tbuckley/cabot-search huggingface dataset:
Exceptional Response to Pembrolizumab in a Metastatic, Chemotherapy/Radiation-Resistant Ovarian Cancer Patient Harboring a PD-L1-Genetic Rearrangement
Authors: Stefania Bellone, Natalia Buza, Jungmin Choi, Luca Zammataro, Laurie Gay, Julia Elvin, David L. Rimm, Yuting Liu, Elena S. Ratner, Peter E. Schwartz, Alessandro D. Santin
Journal: Clinical Cancer Research (2018)

Purpose: Ovarian carcinoma no longer responsive to surgery and chemotherapy remains an incurable disease. Alternative therapeutic options remain desperately needed.Patients and Methods: We describe a heavily pretreated patient with ovarian cancer with recurrent disease experiencing a remarkable clinical response to treatment with the anti-PD1 immune checkpoint inhibitor pembrolizumab. The clinical, pathological, and genomic characteristics of this exceptional ovarian cancer responder were carefully investigated using immunohistochemistry (IHC), quantitative multiplex fluorescence methods (i.e., automated quantitative analysis, AQUA) and whole-exome sequencing (WES) techniques.Results: The patient harbored a recurrent/metastatic radiation and chemotherapy-resistant high-grade ovarian carcinoma with clear cell features. While progressing on any standard treatment modality, she demonstrated a remarkable complete response to the anti-PD1 immune checkpoint inhibitor pembrolizumab. WES results were notable for the presence a relative low number of mutations (tumor mutation load/Mb = 4.31, total mutations = 164) and a peculiar structural variant disrupting the 3' region of the PD-L1 gene causing aberrant PD-L1 surface expression as confirmed by IHC and AQUA technology. Heavy infiltration of the PD-L1-mutated and PD-L1-overexpressing tumor with T-cell lymphocytes (i.e., CD4+/CD8+ TIL), CD68+ macrophages, and CD20+ B cells was detected in the surgical specimen strongly suggesting immune evasion as a key mechanism of tumor growth and survival. Patient's complete clinical responses remain unchanged at the time of the writing of this report with no significant side effects reported to date.Conclusions: Anti-PD1 inhibitors may represent a novel treatment option for recurrent/metastatic human tumors refractory to salvage treatment harboring PD-L1 gene structural variations causing aberrant PD-L1 expression. Clin Cancer Res; 24(14); 3282-91. ©2018 AACRSee related commentary by Lheureux, p. 3233.
Toxicity and Efficacy of a Novel GADD34-expressing Oncolytic HSV-1 for the Treatment of Experimental Glioblastoma
Authors: Hiroshi Nakashima, Tran Nguyen, Kazue Kasai, Carmela Passaro, Hirotaka Ito, William F. Goins, Imran Shaikh, Ronald Erdelyi, Reiko Nishihara, Ichiro Nakano, David A. Reardon, Ana C. Anderson, Vijay Kuchroo, E. Antonio Chiocca
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Glioblastoma (GBM) is the most common primary central nervous system cancer in adults. Oncolytic HSV-1 (oHSV) is the first FDA-approved gene therapy approach for the treatment of malignant melanoma. For GBM, oHSVs need to be engineered to replicate within and be toxic to the glial tumor but not to normal brain parenchymal cells. We have thus engineered a novel oHSV to achieve these objectives. Experimental Design: NG34 is an attenuated HSV-1 with deletions in the genes encoding viral ICP6 and ICP34.5. These mutations suppress virus replication in nondividing brain neurons. NG34 expresses the human GADD34 gene under transcriptional control of a cellular Nestin gene promoter/enhancer element, whose expression occurs selectively in GBM. In vitro cytotoxicity assay and survival studies with mouse models were performed to evaluate therapeutic potency of NG34 against glioblastoma. In vivo neurotoxicity evaluation of NG34 was tested by intracerebral inoculation. Results: NG34 replicates in GBM cells in vitro with similar kinetics as those exhibited by an oHSV that is currently in clinical trials (rQNestin34.5). Dose–response cytotoxicity of NG34 in human GBM panels was equivalent to or improved compared with rQNestin34.5. The in vivo efficacy of NG34 against two human orthotopic GBM models in athymic mice was similar to that of rQNestin34.5, whereas intracerebral injection of NG34 in the brains of immunocompetent and athymic mice showed significantly better tolerability. NG34 was also effective in a syngeneic mouse glioblastoma model. Conclusions: A novel oHSV encoding GADD34 is efficacious and relatively nontoxic in mouse models of GBM. Clin Cancer Res; 24(11); 2574–84. ©2018 AACR.
INCIDENCE AND CAUSES OF 30-DAY READMISSION IN PATIENTS UNDERGOING EARLY INVASIVE VERSUS CONSERVATIVE MANAGEMENT FOR UNSTABLE ANGINA/NON ST ELEVATION MYOCARDIAL INFARCTION: INSIGHTS FROM NATIONAL READMISSION DATABASE
Authors: Shanti Patel, Aparna Saha, Priti Poojary, Sumeet Pawar, Jignesh Patel, Kanika Mahajan, Pratik Mondal, Kinsuk Chauhan, Shivkumar Agarwal, Stephan Kamholz, Gerald Hollander, Jacob Shani, Girish Nadkarni
Journal: Journal of the American College of Cardiology (2018)
Salivary Gland Cancer Patient-Derived Xenografts Enable Characterization of Cancer Stem Cells and New Gene Events Associated with Tumor Progression
Authors: Stephen B. Keysar, Justin R. Eagles, Bettina Miller, Brian C. Jackson, Farshad N. Chowdhury, Julie Reisinger, Tugs-Saikhan Chimed, Phuong N. Le, John J. Morton, Hilary L. Somerset, Marileila Varella-Garcia, Aik-Choon Tan, John I. Song, Daniel W. Bowles, Mary E. Reyland, Antonio Jimeno
Journal: Clinical Cancer Research (2018)

Purpose: Salivary gland cancers (SGC) frequently present with distant metastases many years after diagnosis, suggesting a cancer stem cell (CSC) subpopulation that initiates late recurrences; however, current models are limited both in their availability and suitability to characterize these rare cells.Experimental Design: Patient-derived xenografts (PDX) were generated by engrafting patient tissue onto nude mice from one acinic cell carcinoma (AciCC), four adenoid cystic carcinoma (ACC), and three mucoepidermoid carcinoma (MEC) cases, which were derived from successive relapses from the same MEC patient. Patient and PDX samples were analyzed by RNA-seq and Exome-seq. Sphere formation potential and in vivo tumorigenicity was assessed by sorting for Aldefluor (ALDH) activity and CD44-expressing subpopulations.Results: For successive MEC relapses we found a time-dependent increase in CSCs (ALDH+CD44high), increasing from 0.2% to 4.5% (P=0.033), but more importantly we observed an increase in individual CSC sphere formation and tumorigenic potential. A 50% increase in mutational burden was documented in subsequent MEC tumors, and this was associated with increased expression of tumor-promoting genes (MT1E, LGR5, and LEF1), decreased expression of tumor-suppressor genes (CDKN2B, SIK1, and TP53), and higher expression of CSC-related proteins such as SOX2, MYC, and ALDH1A1. Finally, genomic analyses identified a novel NFIB-MTFR2 fusion in an ACC tumor and confirmed previously reported fusions (NTRK3-ETV6 and MYB-NFIB)Conclusions: Sequential MEC PDX models preserved key patient features and enabled the identification of genetic events putatively contributing to increases in both CSC proportion and intrinsic tumorigenicity, which mirrored the patient's clinical course. Clin Cancer Res; 24(12); 2935-43. ©2018 AACR.
Prevalence of sexually transmitted infections among young people in South Africa: A nested survey in a health and demographic surveillance site
Authors: Suzanna C. Francis, T. Nondumiso Mthiyane, Kathy Baisley, S. Lerato Mchunu, Jane B. Ferguson, Theresa Smit, Tania Crucitti, Dickman Gareta, Siphephelo Dlamini, Tinofa Mutevedzi, Janet Seeley, Deenan Pillay, Nuala McGrath, Maryam Shahmanesh
Journal: PLoS Medicine (2018)

Background Sexually transmitted infections (STIs) and bacterial vaginosis (BV) are associated with increased transmission of HIV, and poor reproductive and sexual health. The burden of STIs/BV among young people is unknown in many high HIV prevalence settings. We conducted an acceptability, feasibility, and prevalence study of home-based sampling for STIs/BV among young men and women aged 15–24 years old in a health and demographic surveillance site (HDSS) in rural KwaZulu-Natal, South Africa. Methods and findings A total of 1,342 young people, stratified by age (15–19 and 20–24 years) and sex were selected from the HDSS sampling frame; 1,171/1,342 (87%) individuals had ≥1 attempted home visit between 4 October 2016 and 31 January 2017, of whom 790 (67%) were successfully contacted. Among the 645 who were contacted and eligible, 447 (69%) enrolled. Consenting/assenting participants were interviewed, and blood, self-collected urine (men), and vaginal swabs (women) were tested for herpes simplex virus type 2 (HSV-2), chlamydia, gonorrhoea, syphilis, trichomoniasis, and BV. Both men and women reported that sample collection was easy. Participants disagreed that sampling was painful; more than half of the participants disagreed that they felt anxious or embarrassed. The weighted prevalence of STIs/BV among men and women, respectively, was 5.3% and 11.2% for chlamydia, 1.5% and 1.8% for gonorrhoea, 0% and 0.4% for active syphilis, 0.6% and 4.6% for trichomoniasis, 16.8% and 28.7% for HSV-2, and 42.1% for BV (women only). Of the women with ≥1 curable STI, 75% reported no symptoms. Factors associated with STIs/BV included having older age, being female, and not being in school or working. Among those who participated in the 2016 HIV serosurvey, the prevalence of HIV was 5.6% among men and 19% among women. Feasibility was impacted by the short study duration and the difficulty finding men at home. Conclusions A high prevalence of STIs/BV was found in this rural setting with high HIV prevalence in South Africa. Most STIs and HIV infections were asymptomatic and would not have been identified or treated under national syndromic management guidelines. A nested STI/BV survey within a HDSS proved acceptable and feasible. This is a proof of concept for population-based STI surveillance in low- and middle-income countries that could be utilised in the evaluation of STI/HIV prevention and control programmes.
Investigating suspected cancer clusters and responding to community concerns: Guidelines from CDC and the Council of State and Territorial Epidemiologists
Authors: B Abrams, H Anderson, C Blackmore, FJ Bove, SK Condon, CR Eheman, J Fagliano, LB Haynes, LS Lewis, J Major, Michael McGeehin, E Simms, K Sircar, J Soler, M Stanbury, SM Watkins, D Wartenberg
Journal: MMWR Recommendations and Reports (2013)
Junior doctors’ all-out strike: voices from the picket lines
Authors: Thomas Cassidy, Thomas Macaulay, Marina Soltan
Journal: BMJ (2016)

“None of us here wants to strike but we feel that, in the interests of patient safety, patients would be better off if we did strike. There’s a lot of spin and different opinions that make it confusing and that’s why we’re out here today, to try to show patients why we’re doing it and the benefits of striking for them.”

“I am taking part in industrial action as I feel it is the only recourse left to bring attention to, and defend against, the threat posed by this government to my patients. My strike effort is being covered by my consultant senior colleagues who are 100% behind our action. The public is really supportive. I’m in the north. Who are people going to trust—all their doctors or a Tory government?”

“Escalating action is a significant move but unfortunately it’s the only possible one. The next action would be a longer period of strike action or a full walk out. Given the state of the contract I would support that. The negative impact of the contract in the long term is going to be significantly worse than any short term strike action we take now. It’s like ripping off a plaster. You either rip it off all at once, or you peel it off nastily and slowly.”

“I am supporting the junior doctors because the new contract carries safety risks for our patients, will affect the quality …
Health Education England consults on cost cutting plans
Authors: Abi Rimmer
Journal: BMJ (2014)

Health Education England (HEE) has launched a consultation on planned changes to its structure, designed to cut running costs and reduce numbers of senior staff.

Its plans are designed to enable the organisation to cut its running costs by a fifth, as required by the Department of Health for England, and to reduce the number of people it pays over £100 000 a year by at least the same proportion.1

The plans are expected to be complete by April 2015. They introduce a “One HEE Programme,” aimed at reducing duplication in the running of …
Abstract P6-13-03: Breast cancer-specific mortality (BCSM) in patients with node-positive (N+) breast cancer (BC) treated based on the 21-gene assay in clinical practice
Authors: S Shak, D McCullough, VI Petkov
Journal: Cancer Research (2018)

Abstract Introduction: The Recurrence Score® (RS) assay was shown in SWOG 8814 to predict chemotherapy (CT) benefit for patients (pts) with N+ BC and RS ≥31 but not RS &amp;lt;18. As we await the randomized RxPONDER results for RS 0-25, we characterized BCSM for RS groups (cutoffs of 11, 18, 25, and 31) in the large population-based SEER study of pts treated based on RS results. Methods: RS results were provided electronically to SEER registries per their linkage methods (Petkov npj Breast Cancer 2016). Eligible pts were diagnosed (Jan 2004 - Dec 2012) with N+ (micrometastases, 1-3 positive nodes), HR+, HER2-negative BC, and had no prior malignancy or multiple tumors. BCSM estimates by reported CT use were computed using standard cutpoints of 18 and 31 and TAILORx/RxPONDER cutpoints of 11 and 25, and should be interpreted cautiously given known under-reporting of CT use to SEER and lack of randomization. Results: Among 6,483 pts with RS results, 1,312 (20%) had RS &amp;lt;11, 2,478 (38%) had RS 11-17, 1,831 (28%) had RS 18-25, 432 (7%) had RS 26-30, and 430 (7%) had RS ≥31. There was a significant association between RS results and BCSM (p&amp;lt;0.001) without and with adjustment for age, tumor size, and grade. Reported CT use and 5-y BCSM increased with increasing RS result (Table). For pts with RS &amp;lt;11 and RS 11-17, CT use was reported in approximately a quarter of pts, and 5-y BCSM was low regardless of CT use. For pts with RS 18-25, CT use was more common and the 5-y BCSM was about 2%. For pts with RS of 26-30 or ≥31, CT was common, and higher 5-y BCSM was observed. 5-y BCSM, by RS Group and Reported CT Use CT reported as ‘No/Unknown’CT reported as ‘Yes’RS groupN (%)5-y BCSM (95% CI)N (%)5-y BCSM (95% CI)&amp;lt;111066 (81%)1.8% (0.7%, 4.6%)246 (19%)1.3% (0.3%, 5.3%)11-171869 (75%)0.5% (0.2%, 1.1%)609 (25%)2.3% (0.9%, 5.8%)18-251034 (56%)2.0% (1.0%, 3.9%)797 (44%)1.9% (0.8%, 4.5%)26-30144 (33%)7.7% (2.8%, 20.3%)288 (67%)4.0% (1.6%, 10.1%)≥3199 (23%)11.9% (5.3%, 25.6%)331 (77%)11.1% (6.9%, 17.6%) Conclusion: Reported CT use and 5-y BCSM in N+ BC increased with increasing RS results in “real-world” clinical practice. 5-y BCSM with RS &amp;lt;18 was less than 2% in pts with no or unknown CT use. 5-y BCSM in pts treated based on RS results appears to increase considerably with RS &amp;gt;25. Citation Format: Shak S, McCullough D, Petkov VI. Breast cancer-specific mortality (BCSM) in patients with node-positive (N+) breast cancer (BC) treated based on the 21-gene assay in clinical practice [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-13-03.
Neuroimmune Axes of the Blood–Brain Barriers and Blood–Brain Interfaces: Bases for Physiological Regulation, Disease States, and Pharmacological Interventions
Authors: Michelle A. Erickson, William A. Banks
Journal: Pharmacological Reviews (2018)

Central nervous system (CNS) barriers predominantly mediate the immune-privileged status of the brain, and are also important regulators of neuroimmune communication. It is increasingly appreciated that communication between the brain and immune system contributes to physiologic processes, adaptive responses, and disease states. In this review, we discuss the highly specialized features of brain barriers that regulate neuroimmune communication in health and disease. In <i>section I</i>, we discuss the concept of immune privilege, provide working definitions of brain barriers, and outline the historical work that contributed to the understanding of CNS barrier functions. In <i>section II</i>, we discuss the unique anatomic, cellular, and molecular characteristics of the vascular blood–brain barrier (BBB), blood–cerebrospinal fluid barrier, and tanycytic barriers that confer their functions as neuroimmune interfaces. In <i>section III</i>, we consider BBB-mediated neuroimmune functions and interactions categorized as five neuroimmune axes: disruption, responses to immune stimuli, uptake and transport of immunoactive substances, immune cell trafficking, and secretions of immunoactive substances. In <i>section IV</i>, we discuss neuroimmune functions of CNS barriers in physiologic and disease states, as well as pharmacological interventions for CNS diseases. Throughout this review, we highlight many recent advances that have contributed to the modern understanding of CNS barriers and their interface functions.
ARTERIAL STIFFNESS INDEPENDENTLY PREDICTS STROKE IN PATIENTS WITH ESSENTIAL HYPERTENSION: DATA FROM A GREEK 8-YEAR-FOLLOW-UP STUDY
Authors: Konstantinos P. Tsioufis, Kyriakos Dimitriadis, Alexandros Kasiakogias, Ioannis Liatakis, Eirini Andrikou, Ioanna Karapati, Dimitris Konstantinidis, Skevos Sideris, George Anoussis, Dimitris Tousoulis
Journal: Journal of the American College of Cardiology (2018)
PMS contracts being cut or abolished, warns NAPC
Authors: Caroline White
Journal: BMJ (2012)

Patients are being “seriously failed” by the continuing erosion of personal medical services (PMS) contracts in general practice, the National Association of Primary Care (NAPC) has warned.

The association said that practices are increasingly reporting that PMS budgets are being slashed or that primary care trusts are forcing them to revert to the general medical services (GMS) contract.

This trend flies in the face of the localism agenda that the government promotes and will make it hard for services to respond to local need, says …
Redefining the learning curve for robotic esophagectomy.
Authors: Ken Lee Meredith, Jamie Huston, Pedro Briceno, Ravi Shridhar
Journal: Journal of Clinical Oncology (2018)

132 Background: Minimally invasive esophagectomy(MIE) has demonstrated superior outcomes compared to open approaches. The myriad of techniques has precluded the recommendation of a standard approach. The robotic approach has increased steadily. We have previously published our series defining the learning curve for this approach. The purpose of this study is to redefine the learning curve for robotic-assisted esophagogastrectomy with respect to operative time, conversion rates, and patient safety. Methods: We have prospectively followed all patients undergoing robotic-assisted esophagogastrectomy and compared operations performed at our institutions by a single surgeon in successive cohorts. Our measures of proficiency included: operative times, conversion rates, and complications. Statistical analyses were undertaken utilizing Spearman regression analysis and Mann-Whitney U test. Significance was accepted with 95 % confidence. Results: We identified 203 patients (166 [81.8%] male: 37 [18.2%] female) of median age of 67.2 (30-90) years who underwent robotic-assisted esophagogastrectomies for malignant esophageal disease. One-hundred sixty six were adenocarcinoma, 26 were squamous cell carcinoma and 11 were other. R0 resections was performed in 202 (99.5%) of patients. The median lymph node harvest was 18 (6-63). Neoadjuvant chemoradiation was administered to 157 (77.4%) patients. A significant reduction in operative times (p &lt;0.005) following completion of 20 procedures was identified (514 ± 106 min vs. 415± 91 min compared to subsequent 80 cases and further reduced with the subsequent 100 cases 397 ± 71.9 min) p&lt;0.001. Complications decreased after the initial learning curve of 29 cases, p=0.04. However there was an increase in complications after 90 cases in which there was an increase in the Charleson morbidity index, p&lt;0.01 indicating higher risk patients which tapered after case 115. Conclusions: For surgeons proficient in performing minimally-invasive esophagogastrectomies, the learning curve for a robotic-assisted procedure appears to begin near proficiency after 20 cases however as more complex cases are undertake there appears to be an additional learning curve which is surpassed after 90 cases.
High Prevalence of Anal Canal High-Risk Human Papillomavirus Infection in Patients With Crohn's Disease
Authors: Lucine Vuitton, Elise Jacquin, Anne-Laure Parmentier, Elise Crochet, Francine Fein, Anne-Claire Dupont-Gossart, Laurianne Plastaras, Charles-Henri Bretagne, Frédéric Mauny, Stéphane Koch, Jean-Luc Prétet, Christiane Mougin, Séverine Valmary-Degano
Journal: Clinical Gastroenterology and Hepatology (2018)
Number of senior paediatricians falls
Authors: Helen Jaques
Journal: BMJ (2013)

The number of consultant paediatricians and specialty, staff, and associate specialist (SAS) grade paediatricians in the UK fell by 1.4% between 2009 and 2011, the Royal College of Paediatrics and Child Health has reported.1

The college’s latest workforce census shows that the number of SAS grade paediatricians working in the NHS fell “significantly.” And although the total number of consultant paediatricians rose slightly between 2009 and 2011, the rate of growth was slower than in 2007-09.

The college said that the slowing growth in the number of consultant posts was a concern given the high number of doctors …
Abstract P180: Ambulatory Blood Pressure Monitoring Phenotypes in Adults With and Without Chronic Kidney Disease Taking Antihypertensive Medication: The Jackson Heart Study
Authors: Stanford Mwasongwe, Rikki M Tanner, Daniel Pugliese, Bessie Young, Marwah Abdalla, Solomon K Musani, Orlando Gutierrezi, Adolfo Correa, Daichi Shimbo, Paul Muntner
Journal: Circulation (2018)

Background: Ambulatory blood pressure monitoring (ABPM) can detect hypertension phenotypes associated with increased risk for chronic kidney disease (CKD) progression. There is a high prevalence of these phenotypes in the general population; however, it is unclear whether they are more common among African Americans (AAs) with versus without CKD. Methods: We examined the prevalence of daytime, nocturnal, white-coat, masked, and sustained hypertension and a non-dipping BP pattern among AAs participating in the Jackson Heart Study. Analyses were restricted to 561 participants taking antihypertensive medication with a complete ABPM recording at baseline (2000-2004). CKD was defined as an estimated glomerular filtration rate &lt; 60 mL/min/1.73 m 2 or the presence of kidney damage indicated by the presence of albumin-creatinine ratio ≥30 mg/g. We used log binomial regression models in a multivariable adjusted model to calculate the association between CKD and ABPM phenotypes. Results: The mean age of participants included in the current analysis was 62 years, 72% were female, and 26% had CKD. Daytime, nocturnal, masked, and sustained hypertension and non-dipping were more common, while white-coat hypertension was less common, among participants with versus without CKD (Table 1). The prevalence of sustained hypertension was 1.46-fold (CI 1.03-2.06) greater among those with CKD compare to those without after multivariable adjustment. Conclusions: In a large community-based study of AAs, ABPM phenotypes were common among adults with CKD. Sustained hypertension was statistically significantly higher in those with versus without CKD.