tbuckley/cabot-search huggingface dataset:
Effects of Celecoxib and Low-dose Aspirin on Outcomes in Adjuvant Aromatase Inhibitor–Treated Patients: CCTG MA.27
Authors: Kathrin Strasser-Weippl, Michaela J Higgins, Judith-Anne W Chapman, James N Ingle, George W Sledge, George T Budd, Matthew J Ellis, Kathleen I Pritchard, Mark J Clemons, Tanja Badovinac-Crnjevic, Lei Han, Karen A Gelmon, Manuela Rabaglio, Catherine Elliott, Lois E Shepherd, Paul E Goss
Journal: JNCI Journal of the National Cancer Institute (2018)

Celecoxib and low-dose aspirin might decrease risk of breast cancer recurrence.In the Canadian Cancer Trials Group MA.27, postmenopausal hormone receptor-positive breast cancer patients were randomly assigned (2 × 2) to adjuvant exemestane or anastrozole, and celecoxib or placebo. Low-dose aspirin of 81 mg or less was a stratification factor. Due to concerns about cardiac toxicity, celecoxib use was stopped in December 2004, while stratification by aspirin use was removed through protocol amendment. We examined the effects of celecoxib and low-dose aspirin on event-free survival (EFS), defined as time from random assignment to time of locoregional or distant disease recurrence, new primary breast cancer, or death from any cause; distant disease-free survival (DDFS); and overall survival (OS). All statistical tests were two-sided.Random assignment to celecoxib (n = 811, 50.0%) or placebo (n = 811, 50.0%) was discontinued after 18 months (n = 1622). At a median of 4.1 years' follow-up, among 1622 patients, 186 (11.5%) patients had an EFS event: 80 (4.9%) had distant relapse, and 125 (7.7%) died from any cause. Celecoxib did not statistically significantly impact EFS, DDFS, or OS in univariate analysis (respectively, P = .92, P = .55, and P = .56) or multivariable analysis (respectively, P = .74, P = .60, and P = .76). Low-dose aspirin use (aspirin users n = 476, 21.5%; non-aspirin users n = 1733, 78.5%) was associated in univariate analyses with worse EFS (hazard ratio [HR] = 1.48, 95% confidence interval [CI] = 1.12 to 1.96, P = 0.006) and worse OS (HR = 1.87, 95% CI = 1.35 to 2.61, P < .001). After adjusting for baseline characteristics and treatment arm, aspirin use showed no statistical association with EFS (P = .08) and DDFS (P = .82), but was associated with statistically worse OS (HR = 1.67, 95% CI = 1.13 to 2.49, P = .01).Random assignment to short-term (≤18 months) celecoxib as well as use of low-dose aspirin showed no effect on DDFS and EFS in multivariable analysis. Low-dose aspirin increased "all-cause" mortality, presumably because of higher preexisting cardiovascular risks.
<i>Notes from the Field</i>: HIV Infection Investigation in a Rural Area — West Virginia, 2017
Authors: Mary E. Evans, Sarah M. Labuda, Vicki Hogan, Christine Agnew-Brune, John Armstrong, Amarnath Babu Periasamy Karuppiah, Deborah Blankinship, Kate Buchacz, Kenya Burton, Sharon Cibrik, William Hoffman, Nathan Kirk, Chang Lee, Dondeena McGraw, M. Cheryl Bañez Ocfemia, Nivedha Panneer, Pamela Reynolds, Bridget Rose, Melinda Salmon, Melissa Scott, Antoine Thompson, David Wills, Sherri A. Young, Rahul Gupta, Loretta Haddy, Paul J. Weidle, Miguella Mark-Carew
Journal: MMWR Morbidity and Mortality Weekly Report (2018)
Working time restrictions may have increased tensions between trainees and consultants, studies find
Authors: Abi Rimmer
Journal: BMJ (2014)

European restrictions on working hours may have increased tensions between junior doctors and their senior colleagues, researchers have found.

Two studies published on BMJ Open showed that doctors saw restrictions on working hours as having reduced junior doctors’ time in training and increased the work carried out by consultants. But the researchers behind the studies said that it was difficult to determine whether doctors’ concerns stemmed from the restrictions themselves or the way that hospitals had implemented them.

One study was a qualitative analysis of 279 unsolicited free text comments about the European Working Time Directive (EWTD).1 The responses—from 1993, 2005, and 2009—were made by three groups of UK medical graduates as part of a wider survey of doctors’ training and career choices. 

This study found that the reduction in junior doctors’ time in training and the increase in work for senior doctors may have created tensions between the two groups. “Some consultants indicated that they felt beleaguered by carrying some of …
Characterization of progressive multifocal leukoencephalopathy (PML) in patients treated with rituximab, brentuximab and ibrutinib: A report from the Southern Oncology Network on Adverse Reactions (SONAR).
Authors: Anuhya Kommalapati, Sri Harsha Tella, Charles L. Bennett
Journal: Journal of Clinical Oncology (2018)

133 Background: Since the advent of Rituximab (R) in 1997, cancer immunotherapy is increasingly used for management of lymphoproliferative disorders. Unexpected cases of PML have been reported in HIV-negative patients in 2005 receiving Rituximab ( R) and subsequently in 2012 and 2014, who received brentuximab vedotin ( B) or ibrutinib ( I), respectively. We sought to compare and contrast clinical characteristics and outcomes of PML in HIV-negative patients who were treated with R, B or I therapy. Methods: Retrospective analysis of the FDA adverse event reporting system (FAERS) and previously published data by our group with confirmed cases of PML associated with R (1997-2008), B and I therapy (2009-2015). Results: PML develops early during the therapy with B and I, compared to that of R group. Confirmation of the diagnosis of PML by MRI in conjunction with JC virus identification in the cerebrospinal fluid or brain biopsy using objective criteria was found only in 40-60% of the cases. Among confirmed cases of R, I, or B-associated PML, mortality was &gt; 90%, usually occurring within weeks to months following diagnostic confirmation. Rare cases of survival were associated with return of immunologic function, including in one case development of an immune reconstitution syndrome. Conclusions: This is the first study that compared the clinical characteristics of PML in R, B and I. PML cases can occur early during the therapy using B and I, while usually occurs late with R. Additional research is needed to quantify the risk factors of PML and to know if this association is causal or incidental. Meanwhile, physicians and patients should be vigilant in detecting and reporting this rare AE to minimize future fatalities [Table: see text]
Circulating Tumor DNA Genomics Correlate with Resistance to Abiraterone and Enzalutamide in Prostate Cancer
Authors: Matti Annala, Gillian Vandekerkhove, Daniel Khalaf, Sinja Taavitsainen, Kevin Beja, Evan W. Warner, Katherine Sunderland, Christian Kollmannsberger, Bernhard J. Eigl, Daygen Finch, Conrad D. Oja, Joanna Vergidis, Muhammad Zulfiqar, Arun A. Azad, Matti Nykter, Martin E. Gleave, Alexander W. Wyatt, Kim N. Chi
Journal: Cancer Discovery (2018)

Abstract Primary resistance to androgen receptor (AR)–directed therapies in metastatic castration-resistant prostate cancer (mCRPC) is poorly understood. We randomized 202 patients with treatment-naïve mCRPC to abiraterone or enzalutamide and performed whole-exome and deep targeted 72-gene sequencing of plasma cell-free DNA prior to therapy. For these agents, which have never been directly compared, time to progression was similar. Defects in BRCA2 and ATM were strongly associated with poor clinical outcomes independently of clinical prognostic factors and circulating tumor DNA abundance. Somatic alterations in TP53, previously linked to reduced tumor dependency on AR signaling, were also independently associated with rapid resistance. Although detection of AR amplifications did not outperform standard prognostic biomarkers, AR gene structural rearrangements truncating the ligand binding domain were identified in several patients with primary resistance. These findings establish genomic drivers of resistance to first-line AR-directed therapy in mCRPC and identify potential minimally invasive biomarkers. Significance: Leveraging plasma specimens collected in a large randomized phase II trial, we report the relative impact of common circulating tumor DNA alterations on patient response to the most widely used therapies for advanced prostate cancer. Our findings suggest that liquid biopsy analysis can guide the use of AR-targeted therapy in general practice. Cancer Discov; 8(4); 444–57. ©2018 AACR. See related commentary by Jayaram et al., p. 392. This article is highlighted in the In This Issue feature, p. 371
GPs should lose long term sickness certification role to new agency, review concludes
Authors: Ingrid Torjesen
Journal: BMJ (2011)

GPs in England should be stripped of much of their responsibility for deciding whether people with long term illness are fit and able to work, recommends a review commissioned by the government.

The Independent Review of Sickness Absence says that the current system pushes people away from work and provides little support for them to return. It recommends that a new government funded Independent Assessment Service rather than a person’s own GP should be responsible for signing off people for long term sick leave.

People could be referred to the service by their employer or GP after they have been off work for four weeks, and health professionals would assess their physical or mental function and provide …
Suicides Among American Indian/Alaska Natives — National Violent Death Reporting System, 18 States, 2003–2014
Authors: Rachel A. Leavitt, Allison Ertl, Kameron Sheats, Emiko Petrosky, Asha Ivey-Stephenson, Katherine A. Fowler
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

Suicide disproportionately affects American Indians/Alaska Natives (AI/AN). The suicide rate among AI/AN has been increasing since 2003 (1), and in 2015, AI/AN suicide rates in the 18 states participating in the National Violent Death Reporting System (NVDRS) were 21.5 per 100,000, more than 3.5 times higher than those among racial/ethnic groups with the lowest rates.* To study completed suicides across all ages of AI/AN, NVDRS data collected from 2003 to 2014 were analyzed by comparing differences in suicide characteristics and circumstances between AI/AN and white decedents. Group differences were assessed using chi-squared tests and logistic regression. Across multiple demographics, incident characteristics, and circumstances, AI/AN decedents were significantly different from white decedents. More than one third (35.7%) of AI/AN decedents were aged 10-24 years (versus 11.1% of whites). Compared with whites, AI/AN decedents had 6.6 times the odds of living in a nonmetropolitan area, 2.1 times the odds of a positive alcohol toxicology result, and 2.4 times the odds of a suicide of a friend or family member affecting their death. Suicide prevention efforts should incorporate evidence-based, culturally relevant strategies at individual, interpersonal, and community levels (2) and need to account for the heterogeneity among AI/AN communities (3,4).
Trainee surgeons want JCST fee to be covered by royal colleges
Authors: Abi Rimmer
Journal: BMJ (2015)

The Association of Surgeons in Training has called for the UK royal surgical colleges to incorporate the cost of the Joint Committee on Surgical Training fee into their membership fees.

In a letter the association has asked the Royal College of Physicians and Surgeons of Glasgow, the Royal College of Surgeons of Edinburgh, and the Royal College of Surgeons of England to make the change. 

The Joint Committee on Surgical Training advises the four surgical royal colleges of the UK and Ireland on all matters relating to surgical training. Surgical trainees pay the fee to …
NHS acute sector spends more than £2.4bn a year on non-permanent staff
Authors: Helen Jaques
Journal: BMJ (2013)

The acute sector of the NHS spends more than £2.4bn (€2.8bn; $3.7bn) a year on non-permanent staff, with wide variation across England in how much each trust spends.

The government has said that the NHS could save up to £230m if all acute trusts kept their expenditure on non-permanent staff in line with the national average of 4% of total workforce spend.

The Department of Health’s procurement development programme for the NHS shows “enormous …
Abstract P2-06-01: Molecular characterization of human malignant phyllodes tumors reveals potential targeted approaches
Authors: H-G Moon, J Yun, BS Hong, E Lee, H-B Lee, W Han, J-I Kim, D-Y Noh, W Heo, S Hur, W Kang, C Lee
Journal: Cancer Research (2018)

Abstract Malignant phyllodes tumor (MPT) which belong to the fibroepithelial neoplasm spectrum is a rare type of breast malignancy, and currently there is no effective targeted approach available for MPT. In this study, we tried to identify key genomic alterations and biologic pathways in MPT by whole exome and RNA sequencing of nine MPT tissues. Whole exome sequencing revealed somatic alterations in EGFR, MED12, PIK3CA, PIK3R1, PDGFRA, PDGFRB, PTEN, and TP53. Transcriptome sequencing showed dysregulation of ECM-receptor interaction, focal adhesion, and PI3K-Akt signaling in MPTs when compared to normal breast or invasive breast cancer tissues. Based on the transcriptome profiles, the MPTs were classified into two subtypes; fibrous subtype with upregulation of stromal genes such as collagens and epithelial subtype with upregulation of E-cadherin and Claudins. The molecular classification of fibrous and epithelial subtypes was validated in 28 paraffin-embedded MPT tissues. The fibrous subtype showed higher mitotic index and increased risk for recurrence when compared to the epithelial subtype. We established a patient-derived xenograft model from one fibrous subtype MPT which harbored somatic mutation in PIK3R1 and PDGFRB. In that model, targeted treatment against PIK3CA/mTOR and PDGFR pathways effectively suppressed the tumor growth in vivo. Our data provide insights on the biologic understanding of MPT and suggest a clinically relevant molecular classification. Furthermore, we show that developing effective targeted approaches in MPT can be possible with genomic profiles and patient-derived xenograft models. The clinical efficacy of targeting PDGFR and PIK3CA/mTOR pathways in MPT should be tested in future clinical trials. Citation Format: Moon H-G, Yun J, Hong BS, Lee E, Lee H-B, Han W, Kim J-I, Noh D-Y, Heo W, Hur S, Kang W, Lee C. Molecular characterization of human malignant phyllodes tumors reveals potential targeted approaches [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 P2-06-01.
I am currently a fourth year medical student. I was hoping for some advice on the academic foundation placements. Do you know how many are available?
Authors: Rebecca Fitzgerald
Journal: BMJ (2007)

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>
Vascular imaging study day course
Authors: Jakub Kaczynski
Journal: BMJ (2012)

Trainees in vascular surgery are expected to be competent in performing endovascular procedures and vascular imaging techniques, but currently there is no formal vascular imaging teaching in the surgical curriculum. The vascular imaging study day provided by the Royal College of Radiologists is an opportunity for surgical trainees to bridge this gap. The course is aimed primarily at radiology trainees, but core and higher surgical trainees would also benefit from attending the course.

Vascular surgery is rapidly evolving, and there is an increasing demand for vascular trainees to be trained in …
Smooth muscle cell and arterial aging: basic and clinical aspects
Authors: Patrick Lacolley, Veronique Regnault, Alberto P Avolio
Journal: Cardiovascular Research (2018)

Arterial aging engages a plethora of key signalling pathways that act in concert to induce vascular smooth muscle cell (VSMC) phenotypic changes leading to vascular degeneration and extracellular matrix degradation responsible for alterations of the mechanical properties of the vascular wall. This review highlights proof-of-concept examples of components of the extracellular matrix, VSMC receptors which connect extracellular and intracellular structures, and signalling pathways regulating changes in mechanotransduction and vascular homeostasis in aging. Furthermore, it provides a new framework for understanding how VSMC stiffness and adhesion to extracellular matrix contribute to arterial stiffness and how interactions with endothelial cells, platelets, and immune cells can regulate vascular aging. The identification of the key players of VSMC changes operating in large and small-sized arteries in response to increased mechanical load may be useful to better elucidate the causes and consequences of vascular aging and associated progression of hypertension, arteriosclerosis, and atherosclerosis.
Onset and maintenance of testosterone suppression in four pivotal trials of subcutaneously administered leuprolide acetate formulated with in-situ forming polymeric delivery technology.
Authors: Przemyslaw Twardowski, John A. McLane, Stuart Atkinson, Debbie Boldt-Houle, A. Oliver Sartor
Journal: Journal of Clinical Oncology (2018)

205 Background: Subcutaneously administered leuprolide acetate (SC-LA) formulated with in-situ forming polymeric delivery technology has demonstrated efficacy in suppressing testosterone (T) levels to achieve and maintain medical castration in patients with advanced prostate cancer (PCa). Increasing evidence suggests that reaching and sustaining the lowest T possible is desirable and correlated with disease specific survival. Data was pooled from four pivotal trials to determine the onset and maintenance of T levels at or lower than castration with SC-LA treatment. Methods: Eugonadal PCa patients received either 7.5 (6 doses), 22.5, 30, 45 mg (2 doses each) injections of SC-LA lasting 1, 3, 4, or 6 months, respectively, in 4 open-label, fixed-dose, pivotal trials. Serum T levels were assessed at screening, baseline (Day 0), and at least once per week throughout the studies. Target T levels were 50, 20, and 10ng/dL. The time when T crossed target level was extrapolated using the following formula: (target T – post-target T) / (pre-target T – post-target T) x (post-target date – pre-target date) = estimated days between crossing target T and post-target measurement Results: In the pooled population (N=437), median onset of T ≤50, ≤20, and ≤10ng/dL were 21 days, 28 days, and 35 days, respectively. Once the target T level was achieved, the mean proportion of time that patients maintained T suppression below each target level was 100% for T≤50 ng/dL, 94-99% for T≤20ng/dL, and 66-85% for T≤10ng/dL (Table). Conclusions: SC-LA achieved rapid onset of T≤50ng/dL in 3 weeks, T≤20ng/dL in 4 weeks, and T≤10ng/dL in 5 weeks. SC-LA maintained consistently low T levels, with over 66%, 95%, and 100% of the treatment period remaining below 10, 20, and 50 ng/dL respectively. This T suppression profile may have relevance for improved patient survival and extended time to disease progression. [Table: see text]
Patients must be told when their doctor is undergoing remediation
Authors: Helen Jaques
Journal: BMJ (2012)

Patients must be told when their doctor is undergoing remediation measures as part of the revalidation process, the House of Commons select committee on health has said.

The committee has called on the General Medical Council to clarify “as a matter of urgency” the arrangements for informing patients when a doctor has been identified by the revalidation process as in need of remediation.

Stephen Dorrell, chairman of the Health Committee and conservative MP for Charnwood, said that the committee welcomed the fact that the GMC was concerned to be fair to all doctors. “But …
Is it the time to shift paradigms in castration naïve prostate cancer (CNPC): A meta-analysis of upfront docetaxel and abiraterone in men with CNPC.
Authors: Guangxi Sun, Xingming Zhang, Junru Chen, Banghua Liao, Jinge Zhao, Pengfei Shen, Hao Zeng
Journal: Journal of Clinical Oncology (2018)

360 Background: To systematically review the relevant literature evaluating the therapeutic efficacy of upfront docetaxel (Doc) or abiraterone (Abi) plus androgen deprivation therapy (ADT) on oncological outcome in patients with CNPC. An attempt to identify subgroups of patients who will benefit most either from Doc or Abi plus ADT and further compare the efficacy and safety between these two combination therapies. Methods: A comprehensive search of the PubMed/Medline, Embase databases, ICTRP, Clinical Trial and Cochrane Central Register of Controlled Trials to July 2017 was performed. Results: Six studies involving 6480 patients were included in this meta-analysis, consisting of over sixty percent (4462/6480) of patients with metastatic CNPC (mCNPC, M1), and 31.1% (2018/6480) of patients with non-metastatic CNPC (M0). Totally, combination therapies (ADT plus Doc or Abi) significantly improved overall survival (OS) and failure-free survival (FFS) for all CNPC patients. For M1 patients, combination therapies were dramatically associated with improved OS and FFS, but for M0 patients, only with moderate improvement in FFS. M1 patients with age &lt; 70 years, ECOG performance status (ECOG PS) 0-1, Gleason score ( &lt; 8) or visceral metastases could get better survival benefit from either combination therapies. In indirect comparisons, among M1 patients with younger age ( &lt; 70 years), ECOG PS 0-1 or aggressive Gleason score (GS ≥ 8), upfront Abi showed superiority to Doc in prolonging FFS. The incidence of severe adverse events (AEs ≥ 3) was comparable between these two therapeutic regimens. Conclusions: Upfront Doc or Abi plus ADT should be considered as a standard of care for mCNPC patients who are suitable for either or both of these combination therapies.