tbuckley/cabot-search huggingface dataset:
Corrigendum re: “Atezolizumab in Platinum-treated Locally Advanced or Metastatic Urothelial Carcinoma: Outcomes by Prior Number of Regimens” [Eur Urol 2018;73:462–8]
Authors: Jose Luis Perez-Gracia, Yohann Loriot, Jonathan E. Rosenberg, Thomas Powles, Andrea Necchi, Syed A. Hussain, Rafael Morales-Barrera, Margitta M. Retz, Günter Niegisch, Ignacio Durán, Christine Théodore, Enrique Grande, Xiaodong Shen, Jingjing Wang, Betty Nelson, Christina L. Derleth, Michiel S. van der Heijden
Journal: European Urology (2018)
1 Real world experience in treating chronic hepatitis C with direct acting antivirals (DAAS) in northern ireland
Authors: H McCaughan, L Stratton, K Patterson, O McCormick, G Wasson, I Cadden, J Cash, R McCorry, N McDougall
Journal: Gut (2017)

Background  Oral direct acting antiviral (DAA) treatments for hepatitis C virus (HCV) have emerged in recent years and show excellent results regarding side effects and clearance of the virus (defined as negative HCV PCR 12 weeks after completion of therapy or SVR12).  Aim  To assess response to new DAAs in Northern Ireland according to genotype, presence of cirrhosis, and previous treatment.  Method  Treatment outcomes were reviewed for all patients treated with a DAA for chronic HCV in Northern Ireland from March 2015 until July 2016.  Results  105 treatments were given to 104 patients (1 patient treated twice) - 68 males, 41 cirrhotic, and 67 with previous treatment failure. Genotype prevalence is shown in Fig 1. 89 received all oral DAA therapy (44 Abbvie product, 28 Harvoni+/- ribavirin, 15 sofosbuvir/daclatasvir/ribavirin) and 16 received sofosbuvir + Peg interferon + ribavirin. Overall 100 (95%) treatments were successful and achieved SVR 12. Three patients (all cirrhotic genotype 1 with prior treatment failure) stopped treatment (Abbvie) within 3 weeks due to decompensation, one of whom achieved SVR12 with subsequent treatment. 1 patient failed with sof/peg/riba and 1 patient failed to attend for SVR12 check (negative at end of treatment).  Conclusions  In our experience, all-oral DAA therapy is highly efficacious provided patients can complete the course. Caution is required with cirrhotic patients even if well compensated before treatment.
Feasibility of a massive online open course to teach skills in primary palliative care for a global audience.
Authors: Ashwini Prafulla Kerkar, Jan DeNofrio, Erika Lauren Tribett, Kavitha Ramchandran
Journal: Journal of Clinical Oncology (2018)

111 Background: Palliative Care Always (PCA) is a massive open online course (MOOC), through Stanford Online, that teaches primary palliative care. Our goal was to provide an accessible avenue for palliative care education on a global level. This is to address persistent and considerable gaps in primary palliative care due to lack of specialist trained experts and training opportunities. Methods: A team of providers including palliative care physician, advanced care nurse practitioner, priest and social worker developed 12 modules covering the scope of palliative care across their specialties. Topics ranged from communication of bad news to hospice initiation, while following the case of an oncology patient. Components include (1) Reflection on assigned readings (2) Patient scenes (3) Multiple choice assessments and (4) Group discussions. Participants were surveyed prior to and on completion of the 12-week course. Results: PCA enrolled 721 applicants from 56 countries. Participants from the US represented 51% of the total cohort. Next highest enrollment was from Brazil, India and Canada. Median age was 40 years. 51% of surveyed participants held advanced degrees and 38% held bachelor’s degrees. At the time of enrollment, 70% of participants were employed, 76% of whom worked in healthcare or social assistance industries. 44% of participants identified themselves as having some level of teaching experience. 75% of teachers reported never covering material on palliative care. The most popular reasons for taking the course included general interest, personal growth and relevance to employment. Post assessment surveys showed 95% of enrollees had a positive experience and were satisfied with what they learned; the most useful module was communication of bad news. Conclusions: Based on participant reports, effective palliative care training and exposure on a global level is feasible and acceptable with a MOOC such as PCA. Participants were from diverse backgrounds and found the course relevant and helpful. Future directions include specialty-specific courses, with a Hepatology course currently underway, evaluation of the impact on practice outcomes, and customized cases for individualized training.
Potential Medicare beneficiary out-of-pocket cost reductions through use of biosimilar filgrastim-sndz over reference filgrastim among patients with lung cancer: A simulation model analysis.
Authors: Sanjeev Balu, Gary Puckrein, Liou Xu, Alan Ryan, Kim Campbell
Journal: Journal of Clinical Oncology (2018)

140 Background: G-CSFs are utilized to lower the incidence of febrile neutropenia (FN) in patients with cancers treated with chemotherapy. In 2015 filgrastim-sndz was the first biosimilar to be approved and launched in the US. Limited data exists on the impact of biosimilars on patient out-of-pocket (OOP) expenditures. The objective of this simulation model is to estimate potential OOP cost savings through use of filgrastim-sndz (FIL-S) over reference filgrastim (FIL-REF) from a Medicare lung cancer patient perspective. Methods: An Excel simulation analysis was conducted among lung cancer patients treated with biosimilar FIL-S or FIL-REF (identified through HCPCS codes). Data from the 2016 Medicare Limited Data Set was used to populate the model. Average Medicare payment to the provider and beneficiary OOP responsibility per claim of either FIL-S or FIL-REF were calculated. The average OOP reduction per claim for a FIL-S beneficiary relative to a FIL-REF beneficiary was multiplied to a hypothetical FN prevalent population of 100,000 beneficiaries (average of 10 claims per beneficiary) to estimate the potential OOP savings. Results: Data from 525 FIL-S and 621 FIL-REF claims were analyzed. The average Medicare allowed charge amount per claim for a FIL-S beneficiary was $381.7 versus $419.1 for a FIL-REF beneficiary, while corresponding average Medicare payments to the provider were $299.3 and $327.4, respectively. On an average, OOP responsibility for a FIL-S beneficiary was lower compared to a FIL-REF beneficiary ($76.4 vs. $85.0) leading to a cost saving per claim of approximately $8.60. When extrapolated to 100,000 beneficiaries (1,000,000 claims), the overall cost saving was projected to be around $8.6 million. Conclusions: Our simulation model estimated potential OOP Medicare lung cancer beneficiary savings of around $8.6 million, based on a hypothetical population of 100,000 FN beneficiaries, with the use of biosimilar FIL-S over FIL-REF. Further real-world analyses are required to evaluate the true cost savings potential with the use of biosimilars over reference biologics.
Association of Transient Palmoplantar Keratoderma With Clinical and Immunologic Characteristics of Bullous Pemphigoid
Authors: Claire Duretz, Frank Antonicelli, Céline Muller, Nina Antonicelli, Julie Plee, Manuelle Viguier, Philippe Bernard
Journal: JAMA Dermatology (2018)

Development of transient palmoplantar keratoderma (PPK) with bullous pemphigoid (BP) has only been described in 2 isolated case reports. The clinical significance and the pathophysiologic mechanisms of this association are unknown.To examine the clinical characteristics and immunological profile of patients with BP who develop transient PPK and analyze therapeutic options and outcomes.In this case series, patients with BP who developed acquired, transient PPK, and were treated at a single institution from January 1, 2015, through December 31, 2017, were studied.Clinical and immunological activity of BP, treatment administrated before and after PPK appearance, and patient outcomes.Six patients with BP and transient PPK were identified and included in the study. There were 5 women and 1 man with a mean age of 72 years. At baseline, all patients had a generalized, multibullous BP and high serum anti-BP180 antibodies (mean, 130 U/mL; range, 73-150), whereas anti-BP230 antibodies were elevated in only 1 case. The PPK appeared a mean 6.2 (range, 2-12) months after BP diagnosis, following a prolonged period of disease activity with recurrent flares. When the PPK occurred, BP was uncontrolled on therapy (mean Bullous Pemphigoid Disease Activity Index [BPDAI] score, 57; range, 34-105; mean anti-BP180 antibodies titer, 122 U/mL; range, 81-150). On administration of additional systemic immunosuppressive therapies, the PPK healed progressively in a mean 4.3 months (range, 2-9), along with BP clinical remission in 4 of 6 patients. No relationship was found between PPK occurrence and anti-BP180/230 antibodies profiles. In contrast, blister fluids collected at the time of PPK displayed a much higher level of interleukin 1β (IL-1β) compared with those collected in the absence of PKK. Expression of IL-17A, IL-17F, and IL-22 was also enhanced in the blister fluid of patients with BP who had PPK.To our knowledge, this is the first report of 6 cases of BP with transient PPK with extensive immunological investigation. The PPK appeared after a prolonged period of clinical BP activity punctuated with recurrent relapses, was transient, and healed after BP control with additional immunosuppressive therapy. Enhanced expression of a particular cytokine panel in the blister fluid at time of PPK could support keratinocyte proliferation as described in patients with psoriasis. Transient PPK could represent a clinical marker of severe, treatment-resistant BP.
A systematic process to enhance selection of a prepared medical decision maker.
Authors: Donna S. Zhukovsky, Ali Haider, Syed Mussadiq Ali Akbar Naqvi, Neeraj Joshi, Pamela T. Soliman, Boby Mathew, Diane C. Bodurka, Larissa Meyer, Shannon Neville Westin, Michael M. Frumovitz, LaShan Archie, Shauna L Fenton, Janet L. Williams, Valentine G Boving
Journal: Journal of Clinical Oncology (2018)

5 Background: Selecting a prepared medical decision maker (MDM) is an integral component of advance care planning (ACP), an interdisciplinary process supported by prognostic awareness. ASCO’s Quality Initiative recommends providers discuss ACP or advance directives (AD) with all new patients with invasive malignancy (NP) by the third office visit (OV). In this quality improvement project, our goal was to increase documented social work (SW), counseling, and education regarding selection of a prepared MDM to 70% and to increase scanned MPOA in EHR 2x by 3 R OV. Methods: All SW received institutional training regarding important elements to include when providing counseling and education regarding selection of a prepared MDM. We collected data from EHR of all NP of five gynecologic oncologist champions, including responses to patient needs survey (PNS), AD questions at first OV and ACP physician/Advanced Practice Provider (MD/APP), and SW ACP notes derived from templates with structured elements. Data were collected during baseline and three intervention cycles (C). C1: coaching RN to ask PNS AD questions from a “culture of yes”, C2: NP viewing brief video about importance of MPOA; C3: providing cards with simple definitions of AD to use with NP. Results are presented for C1-3 versus baseline. Results: Total NP=351 (baseline 133, C1-3 218). Intervention group (IG) patients requested more assistance with AD (15 vs. 5%, p=.005) and wanted more information (16 vs. 8%, p=.02) than baseline. Documented social work ACP notes by the third OV were less frequent in the IG (30 vs. 48%, p=.001); there were fewer documented SW ACP notes in those without scanned MPOA (72 vs. 58% without note, p=.01), and no increase in scanned MPOA (13 vs. 11%, p=.516). Physician documentation of MPOA discussion increased (38 vs. 8%, P.000), but discussion of treatment goals did not (84 vs. 68%, p=.112). Conclusions: Interventions resulted in increased MD/APP discussions of importance of MPOA and NP requests for discussion, but fewer SW ACP discussions. There was no increase in scanned MPOA. Current processes reach only a minority of NP and do not effectively engage NP in selecting a prepared MDM. More proactive approaches systematically incorporating ACP discussions into care in an iterative manner are needed.
蕈样肉芽肿/ Se´zary综合症中的感染性事件
Authors: R. Blaizot, E. Ouattara, A. Fauconneau, M. Beylot-Barry, A. Pham-Ledard
Journal: British Journal of Dermatology (2018)

感染是晚期蕈状肉芽肿 (MF) 或 Sezary 综合征 (SS) 患者死亡的主要原因之一。然而,对于哪种类型的感染是最常见的,以及不同的危险因素,最新数据却很少。因此,这项来自法国的研究查看了 71 名 MF 或 SS 患者的记录。在 40 名患者中记录了 80 起感染事件(即患者遭受感染的事件),包括 28 起皮肤和软组织感染和 25 起肺炎。51.8% 的感染病例需要患者住院治疗。记录了 11 例与感染相关的死亡。SS 比 MF 具有更高的感染风险。该研究确认了感染性事件作为 MF 和 SS 患者发病率和死亡率的主要原因的重要性。一种叫做金黄色葡萄球菌的细菌造成了 78% 的细菌感染,并且 22% 的感染对甲氧西林(一种抗生素)有抗药性,这是在开抗生素处方时需要考虑的一个事实。该研究概述了预防感染的可能方法,如特定的疫苗和药物。
Double-Hit Gene Expression Signature Defines a Distinct Subgroup of Germinal Center B-Cell-Like Diffuse Large B-Cell Lymphoma
Authors: Daisuke Ennishi, Aixiang Jiang, Merrill Boyle, Brett Collinge, Bruno M. Grande, Susana Ben-Neriah, Christopher Rushton, Jeffrey Tang, Nicole Thomas, Graham W. Slack, Pedro Farinha, Katsuyoshi Takata, Tomoko Miyata-Takata, Jeffrey Craig, Anja Mottok, Barbara Meissner, Saeed Saberi, Ali Bashashati, Diego Villa, Kerry J. Savage, Laurie H. Sehn, Robert Kridel, Andrew J. Mungall, Marco A. Marra, Sohrab P. Shah, Christian Steidl, Joseph M. Connors, Randy D. Gascoyne, Ryan D. Morin, David W. Scott
Journal: Journal of Clinical Oncology (2018)

High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBL-DH/TH) has a poor outcome after standard chemoimmunotherapy. We sought to understand the biologic underpinnings of HGBL-DH/TH with BCL2 rearrangements (HGBL-DH/TH- BCL2) and diffuse large B-cell lymphoma (DLBCL) morphology through examination of gene expression.We analyzed RNA sequencing data from 157 de novo germinal center B-cell-like (GCB)-DLBCLs, including 25 with HGBL-DH/TH- BCL2, to define a gene expression signature that distinguishes HGBL-DH/TH- BCL2 from other GCB-DLBCLs. To assess the genetic, molecular, and phenotypic features associated with this signature, we analyzed targeted resequencing, whole-exome sequencing, RNA sequencing, and immunohistochemistry data.We developed a 104-gene double-hit signature (DHITsig) that assigned 27% of GCB-DLBCLs to the DHITsig-positive group, with only one half harboring MYC and BCL2 rearrangements (HGBL-DH/TH- BCL2). DHITsig-positive patients had inferior outcomes after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone immunochemotherapy compared with DHITsig-negative patients (5-year time to progression rate, 57% and 81%, respectively; P < .001), irrespective of HGBL-DH/TH- BCL2 status. The prognostic value of DHITsig was confirmed in an independent validation cohort. DHITsig-positive tumors are biologically characterized by a putative non-light zone germinal center cell of origin and a distinct mutational landscape that comprises genes associated with chromatin modification. A new NanoString assay (DLBCL90) recapitulated the prognostic significance and RNA sequencing assignments. Validating the association with HGBL-DH/TH- BCL2, 11 of 25 DHITsig-positive-transformed follicular lymphomas were classified as HGBL-DH/TH- BCL2 compared with zero of 50 in the DHITsig-negative group. Furthermore, the DHITsig was shared with the majority of B-cell lymphomas with high-grade morphology tested.We have defined a clinically and biologically distinct subgroup of tumors within GCB-DLBCL characterized by a gene expression signature of HGBL-DH/TH- BCL2. This knowledge has been translated into an assay applicable to routinely available biopsy samples, which enables exploration of its utility to guide patient management.
Adjuvant Letrozole and Tamoxifen Alone or Sequentially for Postmenopausal Women With Hormone Receptor–Positive Breast Cancer: Long-Term Follow-Up of the BIG 1-98 Trial
Authors: Thomas Ruhstaller, Anita Giobbie-Hurder, Marco Colleoni, Maj-Britt Jensen, Bent Ejlertsen, Evandro de Azambuja, Patrick Neven, István Láng, Erik Hugger Jakobsen, Laurence Gladieff, Hervé Bonnefoi, Vernon J. Harvey, Simon Spazzapan, Carlo Tondini, Lucia Del Mastro, Corinne Veyret, Edda Simoncini, Lorenzo Gianni, Christoph Rochlitz, Elena Kralidis, Khalil Zaman, Jacek Jassem, Martine Piccart-Gebhart, Angelo Di Leo, Richard D. Gelber, Alan S. Coates, Aron Goldhirsch, Beat Thürlimann, Meredith M. Regan
Journal: Journal of Clinical Oncology (2018)

Purpose Luminal breast cancer has a long natural history, with recurrences continuing beyond 10 years after diagnosis. We analyzed long-term follow-up (LTFU) of efficacy outcomes and adverse events in the Breast International Group (BIG) 1-98 study reported after a median follow-up of 12.6 years. Patients and Methods BIG 1-98 is a four-arm, phase III, double-blind, randomized trial comparing adjuvant letrozole versus tamoxifen (either treatment received for 5 years) and their sequences (2 years of one treatment plus 3 years of the other) for postmenopausal women with endocrine-responsive early breast cancer. When pharmaceutical company sponsorship ended at 8.4 years of median follow-up, academic partners initiated an observational, LTFU extension collecting annual data on survival, disease status, and adverse events. Information from Denmark was from the Danish Breast Cancer Cooperative Group Registry. Intention-to-treat analyses are reported. Results Of 8,010 enrolled patients, 4,433 were alive and not withdrawn at an LTFU participating center, and 3,833 (86%) had at least one LTFU report. For the monotherapy comparison of letrozole versus tamoxifen, we found a 9% relative reduction in the hazard of a disease-free survival event with letrozole (hazard ratio [HR], 0.91; 95% CI, 0.81 to 1.01). HRs for other efficacy end points were similar to those for disease-free survival. Efficacy of letrozole versus tamoxifen for contralateral breast cancer varied significantly over time (0- to 5-, 5- to 10-, and &gt; 10-year HRs, 0.62, 0.47, and 1.35, respectively; treatment-by-time interaction P = .005), perhaps reflecting a longer carryover effect of tamoxifen. Reporting of specific long-term adverse events seemed more effective with national registry than with case-record reporting of clinical follow-up. Conclusion Efficacy end points continued to show trends favoring letrozole. Letrozole reduced contralateral breast cancer frequency in the first 10 years, but this reversed beyond 10 years. This study illustrates the value of extended follow-up in trials of luminal breast cancer.
Chemoprevention and therapeutic treatment of BRCA1 associated breast cancer in conditional knockout mice
Authors: Yohei Tominaga, Joseph A. De Soto, Rui-Hong Wang, Chu-Xia Deng
Journal: Cancer Research (2006)

679  Germline mutations of the breast cancer associated gene 1 (BRCA1) have been identified in about 50% of familial breast cancer cases and about 90% of familial breast and ovarian cancers. BRCA1 mutation carriers have a 50 to 80% lifetime risk for developing breast cancer by age 70. Current screening and chemoprevention strategies are suboptimal and consequently some women who are BRCA1 gene carriers elect to prophylactically have their breasts and/or ovaries removed to reduce their risk. Moreover, current chemopreventative drugs often give adverse effects, primarily due to poor specificity of the compounds to mammary tumor tissues. Thus, there is an urgent need to develop safe and effective drugs for the chemoprevention and therapeutic treatment of breast cancer. In the past years, we have created a mouse model carrying a tissue specific disruption of BRCA1 in mammary epithelium. The mutant mice developed mammary tumors at 7-12 months of age. Our analysis revealed that the tumor progression is accompanied by extensive genetic instability and alteration of a number of oncogenes and tumor suppressor genes. Using this animal model and cell lines derived from mammary tumors, we have been studying effects of genistein, green tea, resveratrol, and Poly(ADP-ribose) polymerase (PARP1) inhibitors on BRCA1-associcated tumor formation in order to provide better understand and therapeutic options of BRCA1-assicated breast cancer. Our study indicated that both genistein and resveratrol inhibit growth of tumor cells in culture, in soft agar colony formation and in an allograft nude mouse model. Genistein treated BRCA1 mutant cells were highly polypoid and displayed extensive chromosome abnormalities. Western blot analysis revealed significant increase of CHK2 phosphorylation upon genistein treatment. These observations suggest that genistein induced activation of cell cycle inhibitors may cause cell cycle arrest and cell death, which account for the reduced growth of mutant cells upon the drug treatment. We found that the apoptosis induced by resveratrol in the tumors is accompanied by the activation of NF-kB pathway, and is also partially due to the activation of CHK2 in DNA damage response. Of note, we failed to detect any preventive or therapeutic effects of green tea in both allograft and BRCA1 conditional animals tested. The effectiveness of PARP-1 inhibitors also seemed more specific to BRCA1 mutant embryonic stem cells rather than BRCA1 mutant mammary tumor cells. These data, although promising, remain to be tested in human BRCA1 associated breast cancer cells. Our long-term goal is to decrease cancer risk of BRCA-mutation carriers and find a safe and effective therapeutic method to cure this disease.
Cast of the Right Bronchial Tree
Authors: Gavitt A Woodard, Georg M Wieselthaler
Journal: New England Journal of Medicine (2018)

A 36-year-old man was admitted to the intensive care unit with an acute exacerbation of chronic heart failure. After a ventricular assist device was placed and anticoagulation therapy initiated, hemoptysis developed, and he expectorated a cast of the right bronchial tree.
Patient whose GP’s religious activities contributed to her mental breakdown is awarded £12 700
Authors: Clare Dyer
Journal: BMJ (2018)

A patient has won £12 700 in damages against a locum doctor at her general practice who befriended her over five months and took her to religious meetings at his Pentecostal church.

Thomas O’Brien told Sally Brayshaw that his wife knew a different way of treatment that did not involve drugs. He and his wife later phoned Brayshaw from his home and heard about her difficult and abusive childhood.

Brayshaw, 54, had an emotionally unstable personality disorder and multiple physical, psychological, and social problems. The …
Decreased physical working capacity in adolescents with Non-Alcoholic fatty liver disease reflects reduced iron bioavailability
Authors: Tim Mitchell, Elizabeth McKinnon, Oyekoya Taiwo Ayonrinde, Leon A. Adams, Debbie Trinder, Anita Chua, Rob Newton, Leon Strakers, John K. Olynyk
Journal: Hepatology (2018)

Background: Non-alcoholic fatty liver disease (NAFLD) is a common, chronic liver disorder related to obesity and insulin resistance. Iron metabolism is impaired in obese patients, often despite elevated serum ferritin levels. In healthy patients, iron deficiency has been associated with physical inactivity, however little is known regarding the relationship between iron metabolism and reduced physical capacity in individuals with NAFLD. We aimed to determine firstly, whether there was an association between iron bioavailability, as measured by mean cell volume (MCV) and transferrin saturation (TSAT), and physical work capacity, and secondly, whether NAFLD influenced this relationship…
Independent Association of Male Sex with Presentation and Clinical Outcomes in Myeloproliferative Neoplasms
Authors: Theodoros Karantanos, Shruti Chaturvedi, Jerry L. Spivak, Linda Resar, Evan M Braunstein, Styliani Karanika, Donna Marie Williams, Ophelia Rogers, Alison R. Moliterno
Journal: Blood (2018)