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Leijuan Gan,1– 3,* Mengran Lang,1– 4,* Xindi Tian,1– 3 Shaohua Ren,1– 3 Guangtao Li,1– 3 Yayue Liu,1– 3 Ruyu Han,1– 3 Kangwei Zhu,1– 3 Huikai Li,1– 3 Qiang Wu,1– 3 Yunlong Cui,1– 3 Wei Zhang,1– 3 Feng Fang,1– 3 Qiang Li,1– 3 Tianqiang Song1– 3 1Department of Hepatobiliary Cancer, Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, People’s Republic of China; 2Key Laboratory of Cancer Prevention and Therapy, Tianjin, People’s Republic of China; 3Tianjin’s Clinical Research Center for Cancer, Tianjin, People’s Republic of China; 4Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Hebei Cancer Hospital, Chinese Academy of Medical Sciences, Langfang, Hebei, 065001, People’s Republic of China*These authors contributed equally to this workCorrespondence: Tianqiang Song, Tel +86-022-23340123, Fax +86 022-23537796, Email songtianqiangtj@163.comPurpose: The purpose of this study was to investigate the triple-combination therapy of lenvatinib plus sintilimab plus arterially-directed therapy as a conversion therapy for initially unresectable hepatocellular carcinoma (HCC).Patients and Methods: We retrospectively analyzed data from all HCC patients who underwent lenvatinib plus sintilimab plus arterially-directed therapy at Tianjin Medical University Cancer Hospital between December 2018 and October 2020. Of 98 enrolled patients, 37 patients were classified as potentially resectable. We compared the potentially resectable population (PRP) with the non-potentially resectable population (NPRP). The primary study endpoint was conversion rate, and secondary endpoints included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety.Results: The baseline characteristics were comparable between populations except for a higher proportion of patients with extrahepatic metastases in the NPRP versus PRP (23/61 [37.7%] vs 3/37 [8.1%], respectively; p=0.003). For PRP, the ORR was 67.6% based on RECIST v1.1 (75.7% based on mRECIST), conversion rate was 40.5% (15/37). Of the 15 patients who underwent surgical resection, three achieved complete pathological remission. The median follow-up for all patients was 28 months (range: 2– 47). For NPRP, the ORR was 22.9% based on RECIST v1.1 (31.1% based on mRECIST), The median PFS for PRP was significantly longer than that of NPRP (25 vs 13 months, p = 0.0025). The median OS for PRP was significantly longer than that of NPRP (not reached VS 21 months, p=0.014). Hypertension was the most common grade ≥ 3 adverse reaction in both PRP and NPRP. No new safety signals were observed for any of the treatments.Conclusion: The triple-combination therapy of lenvatinib plus sintilimab plus arterially-directed therapy can convert potentially unresectable HCC into resectable disease and improve long-term survival.Keywords: lenvatinib, sintilimab, conversion therapy, unresectable hepatocellular carcinoma, TACE, HAIC

We explored the prognostic value of preoperative CA19-9 in α-fetoprotein (AFP)-positive and -negative HCC with hepatitis B virus (HBV) background (HBV-HCC), and explored the underlying mechanism. Recurrence-free survival (RFS) and overall survival (OS) were assessed in HBV-HCC patients who underwent curative resection (Cohort 1). Immunohistochemical staining of CA19-9 in HCC and liver parenchyma were quantified in another cohort of 216 patients with resected HCC (Cohort 2). Immunohistochemical staining of CA19-9 and serum CA19-9 level was also compared between patients with HCC and intrahepatic cholangiocarcinoma (ICC) (Cohort 3). In Cohort 1, CA19-9 ≥ 39 U/mL was an independent risk factor for RFS (HR = 1.507, 95% CI = 1.087-2.091, p = 0.014) and OS (HR = 1.646, 95% CI = 1.146-2.366, p = 0.007). CA19-9 ≥ 39 U/mL was also associated with significantly higher incidence of macrovascular invasion (MaVI) compared with CA19-939 U/mL (23.0% vs. 7.2%, p = 0.002), and elevated aminotransferase and aspartate aminotransferase to platelet ratio index (APRI), and lower albumin. Immunohistochemical staining of CA19-9 revealed that CA19-9 expression was found exclusively in the background liver but not in HCC tumor cells. In contrast, tumor tissue was the main source of CA19-9 in ICC patients. CA19-9 ≥ 39 U/mL was associated with worse OS and RFS in both AFP-positive and negative HCC patients. CA19-9 indicated more severe inflammation and cirrhosis in the liver of HCC patients.

Hepatocellular carcinoma (HCC) has emerged as a leading cause of cancer-related deaths globally, in which hypoxia and activated hypoxia-inducible factors (HIFs) play important roles. The sibling rivalry between HIF-1α and HIF-2α in hypoxic tumor growth and progression still remains to be resolved, including in HCC. In this study, we aimed to analyze the mechanism by which HIF-1α and HIF-2α balance the proliferative response of HCC cells to hypoxia. The expression of HIF-1α, HIF-2α, c-MYC, Rictor and Raptor in corresponding tumor and non-tumor tissues from twenty-six patients with HCC was analyzed. The relationships between HIF-1α and HIF-2α and their respective effects were evaluated further in vitro in hypoxic HCC cells using co-immunoprecipitation, chromatin immunoprecipitation, in situ proximity ligation, annexin V-FITC/PI staining apoptosis and MTT assay. In addition, short hairpin RNA (shRNA) transfections targeting HIF-1α/2α and Rictor and Western blotting were applied in HCC cells to study the underlying mechanism. We found that HIF-2α expression showed a positive correlation with c-MYC expression in tumor tissues, whereas HIF-1α did not. In vitro, increased HCC cell proliferation and an increased interaction between HIF-2α and c-MYC were observed under mild chronic hypoxic conditions. Although mild hypoxia led to HIF-1α, HIF-2α and c-MYC up-regulation, we found that mTORC2-regulated HIF-2α competed with HIF-1α to bind to c-MYC. Moreover, we found that HIF-2α knockdown decreased the expression of downstream c-MYC, suppressed hypoxic cell proliferation, and induced HCC cell apoptosis, whereas HIF-1α knockdown did not. Additionally, we found that the PI3K inhibitor apitolisib counteracted the effect of HIF-2α, thereby inducing HCC cell apoptosis. Our data highlight a role of HIF-2α in activating and binding c-MYC, thereby inducing HCC cell proliferation during mild chronic hypoxia. The PI3K/mTORC2/HIF-2α/c-MYC axis may play a key role in this process. The PI3K inhibitor apitolisib may serve as a potential treatment option for patients suffering from HCC, especially in cases with rapidly growing tumors under mild chronic hypoxic conditions.

Liver hepatocellular carcinoma (LIHC) is the most common primary liver cancer and the main cause of death in patients with cirrhosis. LRP1B is found to involve in a variety of cancers, but the association of LRP1B mutation with tumor mutation burden (TMB) and prognosis of LIHC is rarely studied.Herein, we analyzed the somatic mutation data of 364 LIHC patients from The Cancer Genome Atlas (TCGA) and found that LRP1B showed elevated mutation rate. Calculation of the TMB in LRP1B mutant and LRP1B wild-type groups showed that LRP1B mutant group had higher TMB compared with that in LRP1B wild-type group. Then survival analysis was performed and the survival curve showed that LRP1B mutation was associated with poor survival outcome, and this association remained to be significant after adjusting for multiple confounding factors including age, gender, tumor stage, mutations of BRCA1, BRCA2, and POLE.Collectively, our results revealed that LRP1B mutation was related to high TMB value and poor prognosis in LIHC, indicating that LRP1B mutation is probably helpful for the selection of immunotherapy and prognosis prediction in LIHC.

Purpose Few studies have investigated the efficacy of triple combination therapy with lenvatinib, programmed cell death 1 (PD-1) inhibitors and transarterial therapy in patients with intermediate/advanced hepatocellular carcinoma (HCC). Patients and methods We retrospectively analyzed patients with intermediate/advanced HCC treated at Tianjin Cancer Hospital from December 2018 to October 2020 and compared outcomes of lenvatinib plus PD-1 inhibitors and transarterial therapy (LEN-PD1-TH) versus lenvatinib and PD-1 inhibitors (LENPD1). Propensity score-matching was used. The primary study endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS) and overall response rate (ORR) assessed using modified RECIST. The Cox proportional hazards model was used to identify factors that affected prognosis. Results In total, 152 patients were included. Propensity score matching led to 35 matched patients in each group. The median follow-up time was 14 months (95% CI, 10.1-17.9) as of May 2021. The LEN-PD1-TH group had a longer median PFS and OS versus the LEN-PD1 group (15 vs. 9 months; P=0.004 and 14 months vs. NA; P3, BCLC stage C, and alpha-fetoprotein ≤400 ng/ml showed a tendency to benefit from the triple therapy regimen. The addition of transarterial therapy to lenvatinib and PD-1 inhibitors did not significantly increase adverse reactions. Conclusions LEN-PD1-TH improved survival outcomes for patients with intermediate to advanced HCC compared to LEN-PD1.

Few studies have evaluated the value of endoscopic resection (ER) for the treatment of gastric gastrointestinal (GI) stromal tumors (GISTs) originating from the muscularis propria (MP) in a large population, and no studies have evaluated risk factors for piecemeal resection. This study aimed to evaluate the efficacy and safety of ER for gastric GISTs in a real-world setting and to explore factors associated with piecemeal resection. From January 2013 to December 2019, 185 patients with gastric GISTs originating from the MP were assessed. Clinicopathological and endoscopic data were collected and analyzed. Baseline characteristics of the en bloc resection and piecemeal resection groups were compared to evaluate predictive factors for piecemeal resection. There were 71 males and 114 females with a mean age of 57.0 ± 9.7 years. The mean size of GISTs was 15 mm (range 4–65 mm). A total of 123 were very low risk, 52 were low risk, and ten were moderate risk. In this study, 103 GISTs were treated with endoscopic submucosal excavation (ESE), 68 GISTs were treated with endoscopic full-thickness resection (EFR), and 14 GISTs were treated with submucosal tunneling ER (STER). Either en bloc resection or complete resection was achieved in 160 (86.5%) patients. No recurrence was noted during follow-up. Only five patients experienced minor complications, with a complication rate of 2.7%. Multivariate analysis demonstrated that size (odds ratio [OR] 1.060, 95% confidence interval [CI] 1.004–1.118; P = 0.035) and shape (OR 5.434, 95% CI 1.638–18.027; P = 0.006) were independent predictors of piecemeal resection. ER was effective and safe for the treatment of gastric GISTs originating from the MP. Piecemeal resection did not seem to affect the efficacy of ER, and no recurrence was noted during follow-up. Large size and irregular shape are risk factors related to piecemeal resection of ER.

No study has evaluated the diagnostic value of SpyGlass by comparing SpyGlass results and non-SpyGlass results. In this retrospective study, we aimed to compare the diagnostic value of EUS-guided fine-needle aspiration (EUS-FNA) and EUS-FNA combined with SpyGlass to evaluate whether SpyGlass is valuable for increasing the diagnostic yield of EUS-FNA. From April 2015 to April 2020, 251 patients suspected of having pancreatic cystic lesions (PCLs) by imaging techniques who then underwent EUS-FNA were retrospectively enrolled. Only 98 patients who underwent surgical resection with a pathological diagnosis of pancreatic cystic lesion (PCL) were studied. The diagnostic performance outcomes were compared between the EUS-FNA group (EUS-FNA alone, n = 40) and the SpyGlass group (EUS-FNA combined with SpyGlass, n = 58) to assess the value of SpyGlass in diagnosing PCLs. There were 71 females and 27 males with an overall mean age of 47.6 years. The median diameter of the PCLs was 42.2 mm (range, 11.4–100.0 mm). Approximately 37 cysts were localized in the head/neck of the pancreas, while 61 in the body/tail. The sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy of the EUS-FNA group were 96.4% (27/28), 83.3% (10/12), 93.1% (27/29), 90.9% (10/11) and 92.5% (37/40), while those in the SpyGlass group were 100% (54/54), 75% (3/4), 98.2% (54/55), 100% (3/3) and 98.3% (57/58), respectively. The diagnostic accuracy rate in the SpyGlass group was higher than that in the EUS-FNA group; however, no significant difference was found between the two groups (P = 0.368). The diagnostic accuracy of evaluating specific cyst types in the EUS-FNA group was 85% (34/40), similar to that in the SpyGlass group (85.0% vs 84.5%, P = 0.944). SpyGlass seems less valuable for the diagnosis of PCLs when EUS and EUS-FNA have been performed by experienced endoscopists.

Background: Biliary tract cancer (BTC) refers to malignancies arising from the bile ducts, gallbladder, and ampulla of Vater. ctDNA-based MRD testing has shown promise in identifying surgical patients at high risk of recurrence, although there is a paucity of evidence on its utility in BTC. In this study, we prospectively evaluated the performance of Burning Rock Patient-specific pROgnostic and Potential tHErapeutic marker Tracking (brPROPHET), a patient-specific, tumor-informed MRD assay. Methods: Surgical specimens and two serial blood biopsies (before and approximately 4 weeks after surgery) were collected. The brPROPHET MRD assay (Burning Rock Biotech, China) uses whole exome sequencing for detecting patient-specific somatic alterations from tumor tissues and for blood a personalized panel designed to target up to 50 variants. For head-to-head comparison, the samples were also subjected to a tumor-informed, fixed-panel assay using 520- and 168-gene panels respectively for tumor and blood samples. Results: A total of 17 patients were analyzed. Most were men (11, 64.7%), had extrahepatic cholangiocarcinomas (13, 76.5%), or stage II disease (15, 88.2%). Median age was 64 years (range 57-68). Disease-free survival (DFS) was available for 14 patients at a median follow-up of 11.5 months (range 6.5-16.0). Baseline and postoperative ctDNA positivity rates were 64.7% (11/17) and 11.8% (2/17) with brPROPHET and 17.7% (3/17) and 5.8% (1/17) with the fixed-panel assay using 520- and 168-gene panels. Moreover, of the 3 patients who have relapsed, 1 was postoperatively ctDNA-positive by both assays and 1 only by brPROPHET. These findings suggested superior technical sensitivity of patient-specific over fixed-panel approach in detecting tumor-associated aberrations, and this advantage could translate into more sensitive identification of surgical BTC patients at high risk of recurrence. Furthermore, ctDNA positivity determined brPROPHET by was significantly associated with shorter DFS (log-rank p = 0.003), while that by fixed-panel was not (log-rank p = 0.113), suggesting a stronger association between the patient-specific approach with clinical outcomes. brPROPHET-derived postoperative ctDNA positivity also showed higher negative predictive value (91.7% vs 84.6%) and accuracy (92.9% vs 85.7%) in predicting recurrence. Together, these results supported a better performance of brPROPHET than the fixed panel approach for MRD detection. Conclusions: This prospective study demonstrated the clinical performance of brPROPHET, a patient-specific tumor-informed ctDNA-based MRD test for surgical patients with BTC. Compared with the fixed-panel approach using 520- and 168-gene panels respectively for tumor and blood samples, brPROPHET yields higher sensitivity, accuracy, and negative predictive value in predicting relapse. Citation Format: Tianqiang Song, Qiang Wu, Yunlong Cui, Huikai Li, Wei Zhang, Feng Fang, Qingqing Xiong. A patient-specific, tumor-informed, circulating tumor DNA (ctDNA)-based minimal residual disease (MRD) assay in surgical patients with biliary tract cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6682.

Gastric schwannoma (GS) is not well clinically recognized and surgical resection (SR) remains the mainstay of treatment. Recently, endoscopic resection (ER) appears to be a safe and effective alternative. However, its comparative outcomes with SR is lacking. Our aim was to first compare clinical outcomes and costs between ER and SR in the management of GSs. A total of 46 consecutive patients with GSs who underwent ER (n = 16) or SR (n = 30) in our large tertiary center between July 2007 and Oct 2018 were included. Clinicopathologic features, clinical outcomes, medical costs and follow-up were retrospectively reviewed and compared between two groups. Baseline characteristics are comparable except for a smaller tumor size in ER group (22.9 vs 41.0 mm, p = 0.002). Complete resection was achieved in 87.5% of patients with ER and 100% of patients with SR (p = 0.116). The ER group had a significant shorter operative time (91.6 vs 128.2 min), less blood loss (16.9 vs 62.7 mL) and lower operation cost (21,054.4 vs 30,843.4 RMB) than SR group (all p

The incidence of postoperative stenosis after endoscopic resection of wholly circumferential superficial esophageal squamous cell neoplasms (SESCNs) is extremely high. Between January 2011 and April 2019, 19 patients who underwent autologous skin-grafting surgery (ASGS) after complete circular endoscopic submucosal tunnel dissection (ccESTD) were enrolled to form the ASGS group. Cases in the ASGS group were individually matched at a 1:1 ratio to cases undergoing fully covered esophageal stent (FCES) placement alone (FCES group) based on pathological diagnosis, curative resection, longitudinal length of ulceration, lack of stent migration, time to stent removal, follow-up period and operators. Baseline characteristics and treatment outcomes were compared between the two groups. Baseline characteristics were comparable between the ASGS group and the FCES group. The incidence of patients with esophageal stenosis after removal of the stent in the ASGS group was significantly reduced compared that in the FCES group (36.8% vs 78.9%, p = 0.020). Comparison of preventive methods (ASGS vs FCES alone) between the stenosis group and nonstenosis group revealed that ASGS accounted for a higher proportion than FCES alone in the nonstenosis group (p = 0.020). Compared with FCES placement alone, ASGS appeared to be more effective in preventing esophageal stenosis after ccESTD for SESCNs.

Purpose We retrospectively evaluated the efficacy and safety of apatinib as a first-line treatment for advanced hepatocellular carcinoma (HCC) and explored whether drug -related hypertension (HTN) could predict its efficacy. Patients and methods This retrospective analysis included patients with advanced HCC who received oral treatment with apatinib. We evaluated the effectiveness by overall survival (OS), progression-free survival (PFS), time to progression (TTP), and disease control rate (DCR), and assessed the safety of the drug based on the occurrence of adverse events. In order to explore whether apatinib-related HTN can be used as a predictor of therapeutic effect, patients were divided into an HTN group and a non-HTN group and adjusted for propensity score-matched (PSM) to reduce mixed deviation. Subgroup analyses of negative prognostic factors for advanced HCC were also performed, including alpha-fetoprotein (AFP), Child-Pugh Score, macrovascular invasion, and extrahepatic metastasis. Results A total of 208 patients were analyzed, of which 40.9% (n =85) developed drug-related HTN. For all patients, the OS was 13.4 months (95% CI, 12.2-14.6), the PFS was 5.7 months (95% CI, 5.1-6.3), and the TTP was 6.9 months (95% CI, 6.0-7.8). The OS of the HTN group and the non-HTN group was 17.4 months (m) and 12.5m (p=0.001), and the PFS was 7.4m and 4.7m (p=0.000), respectively. After PSM, the OS (p=0.001) and PFS (p=0.003) of the HTN group were still significantly better than the non-HTN group. Subgroup analysis suggested that overall survival was significantly longer in patients with HTN when serum AFP ≤400 μg/L or extrahepatic metastases. Moreover, OS in the HTN group increased significantly with or without macrovascular invasion. In addition, through the analysis of two groups of patients with PFS>6m and PFS≤6m, we know that the patients with drug-related HTN may develop resistance later, so they have longer survival time. Conclusion Apatinib demonstrates compelling anti-cancer activity and acceptable safety in advanced HCC. Apatinib-related HTN can potentially predict prolonged survival in patients with advanced HCC.

Sorafenib and lenvatinib are currently standard treatments for advanced hepatocellular carcinoma (HCC); however, the therapeutic effect is unsatisfying. Indeed, very few patients with HCC under sorafenib treatment were eligible for surgery in the past ten years. In addition, there is no report of a patient with the opportunity to undergo radical resection after treatment with lenvatinib. Here, we describe five patients with advanced and unresectable HCC that were able to receive curative resection within 1 year of treatment with the tyrosine kinase inhibitor apatinib that selectively inhibits vascular endothelial growth factor receptor 2 (VEGFR2). The five patients with advanced and unresectable HCC were treated with apatinib (250 mg po, qd), and all the five patients obtained an objective response to the treatment, allowing for subsequent resection, and the second patient even obtained a pathological complete response. The latest follow-up date was August 20, 2019, and all patients were alive at the latest follow-up. The disease-free survival of the first patient was 13 months. Lung metastasis was found 12 months later after surgery for patient 5. The other three patients have no recurrence. This is the first report of a single drug with promising therapeutic effects in patients with advanced HCC within one year at a single center. Therefore, apatinib may be promising for some patients with locally advanced HCC to undergo radical resection and improve outcomes.

Unlike apoptosis, necroptosis is a tightly regulated form of programmed cell death (PCD) that occurs in a caspase-independent manner and is mainly triggered by receptor-interacting serine/threonine-protein kinases RIPK1 and RIPK3 and the RIPK3 substrate mixed-lineage kinase domain-like protein (MLKL). A growing body of evidence has documented that necroptosis, as a novel therapeutic strategy to overcome apoptosis resistance, has potential pro- or anti-tumoral effects in tumorigenesis, metastasis, and immunosurveillance. However, comprehensive multi-omics studies on regulators of necroptosis from a pan-cancer perspective are lacking.In the present study, a pan-cancer multi-omics analysis of necroptosis-related regulators was performed by integrating over 10,000 multi-dimensional cancer genomic data across 33 cancer types from TCGA, 481 small-molecule drug response data from CTRP, and normal tissue data from GTEx. Pan-cancer pathway-level analyses of necroptosis were conducted by gene set variation analysis (GSVA), including differential expression, clinical relevance, immune cell infiltration, and regulation of cancer-related pathways.Genomic alterations and abnormal epigenetic modifications were associated with dysregulated gene expression levels of necroptosis-related regulators. Changes in the gene expression levels of necroptosis-related regulators significantly influenced cancer progression, intratumoral heterogeneity, alterations in the immunological condition, and regulation of cancer marker-related pathways. These changes, in turn, caused differences in potential drug sensitivity and the prognosis of patients.Necroptosis-related regulators are expected to become novel biomarkers of prognosis and provide a fresh perspective on cancer diagnosis and treatment.

544 Background: The combination of bevacizumab and immune checkpoint inhibitors (ICI) has demonstrated promising efficacy and safety in the first-line treatment of advanced hepatocellular carcinoma (HCC). However, this combination has not been examined in patients with previous first-line treatment of ICI and tyrosine kinase inhibitor. This study aimed to investigate the effectiveness and safety of bevacizumab combined with atezolizumab or sintilimab as second-line treatment in patients with advanced HCC. Methods: The retrospective study included patients with advanced HCC who received combined therapy of bevacizumab and atezolizumab or sintilimab after failure of lenvatinib plus ICI between July 28, 2020 and March 7, 2022. Baseline patient characteristics were collected. Treatment response, overall response rate (ORR) and disease control rate (DCR) were evaluated according to response evaluation criteria in solid tumors (RECIST) version 1.1. Overall survival (OS) and progression-free survival (PFS) were analyzed by the Kaplan-Meier method. Treatment-related adverse events were graded according to Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. Results: A total of 20 patients with advanced HCC were included, with a median follow-up time of 11.05 (5.03-20.63) months. Eleven patients died by the last follow-up on August 12, 2022. There were 18 males (90%) and two females (10%). The average age was 59.9±12.08 years. Seven patients (35%) had distant metastasis, and nine (45%) had vascular invasion. Liver function was classified as Child-Pugh grade A in 17 patients (85%) and grade B in three (15%). Patients with Barcelona Clinic Liver Cancer (BCLC) stages B, C and D were 1 (5%), 16 (80%) and 3 (15%), respectively. Eighteen patients (90%) had previous topical therapy. Of all patients previously administered lenvatinib plus ICI as first-line treatment, 14 (70%) had PFS longer than three months. ORR and DCR were 15% (95% confidence interval [CI], 3.2-37.9) and 55% (95% CI, 31.5-76.9), respectively. Median OS was 8.00 months (95% CI, 0.00-16.66), while median PFS was 3.80 months (95% CI, 2.41-5.19). Adverse events were observed in 14 patients (70%). Adverse events of grade 3 or worse occurred in six patients (30%). Conclusions: The combination of bevacizumab with atezolizumab or sintilimab had tolerable safety profile but poor response in the second-line treatment of HCC. Despite the satisfying efficacy as first-line therapy, this combination is not a cost-effective recommendation for advanced HCC cases who failed the first-line treatment of lenvatinib plus ICI. [Table: see text]

Background Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related deaths worldwide every year, and most HCC patients are diagnosed with advanced disease and can only receive systemic treatment. TKIs are the most important components of the systemic treatment of HCC and have both good efficacy and adverse events (AEs). Methods This analysis included 207 patients with locally advanced unresectable or metastatic HCC who received oral treatment with apatinib. We analyzed the overall survival (OS) and progression-free survival (PFS) of patients with or without corresponding AEs to evaluate which AEs can predict the efficacy of apatinib. Results Patients with hand-foot syndrome (HFS; p = 0.005), proteinuria (p = 0.006) and diarrhea (p p = 0.006) and proteinuria (p = 0.004) was associated with longer PFS. Conclusion Among all the AEs induced by apatinib in the treatment of advanced HCC, proteinuria could potentially predict PFS, and diarrhea was a potential predictor of OS.

The techniques and indications for endoscopic submucosal dissection (ESD) and endoscopic submucosal tunnel dissection (ESTD) to remove superficial neoplasia at the esophagogastric junction (EGJ) have been developed and expanded. However, the resection of superficial neoplasia at the EGJ by ESD remains challenging, and the long-term clinical outcomes of curative and non-curative resections based on histological criteria remain unclear. We conducted a retrospective analysis on the safety and efficacy of the ESD and ESTD procedure with these patients. The records of 209 consecutive patients at the Chinese PLA General Hospital who received ESD and ESTD to treat EGJ superficial neoplasia from November 2006 to December 2016 were reviewed for this retrospective cohort study. We divided patients into two groups (curative and non-curative resection). Of all 14 additional surgeries, 1 patient in the curative group and 13 in the non-curative group underwent surgical operation with residual tumor in 7 specimens. During a median follow-up period of 46.4 months (range 12.2–142.3 months), the 5-year survival rate was 98.6%. Two patients died 91 months and 66 months after surgery due to subarachnoid hemorrhage and lymphoma, respectively. One patient died of gastric cancer 1 year after the surgery. The 5-year disease-specific survival rate was 99.5%. Local tumor recurrence was detected in 9 of 209 cases. In conclusion, ESD was shown to be a safe and effective treatment strategy for early EGJ neoplasia. Mucosal adhesion may increase the difficulty of piecemeal curative resection, but the superficial depth of such an invasion favors better clinical outcomes. Additional surgical resection is a good choice for non-curative ESD, and re-ESD is also an alternative, in conjunction with intensive follow-up.

4073 Background: Sintilimab plus IBI305, a bevacizumab biosimilar, showed a significant overall survival and progression-free survival benefit versus sorafenib in the first-line setting for patients with unresectable hepatocellular carcinoma. Hepatic arterial infusion chemotherapy is an intraarterial procedure that has been widely used in Asia, with high response rate. This trial was designed to assess the feasibility and efficacy of HAIC combined with sintilimab and IBI305 in advanced unresectable hepatocellular carcinoma. Methods: This is a prospective, single-arm phase II study. Patients with histologically or cytologically diagnosed or clinically confirmed hepatocellular carcinoma, China liver cancer staging (CNLC) stage IIb-IIIb, no previous systemic treatment, Child-Pugh classification A or B, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 were eligible for inclusion. Patients received FOLOFOX-HAIC, followed by intravenous sintilimab (200 mg every 3 weeks, four cycles) and intravenous IBI305 (7.5 mg/kg every 3 weeks, three cycles). The primary endpoint was objective response rate (ORR) per mRECIST. Secondary endpoint were surgical conversion rate, pCR rate and R0 resection rate. The study is registered with Clinicaltrials.gov: NCT05029973. Results: Between May, 2021 to Sep, 2021, a total of 30 eligible patients were enrolled: median age 54.5 years (range 37-73); M:F 27:3; CNLC stage IIb/IIIa/IIIb: 3/16/11; Child-Pugh class A/B: 28/2; ECOG PS 0/1: 26/4. There were 23(76.7%) patients with hepatitis B and 5(16.7%) with hepatitis C. The median tumor size was 8.75 cm (interquartile range [IQR], 4.9-10.5), 60.0% pts present vascular invasion, and 36.7% had extrahepatic metastasis. Of 30 pts evaluable for response, 20 (66.7%; 95% CI: 47.2%-82.7%) achieved confirmed partial response, and became eligible for surgical resection. Finally, 14 of them received surgical resection and all (100%) achieved R0 resection, 3 pts completed radiofrequency ablation (RAF), 3 pts refused resection or RFA. The pCR rate in the patients completed pathological examination was 52.6% (95% CI: 28.9%-75.6%). The most common TRAEs included hypertension (23.3%), rash (16.7%), and abnormal liver function (10.0%). No grade 3-4 TRAEs were observed. Of note, in patients received surgery, 1 developed grade 1 biliary fistula, 1 developed hepatic failure and finally lead to death Conclusions: HAIC Combined With sintilimab and IBI305 resulted in a promising ORR, R0 surgical conversion rate and pCR rate with a manageable safety for initial unresectable advanced hepatocellular carcinoma. Further follow-up is ongoing. Clinical trial information: NCT05029973.

Huaqi Wang,1,&ast; Zhiwei Wang,1,&ast; Zhenyu Hou,1 Xuejiao Yang,1 Keyun Zhu,1 Manqing Cao,2 Xiaolin Zhu,1 Huikai Li,1 Ti Zhang1,3 1Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital; Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital; National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin’s Clinical Research Center for Cancer, Tianjin, 300060, People’s Republic of China; 2Department of Breast Surgery, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, People’s Republic of China; 3Department of Hepatic Surgery, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, 200032, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ti ZhangDepartment of Hepatic Surgery, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, 200032, People’s Republic of ChinaTel/Fax +86-21-6417-5590Email zhangti@shca.org.cnHuikai LiDepartment of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, 24 Bin Shui Road, Hexi District, Tianjin, 300060, People’s Republic of ChinaTel/Fax +86-22-2335-9984Email tjchlhk@126.comPurpose: Patients with hepatocellular carcinoma (HCC) who might benefit most from anti-angiogenesis therapy remain unknown. In recent years, neutrophil-to-lymphocyte ratio (NLR), an indicator of inflammatory response, has received particular attention in HCC. Herein, we explored the prognostic value of pre-treatment NLR in individuals with unresectable intermediate and advanced hepatocellular carcinoma treated with apatinib, a second-line angiogenesis inhibitor. The findings of this study would assist in precision medicine and provide clinical decision support.Patients and Methods: This is a retrospective study in which 171 HCC patients attending Tianjin Medical University Cancer Institute and Hospital and treated with apatinib between January 2016 and July 2018 were enrolled. The prognosis of the patients based on NLR signatures was then analyzed.Results: Patients with a low pre-treatment NLR (NLR < 2.49) presented a significantly longer overall survival (OS) (P < 0.001) and progression-free survival (PFS) (P = 0.043). Furthermore, a low pre-treatment NLR level could be used to predict a longer OS in patients with non-macrovascular invasion (P < 0.001). Independent of serum alpha-fetoprotein (AFP) levels, a low NLR level in this cohort of patients is associated with a longer OS.Conclusion: Pre-treatment NLR predicts the prognosis of patients with unresectable intermediate and advanced HCC treated with apatinib.Keywords: hepatocellular carcinoma, vascular endothelial growth factor receptor - 2, neutrophil to lymphocyte ratio, tyrosine protein kinases inhibitor

Background and Objectives We initially reported EUS-guided lauromacrogol ablation (EUS-LA) to treat pancreatic cystic neoplasms (PCNs); however, its long-term effectiveness remains unknown. This study was performed to further determine the effectiveness of EUS-LA in a larger population with a long-term follow-up based on 5 years of experience with EUS-LA. Materials and Methods From April 2015 to April 2020, 279 patients suspected of having PCNs were prospectively enrolled, and seventy patients underwent EUS-guided ablation using lauromacrogol alone. Fifty-five patients underwent follow-up, 35 of whom had a follow-up duration of at least 12 months. The effectiveness of ablation was determined based on volume changes. Results Among the fifty female and twenty male patients with an overall mean age of 50.3 years, cysts were located in the head/neck of the pancreas in 37 patients (52.9%) and in the body/tail of the pancreas in 33 patients (47.1%). The adverse events rate was 3.6% (3/84), with 14 patients undergoing a second ablation. Among the 55 patients who underwent follow-up, the median cystic volume sharply decreased from 11,494.0 mm3 to 523.6 mm3 (P < 0.001), and the mean diameter decreased from 32.0 mm to 11.0 mm (P < 0.001). Postoperative imaging showed complete resolution (CR) in 26 patients (47.3%) and partial resolution (PR) in 15 (27.3%) patients. CR was observed in 18 (51.4%), and PR was observed in 9 (25.7%) patients among the 35 patients followed for at least 12 months. Conclusions EUS-LA was effective and safe for the treatment of PCNs with stable effectiveness based on at least 12 months of follow-up.

Background and Aim. Although a strong antitumor effect of lenvatinib has been noted for patients with unresectable hepatocellular carcinoma (HCC), its efficacy requires improvement. It is imperative to seek therapeutic strategies that combine Lenvatinib with other anticancer agents. In this study, we investigated the anticancer effect of combining lenvatinib with alisertib, aurora A kinase (AURKA) target drug, against HCC in vitro and in vivo. Methods. Immunohistochemical staining, sequencing, and genetic analysis of liver cancer tissues were performed. The antitumor efficacy of single-agent or combination treatment was measured by cell counting kit-8 assay and colony formation assays. Their antiproliferative and apoptosis activity is evaluated by cell cycle analyses and wound healing assays. The DNA-related proteins were also measured by Western blotting and immunohistochemical staining. The HepG2 xenograft model was used to detect the effects of lenvatinib-alisertib on the antitumor activity. Results. AURKA was found to be upregulated in HCC tissues (77.3%, 17/22). Combined alisertib and lenvatinib treatment significantly enhanced the inhibition of proliferation and migration in HepG2 and Hep3B cell lines compared to single-agent treatments (all P s < 0.01 ). Alisertib alone or in combination with lenvatinib demonstrated a significant increase in the percentage of super-G2 cells (lenvatinib 1 μM vs. lenvatinib 1 μM + alisertib 0.1 μM 8.84 ± 0.84 vs. 34.0 ± 1.54 , P < 0.001 ). Discontinuous spindles and missegregated chromosomes in HCC cells treated with alisertib in combination with lenvatinib were observed. We further revealed that combined treatment inhibited the expression of DNA damage pathway proteins compared to those of single-agent treatments. In nude mice, combined administration of alisertib combined with lenvatinib significantly enhanced the suppression of tumor growth and induced apoptosis (all P s < 0.01 ). Conclusions. Our findings provide evidence for the possible use of alisertib in combination with lenvatinib in the treatment of HCC for better therapeutic outcomes.

Background The prognosis for advanced hepatocellular carcinoma (HCC) remains clinically unsatisfying. Apatinib has proven to be a very effective treatment for advanced HCC in our previous retrospective study. Our aim in this study was to evaluate the efficacy, safety, and toxicity of apatinib in patients with advanced HCC. Methods This single-arm, open-label phase II clinical trial enrolled patients with advanced HCC. These patients received apatinib, 500 mg once daily, until disease progression, unacceptable toxicity, consent withdrawal, or death. One treatment cycle consisted of 4 weeks of apatinib treatment. The response evaluation criteria in solid tumors (RECIST) was used to assess tumor response every 1-2 cycles. The primary endpoint was the objective response rate (ORR), while the secondary endpoints were the overall survival (OS), progression-free survival (PFS), disease control rate (DCR), and toxicity. Results Between December 2016 and June 2018, 23 patients were enrolled in the study, 22 of whom were available for response evaluation. The cutoff date was August 10, 2018. The overall ORR and DCR were 30.4% and 65.2%, respectively. The median OS and PFS were 13.8 (95% CI: 5.3-22.3) and 8.7 (95% CI: 5.9-11.1) months, respectively. The most common treatment-related adverse events were proteinuria (39.1%), hypertension (34.8%), and hand-foot-skin reaction (34.8%). Conclusions Apatinib showed robust clinical activity in patients with advanced HCC. Moreover, apatinib was safe to use, well tolerated, and had acceptable toxicity. (NCT03046979).

Herpesvirus entry mediator (HVEM) displays dual signals in T-cell activation according to the ligands and intracytoplasmic effectors it interacts with. High HVEM expression may play an immunosuppressive role in several malignancies. The present study investigated the clinical impact of HVEM on intrahepatic cholangiocarcinoma (ICC), including its prognostic value, and association with clinicopathological features and immune status. The clinical data of 102 consecutive patients with ICC who underwent surgical treatment from January 2012 to December 2017 were collected. The expression of HVEM and different types of tumor-infiltrating lymphocytes (TILs) were investigated in ICC tissue samples by immunohistochemical staining. HVEM expression was detected in the tumor tissues of 92 (90.2%) patients with ICC. Patients with high HVEM expression were more likely to have increased peripheral blood lymphocyte (PBL) concentrations (P=0.031), decreased CEA (P=0.036), low TNM stage (P=0.043) and high frequencies of small-duct histological type (P=0.021) and BAP1 retained expression (P=0.010). Survival analysis showed that high HVEM expression was a favorable independent predictor of overall postoperative survival (P=0.034, hazard ratio=0.486, 95% confidence interval=0.249-0.945). In addition, no significant association of HVEM expression with CD4+ (P=0.512), CD8+ (P=0.750) or CD45RO+ (P=0.078) TILs was identified in the ICC tissues. These results indicate that HVEM may serve as a favorable prognostic marker for ICC. Furthermore, co-stimulatory signals from HVEM may play a dominant role in the progression of ICCs, which can be explained by an increase in the number of PBLs rather than a change in the number of TILs. However, the function of the HVEM network in ICC progression is complex and requires further study.

Background: Hepatocellular carcinoma (HCC) has emerged as a major cause of cancer deaths globally, in which hypoxia and activated hypoxia-inducible factors (HIFs) play an important role. The sibling rivalry between HIF-1α and HIF-2α in hypoxic tumor growth and progression is still debated, including in HCC. This may be associated with the regulation of unique target genes, like c-MYC and mTOR. Methods: In the current study, twenty-six corresponding tumor- and non-tumor tissues, taken from patients with HCC, who underwent liver resection, were analyzed. In vitro, co-immunoprecipitation (Co-IP), Western blot, MTT assay, colony formation assay and Annexin V-FITC/PI staining apoptosis Assay were used to elucidate the relationship between HIF-1α and HIF-2α in hypoxic HCC cell proliferation and involved mechanism.Results: HIF-2α, but not HIF-1α, has a positive correlation with the expression of c-MYC in tumor tissues. In vitro, rapid HCC cell proliferation and increased interaction of HIF-2α/c-MYC were observed in mild chronic hypoxia. It was confirmed in situ proximity ligation assay and co-immunoprecipitation assay that although mild hypoxia up-regulated all HIF-1α, HIF-2α, and c-MYC, mTORC2-regulated HIF-2α competed with HIF-1α to bind c-MYC. HIF-2α knockdown, but not HIF-1α knockdown, decreased the expression of downstream c-MYC and mTORC1, suppressed hypoxic cell proliferation, and induced more cell apoptosis. Moreover, the inhibition of upstream protein PI3K by inhibitor Apitolisib counteracted this mechanism of adaptation to mild hypoxia hereby inducing cancer cells to apoptosis in HCC. Conclusions: In summary, this study highlights the role of HIF-2α but not HIF-1α in activating and binding c-MYC in HCC cell proliferation during mild chronic hypoxia response. PI3K/mTORC2/ HIF-2α/c-MYC axis plays a key role in this process. PI3K inhibitor Apitolisib is suggested as a potential treatment option for HCC, especially for rapidly growing HCC in mild chronic hypoxia.

Background: The relationship between serum carbohydrate antigen 19-9 (CA19-9) and hepatocellular carcinoma (HCC) is unclear. To explore the prognostic value of preoperative CA19-9 in α-fetoprotein (AFP)-positive and -negative HCC with hepatitis B virus (HBV) background (HBV-HCC).Methods: We evaluated HBV-HCC patients who underwent curative resection (Cohort 1). Recurrence-free survival (RFS) and overall survival (OS) were assessed, and the clinicopathological characteristics were compared according to a CA19-9 cutoff of ≥ 39 U/ml. Immunohistochemical staining of CA19-9 in HCC tumor tissue and background liver were quantified in another cohort of 216 patients with resected HCC (Cohort 2). Immunohistochemical staining or serum CA19-9 level was also compared between patients with intrahepatic cholangiocarcinoma (ICC) (Cohort 3).Results: In Cohort 1, CA19-9 ≥ 39 U/ml was an independent risk factor for RFS (HR=1.507, 95% CI=1.087-2.091, p=0.014) and OS (HR=1.646, 95% CI=1.146-2.366, p=0.007) in both AFP-positive and AFP-negative patients. CA19-9 ≥ 39 U/ml was also associated with significantly higher incidence of macrovascular invasion compared with CA19-9 < 39 U/ml (23.0% vs. 7.2%, p=0.002), elevated aminotransferase and aspartate aminotransferase to platelet ratio index, and lower albumin. In contrast, no association was found between CA19-9 and systemic inflammation. CA19-9 expression was found exclusively in the background liver but not in HCC tumor cells. In contrast, tumor tissue was the main source of CA19-9 in ICC patients.Conclusions: CA19-9 ≥ 39 U/ml was associated with lower OS and RFS in both AFP-positive and negative HCC patients. CA19-9 is secreted by the background liver but not by tumor cells. Thus, CA19-9 is a prognostic marker for liver inflammation and cirrhosis in HCC.

Background This research study explores the effect of miR-361 on the activation of immortalized human and mice hepatic stallate cells (HSCs). Methods 10 liver specimens from healthy volunteers and 20 HBV-relevant HCC tissues from patients. The expressions of miR-361 in HCC patients, HBx transgenic mice, HCC cell lines expressing HBx, and human and mouse HSCs were detected. The influences of miR-361 on the biological processes of HSCs were explored. The target of miR-361 and the effects of p65 on miR-361 were also verified and analyzed. Results Microarray analysis and quantitative real-time PCR (Q-PCR) indicated that miR-361 was decreased in HBV-relevant HCC tissues, HBx transgenic mice, HBx-transfected HepG2 cells, human and mice HSCs. Bio-informatics prediction and dual-luciferase reporter assay (DLRA) suggested that nuclear factor kappa B subunit p65 gene was a target of miR-361. Furthermore, this study showed that p65 expression was upregulated in the HBV-relevant HCC tissues, HBx transgenic mice, HBx-transfected HepG2 cells. MiR-361 upregulation also caused a reduction in p65 expression in both human and mice HSCs. In addition, p65 overexpression counteracted the effect of miR-361 in human and mice HSCs' biological processes. These findings reveal a latent mechanism underlying p65 modulation by miR-361 which is capable of initiating HSC growth and migration. Conclusion miR-361 is potentially functioning as a potent marker for HBV-relevant HCC development or liver fibrosis (LF) progression.

Background Isocitrate dehydrogenase 1/2 (IDH1/2), BAP1, ARID1A and PBRM1 have been reported as the most frequent mutant genes in intrahepatic cholangiocarcinoma (ICC), and their relationships with clinicopathological features and prognosis were researched in this study. Methods We collected clinical data of 130 ICC patients from January 2012 to December 2017. The IDH1/2 mutation and loss of BAP1, ARID1A and PBRM1 expressions were detected by DNA sequencing or immunohistochemical methods, and histological subtype of ICCs was determined by hematoxylin-eosin, Alcian blue and S100P staining. Results IDH1/2 mutation was related to decreased preoperative serum total bilirubin (P = 0.039), ferritin (P = 0.000) and higher histological differentiation (P = 0.024), and was associated with prolonged disease-free survival (P = 0.009) and a trend toward increased overall survival (P = 0.126) in small duct type of ICCs. Immunohistochemical staining results of MsMab-1 were generally consistent with DNA sequencing for IDH1/2 mutant in ICCs (κ = 0.691). Only BAP1 expression loss was correlated to prolonged disease-free survival (P = 0.031) and overall survival (P = 0.041) in large duct type of ICCs. Conclusions IDH1/2 mutation is a favorable predictor and may be related to iron metabolism in small duct type of ICCs. Furthermore, we suggest that the detection of IDH1/2 mutation is indispensable to determine targeted therapy in small duct type ICCs, while it is not necessary in large duct of ICCs. MsMab-1 is a relatively effective multi-specific antibody against IDH1/2 mutant in ICCs. BAP1 expression loss was correlated with improved prognosis only in large duct type ICCs.

With the development of cross-sectional imaging modalities and the increasing attention being paid to physical examinations, the prevalence of pancreatic cystic neoplasms (PCNs) has increased. PCNs comprise a broad differential spectrum with some PCNs having low or no malignant potential and others having high malignant potential. The morbidity and mortality rates related to major pancreatic surgical resection are high. Long-term surveillance may not only increase the financial burden and psychological stress for patients but also result in a missed malignancy. Minimally invasive endoscopic ultrasound (EUS)-guided ethanol ablation was first reported in 2005. Several other agents, such as paclitaxel, lauromacrogol, and gemcitabine, were reported to be effective and safe for the treatment of PCNs. These ablative agents are injected through a needle inserted into the cyst via transgastric or transduodenal puncture. This treatment method has been substantially developed in the last 15 years and is regarded as a promising treatment to replace surgical resection for PCNs. While several reviews of EUS-guided ablation have been published, no systematic review has evaluated this method from patient preparation to follow-up in detail. In the present review, we systematically describe EUS-guided injective ablation with regard to the indications, contraindications, preoperative treatment, endoscopic procedure, postoperative care and follow-up, evaluation method, treatment efficiency, safety profile, tips and tricks, and current controversies and perspectives.

Peroral endoscopic myotomy (POEM) is another branch of DETT. This chapter systematically describes the indications and contraindications, standard procedures, modified POEM, complications, postoperative management and Effectiveness of POEM. In addition, the chapter presents endoscopic classifications for treatment decision, including the Ling classification, endoscopic classification of esophageal mucosal in achalasia and endoscopic classification of submucosal fibrosis.