tbuckley/cabot-search huggingface dataset:
A Novel<i>PRKAR1B-BRAF</i>Fusion in Gastrointestinal Stromal Tumor Guides Adjuvant Treatment Decision-Making During Pregnancy
Authors: Lindsey M. Charo, Adam M. Burgoyne, Paul T. Fanta, Hitendra Patel, Juliann Chmielecki, Jason K. Sicklick, Michael T. McHale
Journal: Journal of the National Comprehensive Cancer Network (2018)

Gastrointestinal stromal tumors (GISTs) are rare in pregnancy, with only 11 reported cases. Adjuvant imatinib therapy, which targets the most common driver mutations in GIST (KIT and PDGFRA), is recommended for patients with high-risk GIST, but it has known teratogenicity in the first trimester. A 34-year-old G3P2 woman underwent exploratory laparotomy at 16 weeks' gestation for a presumed adnexal mass. Surgical findings included normal adnexa and a 14-cm solid small bowel mass. The mass was resected en bloc with a segment of jejunum followed by a primary anastomosis. Histopathology and genomic analyses demonstrated a GIST with high-risk features but lack of KIT/PDGFRA mutations and identified the presence of a previously unreported, pathogenic PRKAR1B-BRAF gene fusion. Given her tumor profile, adjuvant therapy with imatinib was not recommended. GIST is rare in pregnancy, but can masquerade as an adnexal mass in women of childbearing age. Because neoadjuvant/adjuvant imatinib has risks of teratogenicity, tumor molecular profiling is critical as we identified a previously unreported gene fusion of PRKAR1B with BRAF that is predicted to be imatinib-resistant. In this case, testing provided the rationale for not offering adjuvant imatinib to avoid unnecessary toxicity to the patient and fetus.
IMPACT OF LESION PREPARATION STRATEGIES ON OUTCOMES OF LEFT MAIN PCI: THE EXCEL TRIAL
Authors: Nirat Beohar, Shmuel Chen, Nicholas Lembo, Adrian Banning, Patrick W.J. C. Serruys, Martin B. Leon, Marie Morice, Philippe Genereux, David Kandzari, A. Kappetein, Joseph F. Sabik, Ovidiu Dressler, Thomas McAndrew, Gregg Stone
Journal: Journal of the American College of Cardiology (2018)
Prospective, multicenter, noninterventional and registry clinical study of apatinib in patients with advanced gastric cancer.
Authors: Chunmei Bai, Diansheng Zhong, Ruixing Zhang, Xiubao Ren, Likun Liu, Nan Du, Junyan Yu, Mudan Yang, Aimin Zang, Jianfeng Diao, Yuchuan Ren, Zhanzhao Fu, Liwen MA, Lei Zhang, Jinghua Gao, Guozhong Li, Jun Guo, Junping Zhang, Junmei Jia, Wenzheng Zhang
Journal: Journal of Clinical Oncology (2018)

137 Background: The aim of this study was to observe the safety of apatinib in the real world with wider inclusion criteria. The efficacy of apatinib was evaluated including overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR). Methods: This trial enrolled patients from 32 centers in china with advanced gastric adenocarcinoma who had progressed after undergoing at least two lines of systemic chemotherapy, or patients who were considered to benefit from the treatment. We recommended starting from oral administration of 500mg qd, 28 days for a cycle. Dose could be appropriately adjusted according to the patients’ physical condition. Results: Between March 2015 and September 2017, 326 patients were enrolled. The average age was 62 years old, and the ratio of male to female was about 2:1. Patients received perioperative, first-line, second-line, and third-line or more treatment were 1,39,69 and 217 people respectively. There were 192 patients received efficacy evaluation, 9 patients achieved partial response(PR), 125 had disease stability(SD). The ORR and DCR were 4.6% and 69.8% respectively. The median PFS and median OS were 3.7 months and 7.3 months respectively. In the 326 patients, there were 153 patients with initial dose of 500 mg, 3 and 55 patients achieved PR and SD, respectively. The ORR and DCR were 3.3% and 63.7%, respectively. The median PFS and median OS were 3.5 months and 8.4 months, respectively. There were 237 patients in all 326 patients received safety analysis. Common adverse events were hypertension (57%), hand-foot skin reactions (26.6%), fatigue (29.5%), proteinuria (19.0%), bleeding (10.1%) and diarrhea (8.0%). The grade 3 to 4 adverse events were hypertension (6.3%), hand-foot skin reactions (3.8%), proteinuria(3.0%) and bleeding (2.1%). Conclusions: This real-world data in which more patients were given apatinib 500mg or less qd showed similar efficacy to Phase III clinical trial (850mg qd).The incidence of adverse events was consistent with that of Phase III clinical data,there was no new adverse events had been seen. Clinical trial information: NCT02668380.
Regulator starts review of MRCGP pass rate amid claims of bias
Authors: Caroline White
Journal: BMJ (2013)

The General Medical Council has begun an independent review of the pass rates for membership of the Royal College of General Practitioners (MRCGP) examinations, amid concerns that doctors who trained overseas and those of ethnic minority origin are more likely to fail.

Earlier this month the British Association of Physicians of Indian Origin started legal proceedings against the RCGP and the GMC, after talks with the college had failed to resolve its concerns, the association said.

It alleges that the MRCGP exam unlawfully discriminates against international GP trainees, on the grounds that the significant difference in pass rates cannot be explained by a lack of knowledge, skill, or competency.

RCGP …
The GP Contract Made Easy: Getting Paid
Authors: Bill Irish
Journal: BMJ (2005)

Rodger Charlton

Radcliffe Publishing Ltd, 2005, £23.50, 165 pages

ISBN 1-85775-632-0

Rating: ⋆⋆⋆⋆/5



OK, its time to come clean. Like most GPs I know, I still don't understand much of the new general medical services (GMS) contract. The opportunity after 20 long years to drop out of on-call got my vote—at the time the remainder just seemed to be mere details.

Sadly, as a partner in my practice, it has gradually dawned on me that continued ignorance isn't really a viable option. …
Utilization and survival implications of a delayed approach to targeted therapy for metastatic renal cell carcinoma: A nationwide cancer registry study.
Authors: Solomon L. Woldu, Justin T. Matulay, Timothy N Clinton, Nirmish Singla, Yuval N Freifeld, Oner N Sanli, Laura-Maria Krabbe, Ryan C Hutchinson, Yair Lotan, Hans J. Hammers, Raquibul Hannan, James Brugarolas, Aditya Bagrodia, Vitaly Margulis
Journal: Journal of Clinical Oncology (2018)

586 Background: Targeted therapy (TT) is the first-line option for metastatic renal cell carcinoma (mRCC) however, it is not curative and associated with a high-cost and adverse events. Preliminary data suggests TT may be safely delayed in appropriately selected patient, however the utilization and impact of delayed TT has not been evaluated on larger-scale. Methods: The National Cancer Database (NCDB) was queried from 2006-2012 for patients with mRCC treated with cytoreductive nephrectomy and TT. Time to initiation of TT was defined as ‘early’ (within 2 months), ‘moderately delayed’ (2-4 months), and ‘delayed’ (4-6 months), and ‘late’ ( &gt; 6 months) based on time from diagnosis to initiation of therapy. Multivariable logistic regression was performed to determine factors associated with delayed TT. The impact time to initiation of TT on OS was estimated by Kaplan-Meier and Cox multivariable survival analysis. Results: For2,716 patients in the analysis, the median (interquartile range [IQR]) follow-up was 18.8 (9.1-32.9) months, and 71.8% of patients had died at last follow-up. The median (IQR) time from diagnosis to initiation of TT was 2.1 (1.3-3.23) months, with the longest delay being 20.1 months. 1,255 patients (46.2%) had early TT, 1,072 patients (39.5%) had moderately delayed TT, 284 patients (10.5%) had delayed TT, and 105 patients (3.9%) had late TT. Delay in TT was not found to be a predictor of mortality in multivariable analysis; early TT (reference), moderately delayed TT (HR 0.98, p = 0.74), delayed TT (HR 0.95, p = 0.51), and late TT (HR 0.86, p = 0.20). Time from diagnosis to initiation of TT and time from initiation of TT to patient death were not correlated after control for covariates ( r= 0.04, p = 0.08). Conclusions: Delay in initiation of TT for mRCC was not an independent predictor of worse OS. Although this study is subject to limitations of observation study design and selection bias, the results are consistent with the notion that in carefully selected patients, outcomes might not be compromised with initial observation. Prospective, randomized evaluation is warranted.
All doctors must be able to recognise children at risk of trafficking, FGM, or radicalisation, royal colleges say
Authors: Abi Rimmer
Journal: BMJ (2014)

All doctors and other health staff must be able to recognise children at risk of maltreatment or neglect, including trafficking, female genital mutilation (FGM), or radicalisation, a group of medical royal colleges and professional bodies have said. 

A report jointly published by the royal colleges and professional bodies said that clinicians must clearly understand their responsibilities around safeguarding children and young people and that they should be supported …
Abstract BS2-2: The perivascular niche protects dormant disseminated tumor cells from therapy
Authors: CM Ghajar
Journal: Cancer Research (2018)

Abstract In a significant fraction of breast cancer patients, distant metastases emerge after years or even decades of latency. How disseminated tumor cells (DTCs) are kept dormant, and what wakes them up, are fundamental problems in tumor biology. To address these questions, we use metastasis assays in mice and zebrafish and have determined that the perivascular niche of distant sites like the lung, bone marrow and brain regulate DTC dormancy. We have developed organotypic microvascular niches to specify that endothelial cells regulate breast cancer cell growth, and applied proteomics to identify endothelial-derived mediators of DTC dormancy. More recently, we have begun to explore whether the perivascular niche confers therapeutic resistance to DTCs. I will present data that suggests strongly that the perivascular niche regulates therapeutic resistance of DTCs in a manner that is independent from its role in regulating DTC growth. We have uncovered mediators of perivascular signaling that, when targeted, cause dormant DTCs to respond robustly to chemotherapy. Critically, inhibiting these mediators causes chemosensitization without inducing dormant DTCs to re-enter the cell cycle. We are currently testing this treatment paradigm in pre-clinical models to determine the efficacy in killing dormant DTCs through this approach. I will discuss pre-clinical trial design and important caveats to accurately gauging whether eradication of dormant DTCs significantly prolongs metastasis-free survival. Citation Format: Ghajar CM. The perivascular niche protects dormant disseminated tumor cells from therapy [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 BS2-2.
Dietary fat is a key determinant in balancing mitochondrial dynamics in heart failure: a novel mechanism underlying the obesity paradox
Authors: Matteo De Rosa, Jessica Gambardella, Jun Shu, Gaetano Santulli
Journal: Cardiovascular Research (2018)

This editorial refers to 'Enhancing fatty acid utilization ameliorates mitochondrial fragmentation and cardiac dysfunction via rebalancing optic atrophy 1 processing in the failing heart' by Y. Guo et al., pp.979-991.The heart is able to catabolize different substrates in order to meet its high metabolic demand.Such flexibility is crucial to face variations in workload and/or substrate availability and preserve an adequate ejection of blood.Conversely, in heart failure (HF), the heart develops a metabolic inflexibility characterized by shifts in metabolism, leading to impaired metabolic signalling and contractile dysfunction.
Genomics-driven precision medicine for advanced pancreatic ductal carcinoma (PDAC): Early results from the COMPASS trial (NCT02750657).
Authors: Kyaw Lwin Aung, Sandra Fischer, Rob Denroche, Gun Ho Jang, Anna Dodd, Sean Creighton, Grainne M. O'Kane, Hamzeh Albaba, Shari Moura, Spring Holter, Richard Moffitt, Jen Jen Yeh, Paul Krzyzanowski, Neesha C. Dhani, David W. Hedley, Faiyaz Notta, Julie Wilson, Malcolm J. Moore, Steven Gallinger, Jennifer J. Knox
Journal: Journal of Clinical Oncology (2018)

211 Background: COMPASS is a prospective study with the primary aim to identify predictive mutational and transcriptional features in advanced PDAC for improved patient stratification and treatment selection. Methods: Patients with advanced PDAC were prospectively recruited prior to first-line combination chemotherapy for whole genome sequencing (WGS) and RNA sequencing (RNASeq). Fresh tumor tissue was acquired by image guided percutaneous core needle biopsy of locally advanced primary or metastatic tumors. Laser capture microdissection was performed for all cases to ensure high-resolution genomic analyses. Primary endpoint was feasibility to report WGS results prior to first disease assessment CT scan at 8 weeks. The main secondary endpoint was discovery of patient subsets with predictive mutational and transcriptional signatures. Results: Of 63 patients who underwent a tumor biopsy between December 2015 and June 2017, WGS and RNASeq were successful in 62 (98%) and 60 (95%), respectively. Genomic results were reported at a median of 35 days (range 19-52 days) from biopsy, meeting the primary feasibility endpoint. Three patients with an ‘unstable’ genomic subtype, including two with a novel ‘duplicator’ phenotype, responded well to m-FOLFIRINOX. Of two cases with the same germline BRCA2 mutation, only the chemotherapy responder had loss of heterozygosity and genomic hallmarks of double stranded break repair deficiency. Approximately 25% of tumors displayed the basal-like RNA expression signature and these were chemotherapy resistant, with tumor shrinkage mainly observed in those with the classical RNA subtype (P = 0.003). Thirty percent of patients had potentially actionable genetic alterations. Conclusions: Prospective comprehensive genomic profiling of advanced PDAC is feasible and our early data indicate that chemotherapy response differs among patients with different genomic/transcriptomic subtypes providing the impetus for further studies. Clinical trial information: NCT02750657.
BCL2 Expression Identifies a Population with Unmet Medical Need in Previously Untreated (1L) Patients with DLBCL
Authors: Edith Szafer-Glusman, Franklin V. Peale, Guiyuan Lei, Anja Mottok, Pedro Farinha, Jill Ray, Thalia A. Farazi, Martin Kornacker, Mikkel Z. Oestergaard, Juan Liu, Randy D. Gascoyne, Elizabeth Punnoose
Journal: Blood (2017)
Sustained transmission of high-level azithromycin-resistant Neisseria gonorrhoeae in England: an observational study
Authors: Helen Fifer, Michelle Cole, Gwenda Hughes, Simon Padfield, Christa Smolarchuk, Neil Woodford, Adrian Wensley, Nazim Mustafa, Ulf Schaefer, Richard Myers, Kate Templeton, Jill Shepherd, Anthony Underwood
Journal: The Lancet Infectious Diseases (2018)
Brief Report: Association of Quantitative and Topographic Assessment of Heberden's Nodes With Knee Osteoarthritis: Data From the Osteoarthritis Initiative
Authors: Neil M. Kumar, Nima Hafezi‐Nejad, Ali Guermazi, Arya Haj‐Mirzaian, Ida K. Haugen, Frank W. Roemer, Shadpour Demehri
Journal: Arthritis & Rheumatology (2018)

To determine whether the presence, number, and topography (digit location and symmetry) of Heberden's nodes are associated with the incidence and progression of radiographic osteoarthritis (OA) of the knee.We analyzed 8,023 knees (with 8 years of follow-up) from the Osteoarthritis Initiative. Cox regression was performed on Heberden's node presence, total number, location, and symmetry (using 2 symmetry index models) obtained at baseline physical examination as well as self-report of Heberden's node presence for evaluation of association with radiographic knee OA incidence (development of a Kellgren/Lawrence grade of ≥2) and progression (worsening in the medial joint space narrowing score of ≥1). Covariate adjustments relevant to OA outcomes were performed.The presence of Heberden's nodes (in 64% of the subjects) at baseline physical examinations, but not subjective self-report of Heberden's nodes, was associated with radiographic knee OA incidence (hazard ratio [HR] 1.19 and 95% confidence interval [95% CI] 1.001-1.402 [approached statistical significance]). Each additional Heberden's node found on physical examination was associated with knee OA incidence (HR 1.03 [95% CI 1.000-1.054] [approached statistical significance]) and progression (HR 1.04 [95% CI 1.016-1.063]). Knee OA incidence and progression were associated with Heberden's nodes located on the third digit (HR 1.26 [95% CI 1.068-1.487] and 1.18 [95% CI 1.019-1.361], respectively) and first digit (HR 1.186 [95% CI 0.992-1.418] [approached statistical significance] and HR 1.26 [95% CI 1.084-1.453], respectively). Heberden's node symmetry was associated with knee OA incidence (model 1 HR 1.09 [95% CI 0.997-1.185] [approached statistical significance]) and progression (model 2 HR 1.13 [95% CI 1.035-1.234]).The number of Heberden's nodes, their locations, and symmetry were associated with knee OA incidence and progression over 8 years.
RESULTS FROM THE MICROVASCULAR ASSESSMENT OF RANOLAZINE IN NON-OBSTRUCTIVE ATHEROSCLEROSIS (MARINA): A DOUBLE-BLINDED RANDOMIZED CONTROLLED TRIAL
Authors: Arnav Kumar, Rani Rabah, Olivia Hung, Parham Eshtehardi, Hossein Hosseini, Nabil Sabbak, Zakaria Almuwaqqat, Chang Liu, Puja Mehta, Bill Gogas, Habib Samady
Journal: Journal of the American College of Cardiology (2018)
Sixty seconds on . . . WhatsApp
Authors: Nigel Hawkes
Journal: BMJ (2018)

You’re not alone. A recent survey showed around a third of UK clinicians use WhatsApp or a similar messaging tool. WhatsApp is free and offers “a simple, secure, reliable messaging and calling service,” say its owners, Facebook. But you’re going to have to learn to unlove it.

On 25 May the General Data Protection Regulation of the European Union will come into force. It’s a complex …
3D-3-culture: A tool to unveil macrophage plasticity in the tumour microenvironment
Authors: Sofia P. Rebelo, Catarina Pinto, Tatiana R. Martins, Nathalie Harrer, Marta F. Estrada, Pablo Loza-Alvarez, José Cabeçadas, Paula M. Alves, Emilio J. Gualda, Wolfgang Sommergruber, Catarina Brito
Journal: Biomaterials (2018)

The tumour microenvironment (TME) shapes disease progression and influences therapeutic response. Most aggressive solid tumours have high levels of myeloid cell infiltration, namely tumour associated macrophages (TAM). Recapitulation of the interaction between the different cellular players of the TME, along with the extracellular matrix (ECM), is critical for understanding the mechanisms underlying disease progression. This particularly holds true for prediction of therapeutic response(s) to standard therapies and interrogation of efficacy of TME-targeting agents. In this work, we explored a culture platform based on alginate microencapsulation and stirred culture systems to develop the 3D-3-culture, which entails the co-culture of tumour cell spheroids of non-small cell lung carcinoma (NSCLC), cancer associated fibroblasts (CAF) and monocytes. We demonstrate that the 3D-3-culture recreates an invasive and immunosuppressive TME, with accumulation of cytokines/chemokines (IL4, IL10, IL13, CCL22, CCL24, CXCL1), ECM elements (collagen type I, IV and fibronectin) and matrix metalloproteinases (MMP1/9), supporting cell migration and promoting cell-cell interactions within the alginate microcapsules. Importantly, we show that both the monocytic cell line THP-1 and peripheral blood-derived monocytes infiltrate the tumour tissue and transpolarize into an M2-like macrophage phenotype expressing CD68, CD163 and CD206, resembling the TAM phenotype in NSCLC. The 3D-3-culture was challenged with chemo- and immunotherapeutic agents and the response to therapy was assessed in each cellular component. Specifically, the macrophage phenotype was modulated upon treatment with the CSF1R inhibitor BLZ945, resulting in a decrease of the M2-like macrophages. In conclusion, the crosstalk between the ECM and tumour, stromal and immune cells in microencapsulated 3D-3-culture promotes the activation of monocytes into TAM, mimicking aggressive tumour stages. The 3D-3-culture constitutes a novel tool to study tumour-immune interaction and macrophage plasticity in response to external stimuli, such as chemotherapeutic and immunomodulatory drugs.
NHS pension scheme benefits for consultants
Authors: Richard Aspinall
Journal: BMJ (2007)

We welcome your rapid responses, whether in direct response to an article in Career Focus or as a way of sharing your own ideas. As long as it isn9t libellous or offensive, we9ll post it on our website. We print a selection of rapid reponses here and the writer of the best each month wins an <i>Oxford Handbook</i> of their choice. Letter of the month prize is donated by OUP.
Circulating estrogen receptor (ER) mutations and splice variants in men with advanced prostate cancer (APC).
Authors: Liang Qu, Pavel Sluka, Hady Wardan, Ian D. Davis, Carmel Jo Pezaro
Journal: Journal of Clinical Oncology (2018)

363 Background: Circulating DNA and RNA have been studied in APC as biomarkers of potential clinical significance. Candidates include androgen receptor amplification or emergence of splice variants. ER signalling has been associated with prostate cancer progression in vitro but blood-based detection of ER variants has not been studied. Methods: Men with APC were recruited for serial blood collection during routine management, from which cell-free DNA (cfDNA) and cell-free RNA (cfRNA) were extracted. Six well-described ERα mutations (E380Q, L536Q, Y537C, Y537S, Y537N &amp; D538G) and six ER splice variants (ERα-66, ERα-36, ERβ1, ERβ2, ERβ4 &amp; ERβ5) were quantitated using droplet digital polymerase chain reaction. These markers were explored in association with clinical and treatment variables using descriptive statistics. Results: 44 men were included for a total of 92 cfDNA and 94 cfRNA samples, with a median of 2 (range: 1-6) sequential samples per patient. Two mutations (E380Q &amp; D538G) were detected in both cfDNA and cfRNA samples, and two (L536Q &amp; Y537S) were detected in cfRNA samples only. The ER splice variants were widely detected in cfRNA samples, including in non-cancer controls. ERα-36 was detected at lower levels than the other splice variants investigated (p &lt; 0.0001). Despite ubiquitous detection, the levels of splice variants altered consistently with analysis of the following clinical variables: during castration therapy; following castration resistance; and with number of previous treatments. No clear patterns of expression were observed for ER mutants. Serial sample analysis associated increased ERα-36 levels with response to docetaxel or abiraterone therapy. ERβ splice variant levels decreased with progression on all studied therapies. Development of E380Q and L536Q mutations was observed in patients with disease progression. Conclusions: We identified circulating ER mutants and splice variants in men with APC. These variants may be associated with previous treatment use, as well as disease progression on castration therapy or other APC treatments. Further work will explore their utility for predicting treatment response.
Autoimmune Polyendocrine Syndromes
Authors: Eystein S. Husebye, Mark S. Anderson, Olle Kämpe
Journal: New England Journal of Medicine (2018)

Autoimmune polyendocrine syndromes comprise a diverse group of clinical entities involving functional impairment of multiple endocrine glands due to loss of immune tolerance. This article reviews recent discoveries as well as approaches to the care of affected patients.