bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparative mutational analysis of biliary tract cancers.
Authors: Qiu Zhiquan , Ji Jun , Xu Yu , Zhu Yan , Gao Chun-Fang , Wang Guoqiang , Li Chengcheng , Cai Shangli , Liu Hao , Li Bin , Jiang Xiaoqing 
Published: June 2021

e16164 Background: Traditional classifications of tumors have utilized tissue of origin and histologic types. These categories have been refined with comprehensive molecular characterizations across large numbers of tumors. We hereby aimed to identify the similarities and differences of mutational profiles among the cancers along biliary tract, and investigate their prognostic effects. Methods: Mutation and clinical data from 99 BTC patients who received surgical resection (gallbladder cancer [GBC], n=42; cholangiocarcinoma [CCA], n=57) were analyzed. Capture-based targeted deep sequencing was performed using a 520-gene panel, spanning 1.64 Mb of the human genome (Burning Rock Biotech). Results: The mutational frequencies of TP53, BRCA1/2, ATM, and PI3K, WNT, HRR, and cell cycle pathway, gradually decreased with the order of the anatomical position (GBC, dCCA, pCCA, iCCA-large duct, and iCCA-small duct), while the changing trend of BRAF mutational frequency was the opposite (Table). In addition, CCND1/E1 and APC mutations were enriched in metastatic BTCs. As for prognostic effect, mutations of BRAF, TGFBR1/2, ARID1A, and MMR pathway were associated with shorter OS, and these association remained significant after adjustment for tissue of origin, TNM stage, histological grade, surgical margin, and serum CEA level. Conclusions: The differentially mutated genes among the cancers along biliary tract may indicate the potential mechanism of tumor development in different anatomic locations. Deeper understanding of the prognosis-related mutational events might change the postoperative management of BTC by enabling risk stratification, ACT monitoring, and early relapse detection. Mutational rate of the differentially mutated genes among the cancers along biliary tract.[Table: see text]
Characteristics, management and outcomes of patients with hepatocarcinoma in a low-income country.
Authors: Dominguez Jennifer , Macario Bonnie , Ramirez Rixci , Castro Mario Daniel 
Published: June 2021

e16166 Background: Worldwide, every year, there are nearly 905,000 patients diagnosed with liver cancer; it is the sixth most common malignancy and the third most lethal malignancy. Almost three quarters of new patients live in areas with low and medium-income country. Guatemala has the highest mortality and incidence of liver cancer. Objectives: Describe the clinical characteristics, main risk factors, treatment and outcomes of patients with hepatocarcinoma (HCC) in Guatemala. Methods: A retrospective review was performed among patients with HCC from January 2002 to December 2019 in the Instituto Guatemalteco de Seguridad Social (IGSS). Kaplan Meier curves, Cox regression and log-rank test were used to calculate overall survival (OS) and mortality. Results: 140 patients with HCC were analyzed, 114 women and 26 men with a median age of 60 years (20 - 99), 102 patients (73%) have history of excessive alcohol consumption and 11 (8%) has history of chronic hepatitis B or C virus infection. All of the patients have liver cirrhosis, Child-Pugh A 100 patients (71%), B 34 (24%) and C 6 (5%). 10 patients (7%) have HCC BCLC A, 0 (0%) BCLC B, 121 (81%) BCLC C and 9 (6%) BCLC D. All patients with HCC BCLC A received surgical treatment with a median OS of 123 months (95% CI 89 - 156 p < 0.001). 122 patients (89%) received target therapy with Sorafenib with a median OS of 17 months (95% CI 12 - 21 p < 0.001) and 8 patients (6%) underwent to chemoembolization with a median OS of 32 months (95% CI 12 - 52 p < 0.001). At this time, 111 patients (79%) died from the disease, 11 (8%) are alive with the disease and 8 (6%) are alive without disease. Conclusions: The most frequent risk factor for HCC is the excessive alcohol consumption, survival of patients with HCC are associated with treatment at the beginning of the disease.
Prognostic value of dickkopf-1 and ß-catenin expression according to the antitumor immunity of CD8-positive tumor-infiltrating lymphocytes in biliary tract cancer.
Authors: Kim Seoree , Ko Yoon Ho , Won Hye Sung , Yang Ji Hyun , Sun Der Sheng , Yim Kwangil , Hong Soon Auck , Chun Sang Hoon , Kim Kee-Hwan Michael 
Published: June 2021

e16172 Background: Despite recent advancements in the understanding of the molecular biology of biliary tract cancer (BTC), target therapy and immunotherapy have demonstrated only limited efficacy, with cytotoxic systemic therapy still being the most effective treatment in BTC, except for surgery. Thus, this study aimed to analyze the role of DKK1 or β-catenin as a prognostic factor in BTC and determine the clinical association of ß-catenin and DKK1 with CD8+ tumor-infiltrating lymphocyte (TIL). Methods: We used data in The Cancer Genome Atlas (TCGA) Research Network and the clinicopathological data of 145 patients with BTC who had undergone primary radical resection between 2006 and 2016. Immunohistochemistry was performed on formalin-fixed, paraffin-embedded tissue sections, and whole tissue sections of representative tumor samples were used for antigen retrieval. Results: CD8+TIL expression was a significant predictor of favorable overall survival (OS) and recurrence-free survival (RFS) (median OS, 34.9months in TIL-high, 16.7months in TIL-low, P < 0.0001 respectively; median RFS, 27.1months in TIL-high, 10months in TIL-low, P < 0.0001 respectively). Positive ß-catenin expression and high DKK1 expression was also associated with a shorter OS (median OS, 23.95months in positive ß-catenin, 26.1months in negative ß-catenin, P = 0.1009 respectively; median OS, 19.4months in high DKK1, 31.65months in Low DKK1, P = 0.0093 respectively), but not RFS (p = 0.1466, at ß-catenin respectively; p = 0.2924, in DKK1 respectively). In the CD8+TIL-high BTC group, the tumor expression of β-catenin and DKK1 had a significant negative impact on either OS or RFS (p = 0.0146 and p = 0.0112, at ß-catenin respectively; p = 0.0950 and p = 0.3904, in DKK1 respectively). However, in the TIL-low BTC group, there were no differences in OS or RFS according to ß-catenin and DKK1 expression (p = 0.5108 and p = 0.8431, at ß-catenin respectively; p = 0.1127 and p = 0.1095, in DKK1 respectively). Cox regression multivariate analysis demonstrated that CD8+ TIL (hazard ratio [HR], 0.490; 95% confidence interval (CI), 0.303-0.791; p = 0.004) and β-catenin (HR, 1.652; 95% CI, 1.035-2.639; p = 0.036) retained significant association with OS after adjustment for all variables. Conclusions: Among patients with resected BTC, β-catenin and DKK1 protein levels are associated with poor clinical outcomes, whereas high CD8+ TIL levels are associated with good clinical outcomes. This confirms the differential clinical role of Wnt/β-catenin and DKK1 proteins according to TIL expression in BTC.
Cabozantinib in advanced HCC patients previously treated with immune checkpoint inhibitors: A territory-wide cohort study.
Authors: Wong Jeffrey Sum Lung , Dong Yawen , Tang Vikki , Leung Thomas Wai-Tong , Yeung Cynthia SY , Tai Anna , Law Ada , Shum Tracy Cy , Kwok Gin Wai , Li Bryan , Leung Roland Ching-Yu , Chiu Joanne Wing Yan , Ma Ka Wing , She Wong-Hoi , Tsang Wing Yan Josephine , Cheung Tan To , Yau Thomas 
Published: June 2021

e16179 Background: Cabozantinib is licensed for use as second- or third-line treatment for sorafenib-exposed advanced hepatocellular carcinoma (aHCC) based on the phase III CELESTIAL trial. However, its use in the post-immune checkpoint inhibitors (ICI) setting has yet to be described. We evaluated the pattern of use, efficacy, survival and tolerability of cabozantinib in aHCC patients with previous treatment by ICIs. Methods: We did a multi-centre, territory-wide study analysing aHCC patients who received cabozantinib after prior ICIs. Objective response rate (ORR), disease control rate (DCR), time-to-progression (TTP), overall survival (OS) and treatment related adverse events (TRAEs) were assessed. Results: Thirty-one patients were included. The median age was 58.0 (range 41-85) and 77.4% had Child-Pugh A cirrhosis. 51.6% of patients received single agent cabozantinib and 48.4% received cabozantinib in combination with ICIs. ≥80% of patients received cabozantinib beyond the second-line and 93.5% of patients had prior TKIs. All patients received prior anti-PD-1 and 61.3% had prior anti-CTLA-4. The median follow-up was 15.2 months. For single agent cabozantinib patients, the ORR was 6.3%, DCR was 31.3% and median TTP was 3.5 months (95% C.I. 1.2-5.8). For cabozantinib-ICI combination patients, the ORR was 6.7%, DCR was 26.7% and median TTP was 2.3 months (95% C.I. 1.4-3.1). The overall median OS was 8.9 months (95% C.I. 5.7-11.9). Single agent cabozantinib patients had a significantly shorter OS compared to cabozantinib-ICI combination patients (8.3 months (95% C.I. 1.3-15.2) vs. 15.1 months (95% C.I. 11.1-19.2), p = 0.047). There was no significant difference in OS among patients with primary resistance to prior ICI regimes compared to those with acquired resistance (primary resistance 8.28 months (95% C.I. 5.04-11.5) vs. acquired resistance 8.90 months (95% C.I. 3.49-14.3), p = 0.472). Overall, 67.7% and 6.5% of patients experienced TRAEs of all grade and grade ≥3 respectively. The most common TRAE was hand-foot syndrome. 62.5% of single agent cabozantinib patients had any grade TRAE and no such patients had grade ≥3 TRAE. Conclusions: Cabozantinib had good anti-tumour activity and survival outcomes with acceptable toxicity in aHCC patients with previous treatment by ICIs.
Comprehensive genomic profiling analysis of HBV-infected hepatocellular carcinoma patients.
Authors: Liu Xiaoliang , Wang Xiaohui , Yao Jianfei , Chen Shifu , Li Yu 
Published: June 2021

e16180 Background: Hepatocellular carcinoma (HCC) is one of the leading causes of tumor-related death worldwide which is dominantly caused by chronic infection of hepatitis B virus (HBV) and hepatitis C virus (HCV). Recent studies have shown that immune checkpoint inhibitors may enter the first-line treatment of HCC. Comprehensive investigation of the genetic alterations and their correlation with microsatellite instability (MSI) and PD-L1 expression in HBV-infected HCC is helpful to determine the therapy strategy for patients. Methods: The genomic information of HCC patients was obtained from HapLab database. HaploX 605- gene panel was performed to analyze the genomic data of patients. PD-L1 expression was detected by immunochemistry. Results: A total of 349 mutations were found by analyzing the genomic profiles of 115 HBV-infected HCC patients. The frequently mutated genes included TP53 (63%), TERT (27%), CTNNB1 (16%), CSMD3 (15%), LRP1B (14%), AXIN1 (13%), CDKN2A (13%), KIT (13%), MDM4 (12%) and CCND1 (12%). Besides, 279 mutations were identified by analyzing the genomic profiles of 82 HCC patients without HBV-infection. Mutation frequencies for several genes were relatively higher in the HBV-positive patients than that in HBV-negative HCC patients, including TP53 (63% versus 39%), CCND1 (12% versus 5%), RB1(12% versus 4%) and BRCA2 (11% versus 4%). The proportion of MSI-H/L in HBV-infection patients were higher than that in HBV-negative ones (7.83% versus 4.88%). Notably, the proportion of high PD-L1 expression in patients with HBV-infection was 40.57% (43/106), while it was 28.95% (22/76) in patients without HBV-infection. Conclusions: These results highlighted a potential impact of viral infection on the mutational signatures in hepatocarcinogenesis. The PD-L1 expression status and MSI were closely related to HBV-infected HCC. These results may contribute to understanding the mechanism of HBV-infected HCC and the selection of therapy for relative patients.
Nivolumab/pembrolizumab in Child-Pugh grade B/C patients with advanced HCC.
Authors: Wong Jeffrey Sum Lung , Kwok Gin Wai , Tang Vikki , Li Bryan , Leung Roland Ching-Yu , Chiu Joanne Wing Yan , Ma Ka Wing , She Wong-Hoi , Tsang Wing Yan Josephine , Cheung Tan To , Yau Thomas 
Published: June 2021

e16184 Background: Hepatic derangement commonly accompanies advanced HCC (aHCC) and limits the use of systemic therapies. We aimed to evaluate the use of single agent anti-PD-1 nivolumab or pembrolizumab in Child-Pugh (CP) grade B or C patients with aHCC. Methods: Consecutive aHCC patients with CP grade B (CPB) or C (CPC) liver function who received single agent nivolumab or pembrolizumab were analysed. Objective response rate (ORR), time-to-progression (TTP), overall survival (OS), and treatment-related adverse events (TRAEs) were assessed. Results: Between May 2015 and June 2020, 61 patients were included. The median age was 60 (range 28-82). 81% and 4.8% had hepatitis-B and hepatitis-C related HCCs respectively. 72.1% (n = 44) were of CPB and 27.9% (n = 17) were of CPC. Amongst CPB patients, 19 (31.1% of all patients) had CP score 7 (CP7) and 25 (41.0% of all patients) had CP score 8 or 9. The median follow-up was 2.3 months. The ORR of CPB and CPC patients were 6.8% and 0% respectively (p = 0.553). The TTP of CPB and CPC patients were 2.1 months (95% C.I. 1.4-2.8) and 1.4 months (95% C.I. 0.6-2.1) respectively (p = 0.204). CPB patients had significantly better OS than CPC patients (3.1 months (95% C.I. 1.4-4.7), vs. 1.7 months (95% C.I. 1.0-2.4), p = 0.041). Compared to CP score ≥8 (CP≥8) patients, CP7 patients had significantly better OS (median OS CP7 6.7 months (95% C.I. 4.0-9.3), vs. CP≥8 1.8 months (1.2-2.4), p = 0.002). Patients with diuretic-refractory ascites had significantly worse OS compared to those without (1.7 months (95% C.I. 1.0-2.5) vs. 3.7 months (95% C.I. 0.1-7.3), p = 0.004). Portal vein (PV) thrombosis was also significantly associated with inferior survival, with median OS of patients with any PV thrombosis being 1.8 months (95% C.I. 1.0-2.5), compared to 5.3 months (95% C.I. 2.4-8.1) of those without (p = 0.004). The median number of doses given was 3 (range 1-34). Median treatment duration was 5.0 weeks (range 0-77). Overall, 25.4% of patients experienced TRAEs and 4.8% experienced grade ≥3 TRAEs. The most common TRAEs were skin-related (13.1%) and constitutional symptoms (6.6%). Conclusions: Nivolumab/pembrolizumab had acceptable safety in CPB/C patients with aHCC. CP7, absence of diuretic-refractory ascites and lack of PV thrombosis were associated with better survival.
Metronomic oral cyclophosphamide & low dose nivolumab for advanced hepatocellular carcinoma (HCC).
Authors: Chen Jo-Pai , Kao Tsui-Mai , Hsueh Fu-Jen , Lu Wei-Chen , Ma Wei-li , Wu Hsu , Chiang Keng-Man , Chen Hsing-wu , Kuo Sung-Hsin 
Published: June 2021

e16190 Background: Metronomic oral cyclophosphamide would suppress Treg and low dose nivolumab(0.1 mg/kg biweekly) might be still effective for immunogenic cancers. We try to introduce this regimen for immunogenic advanced HCC. Methods: From 2016 to 2021, 65 advanced HCC patients receiving ICIs in Yun-lin Branch of National Taiwan University Hospital were reviewed. Results: In these patients, 46 failed sorafenib; 35 (54%) HBV infected, 23 (35%) HCV infected, 7 (11%) alcoholism. The objective response rate was 48% (31/65) and disease control rate was 74% (48/65), with favorable toxicity profiles. In 43 nivolumab users, dosage from 0.3 to 3 mg/kg biweekly with 58% in 3 mg/kg; 15 receiving second-line low dose biweekly 20 mg nivolumab with oral metronomic cyclophosphamide 50 mg per day produced response rate 53% (8/15) & clinical benefit 73% (11/15). For this special regimen, in 10 HCV-infected patients, ORR was 70% & DCR was 90%; in 4 HBV-infected patients, ORR was 25%. In 10 with lung/LN metas only, ORR was 80%. 7 receiving bevacizumab, nivolumab, & cisplatin had 57% (4/7) response rate. In 7 atezolizumab users, combined with low dose bevacizumab (100 to 200 mg per 3 weeks) for first-line use, 6 were responders (86%). 19 front-line immunotherapy users had 68% (13/19) response rate (5 bevacizumab & atezolizumab; 4 lenvatinib & pembrolizumab; 2 bevacizumab, cisplatin, & nivolumab; 2 nivolumab with SBRT on MPV); 47 later line users had 38% (18/47) response rate (some receiving nivolumab combined with CT; bevacizumab with nivolumab & CT; sorafenib or regorafenib). 13 patients had MPV involvement (7 responders to immunotherapy-54%): 3 patients, using nivolumab after sorafenib failure, all suffered from rapid progression; 3 patients, receiving front-line SBRT over portal vein tumors and nivolumab, had response rate in 67% (2/3) and 100% clinical benefit; 2 responders to front-line lenvatinib & pembrolizumab (ORR 2/2-100%); 1 responder to front-line bevacizumab & atezolizumab (ORR 1/2-100%; another patient responded to second-line lenvatinb & pembrolizumab); 1 responder to front-line bevacizumab, cisplatin, & nivolumab. Conclusions: In our institution, ICIs combined with metronomic chemotherapy, low dose bevacizumab, multi-targeted VEGFR2 TKI, CT(platinum, anthracycline, and 5-fluorouracil), & SBRT could produce favorable response rates(first line 68%; later line 38%)/clinical benefits and toxicity profiles in advanced HCCs, even in heavily-treated patients, MPV involvement, and fulminant spreading status. Metronomic oral cyclophosphamide & low dose nivolumab, all failing sorafenib, seemed feasible and effective with lower toxicity/cost. Patients with HCV infection or lung/lymph nodes metastasis only seemed to respond better. Immune-modulation mechanisms of metronomic oral cyclophosphamide, nivolumab biologically-effective dose, clinical trial design, & biomarkers research are warranted.
Methylation status of eight tumor suppressors in neuroendocrine pancreatic tumors.
Authors: Kit Oleg I. , Trifanov Vladimir S. , Timoshkina Natalya N. , Gvaldin Dmitry Yu. , Mesheryakova Milana Yu. , Kolesnikov Evgeniy N. , Kozhushko Mikhail A. , Averkin Mikhail A. , Mezentsev Stanislav S. , Gabrichidze Petr N. 
Published: June 2021

e16197 Background: Aberrant DNA methylation is a characteristic feature of cancer, affecting gene expression and tumor phenotype. In this study, we quantified the methylation of promoters of eight tumor suppressor genes in pancreatic neuroendocrine tumors (Pan-NET). Methods: The method of pyrosequencing was used to quantity level (Met,%) of methylation of gene promoters - tumor suppressors AHRR, APC1A, DAPK, MGMT, MLH1, P16, RASSF1A, RUNX3 in tumor samples from 55 patients with pancreatic NET (G1-G3) and in the blood of 10 healthy donors. Met for each sample was calculated as the median methylation of CpG sites in triplicate. Results: Hypermethylation was observed for AHRR (75%), APC1A (25%), RASSF1A (30%). In contrast, DAPK, MGMT, MLH1, P16, RUNX3 had low methylation levels ( < 20%). The median of methylation in the blood of healthy donors for AHRR was 91% (76-98); for all other loci it did not exceed 6%. A high incidence of methylation in excess of blood levels in healthy donors was identified for RASSF1A (0.96); AHRR (0.75); MGMT (0.65); RUNX3 (0.41), APC1A (0.25). For tumor suppressor P16, only one case of increased methylation was recorded (Met = 15%), despite the fact that this phenomenon is not uncommon for NETs of other localizations. In 66% of pancreatic NET cases, hypermethylation of more than two promoters of tumor suppressor genes was noted. An association tendency was found between the presence of MEN1 mutations and the RASSF1A methylation level (p = 0.08). Correlation analysis revealed a significant level of negative association between changes in methylation of MLH1 and AHRR (p < 0.01); for the latter, the prognostic value of a high methylation status and a better prognosis for many malignant neoplasms were described. Conclusions: In the present study, significant methylation of the promoters of the APC1A, DAPK, MGMT, RASSF1A, and RUNX3 genes in well-differentiated pancreatic NETs was identified with a high frequency. At the same time, isolated cases of hypermethylation were noted for the well-known tumor suppressors MLH1 and P16.
Dual immune checkpoint blockade in advanced well-differentiated neuroendocrine tumors, a phase II clinical trial.
Authors: Scott Susan Combs , De Jesus-Acosta Ana , Hu Chen , Levy Benjamin Philip , Anagnostou Valsamo , Brahmer Julie R. , Illei Peter Bela , Jaffee Elizabeth M. , Marrone Kristen , Forde Patrick M. , Hann Christine L. 
Published: June 2021

e16201 Background: Limited systemic treatment options are available for progressive well-differentiated neuroendocrine tumors (NET), also called carcinoid tumors. Given emerging evidence for immunotherapy response in high grade NET including small cell lung cancer, we sought to determine the efficacy of combination immunotherapy with ipilimumab and nivolumab in patients with advanced, progressive, well-differentiated NET in an open label phase II clinical trial. Methods: Eligible patients had well-differentiated, nonfunctional NET of lung, pancreas, or GI origin that had progressed within the past 12 months after at least one line of prior therapy. Patients received nivolumab 240 mg every 2 weeks and ipilimumab 1mg/kg every 6 weeks for up to 2 years. Primary endpoint was objective response rate (ORR) by RECIST v1.1. Using a Simon’s 2-stage design, the study planned to accrue up to 56 patients. Based on published response rates to everolimus of 5%, we hypothesized that this regimen would be considered promising if the true ORR is > 15%. Results: Nine patients were enrolled prior to study closure due to funding, including 6 patients with NET of lung origin, 2 pancreatic, and 1 small bowel (Table). Median age was 71 years. All patients had distant metastatic disease at enrollment, with an average of 2 prior lines of therapy. Four of 9 patients achieved the primary endpoint of confirmed objective response, all of whom have ongoing response with a median duration of 15.4 months. Five of 9 patients, including all 4 responders, experienced immune-related toxicity requiring treatment modification or discontinuation. The trial did not accrue the target of 56 patients, however, objective response in 4 of 9 patients (ORR 44.4%, 90% CI: 16.9-74.9%) excluded the response rate target (15%). Conclusions: The impressive ORR of 44% with a median duration of response exceeding 15 months in this small clinical trial warrants further study of combination CTLA-4 and PD-1 inhibition in previously treated well-differentiated NET. Our ongoing immunologic and genomic correlative analysis in responders and non-responders will help inform future study of immunotherapy in this patient population in need of new systemic therapy approaches. Clinical trial information: NCT03420521. [Table: see text]