bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genomic characterization of HBV-infected hepatocellular carcinoma patients using circulating tumor DNA.
Authors: Lin Daniel , Ye Zhong , Wang Chun , Wei Qiang , Bingshan Li , Posey James , Yang Hushan 
Published: February 2020

575 Background: Hepatocellular carcinoma (HCC) is a leading cause of mortality, with Hepatitis B virus (HBV) infection as a dominant etiology. Surgery or ablation may be curative for early-stage HCC. Thus, effective detection strategies are needed. We investigated genomic aberrations in circulating tumor DNA (ctDNA) as a potential diagnostic marker of HCC in HBV-infected patients. Methods: We identified early stage (BCLC 0-A) HCC cases (n = 21) and cancer-free controls (n = 15) from a cohort of Asian patients with HBV, undergoing surveillance at Thomas Jefferson University Hospital between 2013-2017. Blood samples were collected. Circulating cell-free DNA was isolated from plasma and assayed by capture-based next-generation sequencing of a targeted panel of 23 genes implicated in HCC pathogenesis. Sequencing data analysis and somatic mutation identification were conducted using a computational pipeline. Using area under the curve (AUC) in receiver operating characteristic analysis, we evaluated gene alterations and clinical factors (age, gender, cirrhosis) in an exploratory early detection HCC model. Results: Mutant ARID1A, ATM, CDKN2A, CTNNB1, ERBB2, TP53 genes were increased in HCC cases relative to non-cancer patients (85.7% vs 53.3%, P = 0.058; 42.9% vs 6.7%, P = 0.025; 38.1% vs 6.7%, P = 0.051; 42.9% vs 0%, P = 0.005; 52.4% vs 13.3%, P = 0.016; 100% vs 66.7%, P = 0.008, respectively). HCC patients had higher prevalence of cirrhosis than controls (90.5% vs. 60%, P = 0.046). Using the 6 mutant genes alone, the AUC for discriminating HCC from non-cancer patients was 0.827 (95% confidence interval [CI]: 0.701-0.953), which was greater than the AUC for discriminating cirrhosis from non-cirrhosis (0.531). When the 6 mutant genes were combined with clinical factors, the AUC of the exploratory HCC detection model increased to 0.914 ( P= 0.045). Conclusions: We identified 6 genomic aberrations in ctDNA that were more prevalent in HCC patients compared with non-cancer patients. Combining these alterations with clinical factors may identify HCC in HBV-infected patients at an early stage. These findings warrant further validation in future studies.
Gamma-synuclein as a potential novel prognostic marker promoting tumor cell migration in biliary tract carcinoma.
Authors: Takemura Yusuke , Ojima Hidenori , Oshima Go , Shinoda Masahiro , Kitago Minoru , Yagi Hiroshi , Abe Yuta , Hori Shutaro , Nishimura Yoko , Kubota Naoto , Masuda Yuki , Hibi Taizo , Sakamoto Michiie , Kitagawa Yuko 
Published: February 2020

577 Background: Biliary tract carcinoma (BTC) is a highly malignant tumor, but the detailed pathological mechanism of its development and progression remain ill-defined. Gamma-synuclein (SNCG) promotes invasive behavior in pancreatic cancer and a range of other cancers, and SNCG expression is reportedly a prognostic factor. However, the role of SNCG in BTC remains unknown. Consequently, we investigated the clinicopathological significance and function of SNCG in BTC. Methods: Using surgically resected BTC specimens from 149 patients with adenocarcinoma [extrahepatic cholangiocarcinoma (ECC) (n =98); intrahepatic cholangiocarcinoma (ICC) (n =51)], we immunohistochemically evaluated SNCG positivity and checked for correlations with clinicopathological factors and outcomes. Furthermore, cell lines with high expressions of SNCG were selected from 17 BTC cell lines by using immunohistochemistry and qPCR. Cell proliferation and migration assays were then performed in the presence and absence of SNCG (silenced using). Results: SNCG expression was found in 32 of 149 (21.4%) BTC patients. SNCG expression was significantly correlated with poorly differentiated tumor ( P = 0.001) and lymph node metastases ( P = 0.001). SNCG positivity was also correlated with poorly differentiated tumor in both ECC and ICC ( P = 0.008 and P = 0.03, respectively), but was correlated with lymph node metastases only in ECC ( P = 0.003). Multivariate analyses identified SNCG expression as an independent prognostic factor of poor overall survival ( P = 0.008) and poor recurrence-free survival (RFS) ( P = 0.006). SNCG expression in both ECC and ICC was significantly associated with poor prognosis in univariate analysis, and multivariate analysis identified SNCG as an independent prognostic factor of poor RFS for ECC (P = 0.03). High SNCG expression was found in 3 BTC cell lines (NCC-BD1, NCC-BD3, and NCC-CC6-1). Functional analysis revealed that SNCG silencing by siRNA suppressed cell migration significantly in NCC-BD1 and NCC-CC6-1 and downregulated cell proliferation in NCC-CC6-1. Conclusions: Our results suggest that SNCG may promote tumor cell activity and is potentially a novel prognostic marker in BTC.
Circulating free DNA (cfDNA) and tissue next-generation sequencing analysis in a phase II study of infigratinib (BGJ398) for cholangiocarcinoma with FGFR2 fusions.
Authors: Makawita Shalini , Kelley Robin Kate , Roychowdhury Sameek , Weiss Karl Heinz , Abou-Alfa Ghassan K. , Macarulla Teresa , Sadeghi Saeed , Waldschmidt Dirk , Zhu Andrew X. , Goyal Lipika , Yong Wei-Peng , Borbath Ivan , El-Khoueiry Anthony B. , Philip Philip Agop , Moran Susan , Ye Yining , Soifer Harris S. , Li Gary , Berman Craig , Javle Milind M. 
Published: February 2020

579 Background: Fibroblast growth factor receptor 2 (FGFR2) alterations occur in 11% of cholangiocarcinomas, 85% of which are fusions. A multicenter, open-label, phase II study is currently evaluating the efficacy of infigratinib, a selective FGFR1–3 tyrosine kinase inhibitor, in patients with previously treated advanced cholangiocarcinoma containing FGFR2 fusions. We report detailed biomarker analyses from this study. Methods: Patients with advanced or metastatic cholangiocarcinoma containing FGFR2 fusions whose disease had progressed following cisplatin- or gemcitabine-based therapy were eligible. Patients received oral infigratinib 125 mg once daily on days 1–21 every 28 days. Comprehensive genomic profiling (CGP) was performed on tumor tissue and cfDNA collected prior to the start of therapy. The primary endpoint was investigator-assessed overall response rate (ORR) [RECIST version 1.1]. Data cut-off (prespecified): August 8, 2018. Trial registration: NCT02150967. Results: At data cut-off, 71 patients with FGFR2 fusions were included (62% women; median age 53 years; 55% received ≥2 prior lines of therapy). Median duration of treatment was 5.5 months. ORR (confirmed and unconfirmed) was 31.0% (95% CI 20.5–43.1%) and confirmed ORR was 26.9% (95% CI 16.8–39.1%). 33 unique FGFR2 fusion genes were identified in 71 enrolled patients. The most common fusion gene partner was BICC1 (32%; 23/71). Pathogenic variants in 9 other druggable genes were identified in 32% of patients (13/37) who underwent CGP. FGFR2 fusions were concordant in 67% (8/12) of patients with tumor tissue and cfDNA at screening. Conclusions: The large assortment of FGFR2 fusion genes identified in this study underscores the diversity of FGFR2 rearrangements that may drive cholangiocarcinoma. Although cfDNA analysis was performed in a minority, these preliminary data suggest that cfDNA analysis may be valuable for the identification of FGFR2 fusions and to study intratumoral heterogeneity. Clinical trial information: NCT02150967.
Comparison of the clinical features, treatment patterns, and tumor mutations of patients with intrahepatic (ICC) and extrahepatic (ECC) cholangiocarcinoma.
Authors: Pappas Leon , Reyes Stephanie , Lanka Aishwarya , Shroff Rachna T. , Le Tri Minh , Rahma Osama E. , Bocobo Andrea Grace , Borad Mitesh J. , DeLeon Thomas , Mody Kabir , Roth Marc Thomas , Peters Mary Linton Bounetheau , Goff Laura Williams , Boyhen Kylie , VanCott Christine , Horick Nora , Zhu Andrew X. , Javle Milind M. , Kelley Robin Kate , Goyal Lipika 
Published: February 2020

580 Background: Though studies indicate that the genomic profiles of ICC and ECC are distinct, the clinical features that differentiate them still remain to be well characterized. The purpose of this study was to further analyze these differences and patient treatment patterns in a multi-center cohort. Methods: A retrospective chart review was performed at 8 institutions on patients (pts) with ICC or ECC diagnosed after June 2009. Data on demographics, risk factors, treatments, pathology and overall survival (OS) were collected. Tumor genotyping results from CLIA-certified tissue assays were analyzed. Fisher’s exact, Wilcoxon rank sum and log-rank tests were used to compare sub-groups. Results: In a database of 737 pts with cholangiocarcinoma, 538(73%) had ICC and 199(27%) had ECC. Pts with ICC more often presented in later stages, had tumors > 5cm at resection (p < 0.0001) and had metastases to the liver, lymph nodes, lung and/or bone (p < 0.01). Pts with ICC more often received liver directed therapy, targeted therapy and multiple lines of systemic therapy and they more often enrolled in a clinical trial (all p < 0.01). Pts with ECC were more likely to be male, undergo surgery, receive adjuvant chemotherapy and/or chemoradiation (all p < 0.05). Mutation profiling performed in 381 (52%) pts (ICC/ECC = 301/80) showed that pts with ICC were more likely to have IDH1 mutations and FGFR2 fusions, whereas pts with ECC were more likely to have KRAS, APC, SMAD4, WNT, TGFb and TP53 mutations (all < 0.05). Factors that did not differ significantly between pts with ICC and ECC include race, rates of primary sclerosing cholangitis, median diagnosis CA19-9 levels and R1 resection rate. Median OS from diagnosis was 18.9 months in ICC and 17.3 months in ECC (p = 0.8471). Conclusions: While pts with ICC and ECC have some similarities in their clinical features, differences in metastases patterns and molecular profiling significantly impact their management such that pts with ICC receive more liver-directed therapy, targeted therapy and more lines of systemic therapy. Further prospective studies are needed as referral patterns to tertiary care centers may have impacted these results.
Patient-derived organoids for personalized drug screening in intrahepatic cholangiocarcinoma.
Authors: Antonia Ricardo J. , Toriguchi Kan , Karelehto Eveliina , Annuar Dania , Timmerman Luika , Tbeileh Noura , Mattis Aras N. , Corvera Carlos U. , Hirose Kenzo , Nakakura Eric K. , Donner David B. , Warren Robert S. 
Published: February 2020

581 Background: Despite standard treatment with gemcitabine and cisplatin, median survival for unresectable Intrahepatic Cholangiocarcinoma (ICC) is < 1 year. Clearly, novel therapeutic strategies are urgently needed. The paucity of targetable mutations in ICC and the as yet unproven benefit of genetically targeted drugs led us to ask whether a reliable clinical benefit may be revealed by patient-specific therapeutic testing in novel models of ICC. Here we describe our ability to establish patient-derived three-dimensional organoid cultures (PDO) that enable individualized identification of active single agents or drug combinations in surrogate models of ICC. Methods: To model patient-specific drug responses, we used the freshly resected ICCs from small samples of single patient tumors to generate PDXs and PDOs, small spheroidal clusters of tumor cells grown in vitro. We have employed a high-throughput drug screening platform using AI-enhanced robotics (Yamaha Motor Corporation) to identify and distribute single, uniformly sized PDOs into 384-well ultra-low adherent plates. This is coupled with a TECAN D300e drug dispenser that rapidly delivers nanoliter volumes of a 34-drug panel, thereby facilitating rapid, reliable drug response analyses. Results: Our data show that PDOs retain characteristic genomic and histological features of the patients’ tumors. Drug responses were specific to each patient tumor, but PDOs from all patients responded to a greater or lesser degree to mTOR inhibition, suggesting that this pathway is important in ICC. The responses of PDO to the mTOR inhibitor Sapanisertib (INK128), was recapitulated in the same patient’s PDX. Further, INK128 was synergistic with gemcitabine in patient 970 PDOs as well as in vivo in PDX also from patient 970. Conclusions: As it is believed that PDX can predict patient responses to drugs, our results suggest that PDO may also predict patient drug responses. The establishment of PDO may allow economical patient-specific, high throughput drug screens that could ultimately inform clinical practice. [Table: see text]
Association of objective response by mRECIST with better overall survival (OS) in patients with advanced hepatocellular carcinoma (HCC) treated with systemic therapies: A systematic review and meta-analysis of randomized controlled trials.
Authors: Kudo Masatoshi , Chiba Yasutaka , Meyer Tim , Lencioni Riccardo , Llovet Josep M. 
Published: February 2020

586 Background: EASL guidelines for management of HCC recommends assessing tumor response according to mRECIST at all stages of the disease (EASL guidelines, J Hep 2018). Several studies have reported that objective response by mRECIST predicted overall survival (OS) but definitive data are still lacking. Methods: The PubMed database and ASCO meeting library were searched for full reports of randomized trials in patients with advanced HCC treated by systemic therapy up to August 31, 2018. We search strategy used the following terms: HCC, mRECIST, OS and objective response rate (ORR). We assess the association between ORR and OS in a meta-analysis of pooled data by using random effects model comparing patients achieving objective response (complete or partial response) versus non responders (stable disease, progressive disease) and displayed the results as per hazard ratio (HR, 95% CI). Results: Among 14 articles assessing response by mRECIST to systemic therapies in randomized studies in advanced HCC, 4 studies (5 trials) including 1,463 patients were considered eligible. Systemic therapies tested included lenvatinib, sorafenib, brivanib and nintedanib. Overall, ORR as per mRECIST ranged from 11.5% to 18.8%, being the median OS for responders of 18.5 to 27.2 mo (as opposed 8.9 to 11.4 for non-responders). As per random effects model, the HR for overall survival (responders versus non responders) was 0.47 (95% confidence interval 0.34–0.66, p<0.001). Conclusions: Objective response by mRECIST to systemic therapies in patients with advanced HCC is significantly and strongly associated to OS. Patients achieving an objective response can expect a significantly longer OS.
Nationwide survey of pancreaticobiliary maljunction focusing on biliary cancer incidence in Japan.
Authors: Shimada Mitsuo , Ishibashi Hiroki , Morine Yuji , Kubota Masayuki , Fujii Hideki ,   Japanese Study Group on Pancreaticobiliary Maljunction
Published: February 2020

587 Background: Pancreaticobiliary maljunction (PBM) is known to be a unique entity closely related to biliary carcinogenesis. We herein report update analysis of PBM focusing on biliary cancer as third report of Japan-nationwide survey. Methods: From 1990 to 2015, 3,419 patients with PBM were registered at 141 medical institutions in Japan. 3,289 (1,344 pediatric and 1,945 adult patients) out of 3,419 patients were fully investigated, according to presence of bile duct dilatation (BDD), age (pediatric or adult), etc. Results: In pediatric patients, only 3 cases with BDD (0.124%) had bile duct cancers. On the other hand, in adults, biliary cancer incidence was 21.1% in patients with BDD and 43.5% in patients without BDD. The rates were extremely high in comparison with 0.0174% of Japanese prevalence of biliary cancer 2013. The cancer incidences of bile duct, gallbladder and both in adults with BDD/without BDD were 6.7%/4.1%, 13.0%/37.3%, and 1.4%/2.1%, respectively. In patients without associated biliary cancers, extrahepatic bile duct resection (EHBDRx) combined with cholecystectomy was performed in 89.5% of adults with BDD, while, in only 31.2% adults without BDD. Regarding the new biliary cancer occurrence of patients having follow-up data, the rate was 0.3% in 354 patients with BDD who underwent EHBDRx, while that was 4.0% in 75 patients without BDD who underwent simple cholecystectomy. In patients without BDD, cancer incidence (6.7%) in the late period (2010 to 2015) was higher than those (3.3% and 3.5%) in early and middle period (1990 to 1999, and 2000 to 2009). Conclusions: This updated nationwide survey of PBM revealed characteristics of associated and newly occurred biliary cancers, and could be widely used as a reference data for diagnosis and treatment of PBM.
Significance of frailty in prognosis after hepatectomy in older patients with hepatocellular carcinoma.
Authors: Yamada Shinichiro , Shimada Mitsuo , Morine Yuji , Imura Satoru , Ikemoto Tetsuya , Arakawa Yusuke , Saito Yu , Yoshikawa Masato , Miyazaki Katsuki 
Published: February 2020

590 Background: An aging society has come, and “Frailty” is becoming increasingly important in surgery. Recently, clinical frail scale (CFS), which is simple criteria for frailty, has been reported to be useful for prognostic prediction of non-cardiac surgery (Ann Surg. 2018). Herein we report a new knowledge about frailty for patients with hepatocellular carcinoma (HCC) undergoing hepatectomy. Methods: Eighty-one patients over 75 years who underwent hepatectomy for HCC between 2007 and 2018 were enrolled in this study. Frailty was diagnosed as CFS≥4, and patient were divided into 2 groups, frailty (n = 17) and no frailty (n = 64). Clinicopathological factors were compared between 2 groups. Results: Patients’ background, such as age, gender, preoperative comorbidity, and liver function showed no significant difference between 2 groups. Regarding tumor factors, frailty group showed significant larger tumor diameter, more advanced stage (p < 0.05) and tendency of high PIVKA-II (p = 0.15) compared with no frailty group. Frailty group showed significant high CRP level (p < 0.01), high modified Glasgow prognostic score (mGPS, p = 0.04) and tendency of high neutrophil-lymphocyte ratio (NLR, p = 0.14). Frailty group also showed tendency of higher rate of postoperative complication (p = 0.11) and longer postoperative hospital stay (p = 0.09). Overall and disease-free survival rate were significantly worse in frailty group (p = 0.03). In univariate analysis for overall survival, AFP≥10, PIVKA-II≥400, frailty and mGPS high (1, 2) were prognostic factor. Multivariate analysis revealed that frailty was independent prognostic factor. In univariate analysis of disease-free survival, only frailty was detected as prognostic factor. Conclusions: Frailty is an independent prognostic factor for HCC patients who underwent hepatectomy.
Receipt and survival outcomes by age following second-line therapy for metastatic CRC (mCRC): Analysis of 5,289 patients from the ARCAD Clinical Trials Program.
Authors: McCleary Nadine Jackson , Harmsen William S. , VanCutsem Eric , Sobrero Alberto F. , Goldberg Richard M. , Tabernero Josep , Seymour Matt , Saltz Leonard B. , Giantonio Bruce J. , Dirk Arnold , Rothenberg Mace L. , Koopman Miriam , Schmoll Hans-Joachim hans-joachim , Pitot Henry C. , Hoff Paulo Marcelo , Falcone Alfredo , De Gramont Aimery , Shi Qian , Lichtman Stuart M. 
Published: February 2020

6 Background: Rates and survival outcomes for second-line therapy for mCRC for OA vs. YA are poorly understood. Methods: Pts with available subsequent treatment data after progression from 10 1st line trials were included. Associations between key clinical/disease characteristics, time to initial progression (TTiP) and rate of receipt of second-line therapy were evaluated. Time to progression (TTP) and overall survival (OS) were compared between OA and YA who were enrolled on second-line trials by Cox regression, adjusting for age, sex, ECOG PS, number of metastatic sites, presence of metastasis in lung/liver/peritoneum. Results: OA comprised 16.4% of first-line trials. OA and ECOG PS >0 were less likely to receive second-line therapy than YA. Odds of receiving second-line therapy decreased by 11% for each additional decade of life in multivariate analysis (p=0.0117). OA enrolled in second-line trials experience similar mTTP and mOS as YA (5.1 vs. 5.2mos; 11.6 vs 12.4mos, respectively). Conclusions: OA are less likely to receive 2nd line therapy for mCRC. We did not observe a statistical difference in survival outcomes for OA vs. YA following second-line therapy. Further study is needed to examine unmeasured factors, including comorbidity and functional status given observed inferior outcomes among adults with ECOG PS >0, and consideration given to inclusion of geriatric assessment to select OA likely to benefit from 2nd line therapy for mCRC. [Table: see text]
Do socioeconomic factors really have an impact on early detection of hepatocellular carcinoma and colorectal cancer?
Authors: Albawaliz Anas , Zafar Yousaf , Kaur Anahat , Madhusudhana Sheshadri , Shrestha Anuj 
Published: February 2020

60 Background: Improving surveillance in hepatocellular carcinoma (HCC) and colorectal cancer (CRC) is an important topic in the field of gastroenterology and oncology due to significant benefit associated with early detection and better outcomes. Multiple studies have been undertaken to assess the association between the socioeconomic status of the population and adherence to HCC/CRC screening. Most of these studies used self-reporting surveys and faced limitations due to reporting bias. We aimed to assess the relevance of socioeconomic factors in the diagnosis of HCC and CRC in Jackson County, Missouri by means of a census-based survey. Methods: We retrospectively studied 190 HCC and 690 CRC cases at our institution using a census-based analysis, which consisted of geocoding home addresses of patients and then attaching block level census variables for household occupancy, education level and household income. Statistical analysis was performed using Cox proportional hazard model and ordinal logistic regressions. Results: We did not find a statistically significant association between socioeconomic factors and adherence to surveillance guidelines for HCC and CRC. USPSTF-2019 guidelines for CRC and AASLD-2018 guidelines for HCC screening were taken into account. Variables that were analyzed included high school education or better (p = 0.5), four-person households with one or more workers (p = 0.08) and income less than 25 thousand dollars (p = 0.58). Study results were risk adjusted for age, race, and gender. Separate ordinal logistic regression analysis was done to also adjust for the stage at the time of eventual cancer diagnosis, no statistically significant result was obtained. Conclusions: Our study showed no association between demographic variables and participation in HCC or CRC surveillance. The study is limited by a relatively small sample size confined to local patients seen at our institution. Multicenter census-based surveys and meta-analyses need to be conducted to determine whether socioeconomic factors really have an appreciable impact on early screening and detection of HCC and CRC.