tbuckley/cabot-search huggingface dataset:
Combination regimens with PD-1/PD-L1 immune checkpoint inhibitors for gastrointestinal malignancies
Authors: Dongxu Wang, Jianzhen Lin, Xu Yang, Junyu Long, Yi Bai, Xiaobo Yang, Yilei Mao, Xinting Sang, Samuel Seery, Haitao Zhao
Journal: Journal of Hematology & Oncology (2019)

Gastrointestinal (GI) malignant neoplasms have a high global incidence and treatment prospects for patients with advanced GI tumors are dismal. PD-1/PD-L1 inhibitors emerged as a frontline treatment for several types of cancer. However, the shortcomings of PD-1/PD-L1 inhibitors have been observed, including low objective response rates and acquired tumor resistance, especially in patients receiving PD-1/PD-L1 inhibitors as a single treatment. Accumulating evidence from clinical trials increasingly suggests that combined immunotherapies enhance therapeutic responses in patients with malignances, especially for GI tumors which have a complex matrix, and significant molecular and immunological differences. Preclinical and clinical studies suggest there are advantages to combined immunological regimens, which represents the next logical step in this field, although further research is necessary. This literature review explores the current limitations of monotherapies, before critically discussing the rationale behind combination regimens. Then, we provide a summary of the clinical applications for gastrointestinal cancers.
Efficacy and tolerability of neratinib in advanced HER-2 positive breast cancer: A single institution experience
Authors: S.T.C. Shepherd, K. Lee, K. Mohammed, K. Patel, M. Allen, S.R.D. Johnston, M. Parton, A. Ring, N. Turner, A.F.C. Okines
Journal: Annals of Oncology (2019)

Background: Neratinib is an oral small-molecule irreversible pan-HER tyrosine kinase inhibitor in late stage clinical development for advanced HER-2 positive breast cancer. Prophylactic loperamide (4mg qds Day 1, tds days 2-14, bd days 15-28 then prn) and budesonide (9mg od for 28 days) are required to reduce the incidence and severity of diarrhoea. Methods: Patients enrolled within the Puma Biotechnology Neratinib Managed Access Program between 01/01/2016 and 01/06/2018 with advanced HER2 positive breast cancer were identified for this retrospective analysis. Data were collected from electronic patient records. The primary endpoint was progression free survival (PFS). Secondary objectives were overall survival (OS), response rate (RR, RECIST v1.1), clinical benefit rate (CBR) and toxicity graded by CTCAE v4.0. Results: We identified 29 patients, median age 54 years (IQR: 50-61) who received a median of 4 (range 1-6) prior lines of therapy for advanced breast cancer. 15 patients (51.7%) received neratinib 240mg/day as monotherapy (one with sc trastuzumab), 14 (48.2%) in combination with capecitabine 1500mg/m2/day for 2 weeks of a 3 week cycle. Median follow-up was 8.5 months (IQR: 5.1 – 11.6). Median PFS was 7.4 months (95%CI 3.5 – 17.9) and was significantly longer with combination therapy than monotherapy (17.9 (3.5-NR) vs 5.8 months (2.0-10.2), P = 0.043). Median OS was not reached but was not significantly different in the two treatment cohorts. The RR in monotherapy patients was 33% compared to 57% in combination patients. Two combination patients had complete responses which remain ongoing at 17 and 25 months. The CBR was 47% and 79% respectively. Grade 3-4 toxicities were reported in 4 patients (13.8%). Dose delays were required in 19 patients (65.5%), dose reductions in 4 (13.8%) and discontinuation in 4 due to pneumonitis (n = 1); nausea and vomiting (n = 2) and diarrhoea (n = 1). Any grade diarrhoea was reported by 15 patients (51.7%) despite prophylaxis, as above. There was no grade 3-4 diarrhoea. Conclusions: In this cohort of heavily pre-treated HER2 positive advanced breast cancer patients, neratinib demonstrated durable anti-cancer activity with a manageable toxicity profile both as monotherapy and in combination with capecitabine. Legal entity responsible for the study: The Royal Marsden NHS Foundation Trust. Funding: Neratinib was provided by Puma Biotechnology free of charge within a Managed Access Programme; they did not provide any other funding towards this study. Disclosure: S.R.D. Johnston: Advisory boards, consultancy work: Puma Biotechnology. M. Parton: Honoraria for lecture: Pfizer. A.F.C. Okines: Research funding: Pfizer; Honorarium/speakers bureau: Roche. All other authors have declared no conflicts of interest.
SAFETY AND EFFICACY OF NON-ANESTHESIOLOGIST ADMINISTERED SEDATION (NAS) IN GASTROINTESTINAL ENDOSCOPY: A PROSPECTIVE, MONOCENTRIC STUDY OF 9380 PROCEDURES
Authors: S Deiana, T Gabbani, P Soriani, V Mirante, M Manno
Journal: Endoscopy (2019)

Sedation is an integral part of gastrointestinal endoscopy, but the best sedation strategy is still a matter of debate. Non-anesthesiologist (NAS) propofol-based-sedation (PBS) remains controversial because of concerns about safety. The aim of the study was to evaluate safety and efficacy of NAS, comparing traditional sedation with PBS.
Measles: Public Health England urges all parents to get their children vaccinated as cases spike
Authors: Elisabeth Mahase
Journal: BMJ (2019)

Public Health England has urged all parents to get their children vaccinated against measles, mumps, and rubella (MMR), especially if they did not have it when scheduled.

The call comes as new figures show 231 confirmed cases of measles in the first three months of this year—slightly less than in the same period last year but still a large increase since 2017.

From 1 January to 31 October 2018 England had 913 laboratory confirmed measles cases, up from 259 reported in the whole of 2017.1 And 795 cases of …
Hepatocyte Deletion of Triglyceride‐Synthesis Enzyme Acyl CoA: Diacylglycerol Acyltransferase 2 Reduces Steatosis Without Increasing Inflammation or Fibrosis in Mice
Authors: Nina L. Gluchowski, Katlyn R. Gabriel, Chandramohan Chitraju, Roderick T. Bronson, Niklas Mejhert, Sebastian Boland, Kun Wang, Zon Weng Lai, Robert V. Farese, Tobias C. Walther
Journal: Hepatology (2019)

Nonalcoholic fatty liver disease (NAFLD) is characterized by excess lipid accumulation in hepatocytes and represents a huge public health problem owing to its propensity to progress to nonalcoholic steatohepatitis, fibrosis, and liver failure. The lipids stored in hepatic steatosis (HS) are primarily triglycerides (TGs) synthesized by two acyl-CoA:diacylglycerol acyltransferase (DGAT) enzymes. Either DGAT1 or DGAT2 catalyzes this reaction, and these enzymes have been suggested to differentially utilize exogenous or endogenously synthesized fatty acids, respectively. DGAT2 has been linked to storage of fatty acids from de novo lipogenesis, a process increased in NAFLD. However, whether DGAT2 is more responsible for lipid accumulation in NAFLD and progression to fibrosis is currently unknown. Also, it is unresolved whether DGAT2 can be safely inhibited as a therapy for NAFLD. Here, we induced NAFLD-like disease in mice by feeding a diet rich in fructose, saturated fat, and cholesterol and found that hepatocyte-specific Dgat2 deficiency reduced expression of de novo lipogenesis genes and lowered liver TGs by ~70%. Importantly, the reduction in steatosis was not accompanied by increased inflammation or fibrosis, and insulin and glucose metabolism were unchanged. Conclusion: This study suggests that hepatic DGAT2 deficiency successfully reduces diet-induced HS and supports development of DGAT2 inhibitors as a therapeutic strategy for treating NAFLD and preventing downstream consequences.
BATTERY INGESTION COMPLICATIONS IN CHILDREN: CASE SERIES
Authors: PF Souto Bittencourt, M Magalhães Bittencourt, AL Vanolli, VT Giannella Estanislau, A Andrade Franciscani Peixoto, AC Gatto Polo, L Alves da Cruz Texeira, E Fraga Moreira
Journal: Endoscopy (2019)

Accidental ingestion of foreign bodies is common in children and is a medical emergency when it comes to battery intakes. According to data from a study conducted in the USA in the period 1986 – 2009, 56,535 cases of ingestion of batteries were recorded. It is important to note that 90% are asymptomatic or present with sialorrhea, dysphagia, food refusal, vomiting, hematemesis, cough, hematochezia, peritonitis and mediastinitis. The diagnosis is based on anamnesis and imaging tests. The main complications are tracheoesophageal fistula, esophageal perforation, esophageal stricture and death.
Negotiating your job plan as a consultant: understanding the basics
Authors: Kathy Oxtoby
Journal: BMJ (2019)

Negotiating job plans can be baffling for those in their first year as a consultant, and sometimes difficult even for those with experience of the process.

The BMA says that developing a job plan involves looking at what work doctors do for the trust, and where and when.1 A job plan should, it says, include how much time doctors are expected to be available for work; what this work will deliver for the employer, employee, and patients; what resources are necessary for the work to be achieved; and what flexibility there is around these considerations.

It’s also important that doctors know what they can do to shape their job plan, and how best to manage the process. “We need to consider the profession’s wellbeing, and having clearly defined job plans is part of that,” says Alison Wright, a consultant obstetrician and gynaecologist and vice president, UK and global membership, Royal College of Obstetricians and Gynaecologists.

As a former clinical …
COMPARISON OF THE EFFECTIVENESS OF FOUR BOWEL CLEANSING PREPARATIONS BEFORE COLONOSCOPY – RANDOMIZED, SINGLE – BLIND STUDY
Authors: K Kmochova, S Suchanek, O Ngo, M Zavoral
Journal: Endoscopy (2019)

The aim of the study is to compare the effectiveness of bowel cleansing preparations. Polyethylene glycol (PEG) as a gold standard of bowel cleansing and low – volume solutions: sulphate-based solution (SBS), low-volume PEG + ascorbic acid (2L-PEG/Asc) and sodium picosulfate + magnesium citric-acid solution (SP/MC).
Dabigatran for Prevention of Stroke after Embolic Stroke of Undetermined Source
Authors: Hans-Christoph Diener, Ralph L. Sacco, J. Donald Easton, Christopher B. Granger, Richard A. Bernstein, Shinichiro Uchiyama, Jörg Kreuzer, Lisa Cronin, Daniel Cotton, Claudia Grauer, Martina Brueckmann, Marina Chernyatina, Geoffrey Donnan, José M. Ferro, Martin Grond, Bernd Kallmünzer, Jerzy Krupinski, Byung-Chul Lee, Robin Lemmens, Jaime Masjuan, Miroslav Odinak, Jeffrey L. Saver, Peter D. Schellinger, Danilo Toni, Kazunori Toyoda
Journal: New England Journal of Medicine (2019)

Cryptogenic strokes constitute 20 to 30% of ischemic strokes, and most cryptogenic strokes are considered to be embolic and of undetermined source. An earlier randomized trial showed that rivaroxaban is no more effective than aspirin in preventing recurrent stroke after a presumed embolic stroke from an undetermined source. Whether dabigatran would be effective in preventing recurrent strokes after this type of stroke was unclear.
Thyroid hormones treatment for subclinical hypothyroidism: a clinical practice guideline
Authors: G E Bekkering, T Agoritsas, L Lytvyn, A F Heen, M Feller, E Moutzouri, H Abdulazeem, B Aertgeerts, D Beecher, J P Brito, P D Farhoumand, N Singh Ospina, N Rodondi, M van Driel, E Wallace, M Snel, P M Okwen, R Siemieniuk, P O Vandvik, T Kuijpers, M Vermandere
Journal: BMJ (2019)

Abstract Clinical question What are the benefits and harms of thyroid hormones for adults with subclinical hypothyroidism (SCH)? This guideline was triggered by a recent systematic review of randomised controlled trials, which could alter practice. Current practice Current guidelines tend to recommend thyroid hormones for adults with thyroid stimulating hormone (TSH) levels &gt;10 mIU/L and for people with lower TSH values who are young, symptomatic, or have specific indications for prescribing. Recommendation The guideline panel issues a strong recommendation against thyroid hormones in adults with SCH (elevated TSH levels and normal free T4 (thyroxine) levels). It does not apply to women who are trying to become pregnant or patients with TSH &gt;20 mIU/L. It may not apply to patients with severe symptoms or young adults (such as those ≤30 years old). How this guideline was created A guideline panel including patients, clinicians, and methodologists produced this recommendation in adherence with standards for trustworthy guidelines using the GRADE approach. The evidence The systematic review included 21 trials with 2192 participants. For adults with SCH, thyroid hormones consistently demonstrate no clinically relevant benefits for quality of life or thyroid related symptoms, including depressive symptoms, fatigue, and body mass index (moderate to high quality evidence). Thyroid hormones may have little or no effect on cardiovascular events or mortality (low quality evidence), but harms were measured in only one trial with few events at two years’ follow-up. Understanding the recommendation The panel concluded that almost all adults with SCH would not benefit from treatment with thyroid hormones. Other factors in the strong recommendation include the burden of lifelong management and uncertainty on potential harms. Instead, clinicians should monitor the progression or resolution of the thyroid dysfunction in these adults. Recommendations are made actionable for clinicians and their patients through visual overviews. These provide the relative and absolute benefits and harms of thyroid hormones in multilayered evidence summaries and decision aids available in MAGIC ( https://app.magicapp.org/ ) to support shared decisions and adaptation of this guideline.
THE VALUE OF THE UPPER GASTRO-INTESTINAL TRACT ENDOSCOPY IN CASE OF BLEACH INGESTION: ABOUT 80 CASES
Authors: S Bouamama, S Elmansouri, M Tahiri, F Haddad, W Hliwa, A Bellabah, W Badre
Journal: Endoscopy (2019)

It is a retrospective study over 5 years length period, from November 2013 to July 2018, collecting the results of gastrointestinal endoscopy performed on patients who ingested bleach.
Metabolic Reprogramming by MYCN Confers Dependence on the Serine-Glycine-One-Carbon Biosynthetic Pathway
Authors: Yingfeng Xia, Bingwei Ye, Jane Ding, Yajie Yu, Ahmet Alptekin, Muthusamy Thangaraju, Puttur D. Prasad, Zhi-Chun Ding, Eun Jeong Park, Jeong-Hyeon Choi, Bei Gao, Oliver Fiehn, Chunhong Yan, Zheng Dong, Yunhong Zha, Han-Fei Ding
Journal: Cancer Research (2019)

MYCN amplification drives the development of neuronal cancers in children and adults. Given the challenge in therapeutically targeting MYCN directly, we searched for MYCN-activated metabolic pathways as potential drug targets. Here we report that neuroblastoma cells with MYCN amplification show increased transcriptional activation of the serine-glycine-one-carbon (SGOC) biosynthetic pathway and an increased dependence on this pathway for supplying glucose-derived carbon for serine and glycine synthesis. Small molecule inhibitors that block this metabolic pathway exhibit selective cytotoxicity to MYCN-amplified cell lines and xenografts by inducing metabolic stress and autophagy. Transcriptional activation of the SGOC pathway in MYCN-amplified cells requires both MYCN and ATF4, which form a positive feedback loop, with MYCN activation of ATF4 mRNA expression and ATF4 stabilization of MYCN protein by antagonizing FBXW7-mediated MYCN ubiquitination. Collectively, these findings suggest a coupled relationship between metabolic reprogramming and increased sensitivity to metabolic stress, which could be exploited as a strategy for selective cancer therapy. SIGNIFICANCE: This study identifies a MYCN-dependent metabolic vulnerability and suggests a coupled relationship between metabolic reprogramming and increased sensitivity to metabolic stress, which could be exploited for cancer therapy.See related commentary by Rodriguez Garcia and Arsenian-Henriksson, p. 3818.
Development and external validation of 1- and 2-year mortality prediction models in cystic fibrosis
Authors: Sanja Stanojevic, Jenna Sykes, Anne L. Stephenson, Shawn D. Aaron, George A. Whitmore
Journal: European Respiratory Journal (2019)

Introduction We aimed to develop a clinical tool for predicting 1- and 2-year risk of death for patients with cystic fibrosis (CF). The model considers patients' overall health status as well as risk of intermittent shock events in calculating the risk of death. Methods Canadian CF Registry data from 1982 to 2015 were used to develop a predictive risk model using threshold regression. A 2-year risk of death estimated conditional probability of surviving the second year given survival for the first year. UK CF Registry data from 2007 to 2013 were used to externally validate the model. Results The combined effect of CF chronic health status and CF intermittent shock risk provided a simple clinical scoring tool for assessing 1-year and 2-year risk of death for an individual CF patient. At a threshold risk of death of ≥20%, the 1-year model had a sensitivity of 74% and specificity of 96%. The area under the receiver operating curve (AUC) for the 2-year mortality model was significantly greater than the AUC for a model that predicted survival based on forced expiratory volume in 1 s &lt;30% predicted (AUC 0.95 versus 0.68 respectively, p&lt;0.001). The Canadian-derived model validated well with the UK data and correctly identified 79% of deaths and 95% of survivors in a single year in the UK. Conclusions The prediction models provide an accurate risk of death over a 1- and 2-year time horizon. The models performed equally well when validated in an independent UK CF population.
Deprescribing in Older Adults With Cardiovascular Disease
Authors: Ashok Krishnaswami, Michael A. Steinman, Parag Goyal, Andrew R. Zullo, Timothy S. Anderson, Kim K. Birtcher, Sarah J. Goodlin, Mathew S. Maurer, Karen P. Alexander, Michael W. Rich, Jennifer Tjia
Journal: Journal of the American College of Cardiology (2019)
Vision Impairment and Subjective Cognitive Decline–Related Functional Limitations — United States, 2015–2017
Authors: Sharon Saydah, Robert B. Gerzoff, Christopher A. Taylor, Joshua R. Ehrlich, Jinan Saaddine
Journal: MMWR Morbidity and Mortality Weekly Report (2019)

Vision impairment affects approximately 3.22 million persons in the United States and is associated with social isolation, disability, and decreased quality of life (1). Cognitive decline is more common in adults with vision impairment (2,3). Subjective cognitive decline (SCD), which is the self-reported experience of worsening or more frequent confusion or memory loss within the past 12 months, affects 11.2% of adults aged ≥45 years in the United States (4). One consequence of SCD is the occurrence of functional limitations, especially those related to usual daily activities; however, it is not known whether persons with vision impairment are more likely to have functional limitations related to SCD (4). This report describes the association of vision impairment and SCD-related functional limitations using Behavioral Risk Factor Surveillance System (BRFSS) surveys for the years 2015-2017. Adjusting for age group, sex, race/ethnicity, education level, health insurance, and smoking status, 18% of adults aged ≥45 years who reported vision impairment also reported SCD-related functional limitations, compared with only 4% of those without vision impairment. Preventing, reducing, and correcting vision impairments might lead to a decrease in SCD-related functional limitations among adults in the United States.
NO BENEFIT OF PERFORMING ENDOSCOPIC SPHINCTEROTOMY BEFORE STENT PLACEMENT IN PATIENTS WITH DISTAL MALIGNANT BILIARY STRICTURES: A META-ANALYSIS OF RCTS
Authors: A Tringali, E Stasi, M Cintolo, E Forti, F Pugliese, L Dioscoridi, DG Adler, M Mutignani
Journal: Endoscopy (2019)

Endoscopic sphincterotomy (ES) before stent placement in patients with distal malignant biliary obstruction is still a controversial issue. Some authors suggested that ES before stent deployment has a protective role in avoiding the risk of post ERCP pancreatitis but this attitude is not currently evidence-based. We performed a systematic review and meta-analysis to investigate the role of ES versus non endoscopic sphincterotomy (NES) before stent placement in patients with distal malignant biliary strictures.
IL‐6 and IL‐1β expression is increased in autologous serum skin test of patients with chronic spontaneous urticaria
Authors: Laurence de Montjoye, Mathilde Choteau, Anne Herman, Emilie Hendrickx, Paméla Chéou, Marie Baeck, Laure Dumoutier
Journal: Allergy (2019)

Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
ENDOSCOPIC AND CLINICAL OUTCOMES IN CD PATIENTS: RESULTS OF A PROSPECTIVE STUDY
Authors: M State, T Voiosu, A Bengus, B Mateescu
Journal: Endoscopy (2019)

Our aim was to assess clinical and endoscopic outcomes in CD (Crohn's disease) patients enrolled in an IBD prospective cohort and to identify predictors of persistent inflammatory activity at follow-up.
Recipient c-Kit Lineage Cells Repopulate Smooth Muscle Cells of Transplant Arteriosclerosis in Mouse Models
Authors: Zhichao Ni, Jiacheng Deng, Claire M.F. Potter, Witold N. Nowak, Wenduo Gu, Zhongyi Zhang, Ting Chen, Qishan Chen, Yanhua Hu, Bin Zhou, Qingbo Xu, Li Zhang
Journal: Circulation Research (2019)

Transplantation-accelerated arteriosclerosis is one of the major challenges for long-term survival of patients with solid organ transplantation. Although stem/progenitor cells have been implicated to participate in this process, the cells of origin and underlying mechanisms have not been fully defined.The objective of our study was to investigate the role of c-Kit lineage cells in allograft-induced neointima formation and to explore the mechanisms underlying this process.Using an inducible lineage tracing Kit-CreER;Rosa26-tdTomato mouse model, we observed that c-Kit is expressed in multiple cell types in the blood vessels, rather than a specific stem/progenitor cell marker. We performed allograft transplantation between different donor and recipient mice, as well as bone marrow transplantation experiments, demonstrating that recipient c-Kit+ cells repopulate neointimal smooth muscle cells (SMCs) and leukocytes, and contribute to neointima formation in an allograft transplantation model. c-Kit-derived SMCs originate from nonbone marrow tissues, whereas bone marrow-derived c-Kit+ cells mainly generate CD45+ leukocytes. However, the exact identity of c-Kit lineage cells contributing to neointimal SMCs remains unclear. ACK2 (anti-c-Kit antibody), which specifically binds and blocks c-Kit function, ameliorates allograft-induced arteriosclerosis. Stem cell factor and TGF (transforming growth factor)-β1 levels were significantly increased in blood and neointimal lesions after allograft transplantation, by which stem cell factor facilitated c-Kit+ cell migration through the stem cell factor/c-Kit axis and downstream activation of small GTPases, MEK (mitogen-activated protein kinase kinase)/ERK (extracellular signal-regulated kinase)/MLC (myosin light chain), and JNK (c-Jun N-terminal kinase)/c-Jun signaling pathways, whereas TGF-β1 induces c-Kit+ cell differentiation into SMCs via HK (hexokinase)-1-dependent metabolic reprogramming and a possible downstream O-GlcNAcylation of myocardin and serum response factor.Our findings provide evidence that recipient c-Kit lineage cells contribute to vascular remodeling in an allograft transplantation model, in which the stem cell factor/c-Kit axis is responsible for cell migration and HK-1-dependent metabolic reprogramming for SMC differentiation.
Retinoblastoma Loss in Cancer: Casting a Wider Net
Authors: Atish D. Choudhury, Himisha Beltran
Journal: Clinical Cancer Research (2019)

Capturing both genomic and nongenomic mechanisms of retinoblastoma gene dysfunction has potential to improve risk stratification and patient selection for biomarker-driven therapy. A 186-gene expression signature is capable of identifying Rb loss across cancer types, providing a new framework for assessing Rb dysfunction based on transcriptome data.See related article by Chen et al., p. 4290.