Transarterial chemoembolization (TACE)-hepatic arterial infusion chemotherapy (HAIC) combined with PD-1 inhibitors plus lenvatinib as a preoperative conversion therapy for nonmetastatic advanced hepatocellular carcinoma: a single center experience.

Background: The preoperative conversion therapy for advanced hepatocellular carcinoma (HCC) is still being explored. This study reported the potential of combination of transarterial chemoembolization (TACE), hepatic arterial infusion chemotherapy (HAIC), programmed cell death protein-1 (PD-1) inhibitors and lenvatinib as preoperative conversion therapy for nonmetastatic advanced HCC. Methods: This retrospective study gathered data on patients with nonmetastatic advanced HCC who received this combination therapy. We used drug-eluting bead (DEB) instead of conventional iodized oil in TACE. The clinical data, conversion rate, adverse events (AEs) and short-term survival were summarized. A stratified analysis based on whether or not the patient received surgery was conducted. Results: A total of 28 patients were included in the analysis. No grade 4 AEs were observed. The overall objective response rate (ORR) was 64.3%. Ten (35.7%) patients eventually received R0 resection after 2 cycles of combination therapy. Patients succeeding to resection (surgery group) had significantly higher ORR (90.0% vs. 50.0%, P=0.048). The proportion of patients with alpha-fetoprotein (AFP) >1,000 µg/L was significantly lower in surgery group (10.0% vs. 66.7%, P=0.006). After combination therapy, more patients in surgery group experienced significant reduction of >90% in AFP levels (75.0% vs. 23.1%, P=0.03), as well as standardized uptake value (SUV) of 18F-fluorodeoxyglucose (18F-FDG) both in primary tumors and portal vein tumor thrombosis (PVTT) (60.0% vs. 5.6%, P=0.003; 57.1% vs. 8.3%, P=0.04). Of note, 85.7% of PVTT exhibited major pathological response (MPR) in pathological examination although only 28.6% achieved downstage in preoperative imaging examination. MPR was more commonly observed in PVTT than in main tumors (85.7% vs. 20.0%). In non-surgery group, the median overall survival (OS) was 7 months with a 1-year survival rate of 27.8%, while in surgery group, the median OS was not reached and 1-year survival rate was 60.0%. Conclusions: The combination of TACE-HAIC, PD-1 inhibitors and lenvatinib showed its benefit as a preoperative conversion therapy for nonmetastatic advanced HCC. In addition to imaging evaluation, significant reduction of 18F-FDG uptake and AFP can be used as predictors of successful conversion, especially for PVTT.

Efficacy of Lenvatinib in Combination With PD-1 Monoclonal Antibody and Interventional Treatment for Intermediate-Stage Hepatocellular Carcinoma: Impact on Serum Vascular Endothelial Growth Factor and Matrix Metalloproteinase-9 Levels: A Retrospective Study.

Objectives: To scrutinize the therapeutic efficiency and safety profile of lenvatinib, accompanied by the programmed cell death protein-1 (PD-1) monoclonal antibody, and interventional treatment in managing intermediate-stage hepatocellular carcinoma. Methods: Retrospective analysis was performed on clinical data from 93 patients suffering from intermediate to advanced hepatocellular carcinoma, treated at our institution from May 2018 to April 2020. Patients were divided based on the therapeutic regimen: 43 cases constituted the control group receiving lenvatinib plus transhepatic artery chemoembolization (TACE), while the remaining 50 cases in the study group were managed with lenvatinib, PD-1 monoclonal antibody, and TACE. Outcome measures included therapeutic efficacy, tumor markers (carcinoembryonic antigen [CEA], alpha-fetoprotein [AFP], α-L-fucosidase [AFU], carbohydrate antigen 199 [CA199]), immune response indices (CD3+, CD4+, CD8+, CD4+/CD8+ ratio), pertinent cytokine levels (vascular endothelial growth factor [VEGF], matrix metalloproteinase-9 [MMP-9], basic fibroblast growth factor [aFGF], acidic fibroblast growth factor [bFGF]), quality of life (as per Quality of Life Assessment Scale for Cancer Patients [QOL-LC] scores), adverse effects, and survival rates. Results: The study group exhibited a significantly enhanced total effective rate compared to the control group (74.00% vs 53.49%, P < .05). Post-treatment levels of CEA, AFP, AFU, CA199, CD8+, VEGF, MMP-9, aFGF, and bFGF were notably lower in both groups, particularly in the study group. Contrastingly, CD3+, CD4+, CD4+/CD8+ratios, and QOL-LC scores were substantially elevated in the study group (P < .05). Adverse reaction prevalence was analogous between 2 groups (27.91% vs 26.00%; P > .05). Moreover, the study group reported significantly higher 1-, 2-, and 3-year survival rates than the control group (P < .05). Conclusion: The combined use of lenvatinib, PD-1 monoclonal antibody, and interventional treatment for intermediate to advanced hepatocellular carcinoma may have a definitive therapeutic efficacy. This regimen is effective in reducing tumor marker levels, enhancing immune function, modulating VEGF, MMP-9, and other related cytokine levels, and improving patients' quality of life without significantly augmenting adverse effects. This treatment paradigm also contributes to increased survival rates and promises favorable prognosis.

Hepatic arterial infusion chemotherapy combined with bevacizumab plus a PD-1 inhibitor for gallbladder cancer with hepatic oligometastasis: a real-world study.

Background: Gallbladder cancer (GBC) is different from other biliary tract cancers in terms of molecular phenotype and microenvironment. Specific treatments for GBC need to be urgently explored. This study preliminarily investigated the clinical value of hepatic artery infusion chemotherapy (HAIC) combined with bevacizumab plus a programmed death receptor-1 (PD-1) inhibitor for treatment of GBC with hepatic oligometastasis. Methods: We retrospectively collected data on GBC patients with hepatic oligometastasis, who received this combination therapy. The clinical data, conversion rate, treatment response, adverse events (AEs), and short-term survival were summarized. The responses of primary gallbladder lesions and hepatic metastasis, and their effect on prognosis, were investigated. Results: A total of 27 patients were included in the analysis. No grade 4 AEs were observed. The overall objective response rate (ORR) was 55.6% and the disease control rate (DCR) was 85.2%. Median overall survival (OS) time was 15.0 months and the 1-year survival rate was 64.0%. Median progression-free survival (PFS) time was 7.0 months and the 1-year PFS rate was 16.2%. Six patients (22.2%) were successfully converted to resection. Compared with primary gallbladder lesions, it appeared more difficult for patients with hepatic metastasis to achieve remission (ORR: 40.7% vs. 77.8%; P=0.012), but its response appeared to be closely related to the prognosis [median OS: 16.0 months in the complete response (CR) or partial response (PR) group vs. 11.0 months in the stable disease (SD) or progressive disease (PD) group, P=0.070; median PFS: 12.0 months in the CR or PR group vs. 6.5 months in the SD or PD group, P<0.001]. Preoperative CA19-9 of >1,900 U/mL and >5 cm metastatic lesions were associated with an unsatisfactory response, whereas a significant decrease of 18F-fluorodeoxyglucose (18F-FDG) uptake may be a marker of tumor remission. Conclusions: The combination of HAIC, a PD-1 inhibitor, and bevacizumab shows potential for advanced GBC with hepatic oligometastasis. The therapeutic response of hepatic metastasis had a greater influence on prognosis than that of primary gallbladder lesions.

Development and validation of a nomogram model for predicting the risk of gallstone recurrence after gallbladder-preserving surgery.

BACKGROUND: The high incidence of gallstone recurrence was a major concern for laparoscopic gallbladder-preserving surgery. This study aimed to investigate the risk factors for gallstone recurrence after gallbladder-preserving surgery and to establish an individualized nomogram model to predict the risk of gallstone recurrence. METHODS: The clinicopathological and follow-up data of 183 patients who were initially diagnosed with gallstones and treated with gallbladder-preserving surgery at our hospital from January 2012 to January 2019 were retrospectively collected. The independent predictive factors for gallstone recurrence following gallbladder-preserving surgery were identified by multivariate logistic regression analysis. A nomogram model for the prediction of gallstone recurrence was constructed based on the selected variables. The C-index, receiver operating characteristic (ROC) curve and calibration curve were used to evaluate the predictive power of the nomogram model for gallstone recurrence. RESULTS: During the follow-up period, a total of 65 patients experienced gallstone recurrence, and the recurrence rate was 35.5%. Multivariate logistic regression analysis revealed that the course of gallstones > 2 years [odds ratio (OR) = 2.567, 95% confidence interval (CI): 1.270-5.187, P = 0.009], symptomatic gallstones (OR = 2.589, 95% CI: 1.059-6.329, P = 0.037), multiple gallstones (OR = 2.436, 95% CI: 1.133-5.237, P = 0.023), history of acute cholecystitis (OR = 2.778, 95% CI: 1.178-6.549, P = 0.020) and a greasy diet (OR = 2.319, 95% CI: 1.186-4.535, P = 0.014) were independent risk factors for gallstone recurrence after gallbladder-preserving surgery. A nomogram model for predicting the recurrence of gallstones was established based on the above five variables. The results showed that the C-index of the nomogram model was 0.692, suggesting it was valuable to predict gallstone recurrence. Moreover, the calibration curve showed good consistency between the predicted probability and actual probability. CONCLUSIONS: The nomogram model for the prediction of gallstone recurrence might help clinicians develop a proper treatment strategy for patients with gallstones. Gallbladder-preserving surgery should be cautiously considered for patients with high recurrence risks.

Transforming growth factor-ß and peripheral regulatory cells are negatively correlated with the overall survival of hepatocellular carcinoma.

AIM: To understand the cellular and molecular changes in peripheral blood that can lead to the development of hepatocellular carcinoma (HCC) and provide new methods for its diagnosis and treatment. METHODS: Peripheral blood mononuclear cells were isolated from the peripheral blood of HCC patients and normal controls and then analyzed by flow cytometry. The percentage of transforming growth factor-ß (TGF-ß)+ regulatory cells (Tregs) in the peripheral blood was measured, and the expression of TGF-ß was also determined. Then, the relationship between the changes and the 5-year survival of patients was analyzed. In addition, recombinant human TGF-ß (rhTGF-ß) and recombinant human interleukin-6 were added to stimulate the cultured cells, and their effects on HCC were evaluated. RESULTS: The expression of TGF-ß and the percentage of TGF-ß+ Tregs in the peripheral blood of HCC patients increased significantly compared with normal controls. Compared with the low TGF-ß expression group, the high TGF-ß expression group had a significantly lower 5-year survival rate, and the same result was found in the two TGF-ß+ Treg groups, suggesting that TGF-ß and TGF-ß+ Tregs were negatively correlated with the overall survival of the patients. In addition, rhTGF-ß promoted the growth of tumor cells and induced high expression levels of IL-6, which further promoted tumor proliferation. CONCLUSION: The results showed that TGF-ß may promote tumor growth and proliferation by inducing the production of IL-6, and TGF-ß and TGF-ß+ Tregs may serve as new markers for predicting a poor prognosis in HCC.

Novel serum microRNAs panel on the diagnostic and prognostic implications of hepatocellular carcinoma.

AIM: To determine a panel of serum microRNAs (miRNAs) that could be used as novel biomarkers for diagnosis of hepatocellular carcinoma (HCC). METHODS: We initially screened 9 out of 754 serum miRNAs by TaqMan Low Density Array in two pooled samples respectively from 35 HCC and 35 normal controls, and then validated individually by RT-qPCR in another 114 patients and 114 controls arranged in two phases. The changes of the selected miRNAs after operation and their prognostic value were examined. RESULTS: miR-375, miR-10a, miR-122 and miR-423 were found to be significantly higher in HCC than in controls (P < 0.0001), and the area under the receiver-operating-characteristic curve for the 4-miRNA panel was 0.995 (95%CI: 0.985-1). All the four miRNAs were significantly reduced after surgical removal of the tumors (P < 0.0001), while still higher than normal controls (at least P < 0.05). CONCLUSION: The four serum miRNAs (miR-375, miR-10a, miR-122 and miR-423) could potentially serve as novel biomarkers for the diagnostic and prognostic of HCC.

Methylation-Mediated Silencing of GATA5 Gene Suppresses Cholangiocarcinoma Cell Proliferation and Metastasis.

Cholangiocarcinoma (CCA) is one of the most common hepatic and biliary malignancies, accounting for about 3% of all gastrointestinal tumors. GATA5 is a transcription factor capable of suppressing the development of various human cancer types. Transcriptional inactivation and CpG island (CGI) methylation of GATA3 and GATA5, two members of the GATA family of transcription factors, have been observed in some human cancers. But whether high-density CGI methylation of GATA5 is associated with the clinical course of CCA patients has not been clarified. Herein, we observed reduced expression of GATA5 in CCA tissues compared with noncancerous tissues. Treatment with the demethylating agent 5-aza-2'-deoxycytidine restored GATA5 expression in CCA cell lines. Furthermore, GATA5 expression was downregulated after treatment with IL-6 in human intrahepatic biliary epithelial cells. Upregulated GATA5 inhibited CCA cell growth and metastasis. Mechanistically, GATA5 suppressed CCA cell growth and metastasis via Wnt/ß-catenin pathway. Specific ß-catenin inhibitor or siRNA abolished the discrepancy of the proliferation and metastasis capacity between GATA5-overexpression CCA cells and their control cells, which further confirmed that Wnt/ß-catenin was required in GATA5-inhibited CCA cell growth and metastasis.

Percutaneous biliary stenting combined with radiotherapy as a treatment for unresectable hilar cholangiocarcinoma.

Hilar cholangiocarcinoma is often unresectable at the time of the initial diagnosis, and the provision of a definite palliative benefit is important in patients with unresectable hilar cholangiocarcinoma. The aim of the present study was to evaluate the safety of percutaneous biliary stenting and to analyze whether percutaneous biliary stenting combined with radiotherapy (RT) prolonged the stent patency and survival time of patients. In total, the cases of 38 patients with unresectable hilar cholangiocarcinoma that underwent percutaneous biliary stenting at the Navy General Hospital were retrospectively reviewed in the present study. Uncovered metallic stenting (UMS) combined with RT was administered to 25 patients, and UMS alone was administered to 13 patients. The records of early complications subsequent to percutaneous biliary stenting were collected, and the stent patency and survival times of patients were analyzed and compared between the two groups. The technical success rate of the procedure was 100% and the successful drainage rate was 86.8%. The overall early complication rate was 15.8% and the procedure-associated mortality rate was 2.6%. The median stent patency was 326 days in the UMS+RT group and 196 days in the UMS group (P=0.022). The UMS+RT group (median, 367 days) demonstrated a longer survival time compared with the UMS group (median, 267 days; P=0.025). Percutaneous biliary stenting offers a safe and effective method for the palliative treatment of patients with unresectable hilar cholangiocarcinoma, and percutaneous biliary stenting combined with RT may prolong stent patency and patient survival time.

Maslinic acid potentiates the antitumor activities of gemcitabine in vitro and in vivo by inhibiting NF-κB-mediated survival signaling pathways in human gallbladder cancer cells.

Gemcitabine (GEM) is one of the first-line drugs in the treatment of gallbladder cancer (GBC), although the therapeutic effect is not sustained due to resistance to the drug over time. Maslinic acid (MA) has been shown to inhibit transcription factor nuclear factor-κB (NF-κB), resulting in the suppression of survival signaling. The authors of the present study investigated whether MA enhanced the antitumor activity of GEM in GBC. Anti-proliferative effects of MA, GEM and MA+GEM were assessed using the MTT assay. Apoptosis was assessed using Annexin V and by western blot analysis of various mediators of apoptosis. Xenograft tumors of EH-GB2 GBC cells were established in athymic nude mice and were monitored following treatment with MA, GEM and MA+GEM. Immunohistochemistry of the tumors was used to examine various survival proteins. MA inhibited the in vitro proliferation of various GBC cell lines and potentiated the apoptosis and cell invasion inhibition induced by GEM. Western blot analysis showed that the combination of MA and GEM inhibited constitutive NF-κB activation and NF-κB-regulated gene products, including cyclin D1, Bcl-2, Bax, MMP-2 and MMP-9, to a greater extent. In vivo, the group that was treated with MA+GEM showed significant reductions in tumor volume and a decreased expression of NF-κB-regulated gene products. In conclusion, the results suggest that MA potentiates the antitumor effects of GEM in human GBC cell lines by suppressing the activation of NF-κB and its dowstream gene products, which are involved in survival signaling.

Prognostic significance of the combined expression of neutral endopeptidase and dipeptidyl peptidase IV in intrahepatic cholangiocarcinoma patients after surgery resection.

AIM: The aim of this study was to investigate the relationship between the expression of neutral endopeptidase (NEP) and dipeptidyl peptidase IV (DPP IV) proteins, and the clinical significance of the two proteins in patients with intrahepatic cholangiocarcinomas (IHCC). METHODS: Expression patterns and subcellular localizations of NEP and DPP IV proteins in 186 primary IHCC and 60 noncancerous liver tissue specimens were detected by immunohistochemistry. RESULTS: Both the expression of NEP and DPP IV proteins in IHCC tissues were significantly higher than those in noncancerous liver tissues (both P<0.001). Of 186 patients with IHCC, 128 (68.82%) highly expressed both NEP and DPP IV proteins. In addition, the coexpression of NEP and DPP IV proteins was significantly associated with advanced tumor stage (P=0.009), positive lymph node metastasis (P=0.016) and distant metastasis (P=0.013), and the presence of recurrence (P=0.027). Moreover, Kaplan-Meier analysis showed that IHCC patients with high NEP expression, high DPP IV expression, and combined overexpression of NEP and DPP IV proteins all had poorer overall survival and early recurrence after surgery. Furthermore, Cox analysis suggested that NEP expression, DPP IV expression, and combined expression of NEP and DPP IV proteins were all independent prognostic markers for overall survival and recurrence-free survival in patients with IHCC. CONCLUSION: Our data suggest, for the first time, that both the expression of NEP and DPP IV proteins may be upregulated in human IHCC tissues and the combined expression of NEP and DPP IV proteins may play important roles in progression and prognosis of patients with IHCC.

Choice of approach for hepatectomy for hepatocellular carcinoma located in the caudate lobe: isolated or combined lobectomy?

AIM: To investigate the significance of the surgical approaches in the prognosis of hepatocellular carcinoma (HCC) located in the caudate lobe with a multivariate regression analysis using a Cox proportional hazard model. METHODS: Thirty-six patients with HCC underwent caudate lobectomy at a single tertiary referral center between January 1995 and June 2010. In this series, left-sided, right-sided and bilateral approaches were used. The outcomes of patients who underwent isolated caudate lobectomy or caudate lobectomy combined with an additional partial hepatectomy were compared. The survival curves of the isolated and combined resection groups were generated by the Kaplan-Meier method and compared by a log-rank test. RESULTS: Sixteen (44.4%) of 36 patients underwent isolated total or partial caudate lobectomy whereas 20 (55.6%) received a total or partial caudate lobectomy combined with an additional partial hepatectomy. The median diameter of the tumor was 6.7 cm (range, 2.1-15.8 cm). Patients who underwent an isolated caudate lobectomy had significantly longer operative time (240 min vs 170 min), longer length of hospital stay (18 d vs 13 d) and more blood loss (780 mL vs 270 mL) than patients who underwent a combined caudate lobectomy (P < 0.05). There were no perioperative deaths in both groups of patients. The complication rate was higher in the patients who underwent an isolated caudate lobectomy than in those who underwent combined caudate lobectomy (31.3% vs 10.0%, P < 0.05). The 1-, 3- and 5-year disease-free survival rates for the isolated caudate lobectomy and the combined caudate lobectomy groups were 54.5%, 6.5% and 0% and 85.8%, 37.6% and 0%, respectively (P < 0.05). The corresponding overall survival rates were 73.8%, 18.5% and 0% and 93.1%, 43.6% and 6.7% (P < 0.05). CONCLUSION: The caudate lobectomy combined with an additional partial hepatectomy is preferred because this approach is technically less demanding and offers an adequate surgical margin.