tbuckley/cabot-search huggingface dataset:
Disease control and long-term survival in chemotherapy-naive patients with advanced melanoma treated with ipilimumab (MDX- 010) with or without dacarbazine
Authors: E. M. Hersh, J. S. Weber, J. D. Powderly, K. Khan, A. C. Pavlick, W. E. Samlowski, S. J. O’Day, G. Nichol, M. J. Yellin, L. Cramner
Journal: Journal of Clinical Oncology (2008)

9022 Background: Ipilimumab is a fully human monoclonal antibody targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4) that gave durable complete/partial responses [CR/PR] and stable disease [SD]) in previously treated patients with advanced melanoma. The current study evaluated the safety and efficacy of ipilimumab and whether adding dacarbazine (DTIC) would improve outcome. In addition to being cytotoxic, DTIC may also increase the release of tumor neo-antigen, ie, act as an immunosupportive (Peggs et al. Cancer Cell.12:192, 2007) agent. Methods: Chemotherapy-naive patients with advanced melanoma were treated in the randomized, phase II, comparative, multicenter, open-label study MDX-010–08 (first patient, first visit September 2002; last patient, last visit August 2004). Patients received 3 mg/kg ipilimumab every 4 weeks (Q4W) X 4 alone or with up to six 5-day courses of DTIC 250 mg/m2 per day. Efficacy was determined using Response Evaluation Criteria for Solid Tumors. Overall survival data was collected. Results: Seventy-two patients were randomized, treated per protocol, and eligible for analysis (ipilimumab, n = 37; ipilimumab + DTIC, n = 35). The disease control rate (best response of CR + PR + SD) was 21.6% (n = 8) and 31.4% (n = 11) in the monotherapy and combination arms, respectively. In 6 of these 19 patients, disease control lasted ≥24 weeks, including 2 ongoing CRs in the combination arm lasting 40+ and 92+ weeks. Long-term data are available for 54/72 patients: 5/54 patients (9.3%) are still alive (ipilimumab, n = 2/19 [10.5%]; ipilimumab + DTIC, n = 3/27 [11.1%]). The median OS for all patients was 368.5 days [95% CI, 276 - 472]; for the monotherapy and combination groups, respectively, the median OS was 351 [95% CI, 208 - 596] and 386 [95% CI, 253 - 571] days. Updated data will be presented. Conclusions: At least ∼10% of chemotherapy-naive patients with advanced melanoma treated with ipilimumab ± DTIC were alive after 2 to >4 years of follow up. DTIC appeared to augment ipilimumab efficacy. A study is ongoing to determine if ipilimumab administered at 10 mg/kg Q3W X 4 followed by maintenance therapy with DTIC will further improve the efficacy of this combination. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Medarex Amgen, Bristol-Myers Squibb, Medarex, Pfizer, Schering-Plough Medarex Bristol-Myers Squibb Bristol-Myers Squibb, Medarex
The problem with “abstinence is unnecessary”
Authors: Lauri Beekmann
Journal: BMJ (2016)

Conclusions drawn from Mikkelsen and colleagues’1 Danish cohort study on alcohol consumption and fecundability vary widely, from “Drinking a large glass of wine each night damages fertility”2 to “Women’s conception rates ‘not affected by moderate drinking’”3 to wider generalisations, such as, “Alcohol has no effect on women’s fertility.”4 And a …
Hyperfractionated concomitant in-field boost with gemcytabine, paclitaxel followed by surgery in locally advanced pancreatic cancer
Authors: H. Ashamalla, B. Mokhtar, D. Dosik, J. Lebowicz, F. Colella, R. Oldroyd
Journal: Journal of Clinical Oncology (2004)

4166 Background: Management of pancreatic cancer is a daunting task. We studied 21 patients of locally advanced unresectable pancreatic cancer in a phase I/II trial; utilizing hyperfractionated RT of 1.10 Gy/ fraction to a total dose of 63.80 Gy. Paclitaxel was delivered concomitantly in escalating doses from 20 to 70 mg/m2 weekly for 6 cycles. The MTD was observed at 60 mg/m2. The regimen was well tolerated, only one patient developed duodenal stricture and bleeding (RTOG IV morbidity) at 70 mg/m2 (Dose limiting toxicity). (1) Of 17 assessable patients, stable disease was observed in 10, partial response in 3, complete response in 2 and progression in 2. The 1 and 2 year survival rate was 45% and 27% respectively. The median survival of patients receiving ≤ 40 mg/m2 was 8 months, while the median survival for those receiving ≥ 50 mg/m2 had not been reached. Methods: We are currently accruing patients for a phase II study; using IMRT hyperfractionated RT to 63.80 Gy concomitantly with weekly Paclitaxel 60mg/m2 and gemcytabine 75mg/m2 for 6 cycles. Patients who achieve complete or good partial responses are considered for surgical resection 6–8 weeks post-therapy. Results: Regimen is thus far well tolerated. No major treatment interruptions or peri-treatment grades III or IV morbidities were encountered. Conclusions: This is work in progress. The employment of hyperfractionated Radiation therapy allows escalation of radiation dose without major late tissue toxicities. IMRT is currently being utilized in the same study. The addition of Paclitaxel and gemcytabine seems to be tolerated. Accrual is in progress and further results will follow. (1) Ashamalla, H., Zaki,B., Mokhtar, B., et.al., Int J Radiat Oncol Biol Phys; 55: 679–687, 2003 No significant financial relationships to disclose.
Thymostimulin versus placebo for treatment of advanced hepatocellular carcinoma: A randomised, controlled, double-blind, multicenter study
Authors: M. M. Dollinger, C. Lautenschläger, J. Lesske, W. E. Fleig
Journal: Journal of Clinical Oncology (2008)

4519 Background: Thymostimulin is a thymic peptide fraction with immune-mediated cytotoxicity against hepatocellular carcinoma (HCC) in vitro and palliative efficacy in advanced HCC in two independent phase II trials. The aim of this study was to assess its efficacy in a phase III trial. Methods: Patients (age 18 to 75 years) with biopsy-proven HCC not amenable to or failing local and surgical therapy were randomized to receive thymostimulin 75 mg s.c. five times per week or placebo for one year or until progression. Exclusion criteria were Karnofsky score < 60%, severe concomitant disease or decompensated liver function (bilirubin > 5 mg/dl, INR > 2.2). Primary endpoint was overall survival, secondary endpoints progression-free survival, side effects and quality of life (FACT-Hep questionnaire). The Kaplan-Meier-method was used for survival probabilities, the Cox’s proportional hazards model for assessing the effect of treatment or prognostic variables on survival. 55 patients per arm were projected to detect a 20% difference in survival (power 90%, type I error 5%) with a higher number finally included due to drop-out. Results: Between 10/2002 and 03/2005 133 patients (83 % male, median age 63 years) were randomly assigned thymostimulin (n=65) or placebo (n=68). Groups were comparable regarding age, gender, Karnofsky score and tumor stage (UICC, Okuda, CLIP and BCLC). There was no difference in survival with a median cumulative survival of 5.0 months (95% CI 3.7–6.3) in the treatment group vs. 5.2 months (95% CI 3.5–6.9) in the control group or median progression-free survival of 5.3 months (95% CI 2.0–8.6) vs. 2.9 months (95% CI 2.6–3.1), respectively. 6-month survival rates were 40% (treatment group) and 38% (control group), adjustment for liver function (Child-Pugh) or tumor stage did not affect results. Neither quality and quantity of side-effects nor quality of life as assessed in the questionnaire’s subdomains differed between groups. Conclusions: This is the first phase III trial analysing the efficacy of thymostimulin for advanced HCC. There was no survival benefit or improved progression-free survival and thymostimulin cannot be recommended as single-agent treatment. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Cytochemia AG, Germany
Double Haploidentical Hematopoietic Stem Cell Transplantation (HSCT) Enhances Anti-Tumor Activity After Transplant
Authors: Tulin Budak-Alpdogan, Cavan P Bailey, Michelle Panis, Christopher Sauter, Vikas Agrawal, Chandra Biswas, Neal Flomenberg, Onder Alpdogan
Journal: Blood (2012)
Chronic Exposure to Low Doses of Dioxin Promotes Liver Fibrosis Development in the C57BL/6J Diet-Induced Obesity Mouse Model
Authors: Caroline Duval, Fatima Teixeira-Clerc, Alix F. Leblanc, Sothea Touch, Claude Emond, Michèle Guerre-Millo, Sophie Lotersztajn, Robert Barouki, Martine Aggerbeck, Xavier Coumoul
Journal: Environmental Health Perspectives (2016)

Exposure to persistent organic pollutants (POPs) has been associated with the progression of chronic liver diseases, yet the contribution of POPs to the development of fibrosis in non-alcoholic fatty liver disease (NAFLD), a condition closely linked to obesity, remains poorly documented.We investigated the effects of subchronic exposure to low doses of the POP 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an aryl hydrocarbon receptor ligand, on NAFLD progression in diet-induced obese C57BL/6J mice.Male C57BL/6J mice were fed either a 10% low-fat (LFD) or a 45% high-fat (HFD) purified diet for 14 weeks and TCDD-exposed groups were injected once a week with 5 μg/kg TCDD or the vehicle for the last 6 weeks of the diet.Liver histology and triglyceride levels showed that exposure of HFD fed mice to TCDD worsened hepatic steatosis, as compared to either HFD alone or LFD plus TCDD and the mRNA levels of key genes of hepatic lipid metabolism were strongly altered in co-treated mice. Further, increased liver collagen staining and serum transaminase levels showed that TCDD induced liver fibrosis in the HFD fed mice. TCDD in LFD fed mice increased the expression of several inflammation and fibrosis marker genes with no additional effect from a HFD.Exposure to TCDD amplifies the impairment of liver functions observed in mice fed an enriched fat diet as compared to a low fat diet. The results provide new evidence that environmental pollutants promote the development of liver fibrosis in obesity-related NAFLD in C57BL/6J mice. Citation: Duval C, Teixeira-Clerc F, Leblanc AF, Touch S, Emond C, Guerre-Millo M, Lotersztajn S, Barouki R, Aggerbeck M, Coumoul X. 2017. Chronic exposure to low doses of dioxin promotes liver fibrosis development in the C57BL/6J diet-induced obesity mouse model. Environ Health Perspect 125:428-436; http://dx.doi.org/10.1289/EHP316.
Phenytoin for neuroprotection in acute optic neuritis: a randomised, placebo-controlled, phase 2 trial
Authors: R Kapoor, R Raftopoulos, SJ Hickman, A Toosy, B Sharrack, M Shahrukh, D Paling, Altmann, MC Yiannakas, P Malladi, R Sheridan, PG Sarrigiannis, N Hoggard, M Koltzenburg, Camg Wheeler-Kingshott, K Schmierer, G Giovannoni, DH Miller
Journal: The Lancet Neurology (2016)
Follicular Dendrytic Cells Deliver Angiogenesis Signaling To Follicular Lymphoma Cells That Is Hampered By The Pan-PI3K Inhibitor NVP-BKM120
Authors: Alba Matas-Céspedes, Vanina Rodriguez, Susana Kalko, Eva Gine, Elias Campo, Gael Roue, Armando Lopez-Guillermo, Dolors Colomer, Perez-Galan Patricia
Journal: Blood (2013)
Mental illness is not a state of mind
Authors: Marta Balinska
Journal: BMJ (2016)

“You will know very few happy moments in life, so make the most of them.” Those are words I often heard from my late mother, leading me to believe that life was going to be a painful affair. In retrospect I wonder whether she was dealing with chronic depression or whether she was “merely” dogged by unhappiness. But is unhappiness so different from depression? The World Health Organization defines health as “a state of complete physical, mental, and social wellbeing and not merely the absence of disease,” which implies that if you are unhappy, then you are ill.

I am annoyed to see the umpteenth book published on how to cure your depression through mindfulness, …
Aqueous Chlorhexidine for Intravitreal Injection Antisepsis
Authors: Rohan Merani, Zachary E. McPherson, Alan P. Luckie, Jagjit S. Gilhotra, Jim Runciman, Shane Durkin, James Muecke, Mark Donaldson, Albert Aralar, Anupam Rao, Peter E. Davies
Journal: Ophthalmology (2016)
Premedication and incidence of infusion-related reactions in patients with metastatic colorectal cancer treated with cetuximab plus irinotecan-based chemotherapy.
Authors: H. Wilke, S. Siena, A. H. Loos, K. Berghoff, C. Kohne, E. Van Cutsem
Journal: Journal of Clinical Oncology (2010)

3561 Background: The randomized phase III CRYSTAL study (n=1,202) and the large phase II MABEL study (n=1,147) confirmed the benefit of adding cetuximab respectively to infusional 5-fluorouracil, folinic acid, and irinotecan (FOLFIRI) or irinotecan alone in the first- or subsequent-line treatment of patients (pts) with metastatic colorectal cancer (mCRC). Methods: A post hoc analysis of the pooled population of pts receiving cetuximab was performed to investigate the effect of adding corticosteroid to antihistamine prophylactic premedication on the incidence of infusion-related reactions (IRRs) occurring following the first cetuximab infusion. Results: The incidence of grade 3/4 IRRs based on a broad selection of medical conditions (preferred Medical Dictionary for Regulatory Activities terms) was 1.0% in pts who received antihistamine plus corticosteroid as prophylactic premedication compared with 2.7% in those who received antihistamine alone. A comparable trend was seen for any grade IRRs (8.3% vs. 21.0%, respectively). In pts with a known or suspected or without predisposition to allergic reactions, a lower incidence of grade 3/4 and any grade IRRs occurred in each case for pts receiving antihistamine plus corticosteroid compared with antihistamine alone. Conclusions: These retrospective results indicate that the incidence of cetuximab-related grade 3/4 IRRs was reduced to 1.0% by a combined prophylaxis consisting of an antihistamine and a corticosteroid. N IRR incidence, N (%) Grade 3/4 Grade 4 Any grade Pooled population 1,747 Prophylactic pretreatment Antihistamine alone 596 125 (21.0) 16 (2.7) 7 (1.2) Antihistamine plus corticosteroid 1,061 88 (8.3) 11 (1.0) 2 (0.2) Other 90 Patients without predisposition to allergies 1,507 Prophylactic pretreatment Antihistamine alone 531 106 (20.0) 13 (2.4) 6 (1.1) Antihistamine plus corticosteroid 899 70 (7.8) 8 (0.9) 2 (0.2) Other 77 Patients with known or suspected* predisposition to allergies 240 Prophylactic pretreatment Antihistamine alone 65 19 (29.2) 3 (4.6) 1 (1.5) Antihistamine plus corticosteroid 162 18 (11.1) 3 (1.9) 0 Other 13 * For example, asthma, dermatitis (if not clearly of allergic origin). Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck KGaA, Merck Serono Amgen, AstraZeneca, Celgene, Fresenius Biotech, Merck Serono, Roche Amgen, Bristol-Myers Squibb, Merck Serono, Pfizer, Roche, sanofi-aventis Merck Serono
The mTOR pathway in estrogen response: A potential for combining the rapamycin derivative RAD001 with the aromatase inhibitor Letrozole (Femara®) in breast carcinoma
Authors: Joëlle Rudloff, Anne Boulay, Sabine Zumstein-Mecker, Dean B. Evans, Terence O’Reilly, Heidi A. Lane
Journal: Cancer Research (2004)

5620  Fatty acid synthase (FAS) is a 250-270 kd cytosolic multifunctional polypeptide required for the conversion of dietary carbohydrates to fatty acids. While high levels of FAS expression compared to normal tissue have been observed in several cancers, including breast, prostate, colon and lung carcinoma, there is little information regarding gliomas. For the first time, we show high levels of FAS expression associated with glioma cell lines. Western blotting revealed higher FAS expression (4-20 fold increase) in U251, U138, NSB-19, and U373 human glioma cell lines and in C6 rat glioma cells compared to normal rat astrocytes. Cerulenin-mediated inhibition of lipid synthesis was determined using 14C labeled acetic acid. After labeling, total lipids were extracted and counted for 14C by scintillation counting. Endogenous fatty acid synthesis in cerulenin-treated glioma cells decreased by 49%, 49.7% and 51.1% at 2 hours in NSB-19, U251, and C6 cells, respectively. Cell cycle analysis, using flow cytometry, demonstrated that 3 μg/mL of cerulenin resulted in S-phase cell arrest 24h after treatment; the number of G0/G1 and G2/M cells was decreased Further, treatment with cerulenin resulted in dose- and time-dependent decreases in glioma cell viability, assessed using the MTT assay. The mean IC50 values for U251 were 4.5 μg/mL and 2 μg/mL at 24 and 96h, respectively. For NSB-19 glioma cells, that expressed lower levels of FAS protein, the mean IC50 values were 5.5 μg/mL and 2.7 μg/mL at 24 and 96h, respectively. Cerulenin also reduced glioma cell clonogenic survival; incubating NSB-19 cells with 3μg/mL cerulenin reduced clonogenic cell survival 97% compared to controls. Increased apoptotic cell death and activated caspase-3 expression was observed in U251 and NSB-19 cells treated with cerulenin. To test whether FAS inhibition led to selective glioma cell cytotoxicity, primary rat astrocytes that express little FAS were incubated with 0.5-7.5 μg/mL cerulenin for 24h; no decrease in cell viability was observed. These data demonstrate that :(1) human and rat glioma cell lines express high levels of FAS compared with normal brain astrocytes; (2) FAS inhibition is selectively cytotoxic to glioma cells; normal astrocytes are unaffected; and (3) cerulenin mediated cytotoxicity is due in part to apoptotic cell death and cell cycle arrest. These findings suggest that FAS might be a novel target for anti-glioma therapy. (Supported by NIH Grant CA82722)
A Gene Expression Signature of CD34+ Cells to Predict Major Cytogenetic Response in Chronic Phase Chronic Myeloid Leukemia Patients Treated with Imatinib: Potential Involvement of Beta-Catenin in Drug Resistance.
Authors: Shannon McWeeney, Gregory Yochum, Lucy C. Pemberton, Marc Loriaux, Kristina Vartanian, Stephanie G Willis, Beth Wilmot, Yaron Turpaz, Raji Pillai, Mary Mac partlin, Jennifer Snead, Brian J. Druker, Stephen G O'Brien, Junia V. Melo, Thoralf Lange, Christina Harrington, Michael Deininger
Journal: Blood (2009)
P1.44 (also presented as PD2.02): Phase I/II Trial of X-396, A Novel ALK Inhibitor, in Patients With ALK+ NSCLC
Authors: Ticiana Leal, Heather Wakelee, Jeffrey Infante, George Blumenschein, Karen Reckamp, Corey Carter, Saiama Waqar, Jon Gockerman, Christine Lovly, Gary Dukart, Kimberly Harrow, Chris Liang, James Gibbons, Leora Horn
Journal: Journal of Thoracic Oncology (2016)
Efficacy and safety of endothelial growth factor receptor (VEGFR)-tyrosine kinase inhibitors (TKI) after programmed cell death 1 (PD-1) inhibitor treatment in patients with metastatic clear cell renal cell carcinoma (mccRCC).
Authors: Rosa Nadal, Asim Amin, Daniel M. Geynisman, Martin Henner Voss, Matthew Weinstock, Jaime Doyle, Zhe Zhang, Antonio Viudez, Elizabeth R. Plimack, David F. McDermott, Robert Motzer, Brian I. Rini, Hans J. Hammers
Journal: Journal of Clinical Oncology (2015)

4566 Background: Emerging agents blocking the PD-1 pathway show activity and may transform the current treatment landscape of mccRCC. The aim of this study was to evaluate the efficacy and safety of VEGFR -TKI therapy after PD-1 treatment. Methods: Patients (pts) with mccRCC treated with PD-1 monotherapy or in combination - with either cytotoxic T-lymphocyte antigen 4(CTLA4) inhibitor (PD1/CTLA4) or TKI (PD-1/VEGFR-TKI) - who subsequently received VEGFR-TKI, were retrospectively reviewed. The efficacy end points were objective response rate (ORR) and progression-free survival (PFS) stratified by type of prior PD-1 regimen. Safety by type and PD-1 exposure was also evaluated. Results: 63 patients were included, 84% of pts had at least one VEGFR-targeted therapy prior to PD-1-based therapy. The ORR for VEGFR -TKI therapy (68%, 17%, 14% and 1% pts received axitinib, pazopanib, sunitinib and sorafenib, respectively) after any PD-1 combination was 27% (17/63 PR). An additional 26 (41%) pts achieved SD. The median PFS (mPFS) was 6.9 months (mo) (95%, CI: 3.7 to 10.1). In the analysis by type of prior PD-1 therapy, there was a trend toward a higher ORR in pts who had prior therapy with PD1 monotherapy or PD1/CTLA4 therapy 33% versus 14% for pts previously treated with PD-1/VEGFR-TKI therapy (p = 0.094). The mPFS was longer in those pre-treated with PD-1 monotherapy or PD-1/CTLA4 therapy: 8.3 mo (95%, CI: 4.0-12.7) compared to those who previously received PD-1/VEGFR-TKI combinations: 6.4 mo (95%, CI: 3.9-8.8); p = 0.049. The most common adverse events (AEs) (all grades/g3-4) were asthenia (69%/11%), hypertension (41%/2%) and diarrhea (30%/0%). One patient experienced grade-2 immune-related colitis during VEGFR-TKI therapy. Conclusions: The efficacy and safety of VEGFR-TKIs after PD-1 treatment was demonstrated in this retrospective study. The response rate was lower and the mPFS shorter in those pts who received prior PD-1 in combination with VEGFR-TKI. PD-1 exposure does not seem to influence the safety of subsequent VEGFR-TKI treatment compared to historical control and immune-related AEs were rare.
Abstract 18682: Increased Oxidative Stress is Associated With Vascular Endothelial Dysfunction and Central and Peripheral Arterial Stiffening in Patients With Fontan Circulation
Authors: Clara Kurishima, Seiko Kuwata, Yoichi Iwamoto, Hirotaka Ishido, Satoshi Masutani, Hideaki Senzaki
Journal: Circulation (2015)

Background: It is well recognized that oxidative stress is responsible for fat accumulation and tissue inflammation, and causes endothelial cell damage that leads to the initiation of atherosclerosis. We and others have previously reported that vascular stiffness is increased with impaired vascular endothelial function in patients after Fontan operation. We hypothesized that increased oxidative stress is associated with vascular endothelial dysfunction and arterial stiffening in patients with Fontan circulation Methods: Relationship of oxidative stress with endothelial function and arterial stiffness was examined in 16 Fontan patients. Endothelial function and arterial stiffness of forearm artery was measured by flow mediated dilatation. We also measured central arterial stiffness by calculating aortic pulse wave velocity (PWV) during catheter drawback from the ascending aorta to the iliac bifurcation at the time of cardiac catheterization. Oxidative stress was estimated by measuring serum levels of oxidized low-density lipoprotein (LDL) and superoxide dismutase (SOD) activity in the urine as an anti-oxidant. Results: PWV of the ascending aorta but not of the descending aorta was significantly and positively correlated with oxidized LDL level (P&lt;0.05). Ratio of oxidized LDL level and SOD activity, a balance between oxidative stress and antioxidant activity, was also significantly and positively correlated with the ascending aortic PWV. This was also the case even after controlling for age of the patients by multivariate analysis. Vascular stiffness and endothelial function of the forearm artery were correlated with the balance between oxidative stress and antioxidant activity. Enhanced oxidative stress was related to increased central venous pressure and age. Conclusion: Increased oxidative stress is associated with vascular endothelial dysfunction and central and peripheral arterial stiffening in patients with Fontan circulation. Antioxidant therapy may improve vascular health and thereby patient’s outcome after Fontan operation.
Fludarabine and Treosulfan Conditioning for Allogeneic Stem-Cell Transplantation; a Dose- Intense Regimen with Limited Toxicity.
Authors: Avichai Shimoni, Avital Rand, Noga Shem-Tov, Izhar Hardan, Yulia Volchek, Ronit Yerushalmi, Arnon Nagler
Journal: Blood (2010)