tbuckley/cabot-search huggingface dataset:
BMET-32OUTCOMES OF GAMMA KNIFE RADIOSURGERY IN BRAIN METASTASES FROM NEUROENDOCRINE TUMORS
Authors: Anussara Songthong, Randa Tao, Nandita Guha, Ganesh Rao, Pamella Allen, Paul Brown, Susan McGovern
Journal: Neuro-Oncology (2015)

BACKGROUND: Neuroendocrine tumors (NETs) can originate in any organ but most commonly arise from the lungs. Despite cranial irradiation, small cell lung cancer (SCLC) often metastasizes to the brain. Stereotactic radiosurgery (SRS) is an established treatment for brain metastases yet little is known about the utility of SRS in the treatment of NETs especially noting their unique natural history. METHODS: Thirty-three patients with brain metastases from NETs who underwent Gamma Knife radiosurgery (GKRS) were retrospectively reviewed. Median age and Karnofsky performance status were 61 years (range, 30-76 years) and 80 (range, 60-90), respectively. Primary site was lung (87.9%), cervix (6.1%), esophagus (3%) and prostate (3%). Ten patients (30.3%) received upfront GKRS, 7 of whom had NETs other than SCLC. Kaplan-Meier survival and Cox regression analyses were performed to determine prognostic factors for survival. RESULTS: Of 130 evaluable lesions, 116 (89.2%) showed complete or partial response 4 to 6 weeks after GKRS. With median follow-up of 5.3 months, local and distant brain recurrence occurred in 1 patient (3.3%) and 20 patients (66.7%), respectively. The 6 and 12-month local (LRFS) and distant brain recurrence-free survival (DBRFS) were 100%/84% and 40.1%/29.3%, respectively. Median overall survival (OS) after GKRS was 6.9 months. Upfront GKRS and more than 1 GKRS course were prognostic for better OS and the number of brain metastases was prognostic for DBRFS on multivariate analyses. Toxicity developed in 13 lesions (10%) in 9 patients; hemorrhage (n = 2 lesions), necrosis (n = 8 lesions) and edema requiring steroids (n = 10 lesions). No cases of grade 3 or higher necrosis occurred. Patients treated with whole brain radiation prior to GKRS did not have higher toxicity rates than patients treated with upfront GKRS. CONCLUSIONS: GKRS is an effective treatment option for patients with brain metastases from NETs with excellent local control despite slightly higher toxicity rates than expected.
BET bromodomain inhibition enhances T cell persistence and function in adoptive immunotherapy models
Authors: Yuki Kagoya, Munehide Nakatsugawa, Yuki Yamashita, Toshiki Ochi, Tingxi Guo, Mark Anczurowski, Kayoko Saso, Marcus O. Butler, Cheryl H. Arrowsmith, Naoto Hirano
Journal: Journal of Clinical Investigation (2016)

Adoptive immunotherapy is a potentially curative therapeutic approach for patients with advanced cancer. However, the in vitro expansion of antitumor T cells prior to infusion inevitably incurs differentiation towards effector T cells and impairs persistence following adoptive transfer. Epigenetic profiles regulate gene expression of key transcription factors over the course of immune cell differentiation, proliferation, and function. Using comprehensive screening of chemical probes with defined epigenetic targets, we found that JQ1, an inhibitor of bromodomain and extra-terminal motif (BET) proteins, maintained CD8+ T cells with functional properties of stem cell–like and central memory T cells. Mechanistically, the BET protein BRD4 directly regulated expression of the transcription factor BATF in CD8+ T cells, which was associated with differentiation of T cells into an effector memory phenotype. JQ1-treated T cells showed enhanced persistence and antitumor effects in murine T cell receptor and chimeric antigen receptor gene therapy models. Furthermore, we found that histone acetyltransferase p300 supported the recruitment of BRD4 to the BATF promoter region, and p300 inhibition similarly augmented antitumor effects of the adoptively transferred T cells. These results demonstrate that targeting the BRD4-p300 signaling cascade supports the generation of superior antitumor T cell grafts for adoptive immunotherapy.
Medical Examiners, Coroners, and Organ Recovery in the United States
Authors: Randy Hanzlick
Journal: JAMA (1995)

To the Editor.  —The recent article by Ms Shafer and colleagues 1 places undue emphasis on medical examiner/coroner (ME/C) denials to organ procurement organizations (OPOs). Cooperation of ME/Cs is obtained in almost 90% of OPO requests. The rate of organ recovery from ME/C cases is 10 times that of non-ME/C cases, with ME/Cs providing more than 50% of all donors. Trend data show that the increase in ME/C approvals was more than twice the increase in denials, and the adjusted data may have been biased toward ME/C organ denial cases due to changes in the OPOs surveyed. Overall organ recovery rates from ME/C and non-ME/C cases are extremely low, yet the attitudes of most persons favor organ donation, indicating OPO failure to identify and effect consent among many potential donor of all types, particularly non-ME/C donors. 2   The statement that human lives are lost every time that organs are not
Associations between outdoor fungal spores and childhood and adolescent asthma hospitalizations
Authors: Rachel Tham, Don Vicendese, Shyamali C. Dharmage, Rob J. Hyndman, Ed Newbigin, Emma Lewis, Molly O'Sullivan, Adrian J. Lowe, Philip Taylor, Philip Bardin, Mimi L.K. Tang, Michael J. Abramson, Bircan Erbas
Journal: Journal of Allergy and Clinical Immunology (2016)
Activation of the MAP-kinase pathway in the skin of patients treated with sorafenib: Clinical and molecular characterization of skin tumors associated with the multikinase inhibitor sorafenib.
Authors: C. Mateus, J. Arnault, G. Tomasic, E. Hollville, L. Lacroix, J. Wechsler, B. J. Escudier, A. Eychene, J. Soria, C. Robert
Journal: Journal of Clinical Oncology (2010)

9130 Background: Drugs targeting raf proteins like sorafenib or PLX4032 can induce skin neoplasms : keratoacanthomas (KA) and KA-like squamous cell carcinomas (SCC) in about 7% of the patients (pts) with sorafenib and 23% of pts with PLX4032. The occurrence of these borderline or malignant skin tumors in pts treated with anticancer agents is intriguing and has no clear biological explanation. Methods: A prospective ancillary dermatological study was performed on pts treated with sorafenib or placebo for renal cell cancer (RCC) during a randomized double blind study. Biopsies of normal skin were studied for keratinocyte proliferation and expression of proteins involved in the MAP-kinase and PI3-Kinase pathways by immunohistochemistry. 30 skin lesions from additional pts treated with sorafenib for RCC, hepatocarcinoma or melanoma were studied with the same methods. DNA was extracted from these tumors and sequenced for mutation hotspots of BRAF, NRAS, HRAS, KRAS, AKT, PI3KCA genes. Results: Normal skin biopsies from 12 pts treated with sorafenib and 8 pts with placebo showed a moderate increase of keratinocyte proliferation index in normal skin of pts with sorafenib compared to placebo. P-ERK expression was significantly increased in normal skin of sorafenib treated pts vs placebo treated pts. Pathology analysis of 30 proliferating skin lesions occurring on 21 pts during sorafenib tt showed 15 KA or KA-like SCC, 12 cystic lesions and 3 pre-neoplastic keratoses. P-ERK was expressed in all of them and p-AKT in 26/30 (87%). HRAS mutations were found in two benign cystic lesions and one KA. No BRAF mutation was found. Conclusions: Although sorafenib is a potent anticancer agent, it stimulates keratinocyte proliferation and activates ERK phosphorylation in normal skin. There is a continuous spectrum of skin proliferation from cystic lesions to KA and SCC that may involve mutational events like raf protein mutations. Paradoxical activation of the MAP-kinase pathway and tumor induction in the skin by raf inhibition has to be further studied and understood as it might be an issue for more potent raf inhibitors presently in development. No significant financial relationships to disclose.
Phase 3 study of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting during repeated moderately emetogenic chemotherapy (MEC) cycles.
Authors: Matti S. Aapro, Meinolf Karthaus, Lee Steven Schwartzberg, Giorgia Rossi, Giada Rizzi, Maria Elisa Borroni, Marco Palmas, Hope S. Rugo
Journal: Journal of Clinical Oncology (2014)

9502 Background: Antiemetic guidelines recommend co-administration of targeted prophylactic medications aimed at inhibiting several molecular pathways involved in emesis. NEPA is a novel, fixed-dose combination of a new NK1 receptor antagonist (RA), netupitant (NETU 300 mg), and palonosetron (PALO 0.50 mg), a pharmacologically distinct 5-HT3RA. NEPA was previously shown to be superior to PALO after a single chemotherapy (CT) cycle in this study; maintenance of efficacy/safety over continuing cycles has been evaluated as a secondary objective. Methods: This multinational, randomized, double-blind, parallel group study assessed the efficacy/safety of single oral doses of NEPA versus PALO in chemotherapy-naive patients (pts) receiving multiple cycles of anthracycline-based CT. All pts also received oral dexamethasone (DEX) 12 mg (NEPA) or 20 mg (PALO) on Day 1. Efficacy endpoints were complete response (CR: no emesis, no rescue medication) and no significant nausea (<25 mm on 100 mm VAS). Results: 1,455 pts were randomized; 1286 participated in the multiple cycle extension. Patients participated in 5969 total CT cycles; 76% completed at least 4 cycles. Treatment groups were comparable; female (98%), white (80%), mean age of 54 yrs. The superiority of NEPA over PALO for overall (0-120 hr) CR during Cycle 1 was maintained over multiple CT cycles. A greater proportion of NEPA-treated pts also had no significant nausea over repeated cycles. Most frequently reported study drug-related adverse events (AEs) for NEPA included headache (3.5%) and constipation (2.0%) during the multiple cycle extension. The type/incidence of AEs were similar for NEPA and PALO. Conclusions: NEPA, a novel, fixed-dose combination targeting dual antiemetic pathways, is highly effective and safe over multiple cycles of MEC. A single dose of NEPA + DEX on Day 1 of CT offers guideline-based prophylaxis with a convenient, single-day treatment. Clinical trial information: NCT01339260. Overall CR rates (% patients) NEPA PALO P value Cycle 1 N = 724 74.3% N = 725 66.6% 0.001 Cycle 2 N = 635 80.3% N = 651 66.7% <0.0001 Cycle 3 N = 598 83.8% N = 606 70.3% <0.0001 Cycle 4 N = 551 83.8% N = 560 74.6% <0.0001
PD-1 Inhibitor–Related Pneumonitis in Advanced Cancer Patients: Radiographic Patterns and Clinical Course
Authors: Mizuki Nishino, Nikhil H. Ramaiya, Mark M. Awad, Lynette M. Sholl, Jennifer A. Maattala, Myriam Taibi, Hiroto Hatabu, Patrick A. Ott, Philippe F. Armand, F. Stephen Hodi
Journal: Clinical Cancer Research (2016)

Abstract Purpose: Investigate the clinical characteristics, radiographic patterns, and treatment course of PD-1 inhibitor–related pneumonitis in advanced cancer patients. Experimental Design: Among patients with advanced melanoma, lung cancer, or lymphoma treated in trials of nivolumab, we identified those who developed pneumonitis. Chest CT scans were reviewed to assess extent, distribution, and radiographic patterns of pneumonitis. Results: Among 170 patients treated in 10 different trials of nivolumab, 20 patients (10 melanoma, 6 lymphoma, and 4 lung cancer) developed pneumonitis. Five patients received nivolumab monotherapy, and 15 received combination therapy. The median time from therapy initiation to pneumonitis was 2.6 months. Radiographic pattern was cryptogenic organizing pneumonia (COP) in 13, nonspecific interstitial pneumonia (NSIP) in 3, hypersensitivity pneumonitis (HP) in 2, and acute interstitial pneumonia (AIP)/acute respiratory distress syndrome (ARDS) in 2 patients. The AIP/ARDS pattern had the highest grade, followed by COP, whereas NSIP and HP had lower grade (median grade: 3, 2, 1, 1, respectively; P = 0.006). The COP pattern was most common in all tumors and treatment regimens. Most patients (17/20; 85%) received corticosteroids, and 3 (15%) also required infliximab. Seven patients restarted nivolumab therapy; 2 of them developed recurrent pneumonitis and were successfully retreated with corticosteroids. One of the patients experienced a pneumonitis flare after completion of corticosteroid taper without nivolumab retreatment. Conclusions: PD-1 inhibitor–related pneumonitis showed a spectrum of radiographic patterns, reflecting pneumonitis grades. COP was the most common pattern across tumor types and therapeutic regimens. Most patients were successfully treated with corticosteroids. Recurrent pneumonitis and pneumonitis flare were noted in a few patients. Clin Cancer Res; 22(24); 6051–60. ©2016 AACR. See related commentary by Castanon, p. 5956
Novel scoring methodology for screening and evaluation of anticancer drugs.
Authors: H. M. Guirgis
Journal: Journal of Clinical Oncology (2010)

e16509 Background: There is a paucity of quantitave methodology to evaluate anticancer drugs. Objectives: Develop scoring methodology to screen and evaluate anticancer drugs based on survival (S), cost (C), administration (A) and adverse effects (AEs). Methods: Median S and AEs of drugs were quoted. The cost (in U.S. dollars) of the added drug for an entire treatment for one patient weighing 70 kg, or 1.7 m2, was divided by the survival gain (in days) over control (C/S). Point (P) values were assigned. For C/S, P ranged from 10 (C/S < 100) to 1.0 (C/S > 800). For administration (A), P ranged from 2.0 (oral) to 0 (daily injections or prolonged infusion). AEs P ranged from 0 (placebo) to 5.0 (fatalities) using Common Terminology Criteria (CTC) v 3.0. Results were calculated Total Score (Ts)= {C/S + A –AEs} × 8.3 %. OS data were labeled with a star * sign. Results: Scores of advanced/metastatic (a/m) colon, gastrointestinal stromal (GISTs), non-small-cell lung (NSCL), and breast (Br) cancers are shown in Table. Imatinib (Im) in (GISTs) scored the highest followed by erlotinib (Er) in NSCLC. Er + gemcitabine (Gem) in a/m pancreatic (PC) scored the lowest and bevacizumab (BV) combinations scored 29-54%. Conclusions: C/S in days and/or P were a fast tool for screening anticancer drugs. Association of AEs and A with C/S seemed to be feasible. Drugs C US $ S in days C/S P A AEs Total score (Ts) % Im 400 mg po daily × one year, a/m GISTs $22,360 OS >360* 62*, 10.0 2.0 2.5 79* Gem ± Er 100 mg, a/m pancreatic q 28 d × 6 cycles ( Cy) $9,576 15* 638*, 3.0 1.0 3.0 8.3* Weekly Bolus FU/L x ± BV 5.0 mg/kg q 2w × 20 Cy 1st line, mCR $28,000 99* 283*, 8.0 1.0 3.5 46* Er 150 mg po daily x 6 m, refractory NSCLC $11,700 60* 195*, 9.0 2.0 2.5 71* Chemotherapy + BV 15mg/kg iv q 3w × 6 Cy, a/m NSCLC $25,200 PFS, 51 OS, 60* 494. 6.0 420*, 6.0 1.0 3.5 29 29* Paclitaxel + BV 10 mg/kg q 2w × 8 Cy 1st-line, aBC $22,400 PFS, 177 No sig. OS 127*, 9.0 1.0 3.5 54 No significant financial relationships to disclose.
Acquired Resistance to First-Line Afatinib and the Challenges of Prearranged Progression Biopsies
Authors: Meghan Campo, David Gerber, Justin F. Gainor, Rebecca S. Heist, Jennifer S. Temel, Alice T. Shaw, Panos Fidias, Alona Muzikansky, Jeffrey A. Engelman, Lecia V. Sequist
Journal: Journal of Thoracic Oncology (2016)
Vorinostat-based therapy for solid or hematologic malignancies: The combined safety and tolerability profile.
Authors: D. S. Siegel, E. H. Rubin, S. VanBelle, M. A. Hussein, C. P. Belani, F. Robert, E. Galanis, K. T. Boileau, J. E. Eid, T. Graef
Journal: Journal of Clinical Oncology (2010)

e13600 Background: Vorinostat is an orally active histone deacetylase (HDAC) inhibitor, approved by the FDA for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma in patients who have progressive, persistent, or recurrent disease on or following two systemic therapies. Vorinostat is also being investigated as a treatment option for various other solid and hematologic malignancies, in which HDACs are implicated as key regulators of transcription. Here is an overview of the combined safety and tolerability profile of vorinostat from prior clinical experience. Methods: Safety and tolerability data were collated from patients in phase I and II Merck-sponsored clinical trials who received vorinostat as monotherapy, or in combination therapy, for solid or hematologic malignancies. Results: Overall, 854 patients have been analyzed for safety; 452 patients received vorinostat as monotherapy, 402 as part of a combination regimen. For monotherapy, the most common drug-related adverse events (DRAEs) were fatigue (55.3%), nausea (52.4%), and diarrhea (44.7%); the most common grade 3-5 DRAEs were fatigue (10.7%) and thromobocytopenia (9.9%). There were 3 drug-related deaths (ischemic stroke, tumor hemorrhage, unspecified). For combination therapy, the most common DRAEs were nausea (44.0%), diarrhea (33.3%), and fatigue (27.9%); the most common grade 3-5 DRAEs were neutropenia (18.9%) and thrombocytopenia (13.9%). There were 3 DRAEs leading to death (hemoptysis, hypotension, renal failure). Included in the overall data is the randomized phase II/III study of paclitaxel plus carboplatin in combination with vorinostat or placebo in non-small cell lung cancer patients; in 248 evaluable patients, grade 3-5 DRAEs (vorinostat vs. control) included febrile neutropenia (8% vs. 5%), thrombocytopenia (18% vs. 9%), hypokalemia (4% vs. 0%), and hyponatremia (4% vs. 0%). Conclusions: Data from unblinded Merck-sponsored phase I and II trials of the vorinostat clinical trial program show that vorinostat has an acceptable safety and tolerability profile when given investigationally as monotherapy, or usually in a combination regimen, in patients with refractory metastatic cancer. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Celgene, Merck Merck Merck Celgene, Millennium University of Alabama
Fondaparinux Combined with Intermittent Pneumatic Compression (IPC) Versus IPC Alone in the Prevention of Venous Thromboembolism after Major Abdominal Surgery: The Randomized APOLLO Study.
Authors: Alexander G.G. Turpie, Kenneth A. Bauer, Joseph A. Caprini, Philip P. Comp, Michael Gent, James E. Muntz
Journal: Blood (2005)
Emergence of epidemic Neisseria meningitidis serogroup C in Niger, 2015: an analysis of national surveillance data
Authors: Fati Sidikou, Maman Zaneidou, Ibrahim Alkassoum, Stephanie Schwartz, Bassira Issaka, Ricardo Obama, Clement Lingani, Ashley Tate, Flavien Ake, Souleymane Sakande, Sani Ousmane, Jibir Zanguina, Issaka Seidou, Innocent Nzeyimana, Didier Mounkoro, Oubote Abodji, Xin Wang, Muhamed-Kheir Taha, Jean Paul Moulia-Pelat, Assimawe Pana, Goumbi Kadade, Olivier Ronveaux, Ryan Novak, Odile Ouwe Missi Oukem-Boyer, Sarah Meyer
Journal: The Lancet Infectious Diseases (2016)
Risk function had peculiar properties
Authors: J. Duffy, G. Cohen
Journal: BMJ (1995)

consisting of non-drinkers, beer drinkers, spirits drinkers, and beer and spirits drinkers.The drinkers, again, could have ranged from those who drank beer or spirits only once a month to those who had more than five drinks a day.This would falsely increase the risk among those who did not drink wine and give a falsely low risk for those who did drink wine.Indeed, it is difficult to believe that a drink of wine only once a month can reduce the risk of cardiovascular death by 31%.If this is true it supports the premise that drinking wine may be associated with other favourable traits that influence cardiovascular risk.
Alcohol consumption for women trying to conceive
Authors: Annie Britton
Journal: BMJ (2016)

Cutting down together is sensible, but abstinence is unnecessary

In Britain, approximately 12.5% of women experience difficulty trying to conceive within 12 months,1 and rates are similar in other developed countries.2 Infertility can be a devastating experience for couples, with high levels of psychological strain and even risk of suicide.3 This can result in millions of women going through a heart breaking, all consuming process, who will inevitably look for lifestyle modifications, including their alcohol consumption, to improve their chances of having a baby.

The paper by Mikkelsen and colleagues (doi:10.1136/bmj.i4262) will offer some reassurances.4 In a prospective study of more than 6000 Danish women from the general population who were trying to get pregnant, they found that those who were drinking up …
IgE Inhibits Toll‐like Receptor 7– and Toll‐like Receptor 9–Mediated Expression of Interferon‐α by Plasmacytoid Dendritic Cells in Patients With Systemic Lupus Erythematosus
Authors: Liliane Khoryati, Jean‐François Augusto, Emilie Shipley, Cécile Contin‐Bordes, Isabelle Douchet, Stéphane Mitrovic, Marie‐Elise Truchetet, Estibaliz Lazaro, Pierre Duffau, Lionel Couzi, Clément Jacquemin, Thomas Barnetche, Pierre Vacher, Thierry Schaeverbeke, Patrick Blanco, Christophe Richez
Journal: Arthritis & Rheumatology (2016)

Plasmacytoid dendritic cells (PDCs) play a central role in pathogenesis of systemic lupus erythematosus (SLE) through their unique ability to produce large amounts of type I interferon (IFN) upon Toll-like receptor 7 (TLR-7) and TLR-9 triggering. PDCs express specific surface regulatory receptors involved in negative regulation of IFNα secretion. These receptors use the γ-chain of high-affinity Fc receptor (FcR) for IgE, FcɛRI. We undertook this study to test our hypothesis that IgE engagement of FcɛRI on PDCs may impact IFNα production in SLE patients.Serum levels of total IgE were measured in healthy volunteers, SLE patients, and patients with IgE-dependent allergic disorders. FcɛRI expression on PDCs from SLE patients was evaluated by flow cytometry. Purified PDCs were incubated with monoclonal IgE for 24 hours, then stimulated for 18 hours with TLR agonists or immune complexes (ICs). IFNα production by PDCs was detected by quantitative real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay. Expression of TLR-7, TLR-9, and IFN regulatory factor 7 (IRF-7) in PDCs was quantified by quantitative real-time PCR.We observed significantly higher IgE levels in SLE patients with quiescent disease than in those with active disease. In SLE patients, IgE levels correlated inversely with disease activity. IgE levels were not associated with the presence of antinuclear IgE. Purified PDCs treated for 24 hours with monoclonal IgE up-regulated FcɛRI expression in an IgE dose-dependent manner. IgE-treated PDCs significantly decreased IFNα secretion and down-regulated CCR7 expression upon stimulation with TLR-7 and TLR-9 ligands and ICs from lupus patients. IgE treatment down-regulated expression of TLR-9 and IRF-7.Our results support the notion that IgE plays a protective role in SLE pathogenesis through the modulation of inflammatory response by PDCs.
Skin Diseases Modeling using Combined Tissue Engineering and Microfluidic Technologies
Authors: Mohammad Hossein Mohammadi, Behnaz Heidary Araghi, Vahid Beydaghi, Armin Geraili, Farshid Moradi, Parya Jafari, Mohsen Janmaleki, Karolina Papera Valente, Mohsen Akbari, Amir Sanati‐Nezhad
Journal: Advanced Healthcare Materials (2016)

In recent years, both tissue engineering and microfluidics have significantly contributed in engineering of in vitro skin substitutes to test the penetration of chemicals or to replace damaged skins. Organ‐on‐chip platforms have been recently inspired by the integration of microfluidics and biomaterials in order to develop physiologically relevant disease models. However, the application of organ‐on‐chip on the development of skin disease models is still limited and needs to be further developed. The impact of tissue engineering, biomaterials and microfluidic platforms on the development of skin grafts and biomimetic in vitro skin models is reviewed. The integration of tissue engineering and microfluidics for the development of biomimetic skin‐on‐chip platforms is further discussed, not only to improve the performance of present skin models, but also for the development of novel skin disease platforms for drug screening processes.