tbuckley/cabot-search huggingface dataset:
Peranal endoscopic myectomy (PAEM) for rectal lesions with severe fibrosis and exhibiting the muscle-retracting sign
Authors: Takashi Toyonaga, Yoshiko Ohara, Shinichi Baba, Hiroshi Takihara, Manabu Nakamoto, Hitoshi Orita, Junji Okuda
Journal: Endoscopy (2018)

Abstract Background Although endoscopic submucosal dissection has enabled complete tumor resection and accurate pathological assessment in a manner that is less invasive than surgery, the complete resection of lesions with severe fibrosis in the submucosal layer and exhibiting the muscle-retracting sign is often difficult. We have devised a new method, peranal endoscopic myectomy (PAEM), for rectal lesions with severe fibrosis, in which dissection is performed between the inner circular and outer longitudinal muscles, and have examined the usefulness and safety of this new technique. Methods All of the patients who underwent PAEM in our hospital and affiliated hospitals between July 2015 and June 2017 were retrospectively reviewed. Results 10 rectal lesions were treated with PAEM. En bloc resection with a negative vertical margin was achieved in eight patients (80 %), whose lesions were mucosal (n = 2), shallow submucosal (n = 1), deep submucosal (n = 4), and muscle invasive (n = 1). The clinical course of all patients after PAEM was favorable. In patients who underwent additional surgery, anus preservation was achieved on the basis of the pathological results from PAEM. Conclusions PAEM for lesions with severe fibrosis exhibiting the muscle-retracting sign appears to be both safe and useful.
Michael Edward Lockhart Paterson
Authors: John Tidy
Journal: BMJ (2018)

Michael Edward Lockhart Paterson (“Mike”) was born in Irvine, Scotland, on 11 October 1947, but his family soon moved to Stoke, where his father became a local GP. After qualifying he started training in obstetrics and gynaecology. He completed his MD in 1980, studying the risk of malignancy in menopausal women. Mike’s final training position was in Leeds, where he developed his interest in gynaecological oncology under the stewardship of Roger Peel. Mike took up his consultant post in Sheffield in 1982 at the Northern …
New Perspectives in Rheumatology: Implications of the Cardiovascular Safety of Febuxostat and Allopurinol in Patients With Gout and Cardiovascular Morbidities Trial and the Associated Food and Drug Administration Public Safety Alert
Authors: Hyon Choi, Tuhina Neogi, Lisa Stamp, Nicola Dalbeth, Robert Terkeltaub
Journal: Arthritis & Rheumatology (2018)

Recently, the US Food and Drug Administration (FDA) issued a public safety alert, responding to the results of the now-published Cardiovascular Safety of Febuxostat and Allopurinol in Patients With Gout and Cardiovascular Morbidities (CARES) trial. The CARES trial showed no significant difference between allopurinol and febuxostat in the primary composite end point of cardiovascular (CV) events in subjects with gout and established CV comorbidities at baseline. However, there was a significantly increased risk of CV and all-cause mortality with febuxostat. Urate-lowering therapy (ULT) is central to the long-term management of gout, and xanthine oxidoreductase inhibitor (XOI) therapy is the consensus first-line approach. Allopurinol is generally the first XOI used, but febuxostat is an effective XOI option, and is commonly used when allopurinol is not tolerated. These data are further relevant since CV comorbidities are common in gout. Here, we examine why the CARES trial was done, and discuss other, ongoing comparative studies of febuxostat and allopurinol whose results are awaited. We assess the strengths and limitations of the CARES trial, and appraise the robustness and biologic plausibility of the results. The CARES trial does not prove that febuxostat raises CV mortality risk, but suggests greater risk with febuxostat than allopurinol. The CARES trial results do not support first-line use of febuxostat ULT, and raise questions about febuxostat placement at various pharmacologic ULT decision tree branches. Alternatives to febuxostat that are frequently effective include allopurinol dose escalation and uricosuric therapy alone or combined with allopurinol. The FDA safety alert highlights the need for shared ULT medical decision-making with gout patients, including discussion of the CV safety of febuxostat.
A review of current theories and treatments for phantom limb pain
Authors: Kassondra L. Collins, Hannah G. Russell, Patrick J. Schumacher, Katherine E. Robinson-Freeman, Ellen C. O’Conor, Kyla D. Gibney, Olivia Yambem, Robert W. Dykes, Robert S. Waters, Jack W. Tsao
Journal: Journal of Clinical Investigation (2018)

Following amputation, most amputees still report feeling the missing limb and often describe these feelings as excruciatingly painful. Phantom limb sensations (PLS) are useful while controlling a prosthesis; however, phantom limb pain (PLP) is a debilitating condition that drastically hinders quality of life. Although such experiences have been reported since the early 16th century, the etiology remains unknown. Debate continues regarding the roles of the central and peripheral nervous systems. Currently, the most posited mechanistic theories rely on neuronal network reorganization; however, greater consideration should be given to the role of the dorsal root ganglion within the peripheral nervous system. This Review provides an overview of the proposed mechanistic theories as well as an overview of various treatments for PLP.
Understanding the biology of HER3 receptor as a therapeutic target in human cancer
Authors: Hui Lyu, Amy Han, Erik Polsdofer, Shuang Liu, Bolin Liu
Journal: Acta Pharmaceutica Sinica B (2018)

HER3 belongs to the human epidermal growth factor receptor (HER) family which also includes HER1/EGFR/erbB1, HER2/erbB2, and HER4/erbB4. As a unique member of the HER family, HER3 lacks or has little intrinsic tyrosine kinase activity. It frequently co-expresses and forms heterodimers with other receptor tyrosine kinases (RTKs) in cancer cells to activate oncogenic signaling, especially the PI-3K/Akt pathway and Src kinase. Elevated expression of HER3 has been observed in a wide variety of human cancers and associates with a worse survival in cancer patients with solid tumors. Studies on the underlying mechanism implicate HER3 expression as a major cause of treatment failure in cancer therapy. Activation of HER3 signaling has also been shown to promote cancer metastasis. These data strongly support the notion that therapeutic inactivation of HER3 and/or its downstream signaling is required to overcome treatment resistance and improve the outcomes of cancer patients.
Immunochemotherapy With Obinutuzumab or Rituximab for Previously Untreated Follicular Lymphoma in the GALLIUM Study: Influence of Chemotherapy on Efficacy and Safety
Authors: Wolfgang Hiddemann, Anna Maria Barbui, Miguel A. Canales, Paul K. Cannell, Graham P. Collins, Jan Dürig, Roswitha Forstpointner, Michael Herold, Mark Hertzberg, Magdalena Klanova, John Radford, John F. Seymour, Kensei Tobinai, Judith Trotman, Alis Burciu, Günter Fingerle-Rowson, Marcel Wolbers, Tina Nielsen, Robert E. Marcus
Journal: Journal of Clinical Oncology (2018)

Purpose The GALLIUM study ( ClinicalTrials.gov identifier: NCT01332968) showed that obinutuzumab (GA101; G) significantly prolonged progression-free survival (PFS) in previously untreated patients with follicular lymphoma relative to rituximab (R) when combined with cyclophosphamide (C), doxorubicin, vincristine (V), and prednisone (P; CHOP); CVP; or bendamustine. This report focuses on the impact of chemotherapy backbone on efficacy and safety. Patients and Methods A total of 1,202 patients with previously untreated follicular lymphoma (grades 1 to 3a), advanced disease (stage III or IV, or stage II with tumor diameter ≥ 7 cm), Eastern Cooperative Oncology Group performance status 0 to 2, and requiring treatment were randomly assigned 1:1 to G 1,000 mg on days 1, 8, and 15 of cycle 1 and day 1 of subsequent cycles or R 375 mg/m2 on day 1 of each cycle, for six to eight cycles, depending on chemotherapy (allocated nonrandomly by center). Responding patients received G or R for 2 years or until disease progression. Results Baseline Follicular Lymphoma International Prognostic Index risk, bulky disease, and comorbidities differed by chemotherapy. After 41.1 months median follow-up, PFS (primary end point) was superior for G plus chemotherapy (overall hazard ratio [HR], 0.68; 95% CI, 0.54 to 0.87; P = .0016), with consistent results across chemotherapy backbones (bendamustine: HR, 0.63; 95% CI, 0.46 to 0.88; CHOP: HR, 0.72; 95% CI, 0.48 to 1.10; CVP: HR, 0.79; 95% CI, 0.42 to 1.47). Grade 3 to 5 adverse events, notably cytopenias, were most frequent with CHOP. Grade 3 to 5 infections and second neoplasms were most frequent with bendamustine, which was associated with marked and prolonged reductions in T-cell counts. Fatal events were more frequent in patients treated with bendamustine, possibly reflecting differences in patient risk profiles. Conclusion Improved PFS was observed for G plus chemotherapy for all three chemotherapy backbones. Safety profiles differed, although comparisons are confounded by nonrandom chemotherapy allocation.
Continuing progress in endoscopic drainage of walled-off pancreatic necrosis
Authors: Andres Sanchez-Yague, Ravishankar Asokkumar, Thai Nguyen-Tang
Journal: Endoscopy (2018)

See also: Early removal of biflanged metal stents in the management of pancreatic walled-off necrosis: a prospective studyEndoscopy 2018; 50(06): 597-605DOI: 10.1055/s-0043-123575
Evaluation of coordination of cancer care between designated cancer hospitals and primary care providers: Results from a nationwide survey in Japan.
Authors: Taro Tomizuka, Tomone Watanabe, Satoru Kamitani, Takahiro Higashi
Journal: Journal of Clinical Oncology (2018)

84 Background: To improve coordination of cancer care between cancer specialist hospitals and primary care providers (PCPs), the Japanese government accredited cancer specialist hospitals, so called “designated cancer care hospitals (DCCHs)” and introduced “Cancer care coordination instruction fee” which PCPs can receive if they share a cancer critical path (Japanese version of Survivorship Care Plans) of each cancer patient with DCCHs. We sought to assess the current status of coordination of cancer care in Japan and communication between DCCHs and PCPs from PCPs’ point of view. Methods: A cross-sectional mail survey was administered to randomly selected clinic-based PCPs (4,000 clinics) from a nation-wide database of medical institutions authorized by Ministry of Health, Labour and Welfare Japan to treat patients with health insurance (87,869 clinics). The survey evaluated how much PCPs provided cancer follow-up care and how well DCCHs coordinated care and communicated with PCPs in cancer survivorship. Results: 1,873 PCPs returned the questionnaire (response rate: 46.8%). 1,223 (65.3%) answered to provide cancer follow-up care in outpatient setting. Most of the PCPs which provided cancer follow-up care evaluated the care coordination and support by DCCHs were satisfactory (946, 77.4%) but the degree of good evaluation varied by region (highest: 91.3%, lowest: 45.8%). In regression analysis, provision of palliative care by PCPs (OR 1.52 95%CI 1.05-2.17) and use of cancer critical path (OR 2.10 95%CI 1.63-2.71) were significantly correlated with better evaluation of communication and care coordination. Conclusions: DCCHs communicated well with PCPs and PCPs were satisfied with the communication and care coordination by DCCHs. Provision of palliative care by PCPs and use of cancer critical path are likely to lead good care coordination in cancer care.
The SS18-SSX Fusion Oncoprotein Hijacks BAF Complex Targeting and Function to Drive Synovial Sarcoma
Authors: Matthew J. McBride, John L. Pulice, Hannah C. Beird, Davis R. Ingram, Andrew R. D’Avino, Jack F. Shern, Gregory W. Charville, Jason L. Hornick, Robert T. Nakayama, Enrique M. Garcia-Rivera, Dejka M. Araujo, Wei-Lien Wang, Jen-Wei Tsai, Michelle Yeagley, Andrew J. Wagner, P. Andrew Futreal, Javed Khan, Alexander J. Lazar, Cigall Kadoch
Journal: Cancer Cell (2018)

Synovial sarcoma (SS) is defined by the hallmark SS18-SSX fusion oncoprotein, which renders BAF complexes aberrant in two manners: gain of SSX to the SS18 subunit and concomitant loss of BAF47 subunit assembly. Here we demonstrate that SS18-SSX globally hijacks BAF complexes on chromatin to activate an SS transcriptional signature that we define using primary tumors and cell lines. Specifically, SS18-SSX retargets BAF complexes from enhancers to broad polycomb domains to oppose PRC2-mediated repression and activate bivalent genes. Upon suppression of SS18-SSX, reassembly of BAF47 restores enhancer activation, but is not required for proliferative arrest. These results establish a global hijacking mechanism for SS18-SSX on chromatin, and define the distinct contributions of two concurrent BAF complex perturbations.
Response kinetics and factors predicting survival in core-binding factor leukemia
Authors: Prajwal Boddu, Christopher Gurguis, David Sanford, Jorge Cortes, Mary Akosile, Farhad Ravandi, Guillermo Garcia-Manero, Keyur P Patel, Tapan Kadia, Mark Brandt, Rita Maduike, Hagop Kantarjian, Gautam Borthakur
Journal: Leukemia (2018)
Comparative safety of dolutegravir-based or efavirenz-based antiretroviral treatment started during pregnancy in Botswana: an observational study
Authors: Rebecca Zash, Denise L Jacobson, Modiegi Diseko, Gloria Mayondi, Mompati Mmalane, Max Essex, Tendani Gaolethe, Chipo Petlo, Shahin Lockman, Lewis B Holmes, Joseph Makhema, Roger L Shapiro
Journal: The Lancet Global Health (2018)

BackgroundGlobal rollout of dolutegravir-based antiretroviral therapy (ART) has been hampered in part by insufficient safety data in pregnancy. We compared birth outcomes among women initiating dolutegravir-based ART with those among women initiating efavirenz-based ART in pregnancy in Botswana.MethodsIn this observational study, we captured birth outcome data at eight government hospitals throughout Botswana (~45% of all deliveries in the country) in an ongoing study that started on Aug 15, 2014. In 2016, Botswana changed first-line ART from efavirenz-tenofovir-emtricitabine to dolutegravir-tenofovir-emtricitabine, including for pregnant women. This analysis includes women starting either efavirenz-based ART or dolutegravir-based ART during singleton pregnancy (regimen started and delivery occurring between Aug 15, 2014, and Aug 15, 2016, for efavirenz-based ART and between Nov 1, 2016, and Sept 30, 2017, for dolutegravir-based ART). We excluded births to mothers who had switched regimen or stopped ART. The primary outcomes were the combined endpoints of any adverse outcome (stillbirth, preterm birth [<37 weeks' gestation], small for gestational age [SGA; less than the tenth percentile of birthweight by gestational age], or neonatal death [within 28 days of age]) and severe adverse outcomes (stillbirth, neonatal death, very preterm birth [<32 weeks' gestation], and very SGA [less than the third percentile of birthweight by gestational age]). We fitted log-binomial regression models, controlling for maternal age, gravidity, and education, to estimate adjusted risk ratios (aRRs).FindingsOur analysis included 1729 pregnant women who initiated dolutegravir-based ART and 4593 who initiated efavirenz-based ART. The risk for any adverse birth outcome among women on dolutegravir versus efavirenz was similar (33·2% vs 35·0%; aRR 0·95, 95% CI 0·88–1·03), as was the risk of any severe birth outcome (10·7% vs 11·3%; 0·94, 0·81–1·11). We found no significant differences by regimen in the individual outcomes of stillbirth, neonatal death, preterm birth, very preterm birth, SGA, or very SGA.InterpretationAdverse birth outcomes were similar among pregnant women who initiated dolutegravir-based and efavirenz-based ART. Dolutegravir-based ART can be safely initiated in pregnancy.FundingNational Institutes of Health.
Immune recognition of somatic mutations leading to complete durable regression in metastatic breast cancer
Authors: Nikolaos Zacharakis, Harshini Chinnasamy, Mary Black, Hui Xu, Yong-Chen Lu, Zhili Zheng, Anna Pasetto, Michelle Langhan, Thomas Shelton, Todd Prickett, Jared Gartner, Li Jia, Katarzyna Trebska-McGowan, Robert P. Somerville, Paul F. Robbins, Steven A. Rosenberg, Stephanie L. Goff, Steven A. Feldman
Journal: Nature Medicine (2018)
A comparative clinical study of PF-06439535, a candidate bevacizumab biosimilar, and reference bevacizumab, in patients with advanced non-squamous non-small cell lung cancer.
Authors: Mark A. Socinski, Joachim Von Pawel, Kazuo Kasahara, Igor Bondarenko, Konstantinos Syrigos, Vladimir Ivanovich Vladimirov, Maciej Bryl, Manuela Zereu, A H. Bair, Fiona Hilton, Katherine Faye Liau, Roy S. Herbst
Journal: Journal of Clinical Oncology (2018)

109 Background: This ongoing, double-blind, randomized, global clinical trial (NCT02364999) evaluated the efficacy, safety, and immunogenicity of PF-06439535 vs. reference bevacizumab sourced from the EU (bevacizumab-EU), in combination with paclitaxel (P) and carboplatin (C), as first-line therapy in patients with advanced non-squamous non-small cell lung cancer (NSCLC). Methods: Eligible pts were randomized 1:1 to PF-06439535 or bevacizumab-EU plus P/C on Day 1 of every 3-week (wk) cycle followed by PF-06439535 or bevacizumab-EU blinded monotherapy until disease progression or unacceptable toxicity. The primary objective was to compare objective response rate (ORR) by Wk 19 between treatment arms. Secondary objectives included safety, 1 year (yr) PFS, 1 yr survival rate and immunogenicity. Results: 719 pts were randomized: PF-06439535 (n = 358) and bevacizumab-EU (n = 361). The majority of patients were male (65%) with a median age of 61y and newly diagnosed Stage IV NSCLC (76%). For the primary endpoint, relative risk of ORR was 1.015. The 90% confidence interval (CI), 0.886-1.163, was contained within the FDA pre-specified therapeutic equivalence margin of 0.73–1.37. Secondary endpoints further support similarity between the 2 treatment arms (Table). Incidence of treatment-emergent adverse events (AEs) (all-causality) was similar (PF-06439535: 96.6%) and (bevacizumab-EU: 96.1%). AE results indicate no clinically meaningful differences between the two arms for arterial thromboembolic event (TE)/venous TE events, bleeding events, hypertension, GI perforation, and proteinuria. Conclusions: In patients with advanced non-squamous NSCLC, PF-06439535 and bevacizumab-EU showed similar ORR (primary endpoint) PFS, OS, safety and immunogenicity. Clinical trial information: NCT02364999.Efficacy endpoints. PF-06439535 Bevacizumab-EU ORR 45.3% (95%: 40.01%, 50.57%) 44.6% (95%: 39.40%, 49.89%) 1 yr PFS rate 29.4% (95% CI: 23.2%, 35.9%) 29.3% (95% CI: 23.5%, 35.3%) 1 yr survival rate 65.2% (95% CI: 59.0%, 70.7%) 66.4% (95% CI: 59.9%, 72.0%)
Care 001: Multicenter randomized open label phase II trial of neoadjuvant trastuzumabemtansine (T-DM1) in combination with lapatinib and nab-paclitaxel compared with paclitaxel, trastuzumab and pertuzumab in HER 2 neu over-expressed breast cancer patients (TEAL study).
Authors: Tejal Amar Patel, Joe Ensor, Sarah Creamer, Angel Augusto Rodriguez, Polly Ann Niravath, Jorge German Darcourt, Virginia G. Kaklamani, Jane Lowe Meisel, Xiaoxian Li, John G. Kuhn, Roberto R Rosato, Anna Belcheva, Toniva Boone, Jenny Chee Ning Chang
Journal: Journal of Clinical Oncology (2018)

581 Background: Based on data from our phase I study of trastuzumab-emtansine (T-DM1), Lapatinib (L) and Nab Paclitaxel (Nab-P), a multicenter randomized open label phase II neoadjuvant study was conducted comparing this regimen to the standard of care (SOC) Paclitaxel (Pac), Trastuzumab (T), and Pertuzumab (P) in patients with HER2 over-expressed breast cancer. Methods: Patients in the experimental arm received T-DM1 3.0 mg/kg Q3W, L 750mg oral daily and Nab-P 80 mg/m2 weekly (QW) X 12 weeks. Patients in SOC arm received Pac 80mg/m2 QW, T 2mg/kg QW, and P 420mg Q3W X 12 weeks. The primary objective was to evaluate the proportion of patients with residual cancer burden (RCB) 0 or 1. Key secondary objectives included correlative assessments of PIK3CA mutations, PTEN expression, and HER2 subtypes, all of which are ongoing. Results: Thirty of the 33 enrolled patients were evaluable. Patient demographics were.The proportion of patients with RCB 0 & I was significantly higher in the T-DM1, L and Nab-P arm than in the SOC arm (100% vs. 62.5%, p 0.0035). Importantly, the RCB 0 & 1 in the ER positive subset of patients was 100% compared with 25% in SOC (p 0.0035). Common adverse events included elevated liver function tests, fatigue, diarrhea and neuropathy. Conclusions: TDM1 plus L and Nab-P therapy was well tolerated with noteworthy responses in all patients, and especially in the ER positive subset, a group which has historically had lower response rates to neoadjuvant anti-HER2-directed therapy. Further evaluation of this regimen is warranted. Clinical trial information: NCT02073487.Efficacy. Experimental SOC P-value RCB 0 - and I 14 (100) 10 (62.5) 0.0035 ER Negative 6 (100) 8 (100) ER Positive 8 (100) 2 (25) RCB II and III 0 6 (37.50)
Pre-exposure prophylaxis may increase risky behaviour when introduced, study finds
Authors: Jacqui Wise
Journal: BMJ (2018)

Although taking antiretroviral drugs as pre-exposure prophylaxis (PrEP) is highly effective for preventing HIV infection and is recommended by the World Health Organization for high risk populations, an Australian study in the Lancet HIV journal has found that a rapid uptake of PrEP by gay and bisexual men was accompanied by an equally rapid decrease in consistent condom use, which could undermine PrEP’s effectiveness.1

Researchers analysed survey data from 16 827 gay and bisexual men before and after the largescale roll-out of PrEP in publicly funded projects in Victoria and New South Wales. Recent PrEP use by HIV negative men increased from 2% in 2013 (44 of 2324 men) to 24% in 2017 (783 …