g and tumor/blood ratio of 25.2±1.6 at 72 h postinjection compared with 2.7±0.7% ID/g and 7.0±0.9 for 111 In-HuM195 anti-CD33 Fab (significantly different, P 111 In-trastuzumab Fab as early as 24 h postinjection

Trastuzumab Induces an Immediate, Transient Volume Increase in Humans: A Randomised Placebo-Controlled Trial

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Joannes A.A. Reijers

2015-08-01

Interpretation: Single dose administration of trastuzumab in humans is associated with an immediate, transient extracellular volume increase, either as a primary or secondary (compensatory response, which can be detected easily using routine clinical assessments. Echocardiographic changes, both short and long term, could not be found after single dose administration to drug-naive patients.

[A paclitaxel-resistant case of recurrent breast cancer responded to combination therapy of capecitabine and trastuzumab].

Science.gov (United States)

Marutaka, Masahito; Suguri, Takayasu; Miyake, Mikio; Yoshimura, Kouichi

2005-12-01

The patient was a 72-year-old female. Under the supervision of her former doctor, this patient had an operation and adjuvant chemotherapy for progressive breast cancer. During the following period, local recurrence of breast cancer and pulmonary lymphopathia developed. Although medication with paclitaxel was attempted, the focus was resistant to this treatment, and metastasis to the brain was also observed. Due to the dyscrasia above, the patient had difficulty breathing and became bedridden. Subsequently, combination treatment of capecitabine and trastuzumab was attempted. As a result,metastasis in the brain and pulmonary lymphopathia were improved. The patient recovered enough to be discharged at one time. However, his condition took a turn for the worse after the interruption of the combination treatment by a side effect. In conclusion, the combination treatment of capecitabine and trastuzumab is thought to be effective for non-responders to paclitaxel.

Lapatinib or Trastuzumab Plus Taxane Therapy for Human Epidermal Growth Factor Receptor 2-Positive Advanced Breast Cancer: Final Results of NCIC CTG MA.31.

Science.gov (United States)

Gelmon, Karen A; Boyle, Frances M; Kaufman, Bella; Huntsman, David G; Manikhas, Alexey; Di Leo, Angelo; Martin, Miguel; Schwartzberg, Lee S; Lemieux, Julie; Aparicio, Samuel; Shepherd, Lois E; Dent, Susan; Ellard, Susan L; Tonkin, Katia; Pritchard, Kathleen I; Whelan, Timothy J; Nomikos, Dora; Nusch, Arnd; Coleman, Robert E; Mukai, Hirofumi; Tjulandin, Sergei; Khasanov, Rustem; Rizel, Shulamith; Connor, Anne P; Santillana, Sergio L; Chapman, Judith-Anne W; Parulekar, Wendy R

2015-05-10

The efficacy of lapatinib versus trastuzumab combined with taxanes in the first-line setting of human epidermal growth factor receptor 2 (HER2) -positive metastatic breast cancer (BC) is unknown. The MA.31 trial compared a combination of first-line anti-HER2 therapy (lapatinib or trastuzumab) and taxane therapy for 24 weeks, followed by the same anti-HER2 monotherapy until progression. Stratification was by prior (neo)adjuvant anti-HER2 therapy, prior (neo)adjuvant taxane, planned taxane, and liver metastases. The primary end point was intention-to-treat (ITT) progression-free survival (PFS), defined as time from random assignment to progression by RECIST (version 1.0) criteria, or death for patients with locally assessed HER2-positive tumors. The primary test statistic was a stratified log-rank test for noninferiority. PFS was also assessed for patients with centrally confirmed HER2-positive tumors. From July 17, 2008, to December 1, 2011, 652 patients were accrued from 21 countries, resulting in 537 patients with centrally confirmed HER2-positive tumors. Median follow-up was 21.5 months. Median ITT PFS was 9.0 months with lapatinib and 11.3 months with trastuzumab. By ITT analysis, PFS was inferior for lapatinib compared with trastuzumab, with a stratified hazard ratio (HR) of 1.37 (95% CI, 1.13 to 1.65; P = .001). In patients with centrally confirmed HER2-positive tumors, median PFS was 9.1 months with lapatinib and 13.6 months with trastuzumab (HR, 1.48; 95% CI, 1.20 to 1.83; P < .001). More grade 3 or 4 diarrhea and rash were observed with lapatinib (P < .001). PFS results were supported by the secondary end point of overall survival, with an ITT HR of 1.28 (95% CI, 0.95 to 1.72; P = .11); in patients with centrally confirmed HER2-positive tumors, the HR was 1.47 (95% CI, 1.03 to 2.09; P = .03). As first-line therapy for HER2-positive metastatic BC, lapatinib combined with taxane was associated with shorter PFS and more toxicity compared with trastuzumab

PIK3CA mutations, PTEN, and pHER2 expression and impact on outcome in HER2-positive early-stage breast cancer patients treated with adjuvant chemotherapy and trastuzumab

DEFF Research Database (Denmark)

Jensen, J D; Knoop, Ann; Laenkholm, A V

2012-01-01

-stage breast cancer patients treated with adjuvant chemotherapy and trastuzumab. PATIENTS AND METHODS: Two hundred and forty HER2-positive early-stage breast cancer patients receiving adjuvant treatment (cyclophosphamide 600 mg/m(2), epirubicin 60 mg/m(2), and fluorouracil 600 mg/m(2)) before administration...... of 1 year trastuzumab were assessable. PTEN and pHER2 expression were assessed by immunohistochemistry. PIK3CA mutations (exons 9 and 20) were determined by pyrosequencing. RESULTS: Five-year overall survival (OS) and invasive disease-free survival were 87.8% and 81.0%, respectively. Twenty-six percent...... activity had a significantly poorer survival despite adequate treatment with adjuvant chemotherapy and trastuzumab....

High-intensity interval training prevents oxidant-mediated diaphragm muscle weakness in hypertensive mice.

Science.gov (United States)

Bowen, T Scott; Eisenkolb, Sophia; Drobner, Juliane; Fischer, Tina; Werner, Sarah; Linke, Axel; Mangner, Norman; Schuler, Gerhard; Adams, Volker

2017-01-01

Hypertension is a key risk factor for heart failure, with the latter characterized by diaphragm muscle weakness that is mediated in part by increased oxidative stress. In the present study, we used a deoxycorticosterone acetate (DOCA)-salt mouse model to determine whether hypertension could independently induce diaphragm dysfunction and further investigated the effects of high-intensity interval training (HIIT). Sham-treated (n = 11), DOCA-salt-treated (n = 11), and DOCA-salt+HIIT-treated (n = 15) mice were studied over 4 wk. Diaphragm contractile function, protein expression, enzyme activity, and fiber cross-sectional area and type were subsequently determined. Elevated blood pressure confirmed hypertension in DOCA-salt mice independent of HIIT (P HIIT. Myosin heavy chain (MyHC) protein expression tended to decrease (∼30%; P = 0.06) in DOCA-salt vs. sham- and DOCA-salt+HIIT mice, whereas oxidative stress increased (P HIIT further prevented direct oxidant-mediated diaphragm contractile dysfunction (P hypertension induces diaphragm contractile dysfunction via an oxidant-mediated mechanism that is prevented by HIIT.-Bowen, T. S., Eisenkolb, S., Drobner, J., Fischer, T., Werner, S., Linke, A., Mangner, N., Schuler, G., Adams, V. High-intensity interval training prevents oxidant-mediated diaphragm muscle weakness in hypertensive mice. © FASEB.

HER2 copy number of circulating tumour DNA functions as a biomarker to predict and monitor trastuzumab efficacy in advanced gastric cancer.

Science.gov (United States)

Wang, Haixing; Li, Beifang; Liu, Zhentao; Gong, Jifang; Shao, Lin; Ren, Jun; Niu, Yunyun; Bo, Shiping; Li, Zhongwu; Lai, Yumei; Lu, Sijia; Gao, Jing; Shen, Lin

2018-01-01

HER2 status is significant to trastuzumab therapy; however, it is difficult to determine HER2 status accurately with few pieces of biopsies from advanced gastric cancer (AGC) due to highly heterogeneity and invasive behaviour, which will be investigated in this study. Fifty-six patients with AGC were included in this study. Primary tumour tissues and matched plasmas before medication from 36 patients were retrospectively collected, and the other 20 patients with primary tumour tissues and paired plasmas were prospectively collected. HER2 expression and amplification in 56 tumour tissues were determined by immunohistochemistry (IHC) and dual in situ hybridisation (DISH), and HER2 copy number in 135 circulating tumour DNAs (ctDNAs) was judged by next-generation sequencing. For tumour tissues, HER2 amplification by DISH was most commonly found in patients with HER2 score 3+by IHC. For plasmas, HER2 amplification defined as HER2 copy number >2.22 was identified in 26 of 56 patients. There was a high concordance of HER2 amplification between ctDNA and tumour tissues, suggesting that ctDNA could function as an alternative to screen HER2-targeted population. Moreover, the changes of HER2 copy number in ctDNA could efficiently monitor trastuzumab efficacy, the power of which was superior to commonly used markers carcinoembryonic antigen (CEA) and CA199, suggesting its potential role in clinical practice. ctDNA for HER2 analysis was strongly recommended to serve as a surrogate to screen trastuzumab-suitable population and monitor trastuzumab efficacy. Copyright © 2017 Elsevier Ltd. All rights reserved.

A prospective, non-randomized phase II trial of Trastuzumab and Capecitabine in patients with HER2 expressing metastasized pancreatic cancer

Directory of Open Access Journals (Sweden)

Endlicher Esther

2009-01-01

Full Text Available Abstract Background Pancreatic cancer is the fourth most common cause of cancer related death in Western countries. Advantages in surgical techniques, radiation and chemotherapy had almost no impact on the long term survival of affected patients. Therefore, the need for better treatment strategies is urgent. HER2, a receptor tyrosine kinase of the EGFR family, involved in signal transduction pathways leading to cell growth and differentiation is overexpressed in a number of cancers, including breast and pancreatic cancer. While in breast cancer HER2 has already been successfully used as a treatment target, there are only limited data evaluating the effects of inhibiting HER2 tyrosine kinases in patients with pancreatic cancer. Methods Here we report the design of a prospective, non-randomized multi-centered Phase II clinical study evaluating the effects of the Fluoropyrimidine-carbamate Capecitabine (Xeloda ® and the monoclonal anti-HER2 antibody Trastuzumab (Herceptin® in patients with non-resectable, HER2 overexpressing pancreatic cancer. Patients eligible for the study will receive Trastuzumab infusions on day 1, 8 and 15 concomitant to the oral intake of Capecitabine from day 1 to day 14 of each three week cylce. Cycles will be repeated until tumor progression. A total of 37 patients will be enrolled with an interim analysis after 23 patients. Discussion Primary end point of the study is to determine the progression free survival after 12 weeks of bimodal treatment with the chemotherapeutic agent Capecitabine and the anti-HER2 antibody Trastuzumab. Secondary end points include patient's survival, toxicity analysis, quality of life, the correlation of HER2 overexpression and clinical response to Trastuzumab treatment and, finally, the correlation of CA19-9 plasma levels and progression free intervals.

Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer.

Science.gov (United States)

Vogel, Charles L; Cobleigh, Melody A; Tripathy, Debu; Gutheil, John C; Harris, Lyndsay N; Fehrenbacher, Louis; Slamon, Dennis J; Murphy, Maureen; Novotny, William F; Burchmore, Michael; Shak, Steven; Stewart, Stanford J; Press, Michael

2002-02-01

To evaluate the efficacy and safety of first-line, single-agent trastuzumab in women with HER2-overexpressing metastatic breast cancer. One hundred fourteen women with HER2-overexpressing metastatic breast cancer were randomized to receive first-line treatment with trastuzumab 4 mg/kg loading dose, followed by 2 mg/kg weekly, or a higher 8 mg/kg loading dose, followed by 4 mg/kg weekly. The objective response rate was 26% (95% confidence interval [CI], 18.2% to 34.4%), with seven complete and 23 partial responses. Response rates in 111 assessable patients with 3+ and 2+ HER2 overexpression by immunohistochemistry (IHC) were 35% (95% CI, 24.4% to 44.7%) and none (95% CI, 0% to 15.5%), respectively. The clinical benefit rates in assessable patients with 3+ and 2+ HER2 overexpression were 48% and 7%, respectively. The response rates in 108 assessable patients with and without HER2 gene amplification by fluorescence in situ hybridization (FISH) analysis were 34% (95% CI, 23.9% to 45.7%) and 7% (95% CI, 0.8% to 22.8%), respectively. Seventeen (57%) of 30 patients with an objective response and 22 (51%) of 43 patients with clinical benefit had not experienced disease progression at follow-up at 12 months or later. The most common treatment-related adverse events were chills (25% of patients), asthenia (23%), fever (22%), pain (18%), and nausea (14%). Cardiac dysfunction occurred in two patients (2%); both had histories of cardiac disease and did not require additional intervention after discontinuation of trastuzumab. There was no clear evidence of a dose-response relationship for response, survival, or adverse events. Single-agent trastuzumab is active and well tolerated as first-line treatment of women with metastatic breast cancer with HER2 3+ overexpression by IHC or gene amplification by FISH.

The economic value of innovative treatments over the product life cycle: the case of targeted trastuzumab therapy for breast cancer.

Science.gov (United States)

Garrison, Louis P; Veenstra, David L

2009-01-01

Pharmacoeconomic analyses typically project the expected cost-effectiveness of a new product for a specific indication. This analysis develops a dynamic life-cycle model to conduct a multi-indication evaluation using the case of trastuzumab licensed in the United States for both early-stage and metastatic (or late-stage) human epidermal growth factor receptor 2 (HER2)-positive breast cancer therapy (early breast cancer [EBC]; metastatic breast cancer [MBC]), approved in 2006 and 1998, respectively. This dynamic model combined information on expected incremental cost-utility ratios for specific indications with an epidemiologically based projection of utilization by indication over the product life cycle-from 1998 to 2016. Net economic value was estimated as the cumulative quality-adjusted life years (QALYs) gained over the life cycle multiplied by a societal valuation of health gains ($/QALY) minus cumulative net direct treatment costs. Sensitivity analyses were performed under a range of assumptions. We projected that the annual number of EBC patients receiving trastuzumab will be more than three times that of MBC by 2016, in part because adjuvant treatment reduces the future incidence of MBC. Over this life cycle, the estimated overall incremental cost-effectiveness ratio (ICER) was $35,590/QALY with a total of 432,547 discounted QALYs gained. Under sensitivity analyses, the overall ICER varied from $21,000 to $53,000/QALY, and the projected net economic value resulting from trastuzumab treatment ranged from $6.2 billion to $49.5 billion. Average ICERs for multi-indication compounds can increase or decrease over the product life cycle. In this example, the projected overall life-cycle ICER for trastuzumab was less than one half of that in the initial indication. This dynamic perspective-versus the usual static one-highlights the interdependence of drug development decisions and investment incentives, raising important reimbursement policy issues.

Dose-Reduced Trastuzumab Emtansine: Active and Safe in Acute Hepatic Dysfunction

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Adam Sharp

2015-02-01

Full Text Available Breast cancer is the most common cancer in women worldwide. The majority of deaths attributed to breast cancer are a result of metastatic disease, and 30% of early breast cancers (EBC will develop distant disease. The 5-year survival of patients with metastatic disease is estimated at 23%. Breast cancer subtypes continue to be stratified histologically on oestrogen, progesterone and human epidermal growth factor-2 (HER2 receptor expression. HER2-positive breast cancers represent 25% of all breast cancer diagnoses. The therapies available for metastatic breast cancer (MBC are expanding, in particular within the field of HER2-positive disease, with the approval of trastuzumab, pertuzumab, lapatinib and trastuzumab emtansine (TDM-1. Recently, TDM-1 has been shown to improve progression-free survival in HER2 MBC when compared to capecitabine and lapatinib in clinical studies. Its main toxicities are deranged liver function tests and thrombocytopenia. There have also been cases of acute liver failure. Therefore, its use in acute hepatic dysfunction, to our knowledge, has been neither studied nor reported. We report a patient with progressive HER2-positive MBC who had previously responded to multiple HER2-targeted therapies that presented with acute hepatic dysfunction. She was treated with dose-reduced TDM-1 safely, with clear evidence of rapid biochemical, clinical and radiological response. This allowed dose escalation of TDM-1, and the patient maintains an ongoing response.

Modifications in Dynamic Contrast-Enhanced Magnetic Resonance Imaging Parameters After α-Particle-Emitting {sup 227}Th-trastuzumab Therapy of HER2-Expressing Ovarian Cancer Xenografts

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Heyerdahl, Helen, E-mail: Helen.Heyerdahl@rr-research.no [Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital - The Norwegian Radium Hospital, Oslo (Norway); Røe, Kathrine [Department of Oncology, Division of Medicine, Akershus University Hospital, Lørenskog (Norway); Brevik, Ellen Mengshoel [Department of Research and Development, Algeta ASA, Oslo (Norway); Dahle, Jostein [Nordic Nanovector AS, Oslo (Norway)

2013-09-01

Purpose: The purpose of this study was to investigate the effect of α-particle-emitting {sup 227}Th-trastuzumab radioimmunotherapy on tumor vasculature to increase the knowledge about the mechanisms of action of {sup 227}Th-trastuzumab. Methods and Materials: Human HER2-expressing SKOV-3 ovarian cancer xenografts were grown bilaterally in athymic nude mice. Mice with tumor volumes 253 ± 36 mm{sup 3} (mean ± SEM) were treated with a single injection of either {sup 227}Th-trastuzumab at a dose of 1000 kBq/kg body weight (treated group, n=14 tumors) or 0.9% NaCl (control group, n=10 tumors). Dynamic T1-weighted contrast-enhanced magnetic resonance imaging (DCEMRI) was used to study the effect of {sup 227}Th-trastuzumab on tumor vasculature. DCEMRI was performed before treatment and 1, 2, and 3 weeks after therapy. Tumor contrast-enhancement curves were extracted voxel by voxel and fitted to the Brix pharmacokinetic model. Pharmacokinetic parameters for the tumors that underwent radioimmunotherapy were compared with the corresponding parameters of control tumors. Results: Significant increases of k{sub ep}, the rate constant of diffusion from the extravascular extracellular space to the plasma (P<.05), and k{sub el,} the rate of clearance of contrast agent from the plasma (P<.01), were seen in the radioimmunotherapy group 2 and 3 weeks after injection, compared with the control group. The product of k{sub ep} and the amplitude parameter A, associated with increased vessel permeability and perfusion, was also significantly increased in the radioimmunotherapy group 2 and 3 weeks after injection (P<.01). Conclusions: Pharmacokinetic modeling of MRI contrast-enhancement curves evidenced significant alterations in parameters associated with increased tumor vessel permeability and tumor perfusion after {sup 227}Th-trastuzumab treatment of HER2-expressing ovarian cancer xenografts.

Benefit of adjuvant chemotherapy with or without trastuzumab in pT1ab node-negative human epidermal growth factor receptor 2-positive breast carcinomas: results of a national multi-institutional study.

Science.gov (United States)

de Nonneville, Alexandre; Gonçalves, Anthony; Zemmour, Christophe; Classe, Jean M; Cohen, Monique; Lambaudie, Eric; Reyal, Fabien; Scherer, Christophe; Muracciole, Xavier; Colombo, Pierre E; Giard, Sylvia; Rouzier, Roman; Villet, Richard; Chopin, Nicolas; Darai, Emile; Garbay, Jean R; Gimbergues, Pierre; Sabiani, Laura; Coutant, Charles; Sabatier, Renaud; Bertucci, François; Boher, Jean M; Houvenaeghel, Gilles

2017-04-01

Benefit of adjuvant trastuzumab-based chemotherapy for node-positive and/or >1 cm human epidermal growth factor receptor 2-positive (HER2+) breast carcinomas has been clearly demonstrated in randomized clinical trials. Yet, evidence that adjuvant chemotherapy with or without trastuzumab is effective in pT1abN0 HER2+ tumors is still limited. The primary objective of this study was to investigate the impact of adjuvant chemotherapy ± trastuzumab on outcome in this subpopulation. A total of 356 cases of pT1abN0M0 HER2 + breast cancers were retrospectively identified from a large cohort of 22,334 patients, including 1248 HER2+ patients who underwent primary surgery at 17 French centers, between December 1994 and January 2014. The primary end point was disease-free survival (DFS). A multivariate Cox model was built, including adjuvant chemotherapy, tumor size, hormone receptor status, and Scarff Bloom Richardson (SBR) grade. A total of 138 cases (39%) were treated with trastuzumab-based chemotherapy, 29 (8%) with chemotherapy alone, and 189 (53%) received neither trastuzumab nor chemotherapy. Adjuvant chemotherapy ± trastuzumab was associated with a significant DFS benefit (3-year 99 vs. 90%, and 5-year 96 vs. 84%, Hazard ratio, HR 0.26 [0.10-0.67]; p = 0.003, logrank test) which was maintained in multivariate analysis (HR 0.19 [0.07-0.52]; p = 0.001). Metastasis-free survival was also increased (HR 0.25 [0.07-0.86]; p = 0.018, logrank test) at 3-year (99 vs. 95%) and 5-year (98 vs. 89%) censoring. Exploratory subgroup analysis found DFS benefit to be significant in hormone receptor-negative, hormone receptor-positive, and pT1b tumors, but not in pT1a tumors. Adjuvant chemotherapy ± trastuzumab is associated with a significantly reduced risk of recurrence in subcentimeter node-negative HER2+ breast cancers. Most of the benefit may be driven by pT1b tumors.

Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET)

DEFF Research Database (Denmark)

Chan, Arlene; Delaloge, Suzette; Holmes, Frankie A

2016-01-01

BACKGROUND: Neratinib, an irreversible tyrosine-kinase inhibitor of HER1, HER2, and HER4, has clinical activity in patients with HER2-positive metastatic breast cancer. We aimed to investigate the efficacy and safety of 12 months of neratinib after trastuzumab-based adjuvant therapy in patients w...

A single-layer peptide nanofiber for enhancing the cytotoxicity of trastuzumab (anti-HER)

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Malik, Ruchi; Wagh, Anil; Qian, Steven; Law, Benedict, E-mail: Shek.law@ndsu.edu [College of Pharmacy, Nursing, and Allied Sciences, North Dakota State University, Department of Pharmaceutical Sciences (United States)

2013-06-15

A multivalent system is often employed to enhance the effectiveness of a targeted therapy. In the present study, we report a single-layer peptide nanofiber (NFP) as a multivalent targeting platform to improve the cytotoxicity of trastuzumab (anti-HER), a monoclonal antibody targeting the human epidermal growth factor receptor 2 (HER-2) in approximately 20 % of breast cancer patients. The trastuzumab-conjugated nanofiber (anti-HER/NFP) was 100 Multiplication-Sign 4 nm in size and was assembled from multiple peptide units (mPEG-BK(FITC)SGASNRA-kldlkldlkldl-CONH{sub 2}). The optimized preparation was attached with approximately 10 antibodies at the surface. Because of an increase in the multivalency, anti-HER/NFP was able to truncate more cell surface HER-2 and, thus, showed an enhanced cytotoxicity toward HER-2 positive SKBr-3 human breast cancer as compared to the free anti-HER. Western blot analysis and fluorescence microscopic studies confirmed that there was a significant downregulation of the HER-2 level and also inhibition of the cell survival cell signaling pathways including the phosphatidylinositol 3-kinase (PI3K) and the mitogen activated protein kinase (MAPK) pathway. Our data suggested that NFP can be useful as a multivalent platform for immunotherapy, especially in combination with other chemotherapeutic agents in the future.

Imaging of HER2/neu-positive BT-474 human breast cancer xenografts in athymic mice using {sup 111}In-trastuzumab (Herceptin) Fab fragments

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Tang Ying [Division of Nuclear Medicine, University Health Network, Toronto, Ontario, M5G 2C4 (Canada); Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario, M5S 2S2 (Canada); Wang, Judy [Division of Nuclear Medicine, University Health Network, Toronto, Ontario, M5G 2C4 (Canada); Scollard, Deborah A. [Division of Nuclear Medicine, University Health Network, Toronto, Ontario, M5G 2C4 (Canada); Mondal, Hridya [Division of Nuclear Medicine, University Health Network, Toronto, Ontario, M5G 2C4 (Canada); Holloway, Claire [Sunnybrook and Women' s College Health Sciences Center, Toronto, Ontario, M4N 3M5 (Canada); Kahn, Harriette J. [Sunnybrook and Women' s College Health Sciences Center, Toronto, Ontario, M4N 3M5 (Canada); Reilly, Raymond M. [Division of Nuclear Medicine, University Health Network, Toronto, Ontario, M5G 2C4 (Canada) and Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario, M5S 2S2 (Canada) and Department of Medical Imaging, University of Toronto, Toronto, Ontario, M5S 3E2 (Canada)]. E-mail: raymond.reilly@utoronto.ca

2005-01-01

Trastuzumab (Herceptin) Fab were prepared by digestion of intact IgG with immobilized papain, derivatized with diethylenetriaminepentaacetic acid (DTPA) and radiolabeled with {sup 111}In. The dissociation constant (K{sub d}) for binding of Fab to HER2/neu-positive SK-BR-3 human breast cancer cells was two- to threefold higher than for intact IgG (14-36 vs. 8-14 nM). The binding affinity was not significantly decreased after DTPA derivatization (K{sub d}=47 nM). {sup 111}In-trastuzumab Fab localized specifically in HER2/neu-positive BT-474 human breast cancer xenografts in athymic mice with tumor uptake of 7.8{+-}0.7% injected dose (ID)/g and tumor/blood ratio of 25.2{+-}1.6 at 72 h postinjection compared with 2.7{+-}0.7% ID/g and 7.0{+-}0.9 for {sup 111}In-HuM195 anti-CD33 Fab (significantly different, P<.001). Small (3-5 mm in diameter) BT-474 tumors were imaged with {sup 111}In-trastuzumab Fab as early as 24 h postinjection.

Antineoplastic-related cardiotoxicity, morphofunctional aspects in a murine model: contribution of the new tool 2D-speckle tracking

Directory of Open Access Journals (Sweden)

Coppola C

2016-11-01

Full Text Available Carmela Coppola,1 Gennaro Riccio,1 Antonio Barbieri,2 Maria Gaia Monti,3 Giovanna Piscopo,1 Domenica Rea,2 Claudio Arra,2 Carlo Maurea,1 Claudia De Lorenzo,4,5 Nicola Maurea1 1Division of Cardiology, Istituto Nazionale per lo Studio e la Cura dei Tumori “Fondazione G. Pascale”, IRCCS, Naples, Italy; 2Animal Facility Unit, Department of Experimental Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori “Fondazione G. Pascale”, IRCCS, Naples, Italy; 3Department of Translational Medical Sciences, University Federico II, Naples, Italy; 4Department of Molecular Medicine and Medical Biotechnology, University Federico II, Naples, Italy; 5CEINGE Biotecnologie Avanzate, Naples, Italy Objective: Considering that global left ventricular systolic radial strain is a sensitive technique for the early detection of left ventricular dysfunction due to antineoplastics and the analysis of segmental myocardial contractility, we evaluated this technique for early detection of trastuzumab-related cardiotoxicity by comparing it with cardiac structural damage.Methods: Groups of six mice were injected with trastuzumab or doxorubicin, used either as single agents or in combination. Cardiac function was evaluated by transthoracic echocardiography measurements before and after treatment for 2 or 7 days, by using a Vevo 2100 high-resolution imaging system. After echocardiography, mice were euthanized, and hearts were processed for histological evaluations, such as cardiac fibrosis, apoptosis, capillary density, and inflammatory response.Results: Trastuzumab-related cardiotoxicity was detected early by 2D strain imaging. Radial strain was reduced after 2 days in mice treated with trastuzumab alone (21.2%±8.0% vs 40.5%±4.8% sham; P<0.01. Similarly, trastuzumab was found to induce apoptosis, capillary density reduction, and inflammatory response in cardiac tissue after 2 days of treatment, in a fashion similar to doxorubicin. On the contrary, fractional

Characterisation of the HLA-DRB1*07:01 biomarker for lapatinib-induced liver toxicity during treatment of early-stage breast cancer patients with lapatinib in combination with trastuzumab and/or taxanes

DEFF Research Database (Denmark)

Spraggs, C F; Parham, L R; Briley, L P

2018-01-01

HLA-DRB1*07:01 allele carriage was characterised as a risk biomarker for lapatinib-induced liver injury in a large global study evaluating lapatinib, alone and in combination with trastuzumab and taxanes, as adjuvant therapy for advanced breast cancer (adjuvant lapatinib and/or trastuzumab treatm.......The Pharmacogenomics Journal advance online publication, 8 August 2017; doi:10.1038/tpj.2017.39....

Characterisation of the HLA-DRB1*07:01 biomarker for lapatinib-induced liver toxicity during treatment of early-stage breast cancer patients with lapatinib in combination with trastuzumab and/or taxanes

DEFF Research Database (Denmark)

Spraggs, C F; Parham, L R; Briley, L P

2017-01-01

HLA-DRB1*07:01 allele carriage was characterised as a risk biomarker for lapatinib-induced liver injury in a large global study evaluating lapatinib, alone and in combination with trastuzumab and taxanes, as adjuvant therapy for advanced breast cancer (adjuvant lapatinib and/or trastuzumab treatm.......The Pharmacogenomics Journal advance online publication, 8 August 2017; doi:10.1038/tpj.2017.39....

Activation of NADPH oxidase mediates increased endoplasmic reticulum stress and left ventricular remodeling after myocardial infarction in rabbits.

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Li, Bao; Tian, Jing; Sun, Yi; Xu, Tao-Rui; Chi, Rui-Fang; Zhang, Xiao-Li; Hu, Xin-Ling; Zhang, Yue-An; Qin, Fu-Zhong; Zhang, Wei-Fang

2015-05-01

Nicotinamide adenine dinucleotide 3-phosphate (NADPH) oxidase activity and endoplasmic reticulum (ER) stress are increased after myocardial infarction (MI). In this study, we proposed to test whether activation of the NADPH oxidase in the remote non-infarcted myocardium mediates ER stress and left ventricular (LV) remodeling after MI. Rabbits with MI or sham operation were randomly assigned to orally receive an NADPH oxidase inhibitor apocynin or placebo for 30 days. The agents were administered beginning at 1 week after surgery. MI rabbits exhibited decreases in LV fractional shortening, LV ejection fraction and the first derivative of the LV pressure rise, which were abolished by apocynin treatment. NADPH oxidase Nox2 protein and mRNA expressions were increased in the remote non-infarcted myocardium after MI. Immunolabeling further revealed that Nox2 was increased in cardiac myocytes in the remote myocardium. The apocynin treatment prevented increases in the Nox2 expression, NADPH oxidase activity, oxidative stress, myocyte apoptosis and GRP78, CHOP and cleaved caspase 12 protein expression in the remote myocardium. The apocynin treatment also attenuated increases in myocyte diameter and cardiac fibrosis. In cultured H9C2 cardiomyocytes exposed to angiotensin II, an important stimulus for post-MI remodeling, Nox2 knockdown with siRNA significantly inhibited angiotensin II-induced NADPH oxidase activation, reactive oxygen species and GRP78 and CHOP protein expression. We conclude that NADPH oxidase inhibition attenuates increased ER stress in the remote non-infarcted myocardium and LV remodeling late after MI in rabbits. These findings suggest that the activation of NADPH oxidase in the remote non-infarcted myocardium mediates increased ER stress, contributing to myocyte apoptosis and LV remodeling after MI. Copyright © 2015 Elsevier B.V. All rights reserved.

Trastuzumab for HER-2-Positive Advanced Salivary Gland Cancer

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Yi-Tsung Yang

2014-12-01

Full Text Available Salivary gland adenocarcinoma is a rare type of head and neck cancer and often has aggressive behavior with propensity to recur and metastasize. Currently, there are no standard treatment guidelines. Surgery is however, the mainstay of treatment in resectable disease and radiation is also considered for most patients after surgery. Systemic chemotherapy is reserved for metastatic cases, but its results are often disappointing. Recent development of molecular biology has shown that salivary gland caner has several molecular changes which may guide potential therapeutic targets. Here, we report a 67 year-old man diagnosed to have metastasized minor salivary gland adenocarcinoma with diffuse human epidermal growth factor receptor-2 (HER-2-positive, by the immunohistochemical (IHC stain. He was treated with a trastuzumab-containing chemotherapeutic regimen with encouraging results.

Differential behaviors of trastuzumab-sensitive and -resistant SKBR3 cells treated with menadione reveal the involvement of Notch1/Akt/FOXO1 signaling elements.

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Sajadimajd, Soraya; Yazdanparast, Razieh

2015-10-01

Given that HER2 serves as a putative target for therapy in HER2-positive breast cancer, intrinsic and/or acquired resistance to trastuzumab (T) has been proposed to be the major obstacle in treatments. In addition, chemoresistance is commonly attributed to increased antioxidant capacity. In that regard, we evaluated the effect of menadione (M) alone and/or its combination with trastuzumab on proliferation, intracellular GSH and ROS contents as well as HER2 and Notch1 signaling pathways in both trastuzumab-resistant (SKBR3(R)) and -sensitive SKBR3 (SKBR3(S)) cells. In spite of increased level of ROS and reduced level of GSH in M-treated SKBR3(S) cells, M-treated SKBR3(R) cells showed a decreased content of ROS and GSH compared to untreated cells. However, M/T co-treatment of SKBR3 cells indicated no effect on ROS content, while decreased the level of GSH compared to untreated control cells. Based on the extent of apoptosis, colony formation and wound healing assays, M alone, and/or in combination with T had a stronger inhibitory effect on proliferation of SKBR3(R) cells relative to SKBR3(S) cells. These effects might be due to the stronger effects of M and/or M/T on downregulation of p-Akt, Hes1, NICD, and upregulation of FOXO1 among SKBR3(R) cells relative to the sensitive SKBR3 cells. These findings would certainly shed light on some of the signaling factors involved in induction of trastuzumab resistance and would be of value in designing more efficient chemosensitization strategies.

Interrupting violence: how the CeaseFire Program prevents imminent gun violence through conflict mediation.

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Whitehill, Jennifer M; Webster, Daniel W; Frattaroli, Shannon; Parker, Elizabeth M

2014-02-01

Cities are increasingly adopting CeaseFire, an evidence-based public health program that uses specialized outreach workers, called violence interrupters (VIs), to mediate potentially violent conflicts before they lead to a shooting. Prior research has linked conflict mediation with program-related reductions in homicides, but the specific conflict mediation practices used by effective programs to prevent imminent gun violence have not been identified. We conducted case studies of CeaseFire programs in two inner cities using qualitative data from focus groups with 24 VIs and interviews with eight program managers. Study sites were purposively sampled to represent programs with more than 1 year of implementation and evidence of program effectiveness. Staff with more than 6 months of job experience were recruited for participation. Successful mediation efforts were built on trust and respect between VIs and the community, especially high-risk individuals. In conflict mediation, immediate priorities included separating the potential shooter from the intended victim and from peers who may encourage violence, followed by persuading the parties to resolve the conflict peacefully. Tactics for brokering peace included arranging the return of stolen property and emphasizing negative consequences of violence such as jail, death, or increased police attention. Utilizing these approaches, VIs are capable of preventing gun violence and interrupting cycles of retaliation.

Autologous Hematopoietic Stem Cell Transplantation to Prevent Antibody Mediated Rejection After Vascularized Composite Allotransplantation

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2017-10-01

Award Number: W81XWH-16-1-0664 TITLE: Autologous Hematopoietic Stem Cell Transplantation to Prevent Antibody-Mediated Rejection after...Annual 3. DATES COVERED 15 Sep 2016 – 14 Sep 2017 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Autologous Hematopoietic Stem Cell Transplantation to...sensitization, autologous hematopoietic stem cell transplantation, antibody mediated rejection, donor specific antibodies 16. SECURITY CLASSIFICATION OF

Efficacy of weekly trastuzumab and paclitaxel in the treatment of women with HER-2/neu overexpressing metastatic breast cancer. The impact of taxane free interval on treatment outcomes

International Nuclear Information System (INIS)

Janku, P.; Petruzelka, L.; Pribylova, O.; Honova, H.; Pecen, L.; Zimovjanova, M.; Pazdrova, G.; Safanda, M.; Konopasek, B.; Zemanova, M.; Vedralova, J.

2002-01-01

Purpose. Trastuzumab is known as an active agent in HER2/neu overexpressing metastatic breast cancer. In the prospective study we investigated efficacy, safety and toxicity of trastuzumab and paclitaxel in metastatic breast cancer progressing on previous therapy. Patients and methods. We accrued 17 patients with histologically confirmed breast cancer, Karnofsky performance status at least 60 %, median age 50 (36-66), pretreated with at least two regimens. HER-2/neu expression was tested by HercepTest (r) (DAKO) in all 17 patients. Fifteen specimens were 3+ positive and 2 specimens 2+ positive. All patients except one were pretreated with taxanes. Taxane free interval (TFI) was defined as a time from last taxane administration until the beginning of the study for every enrolled patient. TFI longer than 1 year was found in 7 patients. TFI shorter than 1 year was observed in 9 patients. Trastuzumab was given 4 mg/kg i.v. as a loading dose followed by 2 mg/kg i.v. weekly. Paclitaxel was given 80 mg/m 2 i.v. weekly until disease progression or unacceptable toxicity. We assessed the response rate (RR), the time to progression (TTP), the survival (OS) and toxicity. Results. In the intent to treat population we found objective response in 10 patients (59 %), including 2 complete responses (CR). In the subset with TFI > 1 year we observed response in 4 cases including 1 CR (RR 57 %). In TFI ≤ 1 year subgroup we observed response in 6 cases also with 1 CR (RR 67 %). TFI was not statistically significant for response (p 1 year tend to have longer TTP (p = 0,0201). Median OS has not been reached with 10 patients surviving. We administered 599 cycles including 473 cycles of trastuzumab and paclitaxel with no dose adjustment. One patient developed hypersensitivity reaction on the first trastuzumab infusion and was excluded from study. The most common toxicity was trastuzumab infusion related pyretic reaction observed in 6 patients. Dose limiting adverse effect which led to the

Drifts in ADCC-related quality attributes of Herceptin?: Impact on development of a trastuzumab biosimilar

OpenAIRE

Kim, Seokkyun; Song, Jinsu; Park, Seungkyu; Ham, Sunyoung; Paek, Kyungyeol; Kang, Minjung; Chae, Yunjung; Seo, Heewon; Kim, Hyung-Chan; Flores, Michael

2017-01-01

ABSTRACT A biosimilar product needs to demonstrate biosimilarity to the originator reference product, and the quality profile of the latter should be monitored throughout the period of the biosimilar's development to match the quality attributes of the 2 products that relate to efficacy and safety. For the development of a biosimilar version of trastuzumab, the reference product, Herceptin?, was extensively characterized for the main physicochemical and biologic properties by standard or stat...

Safety and efficacy of neratinib in combination with weekly paclitaxel and trastuzumab in women with metastatic HER2‑positive breast cancer: an NSABP Foundation Research Program phase I study.

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Jankowitz, Rachel C; Abraham, Jame; Tan, Antoinette R; Limentani, Steven A; Tierno, Marni B; Adamson, Laura M; Buyse, Marc; Wolmark, Norman; Jacobs, Samuel A

2013-12-01

Neratinib is an oral, small-molecule inhibitor that irreversibly binds to pan-HER (ErbB) receptor tyrosine kinases. Studies suggest that dual anti-HER therapies utilized in breast cancer patients are more efficacious than single agents in both the metastatic and neoadjuvant settings. In this phase I study, neratinib was combined with trastuzumab and paclitaxel in metastatic HER2-positive patients. Twenty-one patients entered this dose-escalation study to determine the maximum-tolerated dose, safety, and efficacy of neratinib (120 up to 240 mg/day) with trastuzumab (4 mg/kg IV loading dose, then 2 mg/kg IV weekly), and paclitaxel (80 mg/m(2) IV days 1, 8, and 15 of a 28-day cycle) in women with HER2-positive metastatic breast cancer previously treated with anti-HER agent(s) and a taxane. The recommended phase II dose of neratinib with trastuzumab and paclitaxel was 200 mg/day. Common grade 3/4 adverse events were diarrhea (38 %), dehydration (14 %), electrolyte imbalance (19 %), and fatigue (19 %). With mandated primary diarrheal prophylaxis, ≥grade 3 diarrhea was not observed. Objective responses, complete (CR) and partial (PR), occurred in eight patients (38 %), with a clinical benefit of CR + PR+ stable disease (SD) ≥24 weeks in 11 patients (52 %). Median time-to-disease progression was 3.7 months. Dual anti-HER blockade with neratinib and trastuzumab resulted in significant clinical benefit despite prior exposure to trastuzumab, lapatinib, T-DM1, a taxane, and multiple lines of chemotherapy. In selected populations, inhibiting multiple ErbB-family receptors may be more advantageous than single-agent inhibition. Based on favorable tolerance and efficacy, this three-drug combination will be further assessed in a randomized phase II neoadjuvant trial (NSABP FB-7:NCT01008150).

64Cu-Labeled Trastuzumab Fab-PEG24-EGF Radioimmunoconjugates Bispecific for HER2 and EGFR: Pharmacokinetics, Biodistribution, and Tumor Imaging by PET in Comparison to Monospecific Agents.

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Kwon, Luke Yongkyu; Scollard, Deborah A; Reilly, Raymond M

2017-02-06

Heterodimerization of EGFR with HER2 coexpressed in breast cancer (BC) promotes tumor growth, and increased EGFR expression is associated with trastuzumab resistance. Our aim was to construct 64 Cu-labeled bispecific radioimmunoconjugates (bsRIC) composed of trastuzumab Fab, which binds HER2 linked through a polyethylene glycol (PEG 24 ) spacer to EGF, and to compare their pharmacokinetic, biodistribution, and tumor imaging characteristics by positron-emission tomography (PET). bsRICs were generated by linking maleimide modified trastuzumab Fab with thiolated EGF through a thioether bond. HER2 and EGFR binding were assessed in vitro in MDA-MB-231 (EGFR mod /HER2 low ), MDA-MB-468 (EGFR high /HER2 neg ), MDA-MB-231-H2N (EGFR mod /HER2 mod ), and SKOV3 (EGFR low /HER2 high ) cells by competition and saturation cell binding assays to estimate the dissociation constant (K d ). The elimination of the 64 Cu-NOTA-trastuzumab Fab-PEG 24 -EGF bsRICs from the blood of Balb/c mice was compared to monospecific 64 Cu-NOTA-trastuzumab Fab and 64 Cu-NOTA-EGF. MicroPET/CT imaging was performed in NOD/SCID mice bearing subcutaneous MDA-MB-468, MDA-MB-231/H2N, or SKOV3 human BC xenografts at 24 and 48 h postinjection (p.i.) of bsRICs. Tumor and normal tissue uptake were quantified by biodistribution studies and compared to monospecific agents. The binding of bsRICs to MDA-MB-231 cells was decreased to 24.5 ± 5.2% by excess EGF, while the binding of bsRICs to SKOV3 cells was decreased to 38.6 ± 5.4% by excess trastuzumab Fab, demonstrating specific binding to both EGFR and HER2. 64 Cu-labeled bsRICs incorporating the PEG 24 spacer were eliminated more slowly from the blood than 64 Cu-bsRICs without the PEG spacer and were cleared much more slowly than 64 Cu-NOTA-Fab or 64 Cu-NOTA-EGF. All three tumor xenografts were visualized by microPET/CT at 24 and 48 h p.i. of bsRICs. Biodistribution studies at 48 h p.i. in NOD/SCID mice with MDA-MB-231/H2N tumors demonstrated significantly

Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

Science.gov (United States)

Chan, Arlene; Delaloge, Suzette; Holmes, Frankie A; Moy, Beverly; Iwata, Hiroji; Harvey, Vernon J; Robert, Nicholas J; Silovski, Tajana; Gokmen, Erhan; von Minckwitz, Gunter; Ejlertsen, Bent; Chia, Stephen K L; Mansi, Janine; Barrios, Carlos H; Gnant, Michael; Buyse, Marc; Gore, Ira; Smith, John; Harker, Graydon; Masuda, Norikazu; Petrakova, Katarina; Zotano, Angel Guerrero; Iannotti, Nicholas; Rodriguez, Gladys; Tassone, Pierfrancesco; Wong, Alvin; Bryce, Richard; Ye, Yining; Yao, Bin; Martin, Miguel

2016-03-01

invasive disease-free survival events had occurred in patients in the neratinib group versus 109 events in those in the placebo group (stratified hazard ratio 0·67, 95% CI 0·50-0·91; p=0·0091). The 2-year invasive disease-free survival rate was 93·9% (95% CI 92·4-95·2) in the neratinib group and 91·6% (90·0-93·0) in the placebo group. The most common grade 3-4 adverse events in patients in the neratinib group were diarrhoea (grade 3, n=561 [40%] and grade 4, n=1 [neratinib and 93 (7%) patients given placebo, and decreases in left ventricular ejection fraction (≥grade 2) in 19 (1%) and 15 (1%) patients, respectively. We recorded serious adverse events in 103 (7%) patients in the neratinib group and 85 (6%) patients in the placebo group. Seven (neratinib group and three patients in the placebo group) unrelated to disease progression occurred after study drug discontinuation. The causes of death in the neratinib group were unknown (n=2), a second primary brain tumour (n=1), and acute myeloid leukaemia (n=1), and in the placebo group were a brain haemorrhage (n=1), myocardial infarction (n=1), and gastric cancer (n=1). None of the deaths were attributed to study treatment in either group. Neratinib for 12 months significantly improved 2-year invasive disease-free survival when given after chemotherapy and trastuzumab-based adjuvant therapy to women with HER2-positive breast cancer. Longer follow-up is needed to ensure that the improvement in breast cancer outcome is maintained. Wyeth, Pfizer, Puma Biotechnology. Copyright © 2016 Elsevier Ltd. All rights reserved.

Hostile Attribution Bias Mediates the Relationship Between Structural Variations in the Left Middle Frontal Gyrus and Trait Angry Rumination

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Yueyue Wang

2018-04-01

Full Text Available Angry rumination is a common mental phenomenon which may lead to negative social behaviors such as aggression. Although numerous neuroimaging studies have focused on brain area activation during angry rumination, to our knowledge no study has examined the neuroanatomical and cognitive mechanisms of this process. In this study, we conducted a voxel-based morphometry analysis, using a region of interest analysis to identify the structural and cognitive mechanisms underlying individual differences in trait angry rumination (as measured by the Angry Rumination Scale in a sample of 82 undergraduate students. We found that angry rumination was positively correlated with gray matter density in the left middle frontal gyrus (left-MFG, which is implicated in inhibition control, working memory, and emotional regulation. The mediation analysis further revealed that hostile attribution bias (as measured by the Social Information Processing–Attribution Bias Questionnaire acted as a cognitive mechanism underlying the positive association between the left-MFG gray matter density and trait angry rumination. These findings suggest that hostile attribution bias may contribute to trait angry rumination, while the left-MFG may play an important role in the development of hostile attribution bias and trait angry rumination. The study reveals the brain mechanisms of trait angry rumination and plays a role in revealing the cognitive mechanisms of the development of trait angry rumination.

THE ECSTACY OF GOLD Patent Expirations for Trastuzumab, Bevacizumab, Rituximab, and Cetuximab.

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Serna-Gallegos, Tasha R; LaFargue, Christopher J; Tewari, Krishnansu S

2017-11-22

Fully humanized monoclonal antibodies have revolutionized the treatment of many solid tumors, including breast, lung, colorectal, and ovarian cancer. Among the most widely used monoclonal antibodies in clinical oncology are cetuximab, trastuzumab, rituximab, and bevacizumab. This article will review these four notable monoclonal antibodies, their role in clinical oncology, and the drug patents that are nearing expiration. They are used in both first and second line treatment regimens for multiple common malignancies. With recent patent expirations, pharmaceutical companies involved in biosimilar manufacture are looking to establish ownership over these financial monopolies. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Radiolabeling of trastuzumab with {sup 177}Lu via DOTA, a new radiopharmaceutical for radioimmunotherapy of breast cancer

Energy Technology Data Exchange (ETDEWEB)

Rasaneh, Samira [Department of Medical Physics, Tarbiat Modares University, Tehran (Iran, Islamic Republic of); Rajabi, Hossein [Department of Medical Physics, Tarbiat Modares University, Tehran (Iran, Islamic Republic of)], E-mail: hrajabi@modares.ac.ir; Babaei, Mohammad Hossein; Daha, Fariba Johari [Department of Radioisotope, Nuclear Science and Technology Research Institute, Tehran (Iran, Islamic Republic of); Salouti, Mojtaba [Department of Biology, School of Sciences, Islamic Azad University - Zanjan Branch, Zanjan (Iran, Islamic Republic of)

2009-05-15

Aim: Trastuzumab is a monoclonal antibody that is used in treating breast cancer. We labeled this monoclonal antibody with lutetium-177 and performed in vitro quality control tests as a first step in the production of a new radiopharmaceutical. Material and Methods: Trastuzumab was labeled with lutetium-177 using DOTA as chelator. Radiochemical purity and stability in buffer and human blood serum were determined using thin layer chromatography. Immunoreactivity and toxicity of the complex were tested on MCF7 breast cancer cell line. Results: The radiochemical purity of the complex was 96{+-}0.9%. The stabilities in phosphate buffer and in human blood serum at 96 h postpreparation were 93{+-}1.2% and 85{+-}3.5%, respectively. The immunoreactivity of the complex was 89{+-}1.4%. At a concentration of 1 nM, the complex killed 70{+-}3% of MCF7 cells. At 1.9 nM, 90{+-}5% of the cells were killed. Conclusions: The results showed that the new complex could be considered for further evaluation in animals and possibly in humans as a new radiopharmaceutical for use in radioimmunotherapy against breast cancer.

In vitro and in vivo studies of the combination of IGF1R inhibitor figitumumab (CP-751,871) with HER2 inhibitors trastuzumab and neratinib.

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Chakraborty, Ashok K; Zerillo, Cynthia; DiGiovanna, Michael P

2015-08-01

The insulin-like growth factor I receptor (IGF1R) has been linked to resistance to HER2-directed therapy with trastuzumab (Herceptin). We examined the anti-tumor activity of figitumumab (CP-751,871), a human monoclonal antibody that blocks IGF1R ligand binding, alone and in combination with the therapeutic anti-HER2 antibody trastuzumab and the pan-HER family tyrosine kinase inhibitor neratinib, using in vitro and in vivo breast cancer model systems. In vitro assays of proliferation, apoptosis, and signaling, and in vivo anti-tumor experiments were conducted in HER2-overexpressing (BT474) and HER2-normal (MCF7) models. We find single-agent activity of the HER2-targeting drugs but not figitumumab in the BT474 model, while the reverse is true in the MCF7 model. However, in both models, combining figitumumab with HER2-targeting drugs shows synergistic anti-proliferative and apoptosis-inducing effects, and optimum inhibition of downstream signaling. In murine xenograft models, synergistic anti-tumor effects were observed in the HER2-normal MCF7 model for the combination of figitumumab with trastuzumab, and, in the HER2-overexpressing BT474 model, enhanced anti-tumor effects were observed for the combination of figitumumab with either trastuzumab or neratinib. Analysis of tumor extracts from the in vivo experiments showed evidence of the most optimal inhibition of downstream signaling for the drug combinations over the single-agent therapies. These results suggest promise for such combinations in treating patients with breast cancer, and that, unlike the case for single-agent therapy, the therapeutic effects of such combinations may be independent of expression levels of the individual receptors or the single-agent activity profile.

Effect of PREDICT on chemotherapy/trastuzumab recommendations in HER2-positive patients with early-stage breast cancer

OpenAIRE

DOWN, SUE K.; LUCAS, OLIVIA; BENSON, JOHN R.; WISHART, GORDON C.

2014-01-01

PREDICT is an online prognostication tool for early-stage breast cancer, which incorporates human epidermal growth factor 2 (HER2) status and stratifies absolute treatment benefits for hormone therapy, chemotherapy and trastuzumab. The present study compared historical multidisciplinary team (MDT) decisions regarding adjuvant treatment with PREDICT estimates, to determine whether certain patients are being over- or undertreated, particularly when stratified by age and oestrogen-receptor (ER) ...

Testing Mediators of Intervention Effects in Randomized Controlled Trials: An Evaluation of Three Depression Prevention Programs

Science.gov (United States)

Stice, Eric; Rohde, Paul; Seeley, John R.; Gau, Jeff M.

2010-01-01

Objective: Evaluate a new 5-step method for testing mediators hypothesized to account for the effects of depression prevention programs. Method: In this indicated prevention trial, at-risk teens with elevated depressive symptoms were randomized to a group cognitive-behavioral (CB) intervention, group supportive expressive intervention, CB…

Epirubicin With Cyclophosphamide Followed by Docetaxel With Trastuzumab and Bevacizumab as Neoadjuvant Therapy for HER2-Positive Locally Advanced Breast Cancer or as Adjuvant Therapy for HER2-Positive Pathologic Stage III Breast Cancer: A Phase II Trial of the NSABP Foundation Research Group, FB-5.

Science.gov (United States)

Smith, John W; Buyse, Marc E; Rastogi, Priya; Geyer, Charles E; Jacobs, Samuel A; Patocskai, Erica J; Robidoux, André; Conlin, Alison K; Ansari, Bilal; Keogh, George P; Stella, Philip J; Gross, Howard M; Lord, Raymond S; Polikoff, Jonathan A; Mauquoi, Celine; Mamounas, Eleftherios P; Swain, Sandra M; Wolmark, Norman

2017-02-01

The purpose of this study was to determine the cardiac safety and clinical activity of trastuzumab and bevacizumab with docetaxel after epirubicin with cyclophosphamide (EC) in patients with HER2-positive locally advanced breast cancer (LABC) or pathologic stage 3 breast cancer (PS3BC). Patients received every 3 week treatment with 4 cycles of EC (90/600 mg/m 2 ) followed by 4 cycles of docetaxel (100 mg/m 2 ). Targeted therapy with standard-dose trastuzumab with bevacizumab 15 mg/kg was given for a total of 1 year. Coprimary end points were (1) rate of cardiac events (CEs) in all patients defined as clinical congestive heart failure with a significant decrease in left ventricular ejection fraction or cardiac deaths; and (2) pathologic complete response (pCR) in breast and nodes in the neoadjuvant cohort. An independent cardiac review panel determined whether criteria for a CE were met. A total of 105 patients were accrued, 76 with LABC treated with neoadjuvant therapy and 29 with PS3BC treated with adjuvant therapy. Median follow-up was 59.2 months. Among 99 evaluable patients for cardiac safety, 4 (4%; 95% confidence interval [CI], 1.1%-10.0%) met CE criteria. The pCR percentage in LABC patients was 46% (95% CI, 34%-59%). Five-year recurrence-free survival (RFS) and overall survival (OS) for all patients was 79.9% and 90.8%, respectively. The regimen met predefined criteria for activity of interest with an acceptable rate of CEs. Although the pCR percentage was comparable with chemotherapy regimens with trastuzumab alone the high RFS and OS are of interest in these high-risk populations. Copyright © 2016 Elsevier Inc. All rights reserved.

Antibody-mediated Prevention of Fusarium Mycotoxins in the Field

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Yu-Cai Liao

2008-10-01

Full Text Available Fusarium mycotoxins directly accumulated in grains during the infection of wheat and other cereal crops by Fusarium head blight (FHB pathogens are detrimental to humans and domesticated animals. Prevention of the mycotoxins via the development of FHB-resistant varieties has been a challenge due to the scarcity of natural resistance against FHB pathogens. Various antibodies specific to Fusarium fungi and mycotoxins are widely used in immunoassays and antibody-mediated resistance in planta against Fusarium pathogens has been demonstrated. Antibodies fused to antifungal proteins have been shown to confer a very significantly enhanced Fusarium resistance in transgenic plants. Thus, antibody fusions hold great promise as an effective tool for the prevention of mycotoxin contaminations in cereal grains. This review highlights the utilization of protective antibodies derived from phage display to increase endogenous resistance of wheat to FHB pathogens and consequently to reduce mycotoxins in field. The role played by Fusarium-specific antibody in the resistance is also discussed.

LEFT ATRIAL APPENDAGE CLOSURE AS AN ALTERNATIVE TO WARFARIN FOR STROKE PREVENTION IN ATRIAL FIBRILLATION: A PATIENT¬LEVEL META¬ANALYSIS

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2015-01-01

Full Text Available Holmes D.R. Jr, Doshi S.K., Kar S., et al. Left Atrial Appendage Closure as an Alternative to Warfarin for Stroke Prevention in Atrial Fibrillation: A Patient­Level Meta­Analysis // J. Am. Coll. Cardiol. – 2015. – Vol. 65. – P. 2614–2623.

HALT-D: A Phase II Evaluation of Crofelemer for the Prevention and Prophylaxis of Diarrhea in Patients With Breast Cancer on Pertuzumab-Based Regimens.

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Gao, Jennifer J; Tan, Ming; Pohlmann, Paula R; Swain, Sandra M

2017-02-01

Approximately 40% to 80% of patients receiving pertuzumab-directed therapy for human epidermal growth factor receptor 2 (HER2)-positive breast cancer will develop chemotherapy-induced diarrhea (CID). Loperamide and octreotide are frequently used to treat CID after diarrhea occurs, but neither is used prophylactically or targets the underlying mechanism. Previous studies suggest blocking epidermal growth factor receptor may cause excess chloride secretion, resulting in diarrhea. Crofelemer is derived from the red latex of the Croton lechleri tree, blocks gastrointestinal cystic fibrosis transmembrane regulator and calcium-activated chloride channels, and is U.S. Food and Drug Administration approved for relief of diarrhea in HIV/AIDS patients on anti-retroviral therapy. Crofelemer is not systemically absorbed, has relatively few side effects, and presents a targeted approach at preventing CID in patients receiving pertuzumab-based therapy. HALT-D (DiarrHeA Prevention and ProphyLaxis with Crofelemer in HER2-Positive Breast Cancer Patients Receiving Trastuzumab, Pertuzumab, and Docetaxel or Paclitaxel with or without Carboplatin, NCT02910219) is a phase II, randomized, open-label trial that aims to recruit 46 patients from 3 MedStar sites. Adults with HER2-positive breast cancer being treated with trastuzumab, pertuzumab, and docetaxel or paclitaxel (THP) or trastuzumab, pertuzumab, docetaxel, and carboplatin (TCHP) will be randomized to receive crofelemer or no medication for diarrhea prophylaxis. The primary endpoint is incidence of all grade diarrhea for ≥ 2 consecutive days during cycles 1 to 2 of THP or TCHP. Secondary endpoints include overall incidence, duration, and severity of diarrhea; time to onset of diarrhea; use of other anti-diarrheal medications; stool frequency and consistency; and quality of life. HALT-D will provide important information about the feasibility and tolerability of crofelemer in preventing diarrhea for patients receiving THP or TCHP

Left atrial appendage occlusion

Directory of Open Access Journals (Sweden)

Ahmad Mirdamadi

2013-01-01

Full Text Available Left atrial appendage (LAA occlusion is a treatment strategy to prevent blood clot formation in atrial appendage. Although, LAA occlusion usually was done by catheter-based techniques, especially percutaneous trans-luminal mitral commissurotomy (PTMC, it can be done during closed and open mitral valve commissurotomy (CMVC, OMVC and mitral valve replacement (MVR too. Nowadays, PTMC is performed as an optimal management of severe mitral stenosis (MS and many patients currently are treated by PTMC instead of previous surgical methods. One of the most important contraindications of PTMC is presence of clot in LAA. So, each patient who suffers of severe MS is evaluated by Trans-Esophageal Echocardiogram to rule out thrombus in LAA before PTMC. At open heart surgery, replacement of the mitral valve was performed for 49-year-old woman. Also, left atrial appendage occlusion was done during surgery. Immediately after surgery, echocardiography demonstrates an echo imitated the presence of a thrombus in left atrial appendage area, although there was not any evidence of thrombus in pre-pump TEE. We can conclude from this case report that when we suspect of thrombus of left atrial, we should obtain exact history of previous surgery of mitral valve to avoid misdiagnosis clotted LAA, instead of obliterated LAA. Consequently, it can prevent additional evaluations and treatments such as oral anticoagulation and exclusion or postponing surgeries including PTMC.

Adjuvant Lapatinib and Trastuzumab for Early Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: Results From the Randomized Phase III Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization Trial.

Science.gov (United States)

Piccart-Gebhart, Martine; Holmes, Eileen; Baselga, José; de Azambuja, Evandro; Dueck, Amylou C; Viale, Giuseppe; Zujewski, Jo Anne; Goldhirsch, Aron; Armour, Alison; Pritchard, Kathleen I; McCullough, Ann E; Dolci, Stella; McFadden, Eleanor; Holmes, Andrew P; Tonghua, Liu; Eidtmann, Holger; Dinh, Phuong; Di Cosimo, Serena; Harbeck, Nadia; Tjulandin, Sergei; Im, Young-Hyuck; Huang, Chiun-Sheng; Diéras, Véronique; Hillman, David W; Wolff, Antonio C; Jackisch, Christian; Lang, Istvan; Untch, Michael; Smith, Ian; Boyle, Frances; Xu, Binghe; Gomez, Henry; Suter, Thomas; Gelber, Richard D; Perez, Edith A

2016-04-01

Lapatinib (L) plus trastuzumab (T) improves outcomes for metastatic human epidermal growth factor 2-positive breast cancer and increases the pathologic complete response in the neoadjuvant setting, but their role as adjuvant therapy remains uncertain. In the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial, patients with centrally confirmed human epidermal growth factor 2-positive early breast cancer were randomly assigned to 1 year of adjuvant therapy with T, L, their sequence (T→L), or their combination (L+T). The primary end point was disease-free survival (DFS), with 850 events required for 80% power to detect a hazard ratio (HR) of 0.8 for L+T versus T. Between June 2007 and July 2011, 8,381 patients were enrolled. In 2011, due to futility to demonstrate noninferiority of L versus T, the L arm was closed, and patients free of disease were offered adjuvant T. A protocol modification required P ≤ .025 for the two remaining pairwise comparisons. At a protocol-specified analysis with a median follow-up of 4.5 years, a 16% reduction in the DFS hazard rate was observed with L+T compared with T (555 DFS events; HR, 0.84; 97.5% CI, 0.70 to 1.02; P = .048), and a 4% reduction was observed with T→L compared with T (HR, 0.96; 97.5% CI, 0.80 to 1.15; P = .61). L-treated patients experienced more diarrhea, cutaneous rash, and hepatic toxicity compared with T-treated patients. The incidence of cardiac toxicity was low in all treatment arms. Adjuvant treatment that includes L did not significantly improve DFS compared with T alone and added toxicity. One year of adjuvant T remains standard of care. © 2015 by American Society of Clinical Oncology.

The role of life skills promotion in substance abuse prevention: a mediation analysis.

Science.gov (United States)

Bühler, Anneke; Schröder, Elke; Silbereisen, Rainer K

2008-08-01

Research has shown that life skills programs are the most effective single activity in school-based substance abuse prevention. However, little is known about the processes through which they are effective. This study examines whether an evidence-based prevention program targeting general competence is effective through the promotion of knowledge about life skills and enhanced related behaviors. Based on a sample of 442 fifth graders participating in a quasi-experimental prevention study, as expected, mediation analyses revealed that increased knowledge about life skills paralleled an increase in students' distant attitudes toward alcohol and nicotine use. Unexpectedly, behaviors manifesting enhanced life skills were found not only among program participants who remained experimental/non-smokers or stopped smoking but also among smokers. In general, findings suggest that favorable prevention outcomes may be influenced through building knowledge about general life skills. The notion of uniform mechanisms of effectiveness in prevention programs is discussed.

Quercetin prevents left ventricular hypertrophy in the Apo E knockout mouse

Directory of Open Access Journals (Sweden)

Elena Ulasova

2013-01-01

Full Text Available Hypercholesterolemia is a risk factor for the development of hypertrophic cardiomyopathy. Nevertheless, there are few studies aimed at determining the effects of dietary compounds on early or mild cardiac hypertrophy associated with dyslipidemia. Here we describe left ventricular (LV hypertrophy in 12 week-old Apo E−/− hypercholesterolemic mice. The LV end diastolic posterior wall thickness and overall LV mass were significantly increased in Apo E−/− mice compared with wild type (WT controls. Fractional shortening, LV end diastolic diameter, and hemodynamic parameters were unchanged from WT mice. Oral low dose quercetin (QCN; 0.1 µmol QCN/kg body weight for 6 weeks significantly reduced total cholesterol and very low density lipoprotein in the plasma of Apo E−/− mice. QCN treatment also significantly decreased LV posterior wall thickness and LV mass in Apo E−/− mice. Myocardial geometry and function were unaffected in WT mice by QCN treatment. These data suggest that dietary polyphenolic compounds such as QCN may be effective modulators of plasma cholesterol and could prevent maladaptive myocardial remodeling.

The effects of left and right monocular viewing on hemispheric activation.

Science.gov (United States)

Wang, Chao; Burtis, D Brandon; Ding, Mingzhou; Mo, Jue; Williamson, John B; Heilman, Kenneth M

2018-03-01

Prior research has revealed that whereas activation of the left hemisphere primarily increases the activity of the parasympathetic division of the autonomic nervous system, right-hemisphere activation increases the activity of the sympathetic division. In addition, each hemisphere primarily receives retinocollicular projections from the contralateral eye. A prior study reported that pupillary dilation was greater with left- than with right-eye monocular viewing. The goal of this study was to test the alternative hypotheses that this asymmetric pupil dilation with left-eye viewing was induced by activation of the right-hemispheric-mediated sympathetic activity, versus a reduction of left-hemisphere-mediated parasympathetic activity. Thus, this study was designed to learn whether there are changes in hemispheric activation, as measured by alteration of spontaneous alpha activity, during right versus left monocular viewing. High-density electroencephalography (EEG) was recorded from healthy participants viewing a crosshair with their right, left, or both eyes. There was a significantly less alpha power over the right hemisphere's parietal-occipital area with left and binocular viewing than with right-eye monocular viewing. The greater relative reduction of right-hemisphere alpha activity during left than during right monocular viewing provides further evidence that left-eye viewing induces greater increase in right-hemisphere activation than does right-eye viewing.

Prospective Biomarker Analysis of the Randomized CHER-LOB Study Evaluating the Dual Anti-HER2 Treatment With Trastuzumab and Lapatinib Plus Chemotherapy as Neoadjuvant Therapy for HER2-Positive Breast Cancer.

Science.gov (United States)

Guarneri, Valentina; Dieci, Maria Vittoria; Frassoldati, Antonio; Maiorana, Antonino; Ficarra, Guido; Bettelli, Stefania; Tagliafico, Enrico; Bicciato, Silvio; Generali, Daniele Giulio; Cagossi, Katia; Bisagni, Giancarlo; Sarti, Samanta; Musolino, Antonino; Ellis, Catherine; Crescenzo, Rocco; Conte, PierFranco

2015-09-01

The CHER-LOB randomized phase II study showed that the combination of lapatinib and trastuzumab plus chemotherapy increases the pathologic complete remission (pCR) rate compared with chemotherapy plus either trastuzumab or lapatinib. A biomarker program was prospectively planned to identify potential predictors of sensitivity to different treatments and to evaluate treatment effect on tumor biomarkers. Overall, 121 breast cancer patients positive for human epidermal growth factor 2 (HER2) were randomly assigned to neoadjuvant chemotherapy plus trastuzumab, lapatinib, or both trastuzumab and lapatinib. Pre- and post-treatment samples were centrally evaluated for HER2, p95-HER2, phosphorylated AKT (pAKT), phosphatase and tensin homolog, Ki67, apoptosis, and PIK3CA mutations. Fresh-frozen tissue samples were collected for genomic analyses. A mutation in PIK3CA exon 20 or 9 was documented in 20% of cases. Overall, the pCR rates were similar in PIK3CA wild-type and PIK3CA-mutated patients (33.3% vs. 22.7%; p = .323). For patients receiving trastuzumab plus lapatinib, the probability of pCR was higher in PIK3CA wild-type tumors (48.4% vs. 12.5%; p = .06). Ki67, pAKT, and apoptosis measured on the residual disease were significantly reduced from baseline. The degree of Ki67 inhibition was significantly higher in patients receiving the dual anti-HER2 blockade. The integrated analysis of gene expression and copy number data demonstrated that a 50-gene signature specifically predicted the lapatinib-induced pCR. PIK3CA mutations seem to identify patients who are less likely to benefit from dual anti-HER2 inhibition. p95-HER2 and markers of phosphoinositide 3-kinase pathway deregulation are not confirmed as markers of different sensitivity to trastuzumab or lapatinib. HER2 is currently the only validated marker to select breast cancer patients for anti-HER2 treatment; however, it is becoming evident that HER2-positive breast cancer is a heterogeneous disease. In addition, more

Quantitative measurements of tumoral p95HER2 protein expression in metastatic breast cancer patients treated with trastuzumab: independent validation of the p95HER2 clinical cutoff.

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Duchnowska, Renata; Sperinde, Jeff; Chenna, Ahmed; Haddad, Mojgan; Paquet, Agnes; Lie, Yolanda; Weidler, Jodi M; Huang, Weidong; Winslow, John; Jankowski, Tomasz; Czartoryska-Arłukowicz, Bogumiła; Wysocki, Piotr J; Foszczyńska-Kłoda, Małgorzata; Radecka, Barbara; Litwiniuk, Maria M; Zok, Jolanta; Wiśniewski, Michał; Zuziak, Dorota; Biernat, Wojciech; Jassem, Jacek

2014-05-15

P95HER2 (p95) is a truncated form of the HER2, which lacks the trastuzumab-binding site and contains a hyperactive kinase domain. Previously, an optimal clinical cutoff of p95 expression for progression-free survival (PFS) and overall survival (OS) was defined using a quantitative VeraTag assay (Monogram Biosciences) in a training set of trastuzumab-treated metastatic breast cancer (MBC) patients. In the current study, the predictive value of the p95 VeraTag assay cutoff established in the training set was retrospectively validated for PFS and OS in an independent series of 240 trastuzumab-treated MBC patients from multiple institutions. In the subset of 190 tumors assessed as HER2-total (H2T)-positive using the quantitative HERmark assay (Monogram Biosciences), p95 VeraTag values above the predefined cutoff correlated with shorter PFS (HR = 1.43; P = 0.039) and shorter OS (HR = 1.94; P = 0.0055) where both outcomes were stratified by hormone receptor status and tumor grade. High p95 expression correlated with shorter PFS (HR = 2.41; P = 0.0003) and OS (HR = 2.57; P = 0.0025) in the hormone receptor-positive subgroup of patients (N = 78), but not in the hormone receptor-negative group. In contrast with the quantitative p95 VeraTag measurements, p95 immunohistochemical expression using the same antibody was not significantly correlated with outcomes. The consistency in the p95 VeraTag cutoff across different cohorts of patients with MBC treated with trastuzumab justifies additional studies using blinded analyses in larger series of patients. ©2014 American Association for Cancer Research.

Phase II Study of HER-2/neu Intracellular Domain Peptide-Based Vaccine Administered to Stage IV HER2 Positive Breast Cancer Patients Receiving Trastuzumab

National Research Council Canada - National Science Library

Disis, Mary L

2007-01-01

The primary purpose of this grant is to determine the overall survival benefit in Stage IV HER2 positive breast cancer patients vaccinated with a HER2 ICD peptide-based vaccine while receiving maintenance trastuzumab...

Phase II Study of HER-2/neu Intracellular Domain Peptide-Based Vaccine Administered to Stage IV HER2 Positive Breast Cancer Patients Receiving Trastuzumab

National Research Council Canada - National Science Library

Disis, Mary L

2006-01-01

The primary purpose of this grant is to determine the overall survival benefit in Stage IV HER2 positive breast cancer patients vaccinated with a HER2 ICD peptide-based vaccine while receiving maintenance trastuzumab...

Monitoring therapeutic response of human ovarian cancer to 17-DMAG by noninvasive PET imaging with {sup 64}Cu-DOTA-trastuzumab

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Niu, Gang; Cao, Qizhen; Chen, Xiaoyuan [Stanford University School of Medicine, The Molecular Imaging Program at Stanford (MIPS), Department of Radiology and Bio-X Program, Stanford, CA (United States); Li, Zibo [Stanford University School of Medicine, The Molecular Imaging Program at Stanford (MIPS), Department of Radiology and Bio-X Program, Stanford, CA (United States); Keck School of Medicine, USC Molecular Imaging Center, Department of Radiology, Los Angeles, CA (United States)

2009-09-15

17-Dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), a heat-shock protein 90 (Hsp90) inhibitor, has been intensively investigated for cancer therapy and is undergoing clinical trials. Human epidermal growth factor receptor 2 (HER-2) is one of the client proteins of Hsp90 and its expression is decreased upon 17-DMAG treatment. In this study, we aimed to noninvasively monitor the HER-2 response to 17-DMAG treatment in xenografted mice. The sensitivity of human ovarian cancer SKOV-3 cells to 17-DMAG in vitro was measured by MTT assay. HER-2 expression in SKOV-3 cells was determined by flow cytometry. Nude mice bearing SKOV-3 tumors were treated with 17-DMAG and the therapeutic efficacy was evaluated by tumor size measurement. Both treated and control mice were imaged with microPET using {sup 64}Cu-DOTA-trastuzumab and {sup 18}F-FDG. Biodistribution studies and immunofluorescence staining were performed to validate the microPET results. SKOV-3 cells are sensitive to 17-DMAG treatment, in a dose-dependent manner, with an IC{sub 50} value of 24.72 nM after 72 h incubation. The tumor growth curve supported the inhibition effect of 17-DMAG on SKOV-3 tumors. Quantitative microPET imaging showed that {sup 64}Cu-DOTA-trastuzumab had prominent tumor accumulation in untreated SKOV-3 tumors, which was significantly reduced in 17-DMAG-treated tumors. There was no uptake difference detected by FDG PET. Immunofluorescence staining confirmed the significant reduction in tumor HER-2 level upon 17-DMAG treatment. The early response to anti-Hsp90 therapy was successfully monitored by quantitative PET using {sup 64}Cu-DOTA-trastuzumab. This approach may be valuable in monitoring the therapeutic response in HER-2-positive cancer patients under 17-DMAG treatment. (orig.)

A Mediation Analysis of a Tobacco Prevention Program for Adolescents in India: How Did Project MYTRI Work?

Science.gov (United States)

Stigler, Melissa Harrell; Perry, Cheryl L.; Smolenski, Derek; Arora, Monika; Reddy, K. Srinath

2011-01-01

This article presents the results of a mediation analysis of Project MYTRI (Mobilizing Youth for Tobacco Related Initiatives in India), a randomized, controlled trial of a multiple-component, school-based tobacco prevention program for sixth- to ninth-graders (n = 14,085) in Delhi and Chennai, India. A mediation analysis identifies "how"…

Clinical use of S-HER2 in breast cancer for detecting metastatic recurrence and monitoring effect of trastuzumab treatment

DEFF Research Database (Denmark)

Kjær, Ina Mathilde; Brandslund, Ivan

2014-01-01

% and the positive predictive value was 47% using a cutoff value of 15 μg/L. Further, we have shown that the S-HER2 value reflects the effect of targeted treatment with trastuzumab. An increase in S-HER2 was correlated with progression of disease in 40 out of 44 clinical courses, whereas a decrease in S-HER2...

Adjuvant Lapatinib and Trastuzumab for Early Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer: Results From the Randomized Phase III Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization Trial

Science.gov (United States)

Holmes, Eileen; Baselga, José; de Azambuja, Evandro; Dueck, Amylou C.; Viale, Giuseppe; Zujewski, Jo Anne; Goldhirsch, Aron; Armour, Alison; Pritchard, Kathleen I.; McCullough, Ann E.; Dolci, Stella; McFadden, Eleanor; Holmes, Andrew P.; Tonghua, Liu; Eidtmann, Holger; Dinh, Phuong; Di Cosimo, Serena; Harbeck, Nadia; Tjulandin, Sergei; Im, Young-Hyuck; Huang, Chiun-Sheng; Diéras, Véronique; Hillman, David W.; Wolff, Antonio C.; Jackisch, Christian; Lang, Istvan; Untch, Michael; Smith, Ian; Boyle, Frances; Xu, Binghe; Gomez, Henry; Suter, Thomas; Gelber, Richard D.; Perez, Edith A.

2016-01-01

Background Lapatinib (L) plus trastuzumab (T) improves outcomes for metastatic human epidermal growth factor 2–positive breast cancer and increases the pathologic complete response in the neoadjuvant setting, but their role as adjuvant therapy remains uncertain. Methods In the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial, patients with centrally confirmed human epidermal growth factor 2–positive early breast cancer were randomly assigned to 1 year of adjuvant therapy with T, L, their sequence (T→L), or their combination (L+T). The primary end point was disease-free survival (DFS), with 850 events required for 80% power to detect a hazard ratio (HR) of 0.8 for L+T versus T. Results Between June 2007 and July 2011, 8,381 patients were enrolled. In 2011, due to futility to demonstrate noninferiority of L versus T, the L arm was closed, and patients free of disease were offered adjuvant T. A protocol modification required P ≤ .025 for the two remaining pairwise comparisons. At a protocol-specified analysis with a median follow-up of 4.5 years, a 16% reduction in the DFS hazard rate was observed with L+T compared with T (555 DFS events; HR, 0.84; 97.5% CI, 0.70 to 1.02; P = .048), and a 4% reduction was observed with T→L compared with T (HR, 0.96; 97.5% CI, 0.80 to 1.15; P = .61). L-treated patients experienced more diarrhea, cutaneous rash, and hepatic toxicity compared with T-treated patients. The incidence of cardiac toxicity was low in all treatment arms. Conclusion Adjuvant treatment that includes L did not significantly improve DFS compared with T alone and added toxicity. One year of adjuvant T remains standard of care. PMID:26598744

Prevention of disease progression by cardiac resynchronization therapy in patients with asymptomatic or mildly symptomatic left ventricular dysfunction: insights from the European cohort of the REVERSE (Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction) trial

DEFF Research Database (Denmark)

Daubert, Claude; Gold, Michael R; Abraham, William T

2009-01-01

were decreased in this patient population in New York Heart Association functional classes I or II. These observations suggest that CRT prevents the progression of disease in patients with asymptomatic or mildly symptomatic LV dysfunction. (REsynchronization reVErses Remodeling in Systolic Left v......OBJECTIVES: The aim of this study was to determine the long-term effects of cardiac resynchronization therapy (CRT) in the European cohort of patients enrolled in the REVERSE (Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction) trial. BACKGROUND: Previous data suggest...... that CRT slows disease progression and improves the outcomes of asymptomatic or mildly symptomatic patients with left ventricular (LV) dysfunction and a wide QRS complex. METHODS: We randomly assigned 262 recipients of CRT pacemakers or defibrillators, with QRS > or =120 ms and LV ejection fraction...

For or against adjuvant trastuzumab for pT1a-bN0M0 breast cancer patients with HER2-positive tumors: a meta-analysis of published literatures.

Directory of Open Access Journals (Sweden)

Qiong Zhou

Full Text Available BACKGROUND: Although the prognosis of patients with small (≤1cm tumors is generally favorable, emerging data suggests that biological behavior varies between intrinsic subtypes in such patients. Furthermore, it still remains unclear whether HER2-positive pT1a-bN0M0 patients could benefit from adjuvant trastuzumab. For further evaluation, we sought to conduct a meta-analysis so as to get a better understanding of the prognosis for HER2-positive pT1a-bN0M0 patients and their survival benefit from adjuvant trastuzumab, accordingly, offering the implications for current practice. METHODS: The PubMed database, the online proceedings of the American Society of Clinical Oncology (ASCO Annual Meetings, the online proceedings of the San Antonio Breast Cancer Symposium, and the CD proceedings of the International St. Gallen Breast Cancer Conference were searched for all relevant studies published before September 2012. Relative risks (RRs were used to compare the prognosis of different intrinsic subtypes for pT1a-bN0M0 breast cancer. Analyses were also performed to estimate the association between adjuvant trastuzumab and various survival outcomes. RESULTS: With eight eligible studies identified, this meta-analysis demonstrated a deleterious effect of HER2+ phenotype on disease-free survival (DFS; RR = 3.677, 95% CI 2.606-5.189, p <0.001 and distant disease-free survival (DDFS; RR = 3.824, 95% CI 2.249-6.501, p<0.001 as compared to HR+/HER2- subgroup. However, significant difference failed to be achieved in terms of any endpoint between HER2+ and triple negative breast cancer (TNBC. Besides, a marked improvement in DFS was observed with the addition of trastuzumab for HER2-positive pT1a-bN0M0 patients (RR = 0.323, 95% CI 0.191-0.547, p<0.001. CONCLUSION: This meta-analysis clarifies that intrinsic subtypes might be a reliable marker to predict the prognosis in pT1a-bN0M0 breast cancer. Besides, even for such early stage HER2-positive

Adjuvant Trastuzumab Therapy for Early HER2-Positive Breast Cancer in Iran: A Cost-Effectiveness and Scenario Analysis for an Optimal Treatment Strategy

NARCIS (Netherlands)

A. Ansaripour (Amir); C.A. Uyl-de Groot (Carin); W.K. Redekop (Ken)

2017-01-01

textabstractIntroduction: Clinical guidelines have recommended a 1-year trastuzumab regimen as standard care for early human epidermal growth factor receptor 2 (HER2)-positive breast cancer; however, this recommendation can have a dramatic impact on total drug expenditures in middle-income countries

Relationship of left ventricular systolic function to persistence or development of electrocardiographic left ventricular hypertrophy in hypertensive patients

DEFF Research Database (Denmark)

Okin, Peter M; Wachtell, Kristian; Gerdts, Eva

2014-01-01

left ventricular systolic function in patients with new or persistent ECG LVH. METHODS: Baseline and year-3 ECG LVH and left ventricular midwall shortening (MWS) were examined in 725 hypertensive patients in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) echocardiographic...... 1.03-3.50, P = 0.040) at year 3. CONCLUSION: Persistence or development of new ECG LVH during antihypertensive therapy is associated with an increased risk of left ventricular systolic dysfunction after 3 years' follow-up. These findings provide insight into a possible mechanism by which changes......BACKGROUND: Persistence or development of ECG left ventricular hypertrophy (LVH) by Cornell product criteria is associated with an increased risk of developing heart failure compared with regression or continued absence of LVH. We postulated that this association might be in part mediated via worse...

Peri-infarct zone pacing to prevent adverse left ventricular remodelling in patients with large myocardial infarction

DEFF Research Database (Denmark)

Stone, Gregg W; Chung, Eugene S; Stancak, Branislav

2016-01-01

AIMS: We sought to determine whether peri-infarct pacing prevents left ventricular (LV) remodelling and improves functional and clinical outcomes in patients with large first myocardial infarction (MI). METHODS AND RESULTS: A total of 126 patients at 27 international sites within 10 days of onset.......92). There were also no significant between-group differences in the change in LV end-systolic volume or ejection fraction over time. Quality of life, as assessed by the Minnesota Living with Heart Failure (HF) and European Quality of Life-5 Dimension questionnaires and New York Heart Association class, was also...

Divergent functions of the left and right central amygdala in visceral nociception.

Science.gov (United States)

Sadler, Katelyn E; McQuaid, Neal A; Cox, Abigail C; Behun, Marissa N; Trouten, Allison M; Kolber, Benedict J

2017-04-01

The left and right central amygdalae (CeA) are limbic regions involved in somatic and visceral pain processing. These 2 nuclei are asymmetrically involved in somatic pain modulation; pain-like responses on both sides of the body are preferentially driven by the right CeA, and in a reciprocal fashion, nociceptive somatic stimuli on both sides of the body predominantly alter molecular and physiological activities in the right CeA. Unknown, however, is whether this lateralization also exists in visceral pain processing and furthermore what function the left CeA has in modulating nociceptive information. Using urinary bladder distension (UBD) and excitatory optogenetics, a pronociceptive function of the right CeA was demonstrated in mice. Channelrhodopsin-2-mediated activation of the right CeA increased visceromotor responses (VMRs), while activation of the left CeA had no effect. Similarly, UBD-evoked VMRs increased after unilateral infusion of pituitary adenylate cyclase-activating polypeptide in the right CeA. To determine intrinsic left CeA involvement in bladder pain modulation, this region was optogenetically silenced during noxious UBD. Halorhodopsin (NpHR)-mediated inhibition of the left CeA increased VMRs, suggesting an ongoing antinociceptive function for this region. Finally, divergent left and right CeA functions were evaluated during abdominal mechanosensory testing. In naive animals, channelrhodopsin-2-mediated activation of the right CeA induced mechanical allodynia, and after cyclophosphamide-induced bladder sensitization, activation of the left CeA reversed referred bladder pain-like behaviors. Overall, these data provide evidence for functional brain lateralization in the absence of peripheral anatomical asymmetries.

De-Escalation Strategies in Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Early Breast Cancer (BC): Final Analysis of the West German Study Group Adjuvant Dynamic Marker-Adjusted Personalized Therapy Trial Optimizing Risk Assessment and Therapy Response Prediction in Early BC HER2- and Hormone Receptor-Positive Phase II Randomized Trial-Efficacy, Safety, and Predictive Markers for 12 Weeks of Neoadjuvant Trastuzumab Emtansine With or Without Endocrine Therapy (ET) Versus Trastuzumab Plus ET.

Science.gov (United States)

Harbeck, Nadia; Gluz, Oleg; Christgen, Matthias; Kates, Ronald Ernest; Braun, Michael; Küemmel, Sherko; Schumacher, Claudia; Potenberg, Jochem; Kraemer, Stefan; Kleine-Tebbe, Anke; Augustin, Doris; Aktas, Bahriye; Forstbauer, Helmut; Tio, Joke; von Schumann, Raquel; Liedtke, Cornelia; Grischke, Eva-Maria; Schumacher, Johannes; Wuerstlein, Rachel; Kreipe, Hans Heinrich; Nitz, Ulrike Anneliese

2017-09-10

Purpose Human epidermal growth factor receptor 2 (HER2)-positive/hormone receptor (HR)-positive breast cancer is a distinct subgroup associated with lower chemotherapy sensitivity and slightly better outcome than HER2-positive/HR-negative disease. Little is known about the efficacy of the combination of endocrine therapy (ET) with trastuzumab or with the potent antibody-cytotoxic, anti-HER2 compound trastuzumab emtansine (T-DM1) with or without ET for this subgroup. The West German Study Group trial, ADAPT (Adjuvant Dynamic Marker-Adjusted Personalized Therapy Trial Optimizing Risk Assessment and Therapy Response Prediction in Early Breast Cancer) compares pathologic complete response (pCR) rates of T-DM1 versus trastuzumab with ET in early HER2-positive/HR-positive breast cancer. Patients and Methods In this prospective, neoadjuvant, phase II trial, 375 patients with early breast cancer with HER2-positive and HR-positive status (n = 463 screened) were randomly assigned to 12 weeks of T-DM1 with or without ET or to trastuzumab with ET. The primary end point was pCR (ypT0/is/ypN0). Early response was assessed in 3-week post-therapeutic core biopsies (proliferation decrease ≥ 30% Ki-67 or cellularity response). Secondary end points included safety and predictive impact of early response on pCR. Adjuvant therapy followed national standards. Results Baseline characteristics were well balanced among the arms. More than 90% of patients completed the therapy per protocol. pCR was observed in 41.0% of patients treated with T-DM1, 41.5% of patients treated with T-DM1 and ET, and 15.1% with trastuzumab and ET ( P < .001). Early responders (67% of patients with assessable response) achieved pCR in 35.7% compared with 19.8% in nonresponders (odds ratio, 2.2; 95% CI, 1.24 to 4.19). T-DM1 was associated with a significantly higher prevalence of grade 1 to 2 toxicities, especially thrombocytopenia, nausea, and elevation of liver enzymes. Overall toxicity was low; seventeen

The Effects of No Child Left Behind on the Prevalence of Evidence-Based Drug Prevention Curricula in the Nation's Middle Schools

Science.gov (United States)

Ringwalt, Chris; Hanley, Sean; Ennett, Susan T.; Vincus, Amy A.; Bowling, J. Michael; Haws, Susan W.; Rohrbach, Louise A.

2011-01-01

Background: Concerns have been expressed that No Child Left Behind (NCLB) may be reducing the amount of classroom time devoted to subjects other than those for which students are tested. The purpose of this article is to explore whether NCLB legislation has affected the provision of evidence-based drug prevention curricula (EBC) in the nation's…

Mapping of the left-sided phrenic nerve course in patients undergoing left atrial catheter ablations.

Science.gov (United States)

Huemer, Martin; Wutzler, Alexander; Parwani, Abdul S; Attanasio, Philipp; Haverkamp, Wilhelm; Boldt, Leif-Hendrik

2014-09-01

Catheter ablation of atrial fibrillation has been associated with left-sided phrenic nerve palsy. Knowledge of the individual left phrenic nerve course therefore is essential to prevent nerve injury. The aim of this study was to test the feasibility of an intraprocedural pace mapping and reconstruction of the left phrenic nerve course and to characterize which anatomical areas are affected. In patients undergoing left atrial catheter ablation, a three-dimensional map of the left atrial anatomical structures was created. The left-sided phrenic nerve course was determined by high-output pace mapping and reconstructed in the map. In this study, 40 patients with atrial fibrillation or atrial tachycardias were included. Left phrenic nerve capture was observed in 23 (57.5%) patients. Phrenic nerve was captured in 22 (55%) patients inside the left atrial appendage, in 22 (55%) in distal parts, in 21 (53%) in medial parts, and in two (5%) in ostial parts of the appendage. In three (7.5%) patients, capture was found in the distal coronary sinus and in one (2.5%) patient in the left atrium near the left atrial appendage ostium. Ablation target was changed due to direct spatial relationship to the phrenic nerve in three (7.5%) patients. No phrenic nerve palsy was observed. Left-sided phrenic nerve capture was found inside and around the left atrial appendage in the majority of patients and additionally in the distal coronary sinus. Phrenic nerve mapping and reconstruction can easily be performed and should be considered prior catheter ablations in potential affected areas. ©2014 Wiley Periodicals, Inc.

Relationship of left atrial enlargement to persistence or development of ECG left ventricular hypertrophy in hypertensive patients: implications for the development of new atrial fibrillation

DEFF Research Database (Denmark)

Okin, Peter M; Gerdts, Eva; Wachtell, Kristian

2010-01-01

Persistence and development of ECG left ventricular hypertrophy (LVH) by Cornell product criteria are associated with an increased risk of atrial fibrillation compared with regression or continued absence of LVH. We postulated that this association might be in part mediated via greater left atrial...... enlargement (LAE) in patients with new and persistent ECG LVH....

In vitro cytotoxicity of {sup 211}At-labeled trastuzumab in human breast cancer cell lines: effect of specific activity and HER2 receptor heterogeneity on survival fraction

Energy Technology Data Exchange (ETDEWEB)

Akabani, Gamal [Department of Radiology, Duke University Medical Center, P.O. Box 3808, Durham, NC 27710 (United States); Carlin, Sean [Department of Radiology, Duke University Medical Center, P.O. Box 3808, Durham, NC 27710 (United States); Welsh, Phil [Department of Radiology, Duke University Medical Center, P.O. Box 3808, Durham, NC 27710 (United States); Zalutsky, Michael R. [Department of Radiology, Duke University Medical Center, P.O. Box 3808, Durham, NC 27710 (United States)]. E-mail: zalut001@mc.duke.edu

2006-04-15

Introduction: Radioimmunotherapy with anti-HER2 monoclonal antibodies (mAbs) such as trastuzumab is a promising strategy for treating HER2-positive breast and ovarian carcinoma patients. The objective of this study was to determine the cytotoxic effectiveness of trastuzumab labeled with the 7.2-h half-life {alpha}-particle emitter {sup 211}At. Methods: Experiments were performed on SKBr-3, BT-474 and the transfected MCF7/HER2-18 human breast carcinoma cell lines. Intrinsic radiosensitivity was determined after exposure to external beam irradiation. The cytotoxicity of {sup 211}At-labeled trastuzumab was measured by clonogenic assays. The distribution of HER2 receptor expression on the cell lines was measured using fluorescence-activated cell sorting. A pharmacokinetic (PK)/microdosimetric model was established to assess the effects of specific activity (SA), HER2 receptor expression and absorbed dose on survival fraction (SF). Results: With external beam irradiation, the 2-Gy SF for BT-474, SKBr-3 and MCF7/HER2-18 cells was 0.78, 0.53 and 0.64 Gy, respectively. Heterogeneous HER2 expression was observed, with a subpopulation of cells lacking measurable receptor (14.5%, SKBr-3; 0.34%, MCF-7/HER2; 1.73%, BT-474). When plotted as a function of activity concentration, SF curves were biphasic and inversely proportional to SA; however, when the model was applied and absorbed doses calculated, the SF curve was monoexponential independent of SA. Thus, the PK model was able to demonstrate the effects of competition between cold and labeled mAb. These studies showed that the relative biological effectiveness of {sup 211}At-labeled trastuzaumab was about 10 times higher than that of external beam therapy. Conclusion: These in vitro studies showed that {sup 211}At-labeled trastuzumab mAb is an effective cytotoxic agent for the treatment of HER2-positive tumor cells. The SA of the labeled mAb and the homogeneity of HER2 receptor expression are important variables influencing

Docosahexaenoic Acid Modulates a HER2-Associated Lipogenic Phenotype, Induces Apoptosis, and Increases Trastuzumab Action in HER2-Overexpressing Breast Carcinoma Cells.

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Ravacci, Graziela Rosa; Brentani, Maria Mitzi; Tortelli, Tharcisio Citrângulo; Torrinhas, Raquel Suzana M M; Santos, Jéssica Reis; Logullo, Angela Flávia; Waitzberg, Dan Linetzky

2015-01-01

In breast cancer, lipid metabolic alterations have been recognized as potential oncogenic stimuli that may promote malignancy. To investigate whether the oncogenic nature of lipogenesis closely depends on the overexpression of HER2 protooncogene, the normal breast cell line, HB4a, was transfected with HER2 cDNA to obtain HER2-overexpressing HB4aC5.2 cells. Both cell lines were treated with trastuzumab and docosahexaenoic acid. HER2 overexpression was accompanied by an increase in the expression of lipogenic genes involved in uptake (CD36), transport (FABP4), and storage (DGAT) of exogenous fatty acids (FA), as well as increased activation of "de novo" FA synthesis (FASN). We further investigate whether this lipogenesis reprogramming might be regulated by mTOR/PPARγ pathway. Inhibition of the mTORC1 pathway markers, p70S6 K1, SREBP1, and LIPIN1, as well as an increase in DEPTOR expression (the main inhibitor of the mTOR) was detected in HB4aC5.2. Based on these results, a PPARγ selective antagonist, GW9662, was used to treat both cells lines, and the lipogenic genes remained overexpressed in the HB4aC5.2 but not HB4a cells. DHA treatment inhibited all lipogenic genes (except for FABP4) in both cell lines yet only induced death in the HB4aC5.2 cells, mainly when associated with trastuzumab. Neither trastuzumab nor GW9662 alone was able to induce cell death. In conclusion, oncogenic transformation of breast cells by HER2 overexpression may require a reprogramming of lipogenic genetic that is independent of mTORC1 pathway and PPARγ activity. This reprogramming was inhibited by DHA.

Docosahexaenoic Acid Modulates a HER2-Associated Lipogenic Phenotype, Induces Apoptosis, and Increases Trastuzumab Action in HER2-Overexpressing Breast Carcinoma Cells

Directory of Open Access Journals (Sweden)

Graziela Rosa Ravacci

2015-01-01

Full Text Available In breast cancer, lipid metabolic alterations have been recognized as potential oncogenic stimuli that may promote malignancy. To investigate whether the oncogenic nature of lipogenesis closely depends on the overexpression of HER2 protooncogene, the normal breast cell line, HB4a, was transfected with HER2 cDNA to obtain HER2-overexpressing HB4aC5.2 cells. Both cell lines were treated with trastuzumab and docosahexaenoic acid. HER2 overexpression was accompanied by an increase in the expression of lipogenic genes involved in uptake (CD36, transport (FABP4, and storage (DGAT of exogenous fatty acids (FA, as well as increased activation of “de novo” FA synthesis (FASN. We further investigate whether this lipogenesis reprogramming might be regulated by mTOR/PPARγ pathway. Inhibition of the mTORC1 pathway markers, p70S6 K1, SREBP1, and LIPIN1, as well as an increase in DEPTOR expression (the main inhibitor of the mTOR was detected in HB4aC5.2. Based on these results, a PPARγ selective antagonist, GW9662, was used to treat both cells lines, and the lipogenic genes remained overexpressed in the HB4aC5.2 but not HB4a cells. DHA treatment inhibited all lipogenic genes (except for FABP4 in both cell lines yet only induced death in the HB4aC5.2 cells, mainly when associated with trastuzumab. Neither trastuzumab nor GW9662 alone was able to induce cell death. In conclusion, oncogenic transformation of breast cells by HER2 overexpression may require a reprogramming of lipogenic genetic that is independent of mTORC1 pathway and PPARγ activity. This reprogramming was inhibited by DHA.

Synthesis and stability test of radioimmunoconjugate 177Lu-DOTA-F(ab′2-trastuzumab for theranostic agent of HER2 positive breast cancer

Directory of Open Access Journals (Sweden)

Sandra Hermanto

2016-10-01

Full Text Available The use of trastuzumab as intact IgG labeling radionuclide for HER2 positive breast cancer theranostic agent is not ideal because it is slowly eliminated from the blood and normal tissues resulting in low tumor/blood (T/B and tumor/normal tissue (T/NT ratios. To overcome this limitation, we developed the trastuzumab F(ab′2 fragments and radiolabeling of the fragments by β and γ-particle of Lutetium-177. F(ab2 fragments were produced by digestion of trastuzumab IgG (Herceptin with pepsin for 18 h at 37 °C. The F(ab′2 fragment fractionated in PD-10 column, followed by the conjugation with 2-(4-isothiocyanatobenzyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (p-SCN-Bn-DOTA as a metal chelator and radiolabeling with 177LuCl3. Molecular weight of fragments was calculated by LCMS (Liquid Chromatography Mass Spectroscopy and the radiochemical purity was evaluated by ITLC-SG (Instan Thin Layer Chromatography. Our study showed that the purity of F(ab′2 fragment generated by PD-10 fractions was >98% and the molecular weight of F(ab′2 was 98.35 kDa. The average numbers of pSCN-Bn-DOTA chelates per antibody fragment were 5.03 ± 1.5 and the optimum conjugation reactions was performed at molar ratio 20:1 (chelator to antibody. The stability test of the radioimmunoconjugate in the human serum albumin (HSA at 37 °C showed the radiochemical purity was 91.96 ± 0.26% after 96 h storage. This indicated that the radioimmunoconjugate is relatively stable when applied to the human body's physiological condition.

Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial

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Martin, Miguel; Holmes, Frankie A; Ejlertsen, Bent

2017-01-01

BACKGROUND: ExteNET showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, significantly improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in women with HER2-positive breast cancer. We report updated efficacy outcomes from...... cancer, who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab with no evidence of disease recurrence or metastatic disease at study entry. Patients who were eligible patients were randomly assigned (1:1) via permuted blocks stratified according to hormone receptor status (hormone....../day or matching placebo. Treatment was given continuously for 1 year, unless disease recurrence or new breast cancer, intolerable adverse events, or consent withdrawal occurred. Patients, investigators, and trial funder were masked to treatment allocation. The predefined endpoint of the 5-year analysis...

Randomized placebo controlled blinded study to assess valsartan efficacy in preventing left ventricle remodeling in patients with dual chamber pacemaker--Rationale and design of the trial.

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Tomasik, Andrzej; Jacheć, Wojciech; Wojciechowska, Celina; Kawecki, Damian; Białkowska, Beata; Romuk, Ewa; Gabrysiak, Artur; Birkner, Ewa; Kalarus, Zbigniew; Nowalany-Kozielska, Ewa

2015-05-01

Dual chamber pacing is known to have detrimental effect on cardiac performance and heart failure occurring eventually is associated with increased mortality. Experimental studies of pacing in dogs have shown contractile dyssynchrony leading to diffuse alterations in extracellular matrix. In parallel, studies on experimental ischemia/reperfusion injury have shown efficacy of valsartan to inhibit activity of matrix metalloproteinase-9, to increase the activity of tissue inhibitor of matrix metalloproteinase-3 and preserve global contractility and left ventricle ejection fraction. To present rationale and design of randomized blinded trial aimed to assess whether 12 month long administration of valsartan will prevent left ventricle remodeling in patients with preserved left ventricle ejection fraction (LVEF ≥ 40%) and first implantation of dual chamber pacemaker. A total of 100 eligible patients will be randomized into three parallel arms: placebo, valsartan 80 mg/daily and valsartan 160 mg/daily added to previously used drugs. The primary endpoint will be assessment of valsartan efficacy to prevent left ventricle remodeling during 12 month follow-up. We assess patients' functional capacity, blood plasma activity of matrix metalloproteinases and their tissue inhibitors, NT-proBNP, tumor necrosis factor alpha, and Troponin T. Left ventricle function and remodeling is assessed echocardiographically: M-mode, B-mode, tissue Doppler imaging. If valsartan proves effective, it will be an attractive measure to improve long term prognosis in aging population and increasing number of pacemaker recipients. ClinicalTrials.org (NCT01805804). Copyright © 2015 Elsevier Inc. All rights reserved.

Native mass spectrometry and ion mobility characterization of trastuzumab emtansine, a lysine-linked antibody drug conjugate.

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Marcoux, Julien; Champion, Thierry; Colas, Olivier; Wagner-Rousset, Elsa; Corvaïa, Nathalie; Van Dorsselaer, Alain; Beck, Alain; Cianférani, Sarah

2015-08-01

Antibody-drug conjugates (ADCs) are biochemotherapeutics consisting of a cytotoxic chemical drug linked covalently to a monoclonal antibody. Two main classes of ADCs, namely cysteine and lysine conjugates, are currently available on the market or involved in clinical trials. The complex structure and heterogeneity of ADCs makes their biophysical characterization challenging. For cysteine conjugates, hydrophobic interaction chromatography is the gold standard technique for studying drug distribution, the naked antibody content, and the average drug to antibody ratio (DAR). For lysine ADC conjugates on the other hand, which are not amenable to hydrophobic interaction chromatography because of their higher heterogeneity, denaturing mass spectrometry (MS) and UV/Vis spectroscopy are the most powerful approaches. We report here the use of native MS and ion mobility (IM-MS) for the characterization of trastuzumab emtansine (T-DM1, Kadcyla(®)). This lysine conjugate is currently being considered for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer, and combines the anti-HER2 antibody trastuzumab (Herceptin(®)), with the cytotoxic microtubule-inhibiting maytansine derivative, DM1. We show that native MS combined with high-resolution measurements and/or charge reduction is beneficial in terms of the accurate values it provides of the average DAR and the drug load profiles. The use of spectral deconvolution is discussed in detail. We report furthermore the use of native IM-MS to directly determine DAR distribution profiles and average DAR values, as well as a molecular modeling investigation of positional isomers in T-DM1. © 2015 The Protein Society.

18F-PEG-biotin: Precursor (boroaryl-PEG-biotin) synthesis, 18F-labelling and an in-vitro assessment of its binding with NeutravidinTM-trastuzumab pre-treated cells

International Nuclear Information System (INIS)

Smith, Tim A.D.; Simpson, Michael; Cheyne, Richard; Trembleau, Laurent

2011-01-01

In terms of nuclear decay 18 F is the most ideal PET nuclide but its short t 1/2 precludes its use for directly labelling whole antibodies due to their long blood residence times. Pre-targeted imaging using affinity systems such as Neutravidin TM -biotin facilitates the application of short-lived nuclides by their attachment to biotin for imaging cell surface proteins targeted with Neutravidin TM -conjugated antibodies. Methods: Boroaryl functionalised biotin was prepared with a PEG linker and radiolabelled by incubation with 18 F in acidified aqueous solution. Cells expressing high (SKBr3), medium (MDA-MB-453) and low (MDA-MB-468) levels of HER-2 were pre-incubated with Neutravidin TM -conjugated trastuzumab, washed, and then incubated with 18 F-PEG-biotin. Results: The 18 F-fluorination of boroaryl-PEG-biotin was much more efficient than reported for other versions of boroaryl-biotin. The novel 18 F-PEG-biotin was demonstrated to bind to HER-2-expressing cells in-vitro pre-incubated with Neutravidin TM -conjugated trastuzumab. Conclusion: Biotin can be functionalised with boroaryl and readily 18 F-radiolabelled in aqueous solution and will bind to cells pre-incubated with Neutravidin TM -antibody conjugates. - Highlights: → Boroaryl-biotin precursor is prepared. → Rapid 18 F-fluorination is demonstrated. → HER-2 expressing breast cancer cells pre-treated with trastuzumab-Neutravidin TM . → 18 F-PEG-biotin binding to pre-treated cells corresponds with HER-2 expression.

Palmitate-induced ER stress increases trastuzumab sensitivity in HER2/neu-positive breast cancer cells

International Nuclear Information System (INIS)

Baumann, Jan; Wong, Jason; Sun, Yan; Conklin, Douglas S.

2016-01-01

HER2/neu-positive breast cancer cells have recently been shown to use a unique Warburg-like metabolism for survival and aggressive behavior. These cells exhibit increased fatty acid synthesis and storage compared to normal breast cells or other tumor cells. Disruption of this synthetic process results in apoptosis. Since the addition of physiological doses of exogenous palmitate induces cell death in HER2/neu-positive breast cancer cells, the pathway is likely operating at its limits in these cells. We have studied the response of HER2/neu-positive breast cancer cells to physiological concentrations of exogenous palmitate to identify lipotoxicity-associated consequences of this physiology. Since epidemiological data show that a diet rich in saturated fatty acids is negatively associated with the development of HER2/neu-positive cancer, this cellular physiology may be relevant to the etiology and treatment of the disease. We sought to identify signaling pathways that are regulated by physiological concentrations of exogenous palmitate specifically in HER2/neu-positive breast cancer cells and gain insights into the molecular mechanism and its relevance to disease prevention and treatment. Transcriptional profiling was performed to assess programs that are regulated in HER2-normal MCF7 and HER2/neu-positive SKBR3 breast cancer cells in response to exogenous palmitate. Computational analyses were used to define and predict functional relationships and identify networks that are differentially regulated in the two cell lines. These predictions were tested using reporter assays, fluorescence-based high content microscopy, flow cytometry and immunoblotting. Physiological effects were confirmed in HER2/neu-positive BT474 and HCC1569 breast cancer cell lines. Exogenous palmitate induces functionally distinct transcriptional programs in HER2/neu-positive breast cancer cells. In the lipogenic HER2/neu-positive SKBR3 cell line, palmitate induces a G2 phase cell cycle delay and

Cardio-oncology: cardiovascular complications of cancer therapy.

Science.gov (United States)

Henning, Robert J; Harbison, Raymond D

2017-07-01

This paper focuses on three classes of commonly used anticancer drugs, which can cause cardiotoxicity: anthracyclines, monoclonal antibodies exemplified by trastuzumab and tyrosine kinase inhibitors. Anthracyclines can induce cardiomyocyte necrosis and fibrosis. Trastuzumab can cause cardiac stunning. The tyrosine kinase inhibitors can increase systemic arterial pressure and impair myocyte contractility. In addition, radiation therapy to the mediastinum or left chest can exacerbate the cardiotoxicity of these anticancer drugs and can also cause accelerated atherosclerosis, myocardial infarction, heart failure and arrhythmias. Left ventricular ejection fraction measurements are most commonly used to assess cardiac function in patients who receive chemo- or radiation-therapy. However, echocardiographic determinations of global longitudinal strain are more sensitive for detection of early left ventricular systolic dysfunction. Information on patient-risk stratification and monitoring is presented and guidelines for the medical treatment of cardiac dysfunction due to cancer therapies are summarized.

Fallopian Tube Herniation through Left Sided Abdominal Drain Site.

Science.gov (United States)

Hussain, Khalid; Masood, Jovaria

2016-06-01

Intra-abdominal drains have been used since long to prevent intra-abdominal collection, and detect any anastomotic leaks. We report a case of left sided fallopian tube herniation from a left lower abdominal drain site in a 27-year female who underwent caesarian section for breach presentation. Several complications related to drain usage has been described but left sided fallopian tube prolapse through drain site has not been reported in literature.

Targeted Therapy for Breast Cancer Prevention

Science.gov (United States)

den Hollander, Petra; Savage, Michelle I.; Brown, Powel H.

2013-01-01

With a better understanding of the etiology of breast cancer, molecularly targeted drugs have been developed and are being testing for the treatment and prevention of breast cancer. Targeted drugs that inhibit the estrogen receptor (ER) or estrogen-activated pathways include the selective ER modulators (tamoxifen, raloxifene, and lasofoxifene) and aromatase inhibitors (AIs) (anastrozole, letrozole, and exemestane) have been tested in preclinical and clinical studies. Tamoxifen and raloxifene have been shown to reduce the risk of breast cancer and promising results of AIs in breast cancer trials, suggest that AIs might be even more effective in the prevention of ER-positive breast cancer. However, these agents only prevent ER-positive breast cancer. Therefore, current research is focused on identifying preventive therapies for other forms of breast cancer such as human epidermal growth factor receptor 2 (HER2)-positive and triple-negative breast cancer (TNBC, breast cancer that does express ER, progesterone receptor, or HER2). HER2-positive breast cancers are currently treated with anti-HER2 therapies including trastuzumab and lapatinib, and preclinical and clinical studies are now being conducted to test these drugs for the prevention of HER2-positive breast cancers. Several promising agents currently being tested in cancer prevention trials for the prevention of TNBC include poly(ADP-ribose) polymerase inhibitors, vitamin D, and rexinoids, both of which activate nuclear hormone receptors (the vitamin D and retinoid X receptors). This review discusses currently used breast cancer preventive drugs, and describes the progress of research striving to identify and develop more effective preventive agents for all forms of breast cancer. PMID:24069582

Phase II Study of Neoadjuvant Anthracycline-Based Regimens Combined With Nanoparticle Albumin-Bound Paclitaxel and Trastuzumab for Human Epidermal Growth Factor Receptor 2-Positive Operable Breast Cancer.

Science.gov (United States)

Tanaka, Satoru; Iwamoto, Mitsuhiko; Kimura, Kosei; Matsunami, Nobuki; Morishima, Hirotaka; Yoshidome, Katsuhide; Nomura, Takashi; Morimoto, Takashi; Yamamoto, Daigo; Tsubota, Yu; Kobayashi, Toshihiro; Uchiyama, Kazuhisa

2015-06-01

We treated patients with operable human epidermal growth factor receptor 2-positive breast cancer with neoadjuvant anthracycline regimens followed by nanoparticle albumin-bound paclitaxel plus trastuzumab. Of the 44 patients, 49% achieved a pathologic complete response (pCR). The pCR rate was 36% and 71% in the patients with estrogen receptor-positive and -negative cancer, respectively. Neoadjuvant therapy using this combination appears to be effective and safe. Introduction: Neoadjuvant chemotherapy plus trastuzumab. Neoadjuvant chemotherapy plus trastuzumab results in a 30% to 50% pathologic complete response (pCR) rate in human epidermal growth factor receptor 2 (HER2)-positive breast cancer and has been associated with improved therapeutic outcomes. Thus, the pCR rate can be useful in evaluating novel agents in this patient population. Nanoparticle albumin-bound (nab)-paclitaxel (PTX) can reduce the toxicity of PTX while maintaining its efficacy. The present study evaluated the activity and safety of nab-PTX as a neoadjuvant treatment of HER2(+) breast cancer. We treated patients with stage I to IIIA breast cancer using neoadjuvant epirubicin/cyclophosphamide (EC) or 5-fluorouracil/epirubicin/cyclophosphamide every 3 weeks (q3w) for 4 cycles, followed by nab-PTX (260 mg/m(2)) plus trastuzumab q3w for 4 cycles. The primary endpoint was the pCR rate. The secondary endpoints included the clinical response rate, disease-free survival, pathologic response rate (defined as pCR or minimal residual invasive disease only in the breast), breast-conserving surgery rate, and safety. Forty-six patients were enrolled. One patient met the exclusion criteria because of the coexistence of another malignant disease; therefore, we evaluated 45 patients in the entire study. One patient experienced rapid disease progression during EC therapy, leaving 44 patients evaluable for nab-PTX treatment. Of the 45 patients, 49% achieved a pCR. The pCR rate was 36% and 71% in those with

Kit for the preparation of 111In-labeled pertuzumab injection for imaging response of HER2-positive breast cancer to trastuzumab (Herceptin)

International Nuclear Information System (INIS)

Lam, Karen; Scollard, Deborah A.; Chan, Conrad; Levine, Mark N.; Reilly, Raymond M.

2015-01-01

We previously reported that 111 In-labeled pertuzumab imaged trastuzumab (Herceptin)-mediated changes in HER2 expression preclinically in breast cancer tumors. To advance 111 In-labeled pertuzumab to a Phase I/II clinical trial, a kit was designed for preparing this agent in a form suitable for human administration. Unit-dose kits containing pertuzumab modified with 2-(4-isothiocyanatobenzyl)-diethylenetriaminepentaacetic acid (BzDTPA) were prepared that labeled to high efficiency (>90%) with 111 In and met specifications for pharmaceutical quality. The kits were stable for 4 months and the final radiopharmaceutical was stable for 24 h. Imaging studies demonstrated high and specific uptake in HER2-positive tumors in mice using this clinical kit formulation. - Highlights: • Kits for preparing 111 In-BzDTPA-pertuzumab were prepared which met specifications for pharmaceutical quality. • The kits were stable for at least 4 months and the final radiopharmaceutical was stable for 24 h when stored at 2–8 °C. • High labeling efficiency (>90%) of the kits was achieved with 111 In. • 111 In-BzDTPA-pertuzumab exhibited stability in human plasma. • Biodistribution and microSPECT imaging showed specific targeting of HER2-positive tumors in mice using the kit formulation

Mediators and Moderators of a School-Based Cognitive-Behavioral Depression Prevention Program.

Science.gov (United States)

Duong, Mylien T; Kelly, Brynn M; Haaland, Wren L; Matsumiya, Brandon; Huey, Stanley J; McCarty, Carolyn A

2016-10-01

This study tested potential moderators and mediators of an indicated depression prevention program for middle school students, Positive Thoughts and Actions (PTA). Participants were 120 students randomly assigned to PTA, or a brief, individually administered supportive intervention (Individual Support Program, or ISP). Youths completed measures of depressive symptoms at baseline, post-intervention, and 12-month follow-up. Hierarchical regression was used to test three moderators-ethnic minority status, gender, and baseline depressive symptoms-and three mediators representing functional outcomes targeted by PTA-parent-child communication, attitude towards school, and health behavior. Ethnic minority status did not moderate PTA effects at post-intervention but did moderate PTA effects at 12-month follow-up. At 12 months, PTA appeared to be more effective for White participants than ethnic minority youth. Follow-up analyses suggested this moderation effect was due to the tendency of ethnic minority youth, especially those with fewer symptoms at baseline, to drop out by 12 months. Neither gender nor baseline depressive symptoms moderated the effects of PTA. Although PTA improved health behavior and attitudes toward school, there was no evidence that any of these functional outcomes measured mediated the impact of PTA on depressive symptoms. Future directions are discussed.

Reasons for Testing Mediation in the Absence of an Intervention Effect: A Research Imperative in Prevention and Intervention Research.

Science.gov (United States)

O'Rourke, Holly P; MacKinnon, David P

2018-03-01

Mediation models are used in prevention and intervention research to assess the mechanisms by which interventions influence outcomes. However, researchers may not investigate mediators in the absence of intervention effects on the primary outcome variable. There is emerging evidence that in some situations, tests of mediated effects can be statistically significant when the total intervention effect is not statistically significant. In addition, there are important conceptual and practical reasons for investigating mediation when the intervention effect is nonsignificant. This article discusses the conditions under which mediation may be present when an intervention effect does not have a statistically significant effect and why mediation should always be considered important. Mediation may be present in the following conditions: when the total and mediated effects are equal in value, when the mediated and direct effects have opposing signs, when mediated effects are equal across single and multiple-mediator models, and when specific mediated effects have opposing signs. Mediation should be conducted in every study because it provides the opportunity to test known and replicable mediators, to use mediators as an intervention manipulation check, and to address action and conceptual theory in intervention models. Mediators are central to intervention programs, and mediators should be investigated for the valuable information they provide about the success or failure of interventions.

Metastatic Extramammary Paget’s Disease of Scrotum Responds Completely to Single Agent Trastuzumab in a Hemodialysis Patient: Case Report, Molecular Profiling and Brief Review of the Literature

Directory of Open Access Journals (Sweden)

Peter Barth

2015-01-01

metastatic the prognosis of EMPD is poor and treatment options are limited. We report a case of a complete response to single agent trastuzumab in a hemodialysis patient with metastatic Her2/neu overexpressed EMPD of the scrotum. Molecular profiling of his case as well as 12 other EMPD and 8 mammary Paget disease (MPD cases was completed and revealed multiple biomarker aberrations. Overexpression of Her2 was frequently noted (30%–40% in both EMPD and MPD patients and when present can be effectively treated with Her2 targeted agents. Trastuzumab therapy can be safely utilized in a hemodialysis patient. In addition, multiple protein overexpression and loss were seen in EMPD including PD-1, PD-L1, PTEN, and AR as well as PIK3CA mutation. These findings may lead to possible therapeutic interventions targeting these pathways in a disease with few effective treatment options.

Prevention of iron- and copper-mediated DNA damage by catecholamine and amino acid neurotransmitters, L-DOPA, and curcumin: metal binding as a general antioxidant mechanism.

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García, Carla R; Angelé-Martínez, Carlos; Wilkes, Jenna A; Wang, Hsiao C; Battin, Erin E; Brumaghim, Julia L

2012-06-07

Concentrations of labile iron and copper are elevated in patients with neurological disorders, causing interest in metal-neurotransmitter interactions. Catecholamine (dopamine, epinephrine, and norepinephrine) and amino acid (glycine, glutamate, and 4-aminobutyrate) neurotransmitters are antioxidants also known to bind metal ions. To investigate the role of metal binding as an antioxidant mechanism for these neurotransmitters, L-dihydroxyphenylalanine (L-DOPA), and curcumin, their abilities to prevent iron- and copper-mediated DNA damage were quantified, cyclic voltammetry was used to determine the relationship between their redox potentials and DNA damage prevention, and UV-vis studies were conducted to determine iron and copper binding as well as iron oxidation rates. In contrast to amino acid neurotransmitters, catecholamine neurotransmitters, L-DOPA, and curcumin prevent significant iron-mediated DNA damage (IC(50) values of 3.2 to 18 μM) and are electrochemically active. However, glycine and glutamate are more effective at preventing copper-mediated DNA damage (IC(50) values of 35 and 12.9 μM, respectively) than L-DOPA, the only catecholamine to prevent this damage (IC(50) = 73 μM). This metal-mediated DNA damage prevention is directly related to the metal-binding behaviour of these compounds. When bound to iron or copper, the catecholamines, amino acids, and curcumin significantly shift iron oxidation potentials and stabilize Fe(3+) over Fe(2+) and Cu(2+) over Cu(+), a factor that may prevent metal redox cycling in vivo. These results highlight the disparate antioxidant activities of neurotransmitters, drugs, and supplements and highlight the importance of considering metal binding when identifying antioxidants to treat and prevent neurodegenerative disorders.

Epidermal growth factor prevents thallium(I)- and thallium(III)-mediated rat pheochromocytoma (PC12) cell apoptosis.

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Pino, María Teresa Luján; Marotte, Clarisa; Verstraeten, Sandra Viviana

2017-03-01

We have reported recently that the proliferation of PC12 cells exposed to micromolar concentrations of Tl(I) or Tl(III) has different outcomes, depending on the absence (EGF - cells) or the presence (EGF + cells) of epidermal growth factor (EGF) added to the media. In the current work, we investigated whether EGF supplementation could also modulate the extent of Tl(I)- or Tl(III)-induced cell apoptosis. Tl(I) and Tl(III) (25-100 μM) decreased cell viability in EGF - but not in EGF + cells. In EGF - cells, Tl(I) decreased mitochondrial potential, enhanced H 2 O 2 generation, and activated mitochondrial-dependent apoptosis. In addition, Tl(III) increased nitric oxide production and caused a misbalance between the anti- and pro-apoptotic members of Bcl-2 family. Tl(I) increased ERK1/2, JNK, p38, and p53 phosphorylation in EGF - cells. In these cells, Tl(III) did not affect ERK1/2 and JNK phosphorylation but increased p53 phosphorylation that was related to the promotion of cell senescence. In addition, this cation significantly activated p38 in both EGF - and EGF + cells. The specific inhibition of ERK1/2, JNK, p38, or p53 abolished Tl(I)-mediated EGF - cell apoptosis. Only when p38 activity was inhibited, Tl(III)-mediated apoptosis was prevented in EGF - and EGF + cells. Together, current results indicate that EGF partially prevents the noxious effects of Tl by preventing the sustained activation of MAPKs signaling cascade that lead cells to apoptosis and point to p38 as a key mediator of Tl(III)-induced PC12 cell apoptosis.

Exercise training prevents the attenuation of anesthetic pre-conditioning-mediated cardioprotection in diet-induced obese rats.

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Li, L; Meng, F; Li, N; Zhang, L; Wang, J; Wang, H; Li, D; Zhang, X; Dong, P; Chen, Y

2015-01-01

Obesity abolishes anesthetic pre-conditioning-induced cardioprotection due to impaired reactive oxygen species (ROS)-mediated adenosine monophosphate-activated protein kinase (AMPK) pathway, a consequence of increased basal myocardial oxidative stress. Exercise training has been shown to attenuate obesity-related oxidative stress. This study tests whether exercise training could normalize ROS-mediated AMPK pathway and prevent the attenuation of anesthetic pre-conditioning-induced cardioprotection in obesity. Male Sprague-Dawley rats were divided into lean rats fed with control diet and obese rats fed with high-fat diet. After 4 weeks of feeding, lean and obese rats were assigned to sedentary conditions or treadmill exercise for 8 weeks. There was no difference in infarct size between lean sedentary and obese sedentary rats after 25 min of myocardial ischemia followed by 120 min reperfusion. In lean rats, sevoflurane equally reduced infarct size in lean sedentary and lean exercise-trained rats. Molecular studies revealed that AMPK activity, endothelial nitric oxide synthase, and superoxide production measured at the end of ischemia in lean rats were increased in response to sevoflurane. In obese rats, sevoflurane increased the above molecular parameters and reduced infarct size in obese exercise-trained rats but not in obese sedentary rats. Additional study showed that obese exercise-trained rats had decreased basal oxidative stress than obese sedentary rats. The results indicate that exercise training can prevent the attenuation of anesthetic cardioprotection in obesity. Preventing the attenuation of this strategy may be associated with reduced basal oxidative stress and normalized ROS-mediated AMPK pathway, but the causal relationship remains to be determined. © 2014 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

Mediators of Effects of a Selective Family-Focused Violence Prevention Approach for Middle School Students

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2013-01-01

This study examined how parenting and family characteristics targeted in a selective prevention program mediated effects on key youth proximal outcomes related to violence perpetration. The selective intervention was evaluated within the context of a multi-site trial involving random assignment of 37 schools to four conditions: a universal intervention composed of a student social-cognitive curriculum and teacher training, a selective family-focused intervention with a subset of high-risk students, a condition combining these two interventions, and a no-intervention control condition. Two cohorts of sixth-grade students (total N=1,062) exhibiting high levels of aggression and social influence were the sample for this study. Analyses of pre-post change compared to controls using intent-to-treat analyses found no significant effects. However, estimates incorporating participation of those assigned to the intervention and predicted participation among those not assigned revealed significant positive effects on student aggression, use of aggressive strategies for conflict management, and parental estimation of student’s valuing of achievement. Findings also indicated intervention effects on two targeted family processes: discipline practices and family cohesion. Mediation analyses found evidence that change in these processes mediated effects on some outcomes, notably aggressive behavior and valuing of school achievement. Results support the notion that changing parenting practices and the quality of family relationships can prevent the escalation in aggression and maintain positive school engagement for high-risk youth. PMID:21932067

Increased infarct wall thickness by a bio-inert material is insufficient to prevent negative left ventricular remodeling after myocardial infarction.

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Aboli A Rane

Full Text Available Several injectable materials have been shown to preserve or improve cardiac function as well as prevent or slow left ventricular (LV remodeling post-myocardial infarction (MI. However, it is unclear as to whether it is the structural support or the bioactivity of these polymers that lead to beneficial effects. Herein, we examine how passive structural enhancement of the LV wall by an increase in wall thickness affects cardiac function post-MI using a bio-inert, non-degradable synthetic polymer in an effort to better understand the mechanisms by which injectable materials affect LV remodeling.Poly(ethylene glycol (PEG gels of storage modulus G' = 0.5±0.1 kPa were injected and polymerized in situ one week after total occlusion of the left coronary artery in female Sprague Dawley rats. The animals were imaged using magnetic resonance imaging (MRI at 7±1 day(s post-MI as a baseline and again post-injection 49±4 days after MI. Infarct wall thickness was statistically increased in PEG gel injected vs. control animals (p<0.01. However, animals in the polymer and control groups showed decreases in cardiac function in terms of end diastolic volume, end systolic volume and ejection fraction compared to baseline (p<0.01. The cellular response to injection was also similar in both groups.The results of this study demonstrate that passive structural reinforcement alone was insufficient to prevent post-MI remodeling, suggesting that bioactivity and/or cell infiltration due to degradation of injectable materials are likely playing a key role in the preservation of cardiac function, thus providing a deeper understanding of the influencing properties of biomaterials necessary to prevent post-MI negative remodeling.

Fractionated therapy of HER2-expressing breast and ovarian cancer xenografts in mice with targeted alpha emitting 227Th-DOTA-p-benzyl-trastuzumab.

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Helen Heyerdahl

Full Text Available BACKGROUND: The aim of this study was to investigate therapeutic efficacy and normal tissue toxicity of single dosage and fractionated targeted alpha therapy (TAT in mice with HER2-expressing breast and ovarian cancer xenografts using the low dose rate radioimmunoconjugate (227Th-DOTA-p-benzyl-trastuzumab. METHODOLOGY/PRINCIPAL FINDINGS: Nude mice carrying HER2-overexpressing subcutaneous SKOV-3 or SKBR-3 xenografts were treated with 1000 kBq/kg (227Th-trastuzumab as single injection or four injections of 250 kBq/kg with intervals of 4-5 days, 2 weeks, or 4 weeks. Control animals were treated with normal saline or unlabeled trastuzumab. In SKOV-3 xenografts tumor growth to 10-fold size was delayed (p<0.01 and survival with tumor diameter less than 16 mm was prolonged (p<0.05 in all TAT groups compared to the control groups. No statistically significant differences were seen among the treated groups. In SKBR-3 xenografts tumor growth to 10-fold size was delayed in the single injection and 4-5 days interval groups (p<0.001 and all except the 4 weeks interval TAT group showed improved survival to the control groups (p<0.05. Toxicity was assessed by blood cell counts, clinical chemistry measurements and body weight. Transient reduction in white blood cells was seen for the single injection and 4-5 days interval groups (p<0.05. No significant changes were seen in red blood cells, platelets or clinical chemistry parameters. Survival without life threatening loss of body weight was significantly prolonged in 4 weeks interval group compared to single injection group (p<0.05 for SKOV-3 animals and in 2 weeks interval group compared with the 4-5 days interval groups (p<0.05 for SKBR-3 animals. CONCLUSIONS/SIGNIFICANCE: The same concentration of radioactivity split into several fractions may improve toxicity of (227Th-radioimmunotherapy while the therapeutic effect is maintained. Thus, it might be possible to increase the cumulative absorbed radiation dose

Correlation between quantitative HER-2 protein expression and risk for brain metastases in HER-2+ advanced breast cancer patients receiving trastuzumab-containing therapy.

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Duchnowska, Renata; Biernat, Wojciech; Szostakiewicz, Barbara; Sperinde, Jeff; Piette, Fanny; Haddad, Mojgan; Paquet, Agnes; Lie, Yolanda; Czartoryska-Arłukowicz, Bogumiła; Wysocki, Piotr; Jankowski, Tomasz; Radecka, Barbara; Foszczynska-Kłoda, Małgorzata; Litwiniuk, Maria; Debska, Sylwia; Weidler, Jodi; Huang, Weidong; Buyse, Marc; Bates, Michael; Jassem, Jacek

2012-01-01

Patients with human epidermal growth factor receptor (HER)-2+ breast cancer are at particularly high risk for brain metastases; however, the biological basis is not fully understood. Using a novel HER-2 assay, we investigated the correlation between quantitative HER-2 expression in primary breast cancers and the time to brain metastasis (TTBM) in HER-2+ advanced breast cancer patients treated with trastuzumab. The study group included 142 consecutive patients who were administered trastuzumab-based therapy for HER-2+ metastatic breast cancer. HER-2/neu gene copy number was quantified as the HER-2/centromeric probe for chromosome 17 (CEP17) ratio by central laboratory fluorescence in situ hybridization (FISH). HER-2 protein was quantified as total HER-2 protein expression (H2T) by the HERmark® assay (Monogram Biosciences, Inc., South San Francisco, CA) in formalin-fixed, paraffin-embedded tumor samples. HER-2 variables were correlated with clinical features and TTBM was measured from the initiation of trastuzumab-containing therapy. A higher H2T level (continuous variable) was correlated with shorter TTBM, whereas HER-2 amplification by FISH and a continuous HER-2/CEP17 ratio were not predictive (p = .013, .28, and .25, respectively). In the subset of patients that was centrally determined by FISH to be HER-2+, an above-the-median H2T level was significantly associated with a shorter TTBM (hazard ratio, [HR], 2.4; p = .005), whereas this was not true for the median HER-2/CEP17 ratio by FISH (p = .4). Correlation between a continuous H2T level and TTBM was confirmed on multivariate analysis (HR, 3.3; p = .024). These data reveal a strong relationship between the quantitative HER-2 protein expression level and the risk for brain relapse in HER-2+ advanced breast cancer patients. Consequently, quantitative assessment of HER-2 protein expression may inform and facilitate refinements in therapeutic treatment strategies for selected subpopulations of patients in this

Trastuzumab emtansine in locally advanced or metastatic HER2 positive breast cancer; GENESIS-SEFH drug evaluation report

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Patricia Miranda Romero

2015-02-01

Full Text Available Trastuzumab emtansina (T-DM1 is an antibody-drug conjugate directed against the HER2 for the treatment of HER2+ mestastatic breast cancer (MBC, who has previously received trastuzumab plus a taxane. According to the results of the EMILIA trial versus lapatinib plus capecitabine T-DM1 shows an improvement in progression-free survival (PFS and the overall survival (OS. It has a favorable profile reducing the incidence of grade 3-4 adverse reactions such as hand-foot syndrome and diarrhea. On the contrary increases significantly severe thrombocytopenia; bleeding risk and liver function should also be monitored. With the current import price T-DM1 has a cost per QALY of over 120,000 €. The price of the drug for the Spanish NHS has not yet been established. Drug cost would be the key factor in the sensitivity analysis and a 50% reduction in the price of the drug would place it close to the threshold of cost-effectiveness usually considered in our midst. According to the budget impact model used, a maximum of 1,218 patients / year and the budgetary impact throughout the Spanish state would be at € 70,490,850. In the initial analysis no advantage was found for T-DM1 in those patients without visceral involvement. Although a subsequent re-analysis of the results of PFS in which the definition of visceral involvement was specified a significant benefit was shown in this subgroup. We believe that this approach introduces a high degree of uncertainty, which does not guarantee the benefit achieved for this subgroup of patients

Why did soft drink consumption decrease but screen time not? Mediating mechanisms in a school-based obesity prevention program

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Chin A Paw, M.J.M.; Singh, A.S.; Brug, J.; Mechelen, van, W.

2008-01-01

Abstract Objectives This paper aims to identify the mediating mechanisms of a school-based obesity prevention program (DOiT). Methods The DOiT-program was implemented in Dutch prevocational secondary schools and evaluated using a controlled, cluster-randomised trial (September 2003 to May 2004). We examined mediators of effects regarding (1) consumption of sugar containing beverages (SCB); (2) consumption of high caloric snacks; (3) screen-viewing behaviour; and (4) active commuting to school...

Pertuzumab Increases 17-AAG-Induced Degradation of ErbB2, and This Effect Is Further Increased by Combining Pertuzumab with Trastuzumab

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Hughes, Juliana Bentes; Rødland, Marianne Skeie; Hasmann, Max; Madshus, Inger Helene; Stang, Espen

2012-01-01

ErbB2 is an important oncogenic protein involved in carcinogenesis of, among others, breast, gastric, and ovarian carcinoma. Over-expression of ErbB2 is found in almost 20% of breast cancers, and this results in proliferative and anti-apoptotic signalling. ErbB2 is therefore an important treatment target. Antibodies recognizing full-length ErbB2 are clinically established, and drugs targeting the ErbB2 stabilizing heat shock protein 90 (Hsp90) are under clinical evaluation. We have investigated effects of the ErbB2-binding antibodies trastuzumab and pertuzumab alone and in combination, as well as the effect of the antibodies in combination with the Hsp90 inhibitor 17-AAG. Our results confirm the notion that combination of different ErbB2-binding antibodies more efficiently down-regulates ErbB2 than does one antibody in isolation. Additionally, our data demonstrate that ErbB2 is most efficiently down-regulated upon incubation with anti-ErbB2 antibodies in combination with Hsp90 inhibitors. The combination of anti-ErbB2 antibodies, and especially the combination of antibodies with 17-AAG, did also increase the inhibition of Akt activation of either agent, which could suggest an anti-proliferative effect. In such case, combining these agents could be beneficial in treatment of tumors not responding to trastuzumab only. PMID:24281706

Pertuzumab Increases 17-AAG-Induced Degradation of ErbB2, and This Effect Is Further Increased by Combining Pertuzumab with Trastuzumab

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Juliana Bentes Hughes

2012-06-01

Full Text Available ErbB2 is an important oncogenic protein involved in carcinogenesis of, among others, breast, gastric, and ovarian carcinoma. Over-expression of ErbB2 is found in almost 20% of breast cancers, and this results in proliferative and anti-apoptotic signalling. ErbB2 is therefore an important treatment target. Antibodies recognizing full-length ErbB2 are clinically established, and drugs targeting the ErbB2 stabilizing heat shock protein 90 (Hsp90 are under clinical evaluation. We have investigated effects of the ErbB2-binding antibodies trastuzumab and pertuzumab alone and in combination, as well as the effect of the antibodies in combination with the Hsp90 inhibitor 17-AAG. Our results confirm the notion that combination of different ErbB2-binding antibodies more efficiently down-regulates ErbB2 than does one antibody in isolation. Additionally, our data demonstrate that ErbB2 is most efficiently down-regulated upon incubation with anti-ErbB2 antibodies in combination with Hsp90 inhibitors. The combination of anti-ErbB2 antibodies, and especially the combination of antibodies with 17-AAG, did also increase the inhibition of Akt activation of either agent, which could suggest an anti-proliferative effect. In such case, combining these agents could be beneficial in treatment of tumors not responding to trastuzumab only.

Using therapeutic jurisprudence and preventive law to examine disputants' best interests in mediating cases about physicians' practices: a guide for medical regulators.

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Ferris, Lorraine E

2004-01-01

Therapeutic jurisprudence (TJ) and preventive law (PL) are used as two theoretical perspectives from which to examine the best interests of parties in mediation because of a dispute about a physician's practice. The focus is mediation provided by and/or for the medical regulator. The paper reviews the literature on TJ and PL, and their relationship to mediation, and demonstrates how medical regulators could benefit by working within a framework reflecting both these perspectives providing it does not involve an egregious matter. A TJ and PL framework would be of particular value in identifying cases for mediation and in evaluating resolutions to mediated disputes.

Prevention of airway hyperresponsiveness induced by left ventricular dysfunction in rats

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Petak Ferenc

2012-12-01

Full Text Available Abstract Background The effectiveness of strategies for treatment of the altered static lung volume and against the development of bronchial hyperreactivity (BHR following a left ventricular dysfunction (LVD induced by myocardial ischaemia was investigated in a rat model of sustained postcapillary pulmonary hypertension. Methods Airway resistance (Raw was identified from the respiratory system input impedance (Zrs in four groups of rats. End-expiratory lung volume (EELV was determined plethysmographically, and Zrs was measured under baseline conditions and following iv infusions of 2, 6 or 18 μg/kg/min methacholine. Sham surgery was performed in the rats in Group C, while the left interventricular coronary artery was ligated and Zrs and its changes following identical methacholine challenges were reassessed in the same rats 8 weeks later, during which no treatment was applied (Group I, or the animals were treated daily with a combination of an angiotensin enzyme converter inhibitor and a diuretic (enalapril and furosemide, Group IE, or a calcium channel blocker (diltiazem, Group ID. The equivalent dose of methacholine causing a 100% increase in Raw (ED50 was determined in each group. Diastolic pulmonary arterial pressure (PapD was assessed by introducing a catheter into the pulmonary artery. Results The sustained presence of a LVD increased PapD in all groups of rats, with variable but significant elevations in Groups I (p = 0.004, ID (p = 0.013 and IE (p = 0.006. A LVD for 8 weeks induced no changes in baseline Raw but elevated the EELV independently of the treatments. In Group I, BHR consistently developed following the LVD, with a significant decrease in ED50 from 10.0 ± 2.5 to 6.9 ± 2.5 μg/kg/min (p = 0.006. The BHR was completely abolished in both Groups ID and IE, with no changes in ED50 (9.5 ± 3.6 vs. 10.7 ± 4.7, p = 0.33 and 10.6 ± 2.1 vs. 9.8 ± 3.5 μg/kg/min p = 0.56, respectively

Gene transfection mediated by polyethyleneimine-polyethylene glycol nanocarrier prevents cisplatin-induced spiral ganglion cell damage

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Guan-gui Chen

2015-01-01

Full Text Available Polyethyleneimine-polyethylene glycol (PEI-PEG, a novel nanocarrier, has been used for transfection and gene therapy in a variety of cells. In our previous study, we successfully carried out PEI-PEG-mediated gene transfer in spiral ganglion cells. It remains unclear whether PEI-PEG could be used for gene therapy with X-linked inhibitor of apoptosis protein (XIAP in the inner ear. In the present study, we performed PEI-PEG-mediated XIAP gene transfection in the cochlea of Sprague-Dawley rats, via scala tympani fenestration, before daily cisplatin injections. Auditory brainstem reflex tests demonstrated the protective effects of XIAP gene therapy on auditory function. Immunohistochemical staining revealed XIAP protein expression in the cytoplasm of cells in the spiral ganglion, the organ of Corti and the stria vascularis. Reverse transcription-PCR detected high levels of XIAP mRNA expression in the cochlea. The present findings suggest that PEI-PEG nanocarrier-mediated XIAP gene transfection results in XIAP expression in the cochlea, prevents damage to cochlear spiral ganglion cells, and protects hearing.

{sup 18}F-PEG-biotin: Precursor (boroaryl-PEG-biotin) synthesis, {sup 18}F-labelling and an in-vitro assessment of its binding with Neutravidin{sup TM}-trastuzumab pre-treated cells

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Smith, Tim A.D., E-mail: t.smith@abdn.ac.uk [Biomedical Physics Building, John Mallard PET Unit, Aberdeen Biomedical Imaging Centre, School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD (United Kingdom); Simpson, Michael; Cheyne, Richard [Biomedical Physics Building, John Mallard PET Unit, Aberdeen Biomedical Imaging Centre, School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD (United Kingdom); School of Natural and Computing Sciences, University of Aberdeen, Aberdeen AB24 3UE (United Kingdom); Trembleau, Laurent [School of Natural and Computing Sciences, University of Aberdeen, Aberdeen AB24 3UE (United Kingdom)

2011-10-15

In terms of nuclear decay {sup 18}F is the most ideal PET nuclide but its short t{sub 1/2} precludes its use for directly labelling whole antibodies due to their long blood residence times. Pre-targeted imaging using affinity systems such as Neutravidin{sup TM}-biotin facilitates the application of short-lived nuclides by their attachment to biotin for imaging cell surface proteins targeted with Neutravidin{sup TM}-conjugated antibodies. Methods: Boroaryl functionalised biotin was prepared with a PEG linker and radiolabelled by incubation with {sup 18}F in acidified aqueous solution. Cells expressing high (SKBr3), medium (MDA-MB-453) and low (MDA-MB-468) levels of HER-2 were pre-incubated with Neutravidin{sup TM}-conjugated trastuzumab, washed, and then incubated with {sup 18}F-PEG-biotin. Results: The {sup 18}F-fluorination of boroaryl-PEG-biotin was much more efficient than reported for other versions of boroaryl-biotin. The novel {sup 18}F-PEG-biotin was demonstrated to bind to HER-2-expressing cells in-vitro pre-incubated with Neutravidin{sup TM}-conjugated trastuzumab. Conclusion: Biotin can be functionalised with boroaryl and readily {sup 18}F-radiolabelled in aqueous solution and will bind to cells pre-incubated with Neutravidin{sup TM}-antibody conjugates. - Highlights: > Boroaryl-biotin precursor is prepared. > Rapid {sup 18}F-fluorination is demonstrated. > HER-2 expressing breast cancer cells pre-treated with trastuzumab-Neutravidin{sup TM}. > {sup 18}F-PEG-biotin binding to pre-treated cells corresponds with HER-2 expression.

Magnetic Resonance Imaging (MRI of Intratumoral Voxel Heterogeneity as a Potential Response Biomarker: Assessment in a HER2+ Esophageal Adenocarcinoma Xenograft Following Trastuzumab and/or Cisplatin Therapy

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Connie Yip

2017-06-01

Full Text Available We evaluated magnetic resonance imaging (MRI voxel heterogeneity following trastuzumab and/or cisplatin in a HER2+ esophageal xenograft (OE19 as a potential response biomarker. OE19 xenografts treated with saline (controls, monotherapy, or combined cisplatin and trastuzumab underwent 9.4-T MRI. Tumor MRI parametric maps of T1 relaxation time (pre/post contrast, T2 relaxation time, T2* relaxation rate (R2*, and apparent diffusion coefficient obtained before (TIME0, after 24 hours (TIME1, and after 2 weeks of treatment (TIME2 were analyzed. Voxel histogram and fractal parameters (from the whole tumor, rim and center, and as a ratio of rim‐to‐center were derived. Tumors were stained for immunohistochemical markers of hypoxia (CA-IX, angiogenesis (CD34, and proliferation (Ki-67. Combination therapy reduced xenograft growth rate (relative change, ∆ +0.58 ± 0.43 versus controls, ∆ +4.1 ± 1.0; P = 0.008. More spatially homogeneous voxel distribution between the rim to center was noted after treatment for combination therapy versus controls, respectively, for contrast-enhanced T1 relaxation time (90th percentile: ratio 1.00 versus 0.88, P = 0.009, T2 relaxation time (mean: 1.00 versus 0.92, P = 0.006; median: 0.98 versus 0.91, P = 0.006; 75th percentile: 1.02 versus 0.94, P = 0.007, and R2* (10th percentile: 0.99 versus 1.26, P = 0.003. We found that combination and trastuzumab monotherapy reduced MRI spatial heterogeneity and growth rate compared to the control or cisplatin groups, the former providing adjunctive tumor response information.

CDC25A Protein Stability Represents a Previously Unrecognized Target of HER2 Signaling in Human Breast Cancer: Implication for a Potential Clinical Relevance in Trastuzumab Treatment

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Emanuela Brunetto

2013-06-01

Full Text Available The CDC25A-CDK2 pathway has been proposed as critical for the oncogenic action of human epidermal growth factor receptor 2 (HER2 in mammary epithelial cells. In particular, transgenic expression of CDC25A cooperates with HER2 in promoting mammary tumors, whereas CDC25A hemizygous loss attenuates the HER2-induced tumorigenesis penetrance. On the basis of this evidence of a synergism between HER2 and the cell cycle regulator CDC25A in a mouse model of mammary tumorigenesis, we investigated the role of CDC25A in human HER2-positive breast cancer and its possible implications in therapeutic response. HER2 status and CDC25A expression were assessed in 313 breast cancer patients and we found statistically significant correlation between HER2 and CDC25A (P = .007. Moreover, an HER2-positive breast cancer subgroup with high levels of CDC25A and very aggressive phenotype was identified (P = .005. Importantly, our in vitro studies on breast cancer cell lines showed that the HER2 inhibitor efficacy on cell growth and viability relied also on CDC25A expression and that such inhibition induces CDC25A down-regulation through phosphatidylinositol 3-kinase/protein kinase B pathway and DNA damage response activation. In line with this observation, we found a statistical significant association between CDC25A overexpression and trastuzumab-combined therapy response rate in two different HER2-positive cohorts of trastuzumab-treated patients in either metastatic or neoadjuvant setting (P = .018 for the metastatic cohort and P = .021 for the neoadjuvant cohort. Our findings highlight a link between HER2 and CDC25A that positively modulates HER2- targeted therapy response, suggesting that, in HER2-positive breast cancer patients, CDC25A overexpression affects trastuzumab sensitivity.

"Heart rate-dependent" electrocardiographic diagnosis of left ventricular hypertrophy.

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Madias, John E

2013-05-01

A case is presented revealing the common phenomenon of heart rate-dependent diagnosis of electrocardiographic (ECG) diagnosis of left ventricular hypertrophy (LVH), which consists of satisfaction of LVH criteria only at faster rates whereas ECGs with a slow heart rate do not satisfy such criteria. The mechanism of the phenomenon has been attributed to the tachycardia-mediated underfilling of the left ventricle bringing the electrical "centroid" of the heart closer to the recording electrodes, which results in augmentation of the amplitude of QRS complexes, particularly in leads V2-V4. ©2012, The Author. Journal compilation ©2012 Wiley Periodicals, Inc.

Mono centric evaluation of the skin and cardiac toxicities of the concomitant administration of trastuzumab and radiotherapy; Evaluation monocentrique de la tolerance de l'association concomitante de trastuzumab et de radiotherapie

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Kirova, Y.M.; Caussa, L.; Dendale, R.; Campana, F.; Tournat, H.; Fourquet, A.; Bollet, M.A. [Institut Curie, Dept. d' Oncologie-Radiotherapie, 75 - Paris (France); Granger, B.; Savignoni, A. [Institut Curie, Service de Bio-Statistique, 75 - Paris (France); Pierga, J.Y. [Institut Curie, Dept. d' Oncologie-Medicale, 75 - Paris (France)

2009-07-15

Purpose Prospective mono centric study of the skin and heart tolerance of a concurrent administration of trastuzumab (T) and radiotherapy (R.T.) for breast cancer (B.C.). Patients and methods From February 2004 to January 2007, 57 patients (pts), were treated by a concomitant administration of T and normo-fractionated R.T. of either whole breast ({+-} boost) or chest. The perfusion of T started either with or after chemotherapy (CT). Left ventricular ejection fractions (L.E.V.F.), assessed at baseline, before start of R.T., after completion of R.T. and then every four to six months with either echocardiography or multiple gated acquisition scanning, were considered normal if greater or equal to 50% or stated so by the cardiologist. Inclusion criteria included a normal L.V.E.F. at baseline. Skin toxicity was evaluated using C.T.C.A.E., V.3 ( for common terminology criteria for adverse events, version 3.0). Median age was 49 years (25-80). CT with anthracycline was administered in 84% (total dose 300 mg/m2). All but one patient (treated weekly) received T every three weeks (8 mg/kg followed by 6 mg/kg) for a median duration of 12 months (6-33). The internal mammary chain was irradiated in 88% of cases. Median follow-up for L.V.E.F. assessment was 13 months (2-33). Results L.V.E.F. at pre-R.T. were normal in 54 pts (100%, three Missing Data [M.D.]), at post-R.T. in 56 pts (98%, no M.D.) and at last follow-up in 53 pts (95%, one M.D.). There were two grade 0, 44 grade I and 11 grade II skin reactions. For the 27 patients with a skin toxicity assessment after six months, late skin toxicity was grade 0 in 22 pts, grade 1 in four, grade 2 in one. Conclusion Provided that the technique is adapted, the acute skin and heart toxicities of the concomitant administration of T-R.T. appeared satisfactory. More patients and longer follow-up are still mandatory. (authors)

Maintenance of Epithelial Stem Cells by Cbl Proteins

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2012-09-01

delivery of cytotoxic drugs conjugated to Trastuzumab. Trastuzumab-MCC-DM1 (T- DM1; DM1 is an anti-mitotic drug based on the Vinca alkaloid Maytansine) is...GL. HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1alpha (HIF-1alpha) synthesis : Novel mechanism for HIF-1-mediated vascular...factor. THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 287, NO. 35, pp. 29442–29456, August 24, 2012 © 2012 by The American Society for Biochemistry and

Prevention of Cerebral Embolism Progression by Emergency Surgery of the Left Atrial Myxoma

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Syuichi Tetsuka

2015-01-01

Full Text Available A 21-year-old woman developed left hemiparesis during work and was hospitalized. Her National Institutes of Health Stroke Scale score was 4. Hyperintense areas in the left basal ganglia, corona radiata, and cortex of the temporal lobe were found by brain diffusion-weighted magnetic resonance imaging, indicating acute cerebral infarction. Echocardiography showed a giant mass of diameter 7 × 4 cm in the left atrium. Therefore, she was diagnosed with cerebral embolism due to a left atrial myxoma. Currently, thrombolytic therapy may continue to be effective because the embolic source may be composed of tumor tissue itself. In case of atrial myxoma, we considered that the use of tPA as emergency treatment in all patients with infarction by atrial myxoma may be questioned. Thus, cardiac tumor extraction was performed the next day after hospitalization without thrombolytic therapy. The excised myxoma measured 7 × 6 × 4 cm. The patient recovered and her neurological symptoms also improved. Furthermore, her National Institutes of Health Stroke Scale score improved to 0. Thirteen days after admission, the patient was discharged from our hospital. Cardiac myxoma is often associated with a high risk of embolic episodes, which emphasizes the need for prompt surgical excision as soon as the diagnosis is confirmed.

Docosahexaenoic Acid Modulates a HER2-Associated Lipogenic Phenotype, Induces Apoptosis, and Increases Trastuzumab Action in HER2-Overexpressing Breast Carcinoma Cells

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Ravacci, Graziela Rosa; Brentani, Maria Mitzi; Tortelli, Tharcisio Citrângulo; Torrinhas, Raquel Suzana M. M.; Santos, Jéssica Reis; Logullo, Angela Flávia; Waitzberg, Dan Linetzky

2015-01-01

In breast cancer, lipid metabolic alterations have been recognized as potential oncogenic stimuli that may promote malignancy. To investigate whether the oncogenic nature of lipogenesis closely depends on the overexpression of HER2 protooncogene, the normal breast cell line, HB4a, was transfected with HER2 cDNA to obtain HER2-overexpressing HB4aC5.2 cells. Both cell lines were treated with trastuzumab and docosahexaenoic acid. HER2 overexpression was accompanied by an increase in the expressi...

Effect of trastuzumab interchain disulfide bond cleavage on Fcγ receptor binding and antibody-dependent tumour cell phagocytosis.

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Suzuki, Mami; Yamanoi, Ayaka; Machino, Yusuke; Ootsubo, Michiko; Izawa, Ken-ichi; Kohroki, Junya; Masuho, Yasuhiko

2016-01-01

The Fc domain of human IgG1 binds to Fcγ receptors (FcγRs) to induce effector functions such as phagocytosis. There are four interchain disulfide bonds between the H and L chains. In this study, the disulfide bonds within the IgG1 trastuzumab (TRA), which is specific for HER2, were cleaved by mild S-sulfonation or by mild reduction followed by S-alkylation with three different reagents. The cleavage did not change the binding activities of TRA to HER2-bearing SK-BR-3 cells. The binding activities of TRA to FcγRIIA and FcγRIIB were greatly enhanced by modification with mild reduction and S-alkylation with ICH2CONH2 or N-(4-aminophenyl) maleimide, while the binding activities of TRA to FcγRI and FcγRIIIA were decreased by any of the four modifications. However, the interchain disulfide bond cleavage by the different modifications did not change the antibody-dependent cell-mediated phagocytosis (ADCP) of SK-BR-3 cells by activated THP-1 cells. The order of FcγR expression levels on the THP-1 cells was FcγRII > FcγRI > FcγRIII and ADCP was inhibited by blocking antibodies against FcγRI and FcγRII. These results imply that the effect of the interchain disulfide bond cleavage on FcγRs binding and ADCP is dependent on modifications of the cysteine residues and the FcγR isotypes. © The Authors 2015. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.

Basis and Statistical Design of the Passive HIV-1 Antibody Mediated Prevention (AMP) Test-of-Concept Efficacy Trials.

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Gilbert, Peter B; Juraska, Michal; deCamp, Allan C; Karuna, Shelly; Edupuganti, Srilatha; Mgodi, Nyaradzo; Donnell, Deborah J; Bentley, Carter; Sista, Nirupama; Andrew, Philip; Isaacs, Abby; Huang, Yunda; Zhang, Lily; Capparelli, Edmund; Kochar, Nidhi; Wang, Jing; Eshleman, Susan H; Mayer, Kenneth H; Magaret, Craig A; Hural, John; Kublin, James G; Gray, Glenda; Montefiori, David C; Gomez, Margarita M; Burns, David N; McElrath, Julie; Ledgerwood, Julie; Graham, Barney S; Mascola, John R; Cohen, Myron; Corey, Lawrence

2017-01-01

Anti-HIV-1 broadly neutralizing antibodies (bnAbs) have been developed as potential agents for prevention of HIV-1 infection. The HIV Vaccine Trials Network and the HIV Prevention Trials Network are conducting the Antibody Mediated Prevention (AMP) trials to assess whether, and how, intravenous infusion of the anti-CD4 binding site bnAb, VRC01, prevents HIV-1 infection. These are the first test-of-concept studies to assess HIV-1 bnAb prevention efficacy in humans. The AMP trials are two parallel phase 2b HIV-1 prevention efficacy trials conducted in two cohorts: 2700 HIV-uninfected men and transgender persons who have sex with men in the United States, Peru, Brazil, and Switzerland; and 1500 HIV-uninfected sexually active women in seven countries in sub-Saharan Africa. Participants are randomized 1:1:1 to receive an intravenous infusion of 10 mg/kg VRC01, 30 mg/kg VRC01, or a control preparation every 8 weeks for a total of 10 infusions. Each trial is designed (1) to assess overall prevention efficacy (PE) pooled over the two VRC01 dose groups vs. control and (2) to assess VRC01 dose and laboratory markers as correlates of protection (CoPs) against overall and genotype- and phenotype-specific infection. Each AMP trial is designed to have 90% power to detect PE > 0% if PE is ≥ 60%. The AMP trials are also designed to identify VRC01 properties (i.e., concentration and effector functions) that correlate with protection and to provide insight into mechanistic CoPs. CoPs are assessed using data from breakthrough HIV-1 infections, including genetic sequences and sensitivities to VRC01-mediated neutralization and Fc effector functions. The AMP trials test whether VRC01 can prevent HIV-1 infection in two study populations. If affirmative, they will provide information for estimating the optimal dosage of VRC01 (or subsequent derivatives) and identify threshold levels of neutralization and Fc effector functions associated with high-level protection, setting a benchmark

Causal mediation analysis with multiple mediators in the presence of treatment noncompliance.

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Park, Soojin; Kürüm, Esra

2018-05-20

Randomized experiments are often complicated because of treatment noncompliance. This challenge prevents researchers from identifying the mediated portion of the intention-to-treated (ITT) effect, which is the effect of the assigned treatment that is attributed to a mediator. One solution suggests identifying the mediated ITT effect on the basis of the average causal mediation effect among compliers when there is a single mediator. However, considering the complex nature of the mediating mechanisms, it is natural to assume that there are multiple variables that mediate through the causal path. Motivated by an empirical analysis of a data set collected in a randomized interventional study, we develop a method to estimate the mediated portion of the ITT effect when both multiple dependent mediators and treatment noncompliance exist. This enables researchers to make an informed decision on how to strengthen the intervention effect by identifying relevant mediators despite treatment noncompliance. We propose a nonparametric estimation procedure and provide a sensitivity analysis for key assumptions. We conduct a Monte Carlo simulation study to assess the finite sample performance of the proposed approach. The proposed method is illustrated by an empirical analysis of JOBS II data, in which a job training intervention was used to prevent mental health deterioration among unemployed individuals. Copyright © 2018 John Wiley & Sons, Ltd.

How did it work? Who did it work for? Mediation in the context of a moderated prevention effect for children of divorce.

Science.gov (United States)

Tein, Jenn-Yun; Sandler, Irwin N; MacKinnon, David P; Wolchik, Sharlene A

2004-08-01

This study presents a reanalysis of data from an effective preventive intervention for children from divorced families to test mediation of program effects. The study involved 157 children, age 9-12 years, who were randomly assigned to a parenting program or a literature control condition. Program effects to reduce posttest internalizing problems were mediated through improvement in mother-child relationship quality. Program effects to reduce externalizing problems at posttest and 6 months were mediated through improvement in posttest parental methods of discipline and mother-child relationship quality. The study also describes a new methodology to test mediation of Program x Baseline Status interactions. Analyses demonstrate mediation effects primarily for children who began the program with poorer scores on discipline, mother-child relationship quality, and externalizing problems.

Tempol improves lipid profile and prevents left ventricular hypertrophy in LDL receptor gene knockout (LDLr-/-) mice on a high-fat diet.

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Viana Gonçalves, Igor Cândido; Cerdeira, Cláudio Daniel; Poletti Camara, Eduardo; Dias Garcia, José Antônio; Ribeiro Pereira Lima Brigagão, Maísa; Bessa Veloso Silva, Roberta; Bitencourt Dos Santos, Gérsika

2017-09-01

Dyslipidemia is associated with increased risk of cardiovascular disease and atherosclerosis, and hence with high morbidity and mortality. This study investigated the effects of the nitroxide 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (Tempol) on lipid profile and cardiac morphology in low-density lipoprotein (LDL) receptor gene knockout (LDLr-/-) mice. Male LDLr-/- mice (three months old, approximately 22 g weight) were divided into the following groups: controls, including (1) standard chow (SC, n=8) and (2) high-fat diet (HFD, n=8); and treatment, including (3) standard chow + Tempol (SC+T, n=8) (30 mg/kg administered by gavage, once daily) and (4) high-fat diet + Tempol (HFD+T, n=8) (30 mg/kg). After 30 days of the diet/treatment, whole blood was collected for analysis of biochemical parameters (total cholesterol, triglycerides [TG], high-density lipoprotein [HDL], LDL, and very low-density lipoprotein [VLDL]). The heart was removed through thoracotomy and histological analysis of the left ventricle was performed. A significant increase in TG, LDL, and VLDL and marked left ventricular hypertrophy (LVH) were demonstrated in the HFD group relative to the SC group (p<0.05), while Tempol treatment (HFD+T group) significantly (p<0.05) prevented increases in the levels of these lipid profile markers and attenuated LVH compared with the HFD group. In this study, Tempol showed potential for the prevention of events related to serious diseases of the cardiovascular system. Copyright © 2017 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.

Examination of the Relationship between Psychosocial Mediators and Intervention Effects in It’s Your Game: An Effective HIV/STI/Pregnancy Prevention Intervention for Middle School Students

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Elizabeth Baumler

2012-01-01

Full Text Available A set of mediation analyses were carried out in this study using data from It’s Your Game. . .Keep It Real (IYG, a successful HIV/STI/pregnancy prevention program. The IYG study evaluated a skill and normbased. HIV/STI/pregnancy prevention program that was implemented from 2004 to 2007 among 907 urban low-income middle school youth in Houston, TX, USA. Analyses were carried out to investigate the degree to which a set of proposed psychosocial measures of behavioral knowledge, perceived self-efficacy, behavioral, and normative beliefs, and perceived risky situations, all targeted by the intervention, mediated the intervention’s effectiveness in reducing initiation of sex. The mediation process was assessed by examining the significance and size of the estimated effects from the mediating pathways. The findings from this study provide evidence that the majority of the psychosocial mediators targeted by the IYG intervention are indeed related to the desired behavior and provide evidence that the conceptual theory underlying the targeted psychosocial mediators in the intervention is appropriate. Two of the psychosocial mediators significantly mediated the intervention effect, knowledge of STI signs and symptoms and refusal self-efficacy. This study suggests that the underlying causal mechanisms of action of these interventions are complex and warrant further analyses.

Isolated left-sided partial anomalous pulmonary venous connection in a child.

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Onan, İsmihan Selen; Sen, Onur; Gökalp, Selman; Onan, Burak

2017-09-01

Isolated left-sided partial anomalous pulmonary venous connection with intact interatrial septum is a rare diagnosis in childhood. In these cases, a vertical vein drains the left upper pulmonary lobe into the brachiocephalic vein and finally to the right atrium. Surgical treatment is performed to prevent right ventricular failure and pulmonary artery disease in advanced age. In this report, the rare entity of isolated left-sided anomalous pulmonary venous connection in a 14-year-old girl and successful minimally invasive surgery without cardiopulmonary bypass are described.

Modulation of left primary motor cortex excitability after bimanual training and intermittent theta burst stimulation to left dorsal premotor cortex.

Science.gov (United States)

Neva, Jason L; Vesia, Michael; Singh, Amaya M; Staines, W Richard

2014-03-15

Bimanual visuomotor movement training (BMT) enhances the excitability of human preparatory premotor and primary motor (M1) cortices compared to unimanual movement. This occurs when BMT involves mirror symmetrical movements of both upper-limbs (in-phase) but not with non-symmetrical movements (anti-phase). The neural mechanisms mediating the effect of BMT is unclear, but may involve interhemispheric connections between homologous M1 representations as well as the dorsal premotor cortices (PMd). The purpose of this study is to assess how intermittent theta burst stimulation (iTBS) of the left PMd affects left M1 excitability, and the possible combined effects of iTBS to left PMd applied before a single session of BMT. Left M1 excitability was quantified using transcranial magnetic stimulation (TMS) in terms of both the amplitudes and spatial extent of motor evoked potentials (MEPs) for the extensor carpi radialis (ECR) before and multiple time points following (1) BMT, (2) iTBS to left PMd or (3) iTBS to left PMd and BMT. Although there was not a greater increase in either specific measure of M1 excitability due to the combination of the interventions, iTBS applied before BMT showed that both the spatial extent and global MEP amplitude for the ECR became larger in parallel, whereas the spatial extent was enhanced with BMT alone and global MEP amplitude was enhanced with iTBS to left PMd alone. These results suggest that the modulation of rapid functional M1 excitability associated with BMT and iTBS of the left PMd could operate under related early markers of neuro-plastic mechanisms, which may be expressed in concurrent and distinct patterns of M1 excitability. Critically, this work may guide rehabilitation training and stimulation techniques that modulate cortical excitability after brain injury. Copyright © 2013 Elsevier B.V. All rights reserved.

In-utero treatment of hypoplastic left heart syndrome

DEFF Research Database (Denmark)

Lytzen, Rebekka; Helvind, Morten; Jørgensen, Finn Stener

2015-01-01

In-utero treatment of fetal aortic stenosis (AS) may prevent hypoplastic left heart syndrome. A girl was diagnosed prenatally with severe AS and was referred to the Women's and Children's Hospital in Linz, Austria, where she underwent an intrauterine valvuloplasty of the aortic valve. Postnatally...

Lapatinib in patients with metastatic breast cancer following initial treatment with trastuzumab: an economic analysis from the Brazilian public health care perspective

Directory of Open Access Journals (Sweden)

Machado M

2012-11-01

Full Text Available Marcio Machado,1 Thomas R Einarson21GlaxoSmithKline Brasil Ltd, Rio de Janeiro, Brazil; 2Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, CanadaObjective: To evaluate, from the perspective of the Brazilian public health care system, the cost-effectiveness of lapatinib plus capecitabine (LAP/CAP versus capecitabine alone (CAP or trastuzumab plus capecitabine (TRAST/CAP in the treatment of women with human epidermal growth factor receptor-2-positive metastatic breast cancer previously treated with trastuzumab.Methods: An economic model was developed to compare costs and clinical outcomes over a 5-year time horizon. Both costs and outcomes were discounted at a 5% rate, in accordance with Brazilian pharmacoeconomic guidelines. Clinical inputs were determined using indirect treatment comparisons. Costs were derived from public reimbursement databases and reported in 2010 Brazilian real (R$1 = USD$0.52. Clinical outcomes included progression-free survival years (PFYs, life-years (LYs and quality-adjusted life-years (QALYs. The economic outcome was the incremental cost per LY, PFY, or QALY gained. The impact of variations in individual inputs (eg, drug cost, drug effectiveness was examined using one-way sensitivity analyses. Overall model robustness was tested using probabilistic sensitivity analyses, varying the ranges of all input parameters within their standard distributions.Results: Expected cost per patient was R$41,195 for CAP, R$95,256 for LAP/CAP, and R$113,686 for TRAST/CAP. Respective LYs were 1.406, 1.695, and 1.465; PFYs were 0.473, 0.711, and 0.612; and QALYS were 0.769, 0.958, and 0.827. LAP/CAP dominated TRAST/CAP for all outcomes. Incremental cost-effectiveness ratios of LAP/CAP over CAP were R$186,563 for LYs, R$226,403 for PFYs, and R$284,864 for QALYs. Results remained unchanged in one-way sensitivity analyses. In probabilistic analyses, LAP/CAP was dominant over TRAST/CAP in 93.5% of simulations.Conclusion: LAP

ROS-mediated PARP activity undermines mitochondrial function after permeability transition pore opening during myocardial ischemia-reperfusion.

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Schriewer, Jacqueline M; Peek, Clara Bien; Bass, Joseph; Schumacker, Paul T

2013-04-18

Ischemia-reperfusion (I/R) studies have implicated oxidant stress, the mitochondrial permeability transition pore (mPTP), and poly(ADP-ribose) polymerase (PARP) as contributing factors in myocardial cell death. However, the interdependence of these factors in the intact, blood-perfused heart is not known. We therefore wanted to determine whether oxidant stress, mPTP opening, and PARP activity contribute to the same death pathway after myocardial I/R. A murine left anterior descending coronary artery (LAD) occlusion (30 minutes) and release (1 to 4 hours) model was employed. Experimental groups included controls and antioxidant-treated, mPTP-inhibited, or PARP-inhibited hearts. Antioxidant treatment prevented oxidative damage, mPTP opening, ATP depletion, and PARP activity, placing oxidant stress as the proximal death trigger. Genetic deletion of cyclophilin D (CypD(-/-)) prevented loss of total NAD(+) and PARP activity, and mPTP-mediated loss of mitochondrial function. Control hearts showed progressive mitochondrial depolarization and loss of ATP from 1.5 to 4 hours of reperfusion, but not outer mitochondrial membrane rupture. Neither genetic deletion of PARP-1 nor its pharmacological inhibition prevented the initial mPTP-mediated depolarization or loss of ATP, but PARP ablation did allow mitochondrial recovery by 4 hours of reperfusion. These results indicate that oxidant stress, the mPTP, and PARP activity contribute to a single death pathway after I/R in the heart. PARP activation undermines cell survival by preventing mitochondrial recovery after mPTP opening early in reperfusion. This suggests that PARP-mediated prolongation of mitochondrial depolarization contributes significantly to cell death via an energetic crisis rather than by mitochondrial outer membrane rupture.

Analysis of Regional Timelines To Set Up a Global Phase III Clinical Trial in Breast Cancer: the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization Experience

OpenAIRE

Metzger-Filho, Otto; Azambuja, Evandro de; Bradbury, Ian; Saini, Kamal S.; Bines, Jose; Simon, Sergio D. [UNIFESP; Van Dooren, Veerle; Aktan, Gursel; Pritchard, Kathleen I.; Wolff, Antonio C.; Smith, Ian; Jackisch, Christian; Lang, Istvan; Untch, Michael; Boyle, Frances

2013-01-01

Purpose. This study measured the time taken for setting up the different facets of Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (ALTTO), an international phase III study being conducted in 44 participating countries.Methods. Time to regulatory authority (RA) approval, time to ethics committee/institutional review board (EC/IRB) approval, time from study approval by EC/IRB to first randomized patient, and time from first to last randomized patient were prospectively collected i...

Mediator phosphorylation prevents stress response transcription during non-stress conditions.

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Miller, Christian; Matic, Ivan; Maier, Kerstin C; Schwalb, Björn; Roether, Susanne; Strässer, Katja; Tresch, Achim; Mann, Matthias; Cramer, Patrick

2012-12-28

The multiprotein complex Mediator is a coactivator of RNA polymerase (Pol) II transcription that is required for the regulated expression of protein-coding genes. Mediator serves as an end point of signaling pathways and regulates Pol II transcription, but the mechanisms it uses are not well understood. Here, we used mass spectrometry and dynamic transcriptome analysis to investigate a functional role of Mediator phosphorylation in gene expression. Affinity purification and mass spectrometry revealed that Mediator from the yeast Saccharomyces cerevisiae is phosphorylated at multiple sites of 17 of its 25 subunits. Mediator phosphorylation levels change upon an external stimulus set by exposure of cells to high salt concentrations. Phosphorylated sites in the Mediator tail subunit Med15 are required for suppression of stress-induced changes in gene expression under non-stress conditions. Thus dynamic and differential Mediator phosphorylation contributes to gene regulation in eukaryotic cells.

Cardiotoxicity of novel HER2-targeted therapies.

Science.gov (United States)

Sendur, Mehmet A N; Aksoy, Sercan; Altundag, Kadri

2013-08-01

-DM1 group experienced reduction of left ventricular ejection fraction (LVEF) and grade III LVEF reduction developed only in one patient (0.2%) in the T-DM1 group compared to the lapatinib plus capacitabine group. In phase I-II trials with neratinib no cardiotoxicity was reported whereas cardiotoxicity was seen between 0-5.3% with afatinib treatment. Although cardiac toxicity has been reported as an adverse event for novel HER2-targeted therapies, cardiac dysfunction rate of the novel HER2-targeted therapies is significantly lower than the trastuzumab and combination of these agents with trastuzumab did not significantly increase the cardiac adverse events.

Deep Vein Thrombosis of the Left Leg: A Case of May-Thurner Syndrome

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Jiten Desai

2018-02-01

Full Text Available A 56-year-old woman presented with gradually worsening shortness of breath associated with dull left leg pain over 5 days. She denied any recent travel, recent surgeries or immobilization. CT pulmonary angiography and CT venography revealed multiple bilateral pulmonary emboli and extensive left pelvic and left lower extremity deep vein thromboses. Contrast-enhanced CT showed that the right common iliac artery crossed the left common iliac vein and compressed it externally, indicative of May–Thurner syndrome. Catheter-directed thrombolysis of the left lower extremity was performed and heparin infusion was started. The patient also underwent left iliac vein balloon angioplasty with stenting and infra-renal inferior vena cava filter placement via the jugular approach to prevent further embolization.

CT findings of a displaced left upper division bronchus in adults: Its importance for performing safe left pulmonary surgery

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Oshiro, Yasuji, E-mail: oshiro4211@yahoo.co.jp [Department of Radiology, National Hospital Organization Okinawa Hospital, 20-14 Ganeko 3-chome, Ginowan city, Okinawa 901-2214 (Japan); Murayama, Sadayuki [Department of Radiology, University of the Ryukus School of Medicine, 207 Uehara, Nishihara-cho, Okinawa 903-0215 (Japan); Ohta, Morio [Department of Surgery, Nakagami Hospital, 6-25-5 Chibana, Okinawa-city, Okinawa 904-2195 (Japan); Teruya, Takao [Second Department of Surgery, University of the Ryukus School of Medicine, 207 Uehara, Nishihara-cho, Okinawa 903-0215 (Japan)

2013-08-15

Purpose: The aim of this study was to describe the CT findings of a displaced left upper division bronchus (DLUDB) in adults. Materials and methods: Ten patients with DLUDB were identified. The following CT features were assessed: origin of the DLUDB; distance between the origin of the DLUDB and the origin of the left upper lobe (LUL) bronchus; height of the origin of the DLUDB against the left pulmonary artery (LPA); difference of the main bronchial length; ventilated segment; course of the left pulmonary artery against the DLUDB; and presence of an accessory fissure or other anomalies. Results: DLUDB arose from the posterolateral or lateral aspect of the left main bronchus immediately proximal to the origin of the LUL bronchus. It tended to course along the posterior wall of the LPA and to ventilate the apicoposterior segment with or without the anterior segment. The LPA passed between the displaced bronchus and the lingular bronchus. The origin of the DLUDB was located lower than the inferior wall of the proximal LPA in 6 patients. The accessory fissure between the associated segment and remaining part of the LUL and right tracheal bronchus coexisted in 7 and 3 patients respectively. Conclusion: DLUDB has characteristic findings on CT. Radiologists should be aware of this entity and inform the surgeon as it can prevent serious complications in a patient who may undergo lobectomy of the left lung.

CT findings of a displaced left upper division bronchus in adults: Its importance for performing safe left pulmonary surgery

International Nuclear Information System (INIS)

Oshiro, Yasuji; Murayama, Sadayuki; Ohta, Morio; Teruya, Takao

2013-01-01

Purpose: The aim of this study was to describe the CT findings of a displaced left upper division bronchus (DLUDB) in adults. Materials and methods: Ten patients with DLUDB were identified. The following CT features were assessed: origin of the DLUDB; distance between the origin of the DLUDB and the origin of the left upper lobe (LUL) bronchus; height of the origin of the DLUDB against the left pulmonary artery (LPA); difference of the main bronchial length; ventilated segment; course of the left pulmonary artery against the DLUDB; and presence of an accessory fissure or other anomalies. Results: DLUDB arose from the posterolateral or lateral aspect of the left main bronchus immediately proximal to the origin of the LUL bronchus. It tended to course along the posterior wall of the LPA and to ventilate the apicoposterior segment with or without the anterior segment. The LPA passed between the displaced bronchus and the lingular bronchus. The origin of the DLUDB was located lower than the inferior wall of the proximal LPA in 6 patients. The accessory fissure between the associated segment and remaining part of the LUL and right tracheal bronchus coexisted in 7 and 3 patients respectively. Conclusion: DLUDB has characteristic findings on CT. Radiologists should be aware of this entity and inform the surgeon as it can prevent serious complications in a patient who may undergo lobectomy of the left lung

Causal mediation analysis with multiple causally non-ordered mediators.

Science.gov (United States)

Taguri, Masataka; Featherstone, John; Cheng, Jing

2018-01-01

In many health studies, researchers are interested in estimating the treatment effects on the outcome around and through an intermediate variable. Such causal mediation analyses aim to understand the mechanisms that explain the treatment effect. Although multiple mediators are often involved in real studies, most of the literature considered mediation analyses with one mediator at a time. In this article, we consider mediation analyses when there are causally non-ordered multiple mediators. Even if the mediators do not affect each other, the sum of two indirect effects through the two mediators considered separately may diverge from the joint natural indirect effect when there are additive interactions between the effects of the two mediators on the outcome. Therefore, we derive an equation for the joint natural indirect effect based on the individual mediation effects and their interactive effect, which helps us understand how the mediation effect works through the two mediators and relative contributions of the mediators and their interaction. We also discuss an extension for three mediators. The proposed method is illustrated using data from a randomized trial on the prevention of dental caries.

Four cycles of adriamycin and cyclophosphamide followed by four cycles of docetaxel (NSABP-B27 with concomitant trastuzumab as neoadjuvant therapy for high-risk, early-stage, HER2-positive breast cancer patients

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Abdel-Razeq H

2018-04-01

Full Text Available Hikmat Abdel-Razeq,1,2 Salwa S Saadeh,1 Mahmoud Abu-Nasser,1 Hazem Abdulelah,1 Lina Marie,1 Murad Salam,1 Basel Al-Haj Ali,1 Mohammad Ibrahim,1 Dalia Rimawi3 1Department of Internal Medicine, Section of Hematology and Medical Oncology, King Hussein Cancer Center, Amman, Jordan; 2School of Medicine, University of Jordan, Amman, Jordan; 3Office of Scientific Affairs and Research, King Hussein Cancer Center, Amman, Jordan Background: The majority of breast cancer patients in Jordan are diagnosed at a young age and present with metastatic or locally advanced disease. The National Surgical Adjuvant Breast and Bowel Project Protocol B27 (NSABP-B27 (four cycles of adriamycin and cyclophosphamide [AC] followed by four cycles of docetaxel is a standard neoadjuvant regimen in our institution. In this study, we report the efficacy of adding trastuzumab to docetaxel in this regimen for high-risk human epidermal growth factor receptor 2 (HER2-positive early-stage disease. Patients and methods: Consecutive HER2-positive breast cancer patients treated with this regimen were included. Treatment was given at standard doses and schedules as reported in NSABP-B27. Trastuzumab was given with docetaxel and then continued for 1 year. Results: A total of 121 patients (mean age 45.4 years were included. The majority had high-risk features including large tumor size, positive axillary lymph nodes, and grade III disease. Three patients did not complete the planned cycles of AC due to a lack of response. Eight (6.6% patients missed at least one cycle of docetaxel. Following neoadjuvant therapy, 119 patients underwent surgery, of whom 59 (49.6% patients achieved pathological complete response. The response was higher in node-negative patients (64.0 vs 45.7%; P=0.03 and in hormone receptor-negative disease patients (69.7 vs 41.9%; P=0.018. Breast-conserving surgery was performed in 21.5% of the patients. The median disease-free survival (DFS for the whole group was not

The mediation as an apt tool for the prevention of crime as result of gender violence

OpenAIRE

Yaíma Águila Gutiérrez; Marileydis Pino Rosa

2017-01-01

Violence based in gender is an actual, social, historical and cultural matter. It affects to million persons around the world in the personal, familiar and social ambit. Violence based in gender could damage relationships and also could become in a crime. Mediation is an apt tool to use before the intervention of law for solving gender violence´s conflicts which could need the intervention of criminal law. Those reasons show that is necessary the prevention of gender violence so is important ...

Organization of left-right coordination of neuronal activity in the mammalian spinal cord

DEFF Research Database (Denmark)

Shevtsova, Natalia A.; Talpalar, Adolfo E.; Markin, Sergey N.

2015-01-01

and the left-right synchronous hopping-like pattern in mutants lacking specific neuron classes, and speed-dependent asymmetric changes of flexor and extensor phase durations. The models provide insights into the architecture of spinal network and the organization of parallel inhibitory and excitatory CIN....... In this study, we construct and analyse two computational models of spinal locomotor circuits consisting of left and right rhythm generators interacting bilaterally via several neuronal pathways mediated by different CINs. The CIN populations incorporated in the models include the genetically identified...... inhibitory (V0D) and excitatory (V0V) subtypes of V0 CINs and excitatory V3 CINs. The model also includes the ipsilaterally projecting excitatory V2a interneurons mediating excitatory drive to the V0V CINs. The proposed network architectures and CIN connectivity allow the models to closely reproduce...

Effects of a combined parent-student alcohol prevention program on intermediate factors and adolescents' drinking behavior: A sequential mediation model.

Science.gov (United States)

Koning, Ina M; Maric, Marija; MacKinnon, David; Vollebergh, Wilma A M

2015-08-01

Previous work revealed that the combined parent-student alcohol prevention program (PAS) effectively postponed alcohol initiation through its hypothesized intermediate factors: increase in strict parental rule setting and adolescents' self-control (Koning, van den Eijnden, Verdurmen, Engels, & Vollebergh, 2011). This study examines whether the parental strictness precedes an increase in adolescents' self-control by testing a sequential mediation model. A cluster randomized trial including 3,245 Dutch early adolescents (M age = 12.68, SD = 0.50) and their parents randomized over 4 conditions: (1) parent intervention, (2) student intervention, (3) combined intervention, and (4) control group. Outcome measure was amount of weekly drinking measured at age 12 to 15; baseline assessment (T0) and 3 follow-up assessments (T1-T3). Main effects of the combined and parent intervention on weekly drinking at T3 were found. The effect of the combined intervention on weekly drinking (T3) was mediated via an increase in strict rule setting (T1) and adolescents' subsequent self-control (T2). In addition, the indirect effect of the combined intervention via rule setting (T1) was significant. No reciprocal sequential mediation (self-control at T1 prior to rules at T2) was found. The current study is 1 of the few studies reporting sequential mediation effects of youth intervention outcomes. It underscores the need of involving parents in youth alcohol prevention programs, and the need to target both parents and adolescents, so that change in parents' behavior enables change in their offspring. (c) 2015 APA, all rights reserved).

Non-compact left ventricle/hypertrabeculated left ventricle

International Nuclear Information System (INIS)

Restrepo, Gustavo; Castano, Rafael; Marmol, Alejandro

2005-01-01

Non-compact left ventricle/hypertrabeculated left ventricle is a myocardiopatie produced by an arrest of the normal left ventricular compaction process during the early embryogenesis. It is associated to cardiac anomalies (congenital cardiopaties) as well as to extracardial conditions (neurological, facial, hematologic, cutaneous, skeletal and endocrinological anomalies). This entity is frequently unnoticed, being diagnosed only in centers with great experience in the diagnosis and treatment of myocardiopathies. Many cases of non-compact left ventricle have been initially misdiagnosed as hypertrophic myocardiopatie, endocardial fibroelastosis, dilated cardiomyopatie, restrictive cardiomyopathy and endocardial fibrosis. It is reported the case of a 74 years old man with a history of chronic arterial hypertension and diabetes mellitus, prechordial chest pain and mild dyspnoea. An echocardiogram showed signs of non-compact left ventricle with prominent trabeculations and deep inter-trabecular recesses involving left ventricular apical segment and extending to the lateral and inferior walls. Literature on this topic is reviewed

Potential role of recombinant secretory leucoprotease inhibitor in the prevention of neutrophil mediated matrix degradation.

Science.gov (United States)

Llewellyn-Jones, C G; Lomas, D A; Stockley, R A

1994-06-01

Neutrophil elastase is able to degrade connective tissue matrices and is thought to be involved in the pathogenesis of destructive lung diseases. The ability of recombinant secretory leucoprotease inhibitor (rSLPI) to inhibit neutrophil mediated degradation of fibronectin in vitro is demonstrated and its efficacy compared with native alpha-1-proteinase inhibitor (n alpha 1-PI), recombinant alpha-1-proteinase inhibitor (r alpha 1-PI), and the chemical elastase inhibitor ICI 200,355. When preincubated with neutrophils both rSLPI and r alpha 1-PI were effective inhibitors of fibronectin degradation although n alpha 1-PI and ICI 200,355 were less effective. Recombinant SLPI was the most effective inhibitor when the cells were allowed to adhere to fibronectin before the addition of the inhibitors. Preincubation of rSLPI (0.1 mumol/l) with the fibronectin plate resulted in almost total inhibition of fibronectin degradation (reduced to 3.3 (SE 0.9)% of control). Pretreating the fibronectin plate with 1 mumol/l rSLPI, r alpha 1-PI and ICI 200,355 followed by thorough washing before the addition of cells resulted in no inhibition of fibronectin degradation with r alpha 1-PI and the ICI inhibitor, but rSLPI retained its inhibitory effect. This effect could be reduced by adding rSLPI in high pH buffer or 2 mol/1 NaCl. It is postulated that rSLPI binds to fibronectin to form a protective layer which prevents its degradation by neutrophil elastase. It may prove to be the most useful therapeutic agent in the prevention of neutrophil mediated lung damage.

Social Anxiety and Internet Addiction among Rural Left-behind Children: The Mediating Effect of Loneliness

OpenAIRE

REN, Yujia; YANG, Jiao; LIU, Liqiong

2017-01-01

Background: At present, the mental health of rural left-behind children is a major social problem in China. Internet addiction, social anxiety, and loneliness are common psychological and behavioral problems among rural left-behind children, but the relationships among these issues have not been clearly identified. Methods: A total of 432 junior year 1 to senior year 3 students were randomly selected from 2 rural middle schools in Hunan Province of China as the research subjects. The Internet...

Left regular bands of groups of left quotients

International Nuclear Information System (INIS)

El-Qallali, A.

1988-10-01

A semigroup S which has a left regular band of groups as a semigroup of left quotients is shown to be the semigroup which is a left regular band of right reversible cancellative semigroups. An alternative characterization is provided by using spinned products. These results are applied to the case where S is a superabundant whose set of idempotents forms a left normal band. (author). 13 refs

Epothilone D prevents binge methamphetamine-mediated loss of striatal dopaminergic markers.

Science.gov (United States)

Killinger, Bryan A; Moszczynska, Anna

2016-02-01

Exposure to binge methamphetamine (METH) can result in a permanent or transient loss of dopaminergic (DAergic) markers such as dopamine (DA), dopamine transporter, and tyrosine hydroxylase (TH) in the striatum. We hypothesized that the METH-induced loss of striatal DAergic markers was, in part, due to a destabilization of microtubules (MTs) in the nigrostriatal DA pathway that ultimately impedes anterograde axonal transport of these markers. To test this hypothesis, adult male Sprague-Dawley rats were treated with binge METH or saline in the presence or absence of epothilone D (EpoD), a MT-stabilizing compound, and assessed 3 days after the treatments for the levels of several DAergic markers as well as for the levels of tubulins and their post-translational modifications (PMTs). Binge METH induced a loss of stable long-lived MTs within the striatum but not within the substantia nigra pars compacta (SNpc). Treatment with a low dose of EpoD increased the levels of markers of stable MTs and prevented METH-mediated deficits in several DAergic markers in the striatum. In contrast, administration of a high dose of EpoD appeared to destabilize MTs and potentiated the METH-induced deficits in several DAergic markers. The low-dose EpoD also prevented the METH-induced increase in striatal DA turnover and increased behavioral stereotypy during METH treatment. Together, these results demonstrate that MT dynamics plays a role in the development of METH-induced losses of several DAergic markers in the striatum and may mediate METH-induced degeneration of terminals in the nigrostriatal DA pathway. Our study also demonstrates that MT-stabilizing drugs such as EpoD have a potential to serve as useful therapeutic agents to restore function of DAergic nerve terminals following METH exposure when administered at low doses. Administration of binge methamphetamine (METH) negatively impacts neurotransmission in the nigrostriatal dopamine (DA) system. The effects of METH include

Advantages in exploring a new environment with the left eye in lizards.

Science.gov (United States)

Bonati, Beatrice; Csermely, Davide; Sovrano, Valeria Anna

2013-07-01

Lizards (Podarcis muralis) preferentially use the left eye during spatial exploration in a binocular condition. Here we allowed 44 adult wild lizards to explore an unknown maze for 20 min under a temporary monocular condition whilst recording their movements, particularly the direction of turns made whilst walking within the maze. Lizards with a patch on their right eye, i.e. using their left eye to monitor the environment, moved faster than lizards with a patch on their left eye when turning both leftward and rightward in a T-cross. Hence, right eye-patched lizards were faster than left eye-patched lizards also in turning right, although their right eye was covered. Thus, lizards that could use the left eye/right hemisphere to attend spatial cues appeared to have more control and to be more prompt in exploring the maze. In addition, female lizards with their left eye covered stopped very frequently when they reached crosses, showing a high level of indecision. Results confirm that P. muralis lizards using their left eye only in exploring a new environment react faster and more efficiently than those using the right eye only in exploration. Hence lateralisation of spatial stimuli mediated by the left eye/right hemisphere could provide an advantage to this species. Copyright © 2013 Elsevier B.V. All rights reserved.

Why did soft drink consumption decrease but screen time not? Mediating mechanisms in a school-based obesity prevention program

Directory of Open Access Journals (Sweden)

Brug Johannes

2008-08-01

Full Text Available Abstract Objectives This paper aims to identify the mediating mechanisms of a school-based obesity prevention program (DOiT. Methods The DOiT-program was implemented in Dutch prevocational secondary schools and evaluated using a controlled, cluster-randomised trial (September 2003 to May 2004. We examined mediators of effects regarding (1 consumption of sugar containing beverages (SCB; (2 consumption of high caloric snacks; (3 screen-viewing behaviour; and (4 active commuting to school. To improve these behaviours the DOiT-program tried to influence the following potentially mediating variables: attitude, subjective norm, perceived behavioural control, and habit-strength. Results Both in boys (n = 418 and girls (n = 436 the DOiT-intervention reduced SCB consumption (between group difference in boys = -303.5 ml/day, 95% CI: -502.4;-104.5, between group difference in girls = -222.3 ml/day, 95% CI: -371.3;-73.2. The intervention did not affect the other examined behaviours. In girls, no intervention effect on hypothetical mediators was found nor evidence of any mediating mechanisms. Boys in intervention schools improved their attitude towards decreasing SCB consumption, while this behaviour became less of a habit. Indeed, attitude and habit strength were significant mediators of the DOiT-intervention's effect (4.5 and 3.8%, respectively on SCB consumption among boys. Conclusion Our findings imply that interventions aimed at EBRB-change should be gender-specific. Future studies aimed at reducing SCB consumption among boys should target attitude and habit strength as mediating mechanisms. Our study did not resolve the mediating mechanisms in girls. Trial registration International Standard Randomised Controlled Trial Number Register ISRCTN87127361

The mediation as an apt tool for the prevention of crime as result of gender violence

Directory of Open Access Journals (Sweden)

Yaíma Águila Gutiérrez

2017-07-01

Full Text Available Violence based in gender is an actual, social, historical and cultural matter. It affects to million persons around the world in the personal, familiar and social ambit. Violence based in gender could damage relationships and also could become in a crime. Mediation is an apt tool to use before the intervention of law for solving gender violence´s conflicts which could need the intervention of criminal law. Those reasons show that is necessary the prevention of gender violence so is important the intervention of criminology.

Video-assisted-thoracoscopic surgery in left-to-right Nuss procedure for pectus excavatum for prevention of serious complications - technical aspects based on 1006 patients.

Science.gov (United States)

Pawlak, Krystian; Gąsiorowski, Łukasz; Gabryel, Piotr; Dyszkiewicz, Wojciech

2018-03-01

Additional use of the video-assisted thoracoscopic surgery (VATS) technique in the Nuss procedure has been globally accepted for the improvement of safety of surgical treatment as well as for decreased frequency of serious intraoperative and postoperative complications. To evaluate VATS in surgical treatment of patients with pectus excavatum by the left-to-right Nuss procedure for prevention of serious intra- and postoperative complications. From 2002 to 2016, 1006 patients with pectus excavatum aged 7 to 62 years (mean: 18.6) underwent the Nuss procedure. There were 796 males and 210 females. The clinical records of all patients were analyzed retrospectively. The follow-up varied from 1 to 172 months (mean: 80.7 ±43). The early 30-day postoperative mortality was zero. Early thoracoscopy-dependent postoperative complications, the majority transient and non-life-threatening, occurred in 35.6% of patients. The most frequent complication was pneumothorax, diagnosed in 24.5% of patients. Two patients required repeat surgery. One patient required VATS pleurectomy due to persistent postoperative air leakage. In another patient left thoracotomy following bleeding from the pleural cavity was performed. The use of VATS in the left-to-right Nuss procedure for pectus excavatum ensures the safety of surgical treatment and minimizes the occurrence of serious intra- and postoperative complications concerning injury of the mediastinum, lung, diaphragm or abdominal cavity.

Hibiscus sabdariffa polyphenols prevent palmitate-induced renal epithelial mesenchymal transition by alleviating dipeptidyl peptidase-4-mediated insulin resistance.

Science.gov (United States)

Huang, Chien-Ning; Wang, Chau-Jong; Yang, Yi-Sun; Lin, Chih-Li; Peng, Chiung-Huei

2016-01-01

Diabetic nephropathy has a significant socioeconomic impact, but its mechanism is unclear and needs to be examined. Hibiscus sabdariffa polyphenols (HPE) inhibited high glucose-induced angiotensin II receptor-1 (AT-1), thus attenuating renal epithelial mesenchymal transition (EMT). Recently, we reported HPE inhibited dipeptidyl-peptidase-4 (DPP-4, the enzyme degrades type 1 glucagon-like peptide (GLP-1)), which mediated insulin resistance signals leading to EMT. Since free fatty acids can realistically bring about insulin resistance, using the palmitate-stimulated cell model in contrast with type 2 diabetic rats, in this study we examined if insulin resistance causes renal EMT, and the preventive effect of HPE. Our findings reveal that palmitate hindered 30% of glucose uptake. Treatment with 1 mg mL(-1) of HPE and the DPP-4 inhibitor linagliptin completely recovered insulin sensitivity and palmitate-induced signal cascades. HPE inhibited DPP-4 activity without altering the levels of DPP-4 and the GLP-1 receptor (GLP-1R). HPE decreased palmitate-induced phosphorylation of Ser307 of insulin receptor substrate-1 (pIRS-1 (S307)), AT-1 and vimentin, while increasing phosphorylation of phosphatidylinositol 3-kinase (pPI3K). IRS-1 knockdown revealed its essential role in mediating downstream AT-1 and EMT. In type 2 diabetic rats, it suggests that HPE concomitantly decreased the protein levels of DPP-4, AT-1, vimentin, and fibronectin, but reversed the in vivo compensation of GLP-1R. In conclusion, HPE improves insulin sensitivity by attenuating DPP-4 and the downstream signals, thus decreasing AT-1-mediated tubular-interstitial EMT. HPE could be an adjuvant to prevent diabetic nephropathy.

Testing Mediators Hypothesized to Account for the Effects of a Dissonance-Based Eating Disorder Prevention Program over Longer Term Follow-Up

Science.gov (United States)

Stice, Eric; Marti, C. Nathan; Rohde, Paul; Shaw, Heather

2011-01-01

Objective: Test the hypothesis that reductions in thin-ideal internalization and body dissatisfaction mediate the effects of a dissonance-based eating disorder prevention program on reductions in eating disorder symptoms over 1-year follow-up. Method: Data were drawn from a randomized effectiveness trial in which 306 female high school students…

The repeatability of left ventricular volume assessment by a new ambulatory radionuclide monitoring system during head-up tilt

International Nuclear Information System (INIS)

Takase, Bonpei; Hosaka, Haruhiko; Kitamura, Katsuhiro

2001-01-01

The precise measurement of changes in left ventricular volume is important to elucidate the mechanisms of neurally mediated syncope. This study was conducted to determine whether or not a brand-new ambulatory radionuclide monitoring system (C-VEST system) can be clinically used to easily and precisely measure left ventricular volume and function in tilt testing. To assess the repeatability of the C-VEST system, 12 healthy volunteers (mean age 24±4 years old) underwent 20 minute head-up tilt testing and we measured the temporal changes in left ventricular volume and ejection fraction twice a day (first and second studies). To investigate the changes in the C-VEST measurements and the detector position in the first and second studies, tilt testing was performed with an 80-degree passive tilt, which is the same as the standard procedure used in diagnosing neurally mediated syncope. The coefficient of repeatability for both the C-VEST and detector position was well within the clinical range (coefficient of repeatability in left ventricular volume ranged from 1.7 to 2.8; coefficient of repeatability in the detector position ranged from 2.3 to 3.1). Precise evaluation of the left ventricular volume can be achieved by an ambulatory radionuclide monitoring system in tilt testing. (author)

Pretreatment of Sialic Acid Efficiently Prevents Lipopolysaccharide-Induced Acute Renal Failure and Suppresses TLR4/gp91-Mediated Apoptotic Signaling

Directory of Open Access Journals (Sweden)

Shih-Ping Hsu

2016-05-01

Full Text Available Background/Aims: Lipopolysaccharides (LPS binding to Toll-like receptor 4 (TLR4 activate NADPH oxidase gp91 subunit-mediated inflammation and oxidative damage. Recognizing the high binding affinity of sialic acid (SA with LPS, we further explored the preventive potential of SA pretreatment on LPS-evoked acute renal failure (ARF. Methods: We determined the effect of intravenous SA 30 min before LPS-induced injury in urethane-anesthetized female Wistar rats by evaluating kidney reactive oxygen species (ROS responses, renal and systemic hemodynamics, renal function, histopathology, and molecular mechanisms. Results: LPS time-dependently reduced arterial blood pressure, renal microcirculation, and increased blood urea nitrogen and creatinine in the rats. LPS enhanced monocyte/macrophage infiltration and ROS production, and subsequently impaired kidneys with the enhancement of TLR4/NADPH oxidase gp91/Caspase 3/poly-(ADP-ribose-polymerase (PARP-mediated apoptosis in the kidneys. SA pretreatment effectively alleviated LPS-induced ARF. The levels of LPS-increased ED-1 infiltration and ROS production in the kidney were significantly depressed by SA pretreatment. Furthermore, SA pretreatment significantly depressed TLR4 activation, gp91 expression, and Caspase 3/PARP induced apoptosis in the kidneys. Conclusion: We suggest that pretreatment of SA significantly and preventively attenuated LPS-induced detrimental effects on systemic and renal hemodynamics, renal ROS production and renal function, as well as, LPS-activated TLR4/gp91/Caspase3 mediated apoptosis signaling.

Tetralogy of Fallot with origin of left pulmonary artery from the ascending aorta

Energy Technology Data Exchange (ETDEWEB)

Robida, A.; Fettich, D.

1985-09-01

Anomalous origin of the left pulmonary artery in tetralogy of Fallot was diagnosed in a 4-year-old boy by cardiac catheterization. Corrective surgery was performed. The child died immediately following the surgical procedure. Postmortem examination revealed obstructive pulmonary vascular disease of the left lung and normal histology of right lung vessels. Early recognition and surgical correction of the anomaly is important with the view to preventing obstructive pulmonary vascular disease.

Targeted delivery of polyamidoamine-paclitaxel conjugate functionalized with anti-human epidermal growth factor receptor 2 trastuzumab

Directory of Open Access Journals (Sweden)

Ma P

2015-03-01

Full Text Available Pengkai Ma,1 Xuemei Zhang,1 Ling Ni,2 Jinming Li,2 Fengpu Zhang,1 Zheng Wang,1 Shengnan Lian,1 Kaoxiang Sun1 1School of Pharmacy, Yantai University, Yantai, Shandong Province, People’s Republic of China; 2State Key Laboratory of Long-acting and Targeting Drug Delivery System, Yantai, Shandong Province, People’s Republic of China Background: Antibody-dendrimer conjugates have the potential to improve the targeting and release of chemotherapeutic drugs at the tumor site while reducing adverse side effects caused by drug accumulation in healthy tissues. In this study, trastuzumab (TMAB, which binds to human epidermal growth factor receptor 2 (HER2, was used as a targeting agent in a TMAB-polyamidoamine (PAMAM conjugate carrying paclitaxel (PTX specifically to cells overexpressing HER2. Methods: TMAB was covalently linked to a PAMAM dendrimer via bifunctional polyethylene glycol (PEG. PTX was conjugated to PAMAM using succinic anhydride as a cross-linker, yielding TMAB-PEG-PAMAM-PTX. Dynamic light scattering and transmission electron microscopy were used to characterize the conjugates. The cellular uptake and in vivo biodistribution were studied by fluorescence microscopy, flow cytometry, and Carestream In Vivo FX, respectively. Results: Nuclear magnetic resonance spectroscopy demonstrated that PEG, PTX, fluorescein isothiocyanate, and cyanine7 were conjugated to PAMAM. Ultraviolet-visible spectroscopy and sodium dodecyl sulfate polyacrylamide gel electrophoresis demonstrated that TMAB was conjugated to PEG-PAMAM. Dynamic light scattering and transmission electron microscopy measurements revealed that the different conjugates ranged in size between 10 and 35 nm and had a spherical shape. In vitro cellular uptake demonstrated that the TMAB-conjugated PAMAM was taken up by HER2-overexpressing BT474 cells more efficiently than MCF-7 cells that expressed lower levels of HER2. Co-localization experiments indicated that TMAB-conjugated PAMAM was

A Mediation Analysis of the ATHENA Intervention for Female Athletes: Prevention of Athletic-Enhancing Substance Use and Unhealthy Weight Loss Behaviors

Science.gov (United States)

Ranby, Krista W; Aiken, Leona S; Elliot, Diane L; Moe, Esther L; McGinnis, Wendy; Goldberg, Linn

2009-01-01

Objective To explain, through mediation analyses, the mechanisms by which ATHENA (Athletes Targeting Healthy Exercise and Nutrition Alternatives), a primary prevention and health promotion intervention designed to deter unhealthy body shaping behaviors among female high school athletes, produced immediate changes in intentions for unhealthy weight loss and steroid/creatine use, and to examine the link to long-term follow-up intentions and behaviors. Methods In a randomized trial of 1668 athletes, intervention participants completed coach-led peer-facilitated sessions during their sport season. Participants provided pre-test, immediate post-test, and 9-month follow-up assessments. Results ATHENA decreased intentions for steroid/creatine use and intentions for unhealthy weight loss behaviors at post-test. These effects were most strongly mediated by social norms and self-efficacy for healthy eating. Low post-test intentions were maintained 9 months later and predicted subsequent behavior. Conclusions ATHENA successfully modified mediators that in turn related to athletic-enhancing substance use and unhealthy weight loss practices. Mediation analyses aid in the understanding of health promotion interventions and inform program development. PMID:19386771

Alzheimer's Disease Brain-Derived Amyloid-{beta}-Mediated Inhibition of LTP In Vivo Is Prevented by Immunotargeting Cellular Prion Protein.

LENUS (Irish Health Repository)

Barry, Andrew E

2011-05-18

Synthetic amyloid-β protein (Aβ) oligomers bind with high affinity to cellular prion protein (PrP(C)), but the role of this interaction in mediating the disruption of synaptic plasticity by such soluble Aβ in vitro is controversial. Here we report that intracerebroventricular injection of Aβ-containing aqueous extracts of Alzheimer\\'s disease (AD) brain robustly inhibits long-term potentiation (LTP) without significantly affecting baseline excitatory synaptic transmission in the rat hippocampus in vivo. Moreover, the disruption of LTP was abrogated by immunodepletion of Aβ. Importantly, intracerebroventricular administration of antigen-binding antibody fragment D13, directed to a putative Aβ-binding site on PrP(C), prevented the inhibition of LTP by AD brain-derived Aβ. In contrast, R1, a Fab directed to the C terminus of PrP(C), a region not implicated in binding of Aβ, did not significantly affect the Aβ-mediated inhibition of LTP. These data support the pathophysiological significance of SDS-stable Aβ dimer and the role of PrP(C) in mediating synaptic plasticity disruption by soluble Aβ.

Comparison of the octadentate bifunctional chelator DFO*-pPhe-NCS and the clinically used hexadentate bifunctional chelator DFO-pPhe-NCS for {sup 89}Zr-immuno-PET

Energy Technology Data Exchange (ETDEWEB)

Vugts, Danielle J.; Klaver, Chris; Sewing, Claudia; Poot, Alex J.; Adamzek, Kevin; Visser, Gerard W.M.; Dongen, Guus A.M.S. van [VU University Medical Center, Department of Radiology and Nuclear Medicine, Amsterdam (Netherlands); Huegli, Seraina; Mari, Cristina; Gasser, Gilles [University of Zurich, Department of Chemistry, Zurich (Switzerland); Valverde, Ibai E. [University of Basel Hospital, Division of Radiopharmaceutical Chemistry, Basel (Switzerland); Mindt, Thomas L. [Institute of Pharmaceutical Sciences, ETH Zurich, Zurich (Switzerland); General Hospital of Vienna, Ludwig Boltzmann Institute for Applied Diagnostics, Vienna (Austria)

2017-02-15

All clinical {sup 89}Zr-immuno-PET studies are currently performed with the chelator desferrioxamine (DFO). This chelator provides hexadentate coordination to zirconium, leaving two coordination sites available for coordination with, e.g., water molecules, which are relatively labile ligands. The unsaturated coordination of DFO to zirconium has been suggested to result in impaired stability of the complex in vivo and consequently in unwanted bone uptake of {sup 89}Zr. Aiming at clinical improvements, we report here on a bifunctional isothiocyanate variant of the octadentate chelator DFO* and the in vitro and in vivo comparison of its {sup 89}Zr-DFO*-mAb complex with {sup 89}Zr-DFO-mAb. The bifunctional chelator DFO*-pPhe-NCS was prepared from previously reported DFO* and p-phenylenediisothiocyanate. Subsequently, trastuzumab was conjugated with either DFO*-pPhe-NCS or commercial DFO-pPhe-NCS and radiolabeled with Zr-89 according to published procedures. In vitro stability experiments were carried out in saline, a histidine/sucrose buffer, and blood serum. The in vivo performance of the chelators was compared in N87 tumor-bearing mice by biodistribution studies and PET imaging. In 0.9 % NaCl {sup 89}Zr-DFO*-trastuzumab was more stable than {sup 89}Zr-DFO-trastuzumab; after 72 h incubation at 2-8 C 95 % and 58 % intact tracer were left, respectively, while in a histidine-sucrose buffer no difference was observed, both products were ≥ 92 % intact. In vivo uptake at 144 h post injection (p.i.) in tumors, blood, and most normal organs was similar for both conjugates, except for skin, liver, spleen, ileum, and bone. Tumor uptake was 32.59 ± 11.95 and 29.06 ± 8.66 % ID/g for {sup 89}Zr-DFO*-trastuzumab and {sup 89}Zr-DFO-trastuzumab, respectively. The bone uptake was significantly lower for {sup 89}Zr-DFO*-trastuzumab compared to {sup 89}Zr-DFO-trastuzumab. At 144 h p.i. for {sup 89}Zr-DFO*-trastuzumab and {sup 89}Zr-DFO-trastuzumab, the uptake in sternum was 0.92 �

Low-scale gaugino mediation, lots of leptons at the LHC

International Nuclear Information System (INIS)

De Simone, Andrea; Fan Jiji; Skiba, Witold; Schmaltz, Martin

2008-01-01

Low-scale gaugino mediation predicts that gauginos are significantly heavier than scalar superpartners. In order of increasing mass the lightest superpartners are the gravitino, right-handed sleptons, and left-handed sleptons (no light neutralino). This implies that squark decay chains pass through one or more sleptons and typical final states from squark and gluino production at the LHC include multiple leptons. In addition, left-handed staus have large branching fractions into right-handed staus and the Higgs. As an example, we compute the spectrum of low-scale deconstructed gaugino mediation. In this model gauginos acquire masses at tree level at 5 TeV while scalar masses are generated radiatively from the gaugino masses.

Tetralogy of Fallot with origin of left pulmonary artery from the ascending aorta

International Nuclear Information System (INIS)

Robida, A.; Fettich, D.

1985-01-01

Anomalous origin of the left pulmonary artery in tetralogy of Fallot was diagnosed in a 4-year-old boy by cardiac catheterization. Corrective surgery was performed. The child died immediately following the surgical procedure. Postmortem examination revealed obstructive pulmonary vascular disease of the left lung and normal histology of right lung vessels. Early recognition and surgical correction of the anomaly is important with the view to preventing obstructive pulmonary vascular disease. (orig.)

Gaugino-assisted anomaly mediation

International Nuclear Information System (INIS)

Kribs, Graham D.

2001-01-01

I present a model of supersymmetry breaking mediated through a small extra dimension. Standard model matter multiplets and a supersymmetry-breaking (or 'hidden') sector are confined to opposite four-dimensional boundaries while gauge multiplets live in the bulk. The hidden sector does not contain a singlet and the dominant contribution to gaugino masses is via anomaly-mediated supersymmetry breaking. Scalar masses get contributions from both anomaly mediation and a tiny hard breaking of supersymmetry by operators on the hidden-sector boundary. These operators contribute to scalar masses at one loop and in most of parameter space, their contribution dominates. Thus it is easy to make all squared scalar masses positive. As no additional fields or symmetries are required below the Planck scale, this is among the simplest working models of anomaly mediation. The gaugino spectrum is left untouched and the phenomenology of the model is roughly similar to anomaly mediated supersymmetry breaking with a universal scalar mass added. Finally, the main differences in the spectrum between this model and other approaches are identified. This talk is based on work [1] done in collaboration with David E. Kaplan

Gaugino-Assisted Anomaly Mediation

International Nuclear Information System (INIS)

Kaplan, David Elazzar; Kribs, Graham D.

2000-01-01

We present a model of supersymmetry breaking mediated through a small extra dimension. Standard model matter multiplets and a supersymmetry-breaking (or ''hidden'') sector are confined to opposite four-dimensional boundaries while gauge multiplets live in the bulk. The hidden sector does not contain a singlet and the dominant contribution to gaugino masses is via anomaly-mediated supersymmetry breaking. Scalar masses get contributions from both anomaly mediation and a tiny hard breaking of supersymmetry by operators on the hidden-sector boundary. These operators contribute to scalar masses at one loop and in most of parameter space, their contribution dominates. Thus it is easy to make all squared scalar masses positive. As no additional fields or symmetries are required below the Planck scale, we consider this the simplest working model of anomaly mediation. The gaugino spectrum is left untouched and the phenomenology of the model is roughly similar to anomaly mediated supersymmetry breaking with a universal scalar mass added. We identify the main differences in the spectrum between this model and other approaches. We also discuss mechanisms for generating the μ term and constraints on additional bulk fields. (author)

Cost-effectiveness analysis of left atrial appendage occlusion compared with pharmacological strategies for stroke prevention in atrial fibrillation.

Science.gov (United States)

Lee, Vivian Wing-Yan; Tsai, Ronald Bing-Ching; Chow, Ines Hang-Iao; Yan, Bryan Ping-Yen; Kaya, Mehmet Gungor; Park, Jai-Wun; Lam, Yat-Yin

2016-08-31

Transcatheter left atrial appendage occlusion (LAAO) is a promising therapy for stroke prophylaxis in non-valvular atrial fibrillation (NVAF) but its cost-effectiveness remains understudied. This study evaluated the cost-effectiveness of LAAO for stroke prophylaxis in NVAF. A Markov decision analytic model was used to compare the cost-effectiveness of LAAO with 7 pharmacological strategies: aspirin alone, clopidogrel plus aspirin, warfarin, dabigatran 110 mg, dabigatran 150 mg, apixaban, and rivaroxaban. Outcome measures included quality-adjusted life years (QALYs), lifetime costs and incremental cost-effectiveness ratios (ICERs). Base-case data were derived from ACTIVE, RE-LY, ARISTOTLE, ROCKET-AF, PROTECT-AF and PREVAIL trials. One-way sensitivity analysis varied by CHADS2 score, HAS-BLED score, time horizons, and LAAO costs; and probabilistic sensitivity analysis using 10,000 Monte Carlo simulations was conducted to assess parameter uncertainty. LAAO was considered cost-effective compared with aspirin, clopidogrel plus aspirin, and warfarin, with ICER of US$5,115, $2,447, and $6,298 per QALY gained, respectively. LAAO was dominant (i.e. less costly but more effective) compared to other strategies. Sensitivity analysis demonstrated favorable ICERs of LAAO against other strategies in varied CHADS2 score, HAS-BLED score, time horizons (5 to 15 years) and LAAO costs. LAAO was cost-effective in 86.24 % of 10,000 simulations using a threshold of US$50,000/QALY. Transcatheter LAAO is cost-effective for prevention of stroke in NVAF compared with 7 pharmacological strategies. The transcatheter left atrial appendage occlusion (LAAO) is considered cost-effective against the standard 7 oral pharmacological strategies including acetylsalicylic acid (ASA) alone, clopidogrel plus ASA, warfarin, dabigatran 110 mg, dabigatran 150 mg, apixaban, and rivaroxaban for stroke prophylaxis in non-valvular atrial fibrillation management.

Enhancement of antibody-dependent cell-mediated cytotoxicity by endowing IgG with FcαRI (CD89) binding.

Science.gov (United States)

Borrok, M Jack; Luheshi, Nadia M; Beyaz, Nurten; Davies, Gareth C; Legg, James W; Wu, Herren; Dall'Acqua, William F; Tsui, Ping

2015-01-01

Fc effector functions such as antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cell-mediated phagocytosis (ADCP) are crucial to the efficacy of many antibody therapeutics. In addition to IgG, antibodies of the IgA isotype can also promote cell killing through engagement of myeloid lineage cells via interactions between the IgA-Fc and FcαRI (CD89). Herein, we describe a unique, tandem IgG1/IgA2 antibody format in the context of a trastuzumab variable domain that exhibits enhanced ADCC and ADCP capabilities. The IgG1/IgA2 tandem Fc format retains IgG1 FcγR binding as well as FcRn-mediated serum persistence, yet is augmented with myeloid cell-mediated effector functions via FcαRI/IgA Fc interactions. In this work, we demonstrate anti-human epidermal growth factor receptor-2 antibodies with the unique tandem IgG1/IgA2 Fc can better recruit and engage cytotoxic polymorphonuclear (PMN) cells than either the parental IgG1 or IgA2. Pharmacokinetics of IgG1/IgA2 in BALB/c mice are similar to the parental IgG, and far surpass the poor serum persistence of IgA2. The IgG1/IgA2 format is expressed at similar levels and with similar thermal stability to IgG1, and can be purified via standard protein A chromatography. The tandem IgG1/IgA2 format could potentially augment IgG-based immunotherapeutics with enhanced PMN-mediated cytotoxicity while avoiding many of the problems associated with developing IgAs.

Alterations of the genes involved in the PI3K and estrogen-receptor pathways influence outcome in human epidermal growth factor receptor 2-positive and hormone receptor-positive breast cancer patients treated with trastuzumab-containing neoadjuvant chemotherapy

International Nuclear Information System (INIS)

Takada, Mamoru; Miyazaki, Masaru; Sato-Otsubo, Aiko; Ogawa, Seishi; Kaneko, Yasuhiko; Higuchi, Toru; Tozuka, Katsunori; Takei, Hiroyuki; Haruta, Masayuki; Watanabe, Junko; Kasai, Fumio; Inoue, Kenichi; Kurosumi, Masafumi

2013-01-01

Chemotherapy with trastuzumab is widely used for patients with human epidermal growth factor receptor 2-positive (HER2+) breast cancer, but a significant number of patients with the tumor fail to respond, or relapse. The mechanisms of recurrence and biomarkers that indicate the response to the chemotherapy and outcome are not fully investigated. Genomic alterations were analyzed using single-nucleotide polymorphism arrays in 46 HER2 immunohistochemistry (IHC) 3+ or 2+/fluorescent in situ hybridization (FISH)+ breast cancers that were treated with neoadjuvant chemotherapy with paclitaxel, cyclophosphamid, epirubicin, fluorouracil, and trastuzumab. Patients were classified into two groups based on presence or absence of alterations of 65 cancer-associated genes, and the two groups were further classified into four groups based on genomic HER2 copy numbers or hormone receptor status (HR+/−). Pathological complete response (pCR) and relapse-free survival (RFS) rates were compared between any two of the groups. The pCR rate was 54% in 37 patients, and the RFS rate at 3 years was 72% (95% CI, 0.55-0.89) in 42 patients. The analysis disclosed 8 tumors with nonamplified HER2 and 38 tumors with HER2 amplification, indicating the presence of discordance in tumors diagnosed using current HER2 testing. The 8 patients showed more difficulty in achieving pCR (P=0.019), more frequent relapse (P=0.018), and more frequent alterations of genes in the PI3K pathway (P=0.009) than the patients with HER2 amplification. The alterations of the PI3K and estrogen receptor (ER) pathway genes generally indicated worse RFS rates. The prognostic significance of the alterations was shown in patients with a HR+ tumor, but not in patients with a HR- tumor when divided. Alterations of the PI3K and ER pathway genes found in patients with a HR+ tumor with poor outcome suggested that crosstalk between the two pathways may be involved in resistance to the current chemotherapy with trastuzumab. We

Possible selves in patients with right- versus left-onset Parkinson's disease.

Science.gov (United States)

Harris, Erica; McNamara, Patrick; Durso, Raymon

2017-03-01

Possible selves can be used to self-regulate and guide behavior towards what is desired to be achieved or avoided in life. Previous work suggests laterality effects exist within the brain regarding approach and avoidance systems to achieve self-regulation. A modified version of the possible selves task was administered to 45 patients with PD (22 right-onset and 23 left-onset) and 25 community dwelling control subjects (CS). Only 11.1% of patients exhibited balance among their hoped-for and feared possible selves versus 28% of CS. More right-onset patients used a promotion strategy whereas more left-onset patients used a prevention strategy. Patients with left-onset PD thought more about their feared selves, exhibiting reduced goal-directed behavior. Findings among the left-onset group indicate relative dependence of self-regulation on right-sided avoidance brain systems. This may point to an inability to move away from negative outcomes and to work towards rewarding outcomes, which could affect psychological health.

Generation of IgE-based immunotherapies against HER-2 overexpressing tumours

International Nuclear Information System (INIS)

Knittelfelder, R.

2010-01-01

same specificity as the original trastuzumab IgG. Moreover, a three-colour flow cytometric assay indicated that even though both antibodies were able to induce tumour cell killing, they used different mechanisms: trastuzumab IgG acted via antibody-dependent cell-mediated phagocytosis (ADCP), whereas trastuzumab IgE elicited mostly antibody-dependent cell-mediated cytotoxicity (ADCC). Based on the presented data we conclude that tumour-specific IgE, induced actively or applied in a passive manner, represents a potent alternative to IgG-based immunotherapies against cancer. (author) [de

Characterisation of the HLA-DRB1*07:01 biomarker for lapatinib-induced liver toxicity during treatment of early-stage breast cancer patients with lapatinib in combination with trastuzumab and/or taxanes.

Science.gov (United States)

Spraggs, C F; Parham, L R; Briley, L P; Warren, L; Williams, L S; Fraser, D J; Jiang, Z; Aziz, Z; Ahmed, S; Demetriou, G; Mehta, A; Jackson, N; Byrne, J; Andersson, M; Toi, M; Harris, L; Gralow, J; Zujewski, J A; Crescenzo, R; Armour, A; Perez, E; Piccart, M

2017-08-08

HLA-DRB1*07:01 allele carriage was characterised as a risk biomarker for lapatinib-induced liver injury in a large global study evaluating lapatinib, alone and in combination with trastuzumab and taxanes, as adjuvant therapy for advanced breast cancer (adjuvant lapatinib and/or trastuzumab treatment optimisation). HLA-DRB1*07:01 carriage was associated with serum alanine aminotransferase (ALT) elevations in lapatinib-treated patients (odds ratio 6.5, P=3 × 10 -26 , n=4482) and the risk and severity of ALT elevation for lapatinib-treated patients was higher in homozygous than heterozygous HLA-DRB1*07:01 genotype carriers. A higher ALT case incidence plus weaker HLA association observed during concurrent administration of lapatinib and taxane suggested a subset of liver injury in this combination group that was HLA-DRB1*07:01 independent. Furthermore, the incidence of ALT elevation demonstrated an expected correlation with geographic HLA-DRB1*07:01 carriage frequency. Robust ALT elevation risk estimates for HLA-DRB1*07:01 may support causality discrimination and safety risk management during the use of lapatinib combination therapy for the treatment of metastatic breast cancer.The Pharmacogenomics Journal advance online publication, 8 August 2017; doi:10.1038/tpj.2017.39.

An elusive persistent left superior vena cava draining into left atrium

NARCIS (Netherlands)

A. Soward; F.J. ten Cate (Folkert); P.M. Fioretti (Paolo); P.W.J.C. Serruys (Patrick); J.R.T.C. Roelandt (Jos)

1986-01-01

textabstractA case report of a persistent left superior vena cava draining into left atrium with a fibromuscular left ventricular outflow tract obstruction and a small atrial septal defect. The anomalous vessel escaped detection during two right and left heart catheterizations from the right arm and

Right Site, Wrong Route - Cannulating the Left Internal Jugular Vein.

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Paik, Peter; Arukala, Sanjay K; Sule, Anupam A

2018-01-09

Central venous catheters are placed in approximately five million patients annually in the US. The preferred site of insertion is one with fewer risks and easier access. Although the right internal jugular vein is preferred, on occasion, the left internal jugular may have to be accessed. A patient was admitted for septic shock, cerebrovascular accident, and non-ST-segment elevation myocardial infarction. A central venous line was needed for antibiotic and vasopressor administration. Due to trauma from a fall to the right side and previously failed catheterization attempts at the left subclavian and femoral veins, the left internal jugular vein was accessed. On chest radiography for confirmation, the left internal jugular central venous catheter was seen projecting down the left paraspinal region. It did not take the expected course across the midline toward the right and into the superior vena cava (SVC). A review of a computed tomography (CT) scan of the chest with contrast done on a prior admission revealed a duplicated SVC on the left side that had not been reported in the original CT scan interpretation. A left-sided SVC is present in approximately 0.3% to 0.5% of the population, with 90% of these draining into the coronary sinus. During placements of central venous lines and pacemakers, irritation of the coronary sinus may result in hypotension, arrhythmia, myocardial ischemia, or cardiac arrest. A widened mediastinum can be an indication of a duplicated SVC. When attempting a left internal jugular vein central venous catheter placement, it is important to be aware of venous anomalies in order to prevent complications.

A Phase 1/2 Trial of a Combination of Paclitaxel and Trastuzumab With Daily Irradiation or Paclitaxel Alone With Daily Irradiation After Transurethral Surgery for Noncystectomy Candidates With Muscle-Invasive Bladder Cancer (Trial NRG Oncology RTOG 0524)

Energy Technology Data Exchange (ETDEWEB)

Michaelson, M. Dror, E-mail: dmichaelson1@partners.org [Massachusetts General Hospital Cancer Center, Boston, Massachusetts (United States); Hu, Chen [NRG Oncology Statistics and Data Management Center, Philadelphia, Pennsylvania (United States); Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Pham, Huong T. [Virginia Mason CCOP, Seattle, Washington (United States); Dahl, Douglas M.; Lee-Wu, Chin [Massachusetts General Hospital Cancer Center, Boston, Massachusetts (United States); Swanson, Gregory P. [University of Texas at San Antonio, San Antonio, Texas (United States); Vuky, Jacqueline [Virginia Mason CCOP, Seattle, Washington (United States); Lee, R. Jeffrey [Intermountain Medical Center, Murray, Utah (United States); Souhami, Luis [McGill University, Montréal, Quebec (Canada); Chang, Brian [Parkview Cancer Center, Parkview Hospital, Fort Wayne, Indiana (United States); George, Asha [NRG Oncology Statistics and Data Management Center, Philadelphia, Pennsylvania (United States); Sandler, Howard [Cedars-Sinai Medical Center, Los Angeles, California (United States); Shipley, William [Massachusetts General Hospital Cancer Center, Boston, Massachusetts (United States)

2017-04-01

Purpose: Bladder preservation therapy is an effective treatment for muscle-invasive urothelial carcinoma (UC). In this study we treated noncystectomy candidates with daily radiation and weekly paclitaxel for 7 weeks. Patients whose tumors showed her2/neu overexpression were additionally treated with weekly trastuzumab. Methods and Materials: Sixty-eight evaluable patients were treated with radiation therapy and either paclitaxel + trastuzumab (group 1) or paclitaxel alone (group 2). Groups were assigned on the basis of her2/neu immunohistochemistry results. Patients received 1.8-Gy fractions to a total dose of 64.8 Gy. The primary endpoint of the study was treatment-related toxicity, and secondary endpoints included complete response (CR) rate, protocol completion rate, and survival. Results: A total of 20 evaluable patients were treated in group 1 and 46 patients in group 2. Acute treatment-related adverse events (AEs) were observed in 7 of 20 patients in group 1 (35%) and 14 of 46 patients in group 2 (30.4%). Protocol therapy was completed by 60% (group 1) and 74% (group 2) of patients. Most incompletions were due to toxicity, and the majority of AEs were gastrointestinal, including 1 grade 5 AE (group 1). Two other deaths (both in group 2) were unrelated to protocol therapy. No unexpected cardiac, hematologic, or other toxicities were observed. The CR rate at 1 year was 72% for group 1 and 68% for group 2. Conclusions: In patients with muscle-invasive UC who are not candidates for cystectomy, daily radiation combined with paclitaxel is an effective treatment strategy with a high completion rate and moderate toxicity. In patients with her2/neu-positive tumors, a group generally considered to have worse outcomes, the addition of trastuzumab appears to result in comparable efficacy and toxicity. Further biomarker-driven trials should be undertaken in advancing treatment of this challenging disease.

Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial.

Science.gov (United States)

Martin, Miguel; Holmes, Frankie A; Ejlertsen, Bent; Delaloge, Suzette; Moy, Beverly; Iwata, Hiroji; von Minckwitz, Gunter; Chia, Stephen K L; Mansi, Janine; Barrios, Carlos H; Gnant, Michael; Tomašević, Zorica; Denduluri, Neelima; Šeparović, Robert; Gokmen, Erhan; Bashford, Anna; Ruiz Borrego, Manuel; Kim, Sung-Bae; Jakobsen, Erik Hugger; Ciceniene, Audrone; Inoue, Kenichi; Overkamp, Friedrich; Heijns, Joan B; Armstrong, Anne C; Link, John S; Joy, Anil Abraham; Bryce, Richard; Wong, Alvin; Moran, Susan; Yao, Bin; Xu, Feng; Auerbach, Alan; Buyse, Marc; Chan, Arlene

2017-12-01

ExteNET showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, significantly improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in women with HER2-positive breast cancer. We report updated efficacy outcomes from a protocol-defined 5-year follow-up sensitivity analysis and long-term toxicity findings. In this ongoing randomised, double-blind, placebo-controlled, phase 3 trial, eligible women aged 18 years or older (≥20 years in Japan) with stage 1-3c (modified to stage 2-3c in February, 2010) operable breast cancer, who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab with no evidence of disease recurrence or metastatic disease at study entry. Patients who were eligible patients were randomly assigned (1:1) via permuted blocks stratified according to hormone receptor status (hormone receptor-positive vs hormone receptor-negative), nodal status (0 vs 1-3 vs or ≥4 positive nodes), and trastuzumab adjuvant regimen (given sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system, to receive 1 year of oral neratinib 240 mg/day or matching placebo. Treatment was given continuously for 1 year, unless disease recurrence or new breast cancer, intolerable adverse events, or consent withdrawal occurred. Patients, investigators, and trial funder were masked to treatment allocation. The predefined endpoint of the 5-year analysis was invasive disease-free survival, analysed by intention to treat. ExteNET is registered with ClinicalTrials.gov, number NCT00878709, and is closed to new participants. Between July 9, 2009, and Oct 24, 2011, 2840 eligible women with early HER2-positive breast cancer were recruited from community-based and academic institutions in 40 countries and randomly assigned to receive neratinib (n=1420) or placebo (n=1420). After a median follow-up of 5·2 years (IQR 2·1-5·3), patients in the neratinib

Trastuzumab use during pregnancy: long-term survival after locally advanced breast cancer and long-term infant follow-up.

Science.gov (United States)

Andrade, Jurandyr M de; Brito, Luiz G O; Moises, Elaine C D; Amorim, Andréa C; Rapatoni, Liane; Carrara, Hélio H A; Tiezzi, Daniel G

2016-04-01

Here, we describe the case of a patient diagnosed with locally advanced breast cancer 8 years ago. Her treatment course was neoadjuvant chemotherapy, followed by mastectomy and then adjuvant radiotherapy and trastuzumab (TTZ). During the use of adjuvant targeted therapy, an incidental pregnancy was diagnosed. Four years later, she developed bone and cerebral metastases, and since then, she has received courses of TTZ, capecitabine, lapatinib, and radiotherapy with intermittent control of the disease. Her 7-year-old son presents a normal physical and long-term neurological developmental curve according to specialized evaluation. This case is unique for several reasons: the patient received the highest dose of TTZ yet described during pregnancy (4400 mg); there has been a long period of disease-free survival after treatment for locally advanced breast cancer and long overall survival despite successive disease progressions during the metastatic phase of the disease (97 months), and there was a monitored pediatric follow-up period (7 years).

Microglia P2Y13 Receptors Prevent Astrocyte Proliferation Mediated by P2Y1 Receptors

Directory of Open Access Journals (Sweden)

Clara Quintas

2018-05-01

Full Text Available Cerebral inflammation is a common feature of several neurodegenerative diseases that requires a fine interplay between astrocytes and microglia to acquire appropriate phenotypes for an efficient response to neuronal damage. During brain inflammation, ATP is massively released into the extracellular medium and converted into ADP. Both nucleotides acting on P2 receptors, modulate astrogliosis through mechanisms involving microglia-astrocytes communication. In previous studies, primary cultures of astrocytes and co-cultures of astrocytes and microglia were used to investigate the influence of microglia on astroglial proliferation induced by ADPβS, a stable ADP analog. In astrocyte cultures, ADPβS increased cell proliferation through activation of P2Y1 and P2Y12 receptors, an effect abolished in co-cultures (of astrocytes with ∼12.5% microglia. The possibility that the loss of the ADPβS-mediated effect could have been caused by a microglia-induced degradation of ADPβS or by a preferential microglial localization of P2Y1 or P2Y12 receptors was excluded. Since ADPβS also activates P2Y13 receptors, the contribution of microglial P2Y13 receptors to prevent the proliferative effect of ADPβS in co-cultures was investigated. The results obtained indicate that P2Y13 receptors are low expressed in astrocytes and mainly expressed in microglia. Furthermore, in co-cultures, ADPβS induced astroglial proliferation in the presence of the selective P2Y13 antagonist MRS 2211 (3 μM and of the selective P2Y12 antagonist AR-C66096 (0.1 μM, suggesting that activation of microglial P2Y12 and P2Y13 receptors may induce the release of messengers that inhibit astroglial proliferation mediated by P2Y1,12 receptors. In this microglia-astrocyte paracrine communication, P2Y12 receptors exert opposite effects in astroglial proliferation as a result of its cellular localization: cooperating in astrocytes with P2Y1 receptors to directly stimulate proliferation and in

Stronger Dopamine D1 Receptor-Mediated Neurotransmission in Dyskinesia.

Science.gov (United States)

Farré, Daniel; Muñoz, Ana; Moreno, Estefanía; Reyes-Resina, Irene; Canet-Pons, Júlia; Dopeso-Reyes, Iria G; Rico, Alberto J; Lluís, Carme; Mallol, Josefa; Navarro, Gemma; Canela, Enric I; Cortés, Antonio; Labandeira-García, José L; Casadó, Vicent; Lanciego, José L; Franco, Rafael

2015-12-01

Radioligand binding assays to rat striatal dopamine D1 receptors showed that brain lateralization of the dopaminergic system were not due to changes in expression but in agonist affinity. D1 receptor-mediated striatal imbalance resulted from a significantly higher agonist affinity in the left striatum. D1 receptors heteromerize with dopamine D3 receptors, which are considered therapeutic targets for dyskinesia in parkinsonian patients. Expression of both D3 and D1-D3 receptor heteromers were increased in samples from 6-hydroxy-dopamine-hemilesioned rats rendered dyskinetic by treatment with 3, 4-dihydroxyphenyl-L-alanine (L-DOPA). Similar findings were obtained using striatal samples from primates. Radioligand binding studies in the presence of a D3 agonist led in dyskinetic, but not in lesioned or L-DOPA-treated rats, to a higher dopamine sensitivity. Upon D3-receptor activation, the affinity of agonists for binding to the right striatal D1 receptor increased. Excess dopamine coming from L-DOPA medication likely activates D3 receptors thus making right and left striatal D1 receptors equally responsive to dopamine. These results show that dyskinesia occurs concurrently with a right/left striatal balance in D1 receptor-mediated neurotransmission.

Fatal stroke after completion pneumonectomy for torsion of left upper lobe following left lower lobectomy

Directory of Open Access Journals (Sweden)

Apostolakis Efstratios

2006-09-01

Full Text Available Abstract Background The lobar torsion after lung surgery is a rare complication with an incidence of 0.09 to 0.4 %. It may occur after twisting of the bronchovascular pedicle of the remaining lobe after lobectomy, usually on the right side. The 180-degree rotation of the pedicle produces an acute obstruction of the lobar bronchus (atelectasis and of the lobar vessels as well. Without prompt treatment it progresses to lobar ischemia, pulmonary infarction and finally fatal gangrene. Case Presentation A 62 years old female patient was admitted for surgical treatment of lung cancer. She underwent elective left lower lobectomy for squamous cell carcinoma (pT2 N0. The operation was unremarkable, and the patient was extubated in the operating room. After eight hours the patient established decrease of pO2 and chest x-ray showed atelectasis of the lower lobe. To establish diagnosis, bronchoscopy was performed, demonstrating obstructed left lobar bronchus. The patient was re-intubated, and admitted to the operating room where reopening of the thoracotomy was performed. Lobar torsion was diagnosed, with the diaphragmatic surface of the upper lobe facing in an anterosuperior orientation. A completion pneumonectomy was performed. At the end of the procedure the patient developed a right pupil dilatation, presumably due to a cerebral embolism. A subsequent brain angio-CT scan established the diagnosis. She died at the intensive care unit 26 days later. Conclusion The thoracic surgeon should suspect this rare early postoperative complication after any thoracic operation in every patient with atelectasis of the neighboring lobe. High index of suspicion and prompt diagnosis may prevent catastrophic consequences, such as, infarction or gangrene of the pulmonary lobe. During thoracic operations, especially whenever the lung or lobe hilum is full mobilized, fixation of the remaining lobe may prevent this life threatening complication.

Understanding how pain education causes changes in pain and disability: protocol for a causal mediation analysis of the PREVENT trial.

Science.gov (United States)

Lee, Hopin; Moseley, G Lorimer; Hübscher, Markus; Kamper, Steven J; Traeger, Adrian C; Skinner, Ian W; McAuley, James H

2015-07-01

Pain education is a complex intervention developed to help clinicians manage low back pain. Although complex interventions are usually evaluated by their effects on outcomes, such as pain or disability, most do not directly target these outcomes; instead, they target intermediate factors that are presumed to be associated with the outcomes. The mechanisms underlying treatment effects, or the effect of an intervention on an intermediate factor and its subsequent effect on outcome, are rarely investigated in clinical trials. This leaves a gap in the evidence for understanding how treatments exert their effects on outcomes. Mediation analysis provides a method for identifying and quantifying the mechanisms that underlie interventions. To determine whether the effect of pain education on pain and disability is mediated by changes in self-efficacy, catastrophisation and back pain beliefs. Causal mediation analysis of the PREVENT randomised controlled trial. Two hundred and two participants with acute low back pain from primary care clinics in the Sydney metropolitan area. Participants will be randomised to receive either 'pain education' (intervention group) or 'sham education' (control group). All outcome measures (including patient characteristics), primary outcome measures (pain and disability), and putative mediating variables (self-efficacy, catastrophisation and back pain beliefs) will be measured prior to randomisation. Putative mediators and primary outcome measures will be measured 1 week after the intervention, and primary outcome measures will be measured 3 months after the onset of low back pain. Causal mediation analysis under the potential outcomes framework will be used to test single and multiple mediator models. A sensitivity analysis will be conducted to evaluate the robustness of the estimated mediation effects on the influence of violating sequential ignorability--a critical assumption for causal inference. Mediation analysis of clinical trials can

Opposing nodal and BMP signals regulate left-right asymmetry in the sea urchin larva.

Directory of Open Access Journals (Sweden)

Yi-Jyun Luo

Full Text Available Nodal and BMP signals are important for establishing left-right (LR asymmetry in vertebrates. In sea urchins, Nodal signaling prevents the formation of the rudiment on the right side. However, the opposing pathway to Nodal signaling during LR axis establishment is not clear. Here, we revealed that BMP signaling is activated in the left coelomic pouch, specifically in the veg2 lineage, but not in the small micromeres. By perturbing BMP activities, we demonstrated that BMP signaling is required for activating the expression of the left-sided genes and the formation of the left-sided structures. On the other hand, Nodal signals on the right side inhibit BMP signaling and control LR asymmetric separation and apoptosis of the small micromeres. Our findings show that BMP signaling is the positive signal for left-sided development in sea urchins, suggesting that the opposing roles of Nodal and BMP signals in establishing LR asymmetry are conserved in deuterostomes.

Can the epirubicin cardiotoxicity in cancer patients be prevented by angiotensin converting enzyme inhibitors?

Science.gov (United States)

Radulescu, D; Buzdugan, E; Ciuleanu, T E; Todor, N; Stoicescu, L

2013-01-01

The aim of this study was to assess whether treatment with angiotensin converting enzyme inhibitors (ACEI) can prevent the alteration of left ventricular systolic and diastolic performance in cancer patients treated with different chemotherapy regimens containing epirubicin. In this prospective study , 68 patients with different malignant tumors treated with epirubicin and perindopril in different chemotherapy protocols (study group), and a gender- and age-matched group of 68 patients with different malignant tumors treated with epirubicin without perindopril in different chemotherapy protocols (control group), were assessed by Doppler echocardiography. Left ventricular systolic function was assessed by measuring left ventricular ejection fraction (EF). Left ventricular diastolic function was assessed by Doppler ultrasound by evaluating the transmitral flow. We also assessed the QTc on the 12 lead electrocardiograms. At the end of chemotherapy the left ventricular systolic function was less altered in the study group compared to the control group and was superior in the study group (epirubicin+ACEI) compared to the control group (epirubicin alone). We documented a significantly deteriorated left ventricular diastolic function in both groups at the completion of chemotherapy. QTc time in both arms was also significantly prolonged. In the present echo-Doppler study we documented a preserved left ventricular systolic performance in patients with various malignancies treated with epirubicin plus perindopril. Although co-treatment with ACEI prevented the alteration of systolic performance, it failed to prevent the deterioration of the left ventricular diastolic performance impairment due to poor left ventricular compliance.

Target-mediated drug disposition model and its approximations for antibody-drug conjugates.

Science.gov (United States)

Gibiansky, Leonid; Gibiansky, Ekaterina

2014-02-01

Antibody-drug conjugate (ADC) is a complex structure composed of an antibody linked to several molecules of a biologically active cytotoxic drug. The number of ADC compounds in clinical development now exceeds 30, with two of them already on the market. However, there is no rigorous mechanistic model that describes pharmacokinetic (PK) properties of these compounds. PK modeling of ADCs is even more complicated than that of other biologics as the model should describe distribution, binding, and elimination of antibodies with different toxin load, and also the deconjugation process and PK of the released toxin. This work extends the target-mediated drug disposition (TMDD) model to describe ADCs, derives the rapid binding (quasi-equilibrium), quasi-steady-state, and Michaelis-Menten approximations of the TMDD model as applied to ADCs, derives the TMDD model and its approximations for ADCs with load-independent properties, and discusses further simplifications of the system under various assumptions. The developed models are shown to describe data simulated from the available clinical population PK models of trastuzumab emtansine (T-DM1), one of the two currently approved ADCs. Identifiability of model parameters is also discussed and illustrated on the simulated T-DM1 examples.

Polymeric mannosides prevent DC-SIGN-mediated cell-infection by cytomegalovirus.

Science.gov (United States)

Brument, S; Cheneau, C; Brissonnet, Y; Deniaud, D; Halary, F; Gouin, S G

2017-09-20

Human cytomegalovirus (HCMV) is a beta-herpesvirus with a high prevalence in the population. HCMV is asymptomatic for immunocompetent adults but is a leading cause of morbidity for new born and immunocompromised patients. It was recently shown that the envelope glycoprotein B (gB) of HCMV interacts with the Dendritic Cell-Specific ICAM-3 Grabbing Non integrin (DC-SIGN) to infect the host. In this work we developed a set of DC-SIGN blockers based on mono-, di-, tetra and polyvalent mannosides. The multivalent mannosides were designed to interact with the carbohydrate recognition domains of DC-SIGN in a chelate or bind and recapture process, and represent the first chemical antiadhesives of HCMV reported so far. Polymeric dextrans coated with triazolylheptylmannoside (THM) ligands were highly potent, blocking the gB and DC-SIGN interaction at nanomolar concentrations. The compounds were further assessed for their ability to prevent the DC-SIGN mediated HCMV infection of dendritic cells. A dextran polymer coated with an average of 902 THM ligands showed an outstanding effect in blocking the HCMV trans-infection with IC 50 values down to the picomolar range (nanomolar when expressed in THM concentration). Each THM moiety on the polymer surpassed the antiadhesive effect of the methylmannoside reference by more than four orders of magnitude. The compound proved non-cytotoxic at the high concentration of 2 mM and therefore represents an interesting antiadhesive candidate against HCMV and potentially against other virus hijacking dendritic cells to infect the host.

An exponential decay model for mediation.

Science.gov (United States)

Fritz, Matthew S

2014-10-01

Mediation analysis is often used to investigate mechanisms of change in prevention research. Results finding mediation are strengthened when longitudinal data are used because of the need for temporal precedence. Current longitudinal mediation models have focused mainly on linear change, but many variables in prevention change nonlinearly across time. The most common solution to nonlinearity is to add a quadratic term to the linear model, but this can lead to the use of the quadratic function to explain all nonlinearity, regardless of theory and the characteristics of the variables in the model. The current study describes the problems that arise when quadratic functions are used to describe all nonlinearity and how the use of nonlinear functions, such as exponential decay, address many of these problems. In addition, nonlinear models provide several advantages over polynomial models including usefulness of parameters, parsimony, and generalizability. The effects of using nonlinear functions for mediation analysis are then discussed and a nonlinear growth curve model for mediation is presented. An empirical example using data from a randomized intervention study is then provided to illustrate the estimation and interpretation of the model. Implications, limitations, and future directions are also discussed.

Being left-behind, mental disorder, and elderly suicide in rural China: a case-control psychological autopsy study.

Science.gov (United States)

Zhou, Liang; Wang, Guojun; Jia, Cunxian; Ma, Zhenyu

2018-04-25

Suicide rate among rural elderly is the highest among all age groups in China, yet little is known about the suicide risks in this rapidly growing vulnerable population. This matched case-control psychological autopsy study was conducted during June 2014 to September 2015. Consecutive samples of suicides aged 60 or above were identified in three provinces (Shandong, Hunan, and Guangxi) in China. Living comparisons were 1:1 matched with the suicides in age (±3 years old), gender, and living location. Risk factors included demographic characteristics, being left-behind, mental disorder, depressive symptoms, stressful life events, and social support. A total of 242 suicides and 242 comparisons were enrolled: 135 (55.8%) were male, mean (s.d.) age was 74 (8) years. The most frequently used suicide means were pesticides (125, 51.7%) and hanging (95, 39.3%). Independent risks of suicide included unstable marital status [odds ratio (OR) 4.19, 95% confidence interval (CI) 1.61-10.92], unemployed (compared with employed, OR 4.43, 95% CI 1.09-17.95), depressive symptoms (OR 1.34, 95% CI 1.21-1.48), and mental disorder (OR 6.28, 95% CI 1.75-22.54). Structural equation model indicated that the association between being left-behind and suicide was mediated by mental disorder, depressive symptoms, stressful life events, and social support. Unstable marital status, unemployed, depressive symptoms, and mental disorder are independent risk factors for suicide in rural elderly. Being left-behind can elevate the suicide risk through increasing life stresses, depressive symptoms, mental disorder, and decreasing social support. Elderly suicide may be prevented by restricting pesticides, training rural physicians, treating mental disorders, mitigating life stress, and enhancing social connection.

Flavoured Dark Matter moving left

Science.gov (United States)

Blanke, Monika; Das, Satrajit; Kast, Simon

2018-02-01

We investigate the phenomenology of a simplified model of flavoured Dark Matter (DM), with a dark fermionic flavour triplet coupling to the left-handed SU(2) L quark doublets via a scalar mediator. The DM-quark coupling matrix is assumed to constitute the only new source of flavour and CP violation, following the hypothesis of Dark Minimal Flavour Violation. We analyse the constraints from LHC searches, from meson mixing data in the K, D, and B d,s meson systems, from thermal DM freeze-out, and from direct detection experiments. Our combined analysis shows that while the experimental constraints are similar to the DMFV models with DM coupling to right-handed quarks, the multitude of couplings between DM and the SM quark sector resulting from the SU(2) L structure implies a richer phenomenology and significantly alters the resulting impact on the viable parameter space.

Frontopolar cortex mediates abstract integration in analogy.

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Green, Adam E; Fugelsang, Jonathan A; Kraemer, David J M; Shamosh, Noah A; Dunbar, Kevin N

2006-06-22

Integration of abstractly similar relations during analogical reasoning was investigated using functional magnetic resonance imaging. Activation elicited by an analogical reasoning task that required both complex working memory and integration of abstractly similar relations was compared to activation elicited by a non-analogical task that required complex working memory in the absence of abstract relational integration. A left-sided region of the frontal pole of the brain (BA 9/10) was selectively active for the abstract relational integration component of analogical reasoning. Analogical reasoning also engaged a left-sided network of parieto-frontal regions. Activity in this network during analogical reasoning is hypothesized to reflect categorical alignment of individual component terms that make up analogies. This parieto-frontal network was also engaged by the complex control task, which involved explicit categorization, but not by a simpler control task, which did not involve categorization. We hypothesize that frontopolar cortex mediates abstract relational integration in complex reasoning while parieto-frontal regions mediate working memory processes, including manipulation of terms for the purpose of categorical alignment, that facilitate this integration.

Systolic left ventricular function according to left ventricular concentricity and dilatation in hypertensive patients

DEFF Research Database (Denmark)

Bang, Casper; Gerdts, Eva; Aurigemma, Gerard P

2013-01-01

Left ventricular hypertrophy [LVH, high left ventricular mass (LVM)] is traditionally classified as concentric or eccentric based on left ventricular relative wall thickness. We evaluated left ventricular systolic function in a new four-group LVH classification based on left ventricular dilatation...... [high left ventricular end-diastolic volume (EDV) index and concentricity (LVM/EDV)] in hypertensive patients....

Preventing Errors in Laterality

OpenAIRE

Landau, Elliot; Hirschorn, David; Koutras, Iakovos; Malek, Alexander; Demissie, Seleshie

2014-01-01

An error in laterality is the reporting of a finding that is present on the right side as on the left or vice versa. While different medical and surgical specialties have implemented protocols to help prevent such errors, very few studies have been published that describe these errors in radiology reports and ways to prevent them. We devised a system that allows the radiologist to view reports in a separate window, displayed in a simple font and with all terms of laterality highlighted in sep...

Interaction of CDCP1 with HER2 Enhances HER2-Driven Tumorigenesis and Promotes Trastuzumab Resistance in Breast Cancer

Directory of Open Access Journals (Sweden)

Abdullah Alajati

2015-04-01

Full Text Available Understanding the molecular pathways that contribute to the aggressive behavior of HER2-positive breast cancers may aid in the development of novel therapeutic interventions. Here, we show that CDCP1 and HER2 are frequently co-overexpressed in metastatic breast tumors and associated with poor patient prognosis. HER2 and CDCP1 co-overexpression leads to increased transformation ability, cell migration, and tumor formation in vivo, and enhanced HER2 activation and downstream signaling in different breast cancer cell lines. Mechanistically, we demonstrate that CDCP1 binds to HER2 through its intracellular domain, thereby increasing HER2 interaction with the non-receptor tyrosine kinase c-SRC (SRC, leading to trastuzumab resistance. Taken together, our findings establish that CDCP1 is a modulator of HER2 signaling and a biomarker for the stratification of breast cancer patients with poor prognosis. Our results also provide a rationale for therapeutic targeting of CDCP1 in HER2-positive breast cancer patients.

Investigation of Mediational Processes Using Parallel Process Latent Growth Curve Modeling

Science.gov (United States)

Cheong, JeeWon; MacKinnon, David P.; Khoo, Siek Toon

2010-01-01

This study investigated a method to evaluate mediational processes using latent growth curve modeling. The mediator and the outcome measured across multiple time points were viewed as 2 separate parallel processes. The mediational process was defined as the independent variable influencing the growth of the mediator, which, in turn, affected the growth of the outcome. To illustrate modeling procedures, empirical data from a longitudinal drug prevention program, Adolescents Training and Learning to Avoid Steroids, were used. The program effects on the growth of the mediator and the growth of the outcome were examined first in a 2-group structural equation model. The mediational process was then modeled and tested in a parallel process latent growth curve model by relating the prevention program condition, the growth rate factor of the mediator, and the growth rate factor of the outcome. PMID:20157639

Depression and anxiety among left-behind children in China: a systematic review.

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Cheng, J; Sun, Y-H

2015-07-01

This study aimed to systematically review evidence of the prevalence and predictors of depression and anxiety among 'left-behind children' in rural China. The electronic databases PubMed/MEDLINE and Chinese National Knowledge Infrastructure/Wanfang (Chinese) were utilized to search for terms including 'depression' or 'depressive disorder', 'anxiety' or 'mental health', combined with 'left behind', 'children' and 'China'. High rates of psychological depression/anxiety have been reported among left-behind children compared with their age-matched peers. Prevalence rates of depression are reported to range from 12.1 to 51.4% and of anxiety are reported to range from 13.2 to 57.6%. Variability between studies is likely attributable to methodological variations relating to measures used and research setting. Potential predictors measured in studies include age and gender, types of being left, age/years of separation, socio-economic status, etc. These high rates of reported psychological problems among this group of young people suggest the need to develop more effective approaches to prevention and management. © 2014 John Wiley & Sons Ltd.

Scuba diving, acute left anterior descending artery occlusion and normal ECG

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Doll, Sébastien Xavier; Rigamonti, Fabio; Roffi, Marco; Noble, Stéphane

2013-01-01

We report the case of an acute proximal occlusion of the left anterior descending coronary (LAD) artery following a scuba diving decompression accident and associated with normal ECG. Following uneventful thromboaspiration and coronary stenting, the patient was discharged on day  4 with secondary preventative therapies. A transthoracic echocardiography performed at this point showed a complete recovery compared with an initial localised akinesia involving the anterior and apical portion of the left ventricle upon admission. This case highlights that significant acute coronary lesions involving the LAD can occur without any ECG anomaly. The presence of acute and persistent angina associated with troponin elevation should prompt physicians to consider coronary angiography without delay, independently of the ECG results. PMID:23376677

Giant left coronary ostial aneurysm after modified Bentall procedure in a Marfan patient.

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Okamoto, Kazuma; Casselman, Filip P; De Geest, Raphael; Vanermen, Hugo

2008-12-01

We performed surgical repair of a giant left coronary ostial aneurysm after aortic root replacement using composite valve graft (modified Bentall procedure) in a patient with Marfan syndrome. Aneurysmal formation in the left main stem itself is very rare. In order to avoid mobilizing the coronary ostium from severe adhesions after previous surgery and to reduce the tension on the anastomosis, the left main trunk was reconstructed using an interposition Dacron graft. In aortic root surgeries in Marfan patients, the size of the side hole on the composite graft should be kept relatively small to fit the diameter of the native coronary arteries for prevention of coronary buttons from forming aneurysms at the level of the coronary button anastomosis. In addition, close observation to the coronary button anastomosis is indispensable in postoperative check-up.

Dgroup: DG01358 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available DG01358 Chemical ... DGroup Trastuzumab ... D03257 ... Trastuzumab (INN); Trastuzumab (genetica...l recombination) (JAN) ... D09980 ... Trastuzumab emtansine (USAN/INN); Trastuzumab emtansine (genetical re

The Mediating Role of Partner Communication Frequency on Condom Use Among African-American Adolescent Females Participating in an HIV Prevention Intervention

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Sales, Jessica M.; Lang, Delia L.; DiClemente, Ralph J.; Latham, Teaniese P; Wingood, Gina M.; Hardin, James W.; Rose, Eve S.

2011-01-01

Objective Although effective HIV prevention interventions have been developed for adolescents, few interventions have explored whether components of the intervention are responsible for the observed changes in behaviors post-intervention. This study examined the mediating role of partner communication frequency on African-American adolescent females’ condom use post-participation in a demonstrated efficacious HIV risk-reduction intervention. Main Outcome Measures Percent condom use in the past 60 days and consistent condom use in the past 6o days across the 12-month follow-up period. Design As part of a randomized controlled trial of African-American adolescent females (N=715), 15-21 years, seeking sexual health services, completed a computerized interview at baseline (prior to intervention) and again 6- and 12-month follow-up post-intervention participation. The interview assessed adolescents’ sexual behavior and partner communication skills, among other variables, at each time point. Using generalized estimating equation (GEE) techniques, both logistic and linear regression models were employed to test mediation over the 12-month follow-up period. Additional tests were conducted to assess the significance of the mediated models. Results Mediation analyses observed that partner communication frequency was a significant partial mediator of both proportion condom-protected sex acts (p =.001) and consistent condom use (p = .001). Conclusion Partner communication frequency, an integral component of this HIV intervention, significantly increased as a function of participating in the intervention partially explaining the change in condom use observed 12-months post-intervention. Understanding what intervention components are associated with behavior change is important for future intervention development. PMID:21843001

Left-handedness and health

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Milenković Sanja

2010-01-01

Full Text Available Hand dominance is defined as a proneness to use one hand rather than another in performing the majority of activities and this is the most obvious example of cerebral lateralization and an exclusive human characteristic. Left-handed people comprise 6-14% of the total population, while in Serbia, this percentage is 5-10%, moving from undeveloped to developed environments, where a socio-cultural pressure is less present. There is no agreement between investigators who in fact may be considered a left-handed person, about the percentage of left-handers in the population and about the etiology of left-handedness. In the scientific literature left-handedness has been related to health disorders (spine deformities, immunological disorders, migraine, neurosis, depressive psychosis, schizophrenia, insomnia, homosexuality, diabetes mellitus, arterial hypertension, sleep apnea, enuresis nocturna and Down Syndrome, developmental disorders (autism, dislexia and sttutering and traumatism. The most reliable scientific evidences have been published about the relationship between left-handedness and spinal deformities in school children in puberty and with traumatism in general population. The controversy of other results in up-to-now investigations of health aspects of left-handedness may partly be explained by a scientific disagreement whether writing with the left hand is a sufficient criterium for left-handedness, or is it necessary to investigate other parameters for laterality assessment. Explanation of health aspects of left-handedness is dominantly based on Geschwind-Galaburda model about 'anomalous' cerebral domination, as a consequence of hormonal disbalance. .

[Left-handedness and health].

Science.gov (United States)

Milenković, Sanja; Belojević, Goran; Kocijancić, Radojka

2010-01-01

Hand dominance is defined as a proneness to use one hand rather than another in performing the majority of activities and this is the most obvious example of cerebral lateralization and an exclusive human characteristic. Left-handed people comprise 6-14% of the total population, while in Serbia, this percentage is 5-10%, moving from undeveloped to developed environments, where a socio-cultural pressure is less present. There is no agreement between investigators who in fact may be considered a left-handed person, about the percentage of left-handers in the population and about the etiology of left-handedness. In the scientific literature left-handedness has been related to health disorders (spine deformities, immunological disorders, migraine, neurosis, depressive psychosis, schizophrenia, insomnia, homosexuality, diabetes mellitus, arterial hypertension, sleep apnea, enuresis nocturna and Down Syndrome), developmental disorders (autism, dislexia and sttutering) and traumatism. The most reliable scientific evidences have been published about the relationship between left-handedness and spinal deformities in school children in puberty and with traumatism in general population. The controversy of other results in up-to-now investigations of health aspects of left-handedness may partly be explained by a scientific disagreement whether writing with the left hand is a sufficient criterium for left-handedness, or is it necessary to investigate other parameters for laterality assessment. Explanation of health aspects of left-handedness is dominantly based on Geschwind-Galaburda model about "anomalous" cerebral domination, as a consequence of hormonal disbalance.

The impact of students with left-behind experiences on childhood: The relationship between negative life events and depression among college students in China.

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Han, Li; Zhao, Sheng-Yu; Pan, Xuan-Ying; Liao, Chuan-Jing

2018-02-01

The number of left-behind children in rural China has increased dramatically over the last decade. It is reported that about 21.88% of child population with an estimated number of 61 million are left-behind children whose parents leave them to work in cities. We conducted a cross-sectional study to explore the impacts of left-behind experience (LBE) on college students' depression and other influencing factors. This study discusses the mediation effect of self-esteem together with psychological resilience on college students with depression and negative life events of left-behind. The study also discusses the regulation effect of LBE. A total of 788 college students were selected from three universities in Sichuan and Chongqing (367 with LBEs, 421 without LBEs). Adolescent Self-Rating Life Events Check List (ASLEC), Self-Esteem Scale (SES), Resilience Scale of Chinese Adolescent (RSCA) and Self-Rating Depression Scale (SDS) were used to measure the negative life events, self-esteem, psychological resilience and depression, respectively. Bootstrap program was used to test the mediation effect, and multiple-group analysis was used to examine the regulation effect for LBE. Scores of ASLEC for the college students with LBEs were higher than those without LBEs (8.59 ± 3.57) vs (7.06 ± 3.38), p ASLEC and SDS were positively correlated with the college students with LBEs ( r = .21 to .29, p < .01), while the scores of RSCA and SES were negatively correlated ( r = -.30 to -.59, p < .01). The mediation effect of college students' self-esteem and psychological resilience between negative life events and depression was significant (mediating effect = .08, .13, .07; p < .01). Thus, the college students' self-esteem and psychological resilience on negative life events had strong mediation effect on depression. The test of Bootstrap showed that the mediation effect of self-esteem and psychological resilience was significant (95% confidence

Relation of osteoprotegerin in severe aortic valve stenosis to postoperative outcome and left ventricular function

DEFF Research Database (Denmark)

Dahl, Jordi S; Videbæk, Lars; Poulsen, Mikael K

2013-01-01

Osteoprotegerin (OPG) is a member of the tumor necrosis factor receptor superfamily and is known to be among the mediators of the calcification process that has been shown to increase in patients with aortic stenosis (AS). The aim of this study was to characterize the association of OPG with left......, 41 patients died of a presumed cardiovascular cause or remained in New York Heart Association functional class III or IV. The risk of a poor postoperative outcome after AVR increased with increasing OPG tertiles (15% vs 33% vs 51%, p = 0.002). In a multivariate model containing age, ejection fraction......, N-terminal pro-brain natriuretic peptide and left atrial volume index, OPG was still significantly associated with postoperative outcome. In addition, OPG levels associated with cardiovascular mortality during follow-up. In conclusion, OPG is associated with LV and left atrial remodeling in patients...

Efficacy and safety of everolimus in combination with trastuzumab and paclitaxel in Asian patients with HER2+ advanced breast cancer in BOLERO-1.

Science.gov (United States)

Toi, Masakazu; Shao, Zhimin; Hurvitz, Sara; Tseng, Ling-Ming; Zhang, Qingyuan; Shen, Kunwei; Liu, Donggeng; Feng, Jifeng; Xu, Binghe; Wang, Xiaojia; Lee, Keun Seok; Ng, Ting Ying; Ridolfi, Antonia; Noel-Baron, Florence; Ringeisen, Francois; Jiang, Zefei

2017-04-11

The current exploratory analysis was performed to evaluate the efficacy and safety of everolimus for treatment of human epidermal growth factor receptor 2-positive (HER2+) advanced breast cancer in the Asian subset of patients in the BOLERO-1 trial. Postmenopausal women with HER2+ advanced breast cancer, who had not received systemic therapy for advanced disease, were randomized 2:1 to receive everolimus or placebo, plus trastuzumab and paclitaxel. The two primary end points were investigator-assessed progression-free survival (PFS) in the full population and in the hormone receptor-negative (HR-) subpopulation. Secondary end points included assessment of the objective response rate, the clinical benefit rate, and safety. In the Asian subset, median PFS was similar in the everolimus (n = 198) and placebo (n = 105) arms in the full analysis set (hazard ratio = 0.82 (95% CI 0.61-1.11)). In the HR- subpopulation, everolimus prolonged median PFS by 10.97 months vs placebo (25.46 vs 14.49 months; hazard ratio = 0.48 (95% CI 0.29-0.79)). In the everolimus arm of the Asian subset, the most common adverse events of any grade were stomatitis (62.2%), diarrhea (48.0%), rash (43.4%) and neutropenia (42.3%). Neutropenia (grade 3: 27.6%; grade 4: 4.6%) and decreased neutrophil count (grade 3: 11.2%; grade 4: 3.6%) were the most frequent grade 3/4 adverse events. Serious adverse events included pneumonia (5.1%), pneumonitis (3.1%), and interstitial lung disease (3.1%). There were three deaths (1.5%) during treatment in the everolimus arm vs none in the placebo arm. The efficacy and safety of everolimus plus trastuzumab and paclitaxel as first-line treatment for HER2+ advanced breast cancer in the Asian subset was consistent with that reported previously in the overall population. ClinicalTrials.gov, NCT00876395 . Registered on 2 April 2009.

Acrolein inhalation alters arterial blood gases and triggers carotid body-mediated cardiovascular responses in hypertensive rats.

Science.gov (United States)

Perez, Christina M; Hazari, Mehdi S; Ledbetter, Allen D; Haykal-Coates, Najwa; Carll, Alex P; Cascio, Wayne E; Winsett, Darrell W; Costa, Daniel L; Farraj, Aimen K

2015-01-01

Air pollution exposure affects autonomic function, heart rate, blood pressure and left ventricular function. While the mechanism for these effects is uncertain, several studies have reported that air pollution exposure modifies activity of the carotid body, the major organ that senses changes in arterial oxygen and carbon dioxide levels, and elicits downstream changes in autonomic control and cardiac function. We hypothesized that exposure to acrolein, an unsaturated aldehyde and mucosal irritant found in cigarette smoke and diesel exhaust, would activate the carotid body chemoreceptor response and lead to secondary cardiovascular responses in rats. Spontaneously hypertensive (SH) rats were exposed once for 3 h to 3 ppm acrolein gas or filtered air in whole body plethysmograph chambers. To determine if the carotid body mediated acrolein-induced cardiovascular responses, rats were pretreated with an inhibitor of cystathionine γ-lyase (CSE), an enzyme essential for carotid body signal transduction. Acrolein exposure induced several cardiovascular effects. Systolic, diastolic and mean arterial blood pressure increased during exposure, while cardiac contractility decreased 1 day after exposure. The cardiovascular effects were associated with decreases in pO2, breathing frequency and expiratory time, and increases in sympathetic tone during exposure followed by parasympathetic dominance after exposure. The CSE inhibitor prevented the cardiovascular effects of acrolein exposure. Pretreatment with the CSE inhibitor prevented the cardiovascular effects of acrolein, suggesting that the cardiovascular responses with acrolein may be mediated by carotid body-triggered changes in autonomic tone. (This abstract does not reflect EPA policy.).

New strict left bundle branch block criteria reflect left ventricular activation differences

DEFF Research Database (Denmark)

Emerek, Kasper Janus Grønn; Risum, Niels; Hjortshøj, Søren Pihlkjær

2015-01-01

AIMS: Pacing lead electrical delays and strict left bundle branch block (LBBB) criteria were assessed against cardiac resynchronization therapy (CRT) outcome. METHODS: Forty-nine patients with LBBB and QRS duration >130 milliseconds underwent CRT-implantation. Sensed right ventricular to left ven....... CONCLUSION: Interventricular electrical delay predicts left ventricular remodeling after CRT and new, strict ECG criteria of LBBB are superior in predicting remodeling.......AIMS: Pacing lead electrical delays and strict left bundle branch block (LBBB) criteria were assessed against cardiac resynchronization therapy (CRT) outcome. METHODS: Forty-nine patients with LBBB and QRS duration >130 milliseconds underwent CRT-implantation. Sensed right ventricular to left...... ventricular electrical delay (RV-LV-IED) was measured. Response to CRT was defined as ≥15% decrease in left ventricular end-systolic volume. RESULTS: Eighteen of 20 (90%) patients with non-ischemic dilated cardiomyopathy (DCM) and 18 of 29 (62%) with ischemic heart disease (IHD) responded to CRT, p

Neural networks mediating sentence reading in the deaf

Directory of Open Access Journals (Sweden)

Elizabeth Ann Hirshorn

2014-06-01

Full Text Available The present work addresses the neural bases of sentence reading in deaf populations. To better understand the relative role of deafness and English knowledge in shaping the neural networks that mediate sentence reading, three populations with different degrees of English knowledge and depth of hearing loss were included – deaf signers, oral deaf and hearing individuals. The three groups were matched for reading comprehension and scanned while reading sentences. A similar neural network of left perisylvian areas was observed, supporting the view of a shared network of areas for reading despite differences in hearing and English knowledge. However, differences were observed, in particular in the auditory cortex, with deaf signers and oral deaf showing greatest bilateral superior temporal gyrus (STG recruitment as compared to hearing individuals. Importantly, within deaf individuals, the same STG area in the left hemisphere showed greater recruitment as hearing loss increased. To further understand the functional role of such auditory cortex re-organization after deafness, connectivity analyses were performed from the STG regions identified above. Connectivity from the left STG toward areas typically associated with semantic processing (BA45 and thalami was greater in deaf signers and in oral deaf as compared to hearing. In contrast, connectivity from left STG toward areas identified with speech-based processing was greater in hearing and in oral deaf as compared to deaf signers. These results support the growing literature indicating recruitment of auditory areas after congenital deafness for visually-mediated language functions, and establish that both auditory deprivation and language experience shape its functional reorganization. Implications for differential reliance on semantic vs. phonological pathways during reading in the three groups is discussed.

Left atrial systolic force in hypertensive patients with left ventricular hypertrophy: the LIFE study

DEFF Research Database (Denmark)

Chinali, M.; Simone, G. de; Wachtell, K.

2008-01-01

In hypertensive patients without prevalent cardiovascular disease, enhanced left atrial systolic force is associated with left ventricular hypertrophy and increased preload. It also predicts cardiovascular events in a population with high prevalence of obesity. Relations between left atrial...... systolic force and left ventricular geometry and function have not been investigated in high-risk hypertrophic hypertensive patients. Participants in the Losartan Intervention For Endpoint reduction in hypertension echocardiography substudy without prevalent cardiovascular disease or atrial fibrillation (n...... = 567) underwent standard Doppler echocardiography. Left atrial systolic force was obtained from the mitral orifice area and Doppler mitral peak A velocity. Patients were divided into groups with normal or increased left atrial systolic force (>14.33 kdyn). Left atrial systolic force was high in 297...

Percutaneous closure of the left atrial appendage in patients with diabetes mellitus.

Science.gov (United States)

Azizy, Obayda; Rammos, Christos; Lehmann, Nils; Rassaf, Tienush; Kälsch, Hagen

2017-09-01

Left atrial appendage closure is a preventive treatment of atrial fibrillation-related thrombo-embolism. Patients with diabetes mellitus have increased risk for a negative outcome in percutaneous cardiac interventions. We assessed whether percutaneous left atrial appendage closure is safe and effective in patients with diabetes mellitus. We included 78 patients (mean age of 74.4 ± 8.3 years) with indication for left atrial appendage closure in an open-label observational single-centre study. Patients with diabetes mellitus ( n = 31) were at higher thrombo-embolic and bleeding risk (CHA 2 DS 2 -VASc: 4.5 ± 0.9, HAS-BLED: 4.7 ± 0.7) compared to patients without diabetes mellitus ( n = 47, CHA 2 DS 2 -VASc: 3.5 ± 1.0, HAS-BLED: 4.1 ± 0.8; p diabetes mellitus (Euro II-Score: 6.6 ± 3.7 vs 3.9 ± 1.9, p diabetes mellitus had no events ( p = 0.672). Follow-up of 6 months revealed no bleeding complication in both groups. No stroke occurred in follow-up, and left atrial appendage flow velocity reduction (55.6 ± 38.6 vs 51.4 ± 19.1 cm/s, p = 0.474) and rate of postinterventional leakage in the left atrial appendage were comparable (0% vs 2.1%, p = 0.672). Despite patients with diabetes mellitus are high-risk patients, the outcome of percutaneous left atrial appendage closure is similar to patients without diabetes mellitus.

Pancreatic Tissue Transplanted in TheraCyte Encapsulation Devices Is Protected and Prevents Hyperglycemia in a Mouse Model of Immune-Mediated Diabetes.

Science.gov (United States)

Boettler, Tobias; Schneider, Darius; Cheng, Yang; Kadoya, Kuniko; Brandon, Eugene P; Martinson, Laura; von Herrath, Matthias

2016-01-01

Type 1 diabetes (T1D) is characterized by destruction of glucose-responsive insulin-producing pancreatic β-cells and exhibits immune infiltration of pancreatic islets, where CD8 lymphocytes are most prominent. Curative transplantation of pancreatic islets is seriously hampered by the persistence of autoreactive immune cells that require high doses of immunosuppressive drugs. An elegant approach to confer graft protection while obviating the need for immunosuppression is the use of encapsulation devices that allow for the transfer of oxygen and nutrients, yet prevent immune cells from making direct contact with the islet grafts. Here we demonstrate that macroencapsulation devices (TheraCyte) loaded with neonatal pancreatic tissue and transplanted into RIP-LCMV.GP mice prevented disease onset in a model of virus-induced diabetes mellitus. Histological analyses revealed that insulin-producing cells survived within the device in animal models of diabetes. Our results demonstrate that these encapsulation devices can protect from an immune-mediated attack and can contain a sufficient amount of insulin-producing cells to prevent overt hyperglycemia.

Long-term effects of adolescent marijuana use prevention on adult mental health services utilization: the midwestern prevention project.

Science.gov (United States)

Riggs, Nathaniel R; Pentz, Mary Ann

2009-01-01

Evaluated were effects of a drug abuse(1) prevention program, previously shown to prevent marijuana use in adolescence, on adulthood mental health service use. Analyses were conducted on 961 6th (41%) and 7th (59%) grade participants randomly assigned to intervention or control groups at baseline in 1984. These participants were followed-up through 2003 representing 15 waves of data collection. Eighty-five percent of participants were Caucasian and 56% were female. The hypothesis was that direct program effects on early adulthood mental health service use would be mediated by program effects on high school marijuana use trajectories. Structural equation models, imputing for missing data, demonstrated that MPP (Midwestern Prevention Project) program effects on mental health were mediated by the marijuana use growth curve intercept. Findings support the role of early adolescent drug use prevention programs in impacting later mental health problems. The study's limitations are noted.

Rapid desensitization of mice with anti-FcγRIIb/FcγRIII mAb safely prevents IgG-mediated anaphylaxis.

Science.gov (United States)

Khodoun, Marat V; Kucuk, Zeynep Yesim; Strait, Richard T; Krishnamurthy, Durga; Janek, Kevin; Clay, Corey D; Morris, Suzanne C; Finkelman, Fred D

2013-12-01

Stimulatory IgG receptors (FcγRs) on bone marrow-derived cells contribute to the pathogenesis of several autoimmune and inflammatory disorders. Monoclonal antibodies that block FcγRs might suppress these diseases, but they can induce anaphylaxis. We wanted to determine whether a rapid desensitization approach can safely suppress IgG/FcγR-mediated anaphylaxis. Mice were injected with serially increasing doses of 2.4G2, a rat mAb that blocks the inhibitory FcγR, FcγRIIb, and the stimulatory receptor, FcγRIII. Rectal temperature was used to detect the development of anaphylaxis. Passive and active IgG-mediated anaphylaxis were evaluated in mice that had been rapidly desensitized with 2.4G2 or mock-desensitized in mice in which monocyte/macrophages, basophils, or neutrophils had been depleted or desensitized and in mice in which FcγRI, FcγRIII, and/or FcγRIV had been deleted or blocked. Rapid desensitization with 2.4G2 prevented 2.4G2-induced shock and completely suppressed IgG-mediated anaphylaxis. Rapid desensitization of ovalbumin-sensitized mice with 2.4G2 was safer and more effective than rapid desensitization with ovalbumin. 2.4G2 treatment completely blocked FcγRIII and removed most FcγRI and FcγRIV from nucleated peripheral blood cells. Because IgG(2a)-mediated anaphylaxis was partially FcγRI and FcγRIV dependent, the effects of 2.4G2 on FcγRI and FcγRIV were probably crucial for its complete inhibition of IgG(2a)-mediated anaphylaxis. IgG(2a)-mediated anaphylaxis was partially inhibited by depletion or desensitization of monocyte/macrophages, basophils, or neutrophils. IgG-mediated anaphylaxis can be induced by ligation of FcγRI, FcγRIII, or FcγRIV on monocycte/macrophages, basophils, or neutrophils and can be safely suppressed by rapid desensitization with anti-FcγRII/RIII mAb. A similar approach may safely suppress other FcγR-dependent immunopathology. Published by Mosby, Inc.

Human left ventral premotor cortex mediates matching of hand posture to object use.

Directory of Open Access Journals (Sweden)

Guy Vingerhoets

Full Text Available Visuomotor transformations for grasping have been associated with a fronto-parietal network in the monkey brain. The human homologue of the parietal monkey region (AIP has been identified as the anterior part of the intraparietal sulcus (aIPS, whereas the putative human equivalent of the monkey frontal region (F5 is located in the ventral part of the premotor cortex (vPMC. Results from animal studies suggest that monkey F5 is involved in the selection of appropriate hand postures relative to the constraints of the task. In humans, the functional roles of aIPS and vPMC appear to be more complex and the relative contribution of each region to grasp selection remains uncertain. The present study aimed to identify modulation in brain areas sensitive to the difficulty level of tool object - hand posture matching. Seventeen healthy right handed participants underwent fMRI while observing pictures of familiar tool objects followed by pictures of hand postures. The task was to decide whether the hand posture matched the functional use of the previously shown object. Conditions were manipulated for level of difficulty. Compared to a picture matching control task, the tool object - hand posture matching conditions conjointly showed increased modulation in several left hemispheric regions of the superior and inferior parietal lobules (including aIPS, the middle occipital gyrus, and the inferior temporal gyrus. Comparison of hard versus easy conditions selectively modulated the left inferior frontal gyrus with peak activity located in its opercular part (Brodmann area (BA 44. We suggest that in the human brain, vPMC/BA44 is involved in the matching of hand posture configurations in accordance with visual and functional demands.

Resveratrol Prevents High Fluence Red Light-Emitting Diode Reactive Oxygen Species-Mediated Photoinhibition of Human Skin Fibroblast Migration.

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Andrew Mamalis

Full Text Available Skin fibrosis is a significant medical problem that leads to a functional, aesthetic, and psychosocial impact on quality-of-life. Light-emitting diode-generated 633-nm red light (LED-RL is part of the visible light spectrum that is not known to cause DNA damage and is considered a safe, non-invasive, inexpensive, and portable potential alternative to ultraviolet phototherapy that may change the treatment paradigm of fibrotic skin disease.The goal of our study was to investigate the how reactive oxygen species (ROS free radicals generated by high fluence LED-RL inhibit the migration of skin fibroblasts, the main cell type involved in skin fibrosis. Fibroblast migration speed is increased in skin fibrosis, and we studied cellular migration speed of cultured human skin fibroblasts as a surrogate measure of high fluence LED-RL effect on fibroblast function. To ascertain the inhibitory role of LED-RL generated ROS on migration speed, we hypothesized that resveratrol, a potent antioxidant, could prevent the photoinhibitory effects of high fluence LED-RL on fibroblast migration speed.High fluence LED-RL generated ROS were measured by flow cytometry analysis using dihydrorhodamine (DHR. For purposes of comparison, we assessed the effects of ROS generated by hydrogen peroxide (H2O2 on fibroblast migration speed and the ability of resveratrol, a well known antioxidant, to prevent LED-RL and H2O2 generated ROS-associated changes in fibroblast migration speed. To determine whether resveratrol could prevent the high fluence LED-RL ROS-mediated photoinhibition of human skin fibroblast migration, treated cells were incubated with resveratrol at concentrations of 0.0001% and 0.001% for 24 hours, irradiated with high fluences LED-RL of 480, 640, and 800 J/cm2.High fluence LED-RL increases intracellular fibroblast ROS and decreases fibroblast migration speed. LED-RL at 480, 640 and 800 J/cm2 increased ROS levels to 132.8%, 151.0%, and 158.4% relative to matched

Improved eating behaviours mediate weight gain prevention of young adults: moderation and mediation results of a randomised controlled trial of TXT2BFiT, mHealth program.

Science.gov (United States)

Partridge, Stephanie R; McGeechan, Kevin; Bauman, Adrian; Phongsavan, Philayrath; Allman-Farinelli, Margaret

2016-04-02

Explanatory evaluation of interventions for prevention of weight gain is required beyond changes in weight, to determine for whom the intervention works and the underlying mechanisms of change. It was hypothesised that participant characteristics moderate intervention effect on weight change and improved eating and physical activity behaviours during the 3-month program mediate the relationship between intervention and weight. In our randomised controlled trial, young adults at risk of weight gain (n = 250) were assigned either to an intervention group that received a 3-month mHealth (TXT2BFiT) program with 6-month maintenance or to a control group. Data were collected via online self-report surveys. Hypothesised moderators and mediators of the intervention effect on weight were independently assessed in PROCESS macro models for 3 and 9-month weight change. Males (P = 0.01), mid-20s age group (P = 0.04), and higher income earners (P = 0.02) moderated intervention effects on weight change at 3-months and males only at 9-months (P = 0.02). Weight change at 3 (-1.12 kg) and 9-months (-1.38 kg) remained significant when 3-month nutrition and physical activity behaviours were specified as mediators (P <0.01 and P = 0.01 respectively). Indirect paths explained 39% (0.72/1.85 kg) and 40 % (0.92/2.3 kg) of total effect on weight change at 3 and 9-months respectively. Increased vegetable intake by intervention group at 3-months accounted for 19 and 17% and decreased sugar-sweetened beverages accounted for 8 and 13% of indirect weight change effects at 3 and 9-months respectively. TXT2BFiT was effective for both young men and women. Small sustained behavioural changes, including increased vegetable intake and decreased sugar-sweetened beverages consumption significantly mediated the intervention's effects on weight change. Improved eating behaviours and increased physical activity accounted for approximately 40% of the weight change. The trial is

The effect of both Z and Z'-mediated flavor-changing neutral currents on Bs → μ+ μ- decay

International Nuclear Information System (INIS)

Sahoo, S.; Maharana, L.; Behera, B.R.

2007-01-01

We study the effect of both Z and Z'-mediated flavor-changing neutral currents (FCNCs) on the B s → μ + μ - rare decay process. Mixing between ordinary and exotic left-handed quarks induces Z-mediated FCNC whereas mixing of right-handed ordinary and exotic quarks induces Z'-mediated FCNC. We find the branching ratio is enhanced from its standard model (SM) value due to the effect of both Z and Z'-mediated FCNCs. (author)

Repair of aorto-left ventricular tunnel arising from the left sinus of valsalva.

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Nezafati, Mohammad Hassan; Maleki, Mahmood Hosseinzadeh; Javan, Hadi; Zirak, Nahid

2010-05-01

Aortico-left ventricular tunnel (ALVT) is a rare congenital cardiac defect that bypasses the aortic valve via a para-valvular connection from the left ventricle to the aorta. In most cases, the tunnel arises from the right aortic sinus. In this case report, we are presenting a case of ALVT, of which the aortic orifice arose from the left aortic sinus, requiring special attention to avoid the left coronary artery injury at the time of surgical repair.

Invasive micropapillary carcinoma of the breast overexpresses MUC4 and is associated with poor outcome to adjuvant trastuzumab in HER2-positive breast cancer.

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Mercogliano, María F; Inurrigarro, Gloria; De Martino, Mara; Venturutti, Leandro; Rivas, Martín A; Cordo-Russo, Rosalía; Proietti, Cecilia J; Fernández, Elmer A; Frahm, Isabel; Barchuk, Sabrina; Allemand, Daniel H; Figurelli, Silvina; Deza, Ernesto Gil; Ares, Sandra; Gercovich, Felipe G; Cortese, Eduardo; Amasino, Matías; Guzmán, Pablo; Roa, Juan C; Elizalde, Patricia V; Schillaci, Roxana

2017-12-28

Invasive micropapillary carcinoma of the breast (IMPC) is a histological tumor variant that occurs with low frequency characterized by an inside-out formation of tumor clusters with a pseudopapillary arrangement. IMPC is an aggressive tumor with poor clinical outcome. In addition, this histological subtype usually expresses human epidermal growth factor receptor 2 (HER2) which also correlates with a more aggressive tumor. In this work we studied the clinical significance of IMPC in HER2-positive breast cancer patients treated with adjuvant trastuzumab. We also analyzed mucin 4 (MUC4) expression as a novel biomarker to identify IMPC. We retrospectively studied 86 HER2-positive breast cancer patients treated with trastuzumab and chemotherapy in the adjuvant setting. We explored the association of the IMPC component with clinicopathological parameters at diagnosis and its prognostic value. We compared MUC4 expression in IMPC with respect to other histological breast cancer subtypes by immunohistochemistry. IMPC, either as a pure entity or associated with invasive ductal carcinoma (IDC), was present in 18.6% of HER2-positive cases. It was positively correlated with estrogen receptor expression and tumor size and inversely correlated with patient's age. Disease-free survival was significantly lower in patients with IMPC (hazard ratio = 2.6; 95%, confidence interval 1.1-6.1, P = 0.0340). MUC4, a glycoprotein associated with metastasis, was strongly expressed in all IMPC cases tested. IMPC appeared as the histological breast cancer subtype with the highest MUC4 expression compared to IDC, lobular and mucinous carcinoma. In HER2-positive breast cancer, the presence of IMPC should be carefully examined. As it is often not informed, because it is relatively difficult to identify or altogether overlooked, we propose MUC4 expression as a useful biomarker to highlight IMPC presence. Patients with MUC4-positive tumors with IMPC component should be more frequently

What's Left of the Left-Right Dimension? Why the Economic Policy Positions of Europeans Do Not Fit the Left-Right Dimension.

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Otjes, Simon

2018-01-01

In political science the economic left-right dimension plays a central role. A growing body of evidence shows that the economic policy preferences of a large segment of citizens do not scale sufficiently. Using Mokken scale analysis, this study determines the causes of this phenomenon. Differences in the extent to which the economic policy preferences of citizens fit the left-right dimension can be explained in terms of the interaction between individual level and political system-level variables: citizens who spend more attention to politicians with views that conform to the left-right dimension, have views that conform to the left-right dimension. There is also a role for the legacy of communist dictatorship: citizens who were socialised in democratic countries have views that fit the left-right dimension better than those socialised during communism.

PREVENTION OF LEFT VENTRICLE SYSTOLIC DYSFUNCTION IN PATIENTS WITH ACUTE CORONARY SYNDROME WITH ST SEGMENT ELEVATION AFTER CARDIAC REVASCULARIZATION

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A. L. Alyavi

2016-01-01

Full Text Available Aim. To study effects of bioflavonoid quercetin (corvitin on left ventricle (LV systolic dysfunction in patients with acute coronary syndrome with ST segment elevation (ACS+ST after cardiac revascularization.Material and methods. 60 patients with ACS+ST (44,2±1,3 y.o. were examined. Patients were admitted to hospital within 6 hours after complaints beginning. Patients were randomized in two groups. 30 patients of group A had standard therapy and cardiac revascularization. 30 patients of group B received corvitin additionally to standard therapy before cardiac revascularization. Echocardiography initially and stress-echocardiography with dobutamine after status stabilization (at 8-10 days of disease were performed.Results. Dobutamine test (with low and high doses showed myocardial viability in patients of group B. Patients of group A had irreversible LV systolic dysfunction in 32 % of segments. Corvitin slowed down LV dilatation progression in patients with ACS+ST. It resulted in the end-diastolic and end-systolic indexes did not change within 10 days. The LV ejection fraction was more increased in patients of group B in comparison with patients of group A.Conclusion. The early corvitin prescribing has positive effects on LV systolic function and prevents post-reperfusion complications. 

PREVENTION OF LEFT VENTRICLE SYSTOLIC DYSFUNCTION IN PATIENTS WITH ACUTE CORONARY SYNDROME WITH ST SEGMENT ELEVATION AFTER CARDIAC REVASCULARIZATION

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A. L. Alyavi

2009-01-01

Full Text Available Aim. To study effects of bioflavonoid quercetin (corvitin on left ventricle (LV systolic dysfunction in patients with acute coronary syndrome with ST segment elevation (ACS+ST after cardiac revascularization.Material and methods. 60 patients with ACS+ST (44,2±1,3 y.o. were examined. Patients were admitted to hospital within 6 hours after complaints beginning. Patients were randomized in two groups. 30 patients of group A had standard therapy and cardiac revascularization. 30 patients of group B received corvitin additionally to standard therapy before cardiac revascularization. Echocardiography initially and stress-echocardiography with dobutamine after status stabilization (at 8-10 days of disease were performed.Results. Dobutamine test (with low and high doses showed myocardial viability in patients of group B. Patients of group A had irreversible LV systolic dysfunction in 32 % of segments. Corvitin slowed down LV dilatation progression in patients with ACS+ST. It resulted in the end-diastolic and end-systolic indexes did not change within 10 days. The LV ejection fraction was more increased in patients of group B in comparison with patients of group A.Conclusion. The early corvitin prescribing has positive effects on LV systolic function and prevents post-reperfusion complications. 

Anatomic relationship between left coronary artery and left atrium in patients undergoing atrial fibrillation ablation.

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Anselmino, Matteo; Torri, Federica; Ferraris, Federico; Calò, Leonardo; Castagno, Davide; Gili, Sebastiano; Rovera, Chiara; Giustetto, Carla; Gaita, Fiorenzo

2017-07-01

Atrial fibrillation transcatheter ablation (TCA) is, within available atrial fibrillation rhythm control strategies, one of the most effective. To potentially improve ablation outcome in case of recurrent atrial fibrillation after a first procedure or in presence of structural myocardial disease, isolation of the pulmonary veins may be associated with extensive lesions within the left atrium. To avoid rare, but potentially life-threatening, complications, thorough knowledge and assessment of left atrium anatomy and its relation to structures in close proximity are, therefore, mandatory. Aim of the present study is to describe, by cardiac computed tomography, the anatomic relationship between aortic root, left coronary artery and left atrium in patients undergoing atrial fibrillation TCA. The cardiac computed tomography scan of 21 patients affected by atrial fibrillation was elaborated to segment left atrium, aortic root and left coronary artery from the surrounding structures and the following distances measured: left atrium and aortic root; left atrium roof and aortic root; left main coronary artery and left atrium; circumflex artery and left atrium appendage; and circumflex artery and mitral valve annulus. Above all, the median distance between left atrium and aortic root (1.9, 1.5-2.1 mm), and between circumflex artery and left atrium appendage ostium (3.0, 2.1-3.4 mm) were minimal (≤3 mm). None of measured distances significantly varied between patients presenting paroxysmal versus persistent atrial fibrillation. The anatomic relationship between left atrium and coronary arteries is extremely relevant when performing atrial fibrillation TCA by extensive lesions. Therefore, at least in the latter case, preablation imaging should be recommended to avoid rare, but potentially life-threatening, complications with the aim of an as well tolerated as possible procedure.

LEFT ATRIUM THROMBOSIS IN PATIENTS WITH RHEUMATIC MITRAL VALVULAR DISEASE

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N. D. Kaverin

2012-01-01

Full Text Available Systemic thromboembolism — fairly common complication of mitral valvular disease, often leading to disability or fatal consequences for the patient. The source of emboli in most cases, are blood clots localized in the left atrium. The survey reflected basic views on the pathogenesis, diagnosis, treatment and prevention of intraatrial thrombosis according to new scientific advances. Articles (reviews, meta-analyzes and original researchs from Pub Med database, as well as domestic literature were used.

The Left Labourites and the General Strike of 1926 in the UK

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Evgeniya G. Blosfeld

2017-12-01

Full Text Available The author analyses the left labourites’ attitude to the interaction of the Labour Party and trade unions and use of general strike as a means of the social struggle. Besides the article analyses the left labourites’ estimation of 1926 general strike and the causes of the defeat, and the strike of the miners who decided to continue it. The left labourites defended the branch principle of the trade unions’ organization based on the shopstewards’ model which was better adopted for the strike struggle. The left labourites took into account that the general structure of the labour movement would remain the same, but the Labour Party would take over the leadership from trade unions. The left labourites supported the peaceful way of transition to socialism and they considered the general strike to be analogy of social revolution or a means of pressure of the government for nationalization of the main economic branches and the improvement of the workers’ life conditions. Under extreme circumstances, the general strike was considered to be a means to prevent antidemocratic revolution. Evaluating the general strike of 1926, the author marks the absence of unity in the leadership, hesitations and inconsistency of the left labourites themselves. They didn’t give a single proposal about the improvement of the working-class movement organization except of state British Trade Unions Congress. As a result, the criticism of the General Council’s renegade position was bestowed upon the leadership of the Miners Federation who didn’t submit to the General Council order to stop the strike.

Why PeV scale left-right symmetry is a good thing

Science.gov (United States)

Yajnik, Urjit A.

2017-10-01

Left-right symmetric gauge theory presents a minimal paradigm to accommodate massive neutrinos with all the known conserved symmetries duly gauged. The work presented here is based on the argument that the see-saw mechanism does not force the new right-handed symmetry scale to be very high, and as such some of the species from the spectrum of the new gauge and Higgs bosons can have masses within a few orders of magnitude of the TeV scale. The scale of the left-right parity breaking in turn can be sequestered from the Planck scale by supersymmetry. We have studied several formulations of such just beyond Standard Model (JBSM) theories for their consistency with cosmology. Specifically, the need to eliminate phenomenologically undesirable domain walls gives many useful clues. The possibility that the exact left-right symmetry breaks in conjunction with supersymmetry has been explored in the context of gauge mediation, placing restrictions on the available parameter space. Finally, we have also studied a left-right symmetric model in the context of metastable supersymmetric vacua and obtained constraints on the mass scale of right-handed symmetry. In all the cases studied, the mass scale of the right-handed neutrino M_R remains bounded from above, and in some of the cases the scale 10^9 GeV favourable for supersymmetric thermal leptogenesis is disallowed. On the other hand, PeV scale remains a viable option, and the results warrant a more detailed study of such models for their observability in collider and astroparticle experiments.

Predictors of Parental Mediation Regarding Children's Smartphone Use.

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Hwang, Yoori; Jeong, Se-Hoon

2015-12-01

Children's addiction to smartphones has become a serious issue, and parental mediation could help prevent children's problematic use of smartphones. This research examined the factors that predict and explain parents' intention to mediate children's behavior over smartphone use. Based on a survey of 460 parents of elementary school students, we found that parental mediation was predicted by (a) parent's own addiction to smartphones, (b) perceived severity of smartphone addiction, and (c) personality traits such as neuroticism, openness, and agreeableness. To the best of our knowledge, this study is the first to examine the predictors of parental mediation regarding children's smartphone addiction, and the findings suggest some strategies to increase parental mediation.

Is parenting the mediator of change in behavioral parent training for externalizing problems of youth?

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Forehand, Rex; Lafko, Nicole; Parent, Justin; Burt, Keith B

2014-12-01

Change in parenting behavior is theorized to be the mediator accounting for change in child and adolescent externalizing problems in behavioral parent training (BPT). The purpose of this review is to examine this assumption in BPT prevention and intervention programs. Eight intervention and 17 prevention studies were identified as meeting all criteria or all but one criterion for testing mediation. Parenting behaviors were classified as positive, negative, discipline, monitoring/supervision, or a composite measure. Forty-five percent of the tests performed across studies to test mediation supported parenting as a mediator. A composite measure of parenting and discipline received the most support, whereas monitoring/supervision was rarely examined. More support for the mediating role of parenting emerged for prevention than intervention studies and when meeting all criteria for testing mediation was not required. Although the findings do not call BPT into question as an efficacious treatment, they do suggest more attention should be focused on examining parenting as a putative mediator in BPT. Copyright © 2014 Elsevier Ltd. All rights reserved.

Rebuilding the US Health Left

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Victor W. Sidel, MD

2010-02-01

Full Text Available With this issue Social Medicine begins a series of invited papers on the topic: “Rebuilding the US Health Left.” In this editorial we will outline our vision for this series. We undertake this project aware that our good friend and mentor, Dr. Walter Lear, one of the leading health activists of the 20th century, lies critically ill. Walter was the creator and custodian of the US Health Left Archives, a collection that is now with the University of Pennsylvania library. The collection reminds us of the important role left health care workers played in US history throughout the 20th century. They advocated for a national health program (Committee on the Costs of Medical Care, Physicians Forum, Medical Care Section/APHA, HealthPAC, Physicians for a National Health Program, National Physicians Alliance, provided international solidarity (American Soviet Medical Society, international brigades during the Spanish Civil War, Central American Solidarity Movement, Committee to Help Chilean Health Workers, Doctors for Global Health, traced the connections between disease and social class (Sigerist Circle, Spirit of 1848, APHA, fought for workers’ health (Councils for Occupational Safety and Health; Occupational Health and Safety Section, APHA participated in anti-war movements (Medical Committee for Human Rights, Physicians for Social Responsibility, International Physicians for the Prevention of Nuclear War, created new models of health care delivery (Health Cooperatives, Prepaid Health Maintenance Organizations, Community Health Centers, National Health Service Corps, Free Clinics, were central to the struggle for women’s rights (Planned Parenthood, Physicians for Reproductive Choice and Health, supported the civil rights movement both in medicine and in the broader society (National Medical Association, Medical Committee for Human Rights, played key roles in the movement for gay rights (ACT-UP, Gay & Lesbian Medical Association, Lesbian, Gay

(−-Epicatechin Reduces Blood Pressure and Improves Left Ventricular Function and Compliance in Deoxycorticosterone Acetate-Salt Hypertensive Rats

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Douglas Jackson

2018-06-01

Full Text Available (−-Epicatechin (E is a flavanol found in green tea and cocoa and has been shown to attenuate tumour necrosis factor alpha (TNF-α-mediated inflammation, improve nitric oxide levels, promote endothelial nitric oxide synthase (eNOS activation and inhibit NADPH oxidase. This study investigated the effect of 28 days of low epicatechin dosing (1 mg/kg/day on the cardiovascular function of deoxycorticosterone acetate (DOCA-salt hypertensive rats. Wistar rats (n = 120, 8 weeks of age underwent uninephrectomy and were randomised into four groups (uninephrectomy (UNX, UNX + E, DOCA, DOCA + E. DOCA and DOCA + E rats received 1% NaCl drinking water along with subcutaneous injections of 25 mg deoxycorticosterone-acetate (in 0.4 mL of dimethylformamide every fourth day. UNX + E and DOCA + E rats received 1 mg/kg/day of epicatechin by oral gavage. Single-cell micro-electrode electrophysiology, Langendorff isolated-heart assessment and isolated aorta and mesenteric organ baths were used to assess cardiovascular parameters. Serum malondialdehyde concentration was used as a marker of oxidative stress. Myocardial stiffness was increased and left ventricular compliance significantly diminished in the DOCA control group, and these changes were attenuated by epicatechin treatment (p < 0.05. Additionally, the DOCA + E rats showed significantly reduced blood pressure and malondialdehyde concentrations; however, there was no improvement in left ventricular hypertrophy, electrophysiology or vascular function. This study demonstrates the ability of epicatechin to reduce blood pressure, prevent myocardial stiffening and preserve cardiac compliance in hypertrophied DOCA-salt rat hearts.

Left ventricular rupture postmitral valve replacement: Surviving a catastrophe

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Samarjit Bisoyi

2015-01-01

Full Text Available One of the dreaded mechanical complications of mitral valve replacement (MVR is rupture of the left ventricle (LV. This report describes the early diagnosis and successful repair of rupture of posterior wall of LV in an elderly patient who underwent MVR. We have discussed the risk factors and perioperative issues implicated in such complication. The anesthesiologist as an intra-operative echocardiographer can aid in identifying the patient at risk. Though important surgical steps are necessary to prevent the complication; nonetheless, the anesthesiologist needs to take key measures in the perioperative period.

The clot thickens: an incompletely ligated left  atrial appendage

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Merrill Thomas

2018-05-01

Full Text Available Our patient presented with known mechanical mitral valve endocarditis documented by 2D transesophageal echocardiogram (TOE from a recent hospitalization at an outside facility. On admission to our center, there was no prior knowledge of an incompletely ligated left atrial appendage (LAA according to patient- or family-reported history, review of outside records or the outside facility’s 2D TOE report. A 3D TOE performed at our center to assess her pathology, since a month had passed from her prior hospitalization, revealed a LAA ligation with evidence of communication to the left atrium and with clot present in the appendage. This case report highlights the common finding of incomplete closure of the LAA following surgical ligation, thus making it inadequate for stroke prevention in patients with atrial fibrillation, and that 3D TOE plays a valuable role in assessing the durability of LAA ligation.

Perioperative management of calves undergoing implantation of a left ventricular assist device.

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Wilson, D V; Kantrowitz, A; Pacholewicz, J; Salat, O; Paules, B R; Zhou, Y; Dawe, E J

2000-01-01

To describe perioperative management of calves that underwent left lateral thoracotomy, aortic cross-clamping, partial left heart bypass and implantation of a left ventricular assist device. A total of 43 healthy castrated male calves, weighing 121 +/- 24 kg. Diazepam (mean +/- SD, 0.26 +/- 0.07 mg/kg), ketamine (5.9 +/- 2.17 mg/kg) and isoflurane were used in the anesthetic management of calves undergoing implantation of a left ventricular assist device in the descending thoracic aorta. Other adjunctive agents administered were fentanyl (11 +/- 5.4 microg/kg), lidocaine (4.9 +/- 3.19 mg/kg), bupivacaine (0.75%) and butorphanol (0.49 +/- 0.13 mg/kg). None of the calves regurgitated at induction or during intubation. A tube was used to drain the rumen and prevent bloat during the procedure. Partial left heart bypass was used to perfuse the caudal half of the body during the period of aortic cross clamp and device implantation. Initial mean systemic blood pressure was 96 +/- 25 mm Hg, and pressures measured in the auricular artery increased during aortic cross-clamping and bypass. Vasoconstrictor therapy was required to treat caudal arterial hypotension during the procedure in 9 calves. Mean systemic arterial pressures returned to baseline values by the end of the anesthetic period. Initial mean pulmonary arterial pressures (PAP) were 22 +/- 3 mm Hg. A significant but transient increase in pulmonary arterial pressure occurred after both heparin and protamine administration. The described anesthetic protocol was effective for thoracotomy and implantation of an intra-aortic left ventricular assist device in normal calves. Partial left ventricular bypass was a useful adjunct during the period of aortic cross clamp. The doses of heparin and protamine administered were effective. Responsibility to monitor oxygenation of the cranial half of the animal continues during the bypass period as hypoxemia due to pulmonary dysfunction will not be detected by the perfusionist.

Emotional and behavioral problems of Chinese left-behind children: a preliminary study.

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Fan, Fang; Su, Linyan; Gill, Mary Kay; Birmaher, Boris

2010-06-01

To examine the behavioral and emotional problems and their correlates in left-behindchildren (LBC) in the Hunan Province of China. A sample of 1,274 schoolchildren (48.7% girls; 12.4 +/- 2.2 years old) completed the Strength and Difficulties Questionnaire and their current caregivers completed questionnaires about caregiver/bio-parent's demographics and teachers' involvement with the family. There were 629 (49%) children with a history of being left behind, of which 486 were currently cared for by a relative (RLC) and 41 by a non-relative (NRC). As much as 102 had a past history of being left behind, but were currently living with one or more biological parents at the time of the survey (PLB). A total of 645 (51%) children had no history of being left behind and were included as controls. LBC had significantly more psychopathology and less pro-social behaviors than the controls. These differences, with the exception of more hyperactivity and less pro-social behaviors, disappeared after adjusting for age, education and socioeconomic status of the children, parents/caregivers, and the involvement of the teachers. The psychopathology of LBC was significantly inversely correlated with these variables. Long duration and being left behind at a younger age were significantly associated with more psychopathology. Overall, NRC showed more psychopathology, followed by PLB and then RLC. However, with the exception of pro-social behaviors, after adjusting for demographic variables and duration of being left behind, all differences disappeared. LBC are at risk to develop emotional/behavior problems, particularly if they are left behind early in life, for longer periods, in the care of young caregivers or nonrelatives with poor education and low socioeconomic status, and with less teacher support. Strategies to prevent the development of psychopathology and its amelioration, and governmental policies to decrease the rates of LBC are warranted.

A Technology-Mediated Behavioral Weight Gain Prevention Intervention for College Students: Controlled, Quasi-Experimental Study.

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West, Delia Smith; Monroe, Courtney M; Turner-McGrievy, Gabrielle; Sundstrom, Beth; Larsen, Chelsea; Magradey, Karen; Wilcox, Sara; Brandt, Heather M

2016-06-13

Both men and women are vulnerable to weight gain during the college years, and this phenomenon is linked to an increased risk of several chronic diseases and mortality. Technology represents an attractive medium for the delivery of weight control interventions focused on college students, given its reach and appeal among this population. However, few technology-mediated weight gain prevention interventions have been evaluated for college students. This study examined a new technology-based, social media-facilitated weight gain prevention intervention for college students. Undergraduates (n =58) in two sections of a public university course were allocated to either a behavioral weight gain prevention intervention (Healthy Weight, HW; N=29) or a human papillomavirus (HPV) vaccination awareness intervention (control; N=29). All students were enrolled, regardless of initial body weight or expressed interest in weight management. The interventions delivered 8 lessons via electronic newsletters and Facebook postings over 9 weeks, which were designed to foster social support and introduce relevant educational content. The HW intervention targeted behavioral strategies to prevent weight gain and provided participants with a Wi-Fi-enabled scale and an electronic physical activity tracker to facilitate weight regulation. A repeated-measures analysis of variance was conducted to examine within- and between-group differences in measures of self-reported weight control practices and objectively measured weight. Use of each intervention medium and device was objectively tracked, and intervention satisfaction measures were obtained. Students remained weight stable (HW: -0.48+1.9 kg; control: -0.45+1.4 kg), with no significant difference between groups over 9 weeks (P =.94). However, HW students reported a significantly greater increase in the number of appropriate weight control strategies than did controls (2.1+4.5 vs -1.1+3.4, respectively; P =.003) and there was no increase in

Intravenous immunoglobulin prevents murine antibody-mediated acute lung injury at the level of neutrophil reactive oxygen species (ROS production.

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John W Semple

Full Text Available Transfusion-related acute lung injury (TRALI is a leading cause of transfusion-associated mortality that can occur with any type of transfusion and is thought to be primarily due to donor antibodies activating pulmonary neutrophils in recipients. Recently, a large prospective case controlled clinical study of cardiac surgery patients demonstrated that despite implementation of male donors, a high incidence of TRALI still occurred and suggested a need for additional interventions in susceptible patient populations. To examine if intravenous immunoglobulin (IVIg may be effective, a murine model of antibody-mediated acute lung injury that approximates human TRALI was examined. When BALB/c mice were injected with the anti-major histocompatibility complex class I antibody 34-1-2s, mild shock (reduced rectal temperature and respiratory distress (dyspnea were observed and pre-treatment of the mice with 2 g/kg IVIg completely prevented these symptoms. To determine IVIg's usefulness to affect severe lung damage, SCID mice, previously shown to be hypersensitive to 34-1-2s were used. SCID mice treated with 34-1-2s underwent severe shock, lung damage (increased wet/dry ratios and 40% mortality within 2 hours. Treatment with 2 g/kg IVIg 18 hours before 34-1-2s administration completely protected the mice from all adverse events. Treatment with IVIg after symptoms began also reduced lung damage and mortality. While the prophylactic IVIg administration did not affect 34-1-2s-induced pulmonary neutrophil accumulation, bone marrow-derived neutrophils from the IVIg-treated mice displayed no spontaneous ROS production nor could they be stimulated in vitro with fMLP or 34-1-2s. These results suggest that IVIg prevents murine antibody-mediated acute lung injury at the level of neutrophil ROS production and thus, alleviating tissue damage.

Intravascular local gene transfer mediated by protein-coated metallic stent.

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Yuan, J; Gao, R; Shi, R; Song, L; Tang, J; Li, Y; Tang, C; Meng, L; Yuan, W; Chen, Z

2001-10-01

To assess the feasibility, efficiency and selectivity of adenovirus-mediated gene transfer to local arterial wall by protein-coated metallic stent. A replication-defective recombinant adenovirus carrying the Lac Z reporter gene for nuclear-specific beta-galactosidase (Ad-beta gal) was used in this study. The coating for metallic stent was made by immersing it in a gelatin solution containing crosslinker. The coated stents were mounted on a 4.0 or 3.0 mm percutaneous transluminal coronary angioplasty (PTCA) balloon and submersed into a high-titer Ad-beta gal viral stock (2 x 10(10) pfu/ml) for 3 min, and then implanted into the carotid arteries in 4 mini-swines and into the left anterior descending branch of the coronary artery in 2 mini-swines via 8F large lumen guiding catheters. The animals were sacrificed 7 (n = 4), 14 (n = 1) and 21 (n = 1) days after implantation, respectively. The beta-galactosidase expression was assessed by X-gal staining. The results showed that the expression of transgene was detected in all animal. In 1 of carotid artery with an intact intima, the beta-gal expression was limited to endothelial cells. In vessels with denuded endothelium, gene expression was found in the sub-intima, media and adventitia. The transfection efficiency of medial smooth muscle cells was 38.6%. In 2 animals sacrificed 7 days after transfection, a microscopic examination of X-gal-stained samples did not show evidence of transfection in remote organs and arterial segments adjacent to the treated arterial site. Adenovirus-mediated arterial gene transfer to endothelial, smooth muscle cells and adventitia by protein-coated metallic stent is feasible. The transfection efficiency is higher. The coated stent may act as a good carrier of adenovirus-mediated gene transfer and have a potential to prevent restenosis following PTCA.

A tale of two hemispheres: Contrasting socioemotional dysfunction in right- versus left-lateralised semantic dementia

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Muireann Irish

Full Text Available ABSTRACT Objective: Semantic dementia, a subtype of frontotemporal lobar degeneration, is characterised by cross-modal loss of conceptual knowledge attributable to progressive degeneration of the left anterior temporal lobe. Much less is known regarding the clinical presentation of SD patients with predominantly right-lateralised atrophy. Recent reports emphasise marked socioemotional and behavioural disturbances in such cases. Given the importance of the right anterior temporal lobes in social cognition, we hypothesised that socioemotional functioning would be disproportionately affected in right versus left-lateralised SD cases. Methods: We assessed well-characterised cases of predominantly right (n=10 and left (n=12 SD and 20 matched healthy controls on tests of emotion processing and interpersonal functioning. Results: Right SD cases showed disproportionate difficulties in the recognition of positive and negative facial emotions, specifically happiness and anger, compared with left SD cases. Deficits in anger recognition persisted in right SD despite covarying for facial and semantic processing. On a contextually rich task of emotion recognition using multimodal videos, no subgroup differences were evident. Finally, empathic concern was rated as significantly lower by caregivers of right versus left SD cases. Overall, the extent of socioemotional disturbance was associated with the degree of behavioural changes in SD. Conclusion: Our results reveal considerable overlap in the extent to which socioemotional processes are disrupted in left and right-lateralised cases of SD. Notably, however, right SD cases show disproportionate deficits for recognition of facial emotions and the capacity for empathic concern, supporting a specialised role for the right anterior temporal lobes in mediating these cognitive functions.

A new "twist" on right heart failure with left ventricular assist systems.

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Houston, Brian A; Shah, Keyur B; Mehra, Mandeep R; Tedford, Ryan J

2017-07-01

Despite significant efforts to predict and prevent right heart failure, it remains a leading cause of morbidity and mortality after implantation of left ventricular assist systems (LVAS). In this Perspective, we review the underappreciated anatomic and physiologic principles that govern the relationship between left and right heart function and contribute to this phenomenon. This includes the importance of considering the right ventricle (RV) and pulmonary arterial circuit as a coupled system; the contribution of the left ventricle (LV) to RV contractile function and the potential negative impact of acutely unloading the LV; the influence of the pericardium and ventricular twist on septal function; the role of RV deformation in reduced mechanical efficiency after device placement; and the potential of ongoing stressors of an elevated right-sided preload. We believe an appreciation of these complex issues is required to fully understand the expression of the unique phenotypes of right heart failure after LVAS implantation and for developing better prognostic and therapeutic strategies. Copyright © 2017 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

Left-Deviating Prism Adaptation in Left Neglect Patient: Reflexions on a Negative Result

Directory of Open Access Journals (Sweden)

Jacques Luauté

2012-01-01

Full Text Available Adaptation to right-deviating prisms is a promising intervention for the rehabilitation of patients with left spatial neglect. In order to test the lateral specificity of prism adaptation on left neglect, the present study evaluated the effect of left-deviating prism on straight-ahead pointing movements and on several classical neuropsychological tests in a group of five right brain-damaged patients with left spatial neglect. A group of healthy subjects was also included for comparison purposes. After a single session of exposing simple manual pointing to left-deviating prisms, contrary to healthy controls, none of the patients showed a reliable change of the straight-ahead pointing movement in the dark. No significant modification of attentional paper-and-pencil tasks was either observed immediately or 2 hours after prism adaptation. These results suggest that the therapeutic effect of prism adaptation on left spatial neglect relies on a specific lateralized mechanism. Evidence for a directional effect for prism adaptation both in terms of the side of the visuomanual adaptation and therefore possibly in terms of the side of brain affected by the stimulation is discussed.

Left atrial appendage closure: Six reasons why I wouldn't choose a percutaneous closure for my appendage.

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Ferlini, Marco; Rossini, Roberta

2018-01-15

Left atrial appendage has been shown as a primary source of thrombi in patients with non-valvular atrial fibrillation (AF). Non vitamin k oral anticoagulants (NOAC) have been shown to be safe and effective in the prevention of embolic complications. Current guidelines on AF state that percutaneous left atrial appendage closure (LAAC) might be considered in patients with contraindication to long term oral anticoagulant therapy (OAC). An overview of the main trials on NOAC and LAAC is provided. Copyright © 2017 Elsevier B.V. All rights reserved.

TMS over the Left Angular Gyrus Impairs the Ability to Discriminate Left from Right

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Hirnstein, Marco; Bayer, Ulrike; Ellison, Amanda; Hausmann, Markus

2011-01-01

The underlying cognitive and neural mechanisms of the ability to discriminate left from right are hardly explored. Clinical studies from patients with impairments of left-right discrimination (LRD) and neuroimaging data suggest that the left angular gyrus is particularly involved in LRD. Moreover, it is argued that the often reported sex…

Curcumin Attenuates Staurosporine-Mediated Death of Retinal Ganglion Cells

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Burugula, Balabharathi; Ganesh, Bhagyalaxmi S.; Chintala, Shravan K.

2011-01-01

The functional effect of curcumin, a free radical scavenger and an herbal medicine from Indian yellow curry spice, Curcuma longa, on protease-mediated retinal ganglion cell death was investigated. These results show, for the first time, that curcumin indeed prevents the protease-mediated death of RGCs, both in vitro and in vivo.

Dyscalculia, Dysgraphia, and Left-Right Confusion from a Left Posterior Peri-Insular Infarct

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S. Bhattacharyya

2014-01-01

Full Text Available The Gerstmann syndrome of dyscalculia, dysgraphia, left-right confusion, and finger agnosia is generally attributed to lesions near the angular gyrus of the dominant hemisphere. A 68-year-old right-handed woman presented with sudden difficulty completing a Sudoku grid and was found to have dyscalculia, dysgraphia, and left-right confusion. Magnetic resonance imaging (MRI showed a focus of abnormal reduced diffusivity in the left posterior insula and temporoparietal operculum consistent with acute infarct. Gerstmann syndrome from an insular or peri-insular lesion has not been described in the literature previously. Pathological and functional imaging studies show connections between left posterior insular region and inferior parietal lobe. We postulate that the insula and operculum lesion disrupted key functional networks resulting in a pseudoparietal presentation.

Dyscalculia, dysgraphia, and left-right confusion from a left posterior peri-insular infarct.

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Bhattacharyya, S; Cai, X; Klein, J P

2014-01-01

The Gerstmann syndrome of dyscalculia, dysgraphia, left-right confusion, and finger agnosia is generally attributed to lesions near the angular gyrus of the dominant hemisphere. A 68-year-old right-handed woman presented with sudden difficulty completing a Sudoku grid and was found to have dyscalculia, dysgraphia, and left-right confusion. Magnetic resonance imaging (MRI) showed a focus of abnormal reduced diffusivity in the left posterior insula and temporoparietal operculum consistent with acute infarct. Gerstmann syndrome from an insular or peri-insular lesion has not been described in the literature previously. Pathological and functional imaging studies show connections between left posterior insular region and inferior parietal lobe. We postulate that the insula and operculum lesion disrupted key functional networks resulting in a pseudoparietal presentation.

Apraxia in left-handers.

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Goldenberg, Georg

2013-08-01

In typical right-handed patients both apraxia and aphasia are caused by damage to the left hemisphere, which also controls the dominant right hand. In left-handed subjects the lateralities of language and of control of the dominant hand can dissociate. This permits disentangling the association of apraxia with aphasia from that with handedness. Pantomime of tool use, actual tool use and imitation of meaningless hand and finger postures were examined in 50 consecutive left-handed subjects with unilateral hemisphere lesions. There were three aphasic patients with pervasive apraxia caused by left-sided lesions. As the dominant hand is controlled by the right hemisphere, they constitute dissociations of apraxia from handedness. Conversely there were also three patients with pervasive apraxia caused by right brain lesions without aphasia. They constitute dissociations of apraxia from aphasia. Across the whole group of patients dissociations from handedness and from aphasia were observed for all manifestations of apraxia, but their frequency depended on the type of apraxia. Defective pantomime and defective tool use occurred rarely without aphasia, whereas defective imitation of hand, but not finger, postures was more frequent after right than left brain damage. The higher incidence of defective imitation of hand postures in right brain damage was mainly due to patients who had also hemi-neglect. This interaction alerts to the possibility that the association of right hemisphere damage with apraxia has to do with spatial aptitudes of the right hemisphere rather than with its control of the dominant left hand. Comparison with data from right-handed patients showed no differences between the severity of apraxia for imitation of hand or finger postures, but impairment on pantomime of tool use was milder in apraxic left-handers than in apraxic right-handers. This alleviation of the severity of apraxia corresponded with a similar alleviation of the severity of aphasia as

Paracrine action of HO-1-modified mesenchymal stem cells mediates cardiac protection and functional improvement.

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Zeng, Bin; Ren, Xiaofeng; Lin, Guosheng; Zhu, Chengang; Chen, Honglei; Yin, Jiechao; Jiang, Hong; Yang, Bo; Ding, Danhua

2008-10-01

The aim has been to determine whether the supernatants of mesenchymal stem cells (MSCs) transfected with adenovirus carrying human heme oxygenase-1 (hHO-1) gene protect cardiomyocytes from ischemic injury. We have found that hHO-1 infected MSCs (hHO-1-MSCs) increased expression of hHO-1 protein. Apoptosis of cultured hHO-1-MSCs exposed to hypoxia was suppressed. Several cytokines, including HGF, bFGF, TGF-beta, VEGF and IL-1beta, were produced by hHO-1-MSCs, some being significantly enhanced under hypoxia stimulation. Meanwhile, those cytokines reduced caspase-3 level and activity in cultured adult rat ventricular cardiomyocytes (ARVCs) exposed to hypoxia. Supernatants obtained from hHO-1-MSCs improved left ventricular function, limited myocardial infarct size, increased microvessel density, and inhibited apoptosis of cardiomyocytes in rat myocardial infarction. It can be concluded hHO-1-modified MSCs prevent myocardial cell injury via secretion of paracrine-acting mediators.

Comparative efficacy of amiodarone with ivabradin combination or amiodarone with bisoprolol combination in the prevention of atrial fibrillation recurrence in pa- tients with left ventricular diastolic dysfunction

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K. G. Adamyan

2015-01-01

Full Text Available Aim. To study the efficacy of use of amiodarone with ivabradine combination or amiodarone with bisoprolol combination in the prevention of atrial fibrillation (AF recurrence in patients (pts with left ventricular diastolic dysfunction (LVDD after conversion to sinus rhythm. Material and methods. 65 patients (40 males, 25 females aged 53±8 years with persistent AF and LVDD were included into the study and randomized into 3 groups to receive ivabradine and amiodarone (22 pts, bisoprolol and amiodarone (22 pts or amiodarone alone (21 pts. Left atrium (LA volume indices, LA longitudinal strain rate (LASR in systole, LV mass index, mean heart rate (HR, 24-hour HR variability and the incidence of AF by 96 h ECG monitoring were measured after the titration period, and after 3 and 6 months of follow-up. Results. After 6 months of follow-up group 1 revealed significantly lower maximum LA volume index (21.3±2.4 vs 25.2±3.0 and 28.7±3.6 ml/m2 in the 2nd and control groups, respectively, P-wave LA volume index (15.3±3.5 versus 18.1±3.8 and 20.4±4.0 ml/m2 in the 2nd and control groups, respectively, and LA systolic volume index (7.3±1.2 versus 9.4±1.6 and 9.6±1.7 ml/m2 in 2nd and control groups, respectively. The incidence of side effects in group 1 was significantly less than that in group 2 and was not different compared with control group. Conclusion. Ivabradine and amiodarone combination provides better prevention of AF recurrence and less side-effects in pts with LVDD and persistent AF after sinus rhythm restoration as compared with bisoprolol and amiodarone combination, it also reduces LA maximum, conduit and systolic volumes, and increases LASR.

Causal mediation analysis with a binary outcome and multiple continuous or ordinal mediators: Simulations and application to an alcohol intervention.

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Nguyen, Trang Quynh; Webb-Vargas, Yenny; Koning, Ina M; Stuart, Elizabeth A

We investigate a method to estimate the combined effect of multiple continuous/ordinal mediators on a binary outcome: 1) fit a structural equation model with probit link for the outcome and identity/probit link for continuous/ordinal mediators, 2) predict potential outcome probabilities, and 3) compute natural direct and indirect effects. Step 2 involves rescaling the latent continuous variable underlying the outcome to address residual mediator variance/covariance. We evaluate the estimation of risk-difference- and risk-ratio-based effects (RDs, RRs) using the ML, WLSMV and Bayes estimators in Mplus. Across most variations in path-coefficient and mediator-residual-correlation signs and strengths, and confounding situations investigated, the method performs well with all estimators, but favors ML/WLSMV for RDs with continuous mediators, and Bayes for RRs with ordinal mediators. Bayes outperforms WLSMV/ML regardless of mediator type when estimating RRs with small potential outcome probabilities and in two other special cases. An adolescent alcohol prevention study is used for illustration.

The Effects of No Child Left Behind on the Prevalence of Evidence-Based Drug Prevention Curricula in the Nation’s Middle Schools*

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Ringwalt, Chris; Hanley, Sean; Ennett, Susan T.; Vincus, Amy A.; Bowling, J. Michael; Haws, Susan W.; Rohrbach, Louise A.

2014-01-01

BACKGROUND Concerns have been expressed that No Child Left Behind (NCLB) may be reducing the amount of classroom time devoted to subjects other than those for which students are tested. The purpose of this article is to explore whether NCLB legislation has affected the provision of evidence-based drug prevention curricula (EBC) in the nation’s middle schools, a subject area that is not assessed by standardized tests. METHODS Data were collected in spring 2005 and spring 2008 from a nationally representative sample of middle schools. Respondents completed a survey regarding their provision of EBC (2005 response rate: 78.1%). We also collected data on schools’ adequate yearly progress (AYP) status as of 2005 as a measure of their compliance with NCLB targets. We restricted our sample to schools that responded to our survey in both waves (n = 1324, or 76.9% of those schools responding in 2005) and conducted logistic regression analyses to determine whether those schools not making AYP in 2005 were less likely to be using an EBC in 2008. RESULTS Our results revealed no relationship between AYP status in 2005 and EBC use in 2008. Analyses of demographic characteristics showed that schools making AYP were more likely to be small and rural, and to serve majority White student populations whose families were characterized by lower levels of poverty. CONCLUSIONS Our failure to find any relationship between AYP status and the provision of EBC suggests that concerns about the potential adverse effects of NCLB on drug use prevention have yet to be validated. Implications of our results are discussed. PMID:21517866

The level of insulin growth factor-1 receptor expression is directly correlated with the tumor uptake of {sup 111}In-IGF-1(E3R) in vivo and the clonogenic survival of breast cancer cells exposed in vitro to trastuzumab (Herceptin)

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Cornelissen, Bart; McLarty, Kristin; Kersemans, Veerle [Department of Pharmaceutical Sciences, University of Toronto, Toronto, ON, M5S 3M2 (Canada); Reilly, Raymond M. [Department of Pharmaceutical Sciences, University of Toronto, Toronto, ON, M5S 3M2 (Canada); Department of Medical Imaging, University of Toronto, Toronto, ON, M5S 3M2 (Canada); Toronto General Research Institute, University Health Network Toronto, Toronto, ON, M5S 3M2 (Canada)], E-mail: raymond.reilly@utoronto.ca

2008-08-15

Introduction: Our objective was to define the relationships between tumor uptake of [{sup 111}In]-IGF-1 and [{sup 111}In]-IGF-1(E3R), an analogue which does not bind insulin growth factor-1 (IGF-1) binding proteins (i.e., IGFBP-3), and the level of IGF-1 receptor (IGF-1R) expression on human breast cancer (BC) xenografts in athymic mice, as well as the feasibility for tumor imaging. A second objective was to correlate IGF-1R (and HER2 density) with the cytotoxicity of trastuzumab in the absence/presence of IGFBP-3 or the IGF-1R tyrosine kinase inhibitor, AG1024. Methods: The tumor and normal tissue uptake of [{sup 111}In]-IGF-1 and [{sup 111}In]-IGF-1(E3R) were determined at 4 h postinjection in mice implanted subcutaneously with MDA-MB-231, H2N, HR2 or MCF-7/HER2-18 human BC xenografts (8.5x10{sup 4}, 1.4x10{sup 4}, 4.0x10{sup 4} and 1.0x10{sup 5} IGF-1R/cell, respectively). The effect of co-injection of IGF-1 (50 {mu}g) or IGFBP-3 (2 or 25 {mu}g) was studied. The relationship between tumor uptake of [{sup 111}In]-IGF-1(E3R) and IGF-1R density was examined. MicroSPECT/CT imaging was performed on mice with MCF-7/HER2-18 tumors injected with [{sup 111}In]-IGF-1(E3R). The surviving fraction of BC cells exposed to trastuzumab (67.5 {mu}g/ml) in the absence/presence of IGFBP-3 (1 {mu}g/ml) or the IGF-1R kinase inhibitor, AG1024 (1 or 5 {mu}g/ml), was determined. Results: [{sup 111}In]-IGF-1 was specifically taken up by MCF-7/HER2-18 xenografts; tumor uptake was decreased twofold when co-injected with IGF-1 (1.9{+-}0.1 vs. 1.0{+-}0.1 %ID/g). Co-injection of IGBP-3 decreased kidney uptake of [{sup 111}In]-IGF-1 up to twofold and increased circulating radioactivity threefold. There was a strong linear correlation (r{sup 2}=0.99) between the tumor uptake of {sup 111}In-IGF-1(E3R) and IGF-1R density. Tumor uptake ranged from 0.4{+-}0.05 %ID/g for H2N to 2.5{+-}0.5 %ID/g for MCF-7/HER2-18 xenografts. MCF-7/HER2-18 tumors were visualized by microSPECT/CT. Resistance of BC

The level of insulin growth factor-1 receptor expression is directly correlated with the tumor uptake of 111In-IGF-1(E3R) in vivo and the clonogenic survival of breast cancer cells exposed in vitro to trastuzumab (Herceptin)

International Nuclear Information System (INIS)

Cornelissen, Bart; McLarty, Kristin; Kersemans, Veerle; Reilly, Raymond M.

2008-01-01

Introduction: Our objective was to define the relationships between tumor uptake of [ 111 In]-IGF-1 and [ 111 In]-IGF-1(E3R), an analogue which does not bind insulin growth factor-1 (IGF-1) binding proteins (i.e., IGFBP-3), and the level of IGF-1 receptor (IGF-1R) expression on human breast cancer (BC) xenografts in athymic mice, as well as the feasibility for tumor imaging. A second objective was to correlate IGF-1R (and HER2 density) with the cytotoxicity of trastuzumab in the absence/presence of IGFBP-3 or the IGF-1R tyrosine kinase inhibitor, AG1024. Methods: The tumor and normal tissue uptake of [ 111 In]-IGF-1 and [ 111 In]-IGF-1(E3R) were determined at 4 h postinjection in mice implanted subcutaneously with MDA-MB-231, H2N, HR2 or MCF-7/HER2-18 human BC xenografts (8.5x10 4 , 1.4x10 4 , 4.0x10 4 and 1.0x10 5 IGF-1R/cell, respectively). The effect of co-injection of IGF-1 (50 μg) or IGFBP-3 (2 or 25 μg) was studied. The relationship between tumor uptake of [ 111 In]-IGF-1(E3R) and IGF-1R density was examined. MicroSPECT/CT imaging was performed on mice with MCF-7/HER2-18 tumors injected with [ 111 In]-IGF-1(E3R). The surviving fraction of BC cells exposed to trastuzumab (67.5 μg/ml) in the absence/presence of IGFBP-3 (1 μg/ml) or the IGF-1R kinase inhibitor, AG1024 (1 or 5 μg/ml), was determined. Results: [ 111 In]-IGF-1 was specifically taken up by MCF-7/HER2-18 xenografts; tumor uptake was decreased twofold when co-injected with IGF-1 (1.9±0.1 vs. 1.0±0.1 %ID/g). Co-injection of IGBP-3 decreased kidney uptake of [ 111 In]-IGF-1 up to twofold and increased circulating radioactivity threefold. There was a strong linear correlation (r 2 =0.99) between the tumor uptake of 111 In-IGF-1(E3R) and IGF-1R density. Tumor uptake ranged from 0.4±0.05 %ID/g for H2N to 2.5±0.5 %ID/g for MCF-7/HER2-18 xenografts. MCF-7/HER2-18 tumors were visualized by microSPECT/CT. Resistance of BC cells to trastuzumab was directly associated with IGF-1R expression, despite co

Left ventricular filling under elevated left atrial pressure

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Gaddam, Manikantam; Samaee, Milad; Santhanakrishnan, Arvind

2017-11-01

Left atrial pressure (LAP) is elevated in diastolic dysfunction, where left ventricular (LV) filling is impaired due to increase in ventricular stiffness. The impact of increasing LAP and LV stiffness on intraventricular filling hemodynamics remains unclear. We conducted particle image velocimetry and hemodynamics measurements in a left heart simulator (LHS) under increasing LAP and LV stiffness at a heart rate of 70 bpm. The LHS consisted of a flexible-walled LV physical model fitted within a fluid-filled chamber. LV wall motion was generated by a piston pump that imparted pressure fluctuations in the chamber. Resistance and compliance elements in the flow loop were adjusted to obtain bulk physiological hemodynamics in the least stiff LV model. Two LV models of increasing stiffness were subsequently tested under unchanged loop settings. LAP was varied between 5-20 mm Hg for each LV model, by adjusting fluid level in a reservoir upstream of the LV. For constant LV stiffness, increasing LAP lowered cardiac output (CO), while ejection fraction (EF) and E/A ratio were increased. For constant LAP, increasing LV stiffness lowered CO and EF, and increased E/A ratio. The implications of these altered hemodynamics on intraventricular filling vortex characteristics will be presented.

A General Model for Testing Mediation and Moderation Effects

Science.gov (United States)

MacKinnon, David P.

2010-01-01

This paper describes methods for testing mediation and moderation effects in a dataset, both together and separately. Investigations of this kind are especially valuable in prevention research to obtain information on the process by which a program achieves its effects and whether the program is effective for subgroups of individuals. A general model that simultaneously estimates mediation and moderation effects is presented, and the utility of combining the effects into a single model is described. Possible effects of interest in the model are explained, as are statistical methods to assess these effects. The methods are further illustrated in a hypothetical prevention program example. PMID:19003535

Left ventricular remodelling in chronic primary mitral regurgitation: implications for medical therapy.

Science.gov (United States)

McCutcheon, Keir; Manga, Pravin

Surgical repair or replacement of the mitral valve is currently the only recommended therapy for severe primary mitral regurgitation. The chronic elevation of wall stress caused by the resulting volume overload leads to structural remodelling of the muscular, vascular and extracellular matrix components of the myocardium. These changes are initially compensatory but in the long term have detrimental effects, which ultimately result in heart failure. Understanding the changes that occur in the myocardium due to volume overload at the molecular and cellular level may lead to medical interventions, which potentially could delay or prevent the adverse left ventricular remodelling associated with primary mitral regurgitation. The pathophysiological changes involved in left ventricular remodelling in response to chronic primary mitral regurgitation and the evidence for potential medical therapy, in particular beta-adrenergic blockers, are the focus of this review.

Intolerance of uncertainty mediates reduced reward anticipation in major depressive disorder.

Science.gov (United States)

Nelson, Brady D; Shankman, Stewart A; Proudfit, Greg H

2014-04-01

Reduced reward sensitivity has long been considered a fundamental deficit of major depressive disorder (MDD). One way this deficit has been measured is by an asymmetry in electroencephalogram (EEG) activity between left and right frontal brain regions. MDD has been associated with a reduced frontal EEG asymmetry (i.e., decreased left relative to right) while anticipating reward. However, the mechanism (or mediator) of this association is unclear. The present study examined whether intolerance of uncertainty (IU) mediated the association between depression and reduced reward anticipation. Data were obtained from a prior study reporting reduced frontal EEG asymmetry while anticipating reward in early-onset MDD. Participants included 156 individuals with early-onset MDD-only, panic disorder-only, both (comorbids), or controls. Frontal EEG asymmetry was recorded during an uncertain reward anticipation task. Participants completed a self-report measure of IU. All three psychopathology groups reported greater IU relative to controls. Across all participants, greater IU was associated with a reduced frontal EEG asymmetry. Furthermore, IU mediated the relationship between MDD and frontal EEG asymmetry and results remained significant after controlling for neuroticism, suggesting effects were not due to broad negative affectivity. MDD participants were limited to those with early-onset depression. Measures were collected cross-sectionally, precluding causal relationships. IU mediated the relationship between MDD and reduced reward anticipation, independent of neuroticism. Explanations are provided regarding how IU may contribute to reduced reward anticipation in depression. Overall, IU appears to be an important mechanism for the association between depression and reduced reward anticipation. Copyright © 2014 Elsevier B.V. All rights reserved.

Role of smoking intention in tobacco use reduction: A mediation analysis of an effective classroom-based prevention/cessation intervention for adolescents.

Science.gov (United States)

Gonzálvez, María T; Morales, Alexandra; Orgilés, Mireia; Sussman, Steve; Espada, José P

2018-09-01

Although some school-based tobacco cessation and prevention programs have been proven to be effective, there remains a lack of understanding of how these programs succeed. This longitudinal study aimed to test smoking intention as a mediator of Project EX's intervention efficacy to reduce tobacco use. Using a computerized random number generator, six high schools located in the Mediterranean coast were randomly selected to participate in the program condition (Spanish version of Project EX) or the waiting-list control group with baseline, immediate-posttest, and 12-month follow-up assessments. At baseline, 685 adolescents aged 14-20 years (mean age: 14.87; SD = 0.92; 47.4% were females) were evaluated using self-administered tests of tobacco, and smoking intention. A biomarker of smoke inhalation, a measurement of exhaled carbon monoxide (ECM), was used. Mediation analyses were conducted using the PROCESS v2.12 macro for Windows. Project EX had a significant effect on smoking intention. Indirect effects indicated that Project EX reduced the ECM level, and number of cigarettes used. This is the first Spanish study that explored intention as a mediator of the long-term efficacy of Project EX to reduce tobacco use in adolescents. Results suggested that interventions that reduce consumption intention at short-term are more likely to be successful in decreasing tobacco use in the long-term. Copyright © 2018 Elsevier Ltd. All rights reserved.

3D culture of Her2+ breast cancer cells promotes AKT to MAPK switching and a loss of therapeutic response.

Science.gov (United States)

Gangadhara, Sharath; Smith, Chris; Barrett-Lee, Peter; Hiscox, Stephen

2016-06-01

The Her2 receptor is overexpressed in up to 25 % of breast cancers and is associated with a poor prognosis. Around half of Her2+ breast cancers also express the estrogen receptor and treatment for such tumours can involve both endocrine and Her2-targeted therapies. However, despite preclinical data supporting the effectiveness of these agents, responses can vary widely in the clinical setting. In light of the increasing evidence pointing to the interplay between the tumour and its extracellular microenvironment as a significant determinant of therapeutic sensitivity and response here we investigated the impact of 3D matrix culture of breast cancer cells on their therapeutic sensitivity. A 3D Matrigel-based culture system was established and optimized for the growth of ER+/Her2+ breast cancer cell models. Growth of cells in response to trastuzumab and endocrine agents in 3D culture versus routine monolayer culture were assessed using cell counting and Ki67 staining. Endogenous and trastuzumab-modulated signalling pathway activity in 2D and 3D cultures were assessed using Western blotting. Breast cancer cells in 3D culture displayed an attenuated response to both endocrine agents and trastuzumab compared with cells cultured in traditional 2D monolayers. Underlying this phenomenon was an apparent matrix-induced shift from AKT to MAPK signalling; consequently, suppression of MAPK in 3D cultures restores therapeutic response. These data suggest that breast cancer cells in 3D culture display a reduced sensitivity to therapeutic agents which may be mediated by internal MAPK-mediated signalling. Targeting of adaptive pathways that maintain growth in 3D culture may represent an effective strategy to improve therapeutic response clinically.

ER, PgR, Ki67, p27Kip1, and histological grade as predictors of pathological complete response in patients with HER2-positive breast cancer receiving neoadjuvant chemotherapy using taxanes followed by fluorouracil, epirubicin, and cyclophosphamide concomitant with trastuzumab

International Nuclear Information System (INIS)

Kurozumi, Sasagu; Inoue, Kenichi; Takei, Hiroyuki; Matsumoto, Hiroshi; Kurosumi, Masafumi; Horiguchi, Jun; Takeyoshi, Izumi; Oyama, Tetsunari

2015-01-01

Neoadjuvant chemotherapy (NAC) with taxanes followed by fluorouracil, epirubicin, and cyclophosphamide (FEC), and concurrent trastuzumab is a potent regimen for HER2 over-expressing breast cancer. A high pathological complete response (pCR) rate has been achieved using this regimen; however, the predictive factors and prognostic effects of pCR currently remain unclear. In the present study, we determined whether pCR was related to histological grade (HG) and several biological factors including p27 Kip1 . We also assessed the prognosis of the pCR and non-pCR groups, and expected differences between those positive and negative for lymph node metastasis after chemotherapy. A total of 129 Japanese women with HER2-positive invasive breast cancer received either paclitaxel or docetaxel followed by FEC, with the concomitant administration of trastuzumab. The statuses of HG, ER, PgR, Ki67, and p27 Kip1 were evaluated to determine their relationship with pCR. Relapse-free survival (RFS) and overall survival (OS) were also analyzed for their relationship with pCR and pathological nodal involvement. pCR was obtained in 84 out of 129 patients and the pCR rate was 65.1 %. The pCR rates related to 5 factors were as follows: HG (grade 3, 70.0 % vs. grades 1–2, 36.8 %), ER (negative, 78.6 % vs. positive, 40.0 %), PgR (negative, 75.3 % vs. positive, 38.9 %), Ki67 (high, 72.0 % vs. low, 47.2 %), and p27 Kip1 (low, 71.0 % vs. high, 50.0 %). RFS was significantly better in the pCR group than in the non-pCR group (p = 0.018). Patients with remaining nodal disease in the pCR group had worse OS (p = 0.0002). High-HG, low-ER, low-PgR, high-Ki67, and low-p27 Kip1 were identified as predictive factors of pCR in NAC with trastuzumab, while pCR and negative nodes were predictive of better survivals. The online version of this article (doi:10.1186/s12885-015-1641-y) contains supplementary material, which is available to authorized users

Utility of Deep Inspiration Breath Hold for Left-Sided Breast Radiation Therapy in Preventing Early Cardiac Perfusion Defects: A Prospective Study

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Zagar, Timothy M., E-mail: zagar@med.unc.edu [Department of Radiation Oncology, University of North Carolina, Chapel Hill, North Carolina (United States); Kaidar-Person, Orit [Department of Radiation Oncology, University of North Carolina, Chapel Hill, North Carolina (United States); Tang, Xiaoli [Memorial Sloan Kettering Cancer Center, West Harrison, New York (United States); Jones, Ellen E.; Matney, Jason; Das, Shiva K.; Green, Rebecca L. [Department of Radiation Oncology, University of North Carolina, Chapel Hill, North Carolina (United States); Sheikh, Arif [Department of Radiology, Columbia University, New York, New York (United States); Khandani, Amir H.; McCartney, William H.; Oldan, Jorge Daniel; Wong, Terence Z. [Department of Radiology, University of North Carolina, Chapel Hill, North Carolina (United States); Marks, Lawrence B. [Department of Radiation Oncology, University of North Carolina, Chapel Hill, North Carolina (United States)

2017-04-01

Purpose: To evaluate early cardiac single photon computed tomography (SPECT) findings after left breast/chest wall postoperative radiation therapy (RT) in the setting of deep inspiration breath hold (DIBH). Methods and Materials: We performed a prospective single-institution single-arm study of patients who were planned for tangential RT with DIBH to the left breast/chest wall (± internal mammary nodes). The DIBH was done by use of a controlled surface monitoring technique (AlignRT, Vision RT Ltd, London, UK). The RT was given with tangential fields and a heart block. Radiation-induced cardiac perfusion and wall motion changes were assessed by pre-RT and 6-month post-RT SPECT scans. A cumulative SPECT summed-rest score was used to quantify perfusion in predefined left ventricle segments. The incidence of wall motion abnormalities was assessed in each of these same segments. Results: A total of 20 patients with normal pre-RT scans were studied; their median age was 56 years (range, 39-72 years). Seven (35%) patients also received irradiation to the left internal mammary chain, and 5 (25%) received an additional RT field to supraclavicular nodes. The median heart dose was 94 cGy (range, 56-200 cGy), and the median V25{sub Gy} was zero (range, 0-0.1). None of the patients had post-RT perfusion or wall motion abnormalities. Conclusions: Our results suggest that DIBH and conformal cardiac blocking for patients receiving tangential RT for left-sided breast cancer is an effective means to avoid early RT-associated cardiac perfusion defects.

Electroencephalographic (eeg coherence between visual and motor areas of the left and the right brain hemisphere while performing visuomotor task with the right and the left hand

Directory of Open Access Journals (Sweden)

Simon Brežan

2007-09-01

Full Text Available Background: Unilateral limb movements are based on the activation of contralateral primary motor cortex and the bilateral activation of premotor cortices. Performance of a visuomotor task requires a visuomotor integration between motor and visual cortical areas. The functional integration (»binding« of different brain areas, is probably mediated by the synchronous neuronal oscillatory activity, which can be determined by electroencephalographic (EEG coherence analysis. We introduced a new method of coherence analysis and compared coherence and power spectra in the left and right hemisphere for the right vs. left hand visuomotor task, hypothesizing that the increase in coherence and decrease in power spectra while performing the task would be greater in the contralateral hemisphere.Methods: We analyzed 6 healthy subjects and recorded their electroencephalogram during visuomotor task with the right or the left hand. For data analysis, a special Matlab computer programme was designed. The results were statistically analysed by a two-way analysis of variance, one-way analysis of variance and post-hoc t-tests with Bonferroni correction.Results: We demonstrated a significant increase in coherence (p < 0.05 for the visuomotor task compared to control tasks in alpha (8–13 Hz in beta 1 (13–20 Hz frequency bands between visual and motor electrodes. There were no significant differences in coherence nor power spectra depending on the hand used. The changes of coherence and power spectra between both hemispheres were symmetrical.Conclusions: In previous studies, a specific increase of coherence and decrease of power spectra for the visuomotor task was found, but we found no conclusive asymmetries when performing the task with right vs. left hand. This could be explained in a way that increases in coherence and decreases of power spectra reflect symmetrical activation and cooperation between more complex visual and motor brain areas.

Topography of the accessory left gastric artery (ALGA) analyzed by CT angiography from the left hepatic artery

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Shioyama, Yasukazu; Takasaka, Isao; Onaya, Hiroaki

2003-01-01

To avoid gastric complications when we perform transcatheter treatment via left hepatic artery, we analyzed the topography of ALGA (accessory left gastric artery) by left hepatic arteriography and CT angiography from left hepatic artery. Six hundred seventy eight cases of CT angiography were performed between 1995 and 2000. Among them, selective left hepatic arteriography was done in 85 cases. We analyzed the frequency and the course of ALGA on the hepatic angiogram and CT angiogram. ALGA were identified in eighteen (21.2 %) of the 85 cases. We classified them into eleven cases of the proximal type and six cases of the distal type. When ALGA bifurcated from the left hepatic artery very close to the bifurcation of A2 (dorsolateral branch) and A3 (ventrolateral branch), we classified them as the distal type on hepatic angiogram. On the other hand, when ALGA bifurcated from the left hepatic artery apart from the bifurcation of A2 and A3 they were classified as the proximal type. In one rare case ALGA originated from the dorsolateral branch of the left hepatic artery. ALGA were classified as the distal and proximal types. Distal type of ALGA often overlapped dorsolateral branch of the left hepatic artery, and it was sometimes difficult to notice the existence of them. We should check the existence of ALGA on the arterial phase of dynamic CT before we plan to make a transcatheter treatment from the left hepatic artery. Then we can avoid gastric complications caused by a transcatheter treatment from the left hepatic artery. (author)

Effect of kinase inhibitors on the therapeutic properties of monoclonal antibodies.

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Duong, Minh Ngoc; Matera, Eva-Laure; Mathé, Doriane; Evesque, Anne; Valsesia-Wittmann, Sandrine; Clémenceau, Béatrice; Dumontet, Charles

2015-01-01

Targeted therapies of malignancies currently consist of therapeutic monoclonal antibodies and small molecule kinase inhibitors. The combination of these novel agents raises the issue of potential antagonisms. We evaluated the potential effect of 4 kinase inhibitors, including the Bruton tyrosine kinase inhibitor ibrutinib, and 3 PI3K inhibitors idelalisib, NVP-BEZ235 and LY294002, on the effects of the 3 monoclonal antibodies, rituximab and obinutuzumab (directed against CD20) and trastuzumab (directed against HER2). We found that ibrutinib potently inhibits antibody-dependent cell-mediated cytotoxicity exerted by all antibodies, with a 50% inhibitory concentration of 0.2 microM for trastuzumab, 0.5 microM for rituximab and 2 microM for obinutuzumab, suggesting a lesser effect in combination with obinutuzumab than with rituximab. The 4 kinase inhibitors were found to inhibit phagocytosis by fresh human neutrophils, as well as antibody-dependent cellular phagocytosis induced by the 3 antibodies. Conversely co-administration of ibrutinib with rituximab, obinutuzumab or trastuzumab did not demonstrate any inhibitory effect of ibrutinib in vivo in murine xenograft models. In conclusion, some kinase inhibitors, in particular, ibrutinib, are likely to exert inhibitory effects on innate immune cells. However, these effects do not compromise the antitumor activity of monoclonal antibodies in vivo in the models that were evaluated.

Left Atrial Decompression by Percutaneous Left Atrial Venting Cannula Insertion during Venoarterial Extracorporeal Membrane Oxygenation Support

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Ha Eun Kim

2016-06-01

Full Text Available Patients with venoarterial extracorporeal membrane oxygenation (ECMO frequently suffer from pulmonary edema due to left ventricular dysfunction that accompanies left heart dilatation, which is caused by left atrial hypertension. The problem can be resolved by left atrium (LA decompression. We performed a successful percutaneous LA decompression with an atrial septostomy and placement of an LA venting cannula in a 38-month-old child treated with venoarterial ECMO for acute myocarditis.

Social aspects of left-handedness

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Belojević Goran

2010-01-01

Full Text Available Throughout human history left-handedness has been considered as sinful. It has been associated with the devil, weakness, female gender, unhealthiness, evil, something that has to be turned to a “good” - right side by force. Left-handedness is being more and more acceptable at rational level, but in everyday life it is still considered to be unusual if someone writes with the left hand. Lessening of the number of lefthanders is associated with ageing. There are about 13% lefthanders among people in twenties and less than 1% lefthanders among those in eighties. This finding may be explaned with more pronounced socio-cultural pressure on left-handed people in the past, compared to nowadays. On the other hand, this may also support the hypothesis about a reduced life span of lefthanded people. With cross-exercising of left-handedness, certain typical characteristics and behavioral patterns appear in these people. This was a sort of provoked behavior and an attack on the integrity of an emotional attitude toward oneself. Stuttering may also appear as a consequence of unsuccessful cross-exercising of left-handedness. The hypothesis about left-handedness as an advantage is supported with the reports about relatively more lefthanders in some specific groups such as: mathematicians, sculptors, architects, painters, musicians, actors, tennis players, as well as famous army commanders and rulers.

Left ventricular assist device implantation via left thoracotomy: alternative to repeat sternotomy.

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Pierson, Richard N; Howser, Renee; Donaldson, Terri; Merrill, Walter H; Dignan, Rebecca J; Drinkwater, Davis C; Christian, Karla G; Butler, Javed; Chomsky, Don; Wilson, John R; Clark, Rick; Davis, Stacy F

2002-03-01

Repeat sternotomy for left ventricular assist device insertion may result in injury to the right heart or patent coronary grafts, complicating intraoperative and postoperative management. In 4 critically ill patients, left thoracotomy was used as an alternative to repeat sternotomy. Anastomosis of the outflow conduit to the descending thoracic aorta provided satisfactory hemodynamic support.

Left Pulmonary Artery Agenesis in a Pediatric Patient – Case Report

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Blesneac Cristina

2016-06-01

Full Text Available Unilateral pulmonary artery agenesis is a rare congenital anomaly, that may develop in isolation, or in association with other congenital cardiovascular anomalies, such as tetralogy of Fallot, septal defects, right-sided aortic arch, or pulmonary atresia. Left-sided pulmonary artery agenesis is less frequent than the right-sided one. Diagnosis of unilateral pulmonary artery agenesis can be difficult. We report the case of a 15 year-old boy who presented with reduced exercise tolerance, shortness of breath and cyanosis. He was diagnosed with left pulmonary artery agenesis, associated with subaortic-ventricular septal defect, right-sided aortic arch, and severe pulmonary arterial hypertension (PAH, that precluded the surgical repair. Pulmonary vasodilator therapy was initiated in this case. The mortality rate of this rare anomaly is high due to its complications. It is essential to establish an early and correct diagnosis, in order to provide adequate treatment and prevent complications in this disease.

Left atrial appendage obliteration in atrial fibrillation patients undergoing bioprosthetic mitral valve replacement.

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Min, X P; Zhu, T Y; Han, J; Li, Y; Meng, X

2016-02-01

Left atrial appendage (LAA) obliteration is a proven stroke-preventive measure for patients with nonvalvular atrial fibrillation (AF). However, the efficacy of LAA obliteration for patients with AF after bioprosthetic mitral valve replacement (MVR) remains unclear. This study aimed to estimate the efficacy of LAA obliteration in preventing embolism and to investigate the predictors of thromboembolism after bioprosthetic MVR. We retrospectively studied 173 AF subjects with bioprosthetic MVR; among them, 81 subjects underwent LAA obliteration using an endocardial running suture method. The main outcome measure was the occurrence of thrombosis events (TEs). The mean follow-up time was 40 ± 17 months. AF rhythm was observed in 136 patients postoperatively. The incidence rate of TEs was 13.97 % for postoperative AF subjects; a dilated left atrium (LA; > 49.5 mm) was identified as an independent risk factor of TEs (OR = 10.619, 95 % CI = 2.754-40.94, p = 0.001). For postoperative AF patients with or without LAA, the incidence rate of TEs was 15.8 % (9/57) and 12.7 % (10/79; p = 0.603), respectively. The incidence rate of TEs was 2.7 % (1/36) and 4.2 % (2/48) for the subgroup patients with a left atrial diameter of  49.5 mm (p = 0.346). Surgical LAA obliteration in patients with valvular AF undergoing bioprosthetic MVR did not reduce TEs, even when the CHA2DS2-VASc score (a score for estimating the risk of stroke in AF) was ≥ 2 points.

Neratinib, an irreversible ErbB receptor tyrosine kinase inhibitor, in patients with advanced ErbB2-positive breast cancer.

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Burstein, Harold J; Sun, Yan; Dirix, Luc Y; Jiang, Zefei; Paridaens, Robert; Tan, Antoinette R; Awada, Ahmad; Ranade, Anantbhushan; Jiao, Shunchang; Schwartz, Gary; Abbas, Richat; Powell, Christine; Turnbull, Kathleen; Vermette, Jennifer; Zacharchuk, Charles; Badwe, Rajendra

2010-03-10

Neratinib is an oral, irreversible pan-ErbB receptor tyrosine kinase inhibitor. The efficacy and safety of neratinib were evaluated in two cohorts of patients with advanced ErbB2-positive breast cancer-those with and those without prior trastuzumab treatment-in an open-label, multicenter, phase II trial. Patients in the two cohorts (prior trastuzumab, n = 66; no prior trastuzumab, n = 70) received oral neratinib 240 mg once daily. The primary end point was the 16-week progression-free survival (PFS) rate for the evaluable population (prior trastuzumab, n = 63; no prior trastuzumab, n = 64), as assessed by independent review. The 16-week PFS rates were 59% for patients with prior trastuzumab treatment and 78% for patients with no prior trastuzumab treatment. Median PFS was 22.3 and 39.6 weeks, respectively. Objective response rates were 24% among patients with prior trastuzumab treatment and 56% in the trastuzumab-naïve cohort. The most common adverse events were diarrhea, nausea, vomiting, and fatigue. Diarrhea was the most frequent grades 3 to 4 adverse event, occurring in 30% of patients with prior trastuzumab treatment and in 13% of patients with no prior trastuzumab treatment, which prompted dose reductions in 29% and 4% of patients, respectively, but treatment discontinuation in only one patient. No neratinib-related, grades 3 or 4 cardiotoxicity was reported. Oral neratinib showed substantial clinical activity and was reasonably well tolerated among both heavily pretreated and trastuzumab-naïve patients who had advanced, ErbB2-positive breast cancer. Diarrhea was the most common adverse effect but was manageable with antidiarrheal agents and dose modification.

VARIATION IN THE OPENINGS (OSTIA OF LEFT PULMONARY VEINS INTO THE LEFT ATRIUM: A CASE REPORT

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Sesi

2015-03-01

Full Text Available During early embryonic development, absorption of pulmonary venous network by the left primitive atrial chamber results in opening of four pulmonary veins which drain independently into its chamber. The extent of absorption and hence, the number of pulmon ary veins which open into the left atrium, may vary. Here we report a variation in the opening of the Left upper (superior pulmonary vein into the Left atrium. A total of six openings observed

Effect of left ventricular diastolic dysfunction on left atrial appendage function and thrombotic potential in nonvalvular atrial fibrillation.

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Demirçelik, Muhammed Bora; Çetin, Mustafa; Çiçekcioğlu, Hülya; Uçar, Özgül; Duran, Mustafa

2014-05-01

We aimed to investigate effects of left ventricular diastolic dysfunction on left atrial appendage functions, spontaneous echo contrast and thrombus formation in patients with nonvalvular atrial fibrillation. In 58 patients with chronic nonvalvular atrial fibrilation and preserved left ventricular systolic function, left atrial appendage functions, left atrial spontaneous echo contrast grading and left ventricular diastolic functions were evaluated using transthoracic and transoesophageal echocardiogram. Patients divided in two groups: Group D (n=30): Patients with diastolic dysfunction, Group N (n=28): Patients without diastolic dysfunction. Categorical variables in two groups were evaluated with Pearson's chi-square or Fisher's exact test. The significance of the lineer correlation between the degree of spontaneous echo contrast (SEC) and clinical measurements was evaluated with Spearman's correlation analysis. Peak pulmonary vein D velocity of the Group D was significantly higher than the Group N (p=0.006). However, left atrial appendage emptying velocity, left atrial appendage lateral wall velocity, peak pulmonary vein S, pulmonary vein S/D ratio were found to be significantly lower in Group D (p=0.028, patrial appendage emptying, filling, pulmonary vein S/D levels and lateral wall velocities respectively (r=-0.438, r=-0.328, r=-0.233, r=-0.447). Left atrial appendage emptying, filling, pulmonary vein S/D levels and lateral wall velocities were significantly lower in SEC 2-3-4 than SEC 1 (p=0.003, p=0.029, patrial fibrillation and preserved left ventricular ejection fraction, left atrial appendage functions are decreased in patients with left ventricular diastolic dysfunction. Left ventricular diastolic dysfunction may constitute a potential risk for formation of thrombus and stroke.

Right colon cancer: Left behind.

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Gervaz, P; Usel, M; Rapiti, E; Chappuis, P; Neyroud-Kaspar, I; Bouchardy, C

2016-09-01

Prognosis of colon cancer (CC) has steadily improved during the past three decades. This trend, however, may vary according to proximal (right) or distal (left) tumor location. We studied if improvement in survival was greater for left than for right CC. We included all CC recorded at the Geneva population-based registry between 1980 and 2006. We compared patients, tumor and treatment characteristics between left and right CC by logistic regression and compared CC specific survival by Cox models taking into account putative confounders. We also compared changes in survival between CC location in early and late years of observation. Among the 3396 CC patients, 1334 (39%) had right-sided and 2062 (61%) left-sided tumors. In the early 1980s, 5-year specific survival was identical for right and left CCs (49% vs. 48%). During the study period, a dramatic improvement in survival was observed for patients with left-sided cancers (Hazard ratio [HR]: 0.42, 95% confidence interval [CI]: 0.29-0.62, p colon cancer patients, those with right-sided lesions have by far the worse prognosis. Change of strategic management in this subgroup is warranted. Copyright © 2016 Elsevier Ltd. All rights reserved.

[Chronic recurrent volvulus of the colonic splenic flexure associated with the eventration of left diaphragm].

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Kim, Hee Sun; Yoo, Jeong Seon; Han, Seok Joo; Park, Hyojin

2007-01-01

The eventration of diaphragm is usually found incidentally on chest X-ray or sometimes presented as acute gastric volvulus. However, colonic volvulus on splenic flexure area complicated by diaphragmatic eventration is extremely rare. A 25 year old man complained of upper abdominal pain for three days. He had a history of brain injury during infant period, and had epilepsy and mental retardation. Plain chest X-ray showed left diaphragmatic eventration and marked dilatation of colon on splenic flexure area which had not been changed for last three years. Barium enema showed bird beak appearance on distal colon near the splenic flexure. Colonoscopic reduction failed. After decompression with rectal and nasogastric tubes, colonic volvulus was relieved. To prevent the recurrence of volvulus, we performed segmental resection of left colon including splenic flexure area and repaired the left diaphragmatic eventration. After the operation, the patient had no further recurrent episode of volvulus although ileus persisted.

Role of the carbohydrate-binding sites of griffithsin in the prevention of DC-SIGN-mediated capture and transmission of HIV-1.

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Bart Hoorelbeke

Full Text Available BACKGROUND: The glycan-targeting C-type DC-SIGN lectin receptor is implicated in the transmission of the human immunodeficiency virus (HIV by binding the virus and transferring the captured HIV-1 to CD4(+ T lymphocytes. Carbohydrate binding agents (CBAs have been reported to block HIV-1 infection. We have now investigated the potent mannose-specific anti-HIV CBA griffithsin (GRFT on its ability to inhibit the capture of HIV-1 to DC-SIGN, its DC-SIGN-directed transmission to CD4(+ T-lymphocytes and the role of the three carbohydrate-binding sites (CBS of GRFT in these processes. FINDINGS: GRFT inhibited HIV-1(IIIB infection of CEM and HIV-1(NL4.3 infection of C8166 CD4(+ T-lymphocytes at an EC50 of 0.059 and 0.444 nM, respectively. The single mutant CBS variants of GRFT (in which a key Asp in one of the CBS was mutated to Ala were about ∼20 to 60-fold less potent to prevent HIV-1 infection and ∼20 to 90-fold less potent to inhibit syncytia formation in co-cultures of persistently HIV-1 infected HuT-78 and uninfected C8166 CD4(+ T-lymphocytes. GRFT prevents DC-SIGN-mediated virus capture and HIV-1 transmission to CD4(+ T-lymphocytes at an EC50 of 1.5 nM and 0.012 nM, respectively. Surface plasmon resonance (SPR studies revealed that wild-type GRFT efficiently blocked the binding between DC-SIGN and immobilized gp120, whereas the point mutant CBS variants of GRFT were ∼10- to 15-fold less efficient. SPR-analysis also demonstrated that wild-type GRFT and its single mutant CBS variants have the capacity to expel bound gp120 from the gp120-DC-SIGN complex in a dose dependent manner, a property that was not observed for HHA, another mannose-specific potent anti-HIV-1 CBA. CONCLUSION: GRFT is inhibitory against HIV gp120 binding to DC-SIGN, efficiently prevents DC-SIGN-mediated transfer of HIV-1 to CD4(+ T-lymphocytes and is able to expel gp120 from the gp120-DC-SIGN complex. Functionally intact CBS of GRFT are important for the optimal action of

Keep-Left Behavior Induced by Asymmetrically Profiled Walls

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Oliveira, C. L. N.; Vieira, A. P.; Helbing, D.; Andrade, J. S.; Herrmann, H. J.

2016-01-01

We show, computationally and analytically, that asymmetrically shaped walls can organize the flow of pedestrians driven in opposite directions through a corridor. Precisely, a two-lane ordered state emerges in which people always walk on the left-hand side (or right-hand side), controlled by the system's parameters. This effect depends on features of the channel geometry, such as the asymmetry of the profile and the channel width, as well as on the density and the drift velocity of pedestrians, and the intensity of noise. We investigate in detail the influence of these parameters on the flow and discover a crossover between ordered and disordered states. Our results show that an ordered state only appears within a limited range of drift velocities. Moreover, increasing noise may suppress such flow organization, but the flow is always sustained. This is in contrast with the "freezing by heating" phenomenon according to which pedestrians tend to clog in smooth channels for strong noise [Phys. Rev. Lett. 84, 1240 (2000)]. Therefore, the ratchetlike effect proposed here acts on the system not only to induce a "keep-left" behavior but also to prevent the freezing by heating clogging phenomenon. Besides pedestrian flow, this new phenomenon has other potential applications in microfluidics systems.

The effect of percutaneous transcatheter occlusion of left atrial appendage on left atrium and adjacent anatomic structure in canine

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Yang Zhihong; Wu Hong; Qin Yongwen; Hu Jianqiang; Ding Zhongru; Liu Zongjun; Liu Biao; Zheng Xing

2009-01-01

Objective: To observe the effect of percutaneous transcatheter occlusion of left atrial appendage (LAA) with a new self-manufactured LAA occluder on left atrium and adjacent anatomic structure in canine. Methods: A new self-manufactured LAA occluder was implanted into the LAA through a transseptal catheter in 20 dogs. Before and after the procedure, the experimental dogs were anaesthetized and examined by transthoracic echocardiography (TTE) to measure the diameter and the volume of the left atrium, the left superior pulmonary vein flow velocity and the left atrioventricular valve flow velocity separately. The contrast radiography of the LAA and the left coronary arteriography were performed. Results: The new LAA occluder was implanted successfully in 14 dogs. No obvious changes in the diameter and the volume of the left atrium, in left superior pulmonary vein flow velocity and in left atrioventricular valve flow velocity were found. On arteriography, left circumflex artery was normally displayed after the procedure. No migration of the occluder was seen on TTE and angiography after procedure. Conclusion: Percutaneous transcatheter occlusion of left atrial appendage with a new self-manufactured LAA occluder has no obvious effect on left atrium and adjacent anatomic structure in experimental canine, which indicates that the new-type device is a safe and feasible occluder for LAA. (authors)

The effects of poverty on childhood brain development: the mediating effect of caregiving and stressful life events.

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Luby, Joan; Belden, Andy; Botteron, Kelly; Marrus, Natasha; Harms, Michael P; Babb, Casey; Nishino, Tomoyuki; Barch, Deanna

2013-12-01

IMPORTANCE The study provides novel data to inform the mechanisms by which poverty negatively impacts childhood brain development. OBJECTIVE To investigate whether the income-to-needs ratio experienced in early childhood impacts brain development at school age and to explore the mediators of this effect. DESIGN, SETTING, AND PARTICIPANTS This study was conducted at an academic research unit at the Washington University School of Medicine in St Louis. Data from a prospective longitudinal study of emotion development in preschool children who participated in neuroimaging at school age were used to investigate the effects of poverty on brain development. Children were assessed annually for 3 to 6 years prior to the time of a magnetic resonance imaging scan, during which they were evaluated on psychosocial, behavioral, and other developmental dimensions. Preschoolers included in the study were 3 to 6 years of age and were recruited from primary care and day care sites in the St Louis metropolitan area; they were annually assessed behaviorally for 5 to 10 years. Healthy preschoolers and those with clinical symptoms of depression participated in neuroimaging at school age/early adolescence. EXPOSURE Household poverty as measured by the income-to-needs ratio. MAIN OUTCOMES AND MEASURES Brain volumes of children's white matter and cortical gray matter, as well as hippocampus and amygdala volumes, obtained using magnetic resonance imaging. Mediators of interest were caregiver support/hostility measured observationally during the preschool period and stressful life events measured prospectively. RESULTS Poverty was associated with smaller white and cortical gray matter and hippocampal and amygdala volumes. The effects of poverty on hippocampal volume were mediated by caregiving support/hostility on the left and right, as well as stressful life events on the left. CONCLUSIONS AND RELEVANCE The finding that exposure to poverty in early childhood materially impacts brain

The New Left in the European Democracies: The Case of the German Radical Left

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Marco Damiani

2015-03-01

Full Text Available The new form of the social and political conflict cannot be explained by the traditional categories of right and left, but it articulates to them on two plans, that of the establishment, intended like plan of the structured political conflict from the traditional actors, and that of the anti-establishment, in which new representations of politics emerge. The New Left is characterized by type of intermittent participation and new perspectives on mobilization inside the parties and the social movements. This type of parties differs moreover from the traditional ones left of the socialist and social democratic left in not arranging of organizations collaterals placed under the direction of the leadership of the same party. The mobilization that spontaneously assumes not conventional forms of active participation of the citizens, or is primed by the action of an associative network of which the same parties take part, than however does not monopo-lize the collective action. In this regard, the attention will be dedicated to the study of Die Linke: an anti-establishment party of the non-socialist German left-wing, heir to the communist tradition. The choice was affected to the German model because: 1 Germany is a country with a strong social democratic tradition, but 25 years after the fall of the Berlin Wall the German political system identifies a new antagonist political party; 2 Die Linke represents an interesting case in the political landscape of the European radical left because is a one-party that gives up at the federation of parties to try to unify the political parties of German radical left-wing.