tbuckley/cabot-search huggingface dataset:
Phase Ib study of concurrent durvalumab and radiation therapy (DUART) followed by adjuvant durvalumab in patients with urothelial cancer of the bladder: BTCRC-GU15-023 study.
Authors: Monika Joshi, Leonard Tuanquin, Matthew Kaag, Yousef Zakharia, Jason Liao, Suzanne Merrill, Dana Musapatika, David DeGraff, Hong Zheng, Joshua Warrick, Sheldon L. Holder, Mark Stein, Joseph J. Drabick
Journal: Journal of Clinical Oncology (2018)

455 Background: There is a significant variation in the treatment of locally advanced unresectable (T2-4 N0-2 M0) or cisplatin-ineligible (non-cis) bladder cancer (BC) patients (pts). The advent of immunotherapy (IO) in non-cis stage IV BC has been promising (response rate [RR] 23%; median survival 16 mo) but we are still in need of novel combinations for locally advanced unresectable BC. Durvalumab (Durva) is a human monoclonal antibody that inhibits the binding of PD-L1 to PD-1 on T-cell receptors. It has shown efficacy in platinum refractory BC with RR of 17%. Radiation (RT) is also effective in BC and can upregulate pro-inflammatory signals allowing for improved antitumor activity of IO. We report the safety data from phase Ib trial of combining RT with Durva (DurvaRT) in locally advanced BC. Methods: Treatment (Rx) naïve or post neoadjuvant chemotherapy pts with T3-4, N0-2, M0 who were either unresectable or unfit for surgery were treated with DurvaRT followed by Durva. Rx naïve locally advanced non-cis pts were also included in the study. DurvaRT: Durva 1500mg D1, D28 plus concurrent RT, 64.8Gy given in 36 fractions over 7weeks starting D1. These patients then started adjuvant Q4 weekly Durva after 4 weeks for 12 months. Primary end point for Ph Ib was safety of combining Durva with RT during 7-weeks period. Results: We enrolled 6 pts on phase Ib. 5/6 pts had completed the DurvaRT phase and none of them had any dose limiting toxicity. The table below summarizes the treatment related adverse events (TRAE). Post DurvaRT 3/4 pts have ongoing ORR; 1 pt. had progression; Rx response evaluation in 2 pts is ongoing. Clinical trial information: NCT02891161. Conclusions: DurvaRT was tolerable in pts with locally advanced unresectable BC, where there is a dearth for good Rx options. No grade 3 immune related AEs were observed during DurvaRT. Further investigation with DurvaRT is ongoing to evaluate the efficacy in this subset of pts (Clinical trial # NCT02891161).[Table: see text]
Chemotherapy Induces Breast Cancer Stemness in Association with Dysregulated Monocytosis
Authors: Liang Liu, Lin Yang, Wei Yan, Jing Zhai, Donald P. Pizzo, Peiguo Chu, Andrew R. Chin, Meng Shen, Chuan Dong, Xianhui Ruan, Xiubao Ren, George Somlo, Shizhen Emily Wang
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Preoperative or neoadjuvant therapy (NT) is increasingly used in patients with locally advanced or inflammatory breast cancer to allow optimal surgery and aim for pathologic response. However, many breast cancers are resistant or relapse after treatment. Here, we investigated conjunctive chemotherapy-triggered events occurring systemically and locally, potentially promoting a cancer stem–like cell (CSC) phenotype and contributing to tumor relapse. Experimental Design: We started by comparing the effect of paired pre- and post-NT patient sera on the CSC properties of breast cancer cells. Using cell lines, patient-derived xenograft models, and primary tumors, we investigated the regulation of CSCs and tumor progression by chemotherapy-induced factors. Results: In human patients and mice, we detected a therapy-induced CSC-stimulatory activity in serum, which was attributed to therapy-associated monocytosis leading to systemic elevation of monocyte chemoattractant proteins (MCP). The post-NT hematopoietic regeneration in the bone marrow highlighted both altered monocyte–macrophage differentiation and biased commitment of stimulated hematopoietic stem cells toward monocytosis. Chemotherapeutic agents also induce monocyte expression of MCPs through a JNK-dependent mechanism. Genetic and pharmacologic inhibitions of the MCP-CCR2 pathway blocked chemotherapy's adverse effect on CSCs. Levels of nuclear Notch and ALDH1 were significantly elevated in primary breast cancers following NT, whereas higher levels of CCR2 in pre-NT tumors were associated with a poor response to NT. Conclusions: Our data establish a mechanism of chemotherapy-induced cancer stemness by linking the cellular events in the bone marrow and tumors, and suggest pharmacologic inhibition of CCR2 as a potential cotreatment during conventional chemotherapy in neoadjuvant and adjuvant settings. Clin Cancer Res; 24(10); 2370–82. ©2018 AACR.
Revision aids for the intercollegiate MRCS parts 1 and 2
Authors: Anna Pozo
Journal: BMJ (2006)

• www.123doc.com

• www.clinicaltutor.com

• www.onexamination.com

• www.pastestonline.com

• www.rcseng.ac.uk/exams/imrcs

• www.surgical-tutor.org.uk



As an adjunct to the traditional textbook and elbow grease approach to revision, trainees are increasingly using practice questions to improve their chances of passing exams. A variety of websites provide questions for surgical trainees sitting the intercollegiate exam for membership of the Royal College of Surgeons (MRCS).

The MRCS exam has two written parts. The two parts concentrate on separate areas of the syllabus, but have plenty of overlap. The most obvious difference is the question format. Part 1, applied …
UHRF1 epigenetically orchestrates smooth muscle cell plasticity in arterial disease
Authors: Leonardo Elia, Paolo Kunderfranco, Pierluigi Carullo, Marco Vacchiano, Floriana Maria Farina, Ignacio Fernando Hall, Stefano Mantero, Cristina Panico, Roberto Papait, Gianluigi Condorelli, Manuela Quintavalle
Journal: Journal of Clinical Investigation (2018)

Adult vascular smooth muscle cells (VSMCs) dedifferentiate in response to extracellular cues such as vascular damage and inflammation. Dedifferentiated VSMCs are proliferative, migratory, less contractile, and can contribute to vascular repair as well as to cardiovascular pathologies such as intimal hyperplasia/restenosis in coronary artery and arterial aneurysm. We here demonstrate the role of ubiquitin-like containing PHD and RING finger domains 1 (UHRF1) as an epigenetic master regulator of VSMC plasticity. UHRF1 expression correlated with the development of vascular pathologies associated with modulation of noncoding RNAs, such as microRNAs. miR-145 — pivotal in regulating VSMC plasticity, which is reduced in vascular diseases — was found to control Uhrf1 mRNA translation. In turn, UHRF1 triggered VSMC proliferation, directly repressing promoters of cell-cycle inhibitor genes (including p21 and p27) and key prodifferentiation genes via the methylation of DNA and histones. Local vascular viral delivery of Uhrf1 shRNAs or Uhrf1 VSMC-specific deletion prevented intimal hyperplasia in mouse carotid artery and decreased vessel damage in a mouse model of aortic aneurysm. Our study demonstrates the fundamental role of Uhrf1 in regulating VSMC phenotype by promoting proliferation and dedifferentiation. UHRF1 targeting may hold therapeutic potential in vascular pathologies.
The role of robotics in colorectal surgery
Authors: Christina L Cheng, Craig Rezac
Journal: BMJ (2018)

<h3>Abstract</h3> Studies of laparoscopic approaches in colorectal surgery support the use of such methods. Compared with the open approach, laparoscopy reduces rates of postoperative complications and decreases length of stay, while providing equivalent oncologic outcomes. Nevertheless, much of colorectal surgery is still being performed by the open approach. This may be partly due to the technical challenges in performing laparoscopy, particularly when working in narrow spaces such as the pelvis. Moreover, some of the current literature has questioned the oncologic outcomes after laparoscopic surgery for rectal cancer. Robotic surgery has been heralded as the minimally invasive tool that can overcome these challenges. It has the advantages that it provides a three dimensional image, uses wristed instruments, and has a computer interface that allows for fluid and accurate movements. Overall, current evidence suggests that robotics is safe and feasible in colorectal surgery, and that short term and long term outcomes are comparable to those seen for laparoscopic approaches. Studies on the costs of robotic surgery show conflicting results, and this is arguably one of the biggest disadvantages of its use. Because robotic surgery is a relatively new technology, few large high quality studies are available. Most of the published studies in this area consist of retrospective reviews, case matched studies, and national database reviews. Large randomized prospective studies are needed to further support its use.
Molecular characterization of brain metastases in patients with metastatic urothelial cancer.
Authors: Amanda Nizam, Donald L. Trump, Jeanny B. Aragon-Ching
Journal: Journal of Clinical Oncology (2018)

509 Background: Urothelial cancers are the 6 th most common cause of all new cancer cases in 2017. Metastatic disease to the brain is rare but has a poor prognosis. There is little information regarding the phenotypic and molecular characteristics of urothelial cancers involving the brain. We sought to evaluate the clinical and tumor molecular characteristics in patients with metastatic urothelial cancer to the brain. Methods: In a single institution retrospective chart review, 48 patients were found to have metastatic bladder cancer from 2006 to 2015, 4 had brain metastases. The demographics, stage, phenotypic characteristics and molecular characteristics using Oncomine, a cancer microarray platform targeting 143 cancer genes, was determined. Results: Of the 4 patients identified with metastatic brain urothelial cancer, 3 were men. 2 had both upper tract and bladder urothelial cancers and 2 had bladder cancer alone. 3 had prior nephroureterectomy and/or radical cystectomy initially and had subsequent development of initial distant metastases at a median of 7.9 months, and time between the first to brain metastases at a median onset of 11.8 months. Median overall survival (OS) was short upon diagnosis of brain metastasis with a median OS of 119 days (range: 96 – 391 days) from the time of brain metastasis diagnosis. All received surgical resection followed by radiation for brain metastases. Three patients had brain tumor examined for comprehensive somatic tumor profiling using the Oncomine panel. Results showed APC mutation in patient 1, loss of TP53, BRCA-2 loss of function mutation with MSH2 deletion in patient 2, as well as FGFR3 gene mutation and TP53 mutation in patient 3. All patients received prior platinum-based systemic therapy with additional FGFR3-therapy for patient 3 and atezolizumab for patient 4. Conclusions: Metastatic brain urothelial cancers are rare events with a uniformly poor prognosis. The role for targeted therapy and immunotherapy is still evolving.
Health and wellbeing support for NHS staff has increased, says survey
Authors: Abi Rimmer
Journal: BMJ (2014)

Health and wellbeing support provided for staff by NHS trusts has increased since 2010, a survey by the Royal College of Physicians has found.1

The college audited NHS trusts in 2013 about their support for health and wellbeing among staff. It received responses from 178 of the 244 NHS trusts in England, covering 862 365 health service staff in England and representing 73% of all NHS staff. The college had …
GATA6 Regulates Aortic Valve Remodeling, and Its Haploinsufficiency Leads to Right-Left Type Bicuspid Aortic Valve
Authors: Lara Gharibeh, Hiba Komati, Yohan Bossé, Munir Boodhwani, Mahyar Heydarpour, Megan Fortier, Romina Hassanzadeh, Janet Ngu, Patrick Mathieu, Simon Body, Mona Nemer
Journal: Circulation (2018)

Bicuspid aortic valve (BAV), the most common congenital heart defect affecting 1% to 2% of the population, is a major risk factor for premature aortic valve disease and accounts for the majority of valve replacement. The genetic basis and mechanisms of BAV etiology and pathogenesis remain largely undefined.Cardiac structure and function was assessed in mice lacking a Gata6 allele. Human GATA6 gene variants were analyzed in 452 BAV cases from the BAV consortium and 1849 controls from the Framingham GWAS (Genome Wide Association Study). GATA6 expression was determined in mice and human tissues using quantitative real-time polymerase chain reaction and immunohistochemistry. Mechanistic studies were carried out in cultured cells.Gata6 heterozygous mice have highly penetrant right-left (RL)-type BAV, the most frequent type in humans. GATA6 transcript levels are lower in human BAV compared with normal tricuspid valves. Mechanistically, Gata6 haploinsufficiency disrupts valve remodeling and extracellular matrix composition through dysregulation of important signaling molecules, including matrix metalloproteinase 9. Cell-specific inactivation of Gata6 reveals an essential role for GATA6 in secondary heart field myocytes because loss of 1 Gata6 allele from Isl- 1-positive cells-but not from endothelial or neural crest cells-recapitulates the phenotype of Gata6 heterozygous mice.The data identify a new cellular and molecular mechanism underlying BAV. The availability of an animal model for the most frequent human BAV opens the way for the elucidation of BAV pathogenesis and the development of much needed therapies.
Phase I/II Study of Pembrolizumab for Progressive Diffuse Large B Cell Lymphoma after Anti-CD19 Directed Chimeric Antigen Receptor Modified T Cell Therapy
Authors: Elise A. Chong, J. Joseph Melenhorst, Jakub Svoboda, Sunita Dwivedy Nasta, Daniel J. Landsburg, Anthony R. Mato, Lifeng Tian, Harit Parakandi, Simon F Lacey, Carl H June, Stephen J. Schuster
Journal: Blood (2017)
ADAM17 is required for EGF-R–induced intestinal tumors via IL-6 trans-signaling
Authors: Stefanie Schmidt, Neele Schumacher, Jeanette Schwarz, Simone Tangermann, Lukas Kenner, Michaela Schlederer, Maria Sibilia, Markus Linder, Annelore Altendorf-Hofmann, Thomas Knösel, Elisabeth S. Gruber, Georg Oberhuber, Julia Bolik, Ateequr Rehman, Anupam Sinha, Juliane Lokau, Philipp Arnold, Anne-Sophie Cabron, Friederike Zunke, Christoph Becker-Pauly, Adele Preaudet, Paul Nguyen, Jennifer Huynh, Shoukat Afshar-Sterle, Ashwini L. Chand, Jürgen Westermann, Peter J. Dempsey, Christoph Garbers, Dirk Schmidt-Arras, Philip Rosenstiel, Tracy Putoczki, Matthias Ernst, Stefan Rose-John
Journal: The Journal of Experimental Medicine (2018)

Colorectal cancer is treated with antibodies blocking epidermal growth factor receptor (EGF-R), but therapeutic success is limited. EGF-R is stimulated by soluble ligands, which are derived from transmembrane precursors by ADAM17-mediated proteolytic cleavage. In mouse intestinal cancer models in the absence of ADAM17, tumorigenesis was almost completely inhibited, and the few remaining tumors were of low-grade dysplasia. RNA sequencing analysis demonstrated down-regulation of STAT3 and Wnt pathway components. Because EGF-R on myeloid cells, but not on intestinal epithelial cells, is required for intestinal cancer and because IL-6 is induced via EGF-R stimulation, we analyzed the role of IL-6 signaling. Tumor formation was equally impaired in IL-6−/− mice and sgp130Fc transgenic mice, in which only trans-signaling via soluble IL-6R is abrogated. ADAM17 is needed for EGF-R–mediated induction of IL-6 synthesis, which via IL-6 trans-signaling induces β-catenin–dependent tumorigenesis. Our data reveal the possibility of a novel strategy for treatment of colorectal cancer that could circumvent intrinsic and acquired resistance to EGF-R blockade.
Independent review criticises procedures and timescale for SJT marking
Authors: Helen Jaques
Journal: BMJ (2013)

An independent review has criticised the marking process and timelines used for the Situational Judgement Test (SJT) sat by foundation programme candidates this year.

In March, 148 medical students had their foundation school allocations changed after marking errors were identified in the SJT papers of more than 350 candidates.12 In response, Health Education England commissioned an independent review by John McLachlan, professor of medical education and associate dean for undergraduate medicine at Durham University. The review sought to understand what went wrong with the marking process.

McLachlan’s report 3 criticised the UK Foundation Programme Office (UKFPO) and the …
Consultants who train should have at least 0.25 SPAs per supervisee
Authors: Helen Jaques
Journal: BMJ (2012)

Consultants who provide training should be allocated at least 0.25 supporting professional activities (SPAs) for each person they supervise, junior doctors have stated.

However, those who do not use their SPA time appropriately towards training or who are not good at education should not be allowed to provide training, delegates at the BMA’s junior doctors conference agreed last week.

Consultants …
Call me doctor
Authors: Nisar A Mir
Journal: BMJ (2007)

Familial Mediterranean fever (FMF), amyloidosis, and colchicine may affect the reproductive system of male and female patients. Colchicine treatment improves female fertility and the outcome of pregnancy and may prevent the development of amyloidosis. However, colchicine may induce oligospermia/azoospermia, but this effect is rare. Overall, colchicine treatment improves the prognosis of patients with FMF and increases their reproductive ability.
PERCUTANEOUS ATRIAL SEPTAL DEFECTS CLOSURE IN ADULTS: DOUBLE VERSUS SINGLE DEVICE CLOSURE OF SECUNDUM DEFECTS - A META-ANALYSIS AND SYSTEMATIC REVIEW
Authors: Ali Abdul Jabbar, Mohammad Jaradat, Mohanad Hasan, Ji Yoo, Ivory Crittendon, Victor Lucas, Tyrone Collins
Journal: Journal of the American College of Cardiology (2018)
Acupuncture for breast cancer related lymphedema: A randomized controlled trial.
Authors: Ting Bao, Kimberly J. Van Zee, Barrie R. Cassileth, Marci Coleton, Qing Susan Li, Babak Mehrara, Emily Vertosick, Andrew J. Vickers, Jun J. Mao
Journal: Journal of Clinical Oncology (2017)

e21706 Background: Up to 20% of breast cancer survivors develop breast cancer related lymphedema (BCRL), and current therapies are limited. In a previous single armed study, acupuncture appeared to reduce BCRL. In this study, we compared our specific protocol of acupuncture (AC) to usual care wait list control (WL). Methods: Women with moderate persistent BCRL were randomized to AC or WL. The AC protocol included twice-weekly manual acupuncture over 6 weeks. The primary endpoint was change in circumference difference between affected/unaffected arms. Responders were defined as having &gt; 30% improvement in arm circumference difference between arms. We also evaluated the change in difference between affected/unaffected arm bioimpedance. We used analysis of covariance for circumference and bioimpedance measurements and Fisher’s exact test for proportion of responders. Results: Among 82 patients, 73 (89%) were evaluable for the primary endpoint (36 in AC and 37 in WL). The median age in AC was 65 (IQR 54, 71) and 58 (IQR 49, 70) in WL. Most patients in both arms had undergone mastectomy (74%) and axillary lymph node dissection (96%), and had a history of prior lymphedema treatment (96%). Median duration of lymphedema was 2.2 years in AC (IQR 1.3, 3.0) and 2.5 years in WL (IQR 1.4, 3.4). We found no evidence of a difference in either arm circumference difference improvement (β -0.38cm, 95% CI -0.89, 0.12, p = 0.14) or bioimpedance difference improvement (β -1.06, 95% CI -7.85, 5.72, p = 0.8) between AC and WL at Week 6. There was also no difference in proportion of responders: 17% AC vs. 11% WL (6% difference, 95% CI -10%, 22%, p = 0.5). No severe adverse events (AE) were reported. Grade 1 treatment-related AEs such as bruising (58%), hematoma (2%), and pain (2%) were reported in patients receiving AC. Among the 837 acupuncture treatments provided, one possibly related grade 2 skin infection was reported. Conclusions: Although it appears to be safe and well tolerated, our acupuncture protocol did not offer additional clinically meaningful reductions in BCRL compared with usual care among patients who had received lymphedema treatment. This regimen should not be recommended for breast cancer survivors with persistent BCRL. Clinical trial information: NCT01706081.
Dual inhibition of AXL and FN14 sensitizes cisplatin in resistant non-small cell lung carcinoma by inducing higher caspase 3 cleavage through FHIT upregulation, both in vivo and in vitro
Authors: S. Mukherjee, D. Suresh, A. Zambre, A. Upendran, R. Kannan
Journal: Annals of Oncology (2018)
Quintupling Inhaled Glucocorticoids to Prevent Childhood Asthma Exacerbations
Authors: Daniel J. Jackson, Leonard B. Bacharier, David T. Mauger, Susan Boehmer, Avraham Beigelman, James F. Chmiel, Anne M. Fitzpatrick, Jonathan M. Gaffin, Wayne J. Morgan, Stephen P. Peters, Wanda Phipatanakul, William J. Sheehan, Michael D. Cabana, Fernando Holguin, Fernando D. Martinez, Jacqueline A. Pongracic, Sachin N. Baxi, Mindy Benson, Kathryn Blake, Ronina Covar, Deborah A. Gentile, Elliot Israel, Jerry A. Krishnan, Harsha V. Kumar, Jason E. Lang, Stephen C. Lazarus, John J. Lima, Dayna Long, Ngoc Ly, Jyothi Marbin, James N. Moy, Ross E. Myers, J. Tod Olin, Hengameh H. Raissy, Rachel G. Robison, Kristie Ross, Christine A. Sorkness, Robert F. Lemanske
Journal: New England Journal of Medicine (2018)

Asthma exacerbations occur frequently despite the regular use of asthma-controller therapies, such as inhaled glucocorticoids. Clinicians commonly increase the doses of inhaled glucocorticoids at early signs of loss of asthma control. However, data on the safety and efficacy of this strategy in children are limited.We studied 254 children, 5 to 11 years of age, who had mild-to-moderate persistent asthma and had had at least one asthma exacerbation treated with systemic glucocorticoids in the previous year. Children were treated for 48 weeks with maintenance low-dose inhaled glucocorticoids (fluticasone propionate at a dose of 44 μg per inhalation, two inhalations twice daily) and were randomly assigned to either continue the same dose (low-dose group) or use a quintupled dose (high-dose group; fluticasone at a dose of 220 μg per inhalation, two inhalations twice daily) for 7 days at the early signs of loss of asthma control ("yellow zone"). Treatment was provided in a double-blind fashion. The primary outcome was the rate of severe asthma exacerbations treated with systemic glucocorticoids.The rate of severe asthma exacerbations treated with systemic glucocorticoids did not differ significantly between groups (0.48 exacerbations per year in the high-dose group and 0.37 exacerbations per year in the low-dose group; relative rate, 1.3; 95% confidence interval, 0.8 to 2.1; P=0.30). The time to the first exacerbation, the rate of treatment failure, symptom scores, and albuterol use during yellow-zone episodes did not differ significantly between groups. The total glucocorticoid exposure was 16% higher in the high-dose group than in the low-dose group. The difference in linear growth between the high-dose group and the low-dose group was -0.23 cm per year (P=0.06).In children with mild-to-moderate persistent asthma treated with daily inhaled glucocorticoids, quintupling the dose at the early signs of loss of asthma control did not reduce the rate of severe asthma exacerbations or improve other asthma outcomes and may be associated with diminished linear growth. (Funded by the National Heart, Lung, and Blood Institute; STICS ClinicalTrials.gov number, NCT02066129 .).
Don’t distract from true issues facing young doctors, BMA tells pay body
Authors: Abi Rimmer
Journal: BMJ (2018)

Generalisations made by the doctors’ pay review body about juniors are a distraction from the real issues trainees face, the BMA has said.

In its evidence to the Review Body on Doctors’ and Dentists’ Remuneration (DDRB), which advises the government on doctors’ pay rates, the BMA challenged the DDRB’s attitude towards junior doctors.

In its most recent report to the government, published in March last year, the DDRB said that “generation Y” doctors—those born in the …