tbuckley/cabot-search huggingface dataset:
Venetoclax–Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia
Authors: John F. Seymour, Thomas J. Kipps, Barbara Eichhorst, Peter Hillmen, James D’Rozario, Sarit Assouline, Carolyn Owen, John Gerecitano, Tadeusz Robak, Javier De la Serna, Ulrich Jaeger, Guillaume Cartron, Marco Montillo, Rod Humerickhouse, Elizabeth A. Punnoose, Yan Li, Michelle Boyer, Kathryn Humphrey, Mehrdad Mobasher, Arnon P. Kater
Journal: New England Journal of Medicine (2018)

Venetoclax inhibits BCL2, an antiapoptotic protein that is pathologically overexpressed and that is central to the survival of chronic lymphocytic leukemia cells. We evaluated the efficacy of venetoclax in combination with rituximab in patients with relapsed or refractory chronic lymphocytic leukemia.In this randomized, open-label, phase 3 trial, we randomly assigned 389 patients to receive venetoclax for up to 2 years (from day 1 of cycle 1) plus rituximab for the first 6 months (venetoclax-rituximab group) or bendamustine plus rituximab for 6 months (bendamustine-rituximab group). The trial design did not include crossover to venetoclax plus rituximab for patients in the bendamustine-rituximab group in whom progression occurred. The primary end point was investigator-assessed progression-free survival.After a median follow-up period of 23.8 months, the rate of investigator-assessed progression-free survival was significantly higher in the venetoclax-rituximab group (32 events of progression or death in 194 patients) than in the bendamustine-rituximab group (114 events in 195 patients); the 2-year rates of progression-free survival were 84.9% and 36.3%, respectively (hazard ratio for progression or death, 0.17; 95% confidence interval [CI], 0.11 to 0.25; P<0.001 by the stratified log-rank test). The benefit was maintained across all clinical and biologic subgroups, including the subgroup of patients with chromosome 17p deletion; the 2-year rate of progression-free survival among patients with chromosome 17p deletion was 81.5% in the venetoclax-rituximab group versus 27.8% in the bendamustine-rituximab group (hazard ratio, 0.13; 95% CI, 0.05 to 0.29), and the 2-year rate among those without chromosome 17p deletion was 85.9% versus 41.0% (hazard ratio, 0.19; 95% CI, 0.12 to 0.32). The benefit of venetoclax plus rituximab over bendamustine plus rituximab was confirmed by an independent review committee assessment of progression-free survival and other secondary efficacy end points. The rate of grade 3 or 4 neutropenia was higher in the venetoclax-rituximab group than in the bendamustine-rituximab group, but the rates of grade 3 or 4 febrile neutropenia and infections or infestations were lower with venetoclax than with bendamustine. The rate of grade 3 or 4 tumor lysis syndrome in the venetoclax-rituximab group was 3.1% (6 of 194 patients).Among patients with relapsed or refractory chronic lymphocytic leukemia, venetoclax plus rituximab resulted in significantly higher rates of progression-free survival than bendamustine plus rituximab. (Funded by Genentech and AbbVie; ClinicalTrials.gov number, NCT02005471 .).
Horizontal bone‐augmentation procedures in implant dentistry: prosthetically guided regeneration
Authors: Matteo Chiapasco, Paolo Casentini
Journal: Periodontology 2000 (2018)

The rehabilitation of partially or totally edentulous patients with implant-supported prostheses has become routine, with excellent long-term outcome. A proper implant position is mandatory to achieve good functional and esthetic outcome and may require an adequate amount of alveolar bone and surrounding soft tissue. When this is lacking because of atrophy, sequelae of periodontal disease, traumas or congenital malformations, increased bone volume and/or keratinized mucosa can be obtained by guided bone regeneration, bone-grafting techniques and alveolar bone expansion. This article presents an evidence-based, prosthetically driven approach for the treatment of edentulous ridges with horizontal defects. The classification of bony defects, the main augmentation techniques, the selection criteria among different surgical procedures for different types of bony defects, and the advantages, disadvantages and limitations of each technique, are described in detail.
Evidence of brain injury
Authors: Vivienne Nathanson
Journal: BMJ (2010)

The BMJ has published an article (Boxing doctor: get involved, BMJ Careers 2009, http://careers03.bmjknowledge.org/careers/advice/view-article.html?id=20000565) that fails to deal with the real issue of boxing—brain injury, which from recent evidence appears to be very widespread and to continue producing biological markers, as …
GP workload could rise by 15% under contract changes in Northern Ireland
Authors: Helen Jaques
Journal: BMJ (2013)

Changes to the general medical services (GMS) contract for GPs in Northern Ireland could increase their workload by up to 15% without providing any additional funding, the BMA’s Northern Ireland General Practitioners Committee has warned.

The Department of Health, Social Services and Public Safety in Northern Ireland has announced proposals for the GMS contract for 2013-14 that are very similar to those put forward for England.1

Tom Black, chairman of the committee, said that the proposals would increase the workload strains already felt by GPs in Northern Ireland. “It is estimated that our workload will …
Prognostic value of contrast enhancement and FLAIR for survival in newly diagnosed glioblastoma treated with and without bevacizumab: results from ACRIN 6686
Authors: Jerrold L Boxerman, Zheng Zhang, Yair Safriel, Jeffrey M Rogg, Ronald L Wolf, Suyash Mohan, Helga Marques, A Gregory Sorensen, Mark R Gilbert, Daniel P Barboriak
Journal: Neuro-Oncology (2018)

ACRIN 6686/RTOG 0825 was a phase III trial of conventional chemoradiation plus adjuvant temozolomide with bevacizumab or without (placebo) in newly diagnosed glioblastoma. This study investigated whether changes in contrast-enhancing and fluid attenuated inversion recovery (FLAIR)–hyperintense tumor assessed by central reading prognosticate overall survival (OS). Two hundred eighty-four patients (171 men; median age 57 y, range 19–79; 159 on bevacizumab) had MRI at post-op (baseline) and pre-cycle 4 of adjuvant temozolomide (22 wk post chemoradiation initiation). Four central readers measured bidimensional lesion enhancement (2D-T1) and FLAIR hyperintensity at both time points. Changes from baseline to pre-cycle 4 for both markers were dichotomized (increasing vs non-increasing). Cox proportional hazards model and Kaplan–Meier survival estimates were used for inference. Adjusting for treatment, increasing 2D-T1 (n = 262, hazard ratio [HR] = 2.07, 95% CI: 1.48–2.91, P < 0.0001) and FLAIR (n = 273, HR = 1.75, 95% CI: 1.26–2.41, P = 0.0008) significantly predicted worse OS. Median OS (days) was significantly shorter for patients with increasing versus non-increasing 2D-T1 for both bevacizumab (443 vs 535, P = 0.004) and placebo (526 vs 887, P = 0.001). Median OS was significantly shorter for patients with increasing versus non-increasing FLAIR for placebo (595 vs 872, P = 0.001), and trended similarly for bevacizumab (499 vs 535, P = 0.0935). Adjusting for 2D-T1 and treatment, increasing FLAIR represented significantly higher risk for death (HR = 1.59 [1.11–2.26], P = 0.01). Increased 2D-T1 significantly predicts worse OS in both treatment groups, implying absence of a substantial proportion of pseudoprogression 22 weeks after initiation of standard therapy. FLAIR adds value beyond 2D-T1 in predicting OS, potentially addressing the pseudoresponse effect by substratifying bevacizumab-treated patients with non-increasing 2D-T1.
Endogenous Sonic Hedgehog limits inflammation and angiogenesis in the ischaemic skeletal muscle of mice
Authors: Caroline Caradu, Alexandre Guy, Chloé James, Annabel Reynaud, Alain-Pierre Gadeau, Marie-Ange Renault
Journal: Cardiovascular Research (2018)

Hedgehog (Hh) signalling has been shown to be re-activated in ischaemic tissues and participate in ischaemia-induced angiogenesis. Sonic Hedgehog (Shh) is upregulated by more than 80-fold in the ischaemic skeletal muscle, however its specific role in ischaemia-induced angiogenesis has not yet been fully investigated. The purpose of the present study was to investigate the role of endogenous Shh in ischaemia-induced angiogenesis.To this aim, we used inducible Shh knock-out (KO) mice and unexpectedly found that capillary density was significantly increased in re-generating muscle of Shh deficient mice 5 days after hind limb ischaemia was induced, demonstrating that endogenous Shh does not promote angiogenesis but more likely limits it. Myosin and MyoD expression were equivalent in Shh deficient mice and control mice, indicating that endogenous Shh is not required for ischaemia-induced myogenesis. Additionally, we observed a significant increase in macrophage infiltration in the ischaemic muscle of Shh deficient mice. Our data indicate that this was due to an increase in chemokine expression by myoblasts in the setting of impaired Hh signalling, using tissue specific Smoothened conditional KO mice. The increased macrophage infiltration in mice deficient for Hh signalling in myocytes was associated with increased VEGFA expression and a transiently increased angiogenesis, demonstrating that Shh limits inflammation and angiogenesis indirectly by signalling to myocytes.Although ectopic administration of Shh has previously been shown to promote ischaemia-induced angiogenesis, the present study reveals that endogenous Shh does not promote ischaemia-induced angiogenesis. On the contrary, the absence of Shh leads to aberrant ischaemic tissue inflammation and a transiently increased angiogenesis.
Diagnostic accuracy of dermatofluoroscopy in cutaneous melanoma detection: results of a prospective multicentre clinical study in 476 pigmented lesions
Authors: A. Forschner, U. Keim, M. Hofmann, I. Spänkuch, D. Lomberg, B. Weide, I. Tampouri, T. Eigentler, C. Fink, C. Garbe, H.A. Haenssle
Journal: British Journal of Dermatology (2018)

Early detection is a key factor in improving survival from melanoma. Today, the clinical diagnosis of cutaneous melanoma is based mostly on visual inspection and dermoscopy. Preclinical studies in freshly excised or paraffin-embedded tissue have shown that the melanin fluorescence spectra after stepwise two-photon excitation, a process termed dermatofluoroscopy, differ between cutaneous melanoma and melanocytic naevi. However, confirmation from a larger prospective clinical study is lacking.The primary end point of this study was to determine the diagnostic accuracy of dermatofluoroscopy in melanoma detection. Secondary end points included the collection of data for improving the computer algorithm that classifies skin lesions based on melanin fluorescence and the assessment of safety aspects.This was a prospective, blinded, multicentre clinical study in patients with pigmented skin lesions (PSLs) indicated for excision either to rule out or to confirm cutaneous melanoma. All included lesions underwent dermoscopy and dermatofluoroscopy in vivo before lesions were excised and subjected to histopathological examination.In total, 369 patients and 476 PSLs were included in the final analysis. In 101 of 476 lesions (21·2%) histopathology revealed melanoma. The observed sensitivity of dermatofluoroscopy was 89·1% (90 of 101 melanomas identified), with an observed specificity of 44·8%. The positive and negative predictive values were 30·3% and 93·9%, respectively. No adverse events occurred.Dermatofluoroscopy is a safe and accurate diagnostic method to aid physicians in diagnosing cutaneous melanoma. Limitations arise from largely amelanotic or regressing lesions lacking sufficient melanin fluorescence.
MDSC clinical assay for cancer detection and monitoring in renal cell carcinoma.
Authors: Arnab Basu, Kanthi Athreya Kollengode, Genevieve Danenberg, Hugh Manoli, Ali Rafatnia, Eesha Chakravartty, Alan L. Epstein, Jacek K. Pinski
Journal: Journal of Clinical Oncology (2018)

TPS713 Background: Human Myeloid Derived Suppressor Cells (MDSCs) have gained recognition as a significant population of cells that arise in cancer patients to mediate immune tolerance. Some studies have shown MDSC concentrations to be associated with overall survival and response to therapy in renal cell carcinoma. MDSCs comprise a heterogenous population that are yet to be fully characterized. We have identified a set of biomarkers uniquely expressed by the suppressive human MDSC phenotype and have developed an assay targeted to these markers. MDSCs are potentially a relatively cheap and easily performed screening and monitoring tool in cancers. This study will examine how a proprietary clinical assay works in detecting and monitoring MDSCs in blood and urine samples from patients with localized or metastatic renal cell cancer. Methods: The pilot research trial will enroll 63 subjects in a 1:1:1 ratio in three groups, normal controls over age 40 without evidence of any malignancy, patients with metastatic disease and localized renal cell carcinoma prior to nephrectomy. This sample size provides 80% power to detect a 1SD difference in MDSC concentrations in these groups on an F test. Blood and urine samples will be drawn at baseline and at 4 months for comparison. The percent CD33+ HLA-DRlow HIF1a+, CD33+ HLADRlow C/EBPb+, CD11b+ HLA-DRlow HIF1a+, and CD11b+ HLA-DRlow C/EBPb+cells as a fraction of PBMC will be determined. Primary Outcome Measures will be 1. Change in MDSC levels in patients with known localized renal cell carcinoma who undergo surgical treatment. 2. Change in MDSC level in patients with known metastatic renal cell carcinoma who initiate systemic treatment and 3. The direction and magnitude of the changes compared with radiographically assessed tumor burden. Secondary outcome measures are to assess MDSC level measurements in urine cytology analysis at baseline and after treatment to determine whether the two tests correlate in any of the 3 groups of patients defined in this study. Conclusion: This pilot study will examine if a MDSC clinical assay works in detecting and monitoring MDSCs. Recruitment is open to patients at the USC Cancer center and LAC+USC medical center. Clinical trial information: NCT02664883.
The E3 Ubiquitin Ligase Siah2 Contributes to Castration-Resistant Prostate Cancer by Regulation of Androgen Receptor Transcriptional Activity
Authors: Jianfei Qi, Manisha Tripathi, Rajeev Mishra, Natasha Sahgal, Ladan Fazli, Susan Ettinger, William J. Placzek, Giuseppina Claps, Leland W.K. Chung, David Bowtell, Martin Gleave, Neil Bhowmick, Ze’ev A. Ronai
Journal: Cancer Cell (2013)
Most remaining CCGs are authorised with conditions
Authors: Helen Jaques
Journal: BMJ (2013)

The final 48 clinical commissioning groups (CCGs) in England have been authorised by the NHS Commissioning Board, but it has imposed conditions on most.

A total of 211 CCGs have now been authorised to take on £65bn of the £95bn NHS commissioning budget from April this year. Overall, 43 (20%) of the 211 CCGs have been fully …
NRL and CRX Define Photoreceptor Identity and Reveal Subgroup-Specific Dependencies in Medulloblastoma
Authors: Alexandra Garancher, Charles Y. Lin, Morgane Morabito, Wilfrid Richer, Nathalie Rocques, Magalie Larcher, Laure Bihannic, Kyle Smith, Catherine Miquel, Sophie Leboucher, Nirmitha I. Herath, Fanny Dupuy, Pascale Varlet, Christine Haberler, Christine Walczak, Nadine El Tayara, Andreas Volk, Stéphanie Puget, François Doz, Olivier Delattre, Sabine Druillennec, Olivier Ayrault, Robert J. Wechsler-Reya, Alain Eychène, Franck Bourdeaut, Paul A. Northcott, Celio Pouponnot
Journal: Cancer Cell (2018)
Abstract MP25: Obesity, Heart Failure Risk &amp; Cardiorespiratory Fitness
Authors: Peter F Kokkinos, Puneet Narayan, Charles Faselis, Jonathan Myers, Carl Lavie, Monica Aiken, Ali Ahmed, Federico Mordini, Hans Moore, Pamela Karasik
Journal: Circulation (2018)

Introduction: Obesity, defined as body mass index (BMI) ≥30 kg/m 2 , is associated with increased incidence of heart failure (HF). Increased cardiorespiratory fitness (CRF), as indicated by increased exercise capacity, is associated with lower risk of cardiovascular disease and HF. However, the CRF-BMI-HF interaction has not been fully explored. Hypothesis: We assessed the hypothesis that the risk of HF associated with increased BMI is moderated by increased CRF. Methods: We identified 19,881 Veterans (mean age: 58.0±11.3 years) who completed an exercise tolerance test (ETT) to assess either CRF status or suspected ischemia at two VA Medical Centers (Washington DC and Palo Alto, CA). None had documented HF at baseline or evidence of ischemia during the ETT. We established four BMI categories: &lt;25 kg/m 2 ; 25-29.9 kg/m 2 ; 30-34.9 kg/m 2 ; and ≥35 kg/m 2 . In addition, we established four CRF categories based on age-stratified quartiles of peak metabolic equivalents (METs) achieved (mean ± SD): Least-Fit (4.5±1.2 METs; n=4,743); Low-Fit (6.6±1.3; n=5,103); Moderate-Fit (8.0±1.3 METs; n=5,084); and High-Fit (11.1±2.4 METs; n=4,951). Multivariable Cox models were used to estimate hazard ratios (HR) and 95% confidence intervals [CI] for incidence of HF across BMI categories for the entire cohort, using BMI 25-29.9 kg/m 2 (lowest HF rate) as the reference group. We then stratified the cohort by the four BMI categories and assessed HF risk across CRF categories within each stratum, using the Least-fit category as the reference group. The models were adjusted for age, race, gender, cardiac risk factors, sleep apnea, alcohol dependence, medications. Results: During follow-up (median=11.8 years), 2,193 developed HF (10.5 per 1,000 person-years of follow-up). The HF risk for normal weight individuals (18.5-24.9 kg/m2) was 10% higher (p=0.93). For obese individuals, the HF risk was 22% higher in those with BMI 30-34.9 kg/m 2 (HR=1.22; 95% CI: 1.09-1.35) and 50% higher (HR=1.50, 95% CI: 1.32-1.72) for those with BMI ≥35 kg/m 2 . When CRF (peak METs achieved) was introduced in the model, the risk for those with BMI 30-34.9 was reduced from 22% to 16% (HR=1.16; 95% CI: 1.04-1.29) and from 50% to 29% (HR=1.29; 95% CI: 1.13-1.48) among those with ≥35 kg/m 2 . For every 1-MET increase in exercise capacity, HF risk was 15% lower (HR=0.85; 95% CI: 0.83-0.87). We then assessed the impact of CRF on the risk of HF within each of the four BMI categories. The HF risk declined progressively (range: 25% to 69%; p&lt;0.01) with increasing fitness within all BMI categories. Conclusions: The obesity-associated increased risk of HF was attenuated by increased CRF. The HF risk was progressively decreased with increased CRF within all BMI categories.
Over 200 physician associate posts are to be created
Authors: Abi Rimmer
Journal: BMJ (2014)

An additional 205 physician associate posts will be created in 2015 to support emergency medicine and primary care, Health Education England has said.

As part of its workforce plan for 2015, HEE said that, to improve patient care, it would invest in “entirely new roles and professions” such as physician associates.1 “This year, we will commission 205 physician associates training posts, representing a 754% increase on last year,” it said

HEE said that physician associates could provide a range of …
Abstract P5-19-03: Factors that influence posttraumatic growth in patients with breast cancer: A longitudinal trial
Authors: U Berndt, Y Gottschlik, B Leplow, C Thomssen
Journal: Cancer Research (2018)

Abstract Objectives: The main focus of previous research into coping with breast cancer, have been mostly with regards to the negative impacts such as emotional stress, anxiety, depression or cognitive dysfunction. However, patients also report positive changes that have come about as a result of their struggle with cancer. This is referred to as posttraumatic growth (PTG). The aim of this study was to assess the presence of PTG in breast cancer patients at two measurements and to explore the association between personality traits (resilience, optimism, self-efficacy) and positive emotions on PTG. Patients and Methods: The study group comprised of 80 women (with a mean age of 53.6 years, SD=10.2) recently diagnosed with stage I to III breast cancer. They completed self-report measures of PTG, resilience, optimism, self-efficacy and positive emotions up to three weeks after diagnose (t1) and then following by an update six months later (t2). Sociodemographic characteristics, emotional distress, anxiety and depression were also recorded. Results: Planned comparison: Breast cancer patients showed an increase of PTG from t1 to t2 (p=.00035). Resilience, optimism, self-efficacy and positive emotions did not change in the total sample from t1 to t2. Emotional distress, anxiety and depression have significantly declined from t1 to t2 (anxiety p=.015, depression p=.029, emotional distress p=.000065). Moreover, we found a significant positive correlation between positive emotions to PTG (r=-.386, p=.0004) and optimism to PTG (r=.334, p=.002) at t2, respectively. Depression t2 correlated negatively to PTG at t2 (r=-.264 p=.018). Explorative results: We also calculated the difference between PTG t2 and t1. We found 67.5% (n=54) of the patients with an increase of PTG and 32.5% (n=26) without or with negative change. In a subgroup analysis we noticed that patients without benefit of PTG showed a decline of resilience (p=.015), self-efficacy (p=.028) and positive emotions (p=.045) between t1 and t2. Furthermore, anxiety and depression did not improve from t1 to t2 in this group. Conclusions: Positive emotions and optimism represent indicators of PTG in breast cancer patients. A decline of anxiety and depression is associated with a higher rate of PTG. Psycho-oncological strategies related to these factors may support PTG in breast cancer patients. Future studies are needed to search for effective interventions to support patients in PTG. Citation Format: Berndt U, Gottschlik Y, Leplow B, Thomssen C. Factors that influence posttraumatic growth in patients with breast cancer: A longitudinal trial [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 P5-19-03.
First histopathological evidence of irreversible pulmonary vascular disease in dasatinib-induced pulmonary arterial hypertension
Authors: Cécile Daccord, Igor Letovanec, Patrick Yerly, Jonathan Bloch, Adam Ogna, Laurent P. Nicod, John-David Aubert
Journal: European Respiratory Journal (2018)

We read with interest the article by Weatherald et al. [1] on the long-term outcomes of pulmonary arterial hypertension (PAH) induced by dasatinib. The authors reported 21 incident cases of PAH confirmed by right heart catheterisation (RHC) and associated with dasatinib. Although a majority of patients improved after dasatinib discontinuation, PAH persisted in over one-third of cases during long-term follow-up and two additional patients had persistent exercise pulmonary hypertension despite normalisation of resting haemodynamic measures. Similarly, Shah et al. [2] reported 41 cases of dasatinib-induced PAH confirmed by RHC with complete resolution of PAH in only 58% of patients, provided that follow-up RHC or echocardiography was most often not documented. As mentioned by Weatherald et al. [1], these data suggest that dasatinib is likely to cause irreversible pulmonary vascular dysfunction and remodelling. An experimental model in rats and human pulmonary endothelial cells supports this hypothesis as it showed that dasatinib causes dose-dependent pulmonary endothelial dysfunction and apoptosis through the production of mitochondrial reactive oxygen species, a phenomenon that was not observed with imatinib [3]. To date, there is no published evidence of such pathological abnormalities in the human lung. We report the case of a patient who developed dasatinib-induced severe PAH that progressed in spite of drug cessation and aggressive PAH-specific therapy and ultimately underwent lung transplantation. The presence of irreversible pulmonary vascular lesions explains why dasatinib-induced PAH can frequently persist <http://ow.ly/MKwI30hRwfc>