tbuckley/cabot-search huggingface dataset:
Is participation in oncology clinical trials using gene therapy products safe
Authors: S. Hirschfeld
Journal: Journal of Clinical Oncology (2004)

6076 Background: Available data indicate the likelihood of receiving some benefit from participation in clinical trials, but few data are available with regard to the risks. This is particularly true for newer types of products such as gene therapy. Methods: A database maintained in MS Access containing all adverse events obtained from spontaneous reports and annual summaries of clinical trials using gene therapy products is being developed at the Center for Biologics Research and Evaluation at the the Food and Drug Administration. Between 11000 and 12000 events obtained from spontaneous filings and annual reports submitted to the FDA have been entered of which about 7500 occurred in cancer patients. This represents about 1800 patients enrolled in about 172 clinical trials. Database queries were constructed to examine general characteristics of the events, diseases, and patients. Results: The most common adverse events recorded were disease progression (15% of all events), injection site pain (6%), pyrexia (4%), injection site reaction (3%), and other pain (2%). The most common serious adverse events (death, prolonged hospitalization, major intervention) occurred in proportion to the use of a product and tended to be disease related. Of 1003 deaths about 770 were considered due to disease progression. The most common diagnoses were metastatic melanoma, glioblastome multiforme, squamous cell carcinoma of the lung, metastatic renal cell carcinoma, disseminated neuroblastoma, metastatic breast cancer and prostate cancer. The second most frequent cause of death was cardiorespiratory arrest, which occurred in about 1% of all patients. The most frequent cause of prolonged hospitalization was febrile neutropenia, occurring in about 3% of all patients. Detailed analysis of the patients, events, and products did not reveal other risk factors in addition to primary cancer diagnosis Conclusions: Participation in oncology gene therapy studies does not appear to carry additional risks beyond those expected of patients with relapsed or refractory disease. No significant financial relationships to disclose.
Multi-institutional trial of the epothilone B analogue BMS-247550 with or without estramustine phosphate (EMP) in patients with progressive castrate-metastatic prostate cancer (PCMPC): Updated results
Authors: W. K. Kelly, M. D. Galsky, E. J. Small, W. Oh, I. Chen, D. Smith, L. Martone, T. Curley, A. Delacruz, H. I. Scher
Journal: Journal of Clinical Oncology (2004)

4509 Background: BMS-247550 is a semi-synthetic analogue of epothilone B with preclinical activity in taxane-resistant cell lines. We have previously shown that BMS-247550 + EMP could be safely administered in PCMPC (Ann Oncol 14:1518, 2003). Subsequently, we initiated a multi-institutional phase II study to determine the efficacy and toxicity of BMS-247550 +/- EMP. Methods: Chemotherapy-naïve patients with PCMPC were eligible. Patients were randomized to BE: BMS-247550 (35 mg/m2 IV over 3 hours every 3 weeks on day 2) + EMP (280 mg PO TID day 1–5) + Coumadin (2 mg daily) or B: BMS-247550 (35 mg/m2 IV over 3 hours every 3 weeks). Results: Accrual has completed with 92 patients enrolled (BE: 45, B: 47). Patients have received a median of 5 cycles (range, 1–12) on BE and 4 cycles (range, 1–25) on B. Twenty-two patients continue on treatment. The major adverse events are detailed in the table. Neuropathy developed after a median of 3 cycles (range, 1–7). On BE, 22/32 (69%; 95% CI, 53–85%) have achieved a ≥ 50% decline in PSA and 8/18 (44%; 95% CI, 21–69%) have had a partial regression (PR) of measurable disease. On B, 18/32 (56%; 95% CI, 39–73%) have achieved a ≥ 50% decline in PSA and 6/26 (23%; 95% CI, 7–40%) have had a PR. At a median follow-up of 6.5 months (range, 0–23), 81 patients are alive and 11 have died. Conclusions: BMS-247550, alone or in combination with EMP, has significant activity in PCMPC. Neuropathy is prominent, has proven manageable, yet requires further characterization. Phase III studies are needed to determine if BMS-247550 confers a survival benefit. Support: CTEP, Prostate Cancer Foundation, NIH N01-CM17105 Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb; Cell Therapeutics; Pfizer Cell Therapeutics AstraZeneca Speakers Bureau Aventis; AstraZeneca; Prostate Cancer Foundation; Millennium Pharmaceuticals ProQuest Investments ProQuest Investments
Response rate and predictive factors of response to Interferon Alfa-2b (IFN) in a prospective phase II trial in progressive digestive endocrine tumor (DET) patients
Authors: C. Lombard-Bohas, F. Mithieux, G. Lledo, C. Du Manoir-Baumgarten, M. G. Lapalus, V. Hervieu, J. A. Chayvialle, P. Artru, J. Cougnard, J.-Y. Scoazec
Journal: Journal of Clinical Oncology (2004)

4165 Background: Previous small phase II trials have demonstrated that IFN had clinical efficacy in DET. Predictive factors of response still remain unclear. Methods: Population: patients (pts) with non resectable progressive histologically proven DET. Tumor size, metastatic status, microvascular density, somatostatin receptor positive scintigraphy (SRS), hypervascularization on CT scan, chromogranin A, Neuron Specific Enolase (NSE), LDH, and Secretory Syndromes (SS) were analysed as prognostic factors to response. Subcutaneous IFN was given 3 times a week first at 1,5 MU per injection and increased to 3 than 5 MU, with morphological evaluation every 3 months. Results: Twenty nine patients were included from 05/00 to 05/03. Patients characteristics : median age 59 (40–75), primary sites : pancreas (18), ileum (7), jejunum (1), bronchi (2), unknown primary (1); metastatic disease (27); pretreated pts (25), primary tumor removed (19), SS 12 pts (carcinoid syndrome 7); PS = 0–1 (26). SRS was positive in 21/27 evaluable pts; 17/26 CT scan showed hypervascular tumors; 13/23 chromogranin A, 5/20 NSE, and 4/21 LDH plasma levels were high. Microvascular density and Ki67 were analysed in respectively 23 and 21 pts. Median follow-up (FU) was 20,3 months (3–38). Response on 27 evaluable pts : 2 OR (7,4%), 2 mR (7,4%),15 SD (55,6%), 8 PD (29,6%), i.e. 70,4% non progressive pts. After one year FU, 9 pts were still treated (8 SD and 1 PD), after 2 years FU, 3 SD, 1 PD. Toxicity ≥ grade 2 : 3 depressive syndromes (treatment stopped), grade 2–3 neutropenia : 3 pts. No correlation was found between the prognostic factors analysed and response to treatment. Conclusions: Our results confirmed the clinical efficacy of IFN in progressive pts with DET (70,4% non progression). None of the tested parameters was predictive of response but more pts need to be studied. No significant financial relationships to disclose.
The natural history of primary sclerosing cholangitis in 781 children: A multicenter, international collaboration
Authors: Mark R. Deneau, Wael El‐Matary, Pamela L. Valentino, Reham Abdou, Khaled Alqoaer, Mansi Amin, Achiya Z. Amir, Marcus Auth, Fateh Bazerbachi, Annemarie Broderick, Albert Chan, Jillian Cotter, Sylvia Doan, Mounif El‐Youssef, Federica Ferrari, Katryn N. Furuya, Madeleine Gottrand, Frederic Gottrand, Nitika Gupta, Matjaz Homan, Binita M. Kamath, Kyung Mo Kim, Kaija‐Leena Kolho, Anastasia Konidari, Bart Koot, Raffaele Iorio, Oren Ledder, Cara Mack, Mercedes Martinez, Tamir Miloh, Parvathi Mohan, Niamh O'Cathain, Alexandra Papadopoulou, Amanda Ricciuto, Lawrence Saubermann, Pushpa Sathya, Eyal Shteyer, Vratislav Smolka, Atushi Tanaka, Raghu Varier, Veena Venkat, Bernadette Vitola, Miriam B. Vos, Marek Woynarowski, Jason Yap, M. Kyle Jensen
Journal: Hepatology (2017)

There are limited data on the natural history of primary sclerosing cholangitis (PSC) in children. We aimed to describe the disease characteristics and long‐term outcomes of pediatric PSC. We retrospectively collected all pediatric PSC cases from 36 participating institutions and conducted a survival analysis from the date of PSC diagnosis to dates of diagnosis of portal hypertensive or biliary complications, cholangiocarcinoma, liver transplantation, or death. We analyzed patients grouped by disease phenotype and laboratory studies at diagnosis to identify objective predictors of long‐term outcome. We identified 781 patients, median age 12 years, with 4,277 person‐years of follow‐up; 33% with autoimmune hepatitis, 76% with inflammatory bowel disease, and 13% with small duct PSC. Portal hypertensive and biliary complications developed in 38% and 25%, respectively, after 10 years of disease. Once these complications developed, median survival with native liver was 2.8 and 3.5 years, respectively. Cholangiocarcinoma occurred in 1%. Overall event‐free survival was 70% at 5 years and 53% at 10 years. Patient groups with the most elevated total bilirubin, gamma‐glutamyltransferase, and aspartate aminotransferase‐to‐platelet ratio index at diagnosis had the worst outcomes. In multivariate analysis PSC–inflammatory bowel disease and small duct phenotypes were associated with favorable prognosis (hazard ratios 0.6, 95% confidence interval 0.5‐0.9, and 0.7, 95% confidence interval 0.5‐0.96, respectively). Age, gender, and autoimmune hepatitis overlap did not impact long‐term outcome. Conclusion : PSC has a chronic, progressive course in children, and nearly half of patients develop an adverse liver outcome after 10 years of disease; elevations in bilirubin, gamma‐glutamyltransferase, and aspartate aminotransferase‐to‐platelet ratio index at diagnosis can identify patients at highest risk; small duct PSC and PSC–inflammatory bowel disease are more favorable disease phenotypes. (H epatology 2017;66:518–527).
Personalized Management of Pancreatic Ductal Adenocarcinoma Patients through Computational Modeling
Authors: Kimiyo N. Yamamoto, Shinichi Yachida, Akira Nakamura, Atsushi Niida, Minoru Oshima, Subhajyoti De, Lauren M. Rosati, Joseph M. Herman, Christine A. Iacobuzio-Donahue, Hiroshi Haeno
Journal: Cancer Research (2017)

Phenotypic diversity in pancreatic ductal adenocarcinoma (PDAC) results in a variety of treatment responses. Rapid autopsy studies have revealed a subgroup of PDAC patients with a lower propensity to develop metastatic disease, challenging the common perception that all patients die of widely metastatic disease, but questions remain about root causes of this difference and the potential impact on treatment strategies. In this study, we addressed these questions through the development of a mathematical model of PDAC progression that incorporates the major alteration status of specific genes with predictive utility. The model successfully reproduced clinical outcomes regarding metastatic patterns and the genetic alteration status of patients from two independent cohorts from the United States and Japan. Using this model, we defined a candidate predictive signature in patients with low metastatic propensity. If a primary tumor contained a small fraction of cells with KRAS and additional alterations to CDKN2A, TP53, or SMAD4 genes, the patient was likely to exhibit low metastatic propensity. By using this predictive signature, we computationally simulated a set of clinical trials to model whether this subgroup would benefit from locally intensive therapies such as surgery or radiation therapy. The largest overall survival benefit resulted from complete resection, followed by adjuvant chemoradiation therapy and salvage therapies for isolated recurrence. While requiring prospective validation in a clinical trial, our results suggest a new tool to help personalize care in PDAC patients in seeking the most effective therapeutic modality for each individual. Cancer Res; 77(12); 3325-35. ©2017 AACR.
Old and new prognostic factors in a series of 910 patients with malignant pleural mesothelioma (MPM).
Authors: Anthony Linton, Nick Pavlakis, Rachel O'Connell, Matthew Soeberg, Steven Chuan-Hao Kao, Stephen John Clarke, Janette L. Vardy, Nico Van Zandwijk
Journal: Journal of Clinical Oncology (2014)

7586 Background: Whilst the prognosis of most MPM patients is poor, a small proportion demonstrate long term survival. We investigate patient and treatment factors associated with survival and the impact of chemotherapy (CT) and surgery in a large patient series. Methods: Data sets of patients registered with the NSW Dust Diseases Board (2002-2009) were reviewed and prognostic factors such as age, gender, histological subtype and stage evaluated using Kaplan-Meier and Cox regression analysis. The impact of treatment, smoking and asbestos exposure were evaluated and subgroup analyses explored long(er) (>20 months) vs. short(er) (< 20 months) survivors. Results: We identified 910 patients: 90% male; median age 72 yrs; histological subtype (epithelioid 60%; biphasic 13%; sarcomatoid 17%; unknown 10%); stage (Tx-I-II 48%; III-IV 52%); calretinin expression (74.8%). Treatment: CT 41%, extrapleural pneumonectomy (EPP) 6%. Median age of first occupational asbestos exposure was 18 yrs; cumulative exposure 24 yrs. Median overall survival (OS) was 10.1 mo. Longer OS (p<0.001) was associated with: age <70yrs (13.5 vs. 8.5 mo.); female gender (12.0 vs. 9.9 mo.); epithelioid subtype (13.4 vs. 6.2 mo.); calretinin expression (11.0 vs. 5.5 mo.); NLR (neutrophil lymphocyte ratio) <5 (12.0 vs. 7.5 mo.); platelets <400 (11.6 vs. 7.1 mo.); and normal hemoglobin (16.6 vs 8.8). Patients undergoing CT (15.6 vs. 6.6 months; p<0.001) and EPP (24.8 vs. 9.5 months; p<0.001) had improved survival. Smoking history and cumulative asbestos exposure did not affect survival. On multivariate analysis, all variables remained significant, including EPP and CT use (time dependent analysis). 24% of patients survived >20 months: 16% underwent EPP, 61% received CT; but 31% received neither. Epithelioid histology, calretinin expression, age, stage and hemoglobin levels were independently associated with survival >20 months. Conclusions: In this large, population-based series, we validated calretinin expression, age, gender, histological subtype, stage and NLR as significant prognostic factors. Patients undergoing EPP/CT demonstrated better survival but 84% and 39% of long survivors respectively did not receive EPP or chemotherapy.
ANGPTL3 Deficiency and Protection Against Coronary Artery Disease
Authors: Nathan O. Stitziel, Amit V. Khera, Xiao Wang, Andrew J. Bierhals, A. Christina Vourakis, Alexandra E. Sperry, Pradeep Natarajan, Derek Klarin, Connor A. Emdin, Seyedeh M. Zekavat, Akihiro Nomura, Jeanette Erdmann, Heribert Schunkert, Nilesh J. Samani, William E. Kraus, Svati H. Shah, Bing Yu, Eric Boerwinkle, Daniel J. Rader, Namrata Gupta, Philippe M. Frossard, Asif Rasheed, John Danesh, Eric S. Lander, Stacey Gabriel, Danish Saleheen, Kiran Musunuru, Sekar Kathiresan
Journal: Journal of the American College of Cardiology (2017)
Prostacyclin synthase (PTGIS) expression and epigenetic regulation in non-small cell lung cancer (NSCLC)
Authors: S. G. Gray, M. C. Cathcart, N. Al-Sarraf, G. P. Pidgeon, K. J. O'Byrne
Journal: Journal of Clinical Oncology (2009)

e22160 Background: Prostacyclin synthase (PTGIS) inhibits platelet aggregation and promotes vasodilation. Overexpression of this gene has been shown to inhibit lung cancer growth in a mouse model. Hypermethylation of the PTGIS promoter resulting in downregulation of PTGIS expression has been implicated in colorectal cancer. In this study we have examined both the expression patterns and epigenetic regulation of PTGIS in NSCLC. Methods: DNA/RNA and protein was extracted from matched tumour/normal samples (Thoracic Oncology Research Group BioBank, St James Hospital). PTGIS in these samples and a panel of retrospective resected lung samples was examined by immunohistochemistry and western blotting. A panel of NSCLC cell lines were treated with inhibitors to histone deacetylases (HDi) and DNA methyltransferases (DNMTi) and PTGIS expression examined by RT-PCR. Chromatin immunoprecipitation (ChIP) was used to examine changes to the PTGIS promoter in response to HDi. Results: PTGIS was found to have variable expression in both tumour samples and a panel of lung cancer cell lines. PTGIS expression was demonstrated in the vascular endothelial and bronchial epithelial cells of normal and cancerous sections. A striking variation in intratumoural PTGIS expression was observed. Methylation analysis of cell lines demonstrated hypermethylation of the PTGIS promoter. Treating cells with epigenetic inhibitors resulted in significant upregulation of PTGIS expression. Direct chromatin remodelling of the PTGIS promoter was confirmed. Conclusions: PTGIS is epigenetically regulated. The discrepancy between PTGIS mRNA and protein levels in tumor samples indicates that post-transcriptional and post-translational regulation of PTGIS is central to expression and requires further elucidation. Increased PTGIS expression is a potential therapeutic strategy for tumour prevention. [Table: see text]
Validation of a Genomic Risk Classifier to Predict Prostate Cancer-specific Mortality in Men with Adverse Pathologic Features
Authors: R. Jeffrey Karnes, Voleak Choeurng, Ashley E. Ross, Edward M. Schaeffer, Eric A. Klein, Stephen J. Freedland, Nicholas Erho, Kasra Yousefi, Mandeep Takhar, Elai Davicioni, Matthew R. Cooperberg, Bruce J. Trock
Journal: European Urology (2017)
Combination of everolimus with R-CHOP (ever R-CHOP) as an initial therapy for diffuse large B-cell lymphoma (DLBCL): A phase I and feasibility study (NCCTG N1085 [Alliance]).
Authors: Patrick B. Johnston, Betsy LaPlant, Grzegorz S. Nowakowski, Ivana N. M. Micallef, Stephen Maxted Ansell, Thomas Matthew Habermann, Joseph Colgan, Thomas E. Witzig
Journal: Journal of Clinical Oncology (2015)

8518 Background: Everolimus was demonstrated to have single agent activity in relapsed DLBCL (Leukemia. 2011; 25(2):341-7). However, the safety and efficacy of everolimus in combination with R-CHOP is unknown. Methods: A phase I study was designed to determine the maximum tolerated dose (MTD) of everolimus on days 1-10 or 1-14 in combination with R-CHOP given every 21 days, with a feasibility cohort to examine response in patients with newly diagnosed CD20+ DLBCL. MTD was defined as the highest safely tolerated dose where at most 1 out of 6 patients experienced DLT. Starting everolimus dose was 10 mg days 1-10 and the planned dose escalation was 10 mg days 1-14. DLT was defined as any grade 3 or higher non-hematologic toxicity or a hematologic toxicity within the first cycle resulting in a delay of the next cycle of chemotherapy. The response was evaluated using PET/CT by standard criteria. A fourteen-patient feasibility extension was planned. Results: In the phase I portion, 3 patients received 10 mg everolimus daily for days 1-10 and 6 patients received 10 mg everolimus daily for days 1-14. No DLT was seen and no MTD was achieved; therefore, the dose for everolimus was determined to be 10 mg daily x 14 for the extension phase. 15 additional patients were enrolled in the feasibility portion. For the 24 patients: median age 58.5 years, 58% male, 50% with stage IV disease. The most common grade 3 and 4 adverse events in patients were febrile neutropenia (21%), anemia (17%), thrombocytopenia (21%), and neutropenia (75%). Grade 3 hypertriglyceridemia occurred in 12.5% and grade 3 pneumonitis occurred in one patient. Overall response rate at completion of 6 cycles was 100% in the phase I cohort (8 CR, 1 PR). The patient achieving a PR became PET negative by 12 months without further therapy, thus achieving a CR. Feasibility cohort data will be available for the presentation. Conclusions: Everolimus when combined with R-CHOP combination immunochemotherapy is well tolerated at 10 mg daily on days 1-10 and 1-14 of a 21-day cycle. The initial response rates in the phase I portion appear promising. A larger trial will be necessary to confirm the benefits of this novel combination. Clinical trial information: NCT01334502.
Phase I-II vaccine trial with MHC class II and MHC class I epitopes from Melan-A/MART-1 for patients with metastatic melanoma
Authors: H. M. Zarour, S. Land, C. Sander, R. Mascari, W. J. Storkus, J. Shipe-Spotloe, L. Stover, R. B. Herberman, S. S. Agarwala, J. M. Kirkwood
Journal: Journal of Clinical Oncology (2004)

2524 Background: Here we present the preliminary data from a Phase I-II clinical trial with subcutaneous and intradermal injections of Montanide ISA 51, peptide MART-1 51–73 alone (Cohort A) or in association with the HLA-A2-restricted peptide, MART-1 27–35 (Cohort B) for HLA-DRB1*0401+ patients with metastatic melanoma. 35 patients with metastatic melanoma have been included in this study: 22 HLA-DRB1*0401+ (cohort A) and 13 HLA-A2+/DRB1*0401+ (cohort B). Methods and Results. The patients were treated every week for the first month then every other week for 3 additional months before clinical evaluation. In cohort A, 4 patients went off of study (death), 12 progressed and 4 were stable, 2 are being treated. In arm B, 1 patient was stable, 1 went off study, 7 progressed and 4 are being treated. Ex vivo IFN-γ and IL-5 ELISPOT assays were performed to assess specific T cell function pre- and post-treatment. The primary comparison is based on the increased reactivity from the baseline sample to the post-treatment sample. Wilcoxon rank sum tests were performed for each peptide to determine whether the median change in reactivity was greater than zero. In cohort A, 8/16 evaluable patients exhibited increases in CD4+ T cell reactivity to peptide MART-1 51–73 post-vaccination (p=0.08). Moreover, 5/8 HLA-A2+ patients also displayed increased CD8+ T cell reactivity to peptide MART-1 27–35 (p=0.062). In cohort B, 5/9 evaluable HLA-A2+/DRB1*0401+patients exhibited post-vaccine increases in MART-1-specific CD4+ T cells (p= 0.02) while only 1/5 patients had increased in MART-1-specific CD8+ T cells. Conclusion. These interim data support the in vivo immunogenicity of the MART-1 51–73 epitope in patients with melanoma. MART-1-specific CD8+ T cell responses increased following vaccination with peptide MART-1 51–73 alone, which suggests intramolecular epitope spreading. Further immunologic analyses are currently being performed in this open trial. No significant financial relationships to disclose.