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Transarterial chemoembolization is a standard treatment for intermediate-stage hepatocellular carcinoma (HCC). This study evaluated the anti-tumor effect of the semi-interpenetrating network (IPN) hydrogel as a novel embolic material for trans-portal vein chemoembolization (TPVE) in vivo. A nude mice orthotopic HCC model was established, followed by TPVE using IPN hydrogel loaded with or without cisplatin. Portal vein blockade was visualized by MRI and the development of tumor was monitored by IVIS Spectrum Imaging. Tumor proliferation and angiogenesis were evaluated by Ki67 and CD34 staining respectively. Intra-tumor caspase 3, Akt, ERK1/2, and VEGF activation were detected by Western Blot. 18 F-FMISO uptake was evaluated by microPET-MRI scanning. IPN hydrogel first embolized the left branch of portal vein within 24 hours and further integrated into the intra-tumor vessels during 2 weeks after the treatment. Mice treated with cisplatin-loaded hydrogels exhibited a significant decrease in tumor growth, along with lower plasma AFP levels as compared to hydrogel-treated and untreated tumor-bearing mice. By Ki67 and CD34 staining, the TPVE with IPN hydrogel suppressed tumor proliferation and angiogenesis. In addition, increased tumor apoptosis shown by up-regulation of caspase 3 with decreased expressions of tumor cell survival indicators Akt and ERK1/2 were observed in the treatment groups. Consistent with the decreased expression of VEGF after TPVE, hypoxia level in the tumor was also reduced as indicated by 18 F-FMISO uptake level. IPN hydrogel-based TPVE significantly suppressed the tumor development by regulating intra-tumor angiogenesis and cell survival in an orthotopic HCC mouse model, suggesting a viable embolic agent for transarterial chemoembolization.

Background The effect of tumor size on account of long-term survival results in perihilar cholangiocarcinoma (PCCA) patients has remained a controversial debate. It is urgent necessary to identify the optimal cutoff value of tumor size in PCCA and integrate tumor size with other prognostic factors into a nomogram to improve the predictive accuracy of prognosis of patients with PCCA. Methods Three hundred sixty-three PCCA patients underwent surgical resection were extracted from the Surveillance, Epidemiology and End Results (SEER) database. X-tile program was used to identify the optimal cutoff value of tumor size. A nomogram including tumor size was established to predict 1-, 3- and 5-year cancer-specific survival (CSS) based on the independent risk factors chosen by Kaplan-Meier methods and multivariable cox regression models. The precision of the nomogram for predicting survival was validated internally and externally. Results PCCA patients underwent surgical resection were classified into 1–19 mm, 20–33 mm and ≥ 34 mm subgroups based on the optimal cutoff for tumor size in terms of CSS. And we noticed that more larger tumor size group had worse tumor grade, advanced T stage, more positive regional lymph nodes and more frequent vascular invasion. The nomogram according to the independent factors was well calibrated and displayed better discrimination power than 7th Tumor-Node-Metastasis (TNM) stage systems. Conclusions The results demonstrated that the larger tumor size of PCCA was, the worse survival would be. The proposed nomogram, which outperforms the conventional TNM staging system, showed relatively good performance and could be considered as convenient individualized predictive tool for prognosis of PCCA patients.

Excessive lipid deposition is a hallmark of NAFLD. Although much has been learned about the enzymes and metabolites involved in NAFLD, few studies have focused on the role of long noncoding RNAs (lncRNAs) in hepatic lipid accumulation. Here, using in vitro and in vivo models of NAFLD, we found that the lncRNA Gm15622 is highly expressed in the liver of obese mice fed a HFD and in murine liver (AML-12) cells treated with free fatty acids. Investigating the molecular mechanism in the liver-enriched expression of Gm15622 and its effects on lipid accumulation in hepatocytes and on NAFLD pathogenesis, we found that Gm15622 acts as a sponge for the microRNA miR-742-3p. This sponging activity increased the expression of the transcriptional regulator SREBP-1c and promoted lipid accumulation in the liver of the HFD mice and AML-12 cells. Moreover, further results indicated that metformin suppresses Gm15622 and alleviates NAFLD-associated lipid deposition in mice. In conclusion, we have identified an lncRNA Gm15622/miR-742-3p/SREBP-1c regulatory circuit associated with NAFLD in mice, a finding that significantly advances our insight into how lipid metabolism and accumulation are altered in this metabolic disorder. Our results also suggest that Gm15622 may be a potential therapeutic target for managing NAFLD.

Colorectal cancer is the third most common cancer in the world and its incidence is on the rise. Dietary intervention has emerged as an attractive strategy to curtail its occurrence and progression. Diet is known to influence the gut microbiome, as dietary factors and gut bacteria can act in concert to cause or protect from colorectal cancer. Several studies have presented evidence for such interactions and have pointed out the different ways by which the diet and gut microbiome can be altered to produce beneficial effects. This review article aims to summarize the interrelationship between diet, gut flora and colorectal cancer so that a better preventive approach can be applied.

Cholangiocarcinoma (CCA), an aggressive tumor with poor prognosis, is a malignant cancer with increasing incidence and mortality rates. It is important to survey crucial genes in CCA to find and design potential drug targets, especially for those genes associated with cell proliferation that is a key biological process in tumorgenesis. Herein, we surveyed genes associated with cell proliferation via a comprehensive pan-cancer analysis. Candidate genes were further analyzed using multiple approaches, including cross-analysis from diverse molecular levels, examination of potential function and interactions, and additional experimental validation. We primarily screened 15 potential genes based on 11 validated genes, and these 26 genes were further examined to delineate their biological functions and potential roles in cancer treatment. Several of them were involved synthetically lethal genetic interactions, especially for RECQL4, TOP2A, MKI67 and ASPM, indicating their potential roles in drug design and cancer treatment. Further experimental validation indicated that some genes were significantly upregulated in several cancer cell lines, implying their important roles in tumorigenesis. Our study identifies some genes associated with cell proliferation, which may be potential future targets in molecular targeted therapy.

Background Presence of inferior vena cava tumor thrombosis (IVCTT) is an unfavorable factor to prognosis for patients with hepatocellular carcinoma (HCC). Case presentation Herein we report a case of HCC with IVC tumor thrombosis extending from the right hepatic vein (RHV) to the IVC, but it had not infiltrated the right atrium. Anterior approach right hepatectomy combined with IVC thrombectomy using trans-diaphragmatic IVC occlusion was performed for this patient. The patient is alive with disease-free at 32 months after treatment. A literature review was also performed. This case was demonstrated with the details and concepts of surgery. Conclusion This case suggested that surgical resection of HCC involving the IVC, but still outside the right atrium (RA), could offer satisfactory surgical outcomes in selected patients.

BackgroundImmune checkpoint inhibitors monotherapy has been studied in patients with advanced biliary tract cancer (BTC). The aim of this study was to assess the efficacy and safety of camrelizumab, plus gemcitabine and oxaliplatin (GEMOX) as first-line treatment in advanced BTC and explored the potential biomarkers associated with response.MethodsIn this single-arm, open-label, phase II study, we enrolled stage IV BTC patients. Participants received camrelizumab (3 mg/kg) plus gemcitabine (800 mg/m2) and oxaliplatin (85 mg/m2). Primary endpoints were 6-month progression-free survival (PFS) rate and safety. Secondary endpoints were objective response rate (ORR), PFS and overall survival (OS). Exploratory endpoints included association between response and tumor mutational burden (TMB), blood TMB, dynamic change of ctDNA and immune microenvironment.Results54 patients with advanced BTC were screened, of whom 38 eligible patients were enrolled. One patient withdrew informed consent before first dose treatment. Median follow-up was 11.8 months. The 6-month PFS rate was 50% (95% CI 33 to 65). Twenty (54%) out of 37 patients had an objective response. The median PFS was 6.1 months and median OS was 11.8 months. The most common treatment-related adverse events (TRAEs) were fatigue (27 (73%)) and fever (27 (73%)). The most frequent grade 3 or worse TRAEs were hypokalemia (7 (19%)) and fatigue (6 (16%)). The ORR was 80% in patients with programmed cell death ligand-1 (PD-L1) tumor proportion score (TPS) ≥1% versus 53.8% in PD-L1 TPS 0.05), except that PFS was associated with blood TMB. Patients with positive post-treatment ctDNA had shorter PFS (p=0.007; HR, 2.83; 95% CI 1.27 to 6.28).ConclusionCamrelizumab plus GEMOX showed a promising antitumor activity and acceptable safety profile as first-line treatment in advanced BTC patients. Potential biomarkers are needed to identify patients who might respond to camrelizumab plus GEMOX.Trial registration numberNCT03486678.

Objectives: This study aimed to evaluate and update incidence trends of soft-tissue sarcoma (STS) and to develop a nomogram to predict cancer-specific survival (CSS) in patients diagnosed with primary STS of the liver. Methods: Patients with hepatic STS were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Joinpoint regression analyses were performed to assess the incidence trends of STS. A nomogram was developed based on the independent risk factors chosen by Cox regression models. The calibration curve, area under the receiver operating characteristic curve (AUC), C‐index, and decision curve analysis (DCA) were used to assess the predictive performance of the nomogram. Results: The incidence of STS increased between 1994 and 2012. There was a sudden decline in the incidence of STS from 2013. The incidence of STS was different in distinct races and genders. The nomogram for predicting the CSS of hepatic STS according to the independent factors was well calibrated and it displayed optimal discrimination power. Conclusion: This study highlights that age, sex, tumor size, quality of surgery, and histologic subtypes may contribute to the prognosis of hepatic STS, and STS may be etiologically distinct and should be considered separately in different races and genders.

The impact of tumor size on account of the long-term survival results in gallbladder cancer (GBC) patients has been controversial. It is urgent necessary to identify the optimal cut-off value of tumor size in resected GBC, and we attempted to integrate tumor size with other prognostic factors into a prognostic nomogram to predict the cancer-specific survival (CSS) of GBC patients. 1639 patients with resected GBC were extracted from the Surveillance, Epidemiology and End Results (SEER) database. X-tile program was used to identify the optimal cut-off value of tumor size. A nomogram including tumor size was established to predict 1-, 3- and 5-year CSS based on the independent risk factors chosen by univariate and multivariable cox analyses. The precision of the nomogram for predicting survival was validated with Harrell’s concordance index (C-index), calibration curves, and receiver operating characteristic curve (ROC) internally and externally. Patients with GBC were classified into 1–13 mm, 14–63 mm and 64 mm subgroup based on the optimal cut-off for tumor size in terms of CSS. The nomogram according to the independent factors was well calibrated and displayed better discrimination power than 7th tumor–node–metastasis (TNM) stage systems. The results demonstrated that increased tumor size is closely associated with the worse CSS. Our novel nomogram, which outperforms the conventional TNM staging system, showed satisfactory accuracy and clinically practicality for predicting the outcome of resected GBC patients.

Background: Liver cancer is the fourth most common cause of cancer-related death and rank sixth in terms of incident cases. With a 5-year survival of 18%, liver cancer is the second most lethal tumor, after pancreatic cancer. We aim to identify a set of miRNAs and a miRNA-based signature related to tumorigenesis and prognosis in patients with hepatocellular carcinoma (HCC). Methods: We analyzed the miRNA sequencing profiles of 373 HCC patients downloaded from The Cancer Genome Atlas LIHC program. The isoform quantification profiles were transformed into 5p and 3p mature miRNA names. Differentially expressed (DE) miRNAs between tumor and adjacent normal tissues were identified by Wald test based on the negative binomial distribution. Prognostic miRNAs associated with overall survival were confirmed by multivariate Cox proportional hazards models. The miRNA-based signatures were obtained from the linear predictors of cox regression, and the prognostic performance was compared by Harrel’s C-index and revealed by the restricted mean survival (RMS) curve. Findings: The selected twelve DE miRNAs showed a good performance to classify tumor tissues from normal tissues. Meanwhile, a miRNA-based prognostic signature of eight mature miRNAs was constructed, which significantly stratified patients into high- vs low-risk groups in terms of overall survival (hazard ratio, 4.11; 95% CI, 2.71-6.24; P

Recently, patients with advanced cancers have been benefited greatly from immune checkpoint blockade immunotherapy. However, immune checkpoint blockade is still suboptimal in HCC treatment and more immune modifications are needed to achieve an efficient therapeutic goal. Here, we investigated the combined administration of a Listeria-based HCC vaccine, Lmdd-MPFG, and the anti-PD-1 immune checkpoint blockade antibody. We found that Lmdd-MPFG promoted the expression of PD-L1 in HCC cells but resensitized the tumor local T cell to respond to the anti-PD-1 immunotherapy. Mechanistically, the Lmdd-MPFG vaccine activates the NF-κB pathway in the tumor-associated macrophages (TAMs) through the TLR2 and MyD88 pathway, and recruits p62 to activate the autophagy pathway. The overall effect is skewing the TAMs from M2-polarized TAMs into the M1-polarized TAMs. Most importantly, it skewed the cytokine profiles into antitumor one in the tumor microenvironment (TME). This change restores the T-cell reactivity to the anti-PD-1 blockade. Our results suggested that Lmdd-MPFG combined with PD-1 blockade exerted synergistic antitumor effects through modifying TAMs in the TME and removing T-cell inhibitory signals, thereby providing a new potential strategy for HCC treatment.

e16146 Background: The synergic combination of anti-PD-1/PD-L1 and antiangiogenic agents has exhibited as an encourage treatment pattern in aHCC. Multi-targeted antiangiogenic TKIs, such as lenvatinib and sorafenib, are approved for 1st-line treatment of aHCC. Sintilimab, a novel selective anti-PD-1 monoclonal antibody, has demonstrated encouraging clinical activities in aHCC. The trial aims to explore the safety and efficacy of sintilimab plus anlotinib (a TKI against angiogenesis) in aHCC. Methods: This is a single-arm phase 2 study. Eligible Pts with aHCC, BCLC stage C or B (not amenable for surgery and chemoembolization), Child-Pugh scores≤7 and ECOG PS ≤ 1 received 1st-line treatment of sintilimab (200mg, iv, D1) plus anlotinib (12mg, po, QD, D1-14) every 3 wks until disease progression or unacceptable toxicity. Primary endpoints were safety and objective response rate (ORR, per RECIST 1.1), and secondary endpoints included disease control rate (DCR), progression free survival (PFS), duration of response (DOR) and overall survival (OS). Results: As of January 15, 2021, 20 pts were enrolled (males 18 ; median age 56 yrs [range 41-70] ; BCLCB/C: 5/15 ; Child-Pugh A/B7: 19/1 ; HBV infection 20). All pts received at least two cycles of treatments with median cycles 7.5 [range 2-22]. Median follow-up was 12 months [range 3-19]. The most common treatment-related adverse events (TRAEs) were grade 1-2 with thrombocytopenia (45.0%), hand-foot syndrome (40.0%), hypertension (35.0%), increased AST (35.0%), ALT (30.0%), decreased neutrophil count (25.0%), leukopenia (25.0%). 8 pts experienced manageable grade 3 TRAEs, and no grade 4/5. 12 pts required dose reduction of anlotinib (9 pts to 10 mg and 3 to 8 mg). No treatment withdraw caused by TRAEs. ORR was 40.0% (8/20) with 1 CR and 7 PR, 11 pts were SD, and DCR was 95.0% (19/20). Median DoR was not reached. 6m-PFS rate was 66.4% (95%CI: 47.7%-92.5%), immature median PFS was 14.65 months (95%CI: 5.06 -not reached) with 8 events. Conclusions: The combination of sintilimab and anlotinib showed promising clinical activities with manageable toxicity for first line treatment of aHCC. Clinical trial information: NCT04052152. Research Sponsor: Innovent Biologics, Inc., Chia-Tai Tianqing Pharmaceutical Group Co Ltd. Clinical trial information: NCT04052152.

536 Background: We conducted a trial to evaluate the efficacy and safety of SHR-1210 (a humanized anti-programmed cell death receptor 1 antibody) plus gemcitabine and oxaliplatin (GEMOX) as in untreated patients (pts) with biliary tract cancer (BTC) (NCT03486678). This study is to explore the predictive biomarkers for efficacy. Methods: Baseline lymphocyte count and lactate dehydrogenase (LDH) level were obtained from routine tests. Gene mutation and tumor mutation burden (TMB) from baseline tissue and blood samples were tested by the next generation sequencing (NGS) with a 425-gene panel. The expressions of PD-L1 and markers for lymphocyte, natural killer cells, and macrophages in baseline tumor tissue samples were analyzed by immunohistochemistry (IHC). Results: The median progression free survival (PFS) and overall survival (OS) in this trial was 6.2m and 12.1m, respectively. Firstly, pts with normal LDH level (≤271 U/L) had a tendency for longer PFS (6.2m vs 5.0m, p = 0.053) and significantly longer OS (p = 12.6m vs 6.8m, p < 0.001) than those with elevated LDH ( > 271 U/L). Low baseline lymphocyte count (≤ 1.1×109/L) was related to worse OS (12.6m vs 6.9m, p < 0.001) and PFS (6.2m vs 3.9m, p = 0.021). Secondly, baseline tissue and ctDNA gene mutations were detected in 33 and 30 pts, respectively. Tissue analysis showed that pts with STK11 (p = 0.0254), CTNNB1 (p < 0.001) and SMARCA4 (p = 0.0181) wild type showed significantly longer PFS than those with mutations. Pts with ARID1A gene wild type showed a tendency for longer PFS (p = 0.0634) and significantly longer OS (p = 0.0149). Gene mutations from baseline ctDNA revealed that pts with wild type SMARCA4, CTNNB1, STK11, and NF1 had longer PFS than those with mutations. Lastly, IHC meant that PD-L1 positivity may be related to longer PFS (TPS > 1%, p = 0.08; IPS > 1%, p = 0.05). Besides, pts with CD68+ HLA-DR+ macrophages > 0.01%, CD68+ HLA-DR- macrophages>2.5%, and CD56bright>1.7% and CD56dim > 0.05 also got PFS benefits (all p < 0.05). TMB (cutoff = 7 muts/mbp) was not associated with PFS. Conclusions: Despite limited sample size, biomarkers from routine blood test, gene mutation and immune microenvironment can be helpful to stratify pts who are sensitive to immunotherapy in advanced BTC. Clinical trial information: NCT03486678.

535 Background: This study aimed to evaluate the efficacy and safety of SHR-1210 (a humanized anti-programmed cell death receptor 1 antibody) plus gemcitabine and oxaliplatin (GEMOX) as first line treatment in patients (pts) with biliary tract cancer (BTC). Methods: This was a single-arm, single-center, exploratory trial, which included advanced BTC pts. Pts received SHR-1210 (3mg/kg, total dose ≤200mg, ivd, D1/2W) combined with gemcitabine (800 mg/m2, ivd, D1/2W) and oxaliplatin (85mg/m2, ivd, D2/2W). Combined chemotherapy lasted for no more than 12 cycles. Once chemotherapy intolerance occurred or at end of 12-cycle combined chemotherapy, pts with stable disease or objective response would continue to take SHR-1210 as single agent until disease progression or intolerable toxicity. The primary endpoint was the 6-month progression free survival (PFS) rate. Results: From February 2018 to April 2019, 37 eligible pts were enrolled. The median age was 64 (range 41-74) years, male/female was 70.3/29.7%, and bile duct cancer/gallbladder cancer was 59.5/40.5%. All 37 pts were included in the safety analysis. The overall AE incidence rate was 97.3%. The incidence of grade ≥3 AEs was 73.0%, which mainly included increased GGT (gammaglutamyltransferase, 18.9%), hypokalemia (18.9%), and fatigue (16.2%). Particularly, the incidence of fever is 73.0%, in which 2 pts experienced grade 3/4 fever. Among 36 evaluable pts, 19 pts got partial response (PR, 52.8%), 14 pts stable disease (SD, 38.9%), and 3 pts progressive disease (PD, 8.3%) at best. The primary endpoint 6-month PFS rate was 50.0% (95% CI 32.4-65.4), which indicated that the primary endpoint of the study was reached, and mPFS was 6.2 months (95% CI 4.2-7.1). The 12-month overall survival (OS) rate was 50.5% (95% CI 30.6-67.4), and mOS was 12.1 months (95% CI 8.0-NA). Conclusions: This study has reached the pre-defined primary endpoint with a high response rate. Predictive biomarker analysis was reported in another abstract. Further study is needed to validate the efficacy of this combination. Clinical trial information: NCT03486678.