tbuckley/cabot-search huggingface dataset:
Application of bioinformatics approach to identify indications for PFKFB3-mediated glycolysis inhibition as potential anticancer treatment.
Authors: Kristina Khodova, Mikhail Pyatnitskiy, Tatiana Eremeeva, Peter Fedichev
Journal: Journal of Clinical Oncology (2017)

e23158 Background: Glycolysis is one of the mechanisms which enables cancer cells to adapt to intermittent oxygen deprivation and obtain the best available metabolic strategy in the lack of resources. Therefore, inhibition of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) enzyme, one of the glycolysis pathway regulators, may result in decreased tumor metabolism, as well as suppressed cell growth. Additionally it has been shown that PFKFB3 is involved in angiogenesis regulation, which contributes to tumor growth, and in immune cells activation, which mediates anti-tumor immune response. Methods: We performed the analysis of available data on the role of PFKFB3 gene expression in various cancer types, i.e. patients’ stratification to identify tumors in which PFKFB3 inhibition improved survival. We exploited TCGA expression data and applied cluster analysis and Cox-regression analysis. The objective was to detect the relation between the increased level of PFKFB3 gene expression and patients’ survival. We also compared the clusters we identified with TCGA metadata to define whether any of them fall down into well-established tumor subtypes. Results: As a result we selected four clusters among solid tumor types, in which increased expression of the target was related to significant decrease in overall survival rate. These include breast cancer, renal cell carcinoma, cervical carcinoma, and leiomyosarcoma. We managed to cross-validate the obtained results on independent datasets. The results show potential indications for PFKFB3 inhibitors. Using our proprietary molecular modelling tool, we designed a series of novel small molecule PFKFB3 inhibitors to target the fructose binding pocket rather than occupying the ATP-pocket which leads to the highly selective inhibition and strong reduction of potential off-target binding. We proved target coverage by performing in vitro biochemical assays. Conclusions: Our current data provide strong rationale for further preclinical and clinical development of PFKFB3 inhibitors as novel anticancer treatment with the potential to overcome resistance to chemo- or radiotherapy.
Role of tumor profiling in rural oncology.
Authors: Ajaz Bulbul, Emilio Araujo Mino, Brittany Flowers, Adriana Bautista, Kelsey Hernandez, Masoud Khorsand-Sahbaie
Journal: Journal of Clinical Oncology (2018)

e24183 Background: Technological advances in high-throughput sequencing (NGS), Immunohistochemical (IHC) biomarker testing, bioinformatics can now be incorporated into standard clinical practice to help clinicians determine most effective treatment. The role these tests play in affecting outcomes in the real-world rural setting is less clear Methods: We retrospectively evaluated 84 patients across three rural cancer centers who had undergone tumor profiling at (73-CARIS, 11-Foundation One) for a metastatic cancer and evaluated Progression free survival among patients treated in concordance or discordance to profiling recommendations. MSI, PDL1 testing was excluded. Statistical analysis was done using descriptive statistics, Chi-square analysis for associations and survival analysis using STATA software Results: Mean age was 64.24±13.5. There was no association between type of biopsy attempted (FNA /Core/ excision) and adequacy of sample (chi square 1.529 p = 0.839). The average number of approved NCCN/FDA therapies recognized by IHC was 2.2 therapies, FISH (Flow in situ hybridization) 2; NGS 2.1; therapies with no benefit by IHC 2.9, FISH 2; NGS 2.4. Oncologists prescribed therapy consistent with profiling 58% (34/59) and discordant in 42% (25/59) of patients with treatment data missing in 17 patients. Median PFS in treatment when consistent with profiling was 8 mo. vs 5 mo. when not consistent [HR 0.65 (0.35 - 1.18)p = 0.15]. Among available data 57% (32/56) of patient are candidates for clinical trials with average 803 miles to nearest trial center and 1.7% (1/58) rural patients being included into clinical trials as a result of profiling Conclusions: We are in the early stages of high utility of tumor profiling in rural clinical practice. Understanding its potential and the limitations will be crucial for providing genomically driven care. More options don’t necessarily mean practically attainable treatments across rural practices. Our goal should be to improve access to trials in concert with providing profiling
Infectious complications in multiple myeloma (MM) patients receiving autologous hematopoietic cell transplantation (AutoHCT) in the contemporary era.
Authors: Shafia Rahman, Lisa A. Rybicki, Sherif B Mossad, Ronald M. Sobecks, Navneet S. Majhail
Journal: Journal of Clinical Oncology (2018)

e20003 Background: The spectrum of infectious complications in autoHCT recipients with MM has not been well described in the recent era where patients receive novel agents for induction and transplant supportive care has improved. Methods: We conducted a single institution retrospective cohort study to estimate incidence of infections and determine their effect on survival. We identified 418 consecutive patients with autoHCT for MM from 2007-2016; 5 patients with prior HCT or planned tandem HCT were excluded. All patients were hospitalized from day of initiation of conditioning to neutrophil engraftment, and received routine prophylactic ciprofloxacin and fluconazole during neutropenia and acyclovir through at least day 100. Results: Among 413 patients, 85 had at least one infection within 100 days. Cumulative incidence (95% CI) of infection events by day 100 were: febrile neutropenia 43% (38-48), any infection 21% (17-25), bacterial 17% (14-21), viral 4% (3-7) and fungal 1% (0.5-3), central line-associated blood stream infection 3% (2-6), C. difficile colitis 6% (4-8). Baseline characteristics, including age, performance status, CD34 dose, and stage were comparable between patients with and without infections.Majority had mobilization with growth factors only (92%) and Melphalan conditioning (83%). Patients with infection had a longer initial transplant hospitalization (median 17 vs 16 days, p < 0.01), more readmissions (31% vs. 8%, p < 0.01), and spent more days in hospital in first 100 days (median 18 vs 16 days, p < 0.01). 100-day mortality was low and similar between groups (2% vs 1%, p = 0.28). In landmark analysis of 404 100-day survivors, survival was worse among patients with infections (median 61 vs 94 months, p = 0.01), and infections were prognostic for higher mortality risk in multivariable analysis (HR 1.54 [1.03-2.30], p = 0.03). Conclusions: Our study describes the spectrum of infections in MM autoHCT recipients in the present era. Infectious complications are common, impact survival, and have significant resource implications. Notwithstanding advances in supportive care, continued focus in this area is needed to improve outcomes.
Abstract 16964: National Experience of Ebstein Anomaly Births: Demographics, Treatment, and Mortality
Authors: Kimberly Holst, Kristine Hanson, Elizabeth Habermann, Patrick O’Leary, Joseph Dearani
Journal: Circulation (2016)

Introduction: Neonatal Ebstein anomaly (EA) is a rare and variable congenital heart lesion with a paucity of large series data. The objectives were to describe the characteristics, concomitant diag...
Allogenic stem cell transplant in patients over the age of 70, including octogenarians, with hematologic malignancies: A single institution experience.
Authors: Robert E. Gaudet, Jan Cerny, Muthalagu Ramanathan, Glen Raffel, Zheng Zhou, Lindsey Shanahan, Jayde Bednarik, Rajneesh Nath
Journal: Journal of Clinical Oncology (2017)

e18538 Background: Patient age is an important factor when considering allogenic stem cell transplant (aSCT) as a treatment modality for hematologic malignancies. Previous series exploring older age and outcome in aSCT have generally not included fit, older adults beyond the age of 80: a group typically considered ineligible for aSCT. This report describes our single-institution experience with aSCT in patients age 70 and older, including octogenarians, from March 2010 through April 2016. Methods: Retrospective analysis was performed on all patients older than 70 years undergoing aSCT at UMass Memorial Medical Center (UMMMC) between March 2010 and April 2016. The study was approved by the UMMMC IRB. Results: 32 patients were identified: 19 men and 13 women. 1 patient underwent a second aSCT in the study period. Median age at time of aSCT was 73 years (range 70-83). 4 patients were age &gt;80. Diseases treated were AML (19 pts.), MDS (12 pts.), and CLL (1 pt.). 24 transplants were performed with unrelated donors: 17 with 10/10 match, 3 with 11/12 match, 3 with 10/12 match, and 1 with 9/12 match. 9 were performed with umbilical cord blood units. Grade II-IV acute GVHD developed in 9 patients (27%). Day 100 survival by age following the transplant were 11/18 (61%) for patients aged 70-75, 6/10 (60%) for patients aged 75-80 and 4/4 (100%) for patients aged 80-85. Conclusions: Allogenic Stem Cell Transplant is a viable treatment modality in highly-selected elderly patients with hematologic malignancies. Further studies are warranted in a prospective fashion. [Table: see text]
Examining clinician confidence in the management of breast cancer (BC) based on subtype.
Authors: Hamsa Jaganathan, Anne Roc, Wendy Turell, Harold J. Burstein, Richard S. Finn
Journal: Journal of Clinical Oncology (2018)

e18835 Background: Despite recent advances in BC management, the heterogeneity of BC and the multiple therapies available for each subtype present a challenge for clinicians to quickly adopt new strategies to provide optimal care for their patients. To explore the education needs of clinicians specializing in BC, 2 continuing medical education (CME) activities were produced, and self-reported participant responses on learner confidence and competence were compared. Methods: Two live web-based CME activities were produced on the management of: (1) HER2+ BC, which attracted 419 learners from June 10, 2016 to June 10, 2017, and (2) HR+, HER2- BC, which attracted 452 learners from June 28 to December 28, 2017. Data from CME test questions, live polling responses, and questions posed during live Q&A were analyzed to determine engagement, lessons learned, and continuing education gaps. Tests of statistical significance were conducted using the McNemar test for matched pairs (learners who completed both pre/post & pre/8-weeks, respectively). Effect size was computed using Cohen's d (for all significant findings). Results: Learners reported that both activities had a positive clinical impact (67% for both activities) and patient experience/outcome for their practice (50 and 54% for activities 1 and 2, respectively). Learner confidence was greater in the ability to manage patients with HER2+ BC compared with patients with HR+, HER2- BC (54% vs. 39%, respectively). Similarly, learner competence was greater in identifying an optimal treatment after disease progression in a case study of HER2+ BC compared with a case study on HR+, HER2- BC (50% vs. 37% increase from baseline to 8-week follow-up, respectively). In contrast, learner confidence was greater with regards to the use of CDK4/6 inhibitors for patients with HR+, HER2- BC (48%) compared with the use of HER2-targeted agents for patients with HER2+ BC (33%). Conclusions: Clinician confidence and competence varied based on the BC subtype and the familiarity of HER2-targeted agents vs newer treatments, such as CDK4/6 inhibitors. Outcomes from these 2 activities support the continuing need for targeted education on BC therapies to improve patient management and care.
Receipt of Timely Addiction Treatment and Association of Early Medication Treatment With Retention in Care Among Youths With Opioid Use Disorder
Authors: Scott E. Hadland, Sarah M. Bagley, Jonathan Rodean, Michael Silverstein, Sharon Levy, Marc R. Larochelle, Jeffrey H. Samet, Bonnie T. Zima
Journal: JAMA Pediatrics (2018)

Retention in addiction treatment is associated with reduced mortality for individuals with opioid use disorder (OUD). Although clinical trials support use of OUD medications among youths (adolescents and young adults), data on timely receipt of buprenorphine hydrochloride, naltrexone hydrochloride, and methadone hydrochloride and its association with retention in care in real-world treatment settings are lacking.
The potential involvement of circular RNA in the development of radiation resistance of esophageal cancer.
Authors: Huafang Su, Xiance Jin, Congying Xie
Journal: Journal of Clinical Oncology (2016)

e15578 Background: Acquired radioresistance during radiotherapy is considered as the most important reason for local tumor recurrence or failure. Circular RNAs (circRNAs) have recently been identified as microRNA sponges and involved in various biological processes. The purpose of this study is to investigate the role of circRNAs in radioresistance of esophageal cancer. Methods: Human parental cell line KYSE-150 and self-established radioresistant esophageal cancer cell line KYSE-150R were cultured, and RNAs were extracted for microarray analyses. Quantitative Real-time PCR was used to confirm the circRNA expression profiles obtained from the microarray data. The circRNA/microRNA interaction was predicted and the differentially expressed circRNAs within all the comparisons were annotated. Results: A total of 3752 human circRNAs expressions from KYSE-150R and KYSE-150 cell smaples were quantitated, in which 74 circRNAs expressions with significant differential expressions (fold change ≥ 2.0 and P＜0.05). There were 57 circRNAs significantly up-regulated and 17 circRNAs significantly down-regulated in KYSE-150R compared with KYSE-150. There were 9 of these candidate circRNAs were validated by real-time PCR (qRT-PCR). Twelve of the 17 down-regulated circRNAs had target MicroRNAs. Most microRNAs were involved in biological processes, and more than 400 target genes enrichment on Wnt signaling pathway. CircRNA_001059 and circRNA_000167 were the two largest nodes in circRNA/microRNA co-expression network. Conclusions: A unique set of circRNAs and their expression profiles were found in radioresistant esophageal cancer cells. Two potential key circRNAs were observed in co-expression network analysis indicating Wnt signaling pathway and dysregulated circRNAs may be involved in the development of radiation resistance of esophageal cancer.
Analysis of the relation between Glasgow Prognostic Score (GPS) and the achievement of complete response in chemo-radiotherapy for advanced esophageal squamous cell carcinoma.
Authors: Takako Yoshii, Hiroki Hara, Yosuke Kumekawa, Satoshi Shimizu, Masako Asayama
Journal: Journal of Clinical Oncology (2016)

e15513 Background: In chemo-radiotherapy (CRT) for treatment of advanced esophageal squamous cell carcinoma (ESCC), decision to salvage surgery is difficult because of its invasiveness and time lag for achievement of complete response (CR) after the treatment completion. A useful predictor for the delayed CR achievement is needed. We evaluated the predictability of Glasgow Prognostic Score (GPS) for the CR achievement in CRT for advanced ESCC. Methods: We conducted retrospective analysis of patients at our hospital who fulfilled the following criteria, i) completed CRT for advanced ESCC, ii) evaluated CRT response by computed tomography and endoscopy, iii) confirmed the CR achievement or progression without salvage surgery, and iv) no severe comorbidity. Chemotherapy consisted of 2 patterns of 5-FU/CDDP infusion (1000 mg/m2: days 1-4; 75 mg/m2: day 1, or 700 mg/m2: days 1–4; 70 mg/m2: day 1) with a 4-week interval. Radiotherapy was concurrently administered to a total 50.4 - 62Gy /30 fractions. GPS was evaluated at two points immediately before the start of CRT (GPS-I) and the second course of chemotherapy (GPS-II), and categorized to two groups (0/1,2). Statistical analysis was performed by chi-square test and Logistic regression analysis in December 2015. Results: From July 2011 to June 2015, 28 patients [median age: 66 years (range: 49–80); PS0/1: 18/10; and cStage IIB/IIIA/IIIB/IIIC/IV: 5/5/5/11/2] fulfilled the criteria. Median follow up time was 284 days (range: 78–1286). According to RECIST, the CR rate increased from 10% (3/28) to 60% (17/28) during the follow-up after the CRT completion. Although univariate analysis showed that GPS-II(0) and cStage ( < IIIa) contributed to the CR achievement, cStage distributed unevenly among the GPS-II states. Analysis among the patients with cStage III/IV (n = 23) showed that only the GPS-II contributed to the CR achievement in univariate and multivariate analyses (OR: 0.49, 95%CI: 0.05-0.533, p = 0.01, and OR: 0.61, 95%CI: 0.005-0.793, p = 0.03). Conclusions: GPS at the interphase of the treatment period could predict the delayed CR achievement in CRT for advanced ESCC.
P35 Treatment of Advanced Non–Small Cell Lung Cancer (NSCLC) in Patients (P) Older Than 70
Authors: E. Richardet, L. Perelli, M. Cortes, I. Magri, M. Molina, L. Acosta, L. Dicalbo, R. Villavicencio, G. Ferreira, M. Richardet
Journal: Journal of Thoracic Oncology (2018)
Two phase 3 studies of the oral proteasome inhibitor (PI) ixazomib for multiple myeloma (MM) in the maintenance setting: TOURMALINE-MM3, and -MM4.
Authors: Antonio Palumbo, Gareth John Morgan, S.Vincent Rajkumar, Sagar Lonial, Wee Joo Chng, Shinsuke Iida, María-Victoria Mateos, Meral Beksac, Hartmut Goldschmidt, Richard Labotka, Kaveri Suryanarayan, Alessandra di Bacco, Eileen Liao, Bingxia Wang, Meletios A. Dimopoulos
Journal: Journal of Clinical Oncology (2016)

TPS8068 Background: Extended treatment for MM, including maintenance therapy, can improve long-term outcomes; however, the feasibility of long-term treatment with current regimens is limited due to toxicities or the need for regular clinic visits. In the phase 3 study TOURMALINE-MM1, the oral PI ixazomib, when added to lenalidomide and dexamethasone, significantly improved progression-free survival (PFS) in patients (pts) with relapsed/refractory MM, with limited toxicities (Moreau et al. ASH 2015). The phase 3 trials TOURMALINE-MM3 (NCT02181413) and -MM4 (NCT02312258) will investigate single-agent ixazomib maintenance therapy in pts who received autologous stem cell transplantation (ASCT), and those who have not undergone ASCT, respectively. Methods: Both trials are randomized, double-blind, placebo-controlled, single-agent, multicenter studies. To be eligible for inclusion in TOURMALINE-MM3, adult pts (N = 652 planned) with newly-diagnosed MM must have received standard-of-care induction therapy including a PI and/or immunomodulatory drug-based regimen, followed by a conditioning regimen containing high-dose melphalan (200 mg/m2) and a single ASCT, within 12 months of diagnosis. Pts must have achieved a partial response (PR) or better by IMWG criteria, and be randomized no later than 115 days after ASCT. For TOURMALINE-MM4, pts (N = 761 planned) who have not undergone ASCT (due to frailty, advanced age [ ≥ 65 yrs], comorbidity, or other reasons) must have completed 6–12 months of initial standard-of-care therapy with a response of PR or better, and be randomized no later than 60 days after the last dose of initial therapy. For both trials, eligible pts will be randomized 3:2 to ixazomib or placebo given on days 1, 8, and 15 of 28-day cycles; 3 mg for cycles 1–4 and 4 mg for cycles 5–26, or until disease progression or intolerable toxicities. The primary endpoint for both trials is PFS, with a key secondary endpoint of overall survival (OS). Other secondary endpoints include response rate, time to first progression, second PFS, assessment of minimal residual disease, safety, and PFS and OS in pts with high-risk cytogenetics. Recruitment is ongoing. Clinical trial information: NCT02181413, NCT02312258.
TCT-367 First Report Showing the Very Long-term Outcomes of Therapeutic Angiogenesis Using Bone Marrow-derived Mononuclear Cell Therapy in No-option Critical Limb Ischemia Patients With Scleroderma
Authors: Keisuke Shoji, Kenji Yanishi, Noriyuki Wakana, Naohiko Naknishi, Kan Zen, Takeshi Nakamura, Satoaki Matoba
Journal: Journal of the American College of Cardiology (2018)
Clinical qualification of plasma androgen receptor (p<i>AR</i>) status and outcome on abiraterone acetate (AA) plus prednisone or dexamethasone (+P/D) in a phase II multi-institutional study in metastatic castration resistant prostate cancer (mCRPC).
Authors: Anuradha Jayaram, Anna Wingate, Mansour Taghavi Azar Sharabiani, Daniel Wetterskog, Fabio Calabro, Lorraine Barwell, Weibke Arlt, Axel Stuart Merseburger, Susan Feyerabend, Alfredo Berruti, Florence Lefresne, Dong Shen, Michael Gormley, Gurpreet Kapoor, Weimin Li, Robert J Jones, Cora N. Sternberg, Bertrand F. TOMBAL, Gerhardt Attard
Journal: Journal of Clinical Oncology (2018)

5067 Background: pAR gene aberrations in mCRPC patients (pts) may be associated with worse outcome on AA+P/D. Methods: This was an international, multi-institutional, open-label phase 2 study of AA (1000mg QD) and 1 of 4 steroid regimens in asymptomatic, chemo-naïve mCRPC pts (NCT01867710). A pre-defined exploratory objective was to evaluate the association of pAR status and radiographic progression free survival (rPFS), PFS and time of long-term ADT to randomisation. We used a validated droplet digital PCR assay to classify pts as pAR copy number (CN) gain. Results: Baseline plasma DNA was collected from 151 pts of the 164 intention-to-treat pts; 135 pts were available for pAR CN analysis, excluding samples with long-fragment DNA. 21(15%) pts had AR CN gain. There was a significant association for AR gain and shorter rPFS (median 5.7 months [m]:pAR gain vs 23.7 m:pAR normal; HR: 2.78; 95% CI 1.34 - 4.6; p = 0.004) and PFS (median, 4.90m: pAR gain vs 16.2m: pAR normal; HR: 2.28; 95% CI 1.3 - 4; p = 0.004). Multivariate analysis is in Table 1. PSA ≥50% decline was 65% for pAR normal vs 53.3% for pAR gain. (OR: 0.6; 95% CI, 0.2 – 1.7; = 0.33). The time from start of long-term ADT to randomisation, was significantly shorter in pts with AR CN gain at castration resistance (8m: pAR gain vs 29.5m: pAR normal; p = 0.004). Conclusions: In this prospectively defined cohort, pAR normal in chemo-naïve mCRPC pts had a significantly longer rPFS with AA+P/D. Previous data suggests shorter response to ADT associates with primary resistance to AA +P/D. The novel observation that these pts are enriched for pAR gain provides a biological rationale for this. Clinical trial information: NCT01867710. rPFS PFS HR 95% CI p HR 95% CI p AR Gain (yes vs no) 2.5 1.2- 5.3 0.01 2.1 1.1 – 4.14 0.03 LDH > ULN vs < ULN 1.1 0.62 – 2.04 0.07 1.1 0.67 – 1.93 0.63 ALP > ULN vs < ULN 0.9 0.5 – 1.7 0.8 1.1 0.61 – 1.79 0.87 Disease Site Bone/bone +Lymph node(LN) vs LN 0.5 0.24 – 1.14 0.1 0.6 0.27 – 1.16 0.12 Visceral vs Bone/Bone+LN 1.1 0.14 – 8.16 0.95 1.3 0.17 – 9.78 0.80 Visceral vs LN 0.5 0.06 – 3.87 0.50 0.4 0.06 – 3.39 0.43 ≥ 5 Bone mets vs < 5 1.0 0.52 – 2.09 0.12 1.3 0.69 – 2.36 0.44 Baseline PSA 1 1 0.17 1 1 0.66