tbuckley/cabot-search huggingface dataset:
Phase1 clinical trial of high doses of Seleno-L-methionine (SLM), in sequential combination with axitinib in previously treated and relapsed clear cell renal cell carcinoma (ccRCC) patients.
Authors: Yousef Zakharia, Rohan Garje, James A. Brown, Kenneth Gerard Nepple, Laila Dahmoush, Katherine Gibson-Corley, Douglas Spitz, Mohammed M. Milhem, Youcef M. Rustum
Journal: Journal of Clinical Oncology (2018)

630 Background: The overexpression of hypoxia induced factor (HIF) 1a/2a in ccRCC leads to up-regulation of vascular endothelial growth factor (VEGF) that results in increased angiogenesis, tumor metastasis, and treatment resistance. Using several preclinical xenograft models, it has been demonstrated that therapeutic doses and schedules of the selenium-containing molecules, seleno-L-methionine (SLM) and methylselenocysteine (MSC) caused enhanced degradation of HIF1α/2α, down-regulation of oncogenic miRNA-210 and 155, up-regulation tumor suppressor miRNA-664 and LET-7b, and stabilization of tumor vasculature, yielding higher tumor drug uptake and protection from toxic side effects when combined with chemotherapeutic and VEGF-targeted agents. Methods: This is a phase I (3+3 design) dose finding trial of SLM (2500, 3000 or 4000 µg) given orally twice daily for 14 days, followed by once a day in combination with the standard dose of axitinib to patients with metastatic RCC. Primary endpoint is safety, secondary endpoint is efficacy including overall response rate (ORR), progression free survival (PFS) and overall survival (OS). Results: To date, 9 patients with metastatic RCC; who failed one or more prior lines of treatment; are enrolled. The first 3 patients were treated at 4000 µg, the second and third 3 patients were treated at 2500 and 3000 µg respectively. No dose limiting toxicity (DLT) is encountered. Six patients are evaluable to date. Of the 4000 µg cohort, 2 patients achieved complete remission (CR) at 18 and 20 months, 1 patient with partial response (PR) at 19 month. Of the 2500 µg cohort, one patient achieved PR at 9 months, 1 patient had stable disease for 9 months before progression, and 1 patient had disease progression at 4 months. The 3000 µg cohort is too early to evaluate for efficacy. Of interest the 4000μg SLM dose yielded a plasma selenium concentration of 40-50μM which is comparable with SLM dose determined synergistic with anti-cancer drugs in preclinical models. Conclusions: High dose SLM is safe in combination with axitinib, with promising efficacy, further data to be presented at the meeting. Clinical trial information: NCT02535533.
Integrative molecular profiling challenges robustness of prognostic signature scores in multifocal prostate cancer.
Authors: Daniel Hovelson, Simpa Samuel Salami, Jeremy B Kaplan, Romain Mathieu, Aaron Udager, Nicole Curci, Matthew Lee, Lorena Lazo De La Vega, Martin Susani, Nathalie Rioux-Leclercq, Daniel Eidelberg Spratt, Todd Matthew Morgan, Matthew Davenport, Mark A. Rubin, Shahrokh F. Shariat, Scott A. Tomlins, Ganesh S. Palapattu
Journal: Journal of Clinical Oncology (2018)

96 Background: Tissue based biomarkers are increasingly utilized in men diagnosed with low grade prostate cancer (PCa) to guide definitive management vs. active surveillance. PCa is uniquely multifocal, suggesting ideal prognostic biomarkers should be robust to both undersampling of a high grade component of a mixed-grade tumor focus, as well as unsampled multifocal high grade tumor foci. Methods: To assess the robustness of prognostic biomarkers to multifocality, we designed a comprehensive multiplexed targeted RNA sequencing assay (mxRNAseq) capable of assessing multiple classes of transcriptional alterations and deriving available prognostic signature scores (e.g. Prolaris CCP and OncotypeDX GPS). We applied this assay to a retrospective cohort of 176 FFPE tissue samples representing the range of PCa progression. Single candidate biomarkers and derived prognostic signatures were analyzed in multifocal cases with only low-grade disease as well as those with extreme grade differences across tumor foci. Results: Our mxRNAseq assay robustly detected known coding gene/lncRNA expression, gene fusions, splice variants, and expressed somatic and germline mutations. Supervised clustering of target gene expression confirmed expected transcriptional module deregulation and derived prognostic signatures across PCa progression. Prognostic biomarkers (including derived signatures) showed no significant expression differences between low grade foci from prostates with and without high grade disease foci and were uniformly higher in high vs. low grade foci from the same case. In four cases of extreme multifocality (Gleason score 6 vs. ≥ 8 foci), prognostic signatures were significantly lower in low vs. high grade foci. In a clinical prostatectomy cohort of 1,418 men with diagnostic biopsy Gleason score 3+3 = 6 or 3+4 = 7, 21 (1.5%) had Gleason score ≥ 4+4 = 8, suggesting the initial biopsy missed or undersampled the most clinically relevant focus. Conclusions: Using a novel comprehensive mxRNAseq assay, our results challenge the robustness of prognostic biomarkers between multifocal low and high grade PCa foci, critically important in the context of un/under-sampled aggressive tumor foci.
HLA-DR MISMATCH PREDICT REJECTION AND LONG-TERM MORTALITY AFTER HEART TRANSPLANTATION
Authors: Francesco Cacciatore, Cristiano Amarelli, Chiara Sabia, Irene Mattucci, Claudio Marra, Gianpaolo Romano, Ciro Maiello, Claudio Napoli
Journal: Journal of the American College of Cardiology (2018)
The Sister Study Cohort: Baseline Methods and Participant Characteristics
Authors: Dale P. Sandler, M. Elizabeth Hodgson, Sandra L. Deming-Halverson, Paula S. Juras, Aimee A. D’Aloisio, Lourdes M. Suarez, Cynthia A. Kleeberger, David L. Shore, Lisa A. DeRoo, Jack A. Taylor, Clarice R. Weinberg
Journal: Environmental Health Perspectives (2017)

Background: The Sister Study was designed to address gaps in the study of environment and breast cancer by taking advantage of more frequent breast cancer diagnoses among women with a sister history of breast cancer and the presumed enrichment of shared environmental and genetic exposures. Objective: The Sister Study sought a large cohort of women never diagnosed with breast cancer but who had a sister (full or half) diagnosed with breast cancer. Methods: A multifaceted national effort employed novel strategies to recruit a diverse cohort, and collected biological and environmental samples and extensive data on potential breast cancer risk factors. Results: The Sister Study enrolled 50,884 U.S. and Puerto Rican women 35–74y of age (median 56 y). Although the majority were non-Hispanic white, well educated, and economically well off, substantial numbers of harder-to-recruit women also enrolled (race/ethnicity other than non-Hispanic white: 16%; no college degree: 35%; household income <$50,000: 26%). Although all had a biologic sister with breast cancer, 16.5% had average or lower risk of breast cancer according to the Breast Cancer Risk Assessment Tool (Gail score). Most were postmenopausal (66%), parous with a first full-term pregnancy <30y of age (79%), never-smokers (56%) with body mass indexes (BMIs) of <29.9 kg/m2 (70%). Few (5%) reported any cancer prior to enrollment. Conclusions: The Sister Study is a unique cohort designed to efficiently study environmental and genetic risk factors for breast cancer. Extensive exposure data over the life-course and baseline specimens provide important opportunities for studying breast cancer and other health outcomes in women. Collaborations are welcome. https://doi.org/10.1289/EHP1923
Myeloma Cells Are Activated in Bone Marrow Microenvironment by the CD180/MD-1 Complex, Which Senses Lipopolysaccharide
Authors: Jiro Kikuchi, Yoshiaki Kuroda, Daisuke Koyama, Naoki Osada, Tohru Izumi, Hiroshi Yasui, Takakazu Kawase, Tatsuo Ichinohe, Yusuke Furukawa
Journal: Cancer Research (2018)

Abstract Multiple myeloma (MM) cells acquire dormancy and drug resistance via interaction with bone marrow stroma cells (BMSC) in a hypoxic microenvironment. Elucidating the mechanisms underlying the regrowth of dormant clones may contribute to further improvement of the prognosis of MM patients. In this study, we find that the CD180/MD-1 complex, a noncanonical lipopolysaccharide (LPS) receptor, is expressed on MM cells but not on normal counterparts, and its abundance is markedly upregulated under adherent and hypoxic conditions. Bacterial LPS and anti-CD180 antibody, but not other Toll-like receptor ligands, enhanced the growth of MM cells via activation of MAP kinases ERK and JNK in positive correlation with expression levels of CD180. Administration of LPS significantly increased the number of CD180/CD138 double-positive cells in a murine xenograft model when MM cells were inoculated with direct attachment to BMSC. Knockdown of CD180 canceled the LPS response in vitro and in vivo. Promoter analyses identified IKZF1 (Ikaros) as a pivotal transcriptional activator of the CD180 gene. Both cell adhesion and hypoxia activated transcription of the CD180 gene by increasing Ikaros expression and its binding to the promoter region. Pharmacological targeting of Ikaros by the immunomodulatory drug lenalidomide ameliorated the response of MM cells to LPS in a CD180-dependent manner in vitro and in vivo. Thus, the CD180/MD-1 pathway may represent a novel mechanism of growth regulation of MM cells in a BM milieu and may be a therapeutic target of preventing the regrowth of dormant MM cells. Significance: This study describes a novel mechanism by which myeloma cells are regulated in the bone marrow, where drug resistance and dormancy can evolve after treatment, with potential therapeutic implications for treating this often untreatable blood cancer. Cancer Res; 78(7); 1766–78. ©2018 AACR.
EFFECTS OF OBSTRUCTIVE SLEEP APNEA ON THE OUTCOMES OF ATRIAL FIBRILLATION: A NATIONWIDE ANALYSIS
Authors: Seyed Hamed Hosseini Dehkordi, Navid Gholitabar, Farid Gholitabar, Syed A. Ahsan, Shawn Lee, Alejandro Lemor, May Bakir, Davendra Mehta
Journal: Journal of the American College of Cardiology (2018)
Trends in Red Blood Cell, Plasma, and Platelet Transfusions in the United States, 1993-2014
Authors: Ruchika Goel, Meera R. Chappidi, Eshan U. Patel, Paul M. Ness, Melissa M. Cushing, Steven M. Frank, Aaron A. R. Tobian
Journal: JAMA (2018)

This study uses National Inpatient Sample survey data to characterize trends in red blood cell, plasma, and platelet transfusions in the United States between 1993 and 2014, a period of time during which trials were demonstrating the safety of restrictive red blood cell transfusion strategies.
Frequency and prognostic utility of MSI and TILs in advanced noncolorectal GI malignancies.
Authors: Uqba Khan, Ameer Hamza, Muhammad S Khurram, Renny Abraham, Paul Mazzara, Tarik H. Hadid, Zyad Kafri
Journal: Journal of Clinical Oncology (2018)

313 Background: Mismatch repair gene mutation status not only has a role in pathogenesis but also has significant clinical implications with respect to treatment with checkpoint inhibitors. Additionally tumor infiltrating lymphocytes (TILs) are also emerging prognostic biomarker and are utilized in adoptive T-cell therapy as well. Methods: This is a retrospective cohort study of patients who were diagnosed with advanced unresectable non-colorectal GI (NCGI) cancers. Biopsy specimens of patients diagnosed between 2009 and 2015 at St. John Hospital and Medical Center were analyzed. Immunohistochemistry panels were performed on a representative tissue sections for microsatellite instability (MSI) testing. TILs were assessed on the hematoxylin and Eosin stained slide of the same tissue section. MSI was interpreted as stable or high and TILs were categorized as ≤5 and &gt; 5 per high power field. Descriptive statistics were generated using frequency distributions, medians and means. Kaplan-Meier analysis was performed to determine the impact of TILs and MSI on survival; differences by factor were assessed with the Log_Rank test. Results: We analyzed 114 patients; the mean age at diagnosis was 66.8 ± 10.7 years, 61.4% were male. All samples were MSI stable. The percentage of patients with TILs ≤ 5 was 46.5. When stratified by tumor stage, overall median survival by TILs level did not differ significantly. When stratified by type of tumor, overall median survival by TILs level was significantly different only for hepatocellular cancers (HCC) (≤ 5 TILs, 86 days vs. &gt; 5 TILs 312 days, p = 0.031) only, (see table). Conclusions: Our study shows that MSI-H tumors are very rare in advanced NCGI malignancies. TILs are definitely present in tumor microenvironment of NCGI malignancies. Though the number of patients of our study was small, there was a statistically significant difference in median overall survival of patients with HCC when stratified by TILs status.[Table: see text]
Have your say in shaping the future of medical education, research and clinical practice
Authors: Tim Underwood
Journal: BMJ (2004)

E ditor In recent years, academic medicine has been placed under increasing pressure by international health service reforms, shortfalls in funding, and a lack of career stability. The explosion of molecular biology has compounded these problems, with large amounts of research funding now targeted towards basic science. In an attempt to help rectify this problem and bring together international partners and stakeholders, the BMJ Publishing Group launched a campaign to promote and revitalise academic medicine in November 2003.1 Since then, more than 40 …
Perspectives of prostate cancer patients about active surveillance.
Authors: Fred Saad, Margaret Fitch, Kittie Pang, Veronique Ouellet, Carmen Loiselle, Simone Chevalier, Darrel Drachenberg, Antonio Finelli, Simon Sutcliffe, Alan I. So, Simon Tanguay, Anne-Marie Mes-Masson
Journal: Journal of Clinical Oncology (2018)

82 Background: In prostate cancer (PC), men diagnosed with low risk disease may be monitored through an active surveillance (AS) approach that runs counter to the traditional message of undergoing treatment as soon as possible following a cancer diagnosis. This research explored the perspectives of men with PC regarding their decision-making process for AS to identify the factors that influenced their decision and assisted health care professionals in discussing AS as an option. Methods: Focus group interviews (n = 7) were held in several Canadian cities with men (n = 52) diagnosed with PC and eligible for AS. The men’s viewpoints were captured regarding their understanding of AS, the factors that influenced their decision to engage in AS, and their experience with the approach. A content and theme analysis was performed on the verbatim transcripts from the interviews. Results: All patients described the perception that their disease was not “large enough” to require treatment. They understood that the waiting process avoided the side effects associated with treatments, and they were comfortable about postponing treatment while undergoing close monitoring. Conversations with their doctor and how AS was described were cited as key influences in their decision. Other influences included availability of information on treatment options, distrust in the health system, personality, experiences and opinions of others, and personal perspectives on quality of life. Conclusions: AS is a relatively new approach for the care of men with low risk PC. Men require a thorough explanation on AS as a safe and valid option, as well as guidance towards supportive resources in their decision-making.
Heterogeneity in quality-of-life of patients before and after brain tumour surgery
Authors: William Sage, Rocio Fernandez Mendez, Beni Allen, Andrew Brodbelt, Stephen Price, Alexis J Joannides
Journal: Neuro-Oncology (2018)

Measurement of health-related quality of life (QoL) in brain tumour patients is increasingly recognised as a means of informing treatment decisions. On this background, we assessed the short-term impact of surgery on QoL across 2 UK neuroscience centres. Patients with a brain tumour were asked to complete the EORTC QLQ-30 with BN20 module at initial assessment and in their first post-operative appointment within 3 months of surgery. Wilcoxon rank sum and Wilcoxon signed rank tests were used to compare baseline scores between centres, and post-operative changes within patients respectively. A total of 57 patients were included in the analysis. There were comparable numbers from each site (29 and 28 respectively), with no significant differences between baseline demographics and tumour types between them. Time between completing the baseline questionnaire and surgery was similar, but the time from surgery to follow-up questionnaire differed between the sites (median[IQR]: 9[6–10] vs. 16[9–35], p=0.024). Baseline scores for global health status and the functional domains were similar across the sites, but significant differences were noted in symptom scores, including pain, communication deficit, headaches, itchy skin and hair loss. Post-operatively, there was no deterioration in global health status despite changes in other symptom scales. In both sites, there was a post-operative deterioration in physical and role functioning. In one site, there was deterioration in pain and headache but improvement in future uncertainty, while in the other there was a deterioration in social functioning but improvement in emotional functioning and nausea and vomiting. There is considerable variation in the QoL of neuro-oncology patients, both in baseline scores at initial diagnosis, as well as change in individual domains following surgery. This highlights the importance of measuring baseline and follow-up QoL dimensions as a means of enabling a bespoke care approach tailored to individual patient need.
Alan McGlennan, Consultant anaesthetist at the Royal Free Hospital, London
Authors: Nana Seiwaa Opare
Journal: BMJ (2008)

At preclinical level, we were never lectured by clinicians. Nowadays, many medical schools are electing to have them teach at this stage. The Royal College of Anaesthetists encourages anaesthetists to volunteer for teaching in physiology and pharmacology as they have thorough knowledge as well as real world experience. Academics are good, but the lectures can become stale. When a student puts up her hand and asks, “Is that really important?” a clinician can respond with experience. The relevance would then be better emphasised and appreciated.

Although I am relatively newly qualified, clinical teaching has changed and continues to change. Training is much more closely supervised now and trainees have “managed education,” competences to be signed off, logbooks to provide experience detail, and very rigid timetables containing clinical work …
Detecting Chemotherapeutic Skin Adverse Reactions in Social Health Networks Using Deep Learning
Authors: Julia D. Ransohoff, Azadeh Nikfarjam, Erik Jones, Brian Loew, Bernice Y. Kwong, Kavita Y. Sarin, Nigam H. Shah
Journal: JAMA Oncology (2018)

This study reports proof-of-principle early detection of chemotherapeutic-associated skin adverse drug reactions from social health networks using a deep learning–based signal generation pipeline to capture how patients describe cutaneous eruptions.
RCGP wins bid to extend GP training to four years
Authors: Helen Jaques
Journal: BMJ (2012)

The Royal College of General Practitioners has been successful in its bid to increase the length of GP training from three years to four years from 2014.

The proposals presented to the Medical Programme Board this week suggest increasing the amount of time GP trainees spend in general practice placements from 12 months to 24 months. Trainees should spend the other 24 months of training in placements in secondary care, community care, and general practice.

Chair of the college Clare Gerada has said she is “absolutely thrilled” with the outcome of the bid, describing Wednesday as “a momentous …
Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: Synopsis of the 2017 American College of Cardiology/American Heart Association Hypertension Guideline
Authors: Robert M. Carey, Paul K. Whelton
Journal: Annals of Internal Medicine (2018)

Description: In November 2017, the American College of Cardiology (ACC) and the American Heart Association (AHA) released a clinical practice guideline for the prevention, detection, evaluation, and treatment of high blood pressure (BP) in adults. This article summarizes the major recommendations. Methods: In 2014, the ACC and the AHA appointed a multidisciplinary committee to update previous reports of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. The committee reviewed literature and commissioned systematic reviews and meta-analyses on out-of-office BP monitoring, the optimal target for BP lowering, the comparative benefits and harms of different classes of antihypertensive agents, and the comparative benefits and harms of initiating therapy with a single antihypertensive agent or a combination of 2 agents. Recommendations: This article summarizes key recommendations in the following areas: BP classification, BP measurement, screening for secondary hypertension, nonpharmacologic therapy, BP thresholds and cardiac risk estimation to guide drug treatment, treatment goals (general and for patients with diabetes mellitus, chronic kidney disease, and advanced age), choice of initial drug therapy, resistant hypertension, and strategies to improve hypertension control.
Sonoanaesthesia: ultrasound guided regional anaesthesia
Authors: Andrew Brammar
Journal: BMJ (2012)

Ultrasound guided regional anaesthesia of upper and lower limb is a two day course run by consultants and senior registrars in anaesthesia who have a strong interest in regional anaesthesia. It is designed to provide anaesthetists with hands on experience of ultrasound anatomy and nerve block techniques.

The course is aimed at anaesthetists of all grades who want to perform nerve blocks under ultrasound guidance as part of their practice. It would also be useful for trainees who are preparing for the Final Examination of the Diploma of Fellowship of the Royal College of Anaesthetists.

I did the course in September 2011 as a specialty registrar year 5 in anaesthesia. The other delegates included …
RACIAL DIFFERENCES IN TRENDS OF ORTHOTOPIC HEART TRANSPLANTATION AND LEFT VENTRICULAR ASSIST DEVISE: IMPACT OF MEDICAID CUTS ON END-STAGE HEART FAILURE LANDSCAPE
Authors: Nirav Patel, Rajat Kalra, Rajkumar Doshi, Navkaranbir Bajaj, Garima Arora, Pankaj Arora
Journal: Journal of the American College of Cardiology (2018)