bluuebunny/crossref_metadata_2025_split huggingface dataset:
A novel subpopulation of circulating tumor cells in patients with cholangiocarcinoma.
Authors: Reduzzi Carolina , Vismara Marta , Silvestri Marco , Celio Luigi , Raimondi Alessandra , Torchio Martina , Pusceddu Sara , Niger Monica , Peverelli Giorgia , De Braud Filippo G. , Daidone Maria Grazia , Cappelletti Vera 
Published: May 2019

e15637 Background: In cholangiocarcinoma (CCA), molecular analysis during disease progression is rarely feasible due to low access to tissue. Circulating tumor cells (CTCs) could overcome this issue. Data on CTCs in CCA are presently insufficient to promote their use in clinical management due to their low detection rates. Improved methods to capture all CTC subpopulation are therefore needed. Methods: Peripheral blood (PB) was longitudinally collected from patients with metastatic/unresectable CCA (intrahepatic, extrahepatic and gallbladder). CTCs were enriched from PB (10mL) with Parsortix, labeled for epithelial and leukocyte markers, and analyzed in the DEPArray to collect i) single CTCs positive for epithelial markers (eCTC) and ii) single double negative cells (DNC) lacking epithelial and leukocyte markers. DNCs underwent WGA and low-pass WGS to detect copy number alterations. DNCs with aberrant genotype were defined as non-conventional CTCs (ncCTCs). Results: Forty-one blood samples were collected from 21 patients receiving gemcitabine and/or platinum-based regimens. We detected 18 eCTCs and 73 ncCTCs, respectively in 8/41 (19%, median number = 1.5, range 1-5) and 31/41 (76%, median number = 2, range 1-7) samples. By considering also ncCTCs, CTC-positivity increased by 4.4-fold (83% of CTC+ samples). All untreated patients were CTC+, and CTC- samples (n = 7) were collected only on-treatment. In 18 patients, the detection of eCTCs ( ≥1eCTC/10mL blood) at baseline was associated with a shorter overall survival than in eCTC- patients (7.0 vs 19 months, p = 0.03). CTC count fluctuations during treatment mirrored patient response. Indeed, in responding patients CTCs were not detectable. In some patients, CTC counts were more informative on treatment outcome than imaging and Ca19.9 levels. Conclusions: We developed a new single-cell protocol to detect two distinct CTC subpopulations (eCTC and ncCTC) in patients with CCA. Baseline eCTCs detected by our method inform prognosis whereas ncCTCs provide hints on treatment response. The possibility to collect and molecularly characterize CTC from all patients with our protocol, opens the way to future treatment planning based on CTC molecular asset.
Mutation profiles in circulating tumor DNA (ctDNA) to predict the efficacy of sorafenib treatment in patients with advanced hepatocellular carcinoma (HCC).
Authors: Yang Ping , Ji Guanghui , Jiang Qionghui , Lu Zejun , Yu Yao , Yang Yadong , Jin Ge 
Published: May 2019

e15648 Background: To find biomarkers from blood samples through ctDNA and leucocyte genomic DNA sequencing to predict the efficacy of sorafenib. Methods: CtDNA and leucocyte genomic DNA were extracted from patients with advanced hepatocellular carcinoma for sequencing analysis before and after targeted therapy with sorafenib. Mutation profiles were obtained by deep sequencing of 620 selected genes for further bioinformatics analysis. Gene mutation frequency and status were further integrated with clinical data to dynamically monitor and predict the efficacy of sorafenib. Results: Twelve patients with advanced hepatocellular carcinoma admitted to our hospital from March 2017 to September 2018 were enrolled. A total of 27 blood samples were collected for further analysis. The results showed that there were significant differences in BRD4 and FANCG gene mutation abundance between therapeutic effect group and poor effect group (p = 0.014). The mutations of BRD4, FANCG and TP53 were associated with shorter PFS (BRD4 mutation type vs wild type: 12 weeks vs 32 weeks, p = 0.0011; FANCG mutation type vs wild type: 16 weeks vs 32 weeks, p = 0.0103; TP53 mutation type vs wild type: 8 weeks vs 32 weeks, p = 0.0095). Furthermore, we found another 19 genes (SDHA, OTUD7A, TMPRSS2, NAV3, AKT1, EIF2S2, DICER1, MAP3K1, RAD9A, TCF3, IRS1, PIK3C2G, CTCF, TSHZ2, ITPKB, KDM5C, STAG2, AMER1, CDC27) associated with therapeutic efficacy, and dynamic changes of these 19 genes mutation alleys could predict therapeutic efficacy. Conclusions: Our results showed that mutations in ctDNA could predict the efficacy and prognosis of sorafenib for advanced hepatocellular carcinoma, and that dynamic monitoring of mutation frequency in ctDNA of peripheral blood samples could be an additional method to monitor therapeutic efficacy of sorafenib. The clinical significance of the mutations of BRD4, FANCG, TP53 and another 19 genes we found needs to be confirmed on a larger scale.
Chromosome 8q24 amplification predicts prognosis for patients with advanced hepatocellular carcinoma (HCC).
Authors: Cheng Yuan , Huang Mengli , Xie Wenzhuan , Gao Chan , Cai Shangli , Ji Jing , Pan Mingxin 
Published: May 2019

e15654 Background: China accounts for over 50% of global liver cancer burden and most patients have advanced disease at the time of diagnosis. Currently, very little is known about the mutational landscape of Chinese HCC patients because it is risky to perform tissue biopsy on late-stage patients. In this study, this problem was overcome by genetic profiling using circulating tumor DNA (ctDNA) and frequently mutated loci were evaluated as biomarkers for prognosis prediction. Methods: Targeted next generation sequencing (NGS) was performed on ctDNA obtained from patients with advanced HCC using a 150-gene panel. The relationship between overall survival (OS) and genetic alterations was analyzed using Kaplan-Meier method. The predictive value of frequently mutated genes was then validated using 607 western HCC cases of the cBioPortal (http://www.cbioportal.org,including TCGA and other two studies). Impact of 8q24 amplification on transcription of other genes was analyzed using mRNA data from TCGA database. Results: Fifty-eight Chinese advanced HCC patients were enrolled and ctDNA was detected in 89.7% of them. The most frequently mutated genes were TP53 (57.7%) and TERT (30.8%) and amplification of chromosome 8q24 occurred at a higher frequency (20.0%) than previously reported for western HCC patients. The 8q24 amplified patients showed significantly shorter OS compared to those without 8q24 amplification (4.9 months vs. Not Reached, p = 0.008). This was confirmed by the cBioPortal database, where 8q24 amplification, which was identified in 10.1% of the HCC cases, was also associated with decreased OS (55.6 months vs.102.7 months, p < 0.001). Gene expression analysis using TCGA mRNA data revealed that upon 8q24 amplification, transcription of 56 genes was upregulated and 169 genes were downregulated, among which ABC transporters, RAS signaling and Hippo signaling pathways were significantly enriched in 8q24 amplified population (p = 0.001, 0.015, 0.027, respectively) as suggested by KEGG analysis. Conclusions: Amplification of chromosome 8q24 ocurred at a higher frequency in Chinese HCC patients and showed promise as a biomarker for prognosis prediction.
Impact on gemcitabine plus cisplatin in unresectable hilar cholangiocarcinoma patients according to effective biliary drainage: A multicenter study.
Authors: Kang Jingu , Lee Jong-Chan , Kim Min Jae , Yang Se Yeol , Woo Sang Myung , Jung Jae Hyup , Hwang Jin-Hyeok 
Published: May 2019

e15658 Background: Hilar cholangiocarcinoma (HC) is known to have a poor prognosis due to cholangitis and lack of effective chemotherapeutic regimen. Since 2010, gemcitabine plus cisplatin (GP) is recommended as first-line chemotherapy in cholangiocarcinoma. However, it is still unclear whether GP is effective on HC. We aimed to evaluate the impact on GP in unresectable HC patients according to effective biliary drainage (EBD). Methods: From 2010 to 2016, 112 patients with unresectable HC confirmed by biopsy at three tertiary referral hospitals in Korea were enrolled. 38 patients received GP [cisplatin (25 mg per square meter of body-surface area) followed by gemcitabine (1000 mg per square meter), each administered on days 1 and 8, every 3 weeks]. 74 patients received best supportive care (BSC). The EBD group was defined as a total bilirubin decrease of less than 2 mg/dl within 2 weeks after the first drainage procedure or 50% reduction than pre-procedure total bilirubin. Overall survival (OS) was evaluated in GP group and BSC group according to EBD achieved using the Kaplan–Meier survival curve and the log-rank test. Results: When compared with the BSC group (n = 74), the GP group (n = 38) obtained a benefit in OS (median OS, 6.14 vs 12.7 months, p < 0.001). Moreover, patients with EBD experienced significantly longer OS compared with ineffective biliary drainage (IEBD) patients (median OS, 8.03 vs 5.01 months, p < 0.005). GP chemotherapy was beneficial for OS in IEBD group (p < 0.001) as well as in EBD group (p < 0.005). In the multivariate analysis, GP chemotherapy (HR 0.33, 95% CI 0.21–0.52, p < 0.001), EBD (HR 0.60, 95% CI 0.40–0.91, p < 0.001) and 2 more metastatic site (HR 3.21, 95% CI 1.66–6.18, p < 0.001) were significant prognostic factors. Conclusions: GP chemotherapy provides longer survival in HC, regardless of effective or ineffective biliary drainage.
Integrated multi-omic analysis to reveal comprehensive tumor heterogeneity and novel immunophenotypic classification in primary liver cancer.
Authors: Zhang Qi , Lou Yu , Bai Xueli , Liang Tingbo 
Published: May 2019

e15662 Background: Hepatocellular carcinoma (HCC) is heterogeneous,especially in multifocal tumors, which decreases the efficacy of clinical treatments. Understanding tumor heterogeneity is critical when developingnovel treatment strategies. However, a comprehensive investigation of tumor heterogeneity in HCC is lacking, and the available evidence regarding tumor heterogeneity has not ledto improvements inclinical practice. Methods: We harvested 42 samples from eight HCC patients and evaluatedtumor heterogeneity using whole-exome sequencing, RNA sequencing, mass spectrometry-based proteomics and metabolomics, cytometry by time-of-flight, and single-cell analysis. Immunohistochemistry and quantitative polymerase chain reactions (qPCRs) were performed to confirm the expression levels of genes. Results: Tumor heterogeneity is considerable with regard to the genomes, transcriptomes, proteomes, and metabolomes of lesions and tumors. The immune status oftheHCC microenvironment had a relatively low level of heterogeneity. Targeting local immunity could be a suitable intervention with balanced precision and practicability. By clustering immune cells in the HCC microenvironment, we identified three distinctive HCC subtypes with immunocompetent, immunodeficient, and immunosuppressive features. We further revealed the specific metabolic features and cytokine/chemokine expression levels of the different subtypes. Determiningthe expression levels of PTPRCand FOXP3using qPCR and immunohistochemistry in two independent HCC cohorts facilitated the correct classification of HCC patients and the prediction of their prognosis. Conclusions: There is comprehensive intratumoral and intertumoral heterogeneity inall dimensions ofHCC. Based on the results, we propose a novel immunophenotypic classification of HCCs that facilitates prognostic prediction and may support decision making with regard to the choice of therapy.
A retrospective analysis of clinical outcomes among patients with infiltrative hepatocellular carcinoma (iHCC): A single institution study.
Authors: Hannan Lindsay Marie , Chiorean E. Gabriela , Cohen Stacey , Coveler Andrew L. , Shankaran Veena , Wong Kit Man , Mieloszyk Rebecca , Johnson Guy E , Park James Oh , Bhargava Puneet , Harris William Proctor 
Published: May 2019

e15667 Background: iHCC is an aggressive disease with poorly characterized treatment outcomes. We sought to describe clinical and radiographic features of iHCC, describe overall survival (OS), and compare outcomes of sorafenib (SOR) use with a cohort of non-infiltrative hepatocellular carcinoma (niHCC) patients. Methods: Radiology reports from the University of Washington with an Li-RADS (LR) assignment, 2013-2017, were reviewed (5037 reports, 1954 patients (pts)) for terms indicative of iHCC. Results: : 102 cases were identified, with 43% arising from known niHCC. iHCC size is difficult to measure but when reported, median was 8cm (interquartile range 5-10cm). Other radiographic features: vascular invasion 72%, R lobe only 62%. Clinical data were obtained via medical record review. The cohort was primarily male (83%), White (65%), age > 55 (88%), HCV (74.5%), heavy alcohol use (67%). At diagnosis: BCLC stage C (76%), ALBI grade 2 (62%) and 3 (21%). Median OS after diagnosis was 5.7 months (m). 38 (37%) pts were too ill to receive therapy. OS for de novo iHCC and for iHCC arising from niHCC did not differ (7.5m vs 5.1m, p = NS). All niHCC pts who received SOR in any line of therapy were identified among pts with a LR 5 lesion in at least one of the aforementioned radiology reports, 2013-2017. Pts who received SOR on trial and/or combined with another agent were excluded. Clinical data for the 83 niHCC pts were abstracted and compared to the 25 iHCC pts who received SOR, any line of therapy. Based on χ2 analyses, the 2 groups did not differ by age, sex, race, BCLC stage at SOR initiation, ECOG status at SOR initiation, HCC etiology, ALBI grade at SOR initiation, or previous locoregional therapy. OS after initiation of SOR was 14.1m for niHCC, 10.5m for iHCC, p = NS. PFS after SOR was 3.7m for niHCC, 7m for iHCC, p = NS. AFP at the time of SOR initiation was higher in iHCC than niHCC (median 1331 vs 48, respectively, p = 0.004), with median %AFP change after 30 days -13% in iHCC and +6% in niHCC, p = NS. Decrease in AFP after 30 days of therapy was associated with improved OS among niHCC (21m versus 7m, p = 0.001) but not among iHCC pts (p = NS). Conclusions: iHCC is a poorly understood subset of HCC with underlying biology not well defined. Compared to niHCC, clinical outcomes with sorafenib do not appear to differ in this cohort. Future characterization of outcomes with Y-90 and immune checkpoint inhibitors is warranted.
Nivolumab for hepatocellular carcinoma (HCC) in a real-world context.
Authors: Rao Nisha , Rizk Emanuelle M. , Hwang Regina , Gartrell Robyn Denise , Makkar Jasnit , Oza Jay , Najjar Marc , Emond Jean , Fox Alyson , Verna Elizabeth , Brejt Sidney , Reis Stephen , Sheynzon Vladimir , Sperling David , Weintraub Joshua , Saenger Yvonne M. 
Published: May 2019

e15675 Background: Novel immunotherapies may be effective in patients with HCC; however, patients with advanced liver disease are often excluded from clinical trials. The goal of our study was to evaluate the safety and efficacy of nivolumab for HCC in a real-world context, including among patients with advanced liver disease. Methods: We examined all cases of HCC initiated on off-study nivolumab alone or in combination with locoregional therapy at our institution from 2/2017 to 7/2018. Our sample included 14 patients. We report participant demographics, baseline liver function, treatment toxicity, and overall survival (OS). Results: The majority of participants were male (71%) and Caucasian (57%). NAFLD (36%) and HCV (43%) were the most frequently cited risk factors for HCC. Patients had variable liver disease at baseline, with 36% Child-Turcotte-Pugh (CTP) A, 36% CTP B, and 21% CTP C disease. Patients received either nivolumab only (50%), or nivolumab with locoregional therapy (LRT) (50%). All patients with CTP C disease received nivolumab alone. Treatment was generally safe, with only grade 1 or 2 toxicities reported, most commonly fatigue. Median OS was 7 months. Of note, one patient with baseline CTP C disease showed complete response to nivolumab treatment but experienced recurrence off nivolumab. Conclusions: Our study is the first to report the use of nivolumab in patients with HCC and CTP C disease. Nivolumab was well-tolerated in a real-world context in this small patient cohort, including among patients with advanced cirrhosis. Further study in larger patient populations is warranted. [Table: see text]
Molecular differences between AFP-negative and AFP-positive hepatocellular carcinoma.
Authors: Ling Wu yu , Li Lifeng , Chen Shifu 
Published: May 2019

e15681 Background: Alpha-fetoprotein (AFP) is a major biomarker for diagnosis of hepatocellular carcinoma (HCC). Screening of molecular differences between AFP-negative and AFP-positive HCC can be helpful for its diagnosis. Methods: Genomic mutations, gene expressions and clinicopathological data of 270 HCC patients were collected from TCGA database. According to preoperative AFP level, patients were categorized into AFP- (0-20ng/mL, n = 112) and AFP+ ( > 20 ng/mL, n = 158) groups. We identified significantly mutated genes and differentially expressed genes (DEGs) between the two groups and analyzed their correlation with prognosis. Results: The 1-, 3-, and 5-year overall survival (OS) rates were 91.5%, 76.3%, and 67.9% in AFP- and 84.3%, 62.5%, and 34.2% in AFP+. The difference was statistically significant (p = 0.0053). To identify AFP-biased mutation genes, we focused on highly mutated genes in each group (≥5% mutation frequency). At FDR = 0.05, we identified 11 AFP-biased genes: CTNNB1, VWA5B2, HERC2, ZFYVE26, SPEN, MUC6, DST, WDR87, DNAH1, PTPN13, and FANCM. The most striking gene identified was CTNNB1, which is a WNT pathway oncogene. CTNNB1 was more frequently mutated in AFP- than in AFP+ (35.8% vs. 17.0%, p = 0.00059). The OS for HCC was calculated on the basis of the mutation of each gene, which showed that MUC6 mutation was negatively associated with OS (p = 0.018), while other ten genes showed no obvious difference. With the mRNA expression data, a total of 949 DEGs were identified, consisting of 718 upregulated in AFP+, and 231 upregulated in AFP-. The enriched pathways of the DEGs included cell cycle, metabolism of xenobiotics by cytochrome P450 and chemical carcinogenesis. AVP, CCL20 and MUC6 genes were identified as hub genes in the PPI network. Conclusions: According to the results of this study, the AFP level is associated with patients’ OS rates, and AFP- patients tend to have higher CCTNB1 mutation rate. Our ongoing study will verify this result by enrolling new HCC patients.
Role of resection of the primary in metastatic well/intermediate-differentiated neuroendocrine tumor (NET).
Authors: Shaib Walid Labib , Penely Mckenna , Zakka Katerina Mary , Jiang Renjian , Akce Mehmet , Wu Christina , Behera Madhusmita , Maithel Shishir K. , Sarmiento Juan , Alese Olatunji B. , El-Rayes Bassel F. 
Published: May 2019

e15693 Background: Resection of the primary tumor in metastatic neuroendocrine tumor (NET) is controversial. The aim of this study is to evaluate survival outcomes and identify prognostic variables of surgical resection of the primary tumor in metastatic NET patients. Methods: Data were obtained from all US hospitals that contributed to the National Cancer Database (NCDB) between 2004 and 2013. Chi-square and ANOVA tests were done to identify factors associated with surgical modality. Univariate and multivariate cox proportional hazards models were used for association between patient characteristics and survival. Kaplan-Meier curves were generated and log-rank tests conducted to compare the survival difference of patient characteristics. Results: A total of 2,361 patients between 18 and 90 years of age with stage IV well/intermediate-differentiated NET were identified. The mean age was 62.1 years (SD±13), with an equal male to female ratio (50.0%). Majority of NET primaries were in the small intestine (33.0%), pancreas (26.3%), and lung (24.4%). The majority were well differentiated tumors (69.6%) and 42.5% of patients underwent surgery at the primary site. On multivariate analysis total surgical resection of the primary (HR 0.44; 0.22-0.90; p < 0.001), female sex, year of diagnosis 2010-2014, negative surgical margin, Charlson-Deyo score < 2, and age < 51 years at diagnosis were associated with better overall survival (OS). Conclusions: Resection of the primary in stage IV well/intermediate-differentiated NET was associated with improved 5-year OS compared to patients with no surgery in small intestine (60.1% vs 44.2%), lung (70.0% vs 20.2%), and pancreas tumors (59.3% vs 30.6%).
Geographic and demographic disparities in neuroendocrine tumors (NETs): A population-based study.
Authors: Gosain Rohit , Ball Somedeb , Rana Navpreet Kaur , Groman Adrienne , Gage-Bouchard Elizabeth , Dasari Arvind , Mukherjee Sarbajit 
Published: May 2019

e15694 Background: The incidence and prevalence of Neuroendocrine Tumors (NETs) are rapidly rising. There are very few studies investigating the role of sociodemographic factors on NETs. The aim of our study was to identify the disparities in the NET population. Methods: We conducted a retrospective analysis utilizing the Surveillance, Epidemiology, and End Results (SEER) database, and studied NETs patient population from 1973 to 2015. Univariate and multivariate analyses were performed to evaluate patients’ disease-specific survival (DSS) and overall survival (OS). Different socio-demographic factors including location of residence: urban area (UA) versus rural area (RA), gender, race, insurance status and marital status were included in the analysis. Results: A total of 53,522[ RA: N = 9,053; UA: N = 43,981] patients were included in the analysis. The incidence of NETs was found to be rising in both RA and UA but more rapidly in UA. RA was associated with more advanced stage at presentation in comparison to UA (p < 0.001). Cause-specific mortality remained higher in RA than UA throughout the study period. In the multivariate model, RA had a trend towards poorer DSS (HR:1.03, p = 0.399) and a worse OS compared to UA (HR = 1.06, p = 0.0003). Blacks had a poorer OS compared to non-Hispanic Whites (HR = 1.16, p < 0.001). Multivariate analysis showed significantly worse DSS and OS in uninsured, single and male patients compared to insured, married and female patients respectively. Conclusions: Our study identified sociodemographic disparities on NET outcomes. Access to healthcare could be a potential contributing factor although differences in environmental exposure, health behavior and tumor biology could also be responsible. Further population-based studies are required to address these disparities.