tbuckley/cabot-search huggingface dataset:
Intraperitoneal Therapy for Ovarian Cancer
Authors: Franco M. Muggia
Journal: Journal of Clinical Oncology (2016)

a letter to the Journal of Clinical Oncology to speak in favor of studying intraperitoneal (IP) therapy. 1 Now, the editorial by Bookman and Brady 2 on the article by Tewari et al 3 merits comments on this longrunning debate.The joint analysis of long-term survival of two Gynecologic Oncology Group (GOG) phase III studies, GOG-0114 and GOG-0172, is an informative tour de force given that the two studies shared identical intravenous (IV) comparator arms and patient entry criteria.Doubters of the survival impact of first-line, cisplatin-based IP therapy on ovarian cancer often readily dismiss GOG-0114 as being a negative study because of its overall survival difference of IP over IV reaching only borderline statistical significance (one-tailed P 5 .51). 4,5As a footnote, Tewari et al 3(p1461) erroneously describe the IP regimen as giving IP cisplatin on day 8-it should be day 2.The editorial by Bookman and Brady 2 covers three take home messages from such joint analyses: extended survival at 10 years was deemed true as, indeed, it is clearly shown; sustained impact of IP therapy on small volume tumors (from only microscopic to 1 cm or less) was deemed of interest and largely unexplained; and six IP cycles demonstrated an advantage vis-a-vis three to five, less than three, and IV therapy (from Fig 4 by Tewari et al 3 ), which was deemed to be subject to interpretation, that is, it should be taken it with a grain of salt.The critiques by Bookman and Brady elicit these thoughts: good points are made, with full agreement that the analysis by Tewari et al 3 showing favorable outcomes for those women who complete six cycles is subject to selection bias.
Circulating cytokines and angiogenic factors (CAFs) in patients with advanced non-clear cell renal cell carcinoma treated with sunitinib: Results from a phase II clinical trial.
Authors: Mehmet Asim Bilen, Amado J. Zurita, Nasreen A. Ilias-Khan, Hsiang-Chun Chen, Xuemei Wang, Sherie Hodges, Zita D. Lim, Eric Jonasch, Aarif Yusuf Khakoo, Nizar M. Tannir
Journal: Journal of Clinical Oncology (2015)

483 Background: Development of hypertension (HTN) during VEGF-directed therapies is associated with improved overall survival (OS) in patients (pts) with clear-cell renal cell carcinoma. There is paucity of data about the molecular determinants of response and survival outcomes in non-clear cell renal cell carcinoma (nccRCC) pts treated with targeted therapies. We investigated CAFs and correlated them and HTN with outcomes of nccRCC pts treated with sunitinib in a phase II trial. Methods: Using a bead-based multiplex assay (Luminex), levels of 30 CAFs (including mediators of inflammation, angiogenesis, immunity, and metastasis) were measured prior to start of sunitinib therapy (baseline) and at 4 weeks after completion of cycle 1. Sunitinib benefit was defined as having partial response (PR) or stable disease (SD) by RECIST lasting ≥4 months. Cox proportional hazards regression models were used to assess the association between CAFs, HTN, and survival outcomes. The Kaplan-Meier method was used to estimate progression-free survival (PFS) and OS. Results: Fifty-seven pts [papillary (27), chromophobe (5), unclassified (8), collecting duct/medullary carcinoma (6), sarcomatoid (7), others (4)] were evaluable. Median follow up was 59.1 months (range, 30.6-82.6); 43 pts (75%) have died and 14 (25%) were alive at last follow up. Sunitinib benefit was seen in 21 pts (8 papillary, 4 chromophobe, 3 unclassified, 3 others, 2 collecting duct/medullary carcinoma, 1 sarcomatoid); 2 pts were not evaluable for response. Median PFS was 2.9 months (95% CI, 1.4-5.5) and median OS 16.8 months (95% CI, 10.7-27.4). 29 pts developed HTN during the first cycle, but there was no significant association between HTN and OS, PFS or sunitinib benefit. Elevated baseline levels of GRO, TGFα, sTNF-RI, sVEGF-R2 and IL-8 were correlated with higher risk of death. Conclusions: In this phase II trial in pts with advanced nccRCC, we found no significant association between HTN and PFS, OS, or sunitinib benefit. Candidate CAFs were identified that could be incorporated into prognostic and predictive models for validation in future studies in nccRCC.
The efficacy of combination chemotherapy with cisplatin and gemcitabine in patients with advanced adrenal cortical carcinoma (ACC)
Authors: M. Menefee, M. Edgerly, M. Velarde, K. Herbert, A. T. Fojo
Journal: Journal of Clinical Oncology (2006)

12033 Background: ACC is a rare, but highly lethal disease for which more effective systemic therapies are needed. Prior studies have concluded that cisplatin and doxorubicin have single agent activity and that combinations of these and other agents, most notably etoposide, may have additive or synergistic effects. However, the majority of responses are neither complete nor durable. Anecdotal evidence of activity by gemcitabine in patients with ACC motivated the present analysis, designed to assess the efficacy of cisplatin and gemcitabine in combination in patients with metastatic ACC. Methods: 18 patients with metastatic disease were evaluated. Patient’s ages ranged from 19 to 63 years with a median age of 46 years. 5 patients were treated at initial presentation, while 13 were treated after disease progression on or following a previous chemotherapy regimen. Among the latter, the median number of prior regimens was 1, with a median of 4 prior drugs. Sites of metastases included lung (10/18), liver (12/18), retroperitoneum/adrenal bed (5/18) and bone (2/20). The starting dosages were 100 mg/m 2 of cisplatin and 1250 mg/m 2 of gemcitabine. A total of 56 cycles were administered to 18 patients, with a range of 2 to 12 cycles and a median of 3. Results: The toxicity of this regimen in this patient population was similar to that reported with this regimen in other tumor types. The partial response rate was 11% with an additional 16% of patients demonstrating cytoreduction that did not meet the criteria for a partial response. Conclusions: We conclude that the combination of cisplatin and gemcitabine has activity in ACC. While the superiority of this combination over single agent platinum is not established, the combination does not appear to be superior enough to warrant its routine use, especially in patients with more indolent disease, where single agent platinum can be followed by single agent gemcitabine. An attribute this combination has over other regimens used in patients with ACC, notably those incorporating doxorubicin and/or etoposide, is that it can be given at full doses without excessive toxicity to patients with hormone producing tumors in combination with ketoconazole. No significant financial relationships to disclose.
Abstract 59: Preservation of Myocardial Structure Is Enhanced by Pim-1 Engineering of Bone Marrow Cells
Authors: Pearl J Quijada, Haruhiro Toko, Kimberlee Fischer, Brandi Bailey, Patrick Reilly, Natalie Gude, Daniele Avitabile, Mark Sussman
Journal: Circulation Research (2012)

Rationale: Bone marrow derived cells to treat myocardial injury improve cardiac function and support beneficial cardiac remodeling. However, survival of stem cells is limited due to low proliferation of transferred cells. Objective: Demonstrate long-term potential of c-kit+ bone marrow stem cells (BMCs) enhanced with Pim-1 kinase to promote positive cardiac remodeling. Methods and Results: Lentiviral modification of c-kit+ BMCs to express Pim-1 (BMCeP) increases proliferation and expression of pro-survival proteins relative to BMCs expressing GFP (BMCe). Intramyocardial delivery of BMCeP at time of infarction supports improvements in anterior wall dimensions and prevents left ventricle dilation compared to hearts treated with vehicle alone. Reduction of the akinetic left ventricular wall was observed in BMCeP treated hearts at 4 and 12 weeks after infarction. Early recovery of cardiac function in BMCeP-injected hearts facilitated modest improvements in hemodynamic function up to 12 weeks post infarction between cell treated groups. Persistence of BMCeP is improved relative to BMCe within the infarct together with increased recruitment of endogenous c-kit+ cells. Delivery of BMC populations promotes cellular hypertrophy in the border and infarcted regions coupled with an up regulation of hypertrophic genes. Thus, BMCeP treatment yields improved structural remodeling of infarcted myocardium compared to control BMCs. Conclusions: Genetic modification of BMCs with Pim-1 may serve as a therapeutic approach to promote recovery of myocardial structure. Future approaches may take advantage of salutary BMC actions in conjunction with other stem cell types to increase efficacy of cellular therapy and improve myocardial performance in the injured myocardium.
Variability in Hospice Care at the Very End of Life
Authors: Eric Widera, Shaida Talebreza
Journal: JAMA Internal Medicine (2016)

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PWE-014 Comparison of predictive scores in patients with suspected upper gastrointestinal bleeding: Abstract PWE-014 Table 1
Authors: JR Schneider, JM Thomson, A Fraser, B Vijayan, JS Leeds
Journal: Gut (2015)

<h3>Introduction</h3> Acute upper gastrointestinal bleeding (UGIB) is a common medical emergency with significant morbidity and mortality. It is essential for clinicians to effectively triage patients into risk groups allowing appropriate allocation of resources. Several scoring systems have been devised following admission with suspected UGIB however the most useful score is debated. The most useful score should rapidly stratify risk and not require endoscopy. The aim of this study was to investigate the performance of 3 pre-endoscopic predictive scoring tools in a single, large cohort of patients admitted with suspected UGIB. <h3>Method</h3> The Aberdeen bleeding unit records demographics, presenting symptoms, co-morbidities, and outcomes on all admissions. Patients were included if they presented with features suggestive of UGIB and all variables required to calculate the 3 scores (admission-Rockall, Glasgow-Blatchford Score (GBS) and pre-endoscopic Baylor score). Receiver operating characteristic (ROC) curves were drawn for each score and the area under the curve (AUROC) calculated for 3 outcomes; requirement for blood transfusion, rebleeding and 30 day mortality. Sensitivity and negative predictive value (NPV) analysis was performed to assess very low scores (Rockall &lt;1, GBS &lt;2, Baylor &lt;6) for potential early discharge. <h3>Results</h3> 6,788 patients (M:F=1.3:1, median age 65) were included in the study. For requirement for blood transfusion, AUROC was significantly higher for GBS (0.92, 95% CI 0.91–0.93, p &lt; 0.001) compared to Rockall (0.68, 95% CI 0.67–0.70) and Baylor scores (0.65, 95% CI 0.64–0.67) respectively. For rebleeding, AUROC was significantly higher for GBS (0.76, 95% CI 0.75–0.78, p &lt; 0.001) compared to Rockall (0.66, 95% CI 0.64–0.68) and Baylor scores (0.61, 95% CI 0.59–0.63). For 30 day mortality, GBS and Rockall were not significantly different (0.75, 95% CI 0.74–0.77 and 0.76, 95% CI 0.74–0.78 respectively) but were both significantly higher than the Baylor score (0.71, 95% CI 0.69–0.73). Table 1shows the sensitivity and NPV analysis. <h3>Conclusion</h3> GBS was superior to both Rockall and Baylor score for predicting transfusion and rebleeding. GBS and Rockall scores were superior to the Baylor score in predicting mortality. Using GBS &lt;2 less than 1 in 300 patients would have an adverse outcome. <h3>Disclosure of interest</h3> None Declared.
Phase I/II study of TH-302 in combination with docetaxel in patients with solid tumors including NSCLC and castrate-resistant prostate cancer (CRPC).
Authors: K. K. Sankhala, E. G. Chiorean, A. J. Armstrong, M. J. Borad, A. M. Traynor, S. M. Gadgeel, V. K. Langmuir, C. Eng, S. Kroll, H. Burris
Journal: Journal of Clinical Oncology (2010)

e13527 Background: TH-302 is a 2-nitroimidazole hypoxia-activated prodrug of the DNA alkylator, bromo-isophosphoramide mustard. In preclinical models, TH-302 was active alone and enhanced the activity of docetaxel (D). A phase I/II study was conducted to evaluate the safety and tolerability and investigate the activity of TH-302 in combination with D. Methods: This study used standard solid tumor eligibility criteria except patients (pts) could not have received prior D. Pts received IV TH-302 on days 1 and 8 and docetaxel 75 mg/m2 on day 1 of a 21 day cycle. A standard 3+3 pts design was used with a TH-302 starting dose of 240 mg/m2. Following the determination of the MTD, a dose expansion component enrolled subjects with CRPC and second-line NSCLC. The objectives of the study were to determine the MTD/RP2D of TH-302 and D and to evaluate the pharmacokinetics (PK) and preliminary efficacy. Results: 26 pts [16M/10F, median age 62y (range 39-76y), ECOG PS 0/1: 17/9] were enrolled at 7 sites and treated at TH-302 dose of 240 (8 pts), 340 (9), 400 (2) and 480 (7) mg/m2. Primary tumor sites: 7 CRPC, 3 NSCLC, 3 melanoma, 2 neuroendocrine, 11 other sites. Treatment is ongoing in 8 pts; 13 pts discontinued prior to Cycle 6 (6 PD, 4 Pt/Physician decision, 3 AE). Neutropenia, with and without fever, was dose-limiting. Grade 3/4 neutropenia, thrombocytopenia and anemia occurred in 60%, 8% and 8% of pts. Skin and mucosal toxicities occurred in 13 (50%) and 13 (40%) pts, including 1 grade 3 event of generalized macular rash. Other common AEs were fatigue (52%), nausea (48%) and alopecia (48%). The MTD was established at a TH-302 dose of 340 mg/m2 with docetaxel 75 mg/m2. There was no PK interaction between TH-302 and D. 3 PRs and 12 SDs were reported in the 20 evaluable pts, including 1 PR and 2 SDs in 4 evaluable pts with CRPC and 1 PR and 1 SD in 2 evaluable pts with NSCLC. 5 of the 7 CRPC pts had a greater than 50% decrease in PSA. Conclusions: TH-302 may be administered in combination with full dose docetaxel. Hematologic toxicity was similar to that seen with docetaxel alone. TH-302-related skin and mucosal toxicities were dose limiting but reversible. Encouraging antitumor activity has been observed. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Threshold Pharmaceuticals Threshold Pharmaceuticals Threshold Pharmaceuticals Threshold Pharmaceuticals
Immunotherapy of Hormone-Refractory Prostate Cancer With Antigen-Loaded Dendritic Cells
Authors: Eric J. Small, Paige Fratesi, David M. Reese, George Strang, Reiner Laus, Madhusudan V. Peshwa, Frank H. Valone
Journal: Journal of Clinical Oncology (2000)

PURPOSE: Provenge (Dendreon Corp, Seattle, WA) is an immunotherapy product consisting of autologous dendritic cells loaded ex vivo with a recombinant fusion protein consisting of prostatic acid phosphatase (PAP) linked to granulocyte-macrophage colony-stimulating factor. Sequential phase I and phase II trials were performed to determine the safety and efficacy of Provenge and to assess its capacity to break immune tolerance to the normal tissue antigen PAP. PATIENTS AND METHODS: All patients had hormone-refractory prostate cancer. Dendritic-cell precursors were harvested by leukapheresis in weeks 0, 4, 8, and 24, loaded ex vivo with antigen for 2 days, and then infused intravenously over 30 minutes. Phase I patients received increasing doses of Provenge, and phase II patients received all the Provenge that could be prepared from a leukapheresis product. RESULTS: Patients tolerated treatment well. Fever, the most common adverse event, occurred after 15 infusions (14.7%). All patients developed immune responses to the recombinant fusion protein used to prepare Provenge, and 38% developed immune responses to PAP. Three patients had a more than 50% decline in prostate-specific antigen (PSA) level, and another three patients had 25% to 49% decreases in PSA. The time to disease progression correlated with development of an immune response to PAP and with the dose of dendritic cells received. CONCLUSION: Provenge is a novel immunotherapy agent that is safe and breaks tolerance to the tissue antigen PAP. Preliminary evidence for clinical efficacy warrants further exploration.
IL-17+ cells immunoexpression in systemic sclerosis pulmonary fibrosis
Authors: Ana Paula Pereira Velosa, Michelle Abdo Paiva, Priscila Cristina Andrade, Romy Beatriz Christmann, Esmeralda Miristeni Eher, Sandra Morais Fernezlian, Edwin Roger Parra, Walcy Rosolia Teodoro, Vera Luiza Capelozzi
Journal: European Respiratory Journal (2014)

Background: Investigators have documented an increased number of IL-17+ cells in peripheral blood, in bronchoalveolar lavage and in skin of patients with systemic sclerosis (SSc). IL-17+ cells have been associated to collagen overexpression in SSc fibroblast. Objectives: To evaluate the expression of IL-17+ cells in the pulmonary fibrosis process of the SSc patients. Patients and methods: Lung biopsies were obtained from 14 female patients with SSc (age 26–56 y): 9 patients had limited SSc, and 5 patients had diffuse according to the American College of Rheumatology criteria. Control samples were collected from necropsies of 6 individuals without pulmonary pathology (CAPPesq 0960/08). The collagen I, III and V deposit in pulmonary interstitium was evaluated by immunofluorescence and quantified by image analysis using the software Image-Pro Plus 6.0. IL17+ cells were immunostained by immunohistochemistry and evaluated by the point counting method. Results: Alveolar septa was 4.7-fold greater in SSc when compared to controls. There was no difference in thickened alveolar septa and collagen content between limited and diffuse SSc. However, in both SSc forms, collagen I was higher expressed than collagen III (p=0.011) and V (p=0.002). The amount of IL-17+ cells in the pulmonary interstitium was higher in SSc patients when compared to controls (p=0.01). Limited and diffuse SSc presented the same amounts of IL-17+ cells. Conclusions: Distorted lung framework found in SSc is associated to IL-17+ cells immunoexpression, thus suggesting that this cytokine is involved in altered pathway of SSc pulmonary fibrosis and may represent a promissory immune therapeutic target.

Financial support: FAPESP, Federico Foundation.
Abstract P360: The Impact of Dietary and Metabolic Risk Factors on the Burden of Cardiovascular Diseases and Diabetes in the Middle East and North Africa; An Analysis from the 2010 Global Burden of Diseases, Injuries, and Risk Factors: Nutrition and Chronic Diseases Expert Group, and Metabolic Risk Factors of Chronic Diseases Collaborating Group
Authors: Ashkan Afshin, Renata Micha, Shahab Khatibzadeh, Saman Fahimi, Peilin Shi, Gitanjali Singh, Mohammad Y Yakoob, Majid Ezzati, Dariush Mozaffarian
Journal: Circulation (2012)

BACKGROUND: The burden of CVD and diabetes is rapidly increasing in the Middle East and North Africa. However, the impact of major dietary and metabolic risk factors on CVD and diabetes has not yet been quantified in this region. OBJECTIVE: To quantify the CVD and diabetes mortality attributable to non-optimal diet and metabolic risk factors in the Middle East and North Africa. METHODS: We used a comparative risk assessment framework to estimate the number of disease-specific deaths attributable to 14 dietary and 4 metabolic risk factors by age and sex. The specific inputs we assessed for this analysis included the current national exposure distribution, the etiological effect of risk factor on disease-specific mortality, the alternative exposure distribution associated with the lowest possible disease risk, and the total number of disease-specific deaths in the population. We obtained these inputs as a part of our work in the 2010 GBD study. Using a multi-level hierarchical Bayesian model, we imputed missing exposure data based on non-missing exposure data from other regions and available data on other characteristics in the region or country with the missing data of interest. The first three inputs were used to compute the disease-specific Population Attributable Fraction (PAF) for each dietary and metabolic risk factor. Disease-specific mortality was determined using the PAF and the fourth input. The robustness of the findings was evaluated by their sensitivity to varying assumptions, including likely effect sizes and feasible optimal levels. RESULTS: In 2008, overweight/obesity and high fasting plasma glucose were responsible for 123,000 and 107,000 cardiometabolic deaths, respectively, in the Middle East and North Africa. Other dietary and metabolic risk factors also caused a substantial number of deaths in this region ( Figure ). CONCLUSIONS: Our findings inform priorities for policy measures to improve diet and reduce metabolic risk factors to prevent CVD and diabetes in the Middle East and North Africa.