tbuckley/cabot-search huggingface dataset:
Safety of continued administration of enzalutamide in patients with prostate cancer who showed benefit from prior exposure: A phase 2 open-label extension study.
Authors: Elaine Tat Lam, Russell Zelig Szmulewitz, Leonard Joseph Appleman, Anthony W. Tolcher, Andrew Krivoshik, Benoit Baron, Niel Malan, Vitalii Ghicavii
Journal: Journal of Clinical Oncology (2018)

303 Background: Enzalutamide (ENZA), an androgen receptor (AR) inhibitor that blocks multiple steps in the AR signaling pathway, is approved for patients (pts) with metastatic castration-resistant prostate cancer. This Phase 2, open-label, extension study (NCT01534052) evaluated long-term safety of continued ENZA administration. Methods: Prostate cancer pts previously treated with ENZA in Phase I studies (NCT01902251; NCT01911728; NCT02225093) continued to receive ENZA 160 mg/day until the investigator considered it no longer beneficial or consent was withdrawn. The primary end point was safety. Baseline data from the parent studies were used. Results: 52 pts were enrolled and received ENZA treatment (median age, 67 years [range, 54–88]). Median treatment duration was 443 days (range, 63–2010) since first administration and 392 days (range, 3–1926) in the extension study. In the extension, 43 pts (82.7%) experienced ≥1 any grade treatment-emergent adverse event (TEAE) with the most common (≥10% of pts) being fatigue (26.9% all grades, 13.5% grade 1, 7.7% grade 2, and 5.8% grade 3); arthralgia and back pain (13.5% each); and diarrhea, hot flush, and decreased appetite (11.5% each). Drug-related TEAEs (investigator assessed) were reported in 27 pts (51.9%) with the most common (≥5% of pts) being fatigue (17.3%); hot flush (11.5%); and diarrhea, hypophosphatemia, and muscle weakness (5.8% each). 17 pts (32.7%) had ≥1 serious TEAE. Eight drug-related serious TEAEs were reported in five pts (malignant neoplasm progression [3.8%]; acute pancreatitis, rectal haemorrhage, cerebrovascular accident, dysarthria, hemiparesis, and hypertensive crisis [1.9% each]). One (1.9%) death due to acute myocardial infarction (not drug-related) and four (7.7%) due to malignant neoplasm progression (two drug-related) were reported. No notable changes from baseline in clinical laboratory parameters or clinically meaningful abnormalities in vital signs, physical examinations, or electrocardiogram were found. Conclusions: Long-term continued ENZA treatment is generally well tolerated, with a safety profile consistent with that previously reported. Clinical trial information: NCT01534052.
Wales launches campaign to boost GP recruitment
Authors: Abi Rimmer
Journal: BMJ (2016)

The Welsh government is set to launch a national and international recruitment campaign to attract more GPs to Wales, it has announced.

In a statement, Vaughan Gething, Welsh cabinet secretary for health, wellbeing, and sport, said that the campaign would be launched on 20 October and would be promoted at the BMJ Careers Fair on 21 and 22 October.

Alongside the campaign, he said that the Welsh government would …
Targeted BiTE Expression by an Oncolytic Vector Augments Therapeutic Efficacy Against Solid Tumors
Authors: Tobias Speck, Johannes P.W. Heidbuechel, Rūta Veinalde, Dirk Jaeger, Christof von Kalle, Claudia R. Ball, Guy Ungerechts, Christine E. Engeland
Journal: Clinical Cancer Research (2018)

Purpose: Immunotherapy with bispecific T-cell engagers has achieved striking success against hematologic malignancies, but efficacy against solid tumors has been limited. We hypothesized that oncolytic measles viruses encoding bispecific T-cell engagers (MV-BiTEs) represent a safe and effective treatment against solid tumors through local BiTE expression, direct tumor cell lysis and in situ tumor vaccination.Experimental Design: To test this hypothesis, we generated MV-BiTEs from the Edmonston B vaccine strain to target two model antigens. Replicative and oncolytic potential were assessed by infection and cell viability assays, respectively. Functionality of virus-derived BiTEs was tested in vitro by complementary binding and cytotoxicity assays. In vivo efficacy of MV-BiTE was investigated using both syngeneic and xenograft mouse models of solid cancers.Results: We verified secretion of functional BiTE antibodies by MV-BiTE-infected cells. Further, we demonstrated therapeutic efficacy of MV-BiTE against established tumors in fully immunocompetent mice. MV-BiTE efficacy was associated with increased intratumoral T-cell infiltration and induction of protective antitumor immunity. In addition, we showed therapeutic efficacy of MV-BiTE in xenograft models of patient-derived primary colorectal carcinoma spheroids with transfer of peripheral blood mononuclear cells.Conclusions: MV-BiTE treatment was effective in two distinct models of solid tumors without signs of toxicity. This provides strong evidence for therapeutic benefits of tumor-targeted BiTE expression by oncolytic MV. Thus, this study represents proof of concept for an effective strategy to treat solid tumors with BiTEs. Clin Cancer Res; 24(9); 2128-37. ©2018 AACR.
Abstract P2-02-01: Withdrawn
Authors: NC Turner, I Garcia-Murillas, N Chopra, M Beaney, RJ Cutts, C Swift, D Kriplani, J Morden, S Hrebien, I Comino-Mendez, M Afentakis, J Bliss, A Skene, D Wheatley, S Russell, A Evans, M Dowsett, IE Smith
Journal: Cancer Research (2018)

Abstract This abstract was withdrawn by the authors.
Six‐month outcome after transcatheter edge‐to‐edge repair of severe tricuspid regurgitation in patients with heart failure
Authors: Mathias Orban, Christian Besler, Daniel Braun, Michael Nabauer, Marion Zimmer, Martin Orban, Thilo Noack, Julinda Mehilli, Christian Hagl, Joerg Seeburger, Michael Borger, Axel Linke, Holger Thiele, Steffen Massberg, Joerg Ender, Philipp Lurz, Jörg Hausleiter
Journal: European Journal of Heart Failure (2018)
SEX DIFFERENCES IN THE CLINICAL PRESENTATION OF SPONTANEOUS CORONARY ARTERY DISSECTION (SCAD) AT MASSACHUSETTS GENERAL HOSPITAL
Authors: M. Ihsan Kaadan, Francesca Ponzini, Shelly Mishra, Jessica Duran, Sarah Tsiaras, Brian Ghoshhajra, Mark Lindsay, Malissa Wood
Journal: Journal of the American College of Cardiology (2018)
CIRCULATING SOLUBLE UROKINASE PLASMINOGEN ACTIVATOR RECEPTOR LEVELS PREDICT MORTALITY IN SUBJECTS WITHOUT OBSTRUCTIVE CORONARY ARTERY DISEASE
Authors: Nabil Sabbak, Ahmed AlBadri, Ayman Samman Tahhan, Pratik Sandesara, Ayman Alkhoder, Salim Hayek, Heval M. Kelli, Mohamad Mazen Gafeer, Naser Abdelhadi, Belal Kaseer, Yi-An Ko, Keyur Patel, Fahad Choudhary, Sonali Kumar, Jamal Hajjari, Arti Patel, Murtuza Jafri, Muaaz Choudhary, Laila Hasnain, Vanessa Engineer, Saqib Qadir, Arianna Sidoti, Laurence Sperling, Puja K. Mehta, Arshed Quyyumi
Journal: Journal of the American College of Cardiology (2018)
Utility of Endoscopic Ultrasound in Evaluating Local Recurrence After Surgery for Pancreatic Cancer
Authors: Gabriel D. Lang, Daniel K. Mullady, Dayna S. Early, Thomas Hollander, Steven A. Edmundowicz, Faris M. Murad, Steven M. Strasberg, Ryan C. Fields, William G. Hawkins, Maria B. Doyle, William C. Chapman, Andrea Wang-Gillam, Vladimir M. Kushnir
Journal: Clinical Gastroenterology and Hepatology (2018)
Monitoring PD-L1 expression on circulating tumor cells (CTCs) in patients with NSCLC treated with PD1 inhibitors.
Authors: Nicolas Marie Guibert, Myriam Delaunay, Amellie Lusque, Sandrine Gouin, Nadia Boubekeur, Isabelle Rouquette, Estelle Clermont, Aurélien Fourtoul, Gilles Favre, Anne Pradines, Julien Mazieres
Journal: Journal of Clinical Oncology (2018)

147 Background: Inhibitors of the immune checkpoint PD-1/PD-L1 have become a standard of care in NSCLC. Patient selection, currently based on PD-L1 expression in tumor tissue, is limited by its temporal and spatial heterogeneity. We hypothesized that monitoring PD-L1 staining of circulating tumor cells (CTCs) could represent a valuable non-invasive biomarker. Methods: Up to 3 blood samples were prospectively collected from patients with advanced NSCLC: i) pretreatment (nivolumab), ii) first follow-up, iii) progression. CTCs were isolated from 10 mL of blood using cell size-based technology (ISET, Rarecells). PD-L1 expression was assessed by immunofluorescence on CTCs and immunohistochemistry on tissue. Results: 162 samples from 96 patients were collected. PD-L1 expression could be assessed pretreatment on tissue and CTCs in 72% and 93%, respectively; and was ≥1% in 37% and 83%; ≥5% in 35% and 79%, respectively. No correlation between tissue and CTCs PD-L1 expressions was observed (Spearman coefficient correlation = 0.04, p = 0.77). At baseline, each 10/7.5 ml increase in CTCs count was associated with increased risk of death and progression (HR[95%CI]: 1.06 [1.005;1.117] p = 0.03 for OS and HR[95%CI]: 1.05 [1.01;1.10] p = 0.02 for PFS). The presence of PD-L1(+)CTC (≥1%) had no prognostic impact (OS: p = 0.89 and PFS: p = 0.55), but pretreatment PD-L1(+)CTCs were more frequent in the “non-responders” group (PFS &lt; 6 months) (p = 0.04). Median CTC count was 30 (n = 96), 68.3 (n = 44) and 50.3 (n = 22) pretreatment, at the first follow-up and at progression, respectively. The changes in CTC count at the first follow-up had no impact on PFS (p = 0.45) or OS (p = 0.68). 96% of patients had PD-L1(+)CTCs at progression. Further analyses are ongoing to assess the prognostic value of the persistence of CTCs and PD-L1(+)CTCs at the first follow up and at progression. Conclusions: Analysis of PD-L1 expression on CTCs is highly feasible. PD-L1 expressions on tissue and CTCs are discordant, CTCs being more likely positives, suggesting false negatives occurring in small biopsies. Further analyses of the kinetics of this biomarker throughout ICI treatment, along with other circulating biomarkers, are ongoing. Clinical trial information: NCT02827344.
Proteolytic Release of the p75NTR Intracellular Domain by ADAM10 Promotes Metastasis and Resistance to Anoikis
Authors: Xin Bao, Jianbo Shi, Furong Xie, Zengying Liu, Jingshuang Yu, Wantao Chen, Zhiyuan Zhang, Qin Xu
Journal: Cancer Research (2018)

Abstract Resistance to anoikis allows cancer cells to survive during systemic circulation; however, the mechanism underlying anoikis resistance remains unclear. Here we show that A disintegrin and metalloprotease 10 (ADAM10)–mediated cleavage of p75 neurotrophin receptor (p75NTR) and subsequent generation of the p75NTR intracellular domain (ICD) endow cancer cells with resistance to anoikis. p75NTR ICD promoted expression of TNF receptor–associated factor 6 (TRAF6), a critical intermediary in p75NTR ICD–mediated signal transduction, at the translational level. Cell detachment–induced activation of EGFR triggered autoubiquitination of TRAF6 by facilitating its dimerization, subsequently activated NFκB, and eventually led to anoikis resistance. ADAM10 and p75NTR ICD also promoted tumor metastasis formation in vivo. Together, our findings uncover a previously unknown function for the ADAM10-p75NTR ICD-TRAF6-NFκB axis in preventing anoikis and suggest ADAM10 and p75NTR ICD as potential cancer therapeutic targets. Significance: These findings identify the ADAM10-p75NTR ICD-TRAF6-NFκB signaling axis as a potential candidate for cancer therapy. Cancer Res; 78(9); 2262–76. ©2018 AACR.
The potential of CRL4DCAF1 and KSR1 as therapeutic targets in merlin-deficient meningioma
Authors: Jade Lyons Rimmer, Daniele Baiz, Emanuela Ercolano, Oliver Hanemann
Journal: Neuro-Oncology (2018)

Merlin-deficient meningiomas are caused by mutations in the Neurofibromin 2 gene and occur in approximately 60% of sporadic meningiomas. Merlin loss is commonly associated with the genetic condition Neurofibromatosis type 2, leading to the development of multiple low grade tumours including schwannoma and meningioma. Currently, the only treatment for low grade meningioma is (radio)surgery therefore identification of novel drug targets is vital. Previous studies have shown that Kinase suppressor of Ras 1 (KSR1) is a potential therapeutic target in schwannoma and that the E3 ubiquitin ligase, CRL4DCAF1, binds to KSR1. The aim of this project is to investigate the interaction between CRL4DCAF1 and KSR1 to determine if targeting this protein complex in meningioma holds therapeutic value. HEK293T cells were transfected with KSR1 constructs and interactions with CRL4DCAF1 were investigated by immunoprecipitation. Immunohistochemistry, cell fractionation and Western blot were used to analyse DCAF1 and KSR1 expression and localization in primary human meningioma. A shRNA construct was used to knock down DCAF1 and APS_2_79 was used to inhibit KSR1. KSR1 interacts via the N-term with DCAF1 and is ubiquitinated at the C-term in the NF+/+ model which may be DCAF1 dependent. Immunohistochemistry showed increased DCAF1 and KSR1 expression in Merlin-deficient meningiomas compared with normal meninges, whereas Western blot analysis showed variable protein expression. DCAF1 knockdown led to a reduction of nuclear pERK1/2 and a significant decrease in proliferation of meningioma cells but pERK1/2 and Cyclin D1 levels were unchanged. Combination of shDCAF1 and APS_2_79, a specific KSR1 inhibitor, reduced pERK and proliferation in both BenMen-1, a benign meningioma cell line and primary meningioma. Therefore, targeting both DCAF1 and KSR1 represents an attractive novel therapeutic strategy in meningioma.
Radiology in Scotland is at breaking point, royal college warns
Authors: Abi Rimmer
Journal: BMJ (2017)

The Royal College of Radiologists has warned that radiology services in Scotland are at breaking point because of a lack of radiologists. Grant Baxter, chairman of the college’s Standing Scottish Committee, said that radiology in Scotland was in a desperate place.1

“There has been a huge increase, year on year, in demand for our services, both diagnostic and interventional, and that has clearly not been matched by any increase in radiology numbers,” he said. “We’re really at a point in time when we are teetering on a precipice; we’re almost at the point of collapse. Radiologists up and down the country are on their knees trying to hold a failing service together. It really is desperate, and I can’t …
PROGNOSTIC SIGNIFICANCE OF NON-ISCHAEMIC MYOCARDIAL FIBROSIS IN PATIENTS WITH NORMAL LV SIZE AND FUNCTION: A LARGE CMR REGISTRY STUDY
Authors: Amrit Lota, Adam Tsao, Amer Al-Balah, Akhil Patel, Simon Newsome, Florence Mouy, Brian Halliday, John Cleland, James Ware, Stuart Cook, Dudley Pennell, Sanjay Prasad
Journal: Journal of the American College of Cardiology (2018)
Royal colleges work to broker a junior contract deal
Authors: Tom Moberly, Abi Rimmer
Journal: BMJ (2016)

Medical royal colleges are working behind the scenes to broker a deal between junior doctors and the government, and prevent the first all out strike by junior doctors in England.

Meetings and discussions between government officials, heads of royal colleges, senior doctors, and senior health service figures have sought to break the deadlock between the government and the BMA over changes to junior doctors’ contracts.

The King’s Fund’s chief executive, Chris Ham, called on the royal colleges to intervene to resolve the current dispute.1 He argued that although contract negotiations lay outside the responsibilities of the medical royal colleges their presidents have on previous occasions stepped outside their formal responsibilities to protect patient care.

A spokesman for the Royal College of Emergency Medicine said that medical royal colleges were considering a move to work together to broker an agreement between doctors and the government.

The Advisory, Conciliation, and Arbitration Service, which previously facilitated talks between the BMA and the government, confirmed that its “door will remain open to both parties.”

Neena Modi, president of the Royal College of Paediatrics and Child Health said, “The medical royal colleges have a role to play …
ATLS instructor course
Authors: Hesham Al-Khateeb
Journal: BMJ (2006)

All ATLS (advanced trauma life support) providers who have performed well on the ATLS student course, providing they are eligible for higher specialist training, can be invited to attend the ATLS instructor course.

The candidates are nominated by the course director and must meet all these criteria:

I have a keen interest in trauma in general and in the ATLS principles and guidelines in particular. As an orthopaedic registrar, management of trauma forms an essential component of my duties and responsibilities. ATLS ensures that everyone speaks a common language in trauma management and follows a strict protocol that prioritises life threatening conditions and ensures …
Meta-analysis in Research on Nutrition—Reply
Authors: Neal D. Barnard, Walter C. Willett, Eric L. Ding
Journal: JAMA (2018)

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IMPACT OF THE AGE OF FRAILTY ON OUTCOMES AFTER PERCUTANEOUS CORONARY INTERVENTION IN ACUTE CORONARY SYNDROMES
Authors: Beatrice Ricci, Edina Cenko, Zorana Vasiljevic, Goran Stankovic, Sasko Kedev, Marija Vavlukis, Oliver Kalpak, Davor Milicic, Olivia Manfrini, Lina Badimon, Raffaele Bugiardini
Journal: Journal of the American College of Cardiology (2018)
68Ga–Prostate-Specific Membrane Antigen PET/CT in Triple-Negative Breast Cancer
Authors: Averilicia Passah, Saurabh Arora, Nishikant Avinash Damle, Madhavi Tripathi, Chandrasekhar Bal, T. Kishan Subudhi, Geetanjali Arora
Journal: Clinical Nuclear Medicine (2018)

The prostate-specific membrane antigen (PSMA) is a transmembrane protein with elevated expression in prostate cancer cells. Breast cancer also shows PSMA expression. We present the case of a 30-year-old woman with triple-negative bilateral breast carcinoma who underwent bilateral mastectomy, chemotherapy, and radiotherapy. She developed a left chest wall and liver recurrence after primary therapy. Her recurrent disease was also triple-negative. In view of the known poor prognosis and very limited therapeutic options, we performed Ga-PSMA PET/CT scan to explore the possibility of PSMA-based therapy as a future option after exhausting standard-of-care treatments.
Gene Promoter Hypermethylation Detected in Sputum Predicts FEV<sub>1</sub> Decline and All-Cause Mortality in Smokers
Authors: Shuguang Leng, Brenda Diergaarde, Maria A. Picchi, David O. Wilson, Frank D. Gilliland, Jian-Min Yuan, Jill M. Siegfried, Steven A. Belinsky
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Gene promoter hypermethylation detected in sputum assesses the extent of field cancerization and predicts lung cancer (LC) risk in ever-smokers. A rapid decline of FEV
Ten-Year Trends in Antiemetic Prescribing in Patients Receiving Highly Emetogenic Chemotherapy
Authors: Ciara C. O'Sullivan, Holly K. Van Houten, Lindsey R. Sangaralingham, Alexis D. Leal, Shivani Shinde, Hongfang Liu, David Ettinger, Charles L. Loprinzi, Kathryn J. Ruddy
Journal: Journal of the National Comprehensive Cancer Network (2018)

Purpose: Prevention of chemotherapy-induced nausea and vomiting is essential to preserve quality of life in patients with cancer receiving highly emetogenic chemotherapy (HEC). Recently, new drugs (eg, fosaprepitant, and the newer neurokinin-1 receptor antagonists [NK1RAs] rolapitant and netupitant) and updated antiemetic guidelines have emerged. However, trends in real-world antiemetic use are understudied. Methods: We identified patients treated with an initial dose of HEC (either cisplatin or doxorubicin/cyclophosphamide) from January 2006 to June 2016 using administrative claims data from a US commercial insurance database (OptumLabs). Antiemetic use was determined by identifying intravenous/oral/transdermal administration within ±1 day of the chemotherapy dose and/or prescription fill from 14 days before to 7 days after chemotherapy. We used descriptive statistics to present patient demographics, chemotherapy drugs administered, presence/absence of a central intravenous access device, and antiemetics used. Results: A total of 23,030 patients (67.3%) received doxorubicin/cyclophosphamide and 11,206 (32.7%) received cisplatin. Dexamethasone and 5-hydroxytryptamine 3 receptor antagonists (5-HT3RAs) were consistently used by 85% to 95% of patients, consistent with guideline recommendations. NK1RAs were underused early on, but use increased to approximately 80% in the most recently evaluated year. Fosaprepitant use increased precipitously starting in 2009, preceding a sharp decrease in aprepitant use beginning in 2011. Receipt of olanzapine, rolapitant, and netupitant was minimal throughout the study period. Conclusions: Dexamethasone and 5-HT3RAs were used by most patients receiving HEC, in accordance with guideline recommendations. NK1RA use was less adherent with guidelines.
Publisher Correction: The transcriptional coactivator TAZ regulates reciprocal differentiation of TH17 cells and Treg cells
Authors: Jing Geng, Shujuan Yu, Hao Zhao, Xiufeng Sun, Xun Li, Ping Wang, Xiaolin Xiong, Lixin Hong, Changchuan Xie, Jiahui Gao, Yiran Shi, Jiaqi Peng, Randy L Johnson, Nengming Xiao, Linrong Lu, Jiahuai Han, Dawang Zhou, Lanfen Chen
Journal: Nature Immunology (2018)
HARD DECISIONS FOR HARD SITUATIONS: HOW SHOULD WE PROCEED IN CARDIAC ELECTRIC DEVICE INFECTIONS BY STAPHYLOCOCCUS AUREUS
Authors: Ana Redondo Palacios, Tomasa Centella, Jose Lopez-Menendez, Laura Varela, Javier Miguelena, Miren Martin Garcia, Javier Cobo, Edmundo Fajardo, Rafael Muñoz, Jorge Rodríguez-Roda
Journal: Journal of the American College of Cardiology (2018)
NATIONWIDE TRENDS AND OUTCOMES OF TEMPORARY MECHANICAL CIRCULATORY SUPPORT FOR CARDIOGENIC SHOCK AFTER CARDIAC SURGERY
Authors: Saraschandra Vallabhajosyula, Shilpkumar Arora, Ankit Sakhuja, Sopan Lahewala, Varun Kumar, Ghanshyam P.S. Shantha, Bernard J. Gersh, Rajiv Gulati, Abhiram Prasad, Abhishek J. Deshmukh
Journal: Journal of the American College of Cardiology (2018)
David Oliver: What might Health Education England’s workforce strategy mean for doctors?
Authors: David Oliver
Journal: BMJ (2018)

It may seem extraordinary but, in the NHS’s entire history, we’ve never seen anything resembling a comprehensive, medium term workforce strategy. The NHS has tended to rely rather complacently on staff from overseas, while failing to consider the growing number of less than full time workers or the effects of new roles in the clinical workforce.

Last week we learnt from NHS Improvement that around 100 000 NHS posts (one in 11) are unfilled, including 8% of medical posts.1 I therefore commend Health Education England’s timeliness in publishing a draft workforce strategy, Facing the Facts, Shaping the Future , in December 2017.2 For this to have happened may have taken a huge workforce crisis—and a storm of protest from …