tbuckley/cabot-search huggingface dataset:
Rise in GP funding will not tackle long term under-resourcing, BMA says
Authors: Tom Moberly
Journal: BMJ (2015)

The rise in GP funding for 2015-16 will not help with the long term problem of under-resourcing or the wider issues facing the primary care workforce, the BMA has warned.

Last week the government accepted the recommendation of the Review Body on Doctors’ and Dentists’ Remuneration (DDRB) to increase GPs’ pay by 1% for 2015-16. …
Safety, Activity, and Biomarkers of SHR-1210, an Anti-PD-1 Antibody, for Patients with Advanced Esophageal Carcinoma
Authors: Jing Huang, Binghe Xu, Hongnan Mo, Weilong Zhang, Xuelian Chen, Dawei Wu, Dong Qu, Xingyuan Wang, Bo Lan, Beibei Yang, Pei Wang, Hongtu Zhang, Qing Yang, Yuchen Jiao
Journal: Clinical Cancer Research (2018)

Purpose: The current management of advanced esophageal squamous cell carcinoma (ESCC) remains unsatisfactory. We investigated the safety, efficacy, and biomarkers of SHR-1210, an anti-PD-1 antibody, in patients with recurrent or metastatic ESCC.Experimental Design: This study was part of a phase I trial in China. Patients with advanced ESCC who were refractory or intolerant to previous chemotherapy were enrolled. Eligible patients received intravenous SHR-1210 at a dose of 60 mg, with escalation to 200 and 400 mg (4-week interval after first dose followed by a 2-week schedule) until disease progression or intolerable toxicity. The associations between candidate biomarkers (PD-L1 and somatic mutation load) and the efficacy of SHR-1210 were also explored.Results: Between May 11, 2016, and December 9, 2016, a total of 30 patients from one site in China were enrolled. Ten patients (33.3%) had an independently assessed objective response. Median progression-free survival was 3.6 months (95% CI, 0-7.2). Three (10.0%) treatment-related grade 3 adverse events were reported: two (6.7%) pneumonitis and one (3.3%) increased cardiac troponin I. No grade 4 or grade 5 treatment-related adverse events were reported. The exome sequencing and analysis showed that the mutational burden and the potential mutation-associated neoantigen count were associated with better responses. An objective response was more common in patients with PD-L1-positive tumors as defined by ≥5% staining (7 of 15 patients) than in those with PD-L1-negative tumors (1 of 9 patients).Conclusions: In this population of ESCC patients, SHR-1210 had a manageable safety profile and promising antitumor activity. Clin Cancer Res; 24(6); 1296-304. ©2018 AACR.
Proximity to Parental Symptom Onset and Amyloid-β Burden in Sporadic Alzheimer Disease
Authors: Sylvia Villeneuve, Jacob W. Vogel, Julie Gonneaud, Alexa Pichet Binette, Pedro Rosa-Neto, Serge Gauthier, Randall J. Bateman, Anne M. Fagan, John C. Morris, Tammie L. S. Benzinger, Sterling C. Johnson, John C. S. Breitner, Judes Poirier
Journal: JAMA Neurology (2018)

Alzheimer disease (AD) develops during several decades. Presymptomatic individuals might be the best candidates for clinical trials, but their identification is challenging because they have no symptoms.To assess whether a sporadic parental estimated years to symptom onset calculation could be used to identify information about amyloid-β (Aβ) levels in asymptomatic individuals with a parental history of AD dementia.This cohort study analyzed Aβ1-42 in cerebrospinal fluid (CSF) specimens from 101 cognitively normal individuals who had a lumbar puncture as part of the Presymptomatic Evaluation of Novel or Experimental Treatments for Alzheimer Disease (PREVENT-AD) cohort from September 1, 2011, through November 30, 2016 (374 participants were enrolled in the cohort during this period). The study estimated each participant's proximity to his/her parent's symptom onset by subtracting the index relative's onset age from his/her current age. The association between proximity to parental symptom onset and Aβ levels was then assessed using apolipoprotein E ε4 (APOE4) status and sex as interactive terms. These analyses were performed again in 2 independent cohorts using CSF and Pittsburgh compound B carbon 11-labeled positron emission tomography (PIB-PET) Aβ biomarkers: the Adult Children Study (ACS) and the Wisconsin Registry for Alzheimer Prevention (WRAP) cohorts.The association between proximity to parental symptom onset and Aβ burden in asymptomatic individuals with a parental history of sporadic AD.The present analysis included a subset of 101 PREVENT-AD individuals (mean [SD] age, 61.8 [5.1] years; 30 [29.7%] male), 128 ACS participants (112 participants underwent CSF measurement: mean [SD] age, 63.4 [5.1] years; 31 [27.7%] male; and 107 underwent PIB-PET: mean [SD] age, 64.6 [5.3] years; 27 [25.2%] male), and 135 WRAP participants (85 participants underwent CSF measurement: mean [SD] age, 59.9 [6.0] years; 27 [31.8%] male; and 135 underwent PIB-PET: mean [SD] age, 59.6 [6.1] years; 43 [31.9%] male). In the PREVENT-AD cohort, individuals approaching their parent's onset age had lower CSF Aβ1-42 levels (range, 402-1597; B = -9.09, P = .04). This association was stronger in APOE4 carriers (B = -17.9, P = .03) and women (B = -19.8, P = .02). In the ACS cohort, the main association was replicated using PIB-PET data, and the sex interaction was replicated using CSF and PIB-PET data. In the WRAP cohort, the results were not replicated using cross-sectional data, but the main association and the APOE interaction were replicated using PIB-PET longitudinal data.These results suggest that proximity to parental symptom onset may help estimate Aβ biomarker changes in women or APOE4 carrier asymptomatic individuals with a parental history of sporadic AD.
NICE, the NHS, and Cancer Drugs
Authors: Andrew Dillon, Linda J. Landells
Journal: JAMA (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Assumptions are dangerous
Authors: William C Fraser
Journal: BMJ (2005)

Dr Chambers' points are useful1 but I feel that point 2 on shortlisting, although undoubtedly meant kindly, would be better omitted. I agree that people should not be interviewed to be “fair”, but only if they meet the person specification for the job. If an applicant is disabled under the terms of the Disability Discrimination Act and you did not shortlist them for a reason related …
Synergy of optimized administration sequence and timing of active DC immunotherapy with a PD1 checkpoint inhibitor in a mouse model of renal cell carcinoma.
Authors: Olga A. Zubkova, Larissa S. Agapova, Armen A. Ovsepyan, Vilena Ivanova, Elmira Zeynalova, Maxim V. Lykov, Artem V. Eremeev, Andrey P. Karpov, Sergey V. Ruchko, Charles A. Nicolette, Alexander M. Shuster
Journal: Journal of Clinical Oncology (2018)

31 Background: AGS-003 is an immunotherapy consisting of autologous dendritic cells electroporated with amplified total tumor RNA plus synthetic CD40L RNA and is currently being tested in combination with standard of care to extend survival of newly diagnosed metastatic renal cell carcinoma (RCC) patients in the Phase 3 ADAPT clinical trial. We set out to establish a model system based on the Renca mouse model to more thoroughly study the AGS-003 mechanism of action and identify optimal combination therapies, including with a PD1 checkpoint inhibitor (aPD1 CPI). Methods: Mouse DC precursors were processed in a similar manner to how human monocytes are processed to manufacture AGS-003. Mature DCs were injected s.c. to treat BALB/c mice in an orthotopic syngeneic RCC model. This model system was utilized to test the efficacy and mechanism of action of the AGS-003-like homologous mouse DCs in combination with a murine monoclonal antibody PD1 CPI (anti-mPD1). Results: Murine DCs with similar properties to AGS-003 in combination with anti-mPD1 and sunitinib, resulted in recruitment and migration of lymphocytes into the tumor microenvironment and an increase in peripheral blood CD8+CD28+CD45RA- memory T cells in vivo. Multiple combination dosing strategies were tested and only one dosing regimen (DCs administered prophylactically followed by aPD1 mAb administered therapeutically) showed a substantial synergistic effect (67 days median OS) while all other DC/aPD1 dosing combinations did not exceed the efficacy of DC monotherapy treatment (44.5-48 days median OS). Control animals treated with PBS had a median OS of 29 days. Conclusions: These data demonstrate the importance of the administration sequence for active immunotherapy and aPD1 CPI combination therapy. Our data suggest that the cellular immune response must be initiated and established prior to administration of the aPD1 CPI/sunitinib combination therapy in order to observe synergy in this RCC mouse model. This model may be useful to explore additional combination therapies and effective treatment regimens with other therapeutic agents to guide future clinical development.
A career in cardiology
Authors: Tushar Kotecha, Sabira Mohammad
Journal: BMJ (2012)

The career in cardiology course is a one day symposium run by the British Cardiovascular Society. In 2011 it was held on 18 February at the Hilton Hotel in Coventry and was timed to precede the national specialty trainee 3 (ST3) recruitment process.

The symposium covers the application process for higher specialty training in cardiology and offers an insight into the subspecialties of cardiology. It is an opportunity to obtain advice and opinions on cardiology ST3 recruitment from people who are highly experienced in the field and involved in the recruitment process.

The symposium was developed by Aung Myat (clinical research fellow for the National Institute for Health Research and specialist registrar in cardiology at Guy’s and St Thomas’ NHS Foundation Trust), Simon Redwood (professor of interventional cardiology at Guy’s and St Thomas’), and Tony Gershlick (professor of interventional cardiology at University Hospitals of Leicester NHS Trust). The faculty included prominent cardiologists from …
Hypercalcaemia in Primary Squamous Cell Carcinoma of the Stomach
Authors: G C Raju, E N Barton, D Marchack, V Naraynsingh
Journal: Journal of the Royal Society of Medicine (1987)

Hypercalcaemia associated with neoplastic disease is well recognized 1,2 , and has potentially serious consequences if not corrected promptly. We report a case of primary squamous cell carcinoma of the stomach associated with hypercalcaemia, an association that seems not to have been reported previously.
Abstract P4-10-11: An active approach to genetic counseling in Trinidadian women with breast cancer
Authors: SH George, GL Bravo, AC Sandoval, S Palacio, J Ali, TR Donenberg, MR Akbari, S Narod, J Hurley
Journal: Cancer Research (2018)

Abstract Introduction Breast cancer (BC) is the leading cause of cancer death in Caribbean women. The prevalence of deleterious mutations in BRCA1/2, PALB2 and RAD51C among unselected BC patients in the Caribbean is 5-25%. We previously reported data on low usage of genetic counseling services by Bahamian women. In order to improve the dissemination of genetic testing results to Caribbean probands and their families we developed a structured approach to genetic test result dissemination and family counseling. Methods After approval by the University of Miami IRB and the Ethics Committee of the Ministry of Health of Trinidad &amp; Tobago, we prospectively evaluated the active approach to genetic counseling in 32 BC mutation carriers in Trinidad &amp; Tobago in 2015. The intervention consisted of: 1) initial appointment with referring oncologist for results discussion; 2) review of family tree with proband to identify all relatives at 25% or 50% risk (ARR) who should attend the genetic counseling session; 3) preschedule a counseling appointment for ARR within 2 weeks; 4) written invitation to genetic counseling session; 5) handouts of genetic information given to proband to distribute to family members; 6) offer assistance with contacting family members; 7) free genetic testing to ARR who attended the family counseling session. Results Twenty-five carriers (78%) consented to enroll in the study. At initial counseling, probands identified 158 ARR, however full family pedigree review at post-result counseling/consultation identified 225 ARR. 101 ARR (64%) attended the information sessions and 76 participants (75.2%) consented to be tested for BC gene mutations. Genetic sequencing revealed 35 ARR (46%) were carriers of at least one mutation. The most frequent reasons for ARR not attending the meetings were: living abroad (18%), unable to be contacted (17%), refusing to participate (17%), not showing up (17%), probands being estranged from ARR (12%) or being afraid to know the results (7%). Conclusions In Trinidad &amp; Tobago, a structured approach to the dissemination of genetic test results leads to a significant improvement in the rate of family participation compared to previous efforts (64% in Trinidad &amp; Tobago vs. 9% in the Bahamas). Citation Format: George SH, Bravo GL, Sandoval AC, Palacio S, Ali J, Donenberg TR, Akbari MR, Narod S, Hurley J. An active approach to genetic counseling in Trinidadian women with breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-10-11.
Exosomal miRNA signature of pancreatic cyst: Liquid biopsies as indicators of pancreatic cancer.
Authors: Virendra Joshi, Dominic Guanzon, Cris Molina, Zarin Nuzhat, Gregory Rice, Carlos saloman Gallo
Journal: Journal of Clinical Oncology (2018)

225 Background: Pancreatic cysts are a group of lesions with malignant potential. Currently, there are no consistently reliable biomarkers or imaging modalities to accurately predict biologic behavior of these cysts. We tested the hypothesis that tumor-derived exosomes (better conserved than free miRNA) can be acquired endoscopically from pancreatic cyst fluid and may allow for improved distinction between benign, premalignant and malignant cysts. Methods: Exosomes were isolated and characterised by differential and buoyant centrifugation from pancreatic cyst fluid obtained from 30 patients with pseudocysts (PS), serous cystic (SC), mucinous cysts (MC), intraductal papillary mucinous neoplasms (IPMN), pancreatitis (PA), and pancreatic cancer (PC) , confirmed with imaging and histology. An Illumina TruSeq Small RNA kit was used to construct a small RNA library, and the libraries were sequenced using the Illumina NextSeq 500 platform. The resulting sequencing FASTQ files were analyzed using miRDeep2 to identify both known and novel miRNAs. Results: Four significant miRNAs which are shared between six of the analyses, specifically hsa-miR-199b-3p, hsa-miR-199a-2-3p, hsa-miR-199a-1-3p and hsa-let-7i-5p were identified. MiRNA hsa-miR-27a-3p was significant and shared between five of the analyses. A total of 15, 12 and 2 significant miRNAs were shared between four, three and two of the analyses, respectively. Importantly, there were a total of 10 significant miRNAs which were unique to each analysis, with the exception of IPMN vs Pseudocyst, and Pancreatic cancer vs Pancreatitis. Specifically these unique miRNAs for each analysis are: hsa-miR-92a-2-3p (Pancreatitis vs Pseudocyst); hsa-miR-92a-1-3p (Serous vs Pseudocyst); hsa-miR-30e-5p (Pancreatic cancer vs Serous), hsa-miR-30b-5p (IPMN vs Pancreatic cancer); and hsa-miR-23b-3p, hsa-miR-99b-5p, hsa-miR-222-3p, hsa-miR-31-5p, hsa-miR-151a-5p, hsa-miR-221-3p (Pancreatic cancer vs. Pseudocyst). Conclusions: Exosomal miRNAs in pancreatic fluid may be used as a biomarker to differentiate between various cyst types and pancreatic cancer. A larger cohort with miRNA quantification and is needed to further validate these findings .
Report on suicides of doctors under GMC investigation planned for publication in September
Authors: Abi Rimmer
Journal: BMJ (2014)

A report on doctors who have taken their own lives while under investigation by the General Medical Council is being prepared for publication in September.

Last year the GMC announced that it was carrying out a review, led by Sarndrah Horsfall, formerly interim chief executive of the National Patient Safety Agency, into cases where doctors had killed themselves while going through fitness …
Sense-Antisense lncRNA Pair Encoded by Locus 6p22.3 Determines Neuroblastoma Susceptibility via the USP36-CHD7-SOX9 Regulatory Axis
Authors: Tanmoy Mondal, Prasanna Kumar Juvvuna, Agnete Kirkeby, Sanhita Mitra, Subazini Thankaswamy Kosalai, Larissa Traxler, Falk Hertwig, Sara Wernig-Zorc, Caroline Miranda, Lily Deland, Ruth Volland, Christoph Bartenhagen, Deniz Bartsch, Sashidhar Bandaru, Anne Engesser, Santhilal Subhash, Tommy Martinsson, Helena Carén, Levent M. Akyürek, Leo Kurian, Meena Kanduri, Maite Huarte, Per Kogner, Matthias Fischer, Chandrasekhar Kanduri
Journal: Cancer Cell (2018)
Zeb1 in Stromal Myofibroblasts Promotes <i>Kras</i>-Driven Development of Pancreatic Cancer
Authors: Irene Sangrador, Xavier Molero, Fiona Campbell, Sebastià Franch-Expósito, Maria Rovira-Rigau, Esther Samper, Manuel Domínguez-Fraile, Cristina Fillat, Antoni Castells, Eva C. Vaquero
Journal: Cancer Research (2018)

The transcription factor Zeb1 has been identified as a crucial player in Kras-dependent oncogenesis. In pancreatic ductal adenocarcinoma (PDAC), Zeb1 is highly expressed in myofibroblasts and correlates with poor prognosis. As Kras mutations are key drivers in PDAC, we aimed here to assess the necessity of Zeb1 for Kras-driven PDAC and to define the role of Zeb1-expressing myofibroblasts in PDAC development. Genetically engineered mice with conditional pancreatic KrasG12D and Trp53 mutations (KPC) were crossed with Zeb1 haploinsufficient mice (Z+/-). Extensive PDAC was prominent in all 20-week-old KPC;Z+/+ mice, whereas only low-grade precursor lesions were detected in age-matched KPC;Z+/- littermates, with PDAC developing eventually in KPC;Z+/- aged animals. Zeb1 expression in myofibroblasts occurred early in tumorigenesis and Zeb1 haploinsufficiency retarded native expansion of stromal myofibroblasts during precursor-to-cancer progression. Zeb1 downregulation in mPSC repressed their activated gene profile, impaired their migratory and proliferative activity, and attenuated their tumor-supporting features. Conditioned media from Z+/+ mouse-activated (myofibroblast-like) pancreatic stellate cells (mPSC) boosted Ras activity in pancreatic cancer cells carrying mutant Kras; this effect was not observed when using conditioned media from Z+/- mPSC, revealing a paracrinal cooperative axis between Zeb1-expressing PSC and oncogenic Kras-bearing tumor cells. We conclude that Zeb1-expressing stromal myofibroblasts enable a heterotypic collaboration with the Kras-fated epithelial compartment, thus supporting pancreatic malignancy.Significance: Zeb1 expression in stromal myofibroblasts supports PDAC development via collaboration with the epithelial compartment bearing oncogenic Kras mutations. Cancer Res; 78(10); 2624-37. ©2018 AACR.
Association of Sulindac and Erlotinib vs Placebo With Colorectal Neoplasia in Familial Adenomatous Polyposis
Authors: N. Jewel Samadder, Scott K. Kuwada, Kenneth M. Boucher, Kathryn Byrne, Priyanka Kanth, Wade Samowitz, David Jones, Sean V. Tavtigian, Michelle Westover, Therese Berry, Kory Jasperson, Lisa Pappas, Laurel Smith, Danielle Sample, Randall W. Burt, Deborah W. Neklason
Journal: JAMA Oncology (2018)

<h3>Importance</h3> Patients with familial adenomatous polyposis (FAP) are at markedly increased risk for colorectal polyps and cancer. A combination of sulindac and erlotinib led to a 71% reduction in duodenal polyp burden in a phase 2 trial. <h3>Objective</h3> To evaluate effect of sulindac and erlotinib on colorectal adenoma regression in patients with FAP. <h3>Design, Setting, and Participants</h3> Prespecified secondary analysis for colorectal adenoma regression was carried out using data from a double-blind, randomized, placebo-controlled trial, enrolling 92 patients with FAP, conducted from July 2010 to June 2014 in Salt Lake City, Utah. <h3>Interventions</h3> Patients were randomized to sulindac, 150 mg twice daily, and erlotinib, 75 mg daily (n = 46), vs placebo (n = 46) for 6 months. <h3>Main Outcomes and Measurements</h3> The total number of polyps in the intact colorectum, ileal pouch anal anastomosis, or ileo-rectum were recorded at baseline and 6 months. The primary outcomes were change in total colorectal polyp count and percentage change in colorectal polyps, following 6 months of treatment. <h3>Results</h3> Eighty-two randomized patients (mean [SD] age, 40 [13] years; 49 [60%] women) had colorectal polyp count data available for this secondary analysis: 22 with intact colon, 44 with ileal pouch anal anastomosis and 16 with ileo-rectal anastomosis; 41 patients received sulindac/erlotinib and 41 placebo. The total colorectal polyp count was significantly different between the placebo and sulindac-erlotinib group at 6 months in patients with net percentage change of 69.4% in those with an intact colorectum compared with placebo (95% CI, 28.8%-109.2%;<i>P</i> = .009). <h3>Conclusion and Relevance</h3> In this double-blind, placebo-controlled, randomized trial we showed that combination treatment with sulindac and erlotinib compared with placebo resulted in significantly lower colorectal polyp burden after 6 months of treatment. There was a reduction in polyp burden in both those with an entire colorectum and those with only a rectal pouch or rectum. <h3>Trial Registration</h3> clinicaltrials.gov Identifier:NCT01187901
Call for duty of candour in Northern Ireland after doctors found unwilling to admit errors
Authors: Anne Gulland
Journal: BMJ (2018)

The chair of an inquiry into the deaths of five children in hospitals in Northern Ireland has called for the introduction of a duty of candour after finding that doctors and managers were unwilling to admit to errors.1

In his final report into the children’s deaths Mr Justice O’Hara said recommendations on transparency and openness had “proved inadequate.”

He was damning of the attitude of some doctors and health service managers.

“It is time that the medical profession and health service managers stopped putting their own reputations and interests first and put the public interest first,” he said.

O’Hara highlighted how difficult it was to “persuade some …
Using doctors inappropriately
Authors: A A Ahmad
Journal: BMJ (2004)

Editor—A lot of doctors in the NHS, particularly in surgical branches, are working as locum registrars and waiting to obtain a trainee spot—the so-called “stuck doctors.” Many of these are foreign graduates and in some cases are fully trained in their country of origin. They amount to a large part of the workforce but as some of them are older and do not have structured research experience they cannot compete with other applicants for …