tbuckley/cabot-search huggingface dataset:
Defects in DNA repair genes and long-term survival in cisplatin-based neoadjuvant chemotherapy for muscle invasive bladder cancer (MIBC).
Authors: Benjamin Miron, Eric A. Ross, Fern Anari, John O'Neill, Jean H. Hoffman-Censits, Matthew R. Zibelman, Alexander Kutikov, Rosalia Viterbo, Richard E. Greenberg, David Chen, Costas D. Lallas, Edouard John Trabulsi, R. Katherine Alpaugh, Essel Dulaimi, Erica Golemis, Robert Uzzo, Elizabeth R. Plimack
Journal: Journal of Clinical Oncology (2019)

4536 Background: Although cisplatin-based neoadjuvant chemotherapy (NAC) has demonstrated an overall survival (OS) benefit in MIBC, only a subset of patients have pathologic complete response (pT0) at cystectomy. ATM, RB1 and FANCC mutations have shown correlation with pT0 to cisplatin-based NAC, as previously published. We now report updated OS and disease specific survival (DSS) from two phase II trials using these gene alterations as biomarkers. Methods: Patients with stage T2-T4 (N0 or N1) MIBC were enrolled in phase II trials of dose-dense NAC with MVAC (methotrexate, vinblastine, adriamycin, and cisplatin; NCT01031420) or GC (gemcitabine and cisplatin; NCT01611662). Patients were treated with NAC with plan for curative cystectomy. DNA from pretreatment tumor tissue was sequenced for coding exons of 287 cancer-related genes and analyzed for mutations. Survival in patients with one or more mutations in ATM, RB1, or FANCC genes was compared to those without mutations. Results: Of 58 pts treated, 38% (22/58 pts) had relevant mutations in the combined group of MVAC (13/34 pts) and GC (9/24 pts) trials. At a median follow-up of 56 months and minimum follow up of 16 months, patients with mutations had statistically significantly greater OS (p = 0.0043) and DSS (p = 0.0015). Median OS/DSS was not reached for patients with a mutation in any group. At 5 years post treatment, OS/DSS were greater in mutated vs non-mutated patients in all groups (see table). Conclusions: Long-term follow up reveals that previously reported improved responses to cisplatin-based NAC associated with mutations in ATM, RB1 and FANCC also confer a clinically meaningful and statistically significant survival benefit in these patients. These alterations may be useful as predictive biomarkers to allow clinicians to prioritize patients most likely to benefit from NAC prior to radical cystectomy. [Table: see text]
Case 9-1985
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, Betty U. McNeely, Charles J. Homcy, Debra A. Bell
Journal: New England Journal of Medicine (1985)

Presentation of CaseA 43-ycar-old woman was admitted to the hospital because of hypertension and hematemesis.She was well until six months earlier, when she began to experience headaches that were accompanied by nausea and vomiting. Intermittent bouts of substernal "heaviness" occurred, with weakness, palpitations, and dyspnea; the episodes were unrelated to exertion but were sometimes precipitated by emotion and lasted for 5 to 10 minutes. During the two months before admission she began to have nausea, sweating, and tachypnea in the morning before going to work; she experienced two-pillow orthopnea, nocturia once or twice nightly, and occasional pedal edema. . . .
Abstract 16334: Inhibition of 14q32 MicroRNAs Drastically Improves Blood Flow Recovery After Ischemia
Authors: Teun Bastiaansen, Sabine Welten, Reginald van der Kwast, Rob de Jong, Margreet de Vries, Erna Peters, Soeren Sheikh, Nicola La Monica, Paul Quax, Yael Nossent
Journal: Circulation (2012)

Arteriogenesis is a multifactorial process in which pre-existing arterioles remodel into mature collateral arteries, restoring blood flow after ischemia. Clinical trials designed to stimulate arter...
Gene expression signature associated with in vitro dexamethasone resistance and post-induction minimal residual disease in pediatric T-cell acute lymphoblastic leukemia.
Authors: Lauren K. Meyer, Cristina Delgado-Martin, Ritu Roy, Benjamin J. Huang, Tiffaney Vincent, Adam Olshen, Brent L. Wood, Yu Liu, Jinghui Zhang, Charles Grenfell Mullighan, Terzah M. Horton, Mignon L. Loh, Meenakshi Devidas, Elizabeth A. Raetz, Robert J. Hayashi, Stuart Winter, Kimberly P. Dunsmore, Stephen Hunger, David T. Teachey, Michelle L. Hermiston
Journal: Journal of Clinical Oncology (2019)

10033 Background: T-cell acute lymphoblastic leukemia (T-ALL) is a genetically heterogeneous disease, which has largely precluded the use of genetic mutations for risk stratification. We hypothesized that despite this heterogeneity, diverse T-ALLs may have functional similarities that underlie patterns of chemotherapy sensitivity. Methods: We used flow cytometry to evaluate in vitro dexamethasone (DEX) sensitivity and baseline expression of signal transduction effectors and BCL2-family proteins in 68 fresh diagnostic T-ALL samples from patients enrolled on the Children’s Oncology Group (COG) trial AALL1231. We also performed RNA-sequencing (RNA-seq) on 40 AALL1231 samples and used hierarchical clustering and linear regression to analyze these and published T-ALL RNA-seq data from COG AALL0434. Comparisons between groups were made using t-tests and Fisher’s exact tests. Results: Of the proteins analyzed, only high BCL2 expression was significantly associated with increased in vitro DEX resistance (p = 0.002). Hierarchical clustering of the AALL1231 RNA-seq data identified two distinct clusters. Cluster 1 was associated with significantly higher BCL2 transcript expression (p = 0.0002) and in vitro DEX resistance (p = 0.04) relative to cluster 2. We defined a gene set consisting of the top 210 differentially expressed genes between these clusters and applied this gene set to the COG AALL0434 cohort. In this analysis, the early T-cell precursor (ETP) and near-ETP samples clustered together (p &lt; 0.0001) in cluster 1 along with 39 of 146 non-ETP samples. Not only did these cluster 1 non-ETP samples have significantly higher BCL2 transcript expression relative to the non-ETP samples in cluster 2 (p &lt; 0.0001), but 54% of these non-ETP samples were minimal residual disease (MRD) positive (≥0.01%) at the end of induction, as opposed to only 16% of the non-ETP samples in cluster 2 (p &lt; 0.0001). Conclusions: Gene expression profiling identifies non-ETP T-ALLs that cluster with ETP/near-ETP T-ALLs and have significantly higher BCL2 expression and increased rates of post-induction MRD.
Integrating endogenous peptides analysis and protease mapping for identification of potential serum biomarkers in gastric adenocarcinoma.
Authors: Nora Manoukian Forones, Talita Mendes de Oliveira, Jose Thales Lacerda, Meiriellen Dias, Maria Anita Mendes, Maria Aparecida Juliano
Journal: Journal of Clinical Oncology (2019)

e15564 Background: Gastric cancer (GC) is the third cause of cancer death in the world. In Brazil 21.000 new cases had been diagnosed in 2018 and the mortality rate is associated with late diagnosis that contributed to poor prognosis. The objective was to study endogenous peptides in serum of patients with GC. Methods: Fifteen serum samples of patients with diagnosis of gastric adenocarcinoma (TNM stage I-IV) and 15 controls were included. Endogenous peptides were extracted and pooled of random mode in 5 biological replicates (n = 3 samples) for each group. The mixture peptides was submitted to nLC-MS/MS analysis and peptide sequences identified were used to protease mapping. Results: A total of 191 peptides (≥ 7 amino acids) were identified corresponding to 36 proteins involved mainly on metabolic and immune system processes, signal transduction, platelet and neutrophils degranulation. Peptidome-based protease mapping identified 59 proteases (29 serine-, 19 metallo-, 8 cisteine- and 3 aspartic-), in which Prothrombin, Plasminogen, MMP14, MMP7 and MMP3 proteases yielded most of peptides. Twenty sequences derived from Fibrinogen A, Fibrinogen B, Complement C3 (C3f), Apolipoprotein A-I (N-terminal), Prothrombin (C-terminal of Activation peptide fragment 2; N-terminal of Thrombin light chain) and Coagulation factor XIII A (N-terminal) were significantly different (p ≤ 0.5). Between these peptides, 14 were up regulated and six downregulated in GC patients. The phosphopeptide 20 ADSpGEGDFLAEGGGVR 35 (Fibrinopeptide A) was significantly increased (p&lt; 0.03) in GC serum samples, while the non-phosphorylated Fibrinopeptide A was decreased (p&lt;0.04), suggesting a higher phosphorylation rate in this protein in GC patients. Further, the peptide 31 QGVNDNEEGFFSAR 44 (Fibrinopeptide B) was downregulated (p&lt;0.04) in GC serum samples; in counterpart, the Fibrinopeptide B derived peptides NDNEEGFF (p&lt;0.0007) and QGVNDNEEGFFS (p&lt;0.0013) was up regulated, suggesting a higher proteolysis in GC serum samples. Conclusions: The investigation of protease/substrate activity relationship may be described such as a novel panorama for discovery of serum biomarkers.
The efficacy of placebo for the treatment of cancer-related fatigue: A systematic review and meta-analysis.
Authors: Carmelia Maria Noia Barreto, Pedro Nazareth Aguiar, Daniel de Iracema Gomes Cubero, Auro Del Giglio
Journal: Journal of Clinical Oncology (2019)

e23157 Background: Cancer-related fatigue (CRF) is a common symptom among patients with cancer. The efficacy of placebo, however, was never the main objective of any meta-analysis. Predicting the efficacy of placebo may facilitate researchers in designing future clinical trials for the treatment of CRF. Methods: We performed a systematic review searching for prospective clinical trials comparing any treatment versus placebo for the treatment of CRF. We included studies that enrolled patients with any primary site of neoplasia and any stage of cancer. We excluded all studies that assessed fatigue related to any treatment. The primary endpoint of this study is the mean effect of placebo on fatigue according to the Functional Assessment of Chronic Illness (FACIT-F) and Brief Fatigue Inventory (BFI) scales. The secondary endpoint was the proportion of patients who reported improvement in fatigue (response rate). Results: We found 520 studies, and 29 studies with 3,758 participants were included in the meta-analysis. Placebo had a mean effect of +4.88 (95%CI +2.45 to +7.29) using the FACIT-F scale, although it was statistically worse than the interventions studied (p = 0.005). Using the BFI scale, placebo had an average effect of +0.64 (95%CI +0.02 to +1.30), although it was also worse than the other interventions studied (p = 0.002). In terms of the response rate, 29% (95%CI 25%–32%) of patients taking a placebo reported a significant improvement in CRF compared to 36% of patients treated with other interventions (p = 0.030). Conclusions: Placebo treatments had a significant effect on CRF, and predicting these effects may help design future studies for CRF.
Clinical verification of circulating tumor RNA (ctRNA) as novel pretreatment predictor and tool for quantitative monitoring of treatment response in metastatic colorectal cancer (mCRC): A biomarker study of the DEEPER trial.
Authors: Yu Sunakawa, Joshua L. Usher, Yolanda S Jaimes, Akihito Tsuji, Manabu Shiozawa, Takanori Watanabe, Hironaga Satake, Hirofumi Ota, Mitsugu Kochi, Hisatsugu Ohori, Dai Manaka, Masato Matsuura, Masahiro Takeuchi, Peter V. Danenberg, Masashi Fujii, Wataru Ichikawa, Heinz-Josef Lenz, KATHLEEN DANENBERG
Journal: Journal of Clinical Oncology (2019)

TPS3621 Background: A randomized phase II trial, DEEPER (JACCRO CC-13) [NCT02515734], is on-going to evaluate FOLFOXIRI plus cetuximab (cet) vs. FOLFOXIRI plus bevacizumab (bev) in terms of depth of response as primary endpoint in 360 mCRC patients (pts) with RAS wild-type tumors, PS0-1, and no previous chemotherapy. This is a head-to-head comparative trial of 2 key monoclonal antibodies in mCRC treatment; therefore, it would be of interest to perform the biomarker study for developing novel predictors of cet or bev. The clinical utility of circulating tumor DNA (ctDNA) analysis has been largely validated for monitoring during treatment and companion diagnostics after chemotherapy. However, there are few published results regarding ctRNA in cancer treatment. Use of ctRNA from liquid biopsies would enhance tumor profiling through the trending of actionable biomarkers not found in ctDNA, and allow for patient monitoring by measuring dynamic changes in levels of gene expressions. Methods: This study will enroll pts with willing to undergo biopsies of both tissue and blood among participants of the DEEPER trial. The estimated number is 250. The main purpose is to find novel predictors for efficacy of cet or bev in mCRC using liquid biopsies, which are performed to obtain ctDNA and ctRNA at 6 time points: pre-treatment, 8 weeks after treatment start, beginning of maintenance phase in FOLFOXIRI-regimen, progression, before and 8 weeks after 2nd-line treatment. The tissue samples collected before chemotherapy will be used for analyzing intra-tumoral genetic alterations. Associations between analytes in blood/tissue and the clinical outcomes of each treatment (with cet or bev) will be assessed using Fisher’s exact test, Kaplan-Meier curves, and log-rank tests in univariate analyses. We will evaluate on whether transcriptomic analysis in ctRNA could predict treatment efficacy more accurately compared to genomic analysis in ctDNA, and verify the clinical utility of ctRNA testing in mCRC treatment. Accrual will continue until the DEEPER trial is completed. Clinical trial information: UMIN000018412.
Can artificial intelligence support the clinical decision making for Barcelona clinic liver cancer stage 0/a hepatocellular carcinoma in China?
Authors: Ze-bin Chen, Shu-Ling Chen, Rui-Ming Liang, Zhen-Wei Peng, Jing-Xian Shen, Wan-Jie Zhu, Bin Li, Sui Peng, Ming Kuang
Journal: Journal of Clinical Oncology (2019)

e15634 Background: Artificial intelligence (AI) is emerging as a revolutionary technology with the power to transform healthcare. IBM Watson for Oncology (WFO), as an AI clinical decision support system (CDSS), has been investigated about its impact on clinical decision making in some cancer types and shown potential to be an effective CDSS in cancer care. However, the feasibility of WFO in Chinese patients with hepatocellular carcinoma (HCC) has not been reported. Methods: Artificial intelligence (AI) is emerging as a revolutionary technology with the power to transform healthcare. IBM Watson for Oncology (WFO), as an AI clinical decision support system (CDSS), has been investigated about its impact on clinical decision making in some cancer types and shown potential to be an effective CDSS in cancer care. However, the feasibility of WFO in Chinese patients with hepatocellular carcinoma (HCC) has not been reported. Results: The overall concordance rate was 60.5%, with 53.7% and 61.4% in BCLC stage 0 and A respectively. After the MDT re-review, the overall, BCLC stage 0 and A concordance rate increased to 67.3%, 65.9% and 67.3%. The main discordance was that MDT recommended more aggressive treatment options (eg. hepatectomy) than WFO did. The increase in concordance rate may be due to the progress of treatment of HCC in the past 5 years. Conclusions: With the concordance and reasonability verified by MDT in this study, WFO may provide practical reference in BCLC stage 0/A HCC. Localization is required to cover the disparity in guideline and patient characteristics between China and the US.
High-dose, short-duration, intra-arterial cisplatin therapy for oral cancer.
Authors: Masatoshi Ohmae, Itsuro Kato, Yusei Fujita, Noritoshi Meshii, Ayako Motoki, Mitsuhiro Nakazawa, Narikazu Uzawa
Journal: Journal of Clinical Oncology (2019)

6038 Background: We developed a superselective intra-arterial chemotherapy (iaCT) approach for oral cancer wherein an intra-arterial catheter is retrogradely inserted via the superficial temporal artery (STA) and/or occipital artery (OA). In most iaCT cases, high-dose anticancer agents are administrated via the intra-arterial catheter weekly or biweekly with daily irradiation. This approach remarkably improves curative efficiency, but some adverse events, e.g., severe mucositis, dysphagia, dysgeusia, dry mouth, and radiation osteonecrosis, mainly because of irradiation, decrease the quality of life. Methods: Thirty-two patients with stage II, III, or IV oral squamous cell carcinoma were treated using this new iaCT approach. The catheter was superselectively placed in the tumor-feeding arteries by cut-down of STA or OA. The catheter was completely placed under the skin and was connected to an infusion reservoir that was subcutaneously implanted around the mastoid process via the subcutaneous tunnel, ensuring little possibility of catheter-related issues such as infection and displacement of catheter. Anticancer agents (30 mg/m 2 of cisplatin with/without 10 mg/m 2 of docetaxel) were intra-arterially administered via the reservoir twice a week for 3 weeks, 180 mg/m 2 /6 times in total, without irradiation. The treatment effect was assessed using computed tomography, positron emission tomography, and biopsy. Results: The response rate of this approach was 100%, with 31 and 1 case having complete response (CR) and partial response (PR), respectively. Five patients with delayed regional lymph node metastasis or PR underwent salvage surgery; 28 patients (87.5%) had disease-free survival, while 2 (6.2%) died due to local recurrence and 2 due to distant metastasis. All patients developed CTCAE v4.0 Grade 2 oral mucositis in the flow area of the intended artery, most of which disappeared in half a year. No dry mouth, dysgeusia, and eating disorder were observed because the patients did not receive radiotherapy. No systemic adverse events such as hematologic toxicity and renal and/or hepatic injuries occurred. Conclusions: This method improved the adverse event of iaCT with radiotherapy, and the main advantage of superselective iaCT was not lost.
Real-world experience in advanced NSCLC using FDA approved NGS CDx.
Authors: Ehab Elkhouly, Li Zhou, Boaz Kurtis, Lan Wang, Anna Israyelyan
Journal: Journal of Clinical Oncology (2019)

e14602 Background: The number one challenge in clinical biomarker testing for non-small cell lung cancer (NSCLC) has been the sample adequacy, given that the majority of patients are diagnosed based on minimally invasive sampling of tumor tissue. The increasingly evolving integration of high-throughput next-generation sequencing (NGS) has redefined molecular diagnostic lab practice allowing for time- and cost-efficient parallel testing of multiple biomarkers with limited specimen. Two NGS companion diagnostic (CDx) tests have been approved by FDA, FoundationOne CDx (F1CDx) and Oncomine Dx Target Test (Oncomine Dx), but with different sample acceptance criteria. The minimum tumor content requirement for F1CDx is 20% while it is 10% for Oncomine Dx. The surface area requirement for F1CDx is 25mm 2 while there is no required minimum surface area for Oncomine Dx. The difference in sample acceptance criteria may have a major impact on the number of advanced NSCLC patient samples that can be accepted and tested successfully, affecting biomarker-directed therapy. Methods: The analysis of 153 NSCLC patient samples tested by Oncomine Dx at Cancer Genetics, Inc. CLIA-certified and CAP-accredited lab from October 2017 to September 2018 evaluated the sample acceptance rate, biomarker results, and testing turn-around time (TAT). Results: Based on the data, a significant portion of the samples submitted for routine clinical testing consists of extremely small specimen, including FNA cytology, with 42% less than 1mm 2 . 83% of samples are acceptable by Oncomine Dx criteria, compared to 14% by F1CDx. Of the 82 samples that would not be acceptable by F1CDx but generated results by Oncomine Dx, 5 were positive for EGFR exon 19 deletions and L858R, 1 for BRAF V600E, 1 for a ROS1 fusion, and the remaining 35 were positive for other actionable alterations. Average TAT was 9.2 days, consistent with recommendation by IASLC/AMP/CAP guideline of within 10 days. Conclusions: The real-world routine clinical testing of NSCLC patient samples demonstrated that a higher number of specimens with limited tumor tissue could be tested with the FDA-approved NGS CDx Oncomine Dx providing rapid TATs, actionable insights, and impacting the patient treatment outcomes.
Impact of discordance in estrogen receptor, progesterone receptor, and Ki-67 after neoadjuvant chemotherapy in breast cancer on survival.
Authors: Yu-Qin Ding, Xiaowen Ding, Kaijing Ding, Wen-Ming Cao, Dehong Zou, Hongjian Yang, Fanrong Zhang, Xiangming He, Wenju Mo, Chengdong Qin, Yurong Zheng
Journal: Journal of Clinical Oncology (2019)

e12079 Background: The expression status of estrogen receptor (ER), progesterone receptor (PR), and Ki-67 antigen (Ki-67) divides breast cancer into different subtypes. Changes in these biomarkers during treatment alter the overall treatment decision and affect prognosis. To date, few studies have investigated the effects of changes in these biomarkers throughout neoadjuvant chemotherapy (NAC) on patient prognosis. Methods: A total of 482 patients who received NAC were enrolled. The expression of ER, PR and Ki-67 between pre- and posttherapy specimens was studied by immunohistochemical methods. Physical and imaging examinations based on the Response Evaluation Criteria in Solid Tumors guidelines version 1.1 were utilized to assess the treatment response. The impact of these biomarkers status changes on survival was then tested for statistical significance using a Cox proportional hazards regression model for univariate and multivariate analyses. Results: The rate of discordance for ER, PR and Ki-67 was 10.37%, 17.01% and 77.39%, respectively, in which the PR positive-to-negative conversion was the most common change. A statistically significant differential overall survival (OS) related to biomarkers status throughout NAC (P&lt;.01) was noted. The risk of death in patients with a PR positive-to-negative conversion was 6.58 times greater than that of stable PR expression (P=.002). The risk of disease recurrence in patients with increased Ki-67 expression was 1.91 times greater than that of stable Ki-67 expression (P=.02). Furthermore, we validated both of them as independent predictors of poor prognosis. Conclusions: We concluded that inconsistent expression of biomarkers can significantly affect patient prognosis. We suggest that biomarkers investigations during NAC may potentially improve patient management and survival. Survival result that compared with concordance and discondance in ER, PR and Ki-67. (N=482).*P&lt;.05. [Table: see text]