bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association between serious immune-related adverse events and survival in patients with advanced HCC treated by nivolumab: A single-center experience.
Authors: Digklia Antonia , Diciolla Antonella , Hocquelet Arnaud 
Published: May 2020

e16661 Background: Nivolumab received accelerated approval by the FDA in 2017 for the treatment of advanced hepatocellular carcinomas (HCC). This study is aimed at evaluating the relationship between serious irAEs leading to treatment pause and survival of patients treated with nivolumab in our center. Methods: we performed a retrospective analysis of the patients treated at our center. The Kaplan Meir method was used to evaluate overall survival(OS). Log-rank test was conducted to compare groups in terms of OS. Adverse events were assessed using NCI CTCAE version 4.03 criteria. Results: Twenty patients with advanced HCC received nivolumab as palliative therapy between 2017-2019. 12/20 received nivolumab as first line treatment, 7/20 as second line. 6/20 patients stopped nivolumab due to serious irAEs including pancreatitis, kidney dysfunction and colitis leading to definitively stop of the therapy. The majority of patients received nivolumab in second line (5/6). The 1 year OS was 44% at the non-serious irAEs group and 84% in the serious irAEs group (p value = 0.0166). Median overall survival for the entire cohort was 11.4 months. The median OS was 8.11 months in patients without serious irAEs and 18.2 months in the group with toxicity. Conclusions: the occurrence of serious irAEs was associated with longer OS at our single center review. These results are in line with reports in other diseases such as lung cancer and melanoma. These retrospective data warrant further evaluation.
Comprehensive molecular profiling of intrahepatic cholangiocarcinoms in Chinese population and therapeutic experience.
Authors: Wang Longrong , Wang Lu 
Published: May 2020

e16663 Background: The genomic alterations of intrahepatic cholangiocarcinoma in Chinese population have not been fully revealed. Molecular profiling may provide reference to clinical management especially targeted therapy. Methods: A prospective study was conducted in 122 intrahepatic cholangiocarcinoma patients accepted chemotherapy with or without targeted therapy. All patients had results of next generation sequencing assay that analyzes 489 cancer-associated genes. Results: The most commonly mutated genes were TP53 (34%), KRAS (25%), ARID1A (17%), CDKN2A (12%), FAT1 (12%), and NOTCH3 (12%). ERBB2 alterations were found in 13 (11%) patients, 10 of 13 were gene amplification. Application of Trastuzumab achieved a disease control rate of 7/8 and response rate of 6/8. Twenty-two patients with wild type KRAS/NRAS/BRAF accepted Cetuximab combined chemotherapy. Disease control rate and response rate were 78% and 47% respectively. Fifty-four patients accepted anti-VEGF treatment combined chemotherapy. Disease control rate and response rate were 85% and 60% respectively. Better therapeutic efficiency (P = 0.001) and longer progress free survival (P = 0.04) were observed in Bevacizumab treated group than chemotherapy alone. Two patients (1.6%) had signatures of microsatellite instability (MSI-H), and both benefited from immunotherapy. Conclusions: This study provides an over view on genetic alterations in Chinese intrahepatic cholangiocarcinoma patients, and indicates the potential clinical implications for targeted therapies.
Classifying inpatient deaths among liver and intrahepatic bile duct cancer and the effect of palliative care utilization on overall health care burden.
Authors: Abbasi Saqib , Kasi Anup , Saeed Anwaar , Sun Weijing , Al-Rajabi Raed Moh'd Taiseer 
Published: May 2020

e16673 Background: Liver cancer and bile duct cancer remain among of the most deadly cancers with a dismal 5 year survival of 2-15%. Patients often end up dying in an in-hospital setting as a result of acute complication of cancer progression. The purpose of this study is to identify annual trends in this sub-population, including cause of admission, palliative care utilization and economic impact on healthcare. Methods: From the years of 2002 to 2014, admissions for patients with a diagnosis of liver and bile duct cancer were identified using the National Inpatient Sample. Annual trends in incidence were compared to overall deaths via the SEER database. Trends were identified in hospital length of stay (LOS), total charges (TC), as well as utilization of palliative care. The effect of palliative care utilization on hospital length of stay and costs were also studied. Results: 73,833 (weighted) patient deaths were recorded from 2002 to 2014, 4,577 in 2002, compared to 6,595 in 2014. Signifying 33% (2002) to 32% (2014) of total deaths related to these cancers. The most common billed primary diagnosis was liver failure at 16.9%, sepsis (15.3%) and renal failure (6.7%). Overall LOS trended down from 5.9 days to 4.8 days (p < 0.001). Palliative consults increased from 8.2% in 2002 to 39.4% in 2014. In 2014, the mean TC for those who received palliative consults versus those who did not was $52,612 and $64,388 respectively (p < 0.001). LOS among these patients did not significantly change at 5.9 and 5.6 days (p = 0.13). When looking at patients with sepsis who did not die, a palliative care consult decreased costs from $87,564 to $75,223 (p < 0.001). LOS was not significantly different at 8.8 days to 8.5 days (p = 0.15). Conclusions: A third of patients with liver and bile duct cancers die in an in-hospital setting. More effort needs to be undertaken to identify these patients and establish appropriate goals of care prior to such an event. Nonetheless, palliative involvement decreased health care resource utilization. Even among patients with sepsis who did not die, a palliative care consult decreased total charges of admission.
The characterization of IDH1 mutations in Chinese biliary tract cancers.
Authors: Wang Kui , Xie Feng , Hu Mingtai , Zheng Yuting , Yuan Zhengang , Zhang Lei , Xue Hui , Liu Jianwei , Yang Zhao , Sui Chengjun , Xie Yanting , Liu Dan , Shi Junping , Hao Qing , Shi Xiaoliang , Liu Angen , Zhang Lin 
Published: May 2020

e16674 Background: Next-generation sequencing (NGS) has been used to identify actionable mutations in biliary tract cancers (BTCs). IDH1 is an enzyme that catalyzes the conversion of isocitrate to alpha-ketoglutarate, and is involved in the tricarboxylic acid cycle. Mutations in IDH1 are associated with aberrant conversion of alpha- ketoglutarate to 2-hydroxyglutarate, which is an oncogenic metabolite. In addition, IDH1 showed an effective biomarker for cholangiocarcinoma targeted therapy in the ClarIDHy study. Therefore, the detection of IDH1 mutations is essential for predicting sensitivity to targeted therapy. Methods: Deep sequencing targeting 450 cancer genes was performed on formalin-fixed, paraffin-embedded (FFPE) tumor tissues and matching blood samples that collected from a cohort of 926 Chinese BTC patients, including 469 intrahepatic (ICC), 203 extrahepatic (ECC), 195 gallbladder cancers (GC), and 59 hilar (HCCA) cholangiocarcinoma. Single nucleotide variations (SNV), short and long insertions/deletions (Indels), copy number variations, gene rearrangements, and fusions, were analyzed. The testing was carried out by a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory. Results: IDH1 mutations were detected in 3.9% patients, with a median age of 59 years old. The rate of IDH1 mutations was 7% in ICC, 1% in ECC, 0.5% in GC, and 0% in HCCA. IDH1 R132C (75.8%) substitution was the most common type of IDH1 mutation in ICC. In BTC patients, ARID1A (25%), TP53 (22%), and PBRM1 (22%) were the top-ranked co-mutation genes with IDH1. Compared with the IDH1 wild-type cohort, the frequencies of KRAS and TP53 mutations were significantly lower in the IDH1 mutated cohort (29.3% vs. 2.8%, p = 0.001; 56.6% vs. 22.2%, p < 0.001). In addition, IDH1 mutations were associated with a significantly lower TMB value compared to the wild-type cases (average TMB: 3.2 vs. 5.8 muts/Mb, p < 0.001). Conclusions: To date, this was the largest cohort used to study the characterization of IDH1 mutations in Chinese BTCs. The mutation frequency of IDH1 was lower in Chinese ICCs compared with non-Asian populations (7.0% vs. 16.5%). Consistent with the results from previous reports, IDH1 R132C substitution was the most common type of IDH1 mutation in ICCs (PMID: 31392056). TMB value and the frequency of TP53 and KRAS mutations were lower in patients with IDH1 mutation, which may provide clues for sensitivity to targeted therapy and prognosis.
Post-registration experience of nivolumab (nivo) therapy in patients with advanced hepatocellular carcinoma (HCC): An international study.
Authors: Fessas Petros , Kaseb Ahmed Omar , Wang Yinghong , Saeed Anwaar , Szafron David , Jun Tomi , Dharmapuri Sirish , Naqash Abdul Rafeh , Khan Uqba , Yu Bo , Paul Sonal D , Nimkar Neil satish , Bettinger Dominik , Hildebrand Hannah , Mohamed Yehia I. , Huang Yi-Hsiang , Rimassa Lorenza , Ang Celina , Marron Thomas Urban , Pinato David James 
Published: May 2020

e16677 Background: Nivo is FDA-approved in sorafenib-experienced, advanced HCC. Post-registration data to portray treatment in a real-world setting is lacking. Methods: We describe safety and efficacy of nivo in patients (pts) from 8 centres (USA n = 181, Asia n = 47, Europe n = 5), documenting overall (OS), progression-free survival (PFS), overall response (ORR) and disease control rates (DCR) (RECIST). Results: We analysed 233 pts, mostly cirrhotic (n = 176, 75%) due to hepatitis C (n = 95, 54.0%) with Barcelona Clinic Stage (BCLC) C HCC (n = 178, 76.4%), Child-Pugh class (CP) A (n = 158, 67.8%) or B (n = 75, 32.2%), and AFP > 400 IU/mL (n = 132, 56.7%). Nivo was given as first (1L, n = 85, 36.5%), second line (2L, n = 130, 55.8%) or > 2L (n = 18, 7.7%), after local (n = 191, 82%) and systemic therapy (n = 148, 63.5%), mostly sorafenib (n = 142, 60.9%). Median duration of nivo was 6.0 months (mo, interquartile range [IQR] 2.6-11.9) and stopped due to progression (n = 109, 46.8%) or toxicity (n = 8, 3.4%). After median follow up of 7 mo (IQR 3.0-12.3), ORR was 22.4% and DCR was 52.1%. Best responses (n = 219, 94%) included complete and partial responses in 18 (7.7%) and 31 (13.3%) pts respectively, stable disease in 65 (27.9%) and progressive disease in 105 (45.1%), not dissimilar by CP (p = 0.26). Median OS was 12.2 mo (95%CI 8.4-16.0) and predicted by CP (CPA 16.3 mo 95%CI 11.7-20.8; CPB 7.3 mo 95%CI 4.2-10.4; hazard ratio [HR] 1.9, p = 0.01), nivo line (1L 16.3 mo 95%CI 8.0-24.5; > 1L 10.4 mo 95%CI 7.4-13.5; HR 0.68, p = 0.05), and PVT (PVT- 13.8 mo 95%CI 11.7-16.0; PVT+ 10.4 mo 95%CI 7.8-13.0; HR 1.8, p = 0.015) but not cirrhosis, AFP, BCLC or steroid use (p > 0.05). Median PFS was 10.1 mo (95%CI 6.1-14.2), predicted by BCLC (A-B 19.0 mo 95%CI 7.1-30.8; C 8.2 mo 95%CI 4.9-11.4; HR 2.8, p = 0.002) and line (1L 18.2 mo 95%CI 10.4-25.9; > 1L 8.2 mo 95% CI 6.2-10.2; HR 0.60, p = 0.021), but not cirrhosis, AFP, or steroid use (p > 0.05). 26 pts (11.2%) suffered > = Grade 2 toxicities, most commonly fatigue (n = 29, 24.7%). Conclusions: Real-world use of nivo in advanced HCC across line of therapy suggests reproducible clinical efficacy and safety compared to prospective trials.
Construction of immune-related risk model for prognosis of hepatocellular carcinoma.
Authors: Li Yue , Xu Ximing 
Published: May 2020

e16683 Background: Hepatocellular carcinoma is the most common malignant tumor. Although the treatment of HCC has significantly improved, the 5-year survival rate is still only 18%. There is increasing evidence that tumor immune microenvironment (TIM) plays critical roles during cancer initiation and progression. Based on the comprehensive exploration of the immunogenomic, an immune-related risk model was constructed to predict hepatocellular carcinoma prognosis. Methods: Transcriptomic data of HCC patients were downloaded from the TCGA database, and the differentially expressed immune-related genes (IRGs) (FDR < 0.01, |log2fold change| > 2) were identified. Functional enrichment analysis was performed to explore potential molecular mechanisms of the differentially expressed IRGs. By univariate and multivariate Cox regression analysis, we identified eight prognosis-related IRGs. Based on the expression levels of IRGs, we constructed the immune-related risk model. The Kaplan‐Meier (K‐M) survival curves, ROC curves, univariate and multivariate analysis were used to evaluate the immune-related risk model. According to the risk score, HCC patients were stratified into low and high-risk groups. CIBERSORT was applied to analyze the profiling difference of infiltrating immune cells between the two groups. Results: A total of 113 differentially expressed IRGs were identified, of which nine IRGs were correlated with the prognosis of HCC patients. Functional enrichment analysis showed that these genes were involved in immune response and immune signal pathway. The immune-related risk model consisted of eight IRGs (FABP6, RBP2, MAPT, BIRC5, PLXNA3, CSPG5, IL17D and STC2). The immune risk score was an independent prognostic factor (HR, 2.63 [1.93−3.58]; P = 8.16E−10) and the patients with a high-risk score tended to have a shorter OS than those with a low-risk score. In the TCGA cohort, high-risk patients tended to have an advanced stage. Moreover, we found that the patients in the high-risk group had higher fractions of T follicular cells helper and macrophages M0. The patients with low-risk scores had higher fractions of CD8+ T cells and CD4+ T cells. Conclusions: We have identified the immune-related risk model of hepatocellular carcinoma based on the expression profiles of eight immune-related genes. This model could predict prognosis and reflect the tumor immune microenvironment of HCC patients, which can provide new insights in the individualized treatment of HCC and potential novel targets for immunotherapy.
Sorafenib as an adjuvant therapy for hepatocellular carcinoma with microvascular invasion after radical resection: A prospective multicenter nonrandomized controlled study.
Authors: Xu Li , Tang Yuhao , Li Hua , Zhou Jie , Zhou Zhongguo , Zhang Yaojun , Chen Minshan 
Published: May 2020

e16685 Background: Hepatocellular carcinoma (HCC) with microvascular invasion (MVI) is established with poorer outcome and more frequent postoperative recurrence. Sorafenib is the first target drug that successfully prolongs the survival of advanced HCC, but it failed to prolong the survival of HCC after radical resection or ablation in the STORM study. After that, series studies revealed that sorafenib could improve the survival of HCC with MVI after surgery, while most studies with positive results were retrospective ones. Methods: A multicenter, prospective non-randomized, open-label study was performed in pts undergoing radical resection, postoperative pathology confirming HCC with MVI (BCLC A or B stage; T2 or part T3aN0M0). Pts in the treatment group (S group) started sorafenib within 4-6 postoperative weeks at the dose of 400mg per day at most 2 years, and the control group (C group) never received sorafenib. The primary endpoint is recurrence-free survival (RFS) rate at the 2nd postoperative year, and the secondary endpoints include postoperative median time to recurrence (TTR), 1-year postoperative RFS, pts’ overall survival (OS), and safety. This study was approved by Ethical Committee of Sun Yat-sen University Cancer Center, and registered at ClinicalTrials.gov with number NCT02867280. Results: Between 1 June 2015 and 31 August 2019, 154 eligible pts from 3 academic hospitals in China were enrolled (83 in C group and 53 in S group). Baseline demographics were balanced between the two groups. The 2-yr RFS rate was 56.1% in the S group vs. 55.7% in the C group, respectively ( P = 0.955), and the median RFS was 15.5 vs. 16.0 months ( P = 0.827).The recurrence rates at the 1st postoperative year were 38.6% vs. 34.0% ( P = 0.568), and the median TTR was the same as the RFS. There were 31 pts (54.4%) of the S group experienced treatment-related adverse events (AEs). The most common AE was hand-foot syndrome (HFS, 19/57, 10 pts ≥ grade-2). Other AEs included diarrhoea (15/57, 26.4%), alopecia (11/57, 19.3%), hypertension (5/57, 8.8%) and decreased platelet (3/57, 5.3%), and gastric ulcer with bleeding (1/57, 1.8%). Sorafenib was interrupted or discontinued in 7 pts due to AEs. Recruiting of this study was closed according to the results of the planned mid-term analysis, and all pts were followed on schedule to observe the other survival data. Conclusions: Postoperative sorafenib treatment with dose of 400mg once daily was well tolerated, but did not improve the RFS and TTR of Chinese HCC pts with MVI. Clinical trial information: NCT02867280 .
Genome-wide CRISPR/Cas9 library screening to identify PAK1 as a critical driver for lenvatinib resistance in HCC.
Authors: Huang Shanzhou , Zhang Chuanzhao , Hou Baohua 
Published: May 2020

e16687 Background: Lenvatinib demonstrated noninferiority to sorafenib in overall survival and a statistically significant increase in progression-free survival in patients with unresectable hepatocellular carcinoma (HCC). However, the development of drug resistance of lenvatinib is becoming common. Methods: Here, we performed the first genome-wide CRISPR/Cas9-based screening on lenvatinib-treated HCC cells to identify essential genes for non-mutational mechanisms related to acquired lenvatinib resistance and/or sensitivity in HCC cells. A genome-scale CRISPR knockout (mGeCKOa) library containing 123,411 single guide RNAs (sgRNAs) was used to identify loss-of-function mutations conferring lenvatinib resistance upon HCC cells. CCK8, wound-healing, transwell and flow cytometry assays were used. Subcutaneous xenotransplantation models were used to investigate the role in vivo. Results: By using genome-wide CRISPR/Cas9 library screening, we identify PAK1, a family member of serine/threonine p21-activating kinases, as a critical driver for lenvatinib resistance and the most-effective genetic suppressor of lenvatinib activity. Analysis of the survival of HCC after hepatic resection revealed that low PAK1 expression shortened overall and tumor-free survival (P < 0.001). Further, loss of PAK1 from HCC cell increased the cytotoxicity of lenvatinib in vivo. Lenvatinib treatment activates series of metabolism, including “Glycolysis/ Gluconeogenesis、Cysteine and methionine metabolism、Selenocompound metabolism、Sphingolipid metabolism、Pyruvate metabolism、Metabolic pathways”. With RNAi knockdown and CRISPR/Cas9 knockout models, we show that loss of PAK1 activates the Glycolysis/ Gluconeogenesis and increase the production related metabolites. Concomitantly, activation of PAK1 reduces ROS level and HCC apoptosis upon Lenvatinib treatment. Lenvatinib treatment activates series of metabolism, including “Glycolysis/ Gluconeogenesis”. With RNAi knockdown and CRISPR/Cas9 knockout models, we show that loss of PAK1 activates the Glycolysis/ Gluconeogenesis and increase the production related metabolites. Concomitantly, activation of PAK1 reduces ROS level and HCC apoptosis upon Lenvatinib treatment. Conclusions: In summary, our results demonstrate that targeting PAK1 is an effective approach to overcome lenvatinib drug resistance in HCC.
Long-term survival of combined ablation therapy and tremelimumab with or without durvalumab in advanced hepatocellular carcinoma.
Authors: Monge B. M. Cecilia , Xie Changqing , McVey John , Mabry-Hrones Donna , Duffy Austin , Wood Bradford J. , Greten Tim F. 
Published: May 2020

e16689 Background: Immune checkpoint inhibitor therapy has recently been approved for the treatment of patients with Hepatocellular Cancer (HCC). Data on long-term survival is lacking and the predictors of good outcomes are unknown. The combination of locoregional therapies (transarterial chemoembolization or radiofrequency ablation) plus tremelimumab (trem) with or without durvalumab (durva) was studied in patients with advanced HCC. We report the long-term survival and analyze predictors of good response in two trials of immune checkpoint and ablation treatment in advanced HCC. Methods: Adult patients (pts) with pathologically confirmed HCC with advanced or sorafenib refractory disease who satisfied the eligibility criteria were enrolled in the studies (NCT02821754, NCT01853618). They received treatment with trem, 10 mg per kilogram every 4 weeks for six doses followed by 3 monthly infusions (23 pts) or trem 75 mg flat dose every 28 days for four doses and then durva 1500 mg flat dose every 28 days (35 pts). Subtotal radiofrequency or chemoablation was done on day 36. Results: The average overall survival in the 58 pts was 10.1 months (range 0.9 to 74.2 months); 41.6% were alive at 12 months and 5.5 % were alive at 61 months. A select group of patients had exceptional overall survivals up to 67 months. Predictors of improved overall survival included the presence of higher grade immune related (irAEs) (OR 0.235, p = 0.075) and a partial or stable disease response per RECIST. No new late toxic effects were noted during this long term follow up. Conclusions: Impressive overall survival times of up to 68.8 months were observed with ICI and subtotal ablation in patients with advanced HCC; the presence of irAEs and the tumor response per RECIST may be predictive of better overall survivals. To our knowledge this has not been previously reported in the literature. Clinical trial information: NCT02821754,NCT01853618 .