tbuckley/cabot-search huggingface dataset:
Pharmacogenomic Approach to Selecting Antiplatelet Therapy in Patients With Acute Coronary Syndromes
Authors: Francesca Maria Notarangelo, Giuseppe Maglietta, Paola Bevilacqua, Marco Cereda, Piera Angelica Merlini, Giovanni Quinto Villani, Paolo Moruzzi, Giampiero Patrizi, Guidantonio Malagoli Tagliazucchi, Antonio Crocamo, Angela Guidorossi, Filippo Pigazzani, Elisa Nicosia, Giorgia Paoli, Marco Bianchessi, Mario Angelo Comelli, Caterina Caminiti, Diego Ardissino
Journal: Journal of the American College of Cardiology (2018)
Abstract P2-02-03: Assessment of an immune response panel of serum protein biomarkers for the non-invasive detection of breast cancer
Authors: PR McQuary, KAF Copeland, NM Sheibani, LA Friedman, RL Korn, JV Fiorica, AP Lourenco, SE Struthers, LK Hesterberg
Journal: Cancer Research (2018)

Abstract Background: Breast cancer screening guidelines (ACS) recommend annual mammography for asymptomatic women ages 45 to 54 and once every two years for women age 55 and older. Women with suspicious screening mammograms are recommended for a diagnostic mammogram and may also undergo MRI or ultrasound. Ultimately, unresolved suspicious findings frequently result in the recommendation of a breast biopsy. Approximately 10% of suspicious diagnostic mammograms are recommended for breast biopsies and a large majority of these biopsies yield benign results. We conducted a screen for serum protein biomarkers and identified a novel panel for the non-invasive detection of breast cancer with the goal of developing a diagnostic test that can reduce the number of patients with benign pathology undergoing invasive biopsies. Methods: Serum samples were collected at 4 US sites from women with suspicious diagnostic mammogram findings (primarily BI-RADS category 4 and breast composition b/c) undergoing biopsy for evaluation of a potential malignancy. Serum samples from 136 patients (87 benign pathology and 49 malignant pathology) were evaluated on the olink® Proteomics Immune Response Panel (92 analytes). Statistical screening methodologies, such as individual t-tests with control for false discovery, were used to identify markers with the potential to distinguish benign from malignant pathology. The candidate markers were further studied and combined using generalized linear modeling to develop potential diagnostic models. Results: A 19-marker model resulted in an AUC of 0.94 with a sensitivity of 90% and a specificity of 80%. A 12-marker model resulted in an AUC of 0.93, yielding a sensitivity of 90% with a specificity of 77%. Conclusions: This study reveals a novel panel of serum protein biomarkers that may allow for the non-invasive and sensitive detection of breast cancer in patients presenting with suspicious findings on mammography, thus reducing the need for invasive biopsies. Citation Format: McQuary PR, Copeland KAF, Sheibani NM, Friedman LA, Korn RL, Fiorica JV, Lourenco AP, Struthers SE, Hesterberg LK. Assessment of an immune response panel of serum protein biomarkers for the non-invasive detection of breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-02-03.
Induction Chemotherapy plus Concurrent Chemoradiotherapy in Endemic Nasopharyngeal Carcinoma: Individual Patient Data Pooled Analysis of Four Randomized Trials
Authors: Yu-Pei Chen, Ling-Long Tang, Qi Yang, Sharon-Shuxian Poh, Edwin P. Hui, Anthony T.C. Chan, Whee-Sze Ong, Terence Tan, Joseph Wee, Wen-Fei Li, Lei Chen, Brigette B.Y. Ma, Macy Tong, Sze-Huey Tan, Shie-Lee Cheah, Kam-Weng Fong, Kiattisa Sommat, Yoke Lim Soong, Ying Guo, Ai-Hua Lin, Ying Sun, Ming-Huang Hong, Su-Mei Cao, Ming-Yuan Chen, Jun Ma
Journal: Clinical Cancer Research (2018)

Purpose: Because of the uneven geographic distribution and small number of randomized trials available, the value of additional induction chemotherapy (IC) to concurrent chemoradiotherapy (CCRT) in nasopharyngeal carcinoma (NPC) remains controversial. This study performed an individual patient data (IPD) pooled analysis to better assess the precise role of IC + CCRT in locoregionally advanced NPC.Experimental Design: Four randomized trials in endemic areas were identified, representing 1,193 patients; updated IPD were obtained. Progression-free survival (PFS) and overall survival (OS) were the primary and secondary endpoints, respectively.Results: Median follow-up was 5.0 years. The HR for PFS was 0.70 [95% confidence interval (CI), 0.56-0.86; P = 0.0009; 9.3% absolute benefit at 5 years] in favor of IC + CCRT versus CCRT alone. IC + CCRT also improved OS (HR = 0.75; 95% CI, 0.57-0.99; P = 0.04) and reduced distant failure (HR = 0.68; 95% CI, 0.51-0.90; P = 0.008). IC + CCRT had a tendency to improve locoregional control compared with CCRT alone (HR = 0.70; 95% CI, 0.48-1.01; P = 0.06). There was no heterogeneity between trials in any analysis. No interactions between patient characteristics and treatment effects on PFS or OS were found. After adding two supplementary trials to provide a more comprehensive overview, the conclusions remained valid and were strengthened. In a supplementary Bayesian network analysis, no statistically significant differences in survival between different IC regimens were detected.Conclusions: This IPD pooled analysis demonstrates the superiority of additional IC over CCRT alone in locoregionally advanced NPC, with the survival benefit mainly associated with improved distant control. Clin Cancer Res; 24(8); 1824-33. ©2018 AACR.
Temozolomide-associated hypermutation in gliomas
Authors: Serah Choi, Yao Yu, Matthew R Grimmer, Michael Wahl, Susan M Chang, Joseph F Costello
Journal: Neuro-Oncology (2018)

Low-grade gliomas cause considerable morbidity and most will recur after initial therapy. At recurrence, low-grade gliomas can undergo transformation to high-grade gliomas (grade III or grade IV), which are associated with worse prognosis. Temozolomide (TMZ) provides survival benefit in patients with glioblastomas, but its value in patients with low-grade gliomas is less clear. A subset of TMZ-treated, isocitrate dehydrogenase‒mutant, low-grade astrocytomas recur as more malignant tumors with thousands of de novo, coding mutations bearing a signature of TMZ-induced hypermutation. Preliminary studies raise the hypothesis that TMZ-induced hypermutation may contribute to malignant transformation, although with highly variable latency. On the other hand, hypermutated gliomas have radically altered genomes that present new opportunities for therapeutic intervention. In light of these findings and the immunotherapy clinical trials they inspired, how do patients and providers approach the risks and benefits of TMZ therapy? This review discusses what is known about the mechanisms and consequences of TMZ-induced hypermutation and outstanding questions regarding its clinical significance.
DOES THE GEOGRAPHY AFFECT OUTCOMES OF ROUTINE VERSUS SELECTIVE INVASIVE STRATEGY IN THE TREATMENT OF UNSTABLE ANGINA AND NON-ST SEGMENT MYOCARDIAL INFARCTION: A META-ANALYSIS
Authors: Chayakrit Krittanawong, Hafeez Ul Hassan Virk, Saurav Chatterjee, Zhen Wang, Jon George, Gregg Pressman, Sanjog Karla, Bing Yue, Xin Wei, Saranapoom Klomjit, Eyal Herzog, Vincent Figueredo, Angela Palazzo
Journal: Journal of the American College of Cardiology (2018)
Phase I study of stereotactic body radiotherapy following radical prostatectomy.
Authors: Leslie Ballas, Monish Aron, Shamim Jhimlee, Igor Shuryak, Tanya B. Dorff, Dongyun Yang, David J. Brenner, Susan G. Groshen
Journal: Journal of Clinical Oncology (2018)

TPS158 Background: Although multiple Phase I/II studies demonstrate safety and low rates of toxicity following stereotactic body radiotherapy (SBRT) to the intact prostate, there are limited data on hypofractionation and SBRT after prostatectomy. This Phase I study was performed to evaluate acute toxicity associated with dose escalation from 3.6 Gy per fraction to 7.1 Gy per fraction to the prostate bed in the post-prostatectomy treatment of prostate cancer. We hypothesize that the toxicity of escalating the dose per fraction to the prostate fossa in the post-operative setting will be well tolerated; and we expect toxicity to be comparable to normal fractionation schedules. Methods: This study (NCT02446366) was designed to look at acute toxicity, defined as toxicity that occurred within the first 10 weeks of RT, of different dose fractionation schemes in the post-prostatectomy setting. The doses chosen for dose escalation on this study are based on an equivalent biological effective dose to a previously published hypofractionated post-prostatectomy study that showed no increase in acute bowel or bladder toxicity. The dose levels are as follows: Level 1 -3.6 Gy x 15 fractions; Level 2- 4.7 Gy x 10 fractions; Level 3 - 7.1 Gy x 5 fractions. Eligibility for participation on the trial was for patients who had pT3N0 disease regardless of margin status in the post-prostatectomy setting, pT2N0 patients with positive margin or with a negative surgical margin and a rising post-operative PSA. Patients could be on concurrent ADT and enroll on this study. Dose was escalated according to a 6+6 schema. For purposes of deciding whether to escalate to a new dose level, expand a dose level or de-escalate from a dose level, we used toxicities and adverse events that occur during the 1 st 10 weeks after completion of radiotherapy. Six patients were enrolled on each new dose level with a total of 12 patients required at the maximum tolerated dose. Dose-limiting toxicity (DLT) was defined as grade 3 or worse fatigue, gastrointestinal (GI) or genitourinary (GU) toxicity by Common Terminology Criteria of Adverse Events (version 4.03). Dose levels 1 and 2 have been completed without any DLT. Dose level 3 has enrolled 9/12 patients without any DLT. Clinical trial information: NCT02446366.
Phenylboronic Acid Functionalized Polycarbonate Hydrogels for Controlled Release of Polymyxin B in <i>Pseudomonas Aeruginosa</i> Infected Burn Wounds
Authors: Sybil Obuobi, Zhi Xiang Voo, Mei W. Low, Bertrand Czarny, Vanitha Selvarajan, Nor L. Ibrahim, Yi Yan Yang, Pui Lai Rachel Ee
Journal: Advanced Healthcare Materials (2018)

Abstract While physically crosslinked polycarbonate hydrogels are effective drug delivery platforms, their hydrophobic nature and lack of side chain functionality or affinity ligands for controlled release of hydrophilic drugs underscore the importance of their chemical compositions. This study evaluates an array of anionic hydrogel systems of phenylboronic acid functionalized triblock copolymers prepared via reversible physical interactions. Variation of key chemical functionalities while maintaining similar core structural features demonstrates the influence of the substitution position and protection of the boronic acid functionality on gel viscoelasticity and mechanical strength at physiological pH. The optimum gel systems obtained from the meta ‐substituted copolymers (m‐PAP) are stable at physiological pH and nontoxic to mammalian dermal cells. The polymyxin B loaded m‐PAP hydrogels demonstrate controlled in vitro drug release kinetics and in vitro antimicrobial activity against Pseudomonas aeruginosa over 48 h. In vivo antimicrobial efficacy of the drug loaded hydrogels further corroborates the in vitro results, demonstrating sustained antimicrobial activity against P. aeruginosa burn wound infections. The current strategy described in this study demonstrates a straightforward approach in designing physiologically relevant boronic acid hydrogel systems for controlled release of cationic antimicrobials for future clinical applications.
Abstract P2-07-06: Multi-omics characterization of claudin-low breast tumors
Authors: RM Pommier, A-P Morel, A Tissier, E Thomas, J Kielbassa, L Tonon, E Sohier, A Viari, P Saintigny, A Puisieux
Journal: Cancer Research (2018)

Abstract Breast tumors display highly heterogeneous characteristics both at transcriptional level and in term of genomic landscape. We recently reported that the differentiation status of the cell-of-origin influences the genetic route toward tumorigenesis1. Indeed, mammary stem cells exhibit the intrinsic property to tolerate the oxidative stress inherent to the oncogenic transformation through the expression of a preemptive program driven by ZEB1, an epithelial-to-mesenchymal transition (EMT)-related transcription factor, and MSRB3, a methionine sulfoxide reductase. Thereby, ZEB1-expressing tumors exhibit low level of DNA damage associated with few genomic alterations and low level of TP53 mutations. Importantly, these tumors share several transcriptional characteristics and features with normal stem cells, and with Claudin-Low (CL) molecular subtype of breast cancers. In the present work, we attempt to decipher molecular traits of CL breast tumors through multi-omics analyses of publicly available databases. This global approach allows us to highlight various CL breast tumors features as clinical attributes, gene expression, copy number alterations (CNA), somatic mutations or drug responses by differential analyses of breast tumors and cancer cell lines. Preliminary results indicate that, independently of tumor purity, CL breast tumors are mostly diploids, present a paucity of genomic rearrangements and a lower mutation rate compared to other breast tumors. They mainly, but not exclusively, show basal features and belong to the integrative cluster 4 (CNA-devoid) described by Christina Curtis and colleagues2. Concerning gene expression, CL breast tumors exhibit a frequent activation of RAS signaling pathway, an observation consistent with their sensitivity to MAPK inhibitors. Other analyses are currently ongoing and aim to better understand the biology of CL breast tumors in order to improve both the diagnosis and the therapeutic strategy used. 1. Morel A-P et al. A stemness-related ZEB1-MSRB3 axis governs cellular pliancy and breast cancer genome stability. Nature Medicine. 2017 Apr 10. 2. Curtis C et al. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature. 2012 Apr 18. Citation Format: Pommier RM, Morel A-P, Tissier A, Thomas E, Kielbassa J, Tonon L, Sohier E, Viari A, Saintigny P, Puisieux A. Multi-omics characterization of claudin-low breast tumors [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-07-06.
Chimeric Antigen Receptor T Cell–Mediated Neurotoxicity in Nonhuman Primates
Authors: Agne Taraseviciute, Victor Tkachev, Rafael Ponce, Cameron J. Turtle, Jessica M. Snyder, H. Denny Liggitt, David Myerson, Luis Gonzalez-Cuyar, Audrey Baldessari, Chris English, Alison Yu, Hengqi Zheng, Scott N. Furlan, Daniel J. Hunt, Virginia Hoglund, Olivia Finney, Hannah Brakke, Bruce R. Blazar, Carolina Berger, Stanley R. Riddell, Rebecca Gardner, Leslie S. Kean, Michael C. Jensen
Journal: Cancer Discovery (2018)

Chimeric antigen receptor (CAR) T-cell immunotherapy has revolutionized the treatment of refractory leukemias and lymphomas, but is associated with significant toxicities, namely cytokine release syndrome (CRS) and neurotoxicity. A major barrier to developing therapeutics to prevent CAR T cell–mediated neurotoxicity is the lack of clinically relevant models. Accordingly, we developed a rhesus macaque (RM) model of neurotoxicity via adoptive transfer of autologous CD20-specific CAR T cells. Following cyclophosphamide lymphodepletion, CD20 CAR T cells expand to 272 to 4,450 cells/μL after 7 to 8 days and elicit CRS and neurotoxicity. Toxicities are associated with elevated serum IL6, IL8, IL1RA, MIG, and I-TAC levels, and disproportionately high cerebrospinal fluid (CSF) IL6, IL2, GM-CSF, and VEGF levels. During neurotoxicity, both CD20 CAR and non-CAR T cells accumulate in the CSF and in the brain parenchyma. This RM model demonstrates that CAR T cell–mediated neurotoxicity is associated with proinflammatory CSF cytokines and a pan–T cell encephalitis.
RANDOMIZED COMPARISON OF CLINICAL EFFECTIVENESS OF PHARMACOLOGIC STRESS MYOCARDIAL PERFUSION IMAGING WITH SINGLE PHOTON EMISSION COMPUTED TOMOGRAPHY (SPECT) AND POSITRON EMISSION TOMOGRAPHY (PET) IN PATIENTS WITH KNOWN CORONARY ARTERY DISEASE PRESENTING WITH SUSPECTED ISCHEMIA
Authors: Krishna Patel, Firas Al Badarin, Arthur McGhie, Staci Courter, Kevin Kennedy, James Case, Timothy Bateman
Journal: Journal of the American College of Cardiology (2018)
Trend Analysis on Reoperation After Lumpectomy for Breast Cancer
Authors: Mu Yang, Wei Bao, Lanjing Zhang
Journal: JAMA Oncology (2018)

To the Editor We read with great interest the article by Morrow et al.1 It highlights an important issue of overtreatment in breast surgery. Despite its scientific rigor and novelty, we believe that there are 3 limitations that the authors may have considered but did not address in the article.
Hepatotoxicity in advanced cancer patients receiving immune-based cancer treatment.
Authors: Anas Alshawa, Takeo Fujii, Hamzah Abu Sbeih, Boris Blechacz, Mehmet Asim Bilen, Kenneth R. Hess, Maria E. Suarez-Almazor, David S. Hong, Apostolia Maria Tsimberidou, Jing Gong, Bettzy Stephen, Vivek Subbiah, Sarina Anne Piha-Paul, Siqing Fu, Tito R. Mendoza, Selvi Thirumurthi, Funda Meric-Bernstam, Aung Naing, Ethan Miller
Journal: Journal of Clinical Oncology (2018)

67 Background: Immune-based cancer treatment (IBCT) is increasingly used to treat a variety of cancers. Despite the promising results, adverse events such as dermatitis, colitis, and hepatitis remain a concern. Hepatitis is usually mild but may be severe, requiring modification or cessation of treatment. Here, we describe several cases of immune-mediated hepatitis. Methods: We identified patients enrolled in clinical trials using IBCT through the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center, between January 2010 and July 2015. Charts were reviewed for mention of “autoimmune hepatitis”, “hepatitis” or abnormal transaminases, all of which were attributed to IBCT by the treating physician. Hepatotoxicity was graded based on CTCAE v4.0. Results: We identified 12 cases of immune-related hepatotoxicity out of 290 patients. Three patients (1.03%) had grade 3 elevation of transaminases, designated as “autoimmune hepatitis.” Each required systemic steroids and transaminases returned to baseline within a month. IBCT was temporarily held in 2 cases and was permanently discontinued in the third due to grade 4 myositis rather than hepatitis. One patient (0.3%) had grade 2, and eight patients (2.8%) had grade 1 transaminases elevations that were possibly attributable to immunotherapy, but which resolved spontaneously without alteration in treatment. Other significant reported immune-related toxicities ≥ grade 3 were: dermatitis (n = 4), enterocolitis (n = 3), myasthenia gravis (n = 2), myositis (n = 2), pneumonitis, pleuritis, and pancreatitis (n = 1 each). Conclusions: 1.03% of patients experienced grade 3 elevation of transaminases that were attributable to immune therapy. Hepatic adverse events related to immunotherapy in our study were manageable. Further studies are needed to develop biomarkers to identify patients at risk to develop such toxicities. [Table: see text]
ENDOTHELIAL DYSFUNCTION IN THE OFFSPRING OF ST ELEVATION ACUTE MYOCARDIAL INFARCTION PATIENTS
Authors: Nuno Cortez-Dias, Filipa Paramés, João Silva Marques, Glória Costa, Sofia Gouveia, Filipa Ferreira, Sérgio Laranjo, José D. Ferreira Martins, A. Nunes Diogo, Fátima F. Pinto
Journal: Journal of the American College of Cardiology (2011)
LEFT VENTRICULAR END-DIASTOLIC PRESSURE AFTER TRANSCATHETER AORTIC VALVE REPLACEMENT IS A PREDICTOR OF 30 DAYS RE-ADMISSION DUE TO HEART FAILURE
Authors: Nobuyasu Ito, Makoto Amaki, Hideaki Kanzaki, Atsushi Okada, Yasuhiro Hamatani, Hiroyuki Takahama, Takuya Hasegawa, Yasuo Sugano, Kizuku Yamashita, Yuta Kume, Yusuke Shimahara, Tomoyuki Fujita, Satoshi Yasuda, Toshihisa Anzai, Junjiro Kobayashi
Journal: Journal of the American College of Cardiology (2018)
Physical literacy: why should we embrace this construct?
Authors: E Paul Roetert, Todd S Ellenbecker, Dean Kriellaars
Journal: British Journal of Sports Medicine (2018)

In this editorial, we provide a brief explanation of the physical literacy construct and its potential to contribute to the education, safety and overall development of a healthy life for the full lifespan. Although there has been a significant focus on teaching the competence component of being physically active, there has been a lack of focus on teaching people the confidence, desire, motivation, enjoyment and social benefits of physical activity.1–3 Therefore, we challenge the sports medicine and health-related professions to embrace and implement physical literacy’s holistic approach (both mind and body) to physical activity. The term physical literacy has been used in the academic literature since the 1930s1; however, it was not until the 1990s that the construct was re-introduced, embraced by several countries and gained significant attention.1–3 Following a number of iterations, the International Physical Literacy Association settled on the following definition: Physical Literacy is the motivation, confidence, physical competence, knowledge, and understanding to value and take responsibility for engagement in physical activities for life .4 Much of the available research thus far has focused on the sport and education sectors and specifically on the younger generation.1 3 5

Focusing on the younger generation can have a substantial impact on the health of future generations. However, as the definition indicates, physical literacy is …
What are the prospects of getting an SpR post in obstetrics and gynaecology in the United Kingdom for overseas doctors with experience and with MD MRCOG?
Authors: Dharani Hapangama
Journal: BMJ (2004)

Have a career or related problem that needs answering? Can't find the right person to point you in the right direction? Log on to the Advice Zone ( www.bmjcareers.com/advicezone ) for reliable medical careers advice. You can post a question or see if one of our 300 advisers has already answered a similar question. Here is a selection of questions and answers posted on the site.
Baclofen is largely ineffective for alcohol use disorders, finds study
Authors: Susan Mayor
Journal: BMJ (2018)

Baclofen is largely ineffective for treating alcohol use disorders, a meta-analysis of randomised trials has found.

“This new meta-analysis shows that baclofen is no more effective than placebo on a range of key outcome measures, suggesting that the current increasing use of baclofen as a treatment for alcohol use disorders is premature,” said coauthor Andy Jones, from the University of Liverpool.

Treatment of alcohol use disorders is challenging, with current treatments having high relapse rates of up to 70% within six months. The UK National Institute for Health …