tbuckley/cabot-search huggingface dataset:
Abstract 18845: Left Ventricular Assist Device Normalizes Multiple Pathogenic Pathways in Both the Left and Right Ventricle in Patients With Dilated Cardiomyopathy
Authors: Nirmal Parajuli, Ratnadeep Basu, Konrad S Famulski, Jayan Nagendran, Daniel H Kim, John C Mullen, Holger Buchholz, Philip F Halloran, Gavin Y Oudit
Journal: Circulation (2014)

Introduction: Heart failure (HF) continues to be a common cause of morbidity and mortality and dilated cardiomyopathy (DCM) is a common cause of adverse ventricular remodeling and HF. Left ventricular assist device (LVAD) has emerged as an important mode of therapy for advanced HF by unloading the LV and maintaining systemic perfusion. The extent to which LVAD mediates beneficial remodeling in the right ventricle (RV) is incompletely understood. Hypothesis: Differential mRNA expression in a chamber-specific manner may elucidate LVAD mediated functional reverse remodeling in end-stage HF. Methods and Results: Right (RV) and left (LV) ventricle tissue from explanted failing and non-failing control (NFC) human hearts were collected within 20 mins of explantation. Global mRNA expression profiling in DCM patients without (n=8; 7M/1F; age 42-54 years; ejection fraction (EF): 17.5% (15-26%) and with (n= 8; 7M/1F; age 44-58 yrs; EF 15% (12.5-25.0%) LVAD (HeartMate II) was compared to NFC (n=6; age 39-56 yrs; 4M/2F). mRNA microarray was performed using Affymetrix PrimeView gene chips and evaluated using the Ingenuity Pathway Analysis ( IPA) program. LVAD use was associated with marked reduction of myocardial hypertrophy, interstitial fibrosis and apoptosis in both the LV and RV. The cleaved caspase-3 and Tunnel-positive cardiomyocytes were reduced in both RV and LV with LVAD. Total gene entities of 991 in the LV and 860 in the RV were differentially expressed in hearts with DCM without LVAD. LVAD use was independently associated with the altered regulation of 280 genes in the LV and 380 genes in the RV. The total up/down regulated genes involved in cardiac hypertrophy ranged from 20-60% and myocardial fibrosis ranged from 10-80% and were altered in both the RV and LV in response to LVAD therapy. In addition, 14-30% of the total apoptotic-related genes and 6-20 % of the cytokine-related genes were changed in both ventricles. Conclusions: LVAD reduced pathological hypertrophy and fibrosis in both LV and RV and is correlated with altered gene expression controlling adverse myocardial remodeling and fibrosis, apoptotic and inflammatory pathways. LVAD therapy represents a viable long-term therapy for HF patients and is associated with improved RV remodeling.
Pharmaceutical involvement in breast cancer clinical trials
Authors: J. M. Peppercorn, E. Blood, E. P. Winer, A. H. Partridge
Journal: Journal of Clinical Oncology (2005)

6057 Background: Since 1992, pharmaceutical industry support has surpassed NIH funding for clinical research in the U.S. We sought to evaluate the impact of private sponsorship on the nature of published breast cancer clinical trials. Methods: We reviewed all published breast cancer clinical trials from 1993, 1998, and 2003 from 10 select English language medical journals to evaluate pharmaceutical involvement over time, and the relationship between pharmaceutical involvement and study design and results. Clinical studies reporting one or more disease specific outcomes from medical therapy for breast cancer were eligible for analysis. Pharmaceutical industry involvement was defined as reported pharmaceutical funding, provision of drug, and/or authorship in the publication. Results: 140 eligible studies were identified, including 45 published in 1993, 39 in 1998, 56 in 2003. 67 (48%) reported pharmaceutical industry involvement; 36 (26%) had at least one pharmaceutical industry author. 97 (69%) of trials involved patients with metastatic disease, 35 (25%) early stage disease, and 8 (6%) other settings. 57 (41%) studies were randomized phase III trials. 100 (71%) studies were considered “positive”. Pharmaceutical involvement was identified in 44% of studies published in 1993, 38% in 1998, 58% in 2003; pharmaceutical authorship was identified in 22% of studies published in 1993, 21% in 1998, 33% in 2003. For studies published in 2003, those reporting pharmaceutical involvement were more likely to be positive (84% vs. 54%, p = 0.02 by Fisher’s exact test), to involve metastatic disease (72% vs. 46%, p = 0.06), and to be non-randomized studies (66% vs. 33%, p = 0.03). Conclusions: Pharmaceutical involvement in published clinical breast cancer trials may affect study design and likelihood of reporting a positive result. Further research, including analysis of unpublished studies, evaluating the impact of increasing pharmaceutical industry involvement on clinical research is warranted. No significant financial relationships to disclose.
Analysis of elderly (≥ 65 yrs) patients’ participation on early phase I clinical trials at two NCI-designated Comprehensive Cancer Centers
Authors: P. Savvides, M. J. Egorin, S. Gerson, R. K. Ramanathan, N. A. Berger, S. Ramalingam, C. Hoppel, C. P. Belani, S. Remick, G. S. Chatta
Journal: Journal of Clinical Oncology (2005)

8133 Purpose The impact of elderly patients’ participation in phase I clinical trials has not been evaluated. A better understanding could allow a more rational approach to drug development and to create enrollment algorithms for this age group. Patients and Methods Independent analyses of patients enrolled at our institutions’ phase I studies have been performed (n(C)= 192, n(P) = 218). Demographic and disease staging information, baseline laboratory values, chemotherapy treatment information, and recorded toxicities were analyzed. Results I. Patients ≥65 yrs represented 38% (73/192) of all patients at C and 37% (81/218) at P. Patients 65–75 yrs. represented 33% (C) and 29% (P) and patients >75 yrs. accounted for 5% (C) to 8% (P). II. Univariate analyses revealed no statistically significant differences between younger (< 65 years) and older patients regarding baseline demographics (sex, race, performance status) or baseline laboratory values (CBC, LFTs, albumin, creatinine). III. For patients with non-hematologic malignancies on chemotherapeutic trials (n(C) = 137, n(P) = 131) grade ≥3 toxicity (any) occurred in 65% (89/137) at C, and 58% (76/131) at P. Grade ≥3 hematologic toxicity was observed in 41% (56/137) at C, and 33% (43 /131) at P. IV. Neither grade 3–4 hematologic toxicity nor non-hematologic toxicity were statistically different in the two groups at either institution. Conclusions Nearly 40% of patients recruited to phase I studies at our centers are elderly, a higher proportion than what has been reported in phase II and III cancer trials. This finding was not anticipated, and the reasons are being evaluated. Thus, for the select group of patients with near normal organ function and a good performance status (required for patients enrolling in our Phase I programs), older age does not appear to be associated with increased toxicity. Further analyses are underway to better characterize the impact of enrolling elderly patients in trials of novel cancer agents and to analyze available pharmacokinetic data. (Supported in part by NIH grants nos.: K12 CA76917, P20 CA103736, U01 CA099168–01, NIH/NCCR?GCRC#5M01 RR 00056, CA62502, P30 CA43703, M01 RR00080 and P20 CA103730) No significant financial relationships to disclose.
TBCRC 019: An open label, randomized, phase II trial of nanoparticle albumin-bound paclitaxel (nab-PAC) with or without the anti-death receptor 5 (DR5) monoclonal antibody tigatuzumab (TIG) in patients with metastatic triple negative breast cancer (TNBC).
Authors: Christos Vaklavas, Vandana Gupta Abramson, Nancy U. Lin, Minetta C. Liu, Hope S. Rugo, Rita Nanda, Anna Maria Storniolo, Tiffany A. Traina, Yufeng Li, Sujata Patil, Daniel F. Hayes, Catherine H. Van Poznak, Julie R. Nangia, William Johnson Irvin, Helen Krontiras, Jennifer F. De Los Santos, Paul Haluska, Antonio C. Wolff, Andres Forero-Torres
Journal: Journal of Clinical Oncology (2013)

1052 Background: TIG, an agonistic anti-DR5 monoclonal antibody, triggers apoptosis in DR5+ human tumor cells without the aid of crosslinking. TIG has shown strong in vitro and in vivo activity against basal-like breast cancer cells that is enhanced by chemotherapy like paclitaxel. Methods: Randomized 2:1 phase II trial of nab-PAC with/without TIG in TNBC patients. Patients stratified by prior exposure to chemotherapy in the metastatic setting. Patients received nab-PAC weekly x 3 and TIG every other week, every 28 days. Primary endpoint was overall response rate (ORR). Secondary objectives were safety, progression free survival (PFS), TIG immunogenicity, and PK. Biopsies and circulating tumor cells were collected. The trial was not powered to compare arms but allowed early stopping for futility and was sized to estimate ORR with 95% CI. Results: 64 patients enrolled, 60 treated; 39 in the combination arm and 21 in the nab-PAC arm. Of the 39 in the combination arm, there were 2 CR, 9 PR (1 near CR, 96% tumor reduction), 11 SD and 17 PD; ORR 28% (95% CI 14%-42%). Of the 21 in the single agent arm, there were no CR, 8 PR, 4 SD and 9 PD; ORR 38% (95% CI 17%-59%). Higher ORRs were seen in the chemotherapy naïve patients (58% vs. 15% combination and 42% vs. 35% single agent). 2 patients with CR, 1 near CR, and 1 PR in the combination arm are still on therapy (602+, 531+, 466+, 460+ days). PFS was similar in both groups (3.6 months); higher in chemotherapy naïve patients. Combination was well tolerated (most toxicities grade 1/2); the most common AEs were fatigue, alopecia, peripheral sensory neuropathy, anemia, neutropenia, nausea, thrombocytopenia, anorexia, diarrhea, and vomiting. No grade 4 or 5 toxicity. No apparent added toxicity with TIG was seen. Conclusions: Combination therapy with nab-PAC + TIG was well tolerated, without apparent improvement in ORR relative to nab-PAC alone; however, 4 subjects treated as first-line had prolonged clinical benefit with the combination, and correlative studies will investigate markers that might predict clinical outcome (Next-Gen genomic analysis). Clinical trial information: F101004001.
Treatment (tx) with tyrosine kinase inhibitors (TKIs) for patients (pts) with differentiated thyroid cancer (DTC): The M. D. Anderson Cancer Center (MDACC) experience
Authors: M. E. Cabanillas, S. G. Waguespack, Y. Bronstein, M. Williams, L. Feng, S. I. Sherman, N. L. Busaidy
Journal: Journal of Clinical Oncology (2009)

6060 Background: DTC is a relatively common tumor and about 20% will develop distant metastases (mets) of which at least 50% will not respond to standard tx. Until recently, tx for pts with progressive, RAI negative disease was limited. However, the identification of biologic targets in DTC has led to several trials with TKIs. Objectives: We sought to describe the MDACC experience with off-label use of TKIs to determine which pts benefit the most. Methods: Adult pts with a diagnosis of DTC treated with single agent sorafenib (SOR) or sunitinib (SUN), and who had a baseline and at least 1 follow-up (f/u) scan after 3 months (mos) of therapy, were included. All imaging data, as well as the TSH-suppressed thyroglobulin (TG) levels corresponding to each scan date were collected. RECIST was used to determine response. Results: We identified 33 pts from our clinical database. 15 pts met inclusion criteria: 9 women, 6 men. No pts were excluded due to progression or death before 3 mos. Median age 61 years (range, 38–83). 7 patients had papillary, 6 follicular (including 2 insular subtypes), 2 Hurthle cell. Most patients had RAI negative disease. SOR was used in 13, SUN in 2. Both SUN pts had been on SOR; 1 failed and 1 had intolerable side effects to SOR. Median time on tx was 42 weeks. All pts had evidence of PD prior to start of tx. Best response was 3 (20%) PR, 9 (60%) SD, 3 (20%) PD. Clinical benefit (PR+SD) = 80%. The SUN pt who was refractory to SOR had a 38% reduction in tumor size. The most noticeable activity occurred in lung (median change: -16%), whereas lymph nodes had PD or SD (median change: +3%). The 2 pts with pleural mets had PD. Four pts had bone mets: 2 had XRT and had SD in bone, while the other 2 did not have XRT and had PD in bone. At 12 mos PFS was 65% and OS was 85%. Median f/u time was 16 mos. All histologic types had similar responses. Log (TG) correlated with response (p = 0.0005). Conclusions: SOR and SUN are effective in pts with widely metastatic, progressive DTC, with most pts achieving SD or PR. The most noticeable responses occurred in the lungs in contrast with minimal changes in nodal mets, suggesting a tissue-specific response to tx. Log (TG) significantly correlated with response to tx and therefore may have value as a surrogate marker of response. [Table: see text]
Aggressiveness of papillary serous carcinoma (PSC) of the uterus and ovary: A need for reappraisal
Authors: T. Singh, S. Saha, M. Ghanem, H. Gayar, A. G. Dan, N. Dutt, J. Metz, D. Wiese, A. Misra, M. Arora
Journal: Journal of Clinical Oncology (2005)

5177 Background: PSC of the uterus (Ut) and ovary (Ov) are often treated similarly because of known similarities in their histology, biological aggressiveness and poor outcomes. In order to identify the need for more standardized treatment, the outcome of PSC of the Ut and Ov were compared in regard to their clinical presentation, treatment, stage at diagnosis, recurrence pattern and survival within the same institution. Methods: From 1991–2004, 327 consecutive patients (pts) were treated for Ut and Ov malignancy by a single oncologic surgeon. Of these, 46 pts were diagnosed as PSC (Ut =14 pts and Ov = 32 pts). The data were obtained from medical records, tumor registry, and follow-up reports. Comparisons were made in regard to age, stage at diagnosis, presentation, treatment, recurrence pattern and disease-free and overall survival. Results: See table. Conclusions: Ovarian PSC presents at a much more advanced stage, recurs more often and has much poorer disease-free and overall survival than uterine PSC. Even though surgery for maximum debulking is necessary for ideal management of both Ut and Ov PSC, aggressive adjuvant chemotherapy in almost all cases of Ov PSC as opposed to less than two thirds of Ut PSC is effective. These two types of tumors appear to have different biological behaviors and hence should be treated differently. No significant financial relationships to disclose.
Incidence of CML in Europe—a Comparison of 19 European Countries with US SEER Data
Authors: Verena S Hoffmann, Doris Lindoerfer, Josef Thaler, Labar Boris, Frederiki Melanthiou, Jiri Mayer, Hele Everaus, Joelle Guilhot, Gabriele Schubert-Fritschle, Fausto Castagnetti, Sandra Lejniece, Laimonas Griskevicius, Noortje Thielen, Tomasz Sacha, Andrzej Hellmann, Anna G. Turkina, Andrey Zaritskey, Andrija Bogdanovic, Karel Indrak, Irena Zupan, Juan Luis Steegmann, Bengt Simonsson, Richard Clark, Martin Hoglund, Ruediger Hehlmann, Joerg Hasford, Michele Baccarani
Journal: Blood (2014)
Activity of sunitinib in advanced malignant melanoma and its correlation with potential predictive biomarkers.
Authors: L. Decoster, B. Neyns, I. Vande Broek, E. Anckaert, D. De Clerck, J. De Mey, F. Majois, J. Baurain, H. Denys, J. De Greve
Journal: Journal of Clinical Oncology (2010)

8518 Background: Sunitinib is a small molecule that inhibits several tyrosine kinase receptors, including VEGFR, PDGFR, c-KIT, FLT3 and RET. These kinases play a key role in neoangiogenesis and in tumour cell proliferation and survival. The effects of sunitinib in cancer treatment may be both anti-angiogenic or related to a direct anti-tumour effect of the drug through drug targets activated in the tumour cell. Treatment options for advanced melanoma after dacarbazine-based chemotherapy remain limited. We provide the results of a phase II study with sunitinib in advanced melanoma patients. Methods: Patients with locally advanced or metastatic melanoma who failed at least one line of dacarbazine-based chemotherapy were enrolled in a Belgian academic multi-centre phase II trial, following a Simon's two-stage design. Patients received treatment with sunitinib in 6 weekly cycles comprising of a 50 mg once daily dosing for 4 weeks, followed by a 2 week off-treatment period. The primary endpoint was RECIST-defined objective response. Angiogenic biomarkers were collected to study their potential predictive value for response. Serum VEGF, VEGFR-1, VEGFR-2 and PlGF were determined by ELISA and circulating endothelial cells were enumerated by FACS at baseline and biweekly during the first cycle. Results: Thirty-six patients with metastatic melanoma were enrolled. Seven patients were not evaluable for response because of early discontinuation of sunitinib, due to adverse events. Three patients (8.3%) demonstrated a partial response with a mean duration of 6.5 months. Nine had stable disease (25%) with a mean duration of 4.1 months (range: 3-8.2 months) and 17 had progressive disease (47.2%). The most frequent grade 3/4 toxicities were asthenia, anorexia and thrombopenia. No correlation between response and baseline VEGF, VEGFR-1, VEGFR-2 or PlGF was observed. Further analysis is ongoing. Conclusions: The present phase II trial met its primary endpoint (3 partial remissions) and a clinical benefit rate of 33% was observed. In a minority of patients significant toxicity was observed. Data from angiogenic biomarker analysis and the correlation with response will be reported. No significant financial relationships to disclose.
First report of the European Cooperative Trial in Operable Breast Cancer II (ECTO II): Effects of primary chemo-endocrine therapy on local-regional disease in ER-positive breast cancer
Authors: M. Zambetti, M. Mansutti, A. Llunch, C. Zamagni, E. De Benedictis, P. Gomez, L. Pavesi, C. Dittrich, P. Valagussa, L. Gianni
Journal: Journal of Clinical Oncology (2008)

588 Background: To improve the pathologic complete remission rate documented in the ECTO trial (ASCO 2002), in June 2005 we activated a randomized phase II two stage-type protocol with concomitant chemo-endocrine therapy in ER-positive breast cancer > 2 cm at diagnosis. Methods: 182 patients were enrolled by end of June 2007. Patients were randomly allocated to 3 chemotherapy regimens: A (AT, doxo 60 mg/m2 + paclitaxel 200 mg/m2, q 3 w x 4 followed by CMF d1+8 q 4 w x 4); B (AT as above followed by CM d1+8 + capecitabine 1,850 mg/m2 for 14 days q 4 w x 4); C (AC, doxo 60 mg/m2 + cyclophosphamide 600 mg/m2 q 3 w x 4 followed by paclitaxel 100 mg/m2 d1+8 + capecitabine as above q 3 w x 4). Exemestane (25 mg/day) was given from the start of chemotherapy till surgery in all 3 regimens, along with LH-RH analogues in all premenopausal women. Results: At the cut-off date of August 31, 2007, 102 patients were assessed for the first step of the analysis plan. Baseline characteristics (age, menopause, PgR and HER2) were well balanced and left ventricular ejection fraction (LVEF) was similar in all 3 groups. Treatment was fairly well tolerated, but more frequently delayed in arms B and C. Median delivered doses of all drugs were similar in all 3 regimens. Grade 3 neutropenia was more frequently observed during AC (7%) than during AT (3%), while no episodes of thrombocytopenia were documented. CTC 3 LVEF modification was documented in one patient in arm C. Rates of complete pathologic absence of invasive cancer in the breast (pCR) and in the breast and axilla (tnpCR) are reported in the Table. Conclusions: Exemestane did not appear to add on the expected pCR rate by chemotherapy in ER-positive cases. The capecitabine-containing regimens were more active than the non-capecitabine one. Regimen A Regimen B Regimen C Patients (n°) 35 32 35 % pCR 5.7 (0.7 - 19.2) 15.6 (5.3 - 32.8) 8.6 (1.8 -23.1) % tnpCR 2.9 (0.1 - 14.9) 12.5 (3.6 - 29.0) 8.6 (1.8 -23.1) 95% confidence limits Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Roche Roche
Prognostic factors in follicular lymphoma: A single-institution study
Authors: N. Jacobi, T. Rogers, B. A. Peterson
Journal: Journal of Clinical Oncology (2005)

6715 Background: Recently developed prognostic models for follicular lymphoma have proven useful in predicting overall survival (OS), but most have used data from multiple centers. Our goal was to look at prognostic factors within a single institution. Methods: We conducted a retrospective study on 77 newly diagnosed patients with follicular lymphoma, focussing on clinical characteristics, symptom duration before diagnosis, pathologic findings, including grade, laboratory data, imaging studies at initial presentation and management. The study population was 53% male. Ages ranged from 25 to 87 years (median 51). By Ann Arbor classification 4% were stage I, 8% stage II, 18% stage II and 69% stage IV. Initial therapy was deferred in 39%. The remaining patients received stage-appropriate therapy. Survival was measured from time of diagnosis to death. Prognostic factors at initial diagnosis that were statistically significant in univariate log rank comparisons of Kaplan-Meier survival curves were used to build a multivariate proportional hazard regression model of OS. Results: Median OS for these patients was 10.3 years. OS differed only with high (> 12 g/dl) versus low (< 12 g/dl) hemoglobin (p=.001) and in younger (< 60 years) versus older (> 60 years) patients (p=.05), as indicated by univariate log-rank tests. Both hemoglobin and age were also significant in a multivariate proportional hazards analysis. Low hemoglobin and increased age were independent predictors of lower OS with hazard ratios of 6.6 (95% CI 2.2–20.1) and 3.7 (95% CI 1.2–11.7), respectively. Median survival for older patients who also had anemia was only 3.1 years. A test for interaction between age and hemoglobin was negative (p=.35). The estimated hazard ratio for an older individual with low hemoglobin was 24.7 (95% CI 4.0–153.3). To assess the proportional hazards assumption we tested for an interaction between time and both age (p=.92) and hemoglobin (p=.66) and found no evidence against proportionality. Conclusion: A hemoglobin < 12 g/dl and age > 60 years at diagnosis are significant predictors of worse OS. No significant financial relationships to disclose.