tbuckley/cabot-search huggingface dataset:
Role of Patient and Disease Factors in Adjuvant Systemic Therapy Decision Making for Early-Stage, Operable Breast Cancer: Update of the ASCO Endorsement of the Cancer Care Ontario Guideline
Authors: N. Lynn Henry, Mark R. Somerfield, Vandana G. Abramson, Nofisat Ismaila, Kimberly H. Allison, Carey K. Anders, Diana T. Chingos, Andrea Eisen, Bruno L. Ferrari, Thomas H. Openshaw, Patricia A. Spears, Praveen Vikas, Vered Stearns
Journal: Journal of Clinical Oncology (2019)

PURPOSE To update the American Society of Clinical Oncology endorsement of the Cancer Care Ontario recommendations on the Role of Patient and Disease Factors in Adjuvant Systemic Therapy Decision Making for Early-Stage, Operable Breast Cancer. METHODS Two phase III trials—the Trial Assigning Individualized Options for Treatment (TAILORx) in women with hormone receptor–positive, node-negative tumors and the Microarray in Node-Negative and 1 to 3 Positive Lymph Node Disease May Avoid Chemotherapy (MINDACT) trial—provided the evidence for this update. UPDATED RECOMMENDATIONS Shared decision making between clinicians and patients is appropriate for adjuvant systemic therapy for breast cancer. For patients older than age 50 years and whose tumors have Onco type DX recurrence scores less than 26, and for patients age 50 years or younger whose tumors have Onco type DX recurrence scores less than 16, there is little to no benefit from chemotherapy. Clinicians may offer endocrine therapy alone for these patients. For patients age 50 years or younger with recurrence scores of 16 to 25, clinicians may offer chemoendocrine therapy. Patients with recurrence scores greater than 30 should be considered candidates for chemoendocrine therapy. Based on informal consensus, the Panel recommends that oncologists may offer chemoendocrine therapy to patients with Onco type DX scores of 26 to 30. The MammaPrint assay could be used to guide decisions on withholding adjuvant systemic chemotherapy in patients with hormone receptor–positive lymph node–negative breast cancer and in select patients with lymph node–positive cancers. In both patients with node-positive and node-negative disease, evidence of clinical utility of the MammaPrint assay was only apparent in those determined to be at high clinical risk; the Panel thus did not recommend use of MammaPrint assay in patients determined to be at low clinical risk. Remaining recommendations from the 2016 ASCO guideline endorsement are unchanged. Additional information is available at www.asco.org/breast-cancer-guidelines .
CODEX2: full-spectrum copy number variation detection by high-throughput DNA sequencing
Authors: Yuchao Jiang, Rujin Wang, Eugene Urrutia, Ioannis N. Anastopoulos, Katherine L. Nathanson, Nancy R. Zhang
Journal: Genome biology (2018)

High-throughput DNA sequencing enables detection of copy number variations (CNVs) on the genome-wide scale with finer resolution compared to array-based methods but suffers from biases and artifacts that lead to false discoveries and low sensitivity. We describe CODEX2, as a statistical framework for full-spectrum CNV profiling that is sensitive for variants with both common and rare population frequencies and that is applicable to study designs with and without negative control samples. We demonstrate and evaluate CODEX2 on whole-exome and targeted sequencing data, where biases are the most prominent. CODEX2 outperforms existing methods and, in particular, significantly improves sensitivity for common CNVs.
PB2038 EVOLUATION OF CLINICAL MANIFESTATION IN FEBRILE NEUTROPENIC PATIENTS
Authors: H.S. Bekoz, Z. Kaya, A. Mert
Journal: HemaSphere (2019)

Background: Neutropenia is one of the most life‐threatening and significant complication of intensive chemotherapy treatments. Febrile neutropenia is the major cause of mortality and morbidity in these patients (1). Aims: The aim of this study, was to evaluate the epidemiology and the surveillance factors in febrile neutropenic patients retrospectively. Methods: This study was undertaken in the our university from December 2014 to December 2017. Blood culture was studied by Bact‐Alert automated system.Antibiotic susceptibility tests were Kirby Baver Discus Fusion Method. Results: A total of 195 patients, 400 febrile neutropenic attacks were assessed. During FEN episodes, 178 of the patients (45%) had piperacillin‐tazobactam, 145(45%) had meropenem, 195(49%) had teicoplanin and 17(4%) had cefepime.In our study, microbiologically documented infection was 31%, clinically documanted infection was 33%, and responding to empirical antibiotic infection was 43%. image In our study, 83 blood culture positivity were studied for resistance, 33 (40%) of them had ESBL and 19 (23%) had carbapenemase‐producing microorganisms. image Summary/Conclusion: For the management and determining empirical antibiotic policies, it is important to identify their pathogenic microorganisms, to determine their antimicrobial susceptibility for improving survival rates in FEN process. In our study, infections foci, culture positivity rates, isolated microorganisms consistent with the rates reported in the literature.
PF760 DYSBIOSIS IN GUT MICROBIOTA AFTER ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION CAN BE DETERMINED BY THE COMBINATION OF CONDITIONING REGIMEN AND ANTIBIOTIC USAGE
Authors: Y. Arai, T. Tsukahara, M. Nagao, T. Kondo, A. Takaori-Kondo
Journal: HemaSphere (2019)

Background: Gut microbiota is known to change drastically after allogeneic hematopoietic stem cell transplantation (allo-HSCT), and the change (“dysbiosis”) can be a predicting factor or the pathophysiological cause of post-transplant intestinal complications such as acute graft-versus-host disease (GVHD). The cause of dysbiosis, however, is not elucidated yet. Aims: In this study, we analyzed gut microbiota consecutively after allo-HSCT along with the comprehensive analysis on metabolites, and determined the effects of conditioning regimens and post-transplant antibiotics. Methods: We included 20 adult patients who underwent allo-HSCT in our institute (Kyoto University Hospital, Kyoto, Japan) after the written informed consent. Stool samples were collected at 7 timepoints in each patient (before conditioning, Day0, 7, 14, 21, 28, and 35), and bacterial population was determined using next generation sequence technique on 16S ribosomal RNA coding region. Sequence data along with metabolome using the same samples were compared with the clinical information. Results: More than 100 samples were subjected the analysis. Shannon index which indicates diversity of microbiota demonstrated the highest values before transplant (4.075 in average), followed by the significant decrease after allo-HSCT (minimal, 2.469 on Day21, p < 0.05) and gradual recovery toward Day35 (2.736 in average). Chao1 index showed the same tendency; 93.478 before allo-HSCT, 43.456 on Day21, and 46.033 on Day35. Decrease of Shannon index and Chao1 index was more severely observed in patients treated with myeloablative conditioning (MAC) regimens than those with reduced-intensity conditioning (RIC). Moreover, loss of microbiome diversity was also related to the residual antibiotic in stool samples; detection of piperacillin, which is derived from tazobactam/piperacillin, and meropenem showed strong correlation in a concentration-dependent manner. Fermentation in gut was not observed in these patients with metabolome analysis. Summary/Conclusion: Types of conditioning regimens (MAC rather than RIC) and antibiotics were closely related to the dysbiosis after allo-HSCT and, as a result, abnormality in metabolome. They can be used as predictive factors for post-transplant gut dysfunction such as aGVHD.
Abstract 15040: A Transient Up-Regulation of Retinoic Acid Signaling Induces Cell-Cycle Arrest in Neonatal Mammalian Heart
Authors: Yusuke Fujikawa, Kazumasa Unno, Shingo Narita, Kazuhisa Kondo, Mikoto Takefuji, Toyoaki Murohara
Journal: Circulation (2017)

Introduction: Although, proliferative potential of cardiomyocytes is preserved during the first week after birth in rodent, the potential is sharply disappeared following several days, making heart...
PF298 LISOCABTAGENE MARALEUCEL TREATMENT OF PATIENTS WITH RELAPSED/REFRACTORY B‐CELL NON‐HODGKIN LYMPHOMA AND SECONDARY CENTRAL NERVOUS SYSTEM LYMPHOMA: INITIAL RESULTS FROM TRANSCEND NHL 001
Authors: J. Abramson, M.L. Palomba, J. Arnason, M. Lunning, S. Solomon, T. Farazi, J. Garcia, B. Xie, K. Newhall, C. Dehner, T. Siddiqi
Journal: HemaSphere (2019)

Background: No clinical studies have yet evaluated chimeric antigen receptor (CAR) T cell therapies in patients with relapsed/refractory (R/R) B‐cell non‐Hodgkin lymphoma (NHL) who have secondary central nervous system (CNS) lymphoma. Aims: To report data from patients with secondary CNS lymphoma receiving lisocabtagene maraleucel (liso‐cel; JCAR017), an investigational, anti‐CD19 CAR T cell product administered as a defined composition of CD4+/CD8+ CAR T cells, in the phase 1 TRANSCEND NHL 001 study. Methods: Eligible patients had confirmed B‐cell NHL with R/R disease after ≥2 prior lines of therapy. Patients with secondary CNS lymphoma were eligible as long as they also had systemic disease or, if it developed on study, patients could continue to receive liso‐cel. After lymphodepleting chemotherapy, liso‐cel was administered at 1 of 2 dose levels; 50 × 10 6 total CAR+ T cells (dose level 1) or 100 × 10 6 total CAR+ T cells (dose level 2). Efficacy was evaluated per the Lugano criteria. Patients achieving a complete response could be retreated with liso‐cel upon progressive disease. Results: At the data cutoff, 9 patients with secondary CNS lymphoma at initial treatment (n = 6), retreatment (n = 2), or cycle 2 (n = 1) received liso‐cel. Four patients were treated at dose level 1 and 5 at dose level 2. The median (range) age was 60 (47–73) years and the number of prior lines of therapy was 3 (2–7). Median (range) time to peak CAR+ T cell expansion was 12.5 (7–112) days. One of 9 patients had grade 2 cytokine release syndrome (CRS) and 1 of 9 patients had a neurological event (NE; grade 3 decreased level of consciousness). No retreatment patients had CRS or NE, however, 1 retreatment patient had an NE of grade 2 temporal edema during the initial treatment with liso‐cel. Five patients received prophylactic levetiracetam. One patient received corticosteroids and tocilizumab. Other toxicities were predominantly cytopenias. There were no treatment‐related deaths. Four patients responded to liso‐cel; all with a best response of complete response, of which 2 are ongoing at 270 and 545 days post‐liso‐cel. All 4 responses occurred after initial liso‐cel treatment; no retreated patients responded. Summary/Conclusion: In the ongoing TRANSCEND NHL 001 study, liso‐cel continues to demonstrate the ability to be safely delivered to patients with R/R B‐cell NHL, including those with secondary CNS lymphoma, a population of patients with a highly unmet medical need. No excess NE was noted in this population. This cohort continues to be evaluated.
PF817 INTENSIVE PLAN OF THERAPEUTIC PLASMA EXCHANGE IN PATIENT WITH EXTREME HYPERTRLIGLYCERIDEMIA DUE TO L‐ASPARAGINASE IN THE CONTEXT OF SMILE PROTOCOL IN T/NK NASAL LYMPHOMA TREATMENT
Authors: E. Sobejano, M. López‐Parra, O. López Villar, V. Higuero, D. Presa, R. Azibeiro, B. Rey, M. Fonseca, A. Avendaño, J. Carrilo, D. Rivera, C. de Ramón, A. Redondo, A. Yeguas, M. Baile, M.L. Martin Mateos, V. Gonzalez de la Calle, M. González Díaz, M. Vidriales
Journal: HemaSphere (2019)

Background: A 42 year‐old male patient was diagnosed in July 2018 of extranodal T / NK lymphoma, nasal type, EBV + CD56 +, IIA Stage, IPI 1, with right thigh mass and inguinal adenopathies. He received chemotherapy according to the SMILE protocol, that included dexamethasone, methotrexate, ifosfamide, etoposide and L‐asparaginase, starting in August 2018 together with local radiotherapy in the mass concomitantly. As a personal medical history, he was under treatment with Rosuvastatin for familial hypercholesterolemia and hypertriglyceridemia, that was well controlled. Aims: To prove that carry out an aggressive prophylactic apheresis schedule, allows to reduce the complications derived from hypertriglyceridemia due to L‐ASA and to administer full chemotherapy that entails greater possibilities of cure. Methods: One T/NK Nasal Lymphoma patient with familial dyslipidemia suffered multiple events of extreme hypertriglyceridemia (TAGs&gt;1200) that required a total of twenty‐two therapeutic plasma exchanges (TPE) to be able to administer Lasparaginase. Results: During the first cycle after the 5th dose of L‐asparaginase the patient presents extreme hypertriglyceridemia (9016 mg /dl) and two TPE was done with very good response, TAGs of 511 mg/dl and 251 mg/dl after the 1st and 2nd apheresis, respectively. Due to it was an unexpected event, conservative management was performed and he did not receive the last two doses of L‐Asa. Due to the importance of L‐ASA,we optimized oral treatment and carried out an intense apheresis program since second cycle and every L‐ASA doses was received. The patient achieve completed metabolic response after the 3 rd cycle. On the day +20 of the 6th cycle, coinciding with the last dose of L‐asa, it was decided not to make prophylactic plasma exchanges for TAG values of less than 1500 mg/dl (1361 mg /dl). 48 hours later he went to the emergency department and was diagnosed of acute acalculous pancreatitis in the context of hypertriglyceridemia secondary to L‐ASA (TAGs 7168 mg / dl). Two plasma exchanges were performed on days +23 and +24, with good response (decrease from 7168 to 580 TAGs). Summary/Conclusion: In patients with a family history of dyslipidemia maintain prophylactic apheresis until the administration of L‐asparaginase has been fully completed, maintaining &lt;1000 TAG level is essential to improve the results. Moreover, an exhaustive follow‐up should be carried out in these patients, confirming 24 hours after the end of treatment that the TAGs value continues to be &lt;1000 mg/dl and the patient is not at risk of developing pancreatitis.
Abstract 14371: Impact of Living Alone on Long-Term Mortality in Patients With Acute Coronary Syndrome Treated With Percutaneous Coronary Intervention
Authors: Mitsuhiro Takeuchi, Manabu Ogita, Shuta Tsuboi, Norihito Takahashi, Taketo Sonoda, Hideki Wada, Satoru Suwa, Hiroyuki Daida
Journal: Circulation (2018)

Background and Objective: Living alone is recognized as increased risk of cardiovascular disease, however, discordant results have been reported on the clinical outcomes in patients with acute coro...
The ETS Inhibitors YK-4-279 and TK-216 Are Novel Antilymphoma Agents
Authors: Filippo Spriano, Elaine Yee Lin Chung, Eugenio Gaudio, Chiara Tarantelli, Luciano Cascione, Sara Napoli, Katti Jessen, Laura Carrassa, Valdemar Priebe, Giulio Sartori, Garrett Graham, Saravana P. Selvanathan, Andrea Cavalli, Andrea Rinaldi, Ivo Kwee, Monica Testoni, Davide Genini, B. Hilda Ye, Emanuele Zucca, Anastasios Stathis, Brian Lannutti, Jeffrey A. Toretsky, Francesco Bertoni
Journal: Clinical Cancer Research (2019)

Transcription factors are commonly deregulated in cancer, and they have been widely considered as difficult to target due to their nonenzymatic mechanism of action. Altered expression levels of members of the ETS-transcription factors are often observed in many different tumors, including lymphomas. Here, we characterized two small molecules, YK-4-279 and its clinical derivative, TK-216, targeting ETS factors via blocking the protein-protein interaction with RNA helicases, for their antilymphoma activity.The study included preclinical in vitro activity screening on a large panel of cell lines, both as single agent and in combination; validation experiments on in vivo models; and transcriptome and coimmunoprecipitation experiments.YK-4-279 and TK-216 demonstrated an antitumor activity across several lymphoma cell lines, which we validated in vivo. We observed synergistic activity when YK-4-279 and TK-216 were combined with the BCL2 inhibitor venetoclax and with the immunomodulatory drug lenalidomide. YK-4-279 and TK-216 interfere with protein interactions of ETS family members SPIB, in activated B-cell-like type diffuse large B-cell lymphomas, and SPI1, in germinal center B-cell-type diffuse large B-cell lymphomas.The ETS inhibitor YK-4-279 and its clinical derivative TK-216 represent a new class of agents with in vitro and in vivo antitumor activity in lymphomas. Although their detailed mechanism of action needs to be fully defined, in DLBCL they might act by targeting subtype-specific essential transcription factors.
Vitamin D Supplementation and Cardiovascular Disease Risks in More Than 83 000 Individuals in 21 Randomized Clinical Trials
Authors: Mahmoud Barbarawi, Babikir Kheiri, Yazan Zayed, Owais Barbarawi, Harsukh Dhillon, Bakr Swaid, Anitha Yelangi, Saira Sundus, Ghassan Bachuwa, Mohammad Luay Alkotob, JoAnn E. Manson
Journal: JAMA Cardiology (2019)

Observational studies have reported an association between low serum vitamin D levels and elevated risk of cardiovascular disease (CVD) events, but such studies cannot prove causation because of possible unmeasured confounding.We conducted a meta-analysis of randomized clinical trials that tested the association of vitamin D supplementation with reduced CVD events and all-cause mortality.Literature search through PubMed, the Cochrane Library, and Embase was completed by 2 reviewers from each database's inception to December 15, 2018.Inclusion criteria were randomized clinical trials that reported the effect of long-term (≥1 year) vitamin D supplementation on CVD events and all-cause mortality. Studies that did not include cardiovascular outcomes were excluded.Data were abstracted independently by 2 authors. Random-effects models were used to report the risk ratios (RRs) and 95% CIs.Major adverse cardiovascular events was the primary outcome, and rates of myocardial infarction, stroke or cerebrovascular accident, CVD mortality, and all-cause mortality were the secondary end points.Twenty-one randomized clinical trials were included (including 83 291 patients, of whom 41 669 received vitamin D and 41 622 received placebos). The mean (SD) age of trial participants was 65.8 (8.4) years; 61 943 (74.4%) were female. Only 4 trials had prespecified CVD as a primary end point. Vitamin D supplementation compared with placebo was not associated with reduced major adverse cardiovascular events (RR, 1.00 [95% CI, 0.95-1.06]; P = .85) nor the secondary end points of myocardial infarction (RR, 1.00 [95% CI, 0.93-1.08]; P = .92), stroke (RR, 1.06 [95% CI, 0.98-1.15]; P = .16), CVD mortality (RR, 0.98 [95% CI, 0.90-1.07]; P = .68), or all-cause mortality (RR, 0.97 [95% CI, 0.93-1.02]; P = .23). Results were generally consistent by sex, baseline 25-hydroxyvitamin D level, vitamin D dosage, formulation (daily vs bolus dosing), and presence or absence of concurrent calcium administration.In this updated meta-analysis, vitamin D supplementation was not associated with reduced major adverse cardiovascular events, individual CVD end points (myocardial infarction, stroke, CVD mortality), or all-cause mortality. The findings suggest that vitamin D supplementation does not confer cardiovascular protection and is not indicated for this purpose.
A Phase I Dose Escalation Study of Once-Weekly Oral Administration of Docetaxel as ModraDoc001 Capsule or ModraDoc006 Tablet in Combination with Ritonavir
Authors: Vincent A. de Weger, Frederik E. Stuurman, Stijn L.W. Koolen, Johannes J. Moes, Jeroen J.M.A. Hendrikx, Emilia Sawicki, Bas Thijssen, Marianne Keessen, Hilde Rosing, Marja Mergui-Roelvink, Alwin D.R. Huitema, Bastiaan Nuijen, Jos H. Beijnen, Jan H.M. Schellens, Serena Marchetti
Journal: Clinical Cancer Research (2019)

Oral bioavailability of docetaxel is poor. Absorption could be improved by development of pharmaceutical formulations based on docetaxel solid dispersions, denoted ModraDoc001 capsule and ModraDoc006 tablet (both 10 mg) and coadministration of ritonavir, an inhibitor of CYP3A4 and P-glycoprotein. In this study, the safety, MTD, recommended phase II dose (RP2D), pharmacokinetics, and preliminary antitumor activity of oral docetaxel combined with ritonavir in a once-weekly continuous schedule was investigated.Patients with metastatic solid tumors were included. Dose escalation was performed using a classical 3+3 design. Pharmacokinetic sampling was performed for up to 48 hours after drug administration. Safety was evaluated using CTCAE v3.0. Antitumor activity was assessed according to RECIST v1.0.Sixty-seven patients were treated at weekly docetaxel dosages ranging from 30 to 80 mg in combination with 100- or 200-mg ritonavir. Most common toxicities were nausea, vomiting, diarrhea and fatigue, mostly of grade 1-2 severity. No hypersensitivity reactions were observed. The area under the plasma concentration-time curve (AUC0-48) of docetaxel at the RP2D of once-weekly 60-mg ModraDoc001 capsule with 100-mg ritonavir was 1,000 ± 687 ng/mL/hour and for once-weekly 60-mg ModraDoc006 tablet with 100-mg ritonavir, the AUC0-48 was 1,790 ± 819 ng/mL/hour. Nine partial responses were reported as best response to treatment.Oral administration of once-weekly docetaxel as ModraDoc001 capsule or ModraDoc006 tablet in combination with ritonavir is feasible. The RP2D for both formulations is 60-mg ModraDoc with 100-mg ritonavir. Antitumor activity is considered promising.
2 The incidence of undiagnosed coeliac disease in patients presenting with stress fracture to a tertiary referral centre
Authors: R Smith, J Baldock, M FitzPatrick, N Jones, J Newton
Journal: British Journal of Sports Medicine (2019)

Aim Stress fracture aetiology is often multifactorial and laboratory blood tests (LBT) can unmask underlying metabolic bone risk factors and disorders. Coeliac disease (CD) is associated with low bone mineral density and an increased risk of fractures. 1 In addition, there are rare reports of occult CD presenting with stress fractures. 2 Anti-tissue transglutaminase antibody (TTG) testing has a high sensitivity and specificity for CD and is used as a screening test. 3 This report examines the incidence of undiagnosed CD in patients presenting with stress fractures to a Sport and Exercise Medicine (SEM) clinic. Methods A retrospective analysis of 100 consecutive patients with radiologically proven stress fractures presenting to a single tertiary NHS SEM clinic was performed. Age, gender, fracture site, co-morbidities, TTG result and subsequent investigations were examined. Records were reviewed to confirm LBT, including TTG, had been performed at the time of diagnosis. Results Seventy patients (70%) were female and mean age was 37 years (range 18–69). Metatarsal (35%) and tibial (21%) fractures were most common. TTG was performed in 85 patients. Two patients were excluded due to pre-existing CD. Five patients (5/83 (6%), mean age 38 years (28–57), 80% female) had a positive TTG; three of whom had CD confirmed by endoscopic biopsy and two are awaiting investigation. Four patients with a positive TTG underwent dual energy X-ray absorptiometry, with osteopenia (T-Score between −1.0 and −2.5) found in 75% of cases, although only one had a Z-score less than -2.0. Conclusion In this cohort, the incidence of undiagnosed CD was between 3.6% to 6%, with a prevalence between 5% to 7%, approximately 5-fold higher than UK population estimates. We recommend that TTG screening should be performed in all patients presenting with stress fractures to identify underlying CD. Further work is required to confirm this association and elucidate potential underlying mechanisms. References Heikkilä K, Pearce J, Mäki M, et al. Celiac disease and bone fractures: a systematic review and meta-analysis. J Clin Endocrinol Metab 2015;100(1):25–34. Gilbody J, Trevett M. Coeliac disease presenting with bilateral fibular stress fractures. Foot Ankle Surg 2009;15:96–100. 3. Downey L, Houten R, Murch S, Longson D, Group GD. Recognition, assessment, and management of coeliac disease: summary of updated NICE guidance. BMJ 2015;351:h4513.