tbuckley/cabot-search huggingface dataset:
Phase Ib evaluation of MPDL3280A (anti-PDL1) in combination with bevacizumab (bev) in patients (pts) with metastatic renal cell carcinoma (mRCC).
Authors: Mario Sznol, David F. McDermott, Suzanne Fields Jones, James Walter Mier, Daniel Waterkamp, Cheryl Rossi, Jeffrey Wallin, Roel Peter Funke, Johanna C. Bendell
Journal: Journal of Clinical Oncology (2015)

410 Background: MPDL3280A, a human anti-PD-L1 IgG1 mAb engineered to remove Fc-effector function, prevents PD-L1 binding to the inhibitory receptors PD-1 and B7.1 on activated T cells. Single-agent MPDL3280A has demonstrated clinical activity in various cancers, including RCC. Bev was postulated to enhance the antitumor effects of MPDL3280A by blocking VEGF-related suppressive effects on immune function and lymphocyte traffic. Therefore, a multicenter Phase Ib study was conducted to determine the safety and activity of MPDL3280A + bev, including in a cohort of mRCC pts. Methods: mRCC pts with clear cell histology and available pre-treatment tumor specimens were enrolled. In addition to the safety and activity endpoints, an exploratory objective was to assess treatment effects on the tumor microenvironment and peripheral biomarkers. Bev 15 mg/kg was given alone on Cycle 1 Day 1 and concurrently with MPDL3280A 20 mg/kg q3w thereafter. On-treatment tumor biopsy was performed during Cycle 1 and 4-6 weeks after the start of Cycle 2. Objective responses were assessed by RECIST v1.1. The clinical data cutoff was July 7, 2014. Results: 12 pts were evaluable for safety. The median age was 64 y, 58% were male and 83% had no prior systemic therapy. The median duration of exposure was 232.5 days. Grade 3-4 AEs included postoperative wound infection, hypercalcemia, tumor pain, acute respiratory failure in a patient with influenza (1 pt each) and hypertension (3 pts). No Grade 3-4 AEs were assessed as related to MPDL3280A. Among first-line mRCC pts with ≥ 1 tumor assessment (n = 10), the ORR was 40% (3 of 4 responses confirmed at the time of the data cutoff). Minimum follow-up was 2.1 mo. Increases in tumor-infiltrating CD8+ T cells were observed on-treatment. Updated data, including biomarkers, will be presented. Conclusions: The combination of MPDL3280A + bev waswell tolerated in clear cell mRCC pts. Promising preliminary clinical activity and immune modulation of the tumor microenvironment were observed. A Phase II trial of MPLD3280A ± bevacizumab vs sunitinib in pts with previously untreated mRCC is currently ongoing. Clinical trial information: NCT01633970.
The Integration of Chemotherapy and Surgery for Bladder Cancer
Authors: Matthew D. Galsky, Harry W. Herr, Dean F. Bajorin
Journal: Journal of the National Comprehensive Cancer Network (2005)

Despite surgery with curative intent, approximately 50% of patients with muscle-invasive transitional cell carcinoma of the bladder will develop distant metastases and succumb to their disease. Attempts to improve outcomes have focused on refining surgical techniques and integrating perioperative chemotherapy. This review summarizes the available literature addressing the role of pelvic lymphadenectomy, neoadjuvant chemotherapy, and adjuvant chemotherapy in the management of patients with muscle-invasive transitional cell carcinoma of bladder.
Germline BAP1 Mutational Landscape of Asbestos-Exposed Malignant Mesothelioma Patients with Family History of Cancer
Authors: Jill A. Ohar, Mitchell Cheung, Jacqueline Talarchek, Suzanne E. Howard, Timothy D. Howard, Mary Hesdorffer, Hongzhuang Peng, Frank J. Rauscher, Joseph R. Testa
Journal: Cancer Research (2016)

Heritable mutations in the BAP1 tumor suppressor gene predispose individuals to mesothelioma and other cancers. However, a large-scale assessment of germline BAP1 mutation incidence and associated clinical features in mesothelioma patients with a family history of cancer has not been reported. Therefore, we examined the germline BAP1 mutation status of 150 mesothelioma patients with a family history of cancer, 50 asbestos-exposed control individuals with a family history of cancers other than mesothelioma, and 153 asbestos-exposed individuals without familial cancer. No BAP1 alterations were found in control cohorts, but were identified in nine of 150 mesothelioma cases (6%) with a family history of cancer. Alterations among these cases were characterized by both missense and frameshift mutations, and enzymatic activity of BAP1 missense mutants was decreased compared with wild-type BAP1. Furthermore, BAP1 mutation carriers developed mesothelioma at an earlier age that was more often peritoneal than pleural (five of nine) and exhibited improved long-term survival compared to mesothelioma patients without BAP1 mutations. Moreover, many tumors harboring BAP1 germline mutations were associated with BAP1 syndrome, including mesothelioma and ocular/cutaneous melanomas, as well as renal, breast, lung, gastric, and basal cell carcinomas. Collectively, these findings suggest that mesothelioma patients presenting with a family history of cancer should be considered for BAP1 genetic testing to identify those individuals who might benefit from further screening and routine monitoring for the purpose of early detection and intervention.
Reply to Nahid Punjani, Nicholas Power, Eric Winquist's Letter to the Editor re: Yvonne Vergouwe, Ewout W. Steyerberg, Richard S. Foster, et al. Predicting Retroperitoneal Histology in Postchemotherapy Testicular Germ Cell Cancer: A Model Update and Multicentre Validation with More Than 1000 Patients. Eur Urol 2007;51:424–32
Authors: Yvonne Vergouwe, Ewout W. Steyerberg
Journal: European Urology (2015)
Live and heat-treated probiotics differently modulate IL10 mRNA stabilization and microRNA expression
Authors: Audrey Demont, Feriel Hacini-Rachinel, Rémi Doucet-Ladevèze, Catherine Ngom-Bru, Annick Mercenier, Guénolée Prioult, Carine Blanchard
Journal: Journal of Allergy and Clinical Immunology (2015)
Short-course Somatostatin Versus Terlipressin Infusion in Combination With Endoscopic Variceal Ligation for the Prevention of Early Esophageal Variceal Rebleeding: A Real-world, Prospective Cohort Study
Authors: Yoen-Young Chuah, Huay-Min Wang, Ping-I. Hsu
Journal: Clinical Gastroenterology and Hepatology (2015)
The use of poly(ADP-ribose) polymerase (PARP1) inhibitors (AG14361, AZD2281, ABT888) in combination with capecitabine, 5-fluorouracil, or paclitaxel in the treatment of hereditary and sporadic breast and ovarian cancer.
Authors: J. A. De Soto, R. Quick-Fountain, T. Velikodvorskaya, N. Fatima
Journal: Journal of Clinical Oncology (2010)

e13120 Background: Poly(ADP-ribose) polymerase (PARP-1) inhibitors have been reported to enhance the cytotoxicity of alkylating agents, topoisomerase inhibitors, and platinum-type alkylating agents by taking advantage of deficits in homologous recombination in BRCA1 and BRCA2 breast and ovarian cancers. Many sporadic breast and ovarian cancers may also be deficient in homologous repair due to deficiencies in RAD51, RAD54, DSS1, RPA1, NBS1, ATR, ATM, CH1, CHK2, FANCD2, FANCA, FANC or a downregulation of BRCA. Methods: Twenty human breast and 10 ovarian cancer cell lines were treated with PARP1 inhibitors (AZD2281, ABT888, AG14361) alone or in combination with one of over 100 chemotherapeutic agents representing the following classes of drugs: alkylating agents, platinum-type alkylating agents, topoisomerase inhibitors, anti-metabolites, anti-mitotics, or DNA intercalators for 72 hours. IC50 values were determined from dose response curves derived from validated MTT assays. PARP1 pharmacodynamic, PARP1 inhibitor activity assays, and the quantification of molecular markers from the apoptotic, DNA repair and mitotic pathways were also performed and correlated with IC50 values. Results: Significant enhancement of the cytotoxicity of alkylating agents, topoisomerase inhibitors, and platinum-type alkylating agents by PARP1 inhibitors in not only hereditary but sporadic breast and ovarian cancer was found. Capecitabine, 5-fluorouracil, and paclitaxel also showed enhancement or synergy with PARP1 inhibitors against breast and ovarian cancer. Conclusions: PARP1 inhibitors in combination with capecitabine, 5-fluorouracil, or paclitaxel may be effective in treating hereditary or sporadic breast and ovarian cancer. No significant financial relationships to disclose.
Impact of omission of completion axillary lymph node dissection (cALND) or axillary radiotherapy (ax RT) in breast cancer patients with micrometastases (pN1mi) or isolated tumor cells (pN0[i+]) in the sentinel lymph node (SN): Results from the MIRROR study
Authors: V. C. Tjan-Heijnen, M. J. Pepels, M. de Boer, G. F. Borm, J. A. van Dijck, C. H. van Deurzen, E. M. Adang, M. B. Menke-Pluymers, P. J. van Diest, P. Bult
Journal: Journal of Clinical Oncology (2009)

CRA506 The full, final text of this abstract will be available in Part II of the 2009 ASCO Annual Meeting Proceedings, distributed onsite at the Meeting on May 30, 2009, and as a supplement to the June 20, 2009, issue of the Journal of Clinical Oncology. No significant financial relationships to disclose.
Late Pseudoprogression in Glioblastoma: Diagnostic Value of Dynamic O-(2-[18F]fluoroethyl)-L-Tyrosine PET
Authors: Sied Kebir, Rolf Fimmers, Norbert Galldiks, Niklas Schäfer, Frederic Mack, Christina Schaub, Moritz Stuplich, Michael Niessen, Theophilos Tzaridis, Matthias Simon, Gabriele Stoffels, Karl-Josef Langen, Björn Scheffler, Martin Glas, Ulrich Herrlinger
Journal: Clinical Cancer Research (2015)

Pseudoprogression (PsP) is characterized by therapy-associated but not tumor growth-associated increases of contrast-enhancing glioblastoma lesions on MRI. Although typically occurring during the first 3 months after radiochemotherapy, PsP may occur later in the course of the disease and may then be particularly difficult to distinguish from true tumor progression. We explored PET using O-(2-[(18)F]fluoroethyl)-L-tyrosine ((18)F-FET-PET) to approach the diagnostic dilemma.Twenty-six patients with glioblastoma that presented with increasing contrast-enhancing lesions later than 3 months after completion of radiochemotherapy underwent (18)F-FET-PET. Maximum and mean tumor/brain ratios (TBRmax and TBRmean) of (18)F-FET uptake as well as time-to-peak (TTP) and patterns of the time-activity curves were determined. The final diagnosis of true progression versus late PsP was based on follow-up MRI using RANO criteria.Late PsP occurred in 7 patients with a median time from radiochemotherapy completion of 24 weeks while the remaining patients showed true tumor progression. TBRmax and TBRmean were significantly higher in patients with true progression than in patients with late PsP (TBRmax 2.4 ± 0.1 vs. 1.5 ± 0.2, P = 0.003; TBRmean 2.1 ± 0.1 vs. 1.5 ± 0.2, P = 0.012) whereas TTP was significantly shorter (mean TTP 25 ± 2 vs. 40 ± 2 min, P < 0.001). ROC analysis yielded an optimal cutoff value of 1.9 for TBRmax to differentiate between true progression and late PsP (sensitivity 84%, specificity 86%, accuracy 85%, P = 0.015).O-(2-[(18)F]fluoroethyl)-L-tyrosine PET provides valuable information in assessing the elusive phenomenon of late PsP. Clin Cancer Res; 22(9); 2190-6. ©2015 AACR.
Cardiovascular and Other Outcomes Postintervention With Insulin Glargine and Omega-3 Fatty Acids (ORIGINALE)
Journal: Diabetes Care (2015)

OBJECTIVE The Outcome Reduction With Initial Glargine Intervention (ORIGIN) trial reported neutral effects of insulin glargine on cardiovascular outcomes and cancers and reduced incident diabetes in high–cardiovascular risk adults with dysglycemia after 6.2 years of active treatment. Omega-3 fatty acids had neutral effects on cardiovascular outcomes. The ORIGIN and Legacy Effects (ORIGINALE) study measured posttrial effects of these interventions during an additional 2.7 years. RESEARCH DESIGN AND METHODS Surviving ORIGIN participants attended up to two additional visits. The hazard of clinical outcomes during the entire follow-up period from randomization was calculated. RESULTS Of 12,537 participants randomized, posttrial data were analyzed for 4,718 originally allocated to insulin glargine (2,351) versus standard care (2,367), and 4,771 originally allocated to omega-3 fatty acid supplements (2,368) versus placebo (2,403). Posttrial, small differences in median HbA1c persisted (glargine 6.6% [49 mmol/mol], standard care 6.7% [50 mmol/mol], P = 0.025). From randomization to the end of posttrial follow-up, no differences were found between the glargine and standard care groups in myocardial infarction, stroke, or cardiovascular death (1,185 vs. 1,165 events; hazard ratio 1.01 [95% CI 0.94–1.10]; P = 0.72); myocardial infarction, stroke, cardiovascular death, revascularization, or hospitalization for heart failure (1,958 vs. 1,910 events; 1.03 [0.97–1.10]; P = 0.38); or any cancer (524 vs. 529 events; 0.99 [0.88–1.12]; P = 0.91) or between omega-3 and placebo groups in cardiovascular death (688 vs. 700; 0.98 [0.88–1.09]; P = 0.68) or other outcomes. CONCLUSIONS During &amp;gt;6 years of treatment followed by &amp;gt;2.5 years of observation, insulin glargine had neutral effects on health outcomes and salutary effects on metabolic control, whereas omega-3 fatty acid supplementation had no effect.
Assessment of the tumor immune-environment in patients with head and neck cancer
Authors: Zipei Feng, Daniel Bethmann, Matthias Kappler, Carmen Ballesteros-Merino, Alexander Eckert, R Bryan Bell, Allen Cheng, Tuan Bui, Rom Leidner, Carlo Bifulco, Claudia Wickenhauser, Bernard A Fox, Barbara Seliger
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Assessment of tumor-infiltrating immune cells using immunohistochemistry (IHC) has been shown to be a powerful way to predict patient prognosis, notably in colon cancer [1, 2]. Similar observations were made in patients with head and neck squamous cell carcinoma (HNSCC), where T
Prominent Canadian researcher loses libel case against documentary makers
Authors: Owen Dyer
Journal: BMJ (2015)

A formerly renowned researcher in the field of nutrition and immunology has lost his court bid to win damages from the Canadian Broadcasting Corporation over a 2006 documentary. The programme alleged that Ranjit Kumar Chandra never conducted published studies into the immune benefits of baby formula and other studies that found a protective effect of multivitamins on cognition and infection in elderly patients.

Ranjit Kumar Chandra published more than 200 articles while working at the Memorial University of Newfoundland and gained international renown in the field of immunology and nutrition, receiving the Order of Canada for his work.

But Chandra’s career began to unravel in 2000 when he …
Hepatocytes: a key cell type for innate immunity
Authors: Zhou Zhou, Ming-Jiang Xu, Bin Gao
Journal: Cellular and Molecular Immunology (2015)

Hepatocytes, the major parenchymal cells in the liver, play pivotal roles in metabolism, detoxification, and protein synthesis. Hepatocytes also activate innate immunity against invading microorganisms by secreting innate immunity proteins. These proteins include bactericidal proteins that directly kill bacteria, opsonins that assist in the phagocytosis of foreign bacteria, iron-sequestering proteins that block iron uptake by bacteria, several soluble factors that regulate lipopolysaccharide signaling, and the coagulation factor fibrinogen that activates innate immunity. In this review, we summarize the wide variety of innate immunity proteins produced by hepatocytes and discuss liver-enriched transcription factors (e.g. hepatocyte nuclear factors and CCAAT/enhancer-binding proteins), pro-inflammatory mediators (e.g. interleukin (IL)-6, IL-22, IL-1β and tumor necrosis factor-α), and downstream signaling pathways (e.g. signal transducer and activator of transcription factor 3 and nuclear factor-κB) that regulate the expression of these innate immunity proteins. We also briefly discuss the dysregulation of these innate immunity proteins in chronic liver disease, which may contribute to an increased susceptibility to bacterial infection in patients with cirrhosis.
Association of eosinophilic esophagitis and hypertrophic cardiomyopathy
Authors: Benjamin P. Davis, Tolly Epstein, Leah Kottyan, Priyal Amin, Lisa J. Martin, Avery Maddox, Margaret H. Collins, Joseph D. Sherrill, J. Pablo Abonia, Marc E. Rothenberg
Journal: Journal of Allergy and Clinical Immunology (2015)
P34 The mechanism behind synergistic action of l-ornithine and phenylacetate to reduce ammonia in bile-duct ligation rats
Authors: M Jover, M L Noiret, A Habtesion, V Balasubramaniyan, Y Sharifi, Manuel Romero-Gomez, N A Davies, R Jalan
Journal: Gut (2010)

Aim  This study was designed to test the hypothesis that OP has additional actions on the key ammonia regulating enzymes glutamine synthetase (GS) and glutaminase (GA), which results in the observed ammonia lowering effect of OP in cirrhotic rats.  Method  11.53 g: 4 sham operated, and 11 BDL. 5 BDL9s received OP (5 days, IP 0.6 g/kg), 5 BDL9s received ornithine (5 days, IP 0.6 g/kg), 5 BDL9s received phenylacetate (5 days, IP 0.6 g/kg) and six received saline (IP). We measured plasma levels for: ammonia and standard biochemical markers. Expressions of GS, GA and ornithine amino transferase (OAT) were determined by Western blot (expressed as a % of sham values) and activity by end-point methods in liver, kidney, gut, muscle and lung.  Results  Plasma ammonia was decreased in BDL-OP rats vs BDL-saline (58.97±6.02 vs 106.2±20.56 μmol/l). BDL-OP rats showed increased GS expression in liver (66% BDL-OP vs 55% BDL-saline; p  Conclusion  OP treatment in BDL rats increased the conversion of glutamate to glutamine by stimulation of OAT and GS in the muscle and also resulted in normalisation of glutaminase expression and activity in the gut, indicating that OP effectively restricts the production of in vivo ammonia in a cirrhotic model explaining the lack of stoichiometry between ammonia reduction and excretion of phenylacetylglutamine. In summary, the mechanism by which OP reduces ammonia in cirrhosis is by increasing glutamine synthesis (action of “O”) and its excretion as phenylacetylglutamine (action of “P”) and concomitantly normalising gut glutaminase activity (action of “O”), demonstrating synergistic effect of “O” and “P”.
Programmed cell death-1 blockade in combination with stereotactic radiation in an orthotopic mouse model of hepatocellular carcinoma
Authors: David Friedman, Jason Baird, Kristina Young, Benjamin Cottam, Zeljka Jutric, Marka Crittenden, Michael Gough, Pippa Newell
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Hepatocellular carcinoma (HCC) develops in an environment of chronic inflammation. Curative treatments are plagued by frequent recurrences locally near the treated tumor, regionally within the inflamed liver, and systemically, and yet no adjuvant therapies are known to prevent
Management of Graves Disease
Authors: Henry B. Burch, David S. Cooper
Journal: JAMA (2015)

<h3>Importance</h3> Graves disease is the most common cause of persistent hyperthyroidism in adults. Approximately 3% of women and 0.5% of men will develop Graves disease during their lifetime. <h3>Observations</h3> We searched PubMed and the Cochrane database for English-language studies published from June 2000 through October 5, 2015. Thirteen randomized clinical trials, 5 systematic reviews and meta-analyses, and 52 observational studies were included in this review. Patients with Graves disease may be treated with antithyroid drugs, radioactive iodine (RAI), or surgery (near-total thyroidectomy). The optimal approach depends on patient preference, geography, and clinical factors. A 12- to 18-month course of antithyroid drugs may lead to a remission in approximately 50% of patients but can cause potentially significant (albeit rare) adverse reactions, including agranulocytosis and hepatotoxicity. Adverse reactions typically occur within the first 90 days of therapy. Treating Graves disease with RAI and surgery result in gland destruction or removal, necessitating life-long levothyroxine replacement. Use of RAI has also been associated with the development or worsening of thyroid eye disease in approximately 15% to 20% of patients. Surgery is favored in patients with concomitant suspicious or malignant thyroid nodules, coexisting hyperparathyroidism, and in patients with large goiters or moderate to severe thyroid eye disease who cannot be treated using antithyroid drugs. However, surgery is associated with potential complications such as hypoparathyroidism and vocal cord paralysis in a small proportion of patients. In pregnancy, antithyroid drugs are the primary therapy, but some women with Graves disease opt to receive definitive therapy with RAI or surgery prior to becoming pregnant to avoid potential teratogenic effects of antithyroid drugs during pregnancy. <h3>Conclusions and Relevance</h3> Management of Graves disease includes treatment with antithyroid drugs, RAI, or thyroidectomy. The optimal approach depends on patient preference and specific patient clinical features such as age, history of arrhythmia or ischemic heart disease, size of goiter, and severity of thyrotoxicosis. Physicians should be familiar with the advantages and disadvantages of each therapy to best counsel their patients.
Mechanisms of Mitral Valve Dysfunction Following Mitral Valve Repair for Degenerative Disease
Authors: Jocelyn N. Spoon, Vuyisile T. Nkomo, Rakesh M. Suri, Sorin V. Pislaru, Daniel B. Spoon, Hector I. Michelena, Maurice E. Sarano, Joseph F. Malouf
Journal: JACC. Cardiovascular imaging (2015)
Rate and Pattern of Rim Area Loss in Healthy and Progressing Glaucoma Eyes
Authors: Na'ama Hammel, Akram Belghith, Christopher Bowd, Felipe A. Medeiros, Lucie Sharpsten, Nadia Mendoza, Andrew J. Tatham, Naira Khachatryan, Jeffrey M. Liebmann, Christopher A. Girkin, Robert N. Weinreb, Linda M. Zangwill
Journal: Ophthalmology (2015)
New Form of Tenofovir
Authors: Rebecca Voelker
Journal: JAMA (2015)

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