tbuckley/cabot-search huggingface dataset:
Use of the CRISPR/Cas9‐based epigenetic gene activation system In Vivo: A new potential therapeutic modality
Authors: Samar H. Ibrahim, Keith D. Robertson
Journal: Hepatology (2018)

1Division of Pediatric Gastroenterology & HepatologyMayo ClinicRochesterMN 2Division of Gastroenterology & HepatologyMayo ClinicRochesterMN 3Department of Molecular Pharmacology and Experimental TherapeuticsMayo ClinicRochesterMN
Old fashioned, but important
Authors: Tom Moberly
Journal: BMJ (2014)

Since 1960 all cars have been subject to annual assessments of roadworthiness, and the tests are still known by the initials of the organisation that introduced them, the old Ministry of Transport (MOT). The MOT has an outdated name and is based on an old idea, but that does not make it any less relevant or important to ensuring that cars are safe to drive.

For over 12 …
What is the best way to respond to this interview question: why do you want to work in this hospital?
Authors: Shaaz Mahboob
Journal: BMJ (2005)

Have a career or related problem that needs answering? Can9t find the right person to point you in the right direction? Log on to the Advice Zone for reliable medical careers advice. You can post a question or see if one of our 300 advisers has already answered a similar question. Here is a selection of questions and answers posted on the site. <b>www.bmjcareers.com/advicezone</b>
Defining the DNA damage repair (DDR) genomic landscape of urothelial carcinoma of the bladder (UCB).
Authors: Shawn Dason, Victor McPherson, Min Yuen Teo, Sumit Isharwal, François Audenet, Aditya Bagrodia, Eugene K. Cha, Michael F. Berger, Ahmet Zehir, Nikolaus Schultz, Dean F. Bajorin, Jonathan E. Rosenberg, Hikmat Al-Ahmadie, Bernard H. Bochner, Eugene J. Pietzak, David B. Solit, Gopa Iyer
Journal: Journal of Clinical Oncology (2018)

502 Background: Impaired DDR is associated with response to platinum-based chemotherapy. Several genomically directed trials have been proposed using DDR alteration status for enrolment. In this study, we characterized the deleterious DDR alteration (DDRa) landscape of UCB across various clinical states. Methods: Targeted exon capture and sequencing of at least 341 cancer-associated genes was performed prospectively on 451 UCB specimens (MSK-IMPACT assay). We assessed sequencing data for deleterious alterations in 34 genes representing canonical DDR pathways. Deleterious alterations included truncating mutations, homozygous deletions, and functionally validated missense mutations. Results: Table 1. In NMIBC, deleterious DDRa were enriched in high-grade disease ([39/136, 28.7%] high grade vs. low-grade [2/28, 7.1%]; p=0.02). The frequency of deleterious DDRa in chemo-naïve MIBC was enriched relative to unmatched post-neoadjuvant chemotherapy (NAC) residual MIBC ([33/112, 29.5%] vs. [8/55, 14.5%]; p=0.01). Patients with metastatic disease had similar rates of deleterious DDRa to MIBC ([31/116, 26.7%] vs. [33/112, 29.5%]). The percentage of patients having any type of DDR alteration was similar across states. The proportion of patients with a deleterious DDRa relative to any DDRa was 41/77 (53.2%) in NMIBC, 33/65 (50.8%) in chemo-naïve MIBC, 8/27(29.6%) in post-NAC residual MIBC, and 31/68 (45.6%) in metastatic disease. Conclusions: DDRa are found across the UCB disease spectrum. ERCC2 and ATM are the most common DDRa although alterations were seen in most other DDR genes. Many alterations are of unknown significance and further characterization is needed to develop genomically directed treatment. [Table: see text]
Patient-reported outcomes in PD-1/PD-L1 inhibitor registration trials: FDA analysis of data submitted and future directions.
Authors: Lynn Jackson Howie, Harpreet Singh, Bellinda King-Kallimanis, Jessica Roydhouse, Marc Robert Theoret, Gideon Michael Blumenthal, Paul Gustav Kluetz
Journal: Journal of Clinical Oncology (2018)

134 Background: Patient-reported outcome measures (PROs) can capture the patient’s experience with disease and treatment. Anti-PD-1/PD-L1 therapies have unique symptomatic side effects; PRO data can help to better understand the patient experience on therapy. Health-related quality of life (HRQL) components most impacted by therapy include disease symptoms, symptomatic toxicity and physical function. Methods: We reviewed FDA registration trials for 5 immunotherapy agents (anti-PD-1/PD-L1) to evaluate trial design and PRO assessment. We assessed whether the PRO strategy assessed physical function and symptomatic immune-related adverse events (irAEs) by reviewing whether trials used a well-defined physical function domain and 8 symptoms related to irAEs reported in product labels (fatigue, diarrhea, cough, shortness of breath, musculoskeletal pain, rash, pruritis and fever). Results: Data from 25 trials across 7 disease types and 1 tumor agnostic indication were evaluated. Of these, 13 were randomized and 22 were open label. Eighteen of 25 contained PRO assessments and all 18 used &gt; 1 instrument. The most common instruments were the EQ-5D (N = 17), followed by EORTC QLQ-C30 (N = 15). Disease-specific PRO tools were included in 8 trials (5 lung, 1 head and neck, 1 melanoma and 1 renal cell), consisting of modules or scales from EORTC (N = 5), FACIT (N = 2) or the Lung Cancer Symptom Scale (N = 1). Sixty percent of the trials (15/25) used an instrument that contained a well-defined physical function (PF) domain. No trial used a PRO strategy assessing all 8 selected symptoms related to irAEs. Conclusions: Collection of PRO data in anti-PD-1/PD-L1 trials submitted to FDA was variable, and did not consistently assess treatment related symptoms and physical function. Use of a HRQL tool with well-defined functional scales supplemented by item banks or libraries to incorporate symptoms associated with irAEs may improve understanding of the patient experience while receiving anti-PD-1/PD-L1 treatment. These data, along with other important clinical data such as hospitalizations, ER visits and supportive care medications can inform the benefit risk assessment for regulatory purposes.
Apatinib as third-line or beyond therapy in patients with chemotherapy-refractory advanced or metastatic adenocarcinoma of stomach or gastroesophageal junction: An open-label, multicenter, post-marketing phase IV study (Ahead-G201).
Authors: Shukui Qin, Wenying Deng, Lu Wen, Junsheng Wang, Guifang Zhang, Haijun Zhong, Tongfu Jia, Jianwei Yang, Yi Ba, Yuxian Bai, Xiaoyan Lin, Mei Wang, Lin Wang, Likun Liu, Yifu He, Min Tao, Congying Xie, Feng Ye, Xiang-yuan Wu, Jin Li
Journal: Journal of Clinical Oncology (2018)

103 Background: The clinical benefit and safety profile of apatinib in advanced gastric cancer have been established in the randomised controlled phase III clinical trial (J Clin Oncol. 34(13):1448-54). A post-marketing study to confirm the safety and efficacy of apatinib is ongoing in a broad range of patients (pts). Methods: This is a single-arm, open-label, multi-center, Phase IV trial with the target sample size of 2000+ (ClinicalTrials.gov Identifier: NCT02426034). Pts were recruited to receive oral apatinib until disease progression, death or unacceptable toxicity. The primary objective was safety, and the secondary objectives included overall response rate (ORR), disease control rate (DCR), progression free survival (PFS) and overall survival (OS). Results: Herein, we report the preliminary data as documented in the EDC System. As of Jul 10, 2017, 1037 pts were enrolled from 138 hospitals across China. Pts characteristics were: median age 59 yrs, male/female 72.0/28.0%, ECOG PS 0/1/≥2 16.6/66.2/17.2%, stage IV 91.0%. 336 (32.4%) pts interrupted treatment and dose modification occurred in 172 (16.6%) pts (reduction 132/12.7%; rise 87/8.4%). Eventually, the mean dosage was 526.2 mg/d. 652 (62.9%) pts had 4407 drug-related adverse events (DRAEs). Grade ≥3 DRAEs occurred in 300 (28.9%) pts. Severe AEs were reported by 221 (21.3%) pts. The most common DRAEs were proteinuria (19.3%), hypertension (18.8%), leukocyte decrease (16.4%), fatigue (14.2%), platelet decrease (13.6%), hand-foot-skin reaction (11.1%) and neutrophil decrease (10.1%). 820 pts were evaluable for efficacy analysis. The best ORR and DCR were 10.7% and 70.0%, respectively. The median PFS and OS were 4.60 (95%CI, 3.25–4.73) and 6.57 (95%CI, 5.78–7.59) months, respectively. Conclusions: Apatinib monotherapy is effective and has a favorable toxicity profile in real-world clinical setting. The preliminary results of this Phase IV study confirmed the safety and efficacy of apatinib demonstrated in the Phase II and III trials. Updated results will be discussed. Clinical trial information: NCT02426034.
Efficacy of Vaginal Estradiol or Vaginal Moisturizer vs Placebo for Treating Postmenopausal Vulvovaginal Symptoms
Authors: Caroline M. Mitchell, Susan D. Reed, Susan Diem, Joseph C. Larson, Katherine M. Newton, Kristine E. Ensrud, Andrea Z. LaCroix, Bette Caan, Katherine A. Guthrie
Journal: JAMA Internal Medicine (2018)

Nearly half of postmenopausal women report bothersome vulvovaginal symptoms, but few data support the efficacy of 2 commonly recommended treatments.To compare the efficacy of a low-dose vaginal estradiol tablet and a vaginal moisturizer, each vs placebo, for treatment of moderate-to-severe postmenopausal vulvovaginal symptoms.This 12-week multicenter randomized clinical trial enrolled postmenopausal women with moderate to severe symptoms of vulvovaginal itching, pain, dryness, irritation, or pain with penetration.Vaginal 10-μg estradiol tablet (daily for 2 weeks, then twice weekly) plus placebo gel (3 times a week) (n = 102) vs placebo tablet plus vaginal moisturizer (n = 100) vs dual placebo (n = 100).The main outcome was decrease in severity (0-3) of most bothersome symptom (MBS) between enrollment and 12 weeks. Additional measures included a composite vaginal symptom score, Female Sexual Function Index (FSFI) score (2-36), modified Female Sexual Distress Score-Revised item 1, treatment satisfaction and meaningful benefit, Vaginal Maturation Index, and vaginal pH.The 302 women had a mean (SD) age of 61 (4) years and were primarily white (267 [88%]), college educated (200 [66%]), and sexually active (245 [81%]). Most women (294 [97%]) provided data for the primary analysis. The most commonly reported MBS was pain with vaginal penetration (182 [60%]), followed by vulvovaginal dryness (63 [21%]). Mean baseline MBS severity was similar between treatment groups: estradiol, 2.4 (95% CI, 2.3 to 2.6); moisturizer, 2.5 (95% CI, 2.3 to 2.6); placebo, 2.5 (95% CI, 2.4 to 2.6). All treatment groups had similar mean reductions in MBS severity over 12 weeks: estradiol, -1.4 (95% CI, -1.6 to -1.2); moisturizer, -1.2 (95% CI, -1.4 to -1.0); and placebo, -1.3 (95% CI, -1.5 to -1.1). No significant differences were seen between estradiol (P = .25) or moisturizer (P = .31) compared with placebo. Mean total FSFI improvement was similar between estradiol (5.4; 95% CI, 4.0 to 6.9) and placebo (4.5; 95% CI, 2.8 to 6.1) (P = .64), and between moisturizer (3.1; 95% CI, 1.7 to 4.5) and placebo (P = .17).Our results suggest that neither prescribed vaginal estradiol tablet nor over-the-counter vaginal moisturizer provides additional benefit over placebo vaginal tablet and gel in reducing postmenopausal vulvovaginal symptoms.clinicaltrials.gov Identifier: NCT02516202.
High neutrophil-to-lymphocyte ratio before starting anti-programmed cell death 1 immunotherapy predicts poor outcome in patients with metastatic melanoma
Authors: Margaux Garnier, Julia Zaragoza, Nathalie Bénéton, Guido Bens, Victoire Meurisse, Mahtab Samimi, Hervé Maillard, Laurent Machet
Journal: Journal of the American Academy of Dermatology (2018)
What you need to know about MRCS from the Intercollegiate Committee
Authors: Peter A Brennan, Lee Smith
Journal: BMJ (2016)

<b>Peter Brennan</b> and <b>Lee Smith</b> from the Intercollegiate Committee for Basic Surgical Examinations (ICBSE) provide up to date information, including future changes to part A, and dispel a few myths about the MRCS.
Using circulating tumor DNA (ctDNA) to predict surgical outcome after neoadjuvant chemoradiation for locally advanced pancreatic cancer (LAPC).
Authors: Susan McDuff, Aparna Raj Parikh, Mehlika Hazar-Rethinam, Hui Zheng, Emily Van Seventer, Brandon Nadres, David P. Ryan, Colin D. Weekes, Jeffrey W. Clark, Carlos Fernandez-del Castillo, Cristina Ferrone, Keith D Lillemoe, Janet E. Murphy, Lipika Goyal, Andrew X. Zhu, Jennifer Yon-Li Wo, Lawrence Scott Blaszkowsky, Jill N. Allen, Ryan Bruce Corcoran, Theodore S. Hong
Journal: Journal of Clinical Oncology (2018)

272 Background: Curative resection is possible following neoadjuvant treatment for LAPC, yet there is no method to identify patients beforehand who will have a favorable surgical outcome. This study was designed to assess the ability of ctDNA measured during neoadjuvant chemoradiation (CRT) to predict surgical outcome for LAPC. Methods: 38 LAPC pts were enrolled at our institution between 10/2015 - 5/2017. Pts received neoadjuvant FOLFIRINOX followed by CRT: either short-course ( n = 9, 25 Gy/5 fractions), or long-course ( n = 29, 50.4 Gy/28 fractions). Serum ctDNA was measured at baseline, weekly during CRT, and preoperatively. After extracting DNA from plasma, a tumor mutation specific droplet digital PCR assay was used to detect the fraction of ctDNA molecules. The following clinical and pathologic outcomes were noted: CA19-9, CEA, RECIST score, tumor grade, T stage, tumor regression grade (TRG), R-resection status, pathologically involved lymph nodes, LVI, and PNI. Results: The median age of the cohort was 67 years (range 42-85 years). Following CRT, 32 (84%) were operable. The overall R0-node negative (R0-NN) resection rate was 66% for the entire cohort. The rate of R0-NN resection was significantly higher among patients with an undetectable preoperative ctDNA ( n= 16) compared to those with a detectable ( n= 22) preoperative ctDNA (88% R0-NN vs 50% R0-NN, respectively, Fisher’s exact p = 0.036). On univariate logistic regression, only ctDNA status was significantly associated with R0-NN resection (p = 0.025), whereas preoperative RECIST score, CA19-9, and CEA were not associated. On multivariable logistic regression, ctDNA remained a borderline significant predictor for R0-NN resection when controlling for CA19-9 ( p = 0.058). For patients who received surgery, the ctDNA allele fraction was significantly correlated with TRG ( Pearson R = 0.399, p = 0.024). Conclusions: Undetectable preoperative ctDNA is associated with R0-NN surgical outcome in a cohort of patients treated with neoadjuvant CRT for LAPC. This approach is worthy of further study to establish guidelines for incorporating ctDNA into clinic with the goal of improving patient selection for surgery.
Targeting Bromodomain and Extra-Terminal (BET) Family Proteins in Castration-Resistant Prostate Cancer (CRPC)
Authors: Jonathan Welti, Adam Sharp, Wei Yuan, David Dolling, Daniel Nava Rodrigues, Ines Figueiredo, Veronica Gil, Antje Neeb, Matthew Clarke, George Seed, Mateus Crespo, Semini Sumanasuriya, Jian Ning, Eleanor Knight, Jeffrey C. Francis, Ashley Hughes, Wendy S. Halsey, Alec Paschalis, Ram S. Mani, Ganesh V. Raj, Stephen R. Plymate, Suzanne Carreira, Gunther Boysen, Arul M. Chinnaiyan, Amanda Swain, Johann S. de Bono
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Persistent androgen receptor (AR) signaling drives castration-resistant prostate cancer (CRPC) and confers resistance to AR-targeting therapies. Novel therapeutic strategies to overcome this are urgently required. We evaluated how bromodomain and extra-terminal (BET) protein inhibitors (BETi) abrogate aberrant AR signaling in CRPC. Experimental Design: We determined associations between BET expression, AR-driven transcription, and patient outcome; and the effect and mechanism by which chemical BETi (JQ1 and GSK1210151A; I-BET151) and BET family protein knockdown regulates AR-V7 expression and AR signaling in prostate cancer models. Results: Nuclear BRD4 protein expression increases significantly (P ≤ 0.01) with castration resistance in same patient treatment-naïve (median H-score; interquartile range: 100; 100–170) and CRPC (150; 110–200) biopsies, with higher expression at diagnosis associating with worse outcome (HR, 3.25; 95% CI, 1.50–7.01; P ≤ 0.001). BRD2, BRD3, and BRD4 RNA expression in CRPC biopsies correlates with AR-driven transcription (all P ≤ 0.001). Chemical BETi, and combined BET family protein knockdown, reduce AR-V7 expression and AR signaling. This was not recapitulated by C-MYC knockdown. In addition, we show that BETi regulates RNA processing thereby reducing alternative splicing and AR-V7 expression. Furthermore, BETi reduce growth of prostate cancer cells and patient-derived organoids with known AR mutations, AR amplification and AR-V7 expression. Finally, BETi, unlike enzalutamide, decreases persistent AR signaling and growth (P ≤ 0.001) of a patient-derived xenograft model of CRPC with AR amplification and AR-V7 expression. Conclusions: BETi merit clinical evaluation as inhibitors of AR splicing and function, with trials demonstrating their blockade in proof-of-mechanism pharmacodynamic studies. Clin Cancer Res; 24(13); 3149–62. ©2018 AACR.
Secondary malignancies following low-dose-rate brachytherapy for prostate cancer in a single institution.
Authors: Kotaro Obayashi, Go Kimura, Shigehiko Kuribayashi, Keita Shibayama, Masayuki Sano, Kuniaki Tanabe, Jun Akatsuka, Tatsuro Hayashi, Yuka Toyama, Tsutomu Hamasaki, Katsuya Maebayashi, Shinichiro Kumita, Yukihiro Kondo
Journal: Journal of Clinical Oncology (2018)

142 Background: Low-dose-rate brachytherapy (BT) is the internal radiation therapy for non-metastatic prostate cancer by implanting radioactive isotope Iodine 125 into the prostate. The carcinogenetic effect of radiation for the treatment of cancer has been proven during the last decades. However, few studies have been reported about brachytherapy-induced secondary malignancies. In this study, we assessed the BT-induced secondary malignancies in our institution. Methods: We reviewed 487 patients treated with low-dose-rate BT from 2006 to 2016 in our hospital. We checked the occurrence of metachronous malignancies (MM) in all the patients and examined the features of MM including the number, organ sites, histology, period from BT to the occurrence, and analyzed whether the features meet the criteria of radiation-induced malignancies. We also examined the relationship between the BT-related radiation doses and the occurrence of MM. We adopted the criteria of radiation-induced cancer proposed by Sakai et al in 1981; different pathological feature from the organ of origin, the follow-up duration after radiation therapy (over 5 years), and whether the lesion is located in the irradiated field. Results: After a median follow-up period of 57 months (range 10-125 months), 23 MM occurred, which were bladder cancer in 4 cases (0.8%), esophageal in 2 (0.4%), gastric in 5 (1.0%), colon in 4 (0.8%), rectal in 3 (0.6%), pancreatic in 1 (0.2%), lung in 3 (0.6%), and brain in 1 (0.2%). Time from initial treatment to MM was 36 months (range 1-85 months). None of the cases had experienced biochemical recurrence. Average radiation dose to the urethra and the rectum including UD90, UD5, U200, R100, R150 showed no significant difference compared to the patients without occurrence of MM. According to the Sakai’s criteria, one bladder and one rectal cancer were judged as radiation-induced secondary malignancies (0.2%). Conclusions: The risk of secondary malignancies in patients undergoing BT was very low. Further studies with longer follow-up are required because it has been only about 10 years since low-dose-rate brachytherapy started in Japan.
Adalimumab-Induced Epstein-Barr Virus–Related Lymphoproliferative Disorder on FDG PET/CT
Authors: John Ward, Ariela Noy, Gary Ulaner, Christopher Riedl
Journal: Clinical Nuclear Medicine (2018)

Adalimumab is a fully human chimeric tumor necrosis factor inhibitor used to treat immune-mediated disorders such as psoriatic arthritis. We present a 51-year-old woman with psoriatic arthritis on methotrexate and infliximab for 12 years. Adalimumab replaced infliximab because of worsening symptoms. Following 3 doses administered 1 week apart, rapidly enlarging cervical lymph nodes developed. Biopsy revealed Epstein-Barr virus-related polymorphic lymphoproliferative disorder. F-FDG PET/CT demonstrated widespread hypermetabolic lymphadenopathy; follow-up at 5 weeks off adalimumab revealed almost complete resolution of this adenopathy. This is most consistent with Epstein-Barr virus-related lymphoproliferative disorder secondary to tumor necrosis factor α inhibition.
RELATIONSHIP BETWEEN THE PROGNOSTIC NUTRITIONAL INDEX AND LONG-TERM CLINICAL OUTCOMES IN PATIENTS WITH STABLE CORONARY ARTERY DISEASE
Authors: Mitsuhiro Takeuchi, Hideki Wada, Tomotaka Dohi, Shuta Tsuboi, Manabu Ogita, Takatoshi Kasai, Shinya Okazaki, Kikuo Isoda, Satoru Suwa, Katsumi Miyauchi, Hiroyuki Daida
Journal: Journal of the American College of Cardiology (2018)
Sexual Dimorphism and the Origins of Human Spinal Health
Authors: Vicente Gilsanz, Tishya A L Wren, Skorn Ponrartana, Stefano Mora, Clifford J Rosen
Journal: Endocrine Reviews (2018)

Recent observations indicate that the cross-sectional area (CSA) of vertebral bodies is on average 10% smaller in healthy newborn girls than in newborn boys, a striking difference that increases during infancy and puberty and is greatest by the time of sexual and skeletal maturity. The smaller CSA of female vertebrae is associated with greater spinal flexibility and could represent the human adaptation to fetal load in bipedal posture. Unfortunately, it also imparts a mechanical disadvantage that increases stress within the vertebrae for all physical activities. This review summarizes the potential endocrine, genetic, and environmental determinants of vertebral cross-sectional growth and current knowledge of the association between the small female vertebrae and greater risk for a broad array of spinal conditions across the lifespan.