tbuckley/cabot-search huggingface dataset:
Abstract P6-08-18: Prognostic multigene testing in breast cancer: Patterns, disparities, and opportunities for advancing standardized patient care
Authors: EB Bernhardt, AG Caffrey, MO Celaya, V Celaya, MD Chamberlin, JR Rees
Journal: Cancer Research (2018)

Abstract Background: The decision to give adjuvant chemotherapy to patients with hormone receptor positive early stage breast cancer is controversial given the overall good prognosis with local therapy (surgery and radiation) plus hormonal therapy alone. In 2004, the 21-gene RT-PCR assay recurrence score (Oncotype) was developed to stratify early stage patients into categories of high, low, and intermediate recurrence rates considering treatment with local and hormonal therapy alone. This was incorporated into the NCCN guidelines in 2008. We sought to compare NCCN guidelines to actual practice patterns. Methods: By retrospective review, data were examined from eight state registries participating in the National Program of Cancer Registries' Comparative Effectiveness Research program: Alaska, Colorado, Florida, Idaho, Louisiana, North Carolina, New Hampshire, and Rhode Island. These were then compared to NCCN guidelines for prognostic multigene testing. Results: Of the 28,372 cases examined, 18.6% were classified as carcinoma in situ, 39.6% were stage I, 24.3% were stage II, 9.1% were stage III, 4.9% were stage IV, and 3.6% were unknown stage. The overwhelming majority of cases, 75.5%, were estrogen receptor (ER) or progesterone receptor (PR) positive, while 15.7% were ER and PR negative, and 8.8% were hormone receptor unknown. Approximately 40% of cases were human epidermal growth factor receptor 2 (HER2) positive, and the remaining 60% were HER2 negative or unknown. Approximately 72% of patients were node negative or had unknown nodal involvement, while the remaining 28% had at least micro-metastatic nodal disease. Invasive ductal carcinoma was the most common histology accounting for 71.4% of cases examined. Median age was 62. Data analysis for the use of prognostic multigene testing in relation to NCCN guidelines, race, age, and the above clinical factors is on-going and will be presented at SABCS 2017. Conclusion: The purpose of this study is to examine the factors associated with the use of prognostic multigene testing according to the NCCN guidelines, including personal and clinical factors. By identifying practice patterns we can then address disparities and opportunities for advancing standardized quality patient care. Citation Format: Bernhardt EB, Caffrey AG, Celaya MO, Celaya V, Chamberlin MD, Rees JR. Prognostic multigene testing in breast cancer: Patterns, disparities, and opportunities for advancing standardized patient care [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 P6-08-18.
SEMI-AUTOMATIC CLASSIFICATION OF CARDIAC BLOOD-FLOW FIELDS USING ECHOCARDIOGRAPHIC PARTICLE IMAGING VELOCIMETRY DATA
Authors: Ali Hama Amin, Sirish Shrestha, Marton Tokodi, Muhammad Ashraf, Grace Verzosa, Mokoto Amaki, Haruhiko Abe, Partho P. Sengupta
Journal: Journal of the American College of Cardiology (2018)
Association of Inhaled Corticosteroids and Long-Acting Muscarinic Antagonists With Asthma Control in Patients With Uncontrolled, Persistent Asthma
Authors: Diana M. Sobieraj, William L. Baker, Elaine Nguyen, Erin R. Weeda, Craig I. Coleman, C. Michael White, Stephen C. Lazarus, Kathryn V. Blake, Jason E. Lang
Journal: JAMA (2018)

Long-acting muscarinic antagonists (LAMAs) are a potential adjunct therapy to inhaled corticosteroids in the management of persistent asthma.To conduct a systematic review and meta-analysis of the effects associated with LAMA vs placebo or vs other controllers as an add-on therapy to inhaled corticosteroids and the use of a LAMA as add-on therapy to inhaled corticosteroids and long-acting β-agonists (LABAs; hereafter referred to as triple therapy) vs inhaled corticosteroids and LABA in patients with uncontrolled, persistent asthma.MEDLINE, EMBASE, Cochrane databases, and clinical trial registries (earliest date through November 28, 2017).Two reviewers selected randomized clinical trials or observational studies evaluating a LAMA vs placebo or vs another controller as an add-on therapy to inhaled corticosteroids or triple therapy vs inhaled corticosteroids and LABA in patients with uncontrolled, persistent asthma reporting on an outcome of interest.Meta-analyses using a random-effects model was conducted to calculate risk ratios (RRs), risk differences (RDs), and mean differences (MDs) with corresponding 95% CIs. Citation screening, data abstraction, risk assessment, and strength-of-evidence grading were completed by 2 independent reviewers.Asthma exacerbations.Of 1326 records identified, 15 randomized clinical trials (N = 7122 patients) were included. Most trials assessed adding LAMA vs placebo or LAMA vs LABA to inhaled corticosteroids. Adding LAMA vs placebo to inhaled corticosteroids was associated with a significantly reduced risk of exacerbation requiring systemic corticosteroids (RR, 0.67 [95% CI, 0.48 to 0.92]; RD, -0.02 [95% CI, -0.04 to 0.00]). Compared with adding LABA, adding LAMA to inhaled corticosteroids was not associated with significant improvements in exacerbation risk (RR, 0.87 [95% CI, 0.53 to 1.42]; RD, 0.00 [95% CI, -0.02 to 0.02]), or any other outcomes of interest. Triple therapy was not significantly associated with improved exacerbation risk vs inhaled corticosteroids and LABA (RR, 0.84 [95% CI, 0.57 to 1.22]; RD, -0.01 [95% CI, -0.08 to 0.07]).In this systematic review and meta-analysis, the use of LAMA compared with placebo as add-on therapy to inhaled corticosteroids was associated with a lower risk of asthma exacerbations; however, the association of LAMA with benefit may not be greater than that with LABA. Triple therapy was not associated with a lower risk of exacerbations.
Phase II trial of SM 88 in non-metastatic biochemical recurrent prostate cancer.
Authors: Mack Roach, Zachary Gostout, Patricia Zawisny, Avi S. Retter, Gerald H. Sokol, Steve Hoffman, Giuseppe Del Priore
Journal: Journal of Clinical Oncology (2018)

175 Background: Despite toxicity and no clear survival benefit, non-metastatic recurrent prostate cancer (nmPC) is typically treated with androgen deprivation therapy (ADT). SM88 is a relatively non-toxic novel combination therapy (amino acid analogue, CYP3a4 inducer, mTOR inhibitor and catalyst) based on the Warburg effect, with activity in a variety of cancers including prostate (JCO 2017 35, e16567). Phase I and II results demonstrated stable or rising testosterone levels while achieving a reduction of CTCs (circulating tumor cells) and no radiographic progression events (Annal Oncol 2017, 28(5):274-5). We now report results for toxicities typically seen with ADT. Methods: Prospective ongoing Phase Ib/II of SM88 (230mg po bid) in recurrent nmPC with rising PSA (PCWG3 definition), detectable CTCs, and no radiographically identified metastases at baseline. Results: Since Sept 2016, there have been 17 consented (of 34 planned) with 10 evaluable (completed &gt; 1 cycle) (median 7, range 1-13). Mean age was 71.2 (53-84); all had prior ADT after curative intent RT (50%) or surgery (50%); with no patient currently on ADT. Mean testosterone level was 307.6 ng/dL before SM88 and 349.2 after (p = 0.07, one-tail T test), rising in (5/10) or remained stable except for one patient who entered the trial castrate ( &lt; 2.5). Overall 70% had some grade 1-2 adverse event (AE) but no drug related serious AE. EORTC-QLQ-C30 relating to mental function domain (Q20-28) and QLQ-PR25 intimacy domains (Q44-50) remained stable, including 9 (90%) reporting no or resolved hot flashes; 7 (70%) reporting an improved or stable “interest in sex”; and 6 (60%) having “excellent” “overall health” and “QOL”. Weight and osteoporosis (measured by Urinary NTX) did not worsen; mean EKG QTc (422 ms); mean arterial pressure (95.1 mmHg); glucose (115.2 mg/dl) and hematocrit (41.5%) were not affected. Conclusions: Toxicities typically associated with ADT were not seen with SM88, a novel non-hormonal anti-neoplastic. Despite the limited follow-up, these data suggest that ADT may be avoided or delayed without progression in selected patients with nmPC. A phase III RCT of SM88 vs patient choice of hormonal or active surveillance is planned for confirmation of these results. Clinical trial information: NCT02796898.
INCESSANT QT PROLONGATION AND RECURRENT VENTRICULAR ARRHYTHMIA IN SUB-ACUTE STRESS-INDUCED CARDIOMYOPATHY
Authors: Hoyle Whiteside, Arun Nagabandi, Tarun Sharma, Pascha Schafer, Haitham Hreibe, John Thornton
Journal: Journal of the American College of Cardiology (2018)
Mental health issues are up by a third among London GPs, preliminary data show
Authors: Caroline White
Journal: BMJ (2013)

The number of general practitioners succumbing to mental health issues has increased sharply over the past couple of years—at least in the capital. GPs comprised 37% of the caseload at the London based Practitioner Health Programme (PHP) in 2010-11, but they now represent over 50%, preliminary figures from the PHP show.

The confidential service, which is funded by clinical commissioning groups in London, treats psychological and addiction problems among doctors and dentists living in London, with referrals accepted from certain other areas in the south of England on a cost per case basis.

The next full report on its activities is not due to be published until October, but …
Combination Approach for Detecting Different Types of Alterations in Circulating Tumor DNA in Leiomyosarcoma
Authors: Joanna Przybyl, Jacob J. Chabon, Lien Spans, Kristen N. Ganjoo, Sujay Vennam, Aaron M. Newman, Erna Forgó, Sushama Varma, Shirley Zhu, Maria Debiec-Rychter, Ash A. Alizadeh, Maximilian Diehn, Matt van de Rijn
Journal: Clinical Cancer Research (2018)

Purpose: The clinical utility of circulating tumor DNA (ctDNA) monitoring has been shown in tumors that harbor highly recurrent mutations. Leiomyosarcoma represents a type of tumor with a wide spectrum of heterogeneous genomic abnormalities; thus, targeting hotspot mutations or a narrow genomic region for ctDNA detection may not be practical. Here, we demonstrate a combinatorial approach that integrates different sequencing protocols for the orthogonal detection of single-nucleotide variants (SNV), small indels, and copy-number alterations (CNA) in ctDNA.Experimental Design: We employed Cancer Personalized Profiling by deep Sequencing (CAPP-Seq) for the analysis of SNVs and indels, together with a genome-wide interrogation of CNAs by Genome Representation Profiling (GRP). We profiled 28 longitudinal plasma samples and 25 tumor specimens from 7 patients with leiomyosarcoma.Results: We detected ctDNA in 6 of 7 of these patients with >98% specificity for mutant allele fractions down to a level of 0.01%. We show that results from CAPP-Seq and GRP are highly concordant, and the combination of these methods allows for more comprehensive monitoring of ctDNA by profiling a wide spectrum of tumor-specific markers. By analyzing multiple tumor specimens in individual patients obtained from different sites and at different times during treatment, we observed clonal evolution of these tumors that was reflected by ctDNA profiles.Conclusions: Our strategy allows for the comprehensive monitoring of a broad spectrum of tumor-specific markers in plasma. Our approach may be clinically useful not only in leiomyosarcoma but also in other tumor types that lack recurrent genomic alterations. Clin Cancer Res; 24(11); 2688-99. ©2018 AACR.
Third and fourth degree perineal tears hands-on repair course
Authors: Ganesh Thiagamoorthy
Journal: BMJ (2012)

Obstetric anal sphincter injuries are a major cause of anal incontinence and can have a devastating effect on a woman’s physical, social, and emotional wellbeing. When undiagnosed they are a frequent source of complaint and litigation. This one day hands-on course gave me the knowledge and practical skills to identify the risk factors and diagnose, classify, and manage obstetric anal sphincter injuries.

I attended the course as a junior registrar in obstetrics and gynaecology because I wanted to understand the basic anatomy and physiology and, most importantly, how to identify obstetric anal sphincter injuries before being taught repair techniques. During postnatal ward rounds I realised how little is taught and known about the consequences of such injuries and how women should be managed in subsequent pregnancies. I chose this course …
Two-Year Outcomes with a Magnetically Levitated Cardiac Pump in Heart Failure
Authors: Mandeep R. Mehra, Daniel J. Goldstein, Nir Uriel, Joseph C. Cleveland, Melana Yuzefpolskaya, Christopher Salerno, Mary N. Walsh, Carmelo A. Milano, Chetan B. Patel, Gregory A. Ewald, Akinobu Itoh, David Dean, Arun Krishnamoorthy, William G. Cotts, Antone J. Tatooles, Ulrich P. Jorde, Brian A. Bruckner, Jerry D. Estep, Valluvan Jeevanandam, Gabriel Sayer, Douglas Horstmanshof, James W. Long, Sanjeev Gulati, Eric R. Skipper, John B. O’Connell, Gerald Heatley, Poornima Sood, Yoshifumi Naka
Journal: New England Journal of Medicine (2018)

In an early analysis of this trial, use of a magnetically levitated centrifugal continuous-flow circulatory pump was found to improve clinical outcomes, as compared with a mechanical-bearing axial continuous-flow pump, at 6 months in patients with advanced heart failure.
Baseline circulating myeloid-derived suppressor cells and response to PD-1 inhibitor in non-small cell lung cancer patients.
Authors: Myriam Delaunay, Nicolas Guibert, Amellie Lusque, Magali Farella, Nadia Boubekeur, Sandrine Gouin, Inge Dormoy, Pierre Fons, Michael Esquerre, Gilles Favre, Anne Pradines, Julien Mazieres
Journal: Journal of Clinical Oncology (2018)

145 Background: Inhibitors of immune checkpoint PD-1/PD-L1 (ICI) have become a care standard in non-small cell lung cancer (NSCLC). Despite promising results, some patients cannot take advantage of immunotherapy effects. Nowadays, neither predictive nor prognostic circulating biomarkers have been found in order to select patients or to predict response to ICI. Myeloid-derived suppressor cells (MDSC) are potent immunity suppressors and may represent both a potential prognostic and a predictive biomarker. Methods: Peripheral blood samples regarding 54NSCLC patients treated with nivolumab and 5 healthy donors were prospectively included. Early-MDSC: e-MDSC (LIN - /CD14 - /CD15 - /HLA-DR - /CD33 + ), monocytic-MDSC: M-MDSC (HLA-DR low/- /CD14 + /CD15 - /CD11b + ), polymorphonuclear-MDSC: PMN-MDSC (HLA-DR low/- /CD14 - /CD15 + /CD11b + ) were analyzed through flow cytometry. MDSC percentage was calculated from viable peripheral blood mononuclear cells. We assessed if e-MDSC,M-MDSC and PMN-MDSC levels detected before anti-PD-1 therapy correlate with both progression-free survival (PFS) and overall survival (OS). Results: 54 patients were prospectively included: 41 with adenocarcinoma and 13 with squamous NSCLC. When compared to healthy donors, patients had significantly higher levels of circulating e-MDSC(median (range): 0.13% (0-10.9) vs0.02%(0.01-0.14), p = 0.04) and M-MDSC (median (range): 4.55% (0.08-24.18) vs1.36% (0.77-3.76), p = 0.01). Cox proportional hazard regression analysis showed that high level of M-MDSC before anti-PD-1 therapy was associated with OS (HR [CI95%]: 1.08 [1.01; 1.15],p = 0.02) and PFS (HR [CI95%]: 1.07 [1.01;1.14], p = 0.02). No prognostic impact was observed regarding e-MDSC and PMN-MDSC. Conclusions: Our study suggests that a baseline circulating high level of M-MDSC is associated with poor survival. M-MDSC may be a predictive and prognostic biomarker in NSCLC patients treated with anti-PD1. Further studies have been scheduled, including MDSC monitoring during anti-PD1 treatment, in order to confirm our findings. These data would be interesting for the development of combined therapy, targeting the suppressive environment, with ICI.
A real-world comparison of multi-modality therapies in locally advanced gastro-esophageal junction (GEJ) cancers.
Authors: Haider Samawi, Derek Tilley, Patricia A. Tang, Jennifer L. Spratlin, Richard M. Lee-Ying, Winson Y. Cheung
Journal: Journal of Clinical Oncology (2018)

96 Background: Trials show that addition of systemic therapy and/or radiation to surgery improves survival in GEJ cancers. However, the different regimens have not been directly compared. We examined population-based outcomes of 3 treatments: 1) neoadjuvant carboplatin and paclitaxel plus radiation (CROSS); 2) perioperative epirubicin, cisplatin, and fluoropyrimidine (MAGIC); and 3) cisplatin and fluoropyrimidine with radiation (CisFP). Methods: We reviewed patients diagnosed with GEJ cancer from 2005 to 2015 who received CROSS, MAGIC, or CisFP at 2 tertiary, 4 regional, and 11 community cancer centers in Alberta, Canada. Survival was assessed with Kaplan-Meier curves and compared with the log-rank test. A Cox proportional hazards model was constructed to evaluate the impact of treatment on overall survival (OS). Results: 331 patients were identified. Median age was 63 (IQR 56-69) years and 86% were men. CROSS was used in 217 (65%) cases followed by CisFP in 72 (22%) and MAGIC in 42 (13%). Age, sex, and stage were not associated with treatment selection (all p &gt; 0.05), but a higher proportion of CROSS and CisFP patients had adenocarcinoma (86% and 85%, respectively) compared to MAGIC patients (41%) ( p &lt; 0.01). CROSS and MAGIC correlated with higher surgical resection rates when compared to CisFP (82% vs. 79% vs. 50%, respectively, p &lt; 0.01). Median OS favored CROSS and MAGIC rather than CisFP, but this was not statistically significant (29 vs. 34 vs. 20 months, respectively, p= 0.17). Adjusting for confounders, OS remained similar for MAGIC (HR 0.8, 95%CI 0.5-1.3, p= 0.36) and CisFP (HR 0.7, 95%CI 0.5-1.1, p= 0.10) when compared to CROSS. In addition, age &gt; 65, advanced stage, and lack of surgical resection were associated with increased risk of death (HR 1.5, 95%CI 1.1-2.0, p= 0.02, HR 2.2, 95%CI 1.2-3.9, p&lt; 0.01 and HR 4.1, 95%CI 2.8-5.9, p&lt; 0.01, respectively). Conclusions: OS was similar across all 3 regimens, but outcomes were inferior to those seen in original trials. This observation suggests that GEJ patients in routine practice are different from study participants or that treatment selection may be driven by factors other than trial eligibility criteria.
Contract uncertainty causes problems for doctors seeking mortgages
Authors: Tom Moberly
Journal: BMJ (2015)

Uncertainty over the junior doctor and consultant contracts is causing problems for doctors applying for mortgages.

Financial rules introduced in April 2014 mean that lenders now seek hard evidence of future income before approving mortgage applications. But, with the dispute over junior doctors’ contract arrangements still ongoing, doctors in training are facing challenges providing evidence for their earnings after August 2015.

The BMA has previously warned that proposed changes to the junior doctors’ contract in England could make it more difficult for doctors to pay their mortgages. Kitty Mohan, former co-chair of the BMA junior doctors …
Evaluation of PUMA and NOXA expression as predictive biomarkers in prostate cancer.
Authors: Sylvie Clairefond, Benjamin Péant, Veronique Ouellet, Veronique Barres, Anne-Marie Mes-Masson, Fred Saad
Journal: Journal of Clinical Oncology (2018)

28 Background: PUMA and NOXA are two pro-apoptotic members of the BH3-only subgroup of the BCL-2 family. These two proteins play a role in the initiation of apoptosis. The objective of this study is to analyse their expression by immunofluorescence, alone or in combination, in benign and tumor prostate tissues to determine if there is a correlation between their expression and patient biochemical recurrence (BCR). Methods: Biomarker antibodies were verified for specificity and optimized by western blot and with tissue microarrays (TMA) containing prostate cancer cell lines and cell line derived xenograft tissues. Subsequently, quantification of expression for both biomarkers was performed on six TMA generated from radical prostatectomy samples (285 patients). The TMA were constructed using two cores of benign adjacent to the tumor and two cores of tumor tissue from each patient. Analysis of biomarker expression was semi-automated using the VisiomorphDP software. To optimize the analysis, we developed 2 different immunofluorescence masks: a cocktail of anti-cytokeratin-8 and -18 antibodies to identify epithelial cells and a combination of anti-p63 and anti-cytokeratin high marker weight to discriminate benign glands within tumor cores. Correlation with patient clinical outcome was determined with SPSS V20 software. Results: There was no correlation of PUMA and NOXA expression and BCR in tumor cores and stroma. In contrast, in benign epithelial cells Kaplan-Meier analysis showed a significant association between an extreme (low or high) PUMA expression and BCR (Log rank = 11.349, p = 0.001). Further analysis revealed a significant association between high NOXA expression in benign epithelial cells and BCR (Log rank = 6.133, p = 0.013). The combination of extreme PUMA and high NOXA identified patients with a poor prognosis (Log rank = 16.041, p = 0.000). In a multivariate Cox regression model, PUMA and NOXA proteins were also identified as independent predictive biomarkers of BCR. Conclusions: By studying benign epithelial cells adjacent to the tumor we identified two potential biomarkers that discriminate high-risk patients, independent of Gleason score or pathologic stage.
STABLE CAVITATION FOR EFFICIENT THROMBOLYSIS IN CORONARY MICRO-CIRCULATION: AN IN-VITRO EXPERIMENTAL STUDY WITH DODECAFLUOROPENTANE ACOUSTIC PHASE-CHANGE NANO-DROPLETS
Authors: Bo Hu, Nan Jiang, Qing Zhou, Sheng Cao, Qing Deng, Jin-Ling Chen, Rui-Qiang Guo
Journal: Journal of the American College of Cardiology (2018)
EFFECT OF SHORT AND LONG SLEEP DURATION IN PREDICTING OBESITY AMONG VARIOUS RACIAL GROUPS OF A LARGE MULTI-ETHNIC ORGANIZATION
Authors: Muhammad Aziz, Tanuja Rajan, Dorty Morency, Mythili Penugonda, Nicole Ross, Muhammad Latif, Maribeth Rouseff, Henry Guzman, Theodore Feldman, Ehimen Aneni, Emir Veledar, Khurram Nasir, West Kendal
Journal: Journal of the American College of Cardiology (2018)