tbuckley/cabot-search huggingface dataset:
Features of polymyalgia rheumatica–like syndrome after immune checkpoint inhibitor therapy
Authors: Gregoire Martin de Fremont, Rakiba Belkhir, Julien Henry, Anne Laure Voisin, Olivier Lambotte, Florent L Besson, Xavier Mariette, Gaetane Nocturne
Journal: Annals of the Rheumatic Diseases (2020)

Features of polymyalgia rheumatica-like syndrome after immune checkpoint inhibitor therapyWe read with great interest the article published by Braaten and colleagues 1 describing inflammatory arthritis (IA) induced by immune checkpoint inhibitors (ICIs) persisting after immunotherapy cessation.With a growing number of patients treated with ICI, more and more immune-related adverse events are described and a classification has been recently proposed for IA under ICI. 2 It questions whether IA under ICI shows distinctive features from well-defined rheumatological conditions.Here, we report a series of 14 patients who developed polymyalgia rheumatica (PMR)-like syndromes under ICI and compared them with a series of 43 patients with classical PMR seen in the same tertiary centre.We included patients with rhizomelic pain under ICI from our tertiary department of rheumatology (AP-HP, Université Paris-Saclay) and the pharmacovigilance registry of the Gustave Roussy Cancer Institute.The diagnosis of PMR was based on trained clinicians' assessment.Among 14 patients, 11 fulfilled the EULAR/ACR 2012 criteria for PMR.The comparison between PMR-like syndromes and classical PMR showed a difference in sex ratio and a higher frequency of peripheral arthritis in the ICI group (57% vs 28%) (table 1).C reactive protein (CRP) was positive (>5 mg/L) in most cases in both groups: 92.3% and 88.1% in ICI group and classical PMR, respectively.Among the five patients of the ICI group who underwent 18 F-FDG PET/ CT imaging before rheumatological treatment, three showed rhizomelic peri-articular 18 F-FDG PET uptakes associated to a volar FDG uptake at the hands. 3Thirteen patients received glucocorticoids with eight good responders.Among the five other patients, one received methotrexate, three received tocilizumab (one who responded, one who had primary failure and one who had drug-induced hepatitis) and one healed after ICI disruption.To sum up, the main finding of this study is the higher prevalence of peripheral arthritis in PMR-like syndromes induced by ICI.The frequency of increased CRP was the same.Lastly, the therapeutic strategies remain the same as what is proposed in classical PMR, but further studies are mandatory to define the optimal treatment strategy and notably the room for biologic disease-modifying antirheumatic drugs.
Adjuvant chemoradiotherapy after radical cystectomy in advanced high risk bladder cancer: A prospective randomized trial
Authors: M. S. Zaghloul, H. M. Khaled, M. Lotayef, H. William
Journal: Journal of Clinical Oncology (2006)

4545 Background: High risk locally advanced bladder cancer patients experienced low survival rates, high local recurrence and extensive distant metastasis. Postoperative radiotherapy (PORT) though improved the survival through improving local control. Methods: A prospective randomized trial was performed at NCI, Cairo, Egypt including 142 patients in 2 arms. Patients who underwent radical cystectomy and pelvic lymphadenectomy had to have one more of the following: P3b or P4a stage, G3 or involved lymphadenopathy. Arm I (71 patients) received PORT 45 G/30 fractions/3 weeks. Arm II (71 patients) received 2 courses of adjuvant chemotherapy (Gemcitabine 1 gm/m 2 D1 and D8 and cisplatin 70 mg/m 2 D2), same PORT regimen followed by another 2 courses of Gemcitabine-cisplatin. Results: Chemotherapy was tolerated with grade 1/2 toxicities. Early radiation reactions were also tolerable in both arms, slightly more in arm II. Delayed toxicity was comparable in both arms. The 2-year DFS was 67.6 ± 5.9% in the whole group. This was affected significantly by performance status (p = 0.009), pathological stage (p = 0.001), tumor cell type (p = 0.053), nodal involvement (p = 0.07) and number of risk factors (p = 0.09). Though there was improvement of DFS from 61.5 ± 7.4% in PORT group to 70.9 ± 6.1% in chemoradiotherapy group, yet it was not statistically significant (p = 0.2). Patients having one risk factor, low pathological stage or no nodal involvement in arm II experienced better DFS than those in arm I (p = 0.07, 0.08 and 0.09 respectively). Conclusions: Adjuvant chemoradiotherapy using Gemcitabine-cisplatin and PORT was tolerable with minimal severe toxicities. There was DFS improvement with the addition of chemotherapy to PORT (not statistically significant yet). Patients with one risk factor, lower pathological stage or no nodal involvement seemed to benefit more from added chemotherapy. No significant financial relationships to disclose.
ACUTE CHANGES IN MITRAL ANNULAR DIMENSIONS ON 3D TRANSESOPHAGEAL ECHOCARDIOGRAPHY AFTER MITRACLIP TREATMENT OF MITRAL REGURGITATION: A PILOT STUDY
Authors: Richard Ro, Stamatios Lerakis, Karthik Seetharam, Sahil Khera, Samin K. Sharma, Annapoorna Subhash Kini, Gilbert Tang
Journal: Journal of the American College of Cardiology (2020)
Targeting of CD38 by the Tumor Suppressor miR-26a Serves as a Novel Potential Therapeutic Agent in Multiple Myeloma
Authors: Yi Hu, Huimin Liu, Chuanfeng Fang, Chen Li, Fjorela Xhyliu, Hayley Dysert, Juraj Bodo, Gabriel Habermehl, Benjamin E. Russell, Wenjun Li, Marcia Chappell, Xiaofeng Jiang, Sarah L. Ondrejka, Eric D. Hsi, Jaroslaw P. Maciejewski, Qing Yi, Kenneth C. Anderson, Nikhil C. Munshi, Geyou Ao, Jason N. Valent, Jianhong Lin, Jianjun Zhao
Journal: Cancer Research (2020)

Multiple myeloma is an incurable refractory hematologic malignancy arising from plasma cells in the bone marrow. Here we investigated miR-26a function in multiple myeloma and tested single-wall carbon nanotube delivery of miR-26a in vitro and in vivo. miR-26a was downregulated in patients with multiple myeloma cells compared with plasma cells from healthy donors. miR-26a overexpression inhibited proliferation and migration and induced apoptosis in multiple myeloma cell lines. To identify the targets of miR-26a, RPMI8226-V-miR-26-GFP and RPMI8226-V-GFP cells were cultured using stable isotope labeling by amino acids in cell culture (SILAC) medium, followed by mass spectrometry analysis. In multiple myeloma cells overexpressing miR-26a, CD38 protein was downregulated and subsequently confirmed to be a direct target of miR-26a. Depletion of CD38 in multiple myeloma cells duplicated the multiple myeloma inhibition observed with exogenous expression of miR-26a, whereas restoration of CD38 overcame the inhibition of miR-26a in multiple myeloma cells. In a human multiple myeloma xenograft mouse model, overexpression of miR-26a inhibited CD38 expression, provoked cell apoptosis, and inhibited cell proliferation. Daratumumab is the first CD38 antibody drug for monotherapy and combination therapy for patients with multiple myeloma, but eventually resistance develops. In multiple myeloma cells, CD38 remained at low level during daratumumab treatment, but a high-quality response is sustained. In daratumumab-resistant multiple myeloma cells, CD38 expression was completely restored but failed to correlate with daratumumab-induced cell death. Therefore, a therapeutic strategy to confer selection pressure to maintain low CD38 expression in multiple myeloma cells may have clinical benefit. SIGNIFICANCE: These results highlight the tumor suppressor function of miR-26a via its targeting of CD38 and suggest the therapeutic potential of miR-26a in patients with multiple myeloma.
Long non-coding RNA HUMT hypomethylation promotes lymphangiogenesis and metastasis via activating FOXK1 transcription in triple-negative breast cancer
Authors: Shaoquan Zheng, Lu Yang, Yutian Zou, Jie-ying Liang, Peng Liu, Guanfeng Gao, Anli Yang, Hailin Tang, Xiaoming Xie
Journal: Journal of Hematology & Oncology (2020)

Abstract Background Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer with highly invasive ability and metastatic nature to the lymph nodes. Long non-coding RNAs (lncRNAs) have been widely explored in cancer tumorigenesis and progression. However, their roles in TNBC lymph node metastasis remains rarely studied. Methods The expression of lncRNA highly upregulated in metastatic TNBC (HUMT) in cell lines and tissues was detected by quantitative real-time PCR (qRT-PCR) and in situ hybridization (ISH). RNA immunoprecipitation (RIP) and RNA pulldown were used to verify the interaction between lncRNA and protein. Chromatin immunoprecipitation (CHIP) and dCas9-gRNA-guided chromatin immunoprecipitation (dCas9-CHIP) were conducted to identify the specific binding site of HUMT-YBX1 complex. Western blot was used to detect the downstream of HUMT. Results HUMT was significantly upregulated in lymph node invasive cells and predicted poorer clinical prognosis. Functional study indicated that HUMT promoted lymphangiogenesis and lymph node metastasis. Bioinformatic analysis and qRT-PCR showed that the high expression of HUMT was correlated with the hypomethylation status of its promoter region. Further, HUMT recruited Y-box binding protein 1 (YBX1) to form a novel transcription complex and activated the expression of forkhead box k1 (FOXK1), thus enhancing the expression of vascular endothelial growth factor C (VEGFC). The therapeutic value was further validated in patient-derived xenograft (PDX) models, and a combined marker panel exhibited a better prognostic value for TNBC in receiver operating characteristic (ROC) analysis. Conclusions Our study identified a novel TNBC lymph node metastasis-associated lncRNA, which promoted TNBC progression and indicated a novel biomarker and potential therapeutic target for TNBC lymph node metastasis.
RELATIONSHIP BETWEEN CHOLESTEROL EFFLUX CAPACITY, APOLIPOPROTEIN A1 AND NONCALCIFIED CORONARY BURDEN IN PSORIASIS
Authors: Mithun Devraj, Amit Dey, Heather Teague, Justin Rodante, Raja Zaghlol, Andrew Keel, Aditya A. Joshi, Marcus Y. Chen, Martin Playford, Nehal Mehta
Journal: Journal of the American College of Cardiology (2020)
Phase 2 study of pembrolizumab in patients with advanced rare cancers
Authors: Aung Naing, Funda Meric-Bernstam, Bettzy Stephen, Daniel D Karp, Joud Hajjar, Jordi Rodon Ahnert, Sarina A Piha-Paul, Rivka R Colen, Camilo Jimenez, Kanwal P Raghav, Renata Ferrarotto, Shi-Ming Tu, Matthew Campbell, Linghua Wang, Sarjeel H Sabir, Coya Tapia, Chantale Bernatchez, Michael Frumovitz, Nizar Tannir, Vinod Ravi, Saria Khan, Jeane M Painter, Abulrahman Abonofal, Jing Gong, Anas Alshawa, Lacey M McQuinn, Mingxuan Xu, Sara Ahmed, Vivek Subbiah, David S Hong, Shubham Pant, Timothy A Yap, Apostolia M Tsimberidou, Ecaterina E Ileana Dumbrava, Filip Janku, Siqing Fu, Richard M Simon, Kenneth R Hess, Gauri R Varadhachary, Mouhammed Amir Habra
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Patients with advanced rare cancers have poor prognosis and few treatment options. As immunotherapy is effective across multiple cancer types, we aimed to assess pembrolizumab (programmed cell death 1 (PD-1) inhibitor) in patients with advanced rare cancers. Methods In this open-label, phase 2 trial, patients with advanced rare cancers whose tumors had progressed on standard therapies, if available, within the previous 6 months were enrolled in nine tumor-specific cohorts and a 10th cohort for other rare histologies. Pembrolizumab 200 mg was administered intravenously every 21 days. The primary endpoint was non-progression rate (NPR) at 27 weeks; secondary endpoints were safety and tolerability, objective response rate (ORR), and clinical benefit rate (CBR). Results A total of 127 patients treated between August 15, 2016 and July 27, 2018 were included in this analysis. At the time of data cut-off, the NPR at 27 weeks was 28% (95% CI, 19% to 37%). A confirmed objective response (OR) was seen in 15 of 110 (14%) evaluable patients (complete response in one and partial response in 14). CBR, defined as the percentage of patients with an OR or stable disease ≥4 months, was 38% (n=42). Treatment was ongoing in 11 of 15 patients with OR at last follow-up. In the cohort with squamous cell carcinoma (SCC) of the skin, the NPR at 27 weeks was 36%, ORR 31%, and CBR 38%. In patients with adrenocortical carcinoma (ACC), NPR at 27 weeks was 31%, ORR 15%, and CBR 54%. In the patients with carcinoma of unknown primary (CUP), NPR at 27 weeks was 33%, ORR 23%, and CBR 54%. In the paraganglioma–pheochromocytoma cohort, NPR at 27 weeks was 43%, ORR 0%, and CBR 75%. Treatment-related adverse events (TRAEs) occurred in 66 of 127 (52%) patients, and 12 (9%) had grade ≥3 TRAEs. The most common TRAEs were fatigue (n=25) and rash (n=17). There were six deaths, all of which were unrelated to the study drug. Conclusions The favorable toxicity profile and antitumor activity seen in patients with SCC of skin, ACC, CUP, and paraganglioma–pheochromocytoma supports further evaluation of pembrolizumab in this patient population. Trial registration number NCT02721732
THE GENDER GAP IN THE PURSUIT OF CARDIAC ELECTROPHYSIOLOGY AS A SUBSPECIALTY AMONG CARDIOVASCULAR FELLOWS IN TRAINING
Authors: Nashwa Abdulsalam, Anne Rzeszut, Anne Gillis, Sena Kilic, Kristin West, Claire Duvernoy, Marie-Noelle S. Langan, Celina M. Yong, Poonam Velagapudi, Edward O’Leary
Journal: Journal of the American College of Cardiology (2020)
BONE MARROW ADIPOSE TISSUE VOLUME INDEPENDENTLY ASSOCIATES WITH ATHEROSCLEROTIC DISEASE BURDEN AND MACE
Authors: Shady Abohashem, Tawseef Ahmad Dar, Michael T. Osborne, Taimur Abbasi, Elizabeth O'Donnell, Miriam A. Bredella, Noopur Raje, Ahmed Tawakol
Journal: Journal of the American College of Cardiology (2020)
CLINICAL PROFILE AND OUTCOMES FOR PERIPARTUM CARDIOMYOPATHY IN NIGERIA: A PROSPECTIVE LONGITUDINAL STUDY
Authors: Kamilu Musa Karaye, Hadiza Sa'idu, Suleiman A. Balarabe, Naser A. Ishaq, Umar G. Adamu, Idris Y. Mohammed, Isa Oboirien, Ejiro M. Umuerri, Vincent Shidali, Abaram Chesa Mankwe, Paschal Njoku, Sotonye Dodiyi-Manuel, Taiwo Olunuga, Veronica Josephs, Amam C. Mbakwem, Okechukwu Ogah
Journal: Journal of the American College of Cardiology (2020)
CORONARY ARTERY CALCIUM SCORING AND OUTCOMES IN PATIENTS WITH SEVERE HYPERCHOLESTEROLEMIA: INSIGHTS FROM CLARIFY
Authors: Sadeer G. Al-Kindi, Nour Tashtish, Imran Rashid, Varun Sundaram, David Zidar, Jared Durieux, Robert C. Gilkeson, Sanjay Rajagopalan
Journal: Journal of the American College of Cardiology (2020)
AGE MODIFIES THE SURVIVAL OF PATIENTS WITH OBSTRUCTIVE SLEEP APNEA WHO DEVELOP ACUTE CORONARY EVENTS: FROM THE NATIONAL INPATIENT SAMPLE
Authors: Ashraf Abugroun, Pragnesh Patel, Sameera Natarajan, Safwan Gaznabi, Ahmed Elawad, Manar Elhassan, Lloyd W. Klein
Journal: Journal of the American College of Cardiology (2020)
PREDICTORS OF ATRIAL FIBRILLATION DURING LONG-TERM ARRHYTHMIA MONITORING FOLLOWING CRYPTOGENIC STROKE
Authors: Michael Riordan, Ayhan Yoruk, Arwa Younis, Adil Ali, Amanda Opaskar, Bogachan Sahin, Scott McNitt, Ilan Goldenberg, Mehmet Aktas
Journal: Journal of the American College of Cardiology (2020)
RELATIVE PROGNOSTIC SIGNIFICANCE OF POSITRON EMISSION TOMOGRAPHY (PET) MYOCARDIAL PERFUSION IMAGING (MPI) MARKERS IN ISCHEMIC AND NON-ISCHEMIC CARDIOMYOPATHY
Authors: Merrill Thomas, Krishna Patel, Poghni Peri-Okonny, Ali Malik, Brett Sperry, Arthur McGhie, Ibrahim Muhammad Saeed, Paul S. Chan, John A. Spertus, Randall Thompson, Timothy Bateman
Journal: Journal of the American College of Cardiology (2020)
Women’s Representation in Leadership Positions in Academic Medical Oncology, Radiation Oncology, and Surgical Oncology Programs
Authors: Mudit Chowdhary, Akansha Chowdhary, Trevor J. Royce, Kirtesh R. Patel, Arpit M. Chhabra, Shikha Jain, Miriam A. Knoll, Neha Vapiwala, Barbara Pro, Gaurav Marwaha
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Women are underrepresented in medical leadership positions; however, representation of women among academic oncology leadership is unknown. <h3>Objectives</h3> To evaluate representation of women overall and in leadership positions in academic medical oncology (MO), radiation oncology (RO), and surgical oncology (SO) programs and to examine the association of women leadership with overall faculty representation of women per program. <h3>Design, Setting, and Participants</h3> In this cross-sectional study, MO, RO, and SO training program websites were queried from October 2018 through June 2019. All faculty from 265 of 273 accredited MO, RO, and SO training programs (97.1%) were included. <h3>Exposure</h3> Gender. <h3>Main Outcomes and Measures</h3> Observed proportions of women in leadership positions compared with the expected proportion of overall women faculty in MO, RO, and SO were assessed. Rates of representation of women across each MO, RO, and SO program's faculty based on the presence or absence of a woman in a leadership position were compared. <h3>Results</h3> Of 6030 total faculty, only 2164 (35.9%) were women. Total representation of women among MO, RO, and SO faculty was 37.1% (1563 of 4215), 30.7% (389 of 1269), and 38.8% (212 of 546), respectively. Women composed only 21.7% (30 of 138), 11.7% (11 of 94), and 3.8% (1 of 26) of MO, RO, and SO chair positions, respectively. The observed proportion of women in chair positions was significantly lower than the expected proportion for MO, RO, and SO. In all, 47.9%, 33%, and 18.5% of MO, RO, and SO programs, respectively, had at least 1 woman in a leadership position (program director or chair). Programs with 1 or more women in a leadership position were associated with a higher mean (SD) percentage of women faculty than those without at least 1 woman leader in MO (40.7% [12.5%] vs 33.1% [11.0%];<i>P</i> &lt; .001) and RO (36.2% [13.3%] vs 23.4% [12.3%];<i>P</i> &lt; .001) but not SO (40.2% [15.4%] vs 31.4% [16.9%];<i>P</i> = .29). <h3>Conclusions and Relevance</h3> Gender disparity exists in academic MO, RO, and SO faculty, which is magnified at the chair level. Programs in MO and RO with a woman physician in a leadership position were associated with a higher percentage of women faculty, but this was not true for SO. These data will serve as a benchmark to monitor progress toward a more balanced workforce.
A pooled analysis of phase II trials of gemcitabine (GEM)-containing doublets plus bevacizumab (BEV): Should combination chemotherapy serve as the backbone in clinical trials of advanced pancreatic cancer (APC)?
Authors: Katherine Van Loon, George P. Kim, Anne Marie Espinoza, David R. Fogelman, Renuka V. Iyer, Vincent J. Picozzi, Robert A. Wolff, Milind M. Javle, Andrew H. Ko
Journal: Journal of Clinical Oncology (2012)

4038 Background: GEM has served as the chemotherapy platform for most phase III clinical trials in APC, inc. CALGB 80303 (GEM +/- BEV). However, GEM-based combination regimens may confer superior outcomes in select pts and represent a preferred backbone in clinical trial design testing targeted agents. Methods: Data was pooled from 5 phase II trials evaluating GEM-based cytotoxic doublets plus BEV in APC. 1 o endpoint was OS. 2 o endpoints included ORR, CA19-9 response, and adverse events (AEs). Kaplan-Meier methods estimated time-to-event endpoints. The Cox proportional hazard model estimated univariate hazard ratios (HR) of death. Results: Of 261 pts, 90.7% were Caucasian, 95.4% had an ECOG PS 0-1, and 91.6% had metastatic disease. Median age = 60y. Pooled OS data (in mos), stratified for PS and stage, is shown in the table. ORR across all trials: CR 1.6%, PR 22.9%, SD 50.8%, PD 20.2%, NA 4.7%. HR for pts who achieved disease control (CR/PR/SD) was 0.35 vs. those with PD (95% CI 0.23-0.54, p&lt;0.001). 76.5% of pts had elevated baseline CA19-9; of these, 62% achieved ≥50% reduction (HR 0.50; 95% CI 0.34-0.73, p&lt;0.001). BEV-related AEs ≥grade 3: HTN (10.6%), hemorrhage (9.5%), VTE (10.1%), cardiac events (3.4%), and bowel perforation (2.2%). Median OS in pts with grade 3-4 HTN was 13.4 mos vs. 9.8 mos in those without (HR 0.77; 95% CI 0.48-1.24, p=0.29). Conclusions: Recognizing the limitations of single-arm phase II trial design and cross-study comparisons, these results compare favorably to those from CALGB 80303. The standard paradigm of GEM +/- drug X in clinical trial development for APC needs to be reconsidered. Based on our data as well as the recent phase III FOLFIRINOX study, building on more intensive combination chemo regimens in future trials may represent a better strategy, especially for pts with good PS. [Table: see text]
Effects of Intensive Glycemic Control on Clinical Outcomes Among Patients With Type 2 Diabetes With Different Levels of Cardiovascular Risk and Hemoglobin A1c in the ADVANCE Trial
Authors: Jingyan Tian, Toshiaki Ohkuma, Mark Cooper, Stephen Harrap, Giuseppe Mancia, Neil Poulter, Ji-Guang Wang, Sophia Zoungas, Mark Woodward, John Chalmers
Journal: Diabetes Care (2020)

OBJECTIVE To study whether the effects of intensive glycemic control on major vascular outcomes (a composite of major macrovascular and major microvascular events), all-cause mortality, and severe hypoglycemia events differ among participants with different levels of 10-year risk of atherosclerotic cardiovascular disease (ASCVD) and hemoglobin A1c (HbA1c) at baseline. RESEARCH DESIGN AND METHODS We studied the effects of more intensive glycemic control in 11,071 patients with type 2 diabetes (T2D), without missing values, in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial, using Cox models. RESULTS During 5 years’ follow-up, intensive glycemic control reduced major vascular events (hazard ratio [HR] 0.90 [95% CI 0.83–0.98]), with the major driver being a reduction in the development of macroalbuminuria. There was no evidence of differences in the effect, regardless of baseline ASCVD risk or HbA1c level (P for interaction = 0.29 and 0.94, respectively). Similarly, the beneficial effects of intensive glycemic control on all-cause mortality were not significantly different across baseline ASCVD risk (P = 0.15) or HbA1c levels (P = 0.87). The risks of severe hypoglycemic events were higher in the intensive glycemic control group compared with the standard glycemic control group (HR 1.85 [1.41–2.42]), with no significant heterogeneity across subgroups defined by ASCVD risk or HbA1c at baseline (P = 0.09 and 0.18, respectively). CONCLUSIONS The major benefits for patients with T2D in ADVANCE did not substantially differ across levels of baseline ASCVD risk and HbA1c.
Variability in Genome Editing Outcomes: Challenges for Research Reproducibility and Clinical Safety
Authors: Lydia Teboul, Yann Herault, Sara Wells, Waseem Qasim, Guillaume Pavlovic
Journal: Molecular Therapy (2020)

Genome editing tools have already revolutionized biomedical research and are also expected to have an important impact in the clinic. However, their extensive use in research has revealed much unpredictability, both off and on target, in the outcome of their application. We discuss the challenges associated with this unpredictability, both for research and in the clinic. For the former, an extensive validation of the model is essential. For the latter, potential unpredicted activity does not preclude the use of these tools but requires that molecular evidence to underpin the relevant risk:benefit evaluation is available. Safe and successful clinical application will also depend on the mode of delivery and the cellular context.