tbuckley/cabot-search huggingface dataset:
Downstaging of unresectable intrahepatic or hilar cholangiocellular carcinoma by selective intra-arterial floxuridine and systemic cisplatin and gemcitabine. A dose finding single center phase IIa study.
Authors: Heike Pietge
Journal: Journal of Clinical Oncology (2018)

478 Background: Patients with unresectable cholangiocarcinomas (CCC) have a poor prognosis even if palliative systemic chemotherapy is offered. A combined approach of systemic and intrahepatic chemotherapy may improve local control rates and allow downstaging. The aim of the study was to determine the maximum tolerated dose (MTD) of systemic intravenous gemcitabine in combination with intravenous cisplatin and hepatic arterial infusion with floxuridine in patients with unresectable intrahepatic or hilar CCC. Safety, toxicity, response rates and resectability rates after 3 months of combination treatment are reported. Methods: 12 patients were treated within a 3+3 dose escalation algorithm with 600, 800 or 1000 mg/m 2 gemcitabine and a fixed dose of cisplatin 25 mg/m 2 systemic chemotherapy on day 1, 8 every 3 weeks for 4 cycles and floxuridine 0,2 mg/kg on day 1-14 continous hepatic intra-arterial chemotherapy every 4 weeks for 3 cycles. PET/CT and/or CT scan was performed after 12 weeks. Results: The MTD of gemcitabine was 800 mg/m 2 in this setting. Dose-limiting toxicities were recurrent biliary tract infections (n = 1) and neutropenic fever (n = 1). Response rates were: 27% partial remission and 73% stable disease. Although none of the patients achieved resectability after 3 months, 3-year-overall survival (OS) was 33%, median OS 21,9 months (1-49) and median progression-free survival 10,5 months (2-40). Conclusions: Combination of systemic gemcitabine and cisplatin plus intraarterial floxuridine is feasible and appears effective in disease control, but achievement of resectability seems challenging. Randomized trials comparing this combination to gemcitabine/cisplatin alone are warranted. Clinical trial information: NCT01692704.
Abstract A03: Perturbation of proteostasis is lethal in SMARCB1-deficient tumors
Authors: Giannicola Genovese, Alessandro Carugo, Rosalba Minelli, None Frederick, Scott Robinson, Pavlos Msaouel, Tim Heffernan, Andrea Viale, Nizar Tannir, Giulio Draetta
Journal: Cancer Research (2018)

Abstract Alterations in chromatin remodeling genes have been increasingly implicated in human oncogenesis. The SWI/SNF complex, specifically, is involved in a plethora of biologic functions including cell cycle regulation, terminal differentiation, and regulation of cell metabolism. The crucial chromatin-remodeling function of the SWI/SNF complex during organogenesis and tissue specification is further supported by clinical data showing that the biallelic inactivation of the core subunits SMARCB1 and SMARCA4 results in the emergence of extremely aggressive pediatric malignancies characterized by a dramatic impairment of cell cycle regulation and cellular differentiation programs, resulting in highly lethal diseases characterized by early onset, widespread metastatic dissemination, and resistance to chemotherapy. So far the lack of conditional genetic models of malignant rhabdoid tumors (MRTs) made difficult to investigate the molecular bases of malignant transformation as well as the existence of dependencies associated with SMARCB1 loss. In order to identify the functional vulnerabilities of SMARCB1-deficient cancers, we developed an embryonic mosaic model of malignant rhabdoid tumors (MRTs) that faithfully recapitulates the clinicopathologic features of human disease. By using this novel experimental system we discovered that, upon SMARCB1 ablation, embryonic epithelial progenitors undergo a profound anabolic reprogramming resulting in a global increase in protein biosynthesis and in the adaptive activation of UPR and ER stress response. As a consequence, murine and human SMARCB1-deficient malignancies display an exquisite sensitivity to agents inducing proteotoxic stress and to the pharmacologic and genetic perturbation of autophagy. Our findings, therefore, have immediate clinical implications, paving the way for drug repositioning trials investigating combinations of agents with already known safety profiles targeting simultaneously UPR and the authopagic catabolic machinery in a class of orphan diseases affecting children with limited therapeutic options. Note: This abstract was not presented at the conference. Citation Format: Giannicola Genovese, Alessandro Carugo, Rosalba Minelli, Frederick, Scott Robinson, Pavlos Msaouel, Tim Heffernan, Andrea Viale, Nizar Tannir, Giulio Draetta. Perturbation of proteostasis is lethal in SMARCB1-deficient tumors [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr A03.
Caring for individuals with a difference of sex development (DSD): a Consensus Statement
Authors: Martine Cools, Anna Nordenström, Ralitsa Robeva, Joanne Hall, Puck Westerveld, Christa Flück, Birgit Köhler, Marta Berra, Alexander Springer, Katinka Schweizer, Vickie Pasterski
Journal: Nature Reviews Endocrinology (2018)

Abstract The term differences of sex development (DSDs; also known as disorders of sex development) refers to a heterogeneous group of congenital conditions affecting human sex determination and differentiation. Several reports highlighting suboptimal physical and psychosexual outcomes in individuals who have a DSD led to a radical revision of nomenclature and management a decade ago. Whereas the resulting recommendations for holistic, multidisciplinary care seem to have been implemented rapidly in specialized paediatric services around the world, adolescents often experience difficulties in finding access to expert adult care and gradually or abruptly cease medical follow-up. Many adults with a DSD have health-related questions that remain unanswered owing to a lack of evidence pertaining to the natural evolution of the various conditions in later life stages. This Consensus Statement, developed by a European multidisciplinary group of experts, including patient representatives, summarizes evidence-based and experience-based recommendations for lifelong care and data collection in individuals with a DSD across ages and highlights clinical research priorities. By doing so, we hope to contribute to improving understanding and management of these conditions by involved medical professionals. In addition, we hope to give impetus to multicentre studies that will shed light on outcomes and comorbidities of DSD conditions across the lifespan.
Measurement of Salivary Pepsin to Detect Gastroesophageal Reflux Disease Is Not Ready for Clinical Application
Authors: Philip Woodland, Maartje M.J. Singendonk, Joanne Ooi, Kornilia Nikaki, Terry Wong, Chung Lee, Esteban Glasinovic, Romy Koning, Rene Lutter, Marc A. Benninga, Michiel P. van Wijk, Daniel Sifrim
Journal: Clinical Gastroenterology and Hepatology (2018)
Cured bronchi! Extending the use of nebulised hypertonic saline outside of cystic fibrosis?
Authors: Clémence Martin, Lucile Regard, Pierre-Régis Burgel
Journal: European Respiratory Journal (2018)

Plugging of the airways by excessive mucus is an important contributor to morbidity and mortality in chronic airway diseases ( e.g. cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), bronchiectasis and primary ciliary dyskinesia (PCD)) [1]. Such findings are the basis for the major interest in drugs that reduce mucus content in airways by targeting mucus production [2] or by increasing clearance of mucus [3]. A single aerosol of hypertonic saline (HS) was shown to enhance clearance of airway secretions in humans >40 years ago [4], and a randomised control trial reported >10 years ago found that long-term nebulisation of HS resulted in decreased rates of pulmonary exacerbations in patients with CF [5]. However, the mechanisms underlying enhanced clearance of airway mucus and clinical benefits have not been fully elucidated [6]. In vitro studies supported the hypothesis that HS increased mucociliary clearance, as the administration of HS increased the volume of airway surface liquid (ASL) in cultured airway epithelial cells, an effect that was larger and more prolonged in cultures from patients with CF than in cultures of controls [7]. Based on these experimental and clinical results, HS is now used in many countries for the treatment of patients with CF [8]. However, there is only limited evidence that HS is effective in other chronic airway diseases. For example, the small number of studies comparing the effects of hypertonic versus isotonic saline in (non-CF) bronchiectasis yielded conflicting results [9, 10], and a recent 3-month crossover trial in patients with PCD found no effect on quality of life and lung function [11]. At first glance, it may be concluded that beneficial effects of HS in airway epithelium are limited to CF airways, with only limited effects in non-CF airways, due to altered ion transport in CF epithelium. However, it has been hypothesised that increase in the magnitude of effects of HS in CF versus normal epithelial cells is not related to cystic fibrosis transmembrane conductance regulator dysfunction itself, but to increased water retention [12] by the hyperconcentrated mucus that is found in CF airways [13, 14]. Hypertonic saline may be effective not only in cystic fibrosis but also in other chronic airway diseases <http://ow.ly/dioH30jGXoa>
Valve-in-Valve Procedure in Failed Transcatheter Aortic Valves
Authors: Erwan Salaun, Anne-Sophie Zenses, Marie-Annick Clavel, Tania Rodriguez-Gabella, Eric Dumont, Siamak Mohammadi, Daniel Doyle, Jean-Michel Paradis, Robert De Larochelliere, Philippe Pibarot, Josep Rodés-Cabau
Journal: JACC. Cardiovascular imaging (2018)
Abstract 12017: New-Onset Diabetes After Heart Transplantation is associated With Worse Long-term Survival: A Propensity Matched Analysis of a National Registry.
Authors: Salil V Deo, Nagaraju Sarabu, Sachin Kumar, Salah Altarabsheh, Shannon M Dunlay, Ahmet Kilic, Guilherme H Oliveira, Gregg C Fonarow
Journal: Circulation (2016)

Introduction: Limited data is available regarding the incidence of new-onset diabetes mellitus (NODM) after heart transplantation and it`s impact on patient survival. Hypothesis: Methods: From the United Network of Organ Sharing database (January 2004 to September 2014), we identified 13,353 patients without pre-operative diabetes mellitus undergoing heart transplantation. Multivariable Cox regression was implemented to determine predictors for the development of NODM. A matched cohort of New-onset Diabetes mellitus (NODM (+)) and NODM (-) was generated by 1:1 nearest neighbor propensity-matching. The association of NODM with long-term survival was then estimated with robust Cox regression. Results are presented at the 95% Confidence level; all tests are two-tailed. Results: During the study period, 1,921 of 13,353 (14%) developed NODM. Estimated freedom from NODM was 97% (96-98%) &amp; 77% (76 - 78%) at the end of 1 and 5 years respectively. Predictors for the development of NODM were recipient age &gt; 50 years (HR 1.2 95% CI1.05, 1.3; p &lt; 0.01), recipient BMI &gt; 30 (HR 1.4 95% CI1.2, 1.6; p &lt; 0.01) and race (African American vs Caucasian (HR 1.3 95% CI1.2, 1.5; p &lt; 0.01)). Cox-regression of a propensity-matched cohort of 1921 NODM+ve and NODM-ve recipient-pairs demonstrates that NODM is associated with poorer survival (HR for mortality: 1.3 95% CI 1.1, 1.5; p &lt; 0.001). Conclusions: More than one in ten heart transplant recipients develop NODM post heart transplantation. Obesity, older age, and African American race patients to be at higher risk for NODM. New onset diabetes was independently associated with an almost 30% reduced long-term survival. More than one in ten heart transplant recipients develop NODM post heart transplantation. Obesity, older age, and African American race patients to be at higher risk for NODM. New onset diabetes was independently associated with an almost 30% reduced long-term survival.
Fall in GP numbers is “extremely concerning,” says BMA
Authors: Abi Rimmer
Journal: BMJ (2018)

The number of full time equivalent GPs in England has fallen by 0.6% in a year, show new figures that the BMA has described as “extremely concerning.”

NHS Digital’s figures showed 32 748 full time equivalent GPs at 31 March 2018 (excluding locum GPs),1 a 0.6% drop from 32 972 in March 2017.2 In August 2017, data had shown an increase of 321 (0.9%) full time equivalent GPs from March to June 2017.3

The total GP headcount also dropped by 0.5% in 2017-18, down from 41 891 at 31 March 2017 to 41 693 at 31 March 2018. …
Abstract 14087: CMR Detected Fibrotic Lesions in the LV Endocardial Layer have a Greater Adverse Effect than those in the LV Epicardial Layer for Peak Longitudinal Strain Measured by TTE in Hypertrophic Cardiomyopathy Patients
Authors: Anna Ishihara, Hiroyuki Takaoka, Nobusada Funabashi, Koya Ozawa, Yoshio Kobayashi
Journal: Circulation (2016)

Introduction:  Peak longitudinal strain (PLS) of the left ventricular (LV) myocardium by transthoracic echocardiogram (TTE) is useful for the early detection of LV myocardial damage.   Hypothesis:  Localization of myocardial fibrosis (MF) in the LV myocardium may differentially influence PLS through the endocardial layer, the epicardial layer, or both the LV endocardial and epicardial layers.   Methods:  A total of eighteen hypertrophic cardiomyopathy (HCM) patients (14 males; mean age, 58 ± 16 years) underwent both 1.5 T cardiac magnetic resonance (CMR) (Achieva, Philips) and TTE (Vivid E9, GE Healthcare), and were included. On two-dimensional speckle tracking TTE, whole layer PLS in each LV myocardial segment among 17 lesions (American Heart Association defined) were calculated offline using Echo PAC, version 113 (GE Healthcare). The presence of MF was assessed by T1 weighted images from CMR with localization in the LV endocardial layer, the LV epicardial layer, or both LV endocardial and epicardial layers for each lesion.   Results:  Of a total of 306 segments, MF was detected in LV endocardial layer only (72 segments), in LV epicardial layer only (68 segments), or in both LV endocardial and epicardial layers (80 segments) by CMR. PLS values were significantly lower in MF segments affecting only the LV endocardial layer (7±4%) and where MF was observed in both LV endocardial and epicardial layers (9±5%) compared with segments without MF (13±7%) (both P 0.05).   Conclusion:  In HCM patients, fibrotic lesions in the LV endocardial layer have a greater adverse effect than those in the LV epicardial layer for PLS as measured by TTE. This has significant implications for those patients with HCM, who have fibrotic lesions within the LV endocardial layer.
Pulmonary Function in Convalescent Poliomyelitic Patients
Authors: Benjamin G. Ferris, Jere Mead, James L. Whittenberger, George A. Saxton
Journal: New England Journal of Medicine (1952)

WHEN function of the muscles of respiration is impaired by poliomyelitis, one of the primary problems in convalescence is the disturbance of the mechanics of respiration, caused in part by atrophic and fibrotic changes in thoracic structures. While the patient is being treated in a mechanical respirator a diminution of thoracic or pulmonary distensibility, or both, can be overcome by use of adequate pressure fluctuations in the respirator. However, such alterations in distensibility, when present, constitute a major handicap to a patient attempting to ventilate his lungs by his own muscular power.A previous report1 has indicated that the resting . . .
Science and literature: a tale of two Dickens
Authors: Alison Shepherd
Journal: BMJ (2018)

The name Charles Dickens is synonymous with Victorian literature; his epic, expansive tales of 19th century London and beyond cemented in the canon of English fiction. But few realise that he was also one of his era’s great scientific communicators.

Friends with Michael Faraday, Charles Darwin, Ada Lovelace, and Florence Nightingale, Dickens, …
Time to surgery in colon cancer: Predictors and association with survival—An analysis of the National Cancer Database (NCDB).
Authors: Mohan Satish, Sarah J Aurit, Yang Zhang, Ryan W Walters
Journal: Journal of Clinical Oncology (2018)

599 Background: Time-to-surgery (TTS) refers to the wait time from the diagnosis of cancer to surgical resection of the primary tumor. In breast and bladder cancers, longer TTS has been shown to be associated with lower long-term survival. Prior evidence in colon cancer, has shown that older age, urban residence, and comorbidity are independent predictors of TTS. However, evaluation of TTS with survival in colon cancer has been limited to mostly single-center studies. Using the NCDB, this study aimed to both evaluate patient and clinical factors associated with TTS, and determine if TTS was associated with overall survival in colon cancer. Methods: Patients with colon cancer who underwent partial or subtotal colectomy/hemicolectomy were included, excluding those receiving neoadjuvant therapy. With prior colon cancer studies showing a median TTS of 15-20 days, we dichotomized the number of days from diagnosis to definitive surgery (TTS) as ≤ 21 days or &gt; 21 days. A modified Poisson regression model was utilized to evaluate relative risk of TTS &gt; 21 days. Overall survival in association with TTS was estimated using both the Kaplan-Meier method and multivariable Cox regression model, adjusting for patient-, disease- and facility-level characteristics. All analyses were conducted with SAS version 9.4, p-values &lt; 0.05 were considered significant. Results: We identified 26,999 colon cancer patients from 2006-2012 from the NCDB. Approximately 25.7% of patients had a TTS &gt; 21 days. Patients with comorbidities, who were older, were African American, with lower disease stage, and treated in academic facilities located in the Northeast, had a significantly increased relative risk of a TTS &gt; 21 days. Considering survival, a TTS &gt; 21 days was associated with a 24.5% decreased adjusted risk of death (95% CI: 21.6% to 27.2%). Conclusions: A longer TTS with colon cancer is understandably associated with older age, greater comorbidity, and lower stage, but questionably so in African American patients. However, given that TTS &gt; 21 days was associated with a lower adjusted risk of death, it may indicate that a reasonable delay could be pursued for more accurate preoperative evaluation and staging in colon cancer.
From somatic variants towards precision oncology: Evidence-driven reporting of treatment options in molecular tumor boards
Authors: Júlia Perera-Bel, Barbara Hutter, Christoph Heining, Annalen Bleckmann, Martina Fröhlich, Stefan Fröhling, Hanno Glimm, Benedikt Brors, Tim Beißbarth
Journal: Genome Medicine (2018)

A comprehensive understanding of cancer has been furthered with technological improvements and decreasing costs of next-generation sequencing (NGS). However, the complexity of interpreting genomic data is hindering the implementation of high-throughput technologies in the clinical context: increasing evidence on gene–drug interactions complicates the task of assigning clinical significance to genomic variants. Here we present a method that automatically matches patient-specific genomic alterations to treatment options. The method relies entirely on public knowledge of somatic variants with predictive evidence on drug response. The output report is aimed at supporting clinicians in the task of finding the clinical meaning of genomic variants. We applied the method to 1) The Cancer Genome Atlas (TCGA) and Genomics Evidence Neoplasia Information Exchange (GENIE) cohorts and 2) 11 patients from the NCT MASTER trial whose treatment discussions included information on their genomic profiles. Our reporting strategy showed a substantial number of patients with actionable variants in the analyses of TCGA and GENIE samples. Notably, it was able to reproduce experts' treatment suggestions in a retrospective study of 11 patients from the NCT MASTER trial. Our results establish a proof of concept for comprehensive, evidence-based reports as a supporting tool for discussing treatment options in tumor boards. We believe that a standardized method to report actionable somatic variants will smooth the incorporation of NGS in the clinical context. We anticipate that tools like the one we present here will become essential in summarizing for clinicians the growing evidence in the field of precision medicine. The R code of the presented method is provided in Additional file 6 and available at https://github.com/jperera-bel/MTB-Report .
Response by Nguyen et al to Letter Regarding Article, “Early Outcomes of Repair of Left Ventricular Apical Aneurysms in Patients with Hypertrophic Cardiomyopathy”
Authors: Anita Nguyen, Hartzell V. Schaff, Rick A. Nishimura, Joseph A. Dearani, Steve R. Ommen
Journal: Circulation (2018)
Prospective randomized controlled trial comparing efficacy of 1-L Peg-Asc with prucalopride and 2-L Peg-Asc for the bowel preparation.
Authors: Seong Ji Choi, Yoon Tae Jeen, Eun Sun Kim, Woojung Kim, Geeho Min, Jae Min Lee, Seung Han Kim, In Kyung Yoo, Hyuk Soon Choi, Bora Keum, Hong Sik Lee, Hoon Jai Chun, Chang Duck Kim
Journal: Journal of Clinical Oncology (2018)

597 Background: Though numerous researches enabled decrease of the bowel preparation solution volume, it is still a major complaint of patients preparing colonoscopy. There have been studied that additional administration of laxatives could lessen the amount of aqueous formula with prokinetic effect. Prucalopride is a serotonin (5-HT4) receptor agonist which stimulate colonic mass movements and provide main propulsive force for defecation. The aim of this study is to compare 2-L PEG-Asc and 1-L PEG-Asc plus prucalopride for quality of bowel cleansing while preparing for colonoscopy and patient compliance. Methods: Two hundred patients were prospectively enrolled. Patients referred for colonoscopy were divided into group A (the split-dose 2-L PEG-Asc) and group B (1-L PEG-Asc + prucalopride) randomly. During colonoscopy, each patient’s bowel preparation quality was evaluated with The Boston Bowel Preparation Scale (BBPS) and Aronchick Preparation Scale (APS). The tolerability and satisfaction of patients was determined based on a questionnaire-based survey. Results: One hundred patients received either 2-L PEG-Asc or 1-L PEG-Asc with prucalopride. Regarding colon cleansing outcome (BPPS and APS), the 1-L PEG-Asc with prucalopride group showed similar, but non-inferior results compared to the 2-L PEG-Asc group on both BBPS (7.65±1.27 vs 7.52±1.40, p = 0.586) and APS scales (93.3% vs 95%, p = 0.717). Tolerability was similar for both 1-L PEG-Asc with prucalopride and 2-L PEG-Asc. Conclusions: 1-L PEG-Asc plus prucalopride preparation showed comparable result to traditional 2-L PEG-Asc preparation. 1-L PEG-Asc plus prucalopride preparation method could be an alternative method for bowel preparation which can relieve patient’s discomfort. Clinical trial information: KCT0002409.
Impact of C-Reactive Protein and Coronary Artery Calcium on Benefit Observed With Atorvastatin
Authors: Michael J. Blaha, Khurram Nasir, Matthew J. Budoff, Zeina A. Dardari, Roger S. Blumenthal, Simcha Pollack, Nathaniel Reichek, Alan D. Guerci
Journal: Journal of the American College of Cardiology (2018)