tbuckley/cabot-search huggingface dataset:
TCT-78 Impact of Collateral Channel Type on the Outcomes of Chronic Total Occlusion Percutaneous Coronary Intervention
Authors: Judit Karacsonyi, Dimitrios Karmpaliotis, Khaldoon Alaswad, Farouc Amin Jaffer, Robert Yeh, Mitul Patel, Ehtisham Mahmud, James Choi, M. Nicholas Burke, Anthony Doing, Catalin Toma, A.J. Conrad Smith, Barry Uretsky, Oleg Krestyaninov, Dmitrii Khelimskii, Elizabeth Holper, R. Michael Wyman, David Kandzari, Santiago Garcia, Ioannis Tsiafoutis, Wissam Jaber, Habib Samady, Jeffrey W. Moses, Nicholas Lembo, Manish Parikh, Ajay Jayant Kirtane, Ziad Ali, Darshan Doshi, Peter Tajti, Iosif Xenogiannis, Imre Ungi, Bavana Rangan, Subhash Banerjee, Emmanouil Brilakis
Journal: Journal of the American College of Cardiology (2018)
BRAF somatic mutation contributes to intrinsic epileptogenicity in pediatric brain tumors
Authors: Hyun Yong Koh, Se Hoon Kim, Jaeson Jang, Hyungguk Kim, Sungwook Han, Jae Seok Lim, Geurim Son, Junjeong Choi, Byung Ouk Park, Won Do Heo, Jinju Han, Hyunjoo Jenny Lee, Daeyoup Lee, Hoon-Chul Kang, Minho Shong, Se-Bum Paik, Dong Seok Kim, Jeong Ho Lee
Journal: Nature Medicine (2018)
Estimation of 10-year (y) cardiovascular disease (CVD) risk after cisplatin-based chemotherapy (CBCT): A multi-institutional study of 459 germ cell tumor (GCT) survivors in the Platinum study.
Authors: Darren R. Feldman, Shirin Ardeshir-Rouhani-Fard, Patrick Monahan, Chunkit Fung, Robert James Hamilton, David J. Vaughn, Clair Beard, Kevin C. Oeffinger, Lawrence H. Einhorn, Sophie D. Fossa, Howard D. Sesso, Lois B. Travis
Journal: Journal of Clinical Oncology (2016)

10083 Background: Although significantly increased rates of CVD among GCT survivors following CBCT have been reported in several studies, identifying a high risk subgroup to target with cardiovascular interventions remains challenging. We applied a validated CVD risk prediction model to a large cohort of CBCT-treated male GCT survivors in an ongoing North American multicenter study. Methods: GCT survivors eligible for analysis were men diagnosed at age < 50 y who completed first-line CBCT (≥ 3 cycles) > 1 y before enrollment. Patients completed questionnaires regarding comorbidities, lifestyle behaviors, and prescription drug use. Systolic and diastolic blood pressure (SBP and DBP), waist circumference, and lipids were measured. We used the Framingham model (D’Agostino, Circulation2008) for men to estimate individual 10 y CVD risk (defined as angina, MI, stroke, TIA, claudication or heart failure). Model variables include age, total cholesterol, HDL, SBP, hypertension treatment, diabetes, and smoking status. We excluded men with baseline CVD or missing data for > 1 risk factor. Results: The first 459 eligible GCT survivors enrolled on study were evaluated. Median age was 37.8 y, 15.7% had SBP ≥ 140 mm Hg, 56.0% had total cholesterol > 200 mg/dL, and 16.6% had HDL < 40 mg/dL; 13.1% were on BP medication, 9.6% were current smokers, and 4.1% had diabetes. One in 6 men had a predicted 10 y CVD rate of ≥ 10% (Table), corresponding to classification as intermediate, high, or very high risk and warranting consideration of management of CVD risk factors. CVD risk increased with age at evaluation; those < 30, 30-39, 40-49, 50-59, and ≥ 60 y had 10 y risks of 1.2%, 3.2%, 8.1%, 14.0%, and 22.3%, respectively. Conclusions: The Framingham model identified a sizable proportion of CBCT-treated GCT patients to be at intermediate or higher risk of CVD within 10 y. Clinicians should be aware of these risks since, despite their young median age, such patients may benefit from targeted interventions. Predicted 10 y Risk of CVD Very Low ( < 5%) Low (5 – < 10%) Intermediate (10 – < 20%) High (20 – < 30%) Very High ( > 30%) N (%) 279 (60.8%) 106 (23.1%) 51 (11.1%) 18 (3.9%) 5 (1.1%)
P04.51 TERT promoter mutation-driven TERT activation is mediated by ETS1 in BRAF V600E mutated glioma
Authors: L Gabler, J Gojo, D Lötsch, D Kirchhofer, S van Schoonhoven, M Stojanovic, H M Schmidt, D Ensle, T Czech, C Haberler, I Slavc, S Spiegl-Kreinecker, W Berger
Journal: Neuro-Oncology (2018)

Malignancies of the central nervous system are characterized by the highest lethality among pediatric tumors. Interestingly, brain tumors such as pleomorphic xanthoastrocytoma or epithelioid glioblastoma often harbor genomic BRAF alterations (e.g. V600E) leading to hyperactivation of the MAPK pathway. Additionally, activating point mutations in the TERT promoter have been described as the most frequent genomic alterations in certain glioma subtypes. However, a crosstalk between BRAF and TERT promoter mutations has not been established so far in these tumors. Herein, we interrogated the impact of BRAF mutations on TERT promoter activity. We have applied cell viability and clonogenicity assays and explored TERT promoter activity by luciferase reporter assays. Gene expression and downstream signaling upon MAPK pathway inhibition or siRNA knock-down were characterized by use of q-RT-PCR and Western blots, respectively. In a curated dataset of 103 BRAFV600E mutated glioma originating from publicly available data sets, we found BRAF and TERT promoter mutated glioma to be significantly enriched in high grade glioma as compared to low grade glioma. Based on this finding, a panel of primary glioma cell lines with differential BRAF and TERT promoter mutation status was established and treated with MAPK pathway inhibitors. Remarkably, TERT expression as well as TERT promoter activity was only downregulated in tumors with both BRAFV600E and TERT promoter mutations, while TERT expression was undetectable in only BRAFV600E mutated cells. As TERT promoter mutations are known to generate de novo ETS-binding sites, we thought to investigate the role of ETS factors in further detail. ETS1 activation and gene expression were significantly downregulated by MAPK inhibitors in BRAFV600E and TERT promoter mutated tumors. In contrast, BRAF inhibition was insufficient to block ETS1 expression in a TERT promoter wildtype background. Intriguingly, knock-down experiments proved the functional role of ETS1 as bridge molecule interconnecting MAPK pathway and telomerase reactivation in double-mutant tumors. Accordingly, tumor cells harboring both mutations were significantly more sensitive towards ETS factor-targeting therapy as compared to cell models of the other genotypes. In conclusion, our data suggest that concomitant BRAFV600E and TERT promoter mutations synergistically drive tumor aggressiveness by promoting cancer cell proliferation and immortalization. ETS1 represents the major driver functionally linking these two highly abundant genomic alterations and might represent a promising therapeutic target specifically in double-mutant glioma. This project was supported by Austrian Science Fund FWF (project number: P30105 to WB) and by Fellinger Krebsforschung (to JG).
Cost-effectiveness of multi-gene panel sequencing (MGPS) for advanced non-small cell lung cancer (aNSCLC) patients.
Authors: Lotte Maria Gertruda Steuten, Bernardo H. L. Goulart, Neal J. Meropol, Daryl Pritchard, Scott David Ramsey
Journal: Journal of Clinical Oncology (2018)

6513 Background: MGPS, compared to single-marker genetic testing (SMGT), has the potential to identify more patients who could benefit from targeted therapies, but the impact on outcomes and total costs of care is uncertain. Our goal was to estimate the cost-effectiveness of MGPS vs SMGT in aNSCLC. Methods: aNSCLC patients (stage IIIB or metastatic) diagnosed between 2011-2016 were identified from the Flatiron Health database, representing curated electronic health record-derived clinical information from > 250 oncology practices nationwide. After stratifying patients in MGPS or SMGT cohorts, we analyzed the percentage of patients that receive targeted treatment; survival; and total costs of care. SMGT included EGFR and ALK testing; MGPS also allowed detection of BRAF, RET, ROS1, HER2 and MET mutations. Cost data sources were the CMS Fee Schedule and 2017 ASP drug cost. We estimated the incremental cost-effectiveness ratio (ICER) and performed sensitivity analyses from a US payer perspective over a lifetime horizon, using a decision model. Results: We identified 5688 aNSCLC patients receiving MGPS (n = 875) or SMGT (n = 4813), of which 22% tested positive for EGFR (18.5% MGPS, 17.3SMGT) or ALK (3.59% MGPS, 3.78% SMGT). Among MGPS tested patients, an additional 8% were found to have BRAF, RET, ROS1, HER2 or MET mutations. Of MGPS tested patients, 21% received targeted treatments vs 19% with SMGT. Model-projected survival was 1.14 life years (LYs) in SMGT vs 1.20 LYs in MGPS. Lifetime total costs were $8,814 higher per patient for MGPS. The ICER of MGPS vs SMGT was $148,478 per LY gained. If all patients with actionable mutations would receive targeted treatment in MGPS-guided care vs the proportion currently receiving targeted treatments under SMGT, the ICER would be $110K/LY gained. Sensitivity analyses shows widely varying ICERs ($139/LY to $661,625/LY). Conclusions: Based on data from a nationwide oncology patient database, MGPS has moderate cost-effectiveness compared to SMGT in aNSCLC patients. Efforts to increase the proportion of patients who receive targeted therapies would improve the cost-effectiveness of MGPS, assuming incremental costs and outcomes of targeted treatments remain unchanged.
Serum frailty biomarkers to predict overall survival in older patients with metastatic solid tumors: A substudy of prospective multi-center cohort study (KCSG PC13-09).
Authors: Se Hyun Kim, Jin Won Kim, In Gyu Hwang, Joung Soon Jang, Soojung Hong, Tae Yong Kim, Ji Yeon Baek, SeongHoon Shin, Der Sheng Sun, Dae Sik Hong, Hyo Jung Kim, Yong Sang Hong, Ju-Hyun Lee, In Sook Woo, Jee Hyun Kim
Journal: Journal of Clinical Oncology (2017)

10041 Background: To determine individualized cancer treatment for older patients, easily measurable markers that predict functional decline and mortality are needed. The purpose of this study was to confirm prognostic value of potential biomarkers of frailty in older patients with metastatic solid tumors. Methods: Serum samples were prospectively collected before first line chemotherapy at 11 academic centers in Korea. All patients were participants in a prospective cohort study of older patients with metastatic solid tumors (KCSG PC13-09, WHO ICTRP number: KCT0001071). Serum levels of C-reactive protein (CRP), CXCL10, SIRT1, VEGF-A, Activin A, C-terminal telopeptide of type I collagen (CTx), total 25-hydroxyvitamin D (vitD) were measured by ELISA and IL-6, Myostatin, Irisin, FGF-19, FGF-21, FGF-23 by luminex mutiplex assay. Overall survival (OS) was studied by means of Kaplan-Meier, Log Rank and Cox methods. Results: Serum samples from 138 patients (median age: 75, range: 70-92) were collected from Feb 2014 to Dec 2016. During a median follow up time of 13.8 months, 72 (52.6%) patients had died. Among 13 serum markers, CRP (log-rank, P=0.006), Activin A (P=0.003), and Myostatin (P=0.043) were significantly correlated with OS in univariate analyses. In a Cox regression analysis, Activin A (HR 2.36, 95% CI 1.41-3.96; P=0.001) and Myostatin (HR 2.70, 95% CI 1.24-5.84; P=0.012) were significantly associated with OS after adjustment of other clinical factors (Age, Gender, ECOG PS, BMI, Geriatric assessment, Chemotherapy response, WBC, Albumin). Conclusions: In older cancer patients, high serum concentration of Activin A and Myostatin are predictive of poor OS. [Table: see text]
Long-term platinum (Pt) change and its associations with cisplatin-related late effects in testicular cancer survivors (TCSs).
Authors: Hege Sagstuen Haugnes, Line Veronika Hjelle, Per Ole Gundersen, Ragnhild Hellesnes, Mette Sprauten, Marianne Brydoy, Torgrim Tandstad, Tom Wilsgaard, Jan Oldenburg, Roy M. Bremnes, Sophie D. Fossa
Journal: Journal of Clinical Oncology (2018)

e22067 Background: In this longitudinal study, we report long-term change in Pt serum concentration and associations between Pt change and cisplatin-related late effects (second cancers and neurotoxicity (NTX)) in TCSs. Methods: In 77 TCSs treated with cisplatin-based chemotherapy during 1984-1990 (cases), blood samples for analyses of Pt and a questionnaire including self-reported NTX symptoms (SCIN; scale for chemotherapy induced neurotoxicity) were collected during two national follow-up surveys median 12 (Survey I; SI) and 20 (Survey II; SII) years after treatment. 17 TCSs treated with surgery only were included as a control group for analyses of Pt change. Pt change was modeled as the change per year from SI to SII (Pt at SI-Pt at SII/years from SI to SII). Information about second cancers after SII was retrieved from the Norwegian Cancer Registry. Associations between Pt change and late effects of interest were analyzed with Cox regression (second cancers) or multivariable ordinal logistic regression (NTX change). Results: The median Pt level for all cases was 75 ng/l (0-377) and 64 ng/l (0-725) at SI and SII, respectively. The median Pt change was higher among cases than controls (4.2 vs. 0.0 ng/l/year, p = 0.005), and for the majority of men a Pt decline from SI to SII. Overall 12 cases (15%) were diagnosed with a second cancer after SII. A larger Pt decline from SI to SII was related to a decreased risk of a second cancer diagnosis (HR 0.78, 95% CI 0.62-0.99 per 10 ng/L/year). All SCIN symptoms among cases at SII were significantly worsened compared with symptoms at SI (p < 0.001 for all). A larger Pt decline from SI to SII was associated with worsening of paresthesias in hands (OR = 1.98, 95% CI 1.09-3.59 per 10 ng/l/year) and tinnitus (OR = 1.51, 95% CI 1.01-2.27 per 10 ng/L/year) from SI to SII, and remained significant when adjusted for cisplatin dose. Conclusions: A larger Pt decline from SI to SII was associated with a decreased risk of second cancer, but with worsening of paresthesias and tinnitus. Hypothetically, different mechanisms are involved according to whether the cisplatin-induced side-effect occurs during/shortly after chemotherapy as for NTX, or several years later as for second cancers.
Prognostic significance of the lymphocyte‐to‐monocyte ratio and the tumor‐infiltrating lymphocyte to tumor‐associated macrophage ratio in patients with stage T3N0M0 esophageal squamous cell carcinoma.
Authors: Yingming Zhu, Jinming Yu, Minghuan Li
Journal: Journal of Clinical Oncology (2017)

e15602 Background: We assessed the prognostic signi cance of, and the relationship between, the pretreatment lymphocyte- to-monocyte ratio (LMR) and the TILs/tumor-associated macrophages (TAMs) ratio, in patients with esophageal squamous cell carcinoma (ESCC) of pathological stage T3N0M0 (pT3N0M0). Methods: A total of 220 newly diagnosed ESCC patients of stage pT3N0M0 who had not undergone neoadjuvant therapy were included. Densities of CD8+ TILs, CD4+ TILs, CD45RO+ TILs, and CD68+ TAMs were assessed by immunohistochemical staining of tissue microarray cores from all 220 pT3N0M0 ESCC patients (who underwent radical resection). Hematological biomarkers including lymphocyte and monocyte counts were obtained from routine preoperative blood test data, and the LMR and TILs/ TAMs ratios calculated. Cutoff nder for survival predic- tion was plotted to nd out the optimal cutoff point for each parameter. Results: The LMR and TILs/TAMs ratios were interrelated. On univariate analyses of data from the entire cohort, the LMR, CD45RO/CD68 ratio, and CD8/CD68 ratio were significantly associated with both OS and disease-free survival. Only the CD45RO/CD68 ratio was independently prognostic of survival on multivariate analysis. Conclusions: The prognostic significance of the CD45RO/ CD68 ratio was higher than that of the LMR. The CD45RO/ CD68 ratio is a useful independent prognostic marker in patients with pT3N0M0 ESCC who have undergone complete resection without neoadjuvant therapy.
The impact of genetic counseling on patients' knowledge about tumor genomic profiling.
Authors: Rebecca D. Pentz, Brianna McDaniels, Cecelia Bellcross, Walid Labib Shaib, Jeffrey M. Switchenko, Margie D Dixon
Journal: Journal of Clinical Oncology (2018)

1592 Background: Molecular testing is increasingly being integrated into cancer management. However, despite rapid advancements in this area, little work has been done to explore strategies for communicating genomic information to patients undergoing tumor profiling. This study evaluated the impact of an educational tool combined with genetic counseling on patients’ understanding of key terms related to tumor genomic profiling. Methods: A genetic counseling intern designed a picture book to explain six words found in prior research to be difficult for patients to understand: mutation, germline mutation, somatic mutation, biomarker, molecular testing, and targeted therapy. The picture book was cognitively tested with oncology patients and revised. After consent, patients who had previously discussed molecular testing with their oncologist were asked to define the six words in their own terms. The same patients then received an explanation of each word from the intern using the picture book, and were asked to redefine each word directly afterwards. All definitions were scored for correctness by two independent coders. The proportion of patients who defined each term correctly and total knowledge scores were compared before and after genetic counseling. Results: Twenty-eight patients with melanoma, colon, lung, or breast cancer were recruited. Correct understanding rates improved for all six terms, with significant improvement for germline mutation (p < 0.001), somatic mutation (p < 0.001), biomarker (p < 0.001) and molecular testing (p < 0.001). Mean total knowledge score significantly improved from 30% to 83.3% (p < 0.001). Conclusions: Our data suggest that the use of a simple educational tool combined with genetic counseling in the setting of genomic tumor testing increases patient knowledge and may improve the process of informed consent. Future studies are warranted to determine the feasibility of providing in person genetic counseling in this setting and whether the picture book can be effectively used by other advanced practice providers with knowledge of genomics.
The potential prognostic value of expression of stem cell marker of CD44s, EpCAM, and OVA66 in patients with gastric adenocarcinoma.
Authors: Ning Yan, Ying chun Xu, Fengchun Zhang, Siyu Chen
Journal: Journal of Clinical Oncology (2017)

e15562 Background: The present study aimed to (i) examine the expression pattern of putative stem cell markers, CD44s, EpCAM, and new tumor specific antigen OVA66, in gastric adenocarcinoma (GA) and normal para-cancer tissues; (ii) determine if the expression of these proteins is associated with overall survival of GA. Methods: 84 GA patients confirmed by histopathology were examined the expressions of CD44s, EpCAM and OVA66 using tissue microarray technique. The immunohistochemistry analysis were carried out to explore the differential expression CD44s , EpCAM and OVA66 in GA compared to normal para-cancer tissues (p = 0.001). Next, Kaplan-Meier analysis was conducted to investigate their effect in overall survival(OS). Results: The immunohistochemistry analysis demonstrated the differential expression CD44s and EpCAM in GA compared to normal para-cancer tissues (p = 0.001), while there was no significant difference of OVA66 expression between cancer and normal specimens (p = 0.366). The upregulated expression of CD44s was well correlated with lymph node metastasis (p = 0.018), however the expression of OVA66 was only associated with gender of the patients (p = 0.025) and age at presentation (p = 0.018). The univariate analysis demonstrated that patients with blood and lymphatic vessel invasion, pT category 3 to 4, pN positive, with faraway metastasis, and stage Ⅲ to Ⅳ had a significantly shorter OS. Both increased expressions of the CD44s and EpCAM was shown in patients with poor OS (p = 0.037) and was confirmed by multivariate analysis. Conclusions: Our study suggested EpCAM is a potential diagnostic marker for gastric cancer and combined with CD44+/EpCAM+ can be regarded as an independent prognostic marker for patients with GA.
The neoantigen landscape and immune regulators in cervical cancer.
Authors: Jason Roszik, Yong Qin, Suhendan Ekmekcioglu, Marie-Andree Forget, Patrick Hwu, Elizabeth A. Grimm, Amir A. Jazaeri
Journal: Journal of Clinical Oncology (2017)

5528 Background: Human papillomaviruses (HPVs) play a major role in development of cervical cancer, and HPV oncoproteins are being targeted by immunotherapies. Although these treatments show promising results in the clinic, many patients do not benefit or the durability is limited. Methods: To explore the landscape of neoantigens in cervix cancer, we predicted all possible mutated neopeptides using exome and RNA sequencing data of a large number of tumors in two independent data sets (n = 194 and 79), and analyzed whether mutation and neoantigen load correlate with expression of genes involved in antigen presentation, infiltrating immune cell type markers, and HPV oncoprotein-associated genes. Normal tissue expression analyses were also performed using data from the Genotype-Tissue Expression project (n = 8,555). Results: We found that potentially immunogenic and targetable neoantigens can be predicted for almost all cervix tumors, including recurrent neoantigens from mutations of known oncogenic driver genes (KRAS G12D, MAPK1 E322K, PIK3CA E545K, PIK3CA E542K, ERBB2 S310F, and ERBB3 V104M). Furthermore, we found that expression of HPV-associated “master regulator” genes is associated with mutation, neoantigen, and HPV load, and also with expression of several important markers in the immune microenvironment. Notably, the OVOL1 master regulator positively correlated with mutation and neoantigen load, and also with PD-L1 and TGFB1 expressions. Furthermore, ENO1 over-expression in cervical cancer was associated with high HPV load, and ENO1 level also positively correlated with PD-L1 and TGFB1 expressions, suggesting that it may be a potential target in cervical cancer. Conclusions: For most of the cervix tumors we report predicted neoantigens, and we also identified recurrent neopeptides derived from mutations in known oncogenes. We have also identified statistically significant associations between neoantigen availability, antigen presentation, cytotoxic T-cell function, suppressive mechanisms, and expression of HPV master regulators to help guide immunotherapies of cervical cancer.