tbuckley/cabot-search huggingface dataset:
Abstract A054: Loss of an androgen-inactivating and isoform-specific HSD17B4 splice form enables emergence of castration-resistant prostate cancer
Authors: Hyun-Kyung Ko, Michael Berk, Yoon-Mi Chung, Belinda Willard, Rohan Bareja, Mark Rubin, Andrea Sboner, Nima Sharifi
Journal: Cancer Research (2018)

Abstract The development of castration-resistant prostate cancer (CRPC) requires tumors to engage metabolic mechanisms that allow sustained concentrations of testosterone and/or dihydrotestosterone, which stimulate tumor progression despite castration. 17βHSD4, encoded by HSD17B4, is an enzyme that is thought to inactive testosterone and dihydrotestosterone by way of conversion to their respective inert 17-keto steroids. Counterintuitively, HSD17B4 expression is known to increase in CRPC and predict for poor prognosis. Here, we show that of 5 alternative splice forms of HSD17B4, only isoform 2 encodes an enzyme capable of testosterone and dihydrotestosterone inactivation. In contrast to other transcripts, functional expression of isoform 2 is specifically suppressed in development of CRPC in patients. Genetically silencing isoform 2 shifts the metabolic balance toward 17β-OH androgens (testosterone and dihydrotestosterone), stimulates PSA expression, and spurs the development of CRPC in xenograft models. Together, our studies specifically implicate HSD17B4 isoform 2 loss in the development of lethal prostate cancer. Citation Format: Hyun-Kyung Ko, Michael Berk, Yoon-Mi Chung, Belinda Willard, Rohan Bareja, Mark Rubin, Andrea Sboner, Nima Sharifi. Loss of an androgen-inactivating and isoform-specific HSD17B4 splice form enables emergence of castration-resistant prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A054.
P05.28 Karnofsky performance score of brain tumor patients depends on clinician status
Authors: D Frappaz, L Taillandier, A Levard-Bonneville, J Sore, D Ricard, C Schiffler, M Weller
Journal: Neuro-Oncology (2018)

Inclusion criteria for oncological protocols often use the Karnofsky performance score (KPS)>=70 or the WHO performance score (WHO PS) 0–2 as a cut-off value. Inclusion of neuro-oncology patients may be hampered, when general condition is preserved, but performance is decreased due to physical handicap. The assessment of KPS is subjective in such situation. The goal of the current study is to compare the KPS assessment according to the status of the clinician. A cross-sectional survey was conducted through ANOCEF and EANO networks. Six different clinical situations concerning patients with brain tumor (from youngest and most fit to oldest and crippled with comorbidities) were described in a questionnaire. Clinicians assessed KPS for each situation. 276 clinicians provided an answer, but only 180 completed the 6 cases and are the subject of this analysis. Clinicians homogeneously attributed decreasing KPS from case 1 to 6. There was no difference of assessment between sexes of the clinicians. When clinicians were grouped by age (<40 vs 41–50 vs > 50 year old), the older group rated significantly worse (p 0.0012) and would include less patients (p0.047) if KPS 70 was considered as a cut off. When clinicians were grouped by speciality (residents/general practionner vs neurosurgeons/neurologists vs oncologists), the former rated worse/included less and the latter rated higher/included more patients in trials (p<0.0001 and <0.0001 respectively). Clinicians that were not used to include patients in trials rated worse (especially for most severe cases) and included less patients in trials (p respectively <0.0001 and <0.0008). French and non-French clinicians rated and included patients in a similar way. In a multivariate analysis, age and speciality (both <0.0001) correlate with KPS rating and with possible inclusion in trial (p 0.007 and <0.0001 respectvely). Karnofsky performance score applied to patients with brain tumor is clinician dependant: younger clinicians, oncologists, and clinicians used to include patients in trial will significantly propose a KPS more elevated, especially >=70 that allow inclusion in a trial. Specific rules should be proposed to homogenise inclusion criteria for patients with neurological deficits. Acknowledgment to clinicians that answered to the questionnaire.
High-risk ipilimumab-related diarrhea/colitis: Experience and use of ancillary tests in changing toxicity management.
Authors: Iván Victoria, Lydia Gaba, Margarita Viladot, Maria Jose Quevedo, Francisco Aya, Carme Font, Estela Pineda, Josep Llach, Aleix Prat, Ana Maria Arance Fernández
Journal: Journal of Clinical Oncology (2016)

e14552 Background: Ipilimumab (Ipi) is an anti-CTLA-4 antibody that has demonstrated to improve survival in patients (pts) with advanced melanoma (MM). The blockade of CTLA-4 may result in a systemic loss of self-tolerance associated with the development of immune-related adverse events (irAEs) such as diarrhea/colitis (D/C). Clinical information guides the management of severe D/C, but endoscopical findings could help us to evaluate the severity of D/C, and, therefore, to apply different strategies to overcome this toxicity. Methods: This retrospective observational study included pts with MM who received Ipi at a single institution. The objective was to summarize the epidemiology, pathogenesis, clinical features and management of Ipi grade 3 o grade 4 associated D/C. Toxicity was graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Results: 92 pts with MM initiated ipi between August 2010 and December 2015. 9 of them (10.2%) developed high-grade diarrhea. Pts were classified as IIIC (22.2%), M1a (11.1%) and M1c-stage (66.7%). Diarrhea occurred after the third dose of ipi in 66.7% of pts (88.9% grade 3 and 11.1% grade 4). A CT scan was performed in 8 pts (88.9%). Radiological findings suggested colonic inflammation in 2 cases (25%). All 9 pts underwent a colonoscopy. Almost all segments were affected (pancolitis 55.6%), being the most frequent findings erythema, edema, friability and ulcerations. Biopsies showed colitis in all pts, being the most frequent findings inflammation/ulcerations (66.7%), and cryptitis/crypt abscesses (33.3%). Six pts (66.7%) required Infliximab. D/C resolved after a median of 25.1 days. In four pts who had endoscopic findings of chronic colitis, symptomatic recovery was longer with respect to the rest of pts (median: 35 vs. 17.2 days). Conclusions: This retrospective study has shown that in most cases colitis has no CT scan translation, and colonoscopy is the most accurate method for D/C evaluation. It provides information that could guide the intensity of the treatment (dosing of corticoids) or define the need for infliximab depending on the severity and chronicity of the findings described.
TCT-232 Diagnostic Accuracy of Machine Learned Algorithms Utilizing a Novel Form of Cardiac Phase Tomography (cPST) versus Single Photon Emission Tomography (SPECT) in the Assessment of CAD
Authors: Tom Stuckey, Frederick Meine, Narendra Singh, Prashant Kaul, Jeremiah Depta, Roger Gammon, John Steuter, Horace Gillins, Tim Burton, Ali Khosousi, Ian Shadforth, Shyam Ramchandani, William Sanders
Journal: Journal of the American College of Cardiology (2018)
Abstract 16751: Baseline Adiponectin Concentration and Clinical Outcomes Among Patients With Diabetes and Recent Acute Coronary Syndrome in the EXAMINE Trial
Authors: Brian A Bergmark, Christopher P Cannon, William B White, Petr Jarolim, David A Morrow
Journal: Circulation (2016)

Introduction: Adiponectin is a pleiotropic adipocytokine with a strong inverse (protective) association with obesity, diabetes (DM), and cardiovascular outcomes in stable patients. In a prior study...
H2AX and topoisomerase II expression as potential predictors of response to treatment with pegylated liposomal doxorubicin in metastatic ovarian cancer.
Authors: Irene Moreno Candilejo, Javier Martinez Useros, Cristina Carames Sanchez, Federico Rojo, Ana Isabel Pino Jimenez, Franklin Idrovo, Aurea Borrero Palacios, Victoria Casado, Tatiana Hernandez Guerrero, Andrea Victoria Correa Noguera, Victor Zenzola De Toma, Roberto Hernandez Lopez, Jesus Garcia Foncillas
Journal: Journal of Clinical Oncology (2016)

e17088 Background: Nearly 75 % of ovarian cancer cases are diagnosed in advanced stages. The standard treatment for metastatic ovarian cancer is based on sensitivity to platinum-based chemotherapy. For a disease that has progressed, we can propose different treatment options which includes pegylated liposomal doxorubicin (PLD). These options have been tested in phase III randomized trials, with little response rates and short progression free survival. For that, a big effort is being made for developing biomarkers that could predict which patients would benefit from this type of treatments. Methods: This study was conducted in Fundación Jiménez Díaz Hospital (Spain). It has been selected a series of 43 patients who have been diagnosed of metastatic ovarian cancer from January 2008 to December 2014 and were treated with PLD (in second or third line). After that, the antibody expression of topoisomerase II and antiH2AX were tested by inmunohistochemistry in the patients paraffine embedded biopsies, showing a correlation of high or low expression. Primary endpoint was time to progression to DLP comparing with these two groups subclassified by the expression of the two antibodies tested. Results: During the study period, 43 patients were included, most of them had a good performance status (93% patients), despite they had an advanced stage at diagnosis (stage III/IV: 90%). Among patients who had a low expression of topoisomerase II, time to progression to DLP was statistically significant (p = 0.050) shorter than the high expression group. According to the H2AX expression, there is a strong tendency towards statistical significance (p = 0.99) that correlationates the low expression of this antibody with a shorter progression free survival. Conclusions: DLP is a beneficial treatment for ovarian cancer, especially in partially platinum-sensitive ovarian cancer patients. However, it is necessary to look for predictive factors to DLP treatment for finding the patients with the higher benefit. We have reported in this little restrospective study two possible predictive factors, that can be measure in an easy way and with not too much cost.
A phase II trial of neoadjuvant gemcitabine/nab-paclitaxel and SBRT for potentially resectable pancreas cancer: An evaluation of acute toxicity.
Authors: Manisha Palta, Brian G. Czito, Eileen Duffy, Mary Malicki, Donna Niedzwiecki, James L. Abbruzzese, Hope Elizabeth Uronis, Gerard C. Blobe, Dan G. Blazer, Christopher Willett
Journal: Journal of Clinical Oncology (2018)

4121 Background: The optimal management of potentially resectable pancreas cancer is unknown. The high rates of local and distant failures following surgical resection highlights the need for improvement in both local and systemic therapies. The combination of newer systemic therapies with ablative radiotherapy could be better tolerated and associated with improved treatment outcomes. Methods: Patients with newly diagnosed, previously untreated, non-metastatic pancreatic cancer who were candidates for resection were prospectively enrolled in this single arm study. Patients received a neoadjuvant regimen of 2 cycles of gemcitabine (1000mg/m2)/nab-paclitaxel (125mg/m2) and SBRT (25Gy in 5 fractions). After neoadjuvant treatment patients were restaged and considered for resection. The primary study endpoint was acute toxicity as assessed by CTCAE V 4.0. The primary study hypothesis was that this neoadjuvant regimen would result in Grade 3+ non-hematologic acute toxicity of < 50% (as per RTOG 97-04). Results: Twenty-five patients were accrued to this study. 28% had resectable and 72% had borderline resectable disease (per NCCN criteria). 96% of patients received both cycles of systemic therapy and all 25 patients went on to SBRT and completed the planned radiotherapy course. The rate of acute non-hematologic Grade 3+ toxicity with the neoadjuvant regimen was 20% (5/25). The rate of overall Grade 3+ toxicity with neoadjuvant gemcitabine/nab-paclitaxel was 52% and Grade 3+ non-hematologic toxicity was 17%; exact 80% CI of (8%, 32%). No Grade 3+ acute toxicity was seen with neoadjuvant SBRT and 28% experienced Grade 2 toxicity. 17/25 (68%) patients went on to surgical resection and 93% achieved an R0 resection. Actuarial local control is 77% and medial overall survival is 24 months. Conclusions: A neoadjuvant approach of gemcitabine and nab-paclitaxel followed by SBRT in patients with potentially resectable pancreatic cancer was well tolerated. Given robust patient accrual, the initial enrollment was expanded to 40 patients and accrual is ongoing. Prospective evaluation of this treatment regimen in a randomized fashion is warranted. Clinical trial information: NCT02318095.
Characteristics of growth factors levels in squamous cell carcinoma and adenocarcinoma of the esophagus.
Authors: Elena Mikhaylovna Frantsiyants, Oleg Ivanovich Kit, Evgeniy N. Kolesnikov, Yulia A. Pogorelova, Natalia D. Cheryarina, Mikhail Anatolievich Kozhushko, Stanislav Stanislavovich Mezentsev, M. N. Chernyak
Journal: Journal of Clinical Oncology (2016)

e15511 Background: Two main types of esophageal tumors, squamous cell carcinoma and adenocarcinoma have different etiology and clinical courses. Significant growth of adenocarcinoma morbidity is observed in more economically developed countries; the reason is not clear. Favorable for tumor growth conditions are mediated by excessive production of growth factors. The purpose of the study was to determine levels of factors of angio- and lymphangiogenesis in tissues of malignant esophageal tumor, peritumoral zone and corresponding intact tissue. Methods: Tissues obtained during the surgery from 20 patients with squamous cell carcinoma (SCC) of the esophagus and 9 (G2) with various degrees of keratinization, рTNM stage II, and 9 patients with adenocarcinoma (A) of the esophagus, median age 59.2±4.7 years, were studied. Levels of VEGF-A, VEGFR-1, VEGF-C and VEGFR-3 were studied by ELISA. Results: VEGF-A and VEGFR-1 levels in SCC were escalated in comparison with intact tissue by 5.6 and 6.4 times, respectively, in A – by 6.1 and 3.3 times. The values in peritumoral zone of SCC were increased by 1.6 and 1.8 times, and in A peritumoral zone they did not differ significantly from the corresponding intact tissue. Levels of VEGF-C и VEGFR-3 were increased compared to intact tissue: in SCC by 3.1 and 1.3 times, respectively, and in A by 8.2 and 1.3 times (p < 0.05). Peritumoral zone of SCC did not show significant differences in these values compared to intact tissue, while in A peritumoral zone they were increased by 2.2 and 1.3 times (p < 0.05), respectively. Intact mucosa in SCC and A differed in levels of VEGFR-1 and VEGFR-3 only: the values in A were 1.8 and 1.2 times lower (p < 0.05). Conclusions: Factors of angio- and lymphangiogenesis are activated in tissues of squamous cell carcinoma and adenocarcinoma of the esophagus. Peritumoral zone of squamous cell carcinoma has only VEGF-A and VEGFR-1 angiogenesis factors activated, and peritumoral zone of adenocarcinoma – only VEGF-C and VEGFR-3 lymphangiogenesis factors.
Genomic distinctions between colon and rectal cancer in young patients.
Authors: Joshua E. Meyer, Ilya Serebriiskii, Christopher Hanyoung Lieu, Garrett Michael Frampton, Mark Bailey, Riley Ennis, Aik-Choon Tan, Jihye Kim, Erica Golemis
Journal: Journal of Clinical Oncology (2016)

3574 Background: Rectal cancer is increasing in incidence in young patients, with emerging data demonstrating differences when compared to colon cancer in tumor biology. Additional data demonstrate differences in the genetic basis of colorectal cancer (CRC) based on patient age at diagnosis. This study investigated genomic differences between rectal and colon cancers in the context of patient age. Methods: To determine genomic differences in tumors from younger and older patients with CRC, DNA was extracted from formalin-fixed, paraffin-embedded sections from 4699 cases of CRC, representing 698 cases of rectal cancer and 4001 of colon cancer. Comprehensive genomic profiling was performed on hybridization-captured, adaptor ligation-based libraries to a mean specimen median sequencing depth of 688X for all coding exons and selected introns of up to 403 cancer-related genes. Patients were binned by age. P values were calculated using Fisher’s exact test. Odds ratios were calculated and 95% confidence intervals (95%CI) were calculated using standard methods. Results: FAM123B showed more frequent truncating mutations and deletions in patients under age 40 with rectal cancer as compared to colon cancer (3.7:1 in patients age < 40; p = 0.022). In older age groups this ratio decreased and then reversed (age 40-55: 1.3:1; p = 0.425 age 56-75: 1:1.5; p = 0.136 age > 75: 1:4.3; p = 0.227). Other genes with differential truncation and deletion mutation rates between rectal and colon cancer within age-matched cohorts included SMAD2 (p = 0.031), MLL2 (p = 0.027), ETV6 (p = 0.017), ASXL1 (p = 0.012), and ARID1A (p = 0.057). Gene amplification events were compared between rectal and colon cancers and demonstrated differences in FLT3 (OR = 0.59, 95%CI: 0.39-0.91), JAK2 (OR = 0.12, 95%CI: 0.01-1.06), CD274 (PD-L1) (OR 0.07, 95%CI: 0-0.84), PDCD1LG2 (OR = 0.07, 95%CI: 0-0.84), and PRKC1 (OR = 0.07, 95%CI: 0-0.84). Conclusions: In this analysis, multiple genomic differences were demonstrated between colon and rectal cancers. These lend support to the subdivision of colorectal cancer by anatomic site. These findings also raise possible therapeutic implications of colorectal subsite origin, and warrant further study.
Capecitabine maintenance in high risk loco-regional colorectal cancer.
Authors: Albina Kibirova, Zelia Ramone Karema Bowman, Sidra Najeeb, Rajesh Nair, Shalu Pahuja, Sijin Wen, Hannah Ludwick, Gerald M. Higa, Miklos L Auber
Journal: Journal of Clinical Oncology (2018)

e15695 Background: The outcome for patients with high-risk loco-regional colorectal cancer (CRC) remains unsatisfactory despite the use of adjuvant chemotherapy. Based on the SEER data, the worst survival rates are observed in patients with stage IIC, IIIB and IIIC disease. Maintenance therapy has been shown to improve outcome in metastatic CRC but its role in high-risk loco-regional CRC remains unknown. Methods: We conducted a retrospective study that included patients with stage IIC, IIIB and IIIC CRC, who underwent treatment in our institution from 2009 to 2017. All patients who received capecitabine maintenance after completion of adjuvant chemotherapy were identified among them and compared with control group patients, who were continued on observation only. Relapse-free (RFS) and overall survival (OS) were estimated in both groups using Kaplan-Meier method. Results: We identified 20 patients who received capecitabine maintenance and 43 matched controls. Main findings are presented in the table below. No significant differences were observed between two groups, however the proportion of patient with stage IIIC disease and adverse risk features was higher in capecitabine maintenance group. Median duration of maintenance therapy was 7.6 months (from 4.6 to 53.8 months). Capecitabine was given in a dose of 661.5±147.6 mg/m2 twice daily on an every other week schedule. After a median follow up of 52.7 months, no difference was shown in 5-year RFS and OS between the groups. Conclusions: This study does not demonstrate improved outcome for patients with high risk loco-regional CRC with capecitabine maintenance after completion of standard adjuvant chemotherapy. Further prospective studies are needed to determine the role of maintenance therapy in this setting. Characteristics Control Capecitabine maintenance p-value Number of patients 43 20 - Age 56.3 57.8 0.690 Stage (%): IIC 5 (11.6) 2 (10.0) IIIB 30 (69.8) 11 (55.0) 0.362 IIIC 8 (18.6) 7 (35.0) Right-sided location 10 (23.3) 8 (40.0) 0.285 Number of examined lymph nodes (LN) 20.4 20.4 0.690 Number of LN with metastases 3.1 3.5 0.693 FOLFOX+XELOX adjuvant regimen 31 (72) 13 (65) 0.720 Duration of adjuvant chemotherapy, months 5.8 5.7 0.892 5-year RFS, % 73.1 66.0 0.576 5-year OS, % 88.8 92.3 0.961
Comprehensive gene analysis including next generation sequencing (NGS) study with immunological parameters to obtain the biomarkers for immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC).
Authors: Yuki Owada, Takumi Yamaura, Naoyuki Okabe, Yuki Matsumura, Mitsunori Higuchi, Daisuke Tanaka, Ryo Kanno, Emi Ito, Hideaki Nanamiya, Jun-ichi Imai, Takao Isogai, Shinya Watanabe, Satoshi Waguri, Hiroyuki Suzuki
Journal: Journal of Clinical Oncology (2016)

e20040 Background: ICIs have been widely developing in the field of NSCLC. Several kinds of biomarkers predicting the efficacy of ICIs, such as PD-L1 expression, frequency of tumor infiltrating lymphocytes (TIL), and smoking history, etc. have been analyzed to date. Lately, mutation burden in tumor, presumably involving to neo-antigens in tumor tissue, thought to be more definitive biomarker for ICIs in patients with NSCLC. However, the evidence which shows mutation burden is an obvious biomarker for ICI is still limited and it is very hard to know the mutation burden routinely in clinic. Therefore, we have planned this study to uncover more definitive and easily detecting biomarker by using NGS and by analyzing conventional immunological and molecular parameters. Methods: 94 patients with NSCLC who undergone complete resection in our institution were subjected for this study. Mutation burden in tumor samples was analyzed by whole exome sequencing using NGS. Also the major gene alteration and gene expression including PD-L1 were analyzed. Besides with these gene analyses, TILs and PD-L1 expression in tumor were immunohistochemically assessed, using SP142 as PD-L1 antibody. Results: The median value of mutation burden was 54 genes (15-363). The factors indicating close connection with higher mutation burden is described Table1. Weak but significant correlation between mutation burden and brinkman index (r = 0.468, p = 0.0079) was also found. Conclusions: Mutation burden in tumor was significantly associated with EGFR-mutation status, TP53 alteration, and mRNA of PD-L1. These profiles could potentially be more simple biomarkers in treating ICIs. Relationship between mutation burden and clinical variables or molecular alterations. Mutation burden TP53 · EGFR mRNA · protein of PD- L1 EGFR higher in negative (p = 0.0017) N.S. N.S. TP53 higher in positive (p < 0.01) N.S. N.S. mRNA of PD- L1 higher in negative (p < 0.02) N.S. N.S. protein of PD- L1 N.S. N.S. N.S. TIL N.S. N.S. N.S. Histology higher in SCC (p < 0.02) N.S. N.S. Gendeer higher in male (p < 0.05) N.S. N.S. N.S.: Not Significant, SCC: Squamous cell carcinoma