tbuckley/cabot-search huggingface dataset:
Cost-effectiveness of genotype-guided aspirin use for colorectal cancer prevention.
Authors: Eman Biltaji, Trang H. Au, Brandon Walker, Jennifer Ose, Cornelia M Ulrich, David D. Stenehjem, Diana I. Brixner
Journal: Journal of Clinical Oncology (2017)

e18318 Background: Colonoscopy is the “gold standard” for colorectal cancer (CRC) screening. However, adherence rates are low and detection is not optimal. Concomitant aspirin chemoprevention is recommended by US Preventive Task Force, but bleeding complications can be limiting. Variant genotypes in aspirin metabolism can modify CRC and adenoma risk. Genotype guided aspirin (ggASA) use will identify a targeted average-risk population for maximal aspirin benefit while minimizing adverse events rates compared to the general population. We conducted a cost-effectiveness analysis (CEA) of primary chemoprevention in CRC using ggASA compared to no intervention, and colonoscopy ±general aspirin in healthy average-risk individuals. Methods: Our Markov decision analytical model consisted of 5 possible health states: no CRC/polyps, adenoma, pre-clinical CRC, CRC, and death. Model probabilities for CRC and its prevalence were estimated using SEER database and published literature. A microsimulation of 10,000 individuals aged 50-64 years was used to estimate cost-effectiveness from US payer perspective over lifetime. One way and probabilistic sensitivity analyses and model validation results will be reported in the final poster. Results: Our results suggest that compared to colonoscopy and no intervention, ggASA was associated with fewer CRC cases, and CRC-related deaths and MI cases. Compared to colonoscopy + general aspirin, ggASA was associated with fewer bleeding events, similar rates of CRC and CRC-related deaths, and fewer MI cases prevented. From a cost-effectiveness standpoint, ggASA use over a lifetime had the lowest costs and highest quality adjusted life years gained compared to other strategies, if testing costs were ignored. Once genetic testing costs exceeds $63, colonoscopy + general aspirin becomes the most cost effective strategy. Between genetic testing cost of $63-283, the costs of using ggASA per quality adjusted life year gained is below $100,000. Conclusions: Genotype-guided aspirin use precisely identifies an average-risk population, and lowers adverse events rates compared to general aspirin. The economic value of genotype-guided aspirin is dependent on the genetic testing costs.
Evaluation of the prognostic value of the OncoMasTR RNA panel in diverse tumor types.
Authors: Bruce Moran, Fiona Lanigan, Niamh Russell, Stephen Barron, Chan-Ju Wang, Karin Jirstrom, Adrian P. Bracken, William M. Gallagher
Journal: Journal of Clinical Oncology (2017)

e23201 Background: Master transcriptional regulators (MTRs) are genes that are highly connected with many other genes and which can contribute to a specific cellular phenotype. The OncoMasTR panel, a set of 10 proliferation-linked MTRs and the key regulator of senescence CDKN2A, was identified in lymph node-negative breast cancer patients using publicly available data (Lanigan et al FEBS 2015 10.1111/febs.13354). Using two prognostic gene signatures and an experimentally defined ‘proliferative’ signature, highly concordant results for the top ranking sets of MTRs were found. One advantage of this process was the distillation of gene signatures into a discrete, mechanistically anchored biomarker set shown to be prognostically relevant, particularly in ER-positive patients, and with an ability to discriminate patients into low versus high risk of recurrence. Our aim here was to determine if the OncoMasTR panel was similarly useful in multiple other cancer types using publicly available transcriptomic data. Methods: The Gene Expression Omnibus was queried for datasets with relevant overall-, disease free- and/or recurrence free-survival information alongside microarray gene expression data. Survival analysis was conducted on 34 datasets using the R statistical environment package ‘survival’. Patient samples were scored based on median or tertile expression which were summed to give a final OncoMasTR RNA score, used to divide the patient samples into two groups (low and high risk) for analysis. Results: Using all 2,047 possible combinations of genes, a total of 23 datasets had significant prognostic associations. Following appropriate correction via multiple testing, this was reduced to 4 datasets representing bladder, lung and colorectal cancers, and multiple myeloma. Hazard ratios for the top 100 combinations in each data set were 1.8 – 2.1, 1.6 – 1.9, 1.1 – 1.3, 1.3 – 1.5 (standard error ±0.2, 0.1, 0.2, 0.1) respectively. All genes were found in the top ten combinations in all 4 datasets, and no specific combination was found to be prevalent across datasets, indicating that every MTR in the OncoMasTR panel contributes to its utility. Conclusions: The OncoMasTR panel is potentially prognostically useful in multiple cancer types.
miR-146a Suppresses SUMO1 Expression and Induces Cardiac Dysfunction in Maladaptive Hypertrophy
Authors: Jae Gyun Oh, Shin Watanabe, Ahyoung Lee, Przemek A. Gorski, Philyoung Lee, Dongtak Jeong, Lifan Liang, Yaxuan Liang, Alessia Baccarini, Susmita Sahoo, Brian D. Brown, Roger J. Hajjar, Changwon Kho
Journal: Circulation Research (2018)

Rationale: Abnormal SUMOylation has emerged as a characteristic of heart failure (HF) pathology. Previously, we found reduced SUMO1 (small ubiquitin-like modifier 1) expression and SERCA2a (sarcoplasmic reticulum Ca 2+ -ATPase) SUMOylation in human and animal HF models. SUMO1 gene delivery or small molecule activation of SUMOylation restored SERCA2a SUMOylation and cardiac function in HF models. Despite the critical role of SUMO1 in HF, the regulatory mechanisms underlying SUMO1 expression are largely unknown. Objective: To examine miR-146a–mediated SUMO1 regulation and its consequent effects on cardiac morphology and function. Methods and Results: In this study, miR-146a was identified as a SUMO1-targeting microRNA in the heart. A strong correlation was observed between miR-146a and SUMO1 expression in failing mouse and human hearts. miR-146a was manipulated in cardiomyocytes through AAV9 (adeno-associated virus serotype 9)-mediated gene delivery, and cardiac morphology and function were analyzed by echocardiography and hemodynamics. Overexpression of miR-146a reduced SUMO1 expression, SERCA2a SUMOylation, and cardiac contractility in vitro and in vivo. The effects of miR-146a inhibition on HF pathophysiology were examined by transducing a tough decoy of miR-146a into mice subjected to transverse aortic constriction. miR-146a inhibition improved cardiac contractile function and normalized SUMO1 expression. The regulatory mechanisms of miR-146a upregulation were elucidated by examining the major miR-146a–producing cell types and transfer mechanisms. Notably, transdifferentiation of fibroblasts triggered miR-146a overexpression and secretion through extracellular vesicles, and the extracellular vesicle–associated miR-146a transfer was identified as the causative mechanism of miR-146a upregulation in failing cardiomyocytes. Finally, extracellular vesicles isolated from failing hearts were shown to contain high levels of miR-146a and exerted negative effects on the SUMO1/SERCA2a signaling axis and hence cardiomyocyte contractility. Conclusions: Taken together, our results show that miR-146a is a novel regulator of the SUMOylation machinery in the heart, which can be targeted for therapeutic intervention.
Phase II trial of neoadjuvant chemotherapy with TS-1/L-OHP (SOX) for resectable advanced rectal cancer (NCCSG-09).
Authors: Yasumasa Takii, Satoshi Maruyama, Mikako Kawahara, Hitoshi Nogami, Hajime Yokomizo, Jun Hasegawa, Tatsuo Tani, Akira Iwaya, Kohei Akazawa, Toshifumi Wakai
Journal: Journal of Clinical Oncology (2016)

e15028 Background: A multicenter, single-arm, open-label phase II study design was used in a planned phase II trial to evaluate the efficacy and safety of SOX as neo-adjuvant therapy for patients with advanced rectal cancer. Methods: Patient inclusion criteria were resectable advanced rectal cancer (Ra or Rb), clinical T3-4 (cT3-4) stage, any N, cMo with confirmed diagnosis of adenocarcinoma, and no previous chemo-radiotherapy. S-1 was administered a daily dose of 80 mg/m2 p.o. on days 1-14, and Oxaliplatin was administered 130 mg/m2 i.v. on day 1 of a 21-day cycle. The primary endpoint was the response rate (RR). The secondary endpoints included relapse-free survival, overall survival, safety, and operation, curative resection, and anus preservation rates. Results: Thirty-six patients were enrolled between February 2013 and December 2014. Thirty-five patients were investigated. The RR, CR, PR, SD, PD, and NE were 48.6%, 0%, 48.6%, 48.6%, 0%, and 0%, respectively. Grade 2, Grade 1b, and Grade 1a, histological RRs were 17.1%, 8.6%, and 54.3%, respectively. On safety analysis, the incidences of Grade 3 or 4 adverse reactions were anorexia (11.4%), leucopenia (2.9%), neutropenia (2.9%), thrombocytopenia (2.9%), nausea (2.9%), diarrhea (2.9%), and fatigue (2.9%). Both the operation and curative resection rates were 100%. Twenty-five of 26 patients who were scheduled to undergo anus-preserving operation, and 3 of 6 patients who were scheduled to undergo APR, underwent anus-preserving operations. Post-operative complication rate was 37.1%, and complications included leakage (14.3%), enteritis, neurogenic bladder, paralytic ileus, UTI, and diarrhea. The mortality rate was 0%. Conclusions: SOX is efficacious and a well-tolerated neo-adjuvant chemotherapy for patients with advanced resectable rectal cancer. Clinical trial information: UMIN000009764.
Analysis of the copy-number variation in the BRCA1 gene in patients with breast cancer in northwest of Mexico.
Authors: Edith Eunice Garcia Alvarez
Journal: Journal of Clinical Oncology (2018)

e13502 Background: Breast cancer (BC) is a multifactorial disease in which genetic and environmental factors contribute to its appearance. In Sinaloa it represents the fourth place at the national level of incidence of 20.66 per 100 thousand women. BRCA1 (Breast Cancer type 1) is a tumor suppressor gene associated with the appearance of hereditary breast and ovarian cancer. It is estimated that there is a risk of early onset ( < 50 years) of 50-80% in carriers with mutations in the BRCA1 gene. So far more than 1,500 mutations have been described for the BRCA1 gene, of which approximately one third represent large genomic rearrangements causing non-functional proteins. It has been shown that patients who start BC treatment in early stages have a higher survival, therefore, identifying women who are at high risk through genetic testing has a very important implication. Methods: We evaluated copy-number variations within the BRCA1 gene in blood of 68 female patients from the Hospital General de zona # 3 and the Instituto Sinaloense de Cancerología, for the presence of unequivocally damaging germline mutations using multiplex ligation-dependent probe amplification assay (MLPA) Results: Breast cancer was diagnosed in 55.88% of the patients, being classified into 2 groups, patients with hereditary BC (n = 19) and sporadic BC (n = 19); The main risk factors associated with BC in the study population are menopause (p = 0.013), lactation (p = 0.022), personal history of previous cancer (p = 0.019) and family history of BC (p = 0.000) and lung cancer (p = 0.001). A heterozygous deletion of a fragment of exon 13 (hg18 location 17-038.488025) was identified in a patient with bilateral invasive ductal carcinoma, triple negative subtype Conclusions: The use of this technique is recommended to perform a rapid screening for the detection of large genomic rearrangements in patients with personal/family characteristics of hereditary BC.
A bi-institutional phase II study of hepatic arterial infusion (HAI) with floxuridine (FUDR) and dexamethasone (Dex) combined with systemic gemcitabine and oxaliplatin (GemOx) for unresectable intrahepatic cholangiocarcinoma (ICC).
Authors: Andrea Cercek, Nancy E. Kemeny, Thomas Boerner, Benjamin R. Tan, Joanne F. Chou, Mithat Gonen, Taryn Mary Boucher, Haley Hauser, Richard K. G. Do, Maeve Aine Lowery, Peter Kingham, Michael Ian D'Angelica, Jeffrey A. Drebin, Peter J. Allen, Neeta Vachharajani, Maria Majella Doyle, Ryan Fields, William G. Hawkins, William C. Chapman, William R. Jarnagin
Journal: Journal of Clinical Oncology (2018)

4092 Background: Despite advances in systemic therapy for unresectable ICC, median survival remains less than 12 months (mo). HAI FUDR alone and combination systemic therapy both have activity in these patients. This trial investigated HAI FUDR/Dex plus GemOx. Methods: Thirty nine patients (pts) with unresectable ICC were enrolled at two institutions between 2013-17. Pts were treated with HAI FUDR and GemOx every 2 weeks. Progression-free survival (PFS) was calculated from date of HAI to progression of disease (POD) or death and compared to historical controls. Secondary outcomes included overall survival (OS), conversion to resection, response rates, and toxicity. PFS and OS were estimated using Kaplan-Meier methods. Twenty nine pts from MSK underwent targeted next generation tumor sequencing of > 400 genes (MSK-IMPACT). Results: Median age was 61 (range 38-80), 13 (33%) male. The median PFS was 11.5 mo, (90% CI:9.7mo), exceeding the historical controls of 6-8 mo. Eighteen pts (46%) had partial response (PR) and 20 (51%) had stable disease (SD), for a 97% disease control (PR+SD) rate. Three pts were converted to resectability and were censored at 12, 12 and 16 mo, respectively. Four pts (10%) had grade 4 toxicities requiring removal from the study, including portal hypertension, GDA aneurysm and GDA extravasation related to HAI catheter, and hyperbilirubinemia. The most common grade 3 toxicities were elevated liver enzymes (ALT 54%, AST 33% and bilirubin 18%), abdominal pain 13% and anemia 12%. At a median follow up of 17 mo, the 1 year OS was 86.4% [95%CI:70-94%] and the 2 year OS was 53% [95%CI: 32%-69%]. Most prevalent mutations were IDH1/2 ( 9/26, 34.6%), BAP1 (8/26, 30.7%), TP53 (4/26, 15.3%). IDH1/2 mutations were associated with OS benefit (p = 0.018). Conclusions: Combined HAI FUDR plus GemOx is effective therapy for unresectable ICC due to its high rate of tumor response and control, PFS benefit, and manageable toxicities. The regimen warrants further investigation in a randomized trial. Clinical trial information: NCT01862315.
Improved prognostic accuracy of alternative MGMT methylation status cutpoint: A single institution experience.
Authors: Jacob Easaw, Roldan Gloria, Eugene Batuyong, Elizabeth Kornaga, Abdullah Almuqate, Wajid Sayeed, Doha Itani
Journal: Journal of Clinical Oncology (2018)

2052 Background: We evaluated the clinical relevance of the current cutpoint used to define methylation status in patients (pts) with glioblastoma (GB) in comparison to a proposed alternative cutpoint (PAC) that was derived based on clinical outcomes of pts from Calgary, AB, Canada. Methods: We identified and reviewed all pts diagnosed with GB treated in our institution between2015 and 2016. We analyzed prognostic value, sensitivity and specificity of the current cutpoint (9%) and PAC (12.2%) for MGMT promoter methylation status. Results: We included 153 pts with a median age of 61.7 years (range; 29 – 86); 53% male. Maximal safe tumor resection was subtotal in 61 (39.0%) and gross-total in 75 (49%) of pts. A biopsy was performed in 17 cases (11.1%). Thirteen pts (8.5%) did not receive any postoperative treatment, 105 (68.8%) of pts received standard concurrent temozolomide (TMZ) with radiotherapy (RT) followed by monthly TMZ; and the rest received mostly RT alone +/- sequential TMZ. MGMT methylation status, extent of resection, age and KPS ( < vs ≥ 70) were included in multivariate analysis and only MGMT status and age were independently associated with median overall survival (p < 0.001 and p < 0.003, respectively) using either cutpoints. However, there was an improvement in accuracy using the PAC. Conclusions: In this cohort we found an alternative cutpoint with improved correlation with overall survival in patients with newly diagnosed GB. This finding warrant further evaluation as deeming a tumor as unmethylated implies not only a worse prognosis but may impact therapeutic options; i.e. clinical trial participation. Current MGMT cutpoint (9%) Proposed alternative cutpoint (12.2 %) Sensitivity 59 60 Specificity 63.2 67.6 Positive Predictive Value 35.4 38.2 Negative Predictive Value 81.8 83.5 Accuracy 62.1 65.7
Longer term preplanned efficacy and safety analysis of abiraterone acetate + prednisone (AA + P) in patients (pts) with newly diagnosed high-risk metastatic castration-naïve prostate cancer (NDx-HR mCNPC) from the phase 3 LATITUDE trial.
Authors: Karim Fizazi, Susan Feyerabend, Nobuaki Matsubara, Mustafa Ozguroglu, Luis Enrique Fein, Alfredo Rodríguez Antolín, Boris Yakovlevich Alekseev, Giri Sulur, Andrew Protheroe, Peter De Porre, Susan Li, Youn C. Park, Suneel Mundle, Namphuong Tran, Kim N. Chi
Journal: Journal of Clinical Oncology (2018)

5023 Background: The LATITUDE study in pts with NDx-HR mCNPC found significant improvements in OS, rPFS, and all secondary end points, including pt-reported outcomes when combining AA + P with androgen deprivation therapy (ADT) vs placebos (PBOs) + ADT, which led to unblinding of the study at first interim analysis. Methods: 1199 NDx-HR mCNPC pts were randomized 1:1 to AA (1 g QD) + P (5 mg QD) + ADT or PBOs + ADT. Co-primary end points were OS and rPFS. A stratified proportional hazards model assessed longer term follow-up on OS, secondary end points, and adverse events (AEs), including those associated with mineralocorticoid excess, from the preplanned second interim analysis, when approximately 65% (≈554) of expected deaths were observed. Results: With a median follow-up of 41 mo (range, 0.1-54.0), 205 (34%) pts in the AA + P arm and 70 (12%) in the PBOs arm (of whom 57 [81%] had crossed over to AA + P) remained on treatment. Updated OS continued to favor the AA + P arm (HR [95% CI] 0.638 [0.538-0.758]; p < 0.0001) as did secondary end points (Table). Serious AEs occurred in 27% of pts on AA + P and 20% of pts on PBOs. Grade 3/4 AEs included (AA + P vs PBOs; %): hypertension (21 vs 10), hepatotoxicity (8 vs 3), hypokalemia (12 vs 2), fluid retention (1 vs 1), and cardiac disorders (4 vs 1). 328 pts (54%) from the PBOs arm received a life-prolonging therapy. Conclusions: This long-term analysis continues to demonstrate the OS benefit of adding AA + P to ADT in NDx-HR mCNPC pts, with a 36% reduction in the risk of death, although most pts remaining on PBOs treatment had crossed over to AA + P. The secondary end points also continued to favor the AA + P arm, underscoring AA + P as a standard of care for pts with NDx-HR mCNPC. Clinical trial information: NCT01715285. AA + P + ADT (n = 597) PBOs + ADT (n = 602) HR (95% CI) p Value Primary end point, median mo OS NR 36.7 0.638 (0.538-0.758) < 0.0001 Secondary end points, median time to, mo Pain progression 47.4 17.9 0.723 (0.608-0.860) 0.0002 Skeletal-related event NR NR 0.739 (0.579-0.943) 0.0148 Chemotherapy initiation NR 47.3 0.471 (0.378-0.586) < 0.0001 Subsequent PC therapy NR 21.2 0.428 (0.361-0.507) < 0.0001 NR, not reached.
TCT-205 Incidence, Predictors and Outcomes of Urgent Percutaneous Coronary Intervention Following Coronary Artery Bypass Grafting
Authors: Fahad Alqahtani, Vinay Badhwar, None khaled Ziada, Gurpreet Sandhu, Chet Rihal, Mohamad Adnan Alkhouli
Journal: Journal of the American College of Cardiology (2018)
HDP-101: Preclinical evaluation of a novel anti-BCMA antibody drug conjugates in multiple myeloma.
Authors: Andreas Pahl, Jonathan Ko, Christian Breunig, Vianiuhini Figueroa, Nicola Lehners, Anja Baumann, Anikó Pálfi, Christoph Mueller, Christian Lutz, Torsten Hechler, Michael Kulke, Carsten Mueller-Tidow, Hartmut Goldschmidt, Marc Raab
Journal: Journal of Clinical Oncology (2018)

e14527 Background: Currently, numerous antibody-drug conjugates (ADCs) are evaluated for hematologic malignancies with toxic payloads mainly affecting only proliferating cells, and thus resulting in limited efficacy in diseases with low proliferation. We focus on amanitin based ADCs (ATACs: antibody-targeted Amanitin conjugates) targeting BCMA (B Cell Maturation Antigen; CD269). Amanitin binds to RNA pol II and thereby inhibits the cellular transcription process at very low concentrations independent of cell proliferation. BCMA is selectively expressed on malignant plasma cells like in Multiple Myeloma (MM) and hence considered an ideal target for Amanitin based ADCs. Methods: Cell proliferation assay; subcutaneous and metastatic Mouse xenograft tumor models; tolerability in mice and non-human primates (NHP). Results: In vitro cytotoxic potency of HDP-101 was tested on BCMA-positive myeloma cell lines, as well as on non-proliferating primary CD138+ cells isolated from MM patients. In these cells, cytotoxic effects were already seen at pico- to nanomolar concentrations of HDP-101, in contrast to BCMA-negative control cells. In subcutaneous MM mouse xenograft models, HDP-101 caused dose-dependent tumor regression including complete remissions after a single i.v. dose of 2.0 mg/kg and 4.0 mg/kg. In disseminating MM models, this effect was already achieved after a single i.v. dose of 0.1 mg/kg. Safety profiling in non-human primates (NHP) revealed a good tolerability and wide therapeutic index after sequentially applied doses of 0.3 mg/kg, 1.0 mg/kg, and multiple dose applications of 4 x 3.0 mg/kg. Hematology and clinical chemistry parameters were unaffected except for a mild to moderate transient increase in liver enzymes and lactate dehydrogenase. The half-life of the HDP-101 in serum was ~12 days. Conclusions: The mode of action of amanitin led to an efficient anti-tumor response in vitro and in vivo with good tolerability in NHP yielding a very good therapeutic index. Amanitin-based ADCs in the therapy of multiple myeloma are a novel promising approach with a distinct mode of action to overcome drug resistance and improve patient outcome. A first-in-human trial with HDP-101 is expected to start in 2019.