tbuckley/cabot-search huggingface dataset:
Hypofractionated, dose escalation radiotherapy for high-risk prostate cancer: The primary endpoint of a group led phase III trial. (PCS5).
Authors: Tamim Niazi, Abdenour Nabid, Redouane Bettahar, Linda S. Vincent, Andre-Guy Martin, Marjory Jolicoeur, Michael Yassa, Maroie Barkati, Levon Igidbashian, Boris Bahoric, Robert Archambault, Hugo Villeneuve, James M Tsui, MD Mohiuddin
Journal: Journal of Clinical Oncology (2018)

123 Background: The low α\β ratio of prostate cancer (PCa), 1.5-2, suggests high radiation-fraction sensitivity and predicts a therapeutic advantage of hypofractionated radiation treatment (HFRT). Most available data of moderate HFRT have focused on low, intermediate and/or mixed risk groups. We therefore conducted the first randomized trial of moderately HFRT in high-risk PCa patients and present the primary safety analysis of side effects at 2 years. Methods: We conducted a Canadian multi-centric phase III trial of conventional fractionated radiation therapy (CFRT) vs. intensity-modulated HFRT in men with high-risk PCa as per NCCN definition. From February 2012 to March 2015, 329 patients were randomized in a 1:1 ratio to receive either CFRT or HFRT. All patients received neo-adjuvant, concurrent and adjuvant androgen suppression, with a median duration of 24 months. CFRT consisted of 76 Gy in 2 Gy per fraction to the prostate where 46 Gy was delivered to the pelvic lymph nodes. HFRT consisted of concomitant dose escalation of 68 Gy in 2.72 Gy per fraction to the prostate and 45 Gy, in 1.8Gy per fraction to the pelvic lymph nodes. The primary endpoint was to compare the toxicities at 6 months and at 24 months using the CTCAE v.4. Results: Of the329 patients, 164 were randomized to HFRT and 165 to CFRT. The minimum, median and maximum follow-up were 24, 40 and 60 months respectively. At 24 months, 12 patients in the CFRT arm and 15 patients in the HFRT arm had grade 2 or worse gastrointestinal (GI)-related adverse events (HR:1.32 [0.62.2.83] 95% CI; P=NS). Similarly, 11 patients in the CFRT arm and 3 patients in HFRT arm had grade 2 or higher genitourinary (GU) toxicities (HR:0.26 [0.07-0.94] 95% CI; P=0.037). In the HFRT arm, there were 3 grade 3 GI and one grade 3 GU related toxicities. In the CFRT arm there were 3 grade 3 GU and no grade 3 GI related toxicities. There were no grade 4 toxicities in either arm. Conclusions: This is the first hypofractionated dose escalated radiotherapy study in high-risk PCa patients treated with contemporary radiation and androgen suppression. Our results indicate that moderate HFRT to high risk PCa patients is equally well tolerated as CFRT at 2 years. Clinical trial information: NCT01444820.
I have just come back from work after a day of being bullied. I cannot carry on like this any longer and I feel I need help. Could you suggest anything?
Authors: Rebecca Viney
Journal: BMJ (2005)

Have a career or related problem that needs answering? Can9t find the right person to point you in the right direction? Log on to the Advice Zone for reliable medical careers advice. You can post a question or see if one of our 300 advisers has already answered a similar question. Here is a selection of questions and answers posted on the site. <b>www.bmjcareers.com/advicezone</b>
Abstract 17172: Contrary to the General Population, Upward Increments in Serum High-density Lipoprotein Cholesterol Over Time Are Associated With Worse Survival in Incident Hemodialysis Patients
Authors: Tae Ik Chang, Elani Streja, Connie M Rhee, Moti L Kashyap, Nosratola D Vaziri, Kamyar Kalantar-Zadeh, Hamid Moradi
Journal: Circulation (2016)

Introduction:  We have previously reported that elevated serum high-density lipoprotein (HDL) cholesterol level was associated with poor cardiovascular (CV) and all-cause mortality in hemodialysis (HD) patients. However, the association between change in HDL over time and mortality in HD patients has not been fully examined.   Hypothesis:  We hypothesized that increasing serum HDL levels over time would not be associated with improved survival.   Methods:  In a national US cohort of 21,074 patients who initiated HD over a 5-year period (2007-2011) and had available HDL data at baseline and 6 months after HD initiation, we studied the association of change in HDL cholesterol during the first 6 months of HD with all-cause and CV mortality. Associations were examined with Cox proportional hazard models with 3 adjustment levels: unadjusted, case-mix, and case-mix plus malnutrition-inflammation-cachexia syndrome (MICS) adjusted.   Results:  In case-mix models, there was a J-shape association between changes in HDL and all-cause (HR, 1.32 [95% CI, 1.21-1.45] and 1.09 [1.01-1.18]) and CV mortality (1.30 [1.12-1.52] and 1.16 [1.02-1.33]) with significantly higher mortality in quartiles 1 (   Conclusions:  Increasing serum HDL cholesterol over time is paradoxically associated with worse CV and overall outcomes in incident HD patients. While malnutrition and some markers of inflammation may explain the increased risk of mortality in patients with decreasing serum HDL concentrations, these indices do not mitigate the elevated risk in patients with increasing serum HDL cholesterol.
GERIATRIC NUTRITIONAL RISK INDEX PROVIDES THE ADDITIONAL LONG-TERM PROGNOSTIC INFORMATION TO ADHERE RISK LEVEL IN PATIENTS ADMITTED FOR ACUTE DECOMPENSATED HEART FAILURE
Authors: Takahisa Yamada, Takashi Morita, Yoshio Furukawa, Shunsuke Tamaki, Yusuke Iwasaki, Masato Kawasaki, Masato Kawasaki, Atsushi Kikuchi, Tsutomu Kawai, Masahiro Seo, Iyo Ikeda, Eiji Fukuhara, Jun Nakamura, Makoto Abe, Kazuya Tanabe, Kiyomi Kayama, Masatsugu Kawahira, Masatake Fukunami
Journal: Journal of the American College of Cardiology (2018)
HIGH SENSITIVE TROPONIN T AS PREDICTOR OF ACUTE CORONARY OCCLUSIONS IN PATIENTS WITH NON-ST SEGMENT ELEVATION ACUTE CORONARY SYNDROME
Authors: Santiago Ordonez, Rocio C. Baro, Victoria Galizia Brito, Ivan E. Chillik, Josefina B. Parodi, Marcelo S. Trivi, Juan P. Costabel
Journal: Journal of the American College of Cardiology (2018)
Prominent Pulmonary Metastases Without Concurrent Intra-abdominal Metastasis in a Case of Ovarian Carcinoma
Authors: Junjun Cheng, Xiaohong Ou, Yunxia Ye
Journal: Clinical Nuclear Medicine (2018)

Abstract Because ovarian cancer often advances by dissemination, pulmonary metastases are rarely unaccompanied by intra-abdominal metastases. We report a case of ovarian clear cell carcinoma having multiple bilateral lung metastases and without concurrent intra-abdominal lesions, as demonstrated by FDG PET/CT scan.
Starting from a firm foundation
Authors: Tom Moberly
Journal: BMJ (2014)

From professional integrity and the future role of the doctor to the shifting boundaries of healthcare roles and the decisions underpinning career choices, BMJ Careers covers some of the fundamental issues affecting doctors’ careers. In recent articles we have heard NHS England’s deputy chairman warning of the risks of over-regulation (http://careers.bmj.com/careers/advice/view-article.html?id=20020142) and the medical director of Health Education England arguing that those responsible for …
Creating an open door for all talent
Authors: Tom Moberly
Journal: BMJ (2016)

For too long, the United Kingdom has relied on a plentiful supply of privileged and affluent young students to supply its next generation of doctors. This week Patrice Baptiste argues that more needs to be done to encourage students from a wider range of backgrounds to apply to medical school (http://careers.bmj.com/careers/advice/Medical\_school\_should\_not\_be\_the\_preserve\_of\_the_elite).

At the moment …
Modulation of colonic hydrogen sulfide production by diet and mesalazine utilizing a novel gas-profiling technology
Authors: Chu K. Yao, Asaf Rotbart, Jian Z. Ou, Kourosh Kalantar-Zadeh, Jane G. Muir, Peter R. Gibson
Journal: Gut Microbes (2018)

Excessive hydrogen sulfide (H2S) production from gut microbial metabolism may have clinically important relevance in the pathogenesis of gut disorders, including ulcerative colitis. However, little is known regarding factors that alter its production. Using a newly-designed in vitro gas-profiling technology, the study aimed to verify real-time H2S measurement reproducibility and thereafter, assess its production following exposure to dietary factors and 5-aminosalicylate acid (5-ASA). Measurements of H2S, carbon dioxide, hydrogen and methane measurements were compared between gas-profiling systems. Homogenized slurries were prepared from freshly-passed healthy human feces. Fifty ml slurries were aliquoted into separate fermentation chambers and substrates added including 1 g highly fermentable fructo-oligosaccharides (FOS) or resistant starch Hi-Maize (RS), or minimally fermentable psyllium or sterculia, 1 g cysteine, 0.9 g sodium sulfate or 1.2 mL of 1 M 5-ASA alone or in combinations. H2S release was sampled every 5 mins over 4-h and expressed relative to unspiked controls. RS suppressed H2S production by a mean 89.0 (SEM 4.8)% and FOS by 82.2 (6.2)% compared to <35 (17)% by psyllium and sterculia (p<0.001, two-way ANOVA). Cysteine stimulated H2S production by 1557 (532)%. The addition of FOS to slurries containing cysteine significantly suppressed H2S by 90 (2)% over the addition of 5-ASA (0.3 (2)%, p<0.001). Sulfate and 5-ASA had minimal overall effects. In conclusion, the H2S-profiling technology is a reproducible tool. Production of H2S is greatly enhanced by sulfur-amino acids but not inorganic sulfate, and is effectively suppressed by readily fermentable fibers. These findings inform potential designs of dietary therapies to reduce H2S production in vivo.
A phase 1b/2 study of CPI-1205, a small molecule inhibitor of EZH2, combined with enzalutamide (E) or abiraterone/prednisone (A/P) in patients with metastatic castration resistant prostate cancer (mCRPC).
Authors: Mary-Ellen Taplin, Arif Hussain, Neal D. Shore, Bill Bradley, Patrick Trojer, Claudia Lebedinsky, Adrian Mario Senderowicz, Emmanuel S. Antonarakis
Journal: Journal of Clinical Oncology (2018)

TPS398 Background: EZH2 is frequently mutated and overexpressed in human cancer. High levels of expression are correlated with disease stage, aggressiveness, and poor outcome in patients with prostate cancer (Varambally, 2002). EZH2 inhibition restores androgen receptor expression and sensitivity to antiandrogen therapy in preclinical models of advanced prostate cancer, suggesting epigenetic reprogramming as an approach to overcome resistance to antiandrogen therapy (Ku, 2017). CPI-1205 is a potent, selective and cofactor-competitive EZH2 inhibitor, that inhibits both wild-type and mutant EZH2 catalytic activity in a reversible manner. Preclinical studies have shown profound anti-proliferative effects of CPI-1205 in treating both lymphoma and prostate cancer cell models. Antitumor activity of EZH2 methyltransferase inhibitors has been observed in patients with non-Hodgkin’s lymphoma. These observations support the clinical evaluation of CPI-1205 with standard doses of A/P or E in mCRPC. Methods: We present a Phase 1b/2 study to explore the safety and efficacy of two regimens of CPI-1205 in combination with either E or A/P. Key eligibility criteria include progressive mCRPC in patients previously treated with a second generation androgen inhibitor, ECOG 0-1 and measurable or non- measurable disease. Key exclusion criteria include &gt; 1 second generation androgen inhibitor. During the phase 1b, sequentially enrolled cohorts will receive CPI-1205 at continuous – 28-day cycles combined with either standard dose of E (160mg PO once daily) or A/P (1000mg PO once daily/ 5 mg BID). The primary objective is to determine the maximum tolerated dose and recommended phase 2 dose (RP2D) of each regimen. Secondary objectives include safety, pharmacokinetic, pharmacodynamics profiles and activity (PSA, circulating tumor cells, imaging) in mCRPC. Once RP2D is established, we will start a Phase 2 trial of a 2 nd generation androgen inhibitor combined with CPI-1205.
THE EFFECT OF CESSATION OF 2ND GENERATION P2Y12 INHIBITOR THERAPY ON PLATELET REACTIVITY IN PATIENTS AFTER ACUTE MYOCARDIAL INFARCTION
Authors: Guy Witberg, Jalal Bathish, Alejandro Solodky, Tamir Bental, Ran Kornowski, Eli Lev
Journal: Journal of the American College of Cardiology (2018)
Phase II study of olaparib (without ADT) in men with high-risk biochemically-recurrent prostate cancer following prostatectomy, with integrated biomarker analysis.
Authors: Benjamin A. Teply, Hao Wang, Rana Sullivan, Serina King, Catherine Handy, Tamara L. Lotan, Emmanuel S. Antonarakis
Journal: Journal of Clinical Oncology (2018)

TPS386 Background: Patients with a high-risk biochemical recurrence (BCR) of prostate cancer after local therapy, defined by a rapid PSA doubling time (≤6 mo), are likely to experience metastases and subsequently death from their disease. Early use of androgen deprivation therapy (ADT) in these patients is controversial and is associated with side effects. Non-hormonal therapies that alter the natural history of BCR disease are needed. Olaparib is a PARP inhibitor that produces responses in some men with advanced prostate cancer, particularly those with dysregulation of DNA repair genes (i.e. synthetic lethality). Preclinical data support the activity of olaparib in prostate cancer beyond the DNA repair-deficient subset, yet the optimal biomarker for treatment selection is unknown. We hypothesized that olaparib monotherapy would show activity in men with high risk BCR and sought to further define the optimal patient population for olaparib in this setting. Methods: In this investigator-initiated multi-center open-label study, eligible patients will have non-metastatic BCR after prostatectomy, with a PSA doubling time of ≤6 mo. Prior limited ADT is allowed, but testosterone must have recovered (≥150 ng/dL). Patients will receive 300mg olaparib twice daily, with disease evaluation by PSA monthly and radiographic studies every 6 mo. Patients continue olaparib until evidence of metastasis or until PSA doubles from baseline, with a minimum exposure of 3 months. The primary endpoint is the rate of decline in PSA to ≥50% from baseline (PSA50 response). Secondary endpoints include safety, progression-free survival, and the rate of durable responses. Exploratory analysis will involve biomarker discovery including somatic DNA mutation analysis, RNA expression analysis, and immunohistochemistry for DNA damage markers, done on prostatectomy specimens. The study will initially enroll an all-comer (unselected) population and will then proceed via a staged-adaptive design; if futility is observed in the all-comer population at interim analyses, enrichment with biomarker-selected patients will occur. Clinical trial information: NCT03047135.
Academic general practice
Authors: Peter Aquino
Journal: BMJ (2005)

Thank you for your interest in spreading the word about The BMJ.NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address. Username * Your Email * Send To * You are going to email the following Academic general practice Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
The Most N-Terminal Region of THSD7A Is the Predominant Target for Autoimmunity in THSD7A-Associated Membranous Nephropathy
Authors: Larissa Seifert, Elion Hoxha, Anna M. Eichhoff, Gunther Zahner, Silke Dehde, Linda Reinhard, Friedrich Koch-Nolte, Rolf A.K. Stahl, Nicola M. Tomas
Journal: Journal of the American Society of Nephrology (2018)

Background Thrombospondin type 1 domain–containing 7A (THSD7A) has been identified as a pathogenic autoantigen in membranous nephropathy (MN). However, the THSD7A epitopes targeted by patient autoantibodies are unknown. Methods We performed an in silico analysis of the THSD7A multidomain structure, expressed the folded domains in HEK293 cells, and tested for domain reactivity with 31 serum samples from patients with THSD7A-associated MN using Western and native blotting. Immunogenicity of the antigen domains was further investigated by cDNA immunization of rabbits and mice. Results We characterized the extracellular topology of THSD7A as a tandem string of 21 thrombospondin type 1 domains. Overall, 28 serum samples (90%) recognized multiple epitope domains along the molecule. Detailed epitope mapping revealed that the complex consisting of the first and second N-terminal domains (amino acids 48–192) was recognized by 27 of 31 patient serum samples (87%). Serum recognizing one or two epitope domains showed lower anti-THSD7A antibody levels than serum recognizing three or more epitope domains. During follow-up, a loss of epitope recognition was observed in seven of 16 patients, and it was accompanied by decreasing antibody levels and remission of proteinuria. In four of 16 patients, epitope recognition patterns changed during follow-up. Notably, immunization experiments in rabbits and mice revealed that induced antibodies, like patient autoantibodies, preferentially bound to the most N-terminal domains of THSD7A. Conclusions Our data show that the immune response in THSD7A-associated MN is polyreactive and that autoantibodies predominantly target the most N-terminal part of THSD7A.
Bone marrow niche trafficking of miR-126 controls the self-renewal of leukemia stem cells in chronic myelogenous leukemia
Authors: Bin Zhang, Le Xuan Truong Nguyen, Ling Li, Dandan Zhao, Bijender Kumar, Herman Wu, Allen Lin, Francesca Pellicano, Lisa Hopcroft, Yu-Lin Su, Mhairi Copland, Tessa L Holyoake, Calvin J Kuo, Ravi Bhatia, David S Snyder, Haris Ali, Anthony S Stein, Casey Brewer, Huafeng Wang, Tinisha McDonald, Piotr Swiderski, Estelle Troadec, Ching-Cheng Chen, Adrienne Dorrance, Vinod Pullarkat, Yate-Ching Yuan, Danilo Perrotti, Nadia Carlesso, Stephen J Forman, Marcin Kortylewski, Ya-Huei Kuo, Guido Marcucci
Journal: Nature Medicine (2018)
Contract negotiations should not be a “cost cutting exercise,” says BMA
Authors: Helen Jaques
Journal: BMJ (2013)

Changes to the junior doctor and consultant contracts should not be driven by financial goals, the BMA has insisted, after starting discussions on renegotiating hospital doctor contracts.

The association has had its first meeting with NHS Employers and other stakeholders to discuss renegotiation of hospital doctor contracts. Speaking after the meeting on 29 January, the chairman of the BMA council, Mark Porter, said that any changes to doctors’ contracts must not be approached as a “cost cutting exercise.”

“I made it clear that doctors can help drive up quality while saving money and improving the patient experience,” he said. “However, I also stressed that this is becoming increasingly difficult as we are faced with the biggest structural reorganisation of the NHS since its inception, a multi-year pay freeze, the introduction of …
Urinary toxicity in men treated with stereotactic body radiation therapy (SBRT) for localized prostate cancer following procedures for benign prostatic hyperplasia (BPH).
Authors: Shaan Kataria, Harry Tsou, Subhradeep Datta, Marie Kate Gurka, Siyuan Lei, Marilyn Ayoob, Malika Danner, Thomas M. Yung, Brian Timothy Collins, Pranay Krishnan, Simeng Suy, John J. Lynch, Sean P. Collins
Journal: Journal of Clinical Oncology (2018)

91 Background: Patients with a history of procedures for BPH experience worse urinary toxicity following interstitial brachytherapy for localized prostate cancer. This retrospective study sought to evaluate the rates of urinary toxicity following SBRT in men with a history of procedures for BPH. Methods: Localized prostate cancer patients, treated with SBRT from August 2009 to February 2015 and a minimum follow up of 2 years, with a history of at least 1 procedure for BPH associated with a prostatic defect identified on the treatment planning MRI were evaluated. Radiotherapy was delivered in 5 fractions to a dose of 35 or 36.25 Gy using the CyberKnife system with fiducial tracking. Urinary QOL was assessed pre- and post-treatment using the International Prostate Symptom Score (IPSS) and the Expanded Prostate Cancer Index Composite (EPIC-26). Cystoscopy findings were retrospectively reviewed. Toxicities were scored using the CTCAE v4. Results: Thirty nine men with a median age of 72 years, 7 with a history of more than 1 procedure for BPH, were treated with a median follow up of 49 months. Grade 1, grade 2, and grade 3 urinary toxicity occurred in 11, 24, and 3 men, respectively; there were no grade 4 or 5 toxicities. Overall, 22 men experienced hematuria; the median time to the onset hematuria from the start of SBRT was 13 months (range 1-70). Cystoscopy was performed on 12 of these patients and bladder neck/prostatic urethra hyperemia were found in a majority of cases. Active bleeding from the bladder neck or prostatic urethra was found in 4 men. A mean baseline IPSS score of 9 did not significantly change at any point during follow up. A mean baseline EPIC-26 obstructive/irritative score of 84 significantly decreased to 76 at 1 month (p = 0.023). There was no significant change from the mean baseline EPIC-26 urinary incontinence score at any point during follow up. Conclusions: A history of procedures for BPH may lead to worse urinary quality of life and high rates of hematuria following SBRT for localized prostate cancer. Stricter urethra/bladder neck dose constraints or an alternative fractionation schedule may be required to decrease the risk of urinary toxicity.
Provision of Induced Abortion in Wessex Health Region: Unmet Need and Feasibility of Compensatory Day Care
Authors: John R Ashton
Journal: Journal of the Royal Society of Medicine (1980)

A study of routinely collected data showed that in 1975 only 42% of Wessex abortion patients obtained a National Health Service operation in their own region. Within this average the range for own district National Health Service operations was from 8.7% (Central Hampshire) to 68% (South West Hampshire) when known paybed operations had been excluded. Most of the remaining patients obtained private operations outside the region and of these about 50% obtained an operation at the British Pregnancy Advisory Service Clinic (BPAS) at Brighton.A survey of Wessex women obtaining induced abortions at BPAS, Brighton, found that 85% of a sample of patients interviewed would have been willing to have a National Health Service operation locally but it had not been available. Only 24% of these women had been referred by way of a formal and accepted path, and had obtained their operation before ten weeks gestation, a suggested maximum for day-care provision.It this proportion is representative of Wessex patients obtaining operations outside the region, the numbers of patients involved in 1975 would have been 643 and the feasibility of a day surgical unit specially providing for this number would be questionable.It is suggested that by reducing delays in the referral process and accepting patients by nontraditional referral paths at least a further 21% of the patients would have qualified for day care. On the basis of this estimate a Regional Day Abortion Unit is probably a practicable proposition.