tbuckley/cabot-search huggingface dataset:
Reevaluating Mohs Surgery Appropriate Use Criteria for Primary Superficial Basal Cell Carcinoma
Authors: Howard K. Steinman, Anthony Dixon, Christopher B. Zachary
Journal: JAMA Dermatology (2018)

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Phase II trial of afatinib in patients with advanced/metastatic urothelial carcinoma (UC) with genetic alterations in ERBB receptors 1-3 who failed on platinum-based chemotherapy (CT).
Authors: Albert Font Pous, Javier Puente, Daniel E. Castellano, Francisco X. Real, Miguel A. Climent, Aranzazu Aranzazu Gonzalez del Alba, Stephane Oudard, Federico Jose Vazquez Mazon, Rafael Morales Barrera, Juan Virizuela Virizuela, Nuria Sala, Begoña Pérez-Valderrama, Xavier Garcia del Muro, Pedro L. Fernandez, Pedro Jares, Iban Aldecoa, Neil Gibson, Josep Serra, Esteban Rodrigo Imedio, Begona Mellado
Journal: Journal of Clinical Oncology (2018)

TPS540 Background: First-line treatment of patients (pts) with advanced/metastatic UC consists of platinum-based CT, with no well-established subsequent therapy for platinum-refractory disease. Although checkpoint inhibitors have shown promising results recently, targeted agents have generally not demonstrated significant clinical activity in this setting. Around 20% of UC harbor ERBB family genetic alterations, as such it may be a suitable therapeutic target (Knowles, Nat Rev Cancer 2015;15:25–41). The irreversible ERBB family blocker, afatinib, has shown activity in a Phase II trial in a subset of pts with UC who had ERBB2/ERBB3 aberrations (Choudhury, J Clin Oncol 2016;34:2165–71). This Phase II trial will evaluate afatinib in pts with UC molecularly selected for ERBB receptor alterations. Methods: This single-arm trial will assess the efficacy and safety of afatinib in pts with UC harboring ERBB2/ERBB3 mutations or ERBB2 amplification (Cohort A), or EGFR (ERBB1) amplification (Cohort B). Eligible pts are ≥18 years of age with ECOG PS 0–1, histologically confirmed advanced/metastatic UC of the bladder, upper tract or urethra, not amenable to surgery and progressing during or after platinum-based CT, with available archival tissue samples for pre-screening biomarker analysis. Pts will receive oral afatinib 40 mg/day until disease progression or discontinuation. Cohort A is enrolling in two stages, with Stage 2 enrollment based on anti-tumor activity observed. The primary endpoint is progression-free survival (PFS) rate at 6 months; secondary endpoints include objective response rate, PFS, overall survival, disease control rate, duration of response and tumor shrinkage. Trial objectives will be analyzed separately for the two cohorts. Safety and biomarker assessments will also be performed. The trial commenced in June 2016; as of October 4, 2017, 201 samples have been analyzed, with 24.3% and 8% of pts with genetic alterations potentially eligible for inclusion in Cohort A and B, respectively. To date, 12 pts have received study treatment in Cohort A and 6 in Cohort B; recruitment is ongoing. Clinical trial information: NCT02780687.
Outcome and undertreatment of mitral regurgitation: a community cohort study
Authors: Volha Dziadzko, Marie-Annick Clavel, Mikhail Dziadzko, Jose R Medina-Inojosa, Hector Michelena, Joseph Maalouf, Vuyisile Nkomo, Prabin Thapa, Maurice Enriquez-Sarano
Journal: The Lancet (2018)
CC-122, a novel cereblon-modulating agent, in combination with obinutuzumab (GA101) in patients with relapsed and refractory (R/R) B-cell non-hodgkin lymphoma (NHL)
Authors: J.-M. Michot, R. Bouabdallah, J.K. Doorduijn, U. Vitolo, M.J. Kersten, A. Chiappella, P.L. Zinzani, M. Pourdehnad, Z. Nikolova, V. Ribrag
Journal: Annals of Oncology (2018)
Hypofractionated external beam radiation therapy in combination with HDR boost for localized prostate cancer: Quality of life outcomes.
Authors: Tiffany Morgan, Robert H. Press, Patrick Cutrell, Chao Zhang, Zhengjia Chen, Sara Rahnema, Martin George Sanda, John Pattaras, Pretesh R Patel, Ashesh B. Jani, Peter John Rossi
Journal: Journal of Clinical Oncology (2018)

62 Background: There is limited data to support the use of hypofractionated external beam radiation (HypoF) in combination with high dose rate brachytherapy (HDR). We report our quality of life (QOL) outcomes when treating intermediate (IR) and high risk (HR) prostate cancer patients with external beam radiation (EBRT) plus HDR. Methods: The charts of 54 patients with localized adenocarcinoma of the prostate treated with standard fractionation (SF) or HypoF EBRT plus HDR boost at a single institution between 2012 and 2015 were reviewed. All patients completed the American Urological Association Symptom Score (AUASS) and Expanded Prostate Index for Prostate Cancer – Clinical Practice (EPIC-CP) quality of life assessments prior to treatment and completed at least one follow-up survey. Linear mixed models were performed to test whether there was any significant change over time for each outcome and to detect whether there was any significant difference in each outcome between the different treatments. Results: Thirty-eight patients were treated with SF and 16 with HypoF. Median age at treatment was 68 years (range 55-82 years). Median follow-up for the cohort was 22.2 months (range 1.57-50.60 months). A majority of patients had clinical T1c disease (n = 35), Gleason score of 7 (n = 35), and a PSA &lt; 10 (n = 39). Thirty-one patients had NCCN IR, and 23 had HR disease. There was no significant difference in AUA score (p = 0.98), incontinence and urinary irritation/obstruction scores (p = 0.81 and p = 0.62, respectively), and rectal toxicity (p = 0.97) between the two dosing groups over time, or at any discrete time point. Likewise, sexual function, vitality score, and QOL scores were not significantly different between the dose groups over time (p = 0.59, p = 0.37, and p = 0.71, respectively). All QOL categories, except sexual function, trended toward baseline with increasing time from intervention. Conclusions: Our study suggests HypoF EBRT can be delivered in combination with HDR for patients with IR and HR adenocarcinoma of the prostate without increasing toxicity compared to SF with an HDR boost. This has important implications in terms of patient convenience and resource utilization.
EMQs for Surgery
Authors: Justin Yeung
Journal: BMJ (2005)

Eds Louis J Fligelstone and Alun H Davies

Tfm Publishing, 2005, £25, 334 pages ISBN: 1 903378 15 X

Rating: ⋆⋆⋆⋆/5



True or false: multiple choice questions have always been commonly used in medical examinations. However, there has been a change in the format of the MRCS examination since the introduction of the intercollegiate exam, which utilises EMQs (extended matching questions). Unfortunately, few people have had experience of this type of exam. Put simply, …
Inhibition of Nr4a Receptors Enhances Antitumor Immunity by Breaking Treg-Mediated Immune Tolerance
Authors: Sana Hibino, Shunsuke Chikuma, Taisuke Kondo, Minako Ito, Hiroko Nakatsukasa, Setsuko Omata-Mise, Akihiko Yoshimura
Journal: Cancer Research (2018)

Abstract Enhanced infiltration of regulatory T cells (Treg) into tumor tissue is detrimental to patients with cancer and is closely associated with poor prognosis as they create an immunosuppressive state that suppresses antitumor immune responses. Therefore, breaking Treg-mediated immune tolerance is important when considering cancer immunotherapy. Here, we show that the Nr4a nuclear receptors, key transcription factors maintaining Treg genetic programs, contribute to Treg-mediated suppression of antitumor immunity in the tumor microenvironment. Mice lacking Nr4a1 and Nr4a2 genes specifically in Tregs showed resistance to tumor growth in transplantation models without exhibiting any severe systemic autoimmunity. The chemotherapeutic agent camptothecin and a common cyclooxygenase-2 inhibitor were found to inhibit transcriptional activity and induction of Nr4a factors, and they synergistically exerted antitumor effects. Genetic inactivation or pharmacologic inhibition of Nr4a factors unleashed effector activities of CD8+ cytotoxic T cells and evoked potent antitumor immune responses. These findings demonstrate that inactivation of Nr4a in Tregs breaks immune tolerance toward cancer, and pharmacologic modulation of Nr4a activity may be a novel cancer treatment strategy targeting the immunosuppressive tumor microenvironment. Significance: This study reveals the role of Nr4a transcription factors in Treg-mediated tolerance to antitumor immunity, with possible therapeutic implications for developing effective anticancer therapies. Cancer Res; 78(11); 3027–40. ©2018 AACR.
Intestinal microbiota to predict risk for immune-related diarrhea in patients with lung cancer patients.
Authors: Tian Liu, Yi Hu
Journal: Journal of Clinical Oncology (2018)

132 Background: Anti-programmed cell death 1 (PD-1) inhibitors, which enhance cellular immunity via blockade of PD-1, represent an effective option for the treatment of lung cancer and have shown some impressive efficacy. However, the inhibitors can also result in immune-related adverse events, such as immune-related diarrhea. Researches have shown that intestinal microbiota plays a vital role in gastrointestinal dysregulation. Whereas, the relationship between PD-1 inhibitors and immune-related diarrhea is still elusive. In our study, we aim to identify the correlation of intestinal microbiota and immune-related diarrhea, and hope to find specific bacteria as potential biomarkers of immune-related diarrhea. Methods: Twenty-six lung cancer patients who were treated with PD-1 inhibitors from 301 hospital were enrolled for retrospective analysis. And the fecal samples were obtained from patients before the first dose of PD-1 inhibitor. Based on whether they develop diarrhea or not, the patients were subgroup into progressed to diarrhea(PtD) group and diarrhea-free(D-F) group. Immune-related diarrhea was graded according to the National Cancer Institute Common Toxicity Criteria (CTC, version 4.0). And 16S rRNA sequencing was used to profile fecal bacterial composition. Results: There was no significant difference in baseline characteristics, such as microbial richness between PtD group and D-F group (P &gt; 0.05). However, At the phylum level, Bacteroidetes were richer in D-F group, while Firmicutes were poorer, than that in PtD group. At the genus level, two families of the Bacteroidetes phylum ( Bacteroides and Parabacteroides) and a family of the Firmicutes phylum (Phascolarctobacterium) were more abundant in D-F group. Veillonella from Proteobacteria phylum was lower in D-F group than that in PtD group (all P &lt; 0.05). Conclusions: Our study indicates that microbiota variation probably participates in the onset of immune-related diarrhea. Identifying these biomarkers may help us to diagnose the side effect earlier, and provides a novel treatment for immune-related diarrhea due to PD-1 inhibitors.
Health department warns MPs of oversupply of consultants
Authors: Helen Jaques
Journal: BMJ (2012)

The Department of Health is predicting a continued increase in the number of consultants and is concerned about issues of oversupply and affordability, the House of Commons select committee on health heard this week.

Last month the Centre for Workforce Intelligence predicted that the NHS will train 60% more consultants than the service needs in the years up until 2020, at an additional annual cost of £2.2bn more than in 2010 if all eligible doctors become consultants ( BMJ Careers 10 Feb, http://careers.bmj.com/careers/advice/view-article.html?id=20006582). 

The number of specialty trainees has reduced from 7000 a year to around 6500 a year in response to this problem, Patricia Hamilton, the …
MEPs devise strategy to tackle vaccine hesitancy among public
Authors: Rory Watson
Journal: BMJ (2018)

The European parliament is urging health authorities to step up efforts to boost public confidence in the benefits of vaccination. The move comes amid signs of what MEPs, in a wide ranging policy statement, identify as “the worrying phenomenon of vaccine hesitancy.”

Renate Sommer, a German Christian Democrat MEP, is a leading member of the cross party group pressing national governments and EU institutions to tackle the problem.

“It is extremely worrying that the use of vaccines in member states is dropping rapidly. Just because the problem does not necessarily affect each one of us individually, we cannot …
Prediction of adverse pathology after radical prostatectomy on MPMRI in the PIRADS v2 era.
Authors: Kareem Rayn, Jonathan Bloom, Samuel Gold, Graham R. Hale, Youssef A Elnabawi, Sherif Mehralivand, Brad J. Wood, Baris Turkbey, Peter A. Pinto
Journal: Journal of Clinical Oncology (2018)

121 Background: As the use of MRI in the diagnosis of prostate cancer (PCa) becomes more established, knowledge of its utility as a prognostic tool is needed to better counsel patients. Here, we aim to assess the ability of mpMRI to predict adverse pathologic factors, such as extraprostatic extension (EPE), seminal vesicle invasion (SVI) or lymph node involvement (LNI) on final pathology after radical prostatectomy (RP). Methods: A prospectively maintained database was queried for all men who underwent mpMRI with current PI-RADS v2 scoring system, MRI/TRUS fusion biopsy (FBx), and RP at our institution (n = 112). Patient demographics, clinical data, imaging and pathology were recorded. Patients were stratified by presence of adverse pathology (AP), defined as EPE, SVI or LNI. Statistical analyses were used to identify mpMRI characteristics predictive of AP using STATA 13. Results: Patients with adverse pathology were middle aged, predominantly caucasian, and significantly higher PSA at baseline (Table 1). Having a PI-RADS 5 lesion was positively associated with AP (adjusted OR = 4.37, 95% CI = 1.20-15.87, p = 0.02). Mean lesion diameter on mpMRI was greater in patients with AP (p &lt; 0.01). However, number of lesions (p = 0.12) and prostate volume on mpMRI (p = 0.88) were not associated with AP. Conclusions: The results of this study demonstrate that features on mpMRI, particularly a PI-RADS score of 5 and large lesion diameter, are predictive of adverse pathology. This information will prove valuable in developing an imaging-based prognostic model in the era of MRI and FBx. This research was supported by the Intramural Research Program of the National Cancer Institute, NIH and NIH Medical Research Scholars Program[Table: see text]
Derivation of dose/volume constraints for the anorectum from clinician-reported outcomes (CRO) in the CHHiP trial of radiotherapy (RT) fractionation.
Authors: Anna Wilkins, Olivia Frances Naismith, Douglas Brand, Katie Fernandez, Emma Hall, David P. Dearnaley, Sarah Gulliford
Journal: Journal of Clinical Oncology (2018)

87 Background: CHHiP (ISRCTN97182923, CRUK/06/016) randomised 3216 men with localised prostate cancer (1:1:1) to 3 RT fractionation schedules: 74Gy/37 fractions (f) over 7.4 weeks, 60Gy/20f/4 weeks and 57Gy/19f/3.8 weeks. Literature-based dose constraints were applied with adjustment for the hypofractionated arms. For standard fractionation the constraints (absolute dose) included V30 Gy ≤80%, V40 Gy ≤70%, V50 Gy ≤60%, V60 Gy ≤50%, V70 Gy ≤15%. This study aimed to derive anorectal dose constraints based on prospectively collected CRO. Methods: A case-control study design was used, 4 bowel symptoms were independently evaluated. Cases were patients experiencing a moderate or worse grade symptom 1 to 5 years post RT, who had not had the symptom pre-RT. Controls did not experience the symptom between 1 and 5 years post RT. The anorectum was re-contoured from the anal verge to the recto-sigmoid junction using VODCA software. Dose/volume parameters were extracted and hypofractionated dose schedules were converted to 2Gy equivalent schedules using an α/β ratio of 3Gy. Bootstrapped ROC analysis (1000 replicates, balanced outcomes) was used to derive dose constraints using both the Youden index and “Closest top Left” (CtL). Only AUC with a lower limit of the 95% confidence interval &gt;0.5 were considered statistically significant. Any constraint derived in &lt;99% of bootstraps was excluded. Results: Statistically significant dose constraints were derived for rectal bleeding, increased bowel frequency, faecal incontinence and rectal pain (table). Conclusions: Dose constraints differed between symptoms, indicating potentially different pathogenesis of each radiation-induced side effect. Derived dose constraints were tighter than those used in CHHiP; use of these may reduce anorectal symptoms post RT. Comparable data derived from the hypofractionated cohorts will be presented. [Table: see text]
Hedgehog pathway mutations drive oncogenic transformation in high-risk T-cell acute lymphoblastic leukemia
Authors: Melissa A. Burns, Zi Wei Liao, Natsuko Yamagata, Gayle P. Pouliot, Kristen E. Stevenson, Donna S. Neuberg, Aaron R. Thorner, Matthew Ducar, Emily A. Silverman, Stephen P. Hunger, Mignon L. Loh, Stuart S. Winter, Kimberly P. Dunsmore, Brent Wood, Meenakshi Devidas, Marian H. Harris, Lewis B. Silverman, Stephen E. Sallan, Alejandro Gutierrez
Journal: Leukemia (2018)
O005 SMOC2 has differential effects on cartilage and bone formation
Authors: T Peeters, R Lories, F Cailotto
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Introduction</h3> SMOC2, a secreted calcium-binding protein of the BM-40/SPARC family was identified from a chondrogenic extract of articular cartilage and is increased in osteoarthritic cartilage. Alterations in bone and cartilage resulting from dysregulated signalling pathways are a hallmark of osteoarthritis. <h3>Objectives</h3> To evaluate the role of SMOC2 in <i>in vitro</i> osteogenesis and chondrogenesis and its interaction with Wnt signalling. <h3>Methods</h3> Wild-type Smoc2 (Smoc2+) or Smoc2 lacking the calcium binding domain (?CaBD) were stably overexpressed and wild-type Smoc2 was silenced (Smoc2-). Alkaline phosphatase (ALP) activity assay and Alizarin Red staining were performed in MC3T3 cells and human periosteal derived cells (hPDCs). Proteoglycan content and mineralization were assessed in ATDC5 micromasses by Alcian blue and Alizarin Red staining. Mice femoral head caps (FHC) were stimulated with recombinant IL-1b and SMOC2. Cartilage loss was evaluated by DMMB assay and Safranin O staining. TCF1 levels were analysed by immunohistochemistry. Human articular chondrocytes (hACs) were stimulated with recombinant SMOC2. Gene expression of osteoblast markers (<i>Opn, Osx, Col1a2</i>), chondrogenic markers (<i>Acan, Col2a1, Col10a1, Mmp13</i>) and canonical Wnt target genes (<i>Axin2, Lef1</i>) were analysed by qPCR and Wnt signalling by Western blot. <h3>Results</h3> Alizarin red staining and ALP activity were reduced in Smoc2 +MC3 T3 cells. Osteoblast gene expression levels were altered in Smoc2 +cells. ?CaBD cells and calcium supplementation to Smoc2 +showed a partial rescue of the effects of Smoc2 +cells. We validated these results in hPDCs. We could not observe an effect on osteogenesis when silencing Smoc2. Smoc2 +ATDC5 micromasses showed reduced chondrogenic gene expression and Alcian blue and Alizarin Red staining intensity. We observed a reverse pattern with an increased chondrogenic gene expression in Smoc2- ATDC5 micromasses. Smoc2 +and Smoc2- ATDC5 cells altered canonical Wnt signalling in opposite directions. SMOC2 also alters protein levels of CamKII. IL-1b triggered cartilage loss was increased and TCF1 levels were reduced in mice FHC stimulated with recombinant SMOC2. In hACs, we observed a negative effect of SMOC2 on chondrocyte markers and canonical Wnt target genes. <h3>Conclusions</h3> Our results suggest an inhibitory role of Smoc2 on mineralization. The inhibitory effects on mineralization are at least partially regulated through interaction with calcium. Moreover, Smoc2 is a regulator of chondrogenic differentiation and cartilage homeostasis by regulating canonical and non-canonical Wnt signalling. <h3>Disclosure of interest</h3> None declared
Abstract 14799: Clinical Outcomes and Health-related Quality of Life of Catheter Ablation vs. Anti-arrhythmia Drug Therapy Among Atrial Fibrillation Patients in China
Authors: Xin Du, Jiahui Wu, Xueyuan Guo, Songnan Li, Caihuai Sang, Ronghui Yu, Deyong Long, Jianzeng Dong, Yu Jia, Jianwei Xuan, Changsheng Ma
Journal: Circulation (2015)

Introduction: Although catheter ablation of atrial fibrillation(AF) has been demonstrated to be associated with significantly better rhythm control compared with anti-arrhythmia drug therapy (AAD),whether this treatment can improve Health-Related Quality of Life (HRQOL) remains unknown. Methods: This is a prospective, single center study conducted in Beijing Anzhen Hospital. Patients were treated at the discretion of their physician and propensity score matching was performed to ensure the comparability of patients in the ablation and AAD arms. HRQOL evaluated at each 3-month follow up period was the primary endpoint of this study. The first 3 month after enrollment was excluded as a blanking period. HRQOL were measured using Short Form-36 (SF-36) and Atrial Fibrillation Effect on Quality-of-life questionnaire (AFEQT). Results: This study enrolled 318 and 151 subjects in the drug treatment and catheter ablation arms respectively. For the matched 75 pairs of paroxysmal AF subjects, 82.0% in the ablation arm and 22.4% in the AAD arm was in sinus rhythm at 12 month follow up. For the matched 57 pairs of persistent AF, 65.3% and 19.3% patients was in sinus rhythm in the ablation and AAD arms respectively. In the ablation arm, the subjects showed significant improvement in their SF36 and AFEQT scores compared with subjects in the AAD arm (all p&lt;0.001 when compared with AAD subjects at the same follow up period, Figure 1) Conclusion: The ablation treatment has demonstrated significantly improved quality of life compared with anti-arrhythmia drug therapy in Chinese AF patients. Table of Contents