SOD1 inhibition enhances sorafenib efficacy in HBV-related hepatocellular carcinoma by modulating PI3K/Akt/mTOR pathway and ROS-mediated cell death.

Hepatitis B Virus (HBV) infection significantly elevates the risk of hepatocellular carcinoma (HCC), with the HBV X protein (HBx) playing a crucial role in cancer progression. Sorafenib, the primary therapy for advanced HCC, shows limited effectiveness in HBV-infected patients due to HBx-related resistance. Numerous studies have explored combination therapies to overcome this resistance. Sodium diethyldithiocarbamate (DDC), known for its anticancer effects and its inhibition of superoxide dismutase 1 (SOD1), is hypothesized to counteract sorafenib (SF) resistance in HBV-positive HCCs. Our research demonstrates that combining DDC with SF significantly reduces HBx and SOD1 expressions in HBV-positive HCC cells and human tissues. This combination therapy disrupts the PI3K/Akt/mTOR signalling pathway and promotes apoptosis by increasing reactive oxygen species (ROS) levels. These cellular changes lead to reduced tumour viability and enhanced sensitivity to SF, as evidenced by the synergistic suppression of tumour growth in xenograft models. Additionally, DDC-mediated suppression of SOD1 further enhances SF sensitivity in HBV-positive HCC cells and xenografted animals, thereby inhibiting cancer progression more effectively. These findings suggest that the DDC-SF combination could serve as a promising strategy for overcoming SF resistance in HBV-related HCC, potentially optimizing therapy outcomes.

Safety and outcome of treatment of latent tuberculosis infection in liver transplant recipients.

PURPOSE: Liver transplant (LT) recipients have an increased risk of tuberculosis (TB), which is associated with higher mortality rates. This retrospective cohort study assessed the outcome and tolerability of screening and treatment of latent tuberculosis infection (LTBI) in LT recipients. METHODS: Between March 2020 and February 2022, all adult LT candidates at our institution were screened for LTBI. The candidates who tested positive for interferon-γ-releasing assay or met epidemiological or clinical-radiological criteria for LTBI were treated and monitored. RESULTS: Among the 857 LT recipients, 199 (23.2%) were diagnosed with LTBI, of which 171 (85.9%) initiated LTBI treatment. The median duration of follow-up was 677 days. Adequate LTBI treatment occurred in 141/171 (82.5%) patients and was discontinued prematurely in 30/171 (17.5%) patients. The most common reason for discontinuation was liver enzyme elevation (11/30, 36.7%), although only five discontinued treatment due to suspicion of isoniazid-associated hepatotoxicity. None of the LTBI-treated patients developed active TB during the follow-up period, while 3.6% (1/28) of untreated LTBI patients and 0.6% (4/658) of patients without LTBI developed TB. CONCLUSION: These findings demonstrate that LTBI screening and treatment is a safe and effective strategy to prevent TB in LT recipients. However, monitoring for adverse events and liver enzyme elevation is recommended.

Outcome of ABO-incompatible adult living-donor liver transplantation for patients with hepatocellular carcinoma.

BACKGROUND & AIMS: Living-donor liver transplantation (LDLT) can simultaneously cure hepatocellular carcinoma (HCC) and underlying liver cirrhosis, improving long-term results in patients with HCC. ABO-incompatible LDLT could expand the living-donor pool, reduce waiting times for deceased-donor liver transplantation, and improve long-term survival for some patients with HCC. METHODS: We retrospectively reviewed the medical records of patients undergoing LDLT for HCC from November 2008 to December 2015 at a single institution in Korea. In total, 165 patients underwent ABO-incompatible and 753 patients underwent ABO-compatible LDLT for HCC. ABO-incompatible recipients underwent desensitization to overcome the ABO blood group barrier, including pretransplant plasma exchange and rituximab administration (300-375 mg/m2 /body surface area). RESULTS: We performed 1:1 propensity score matching and included 165 patients in each group. 82.4% of ABO-incompatible and 83.0% of -compatible LDLT groups had HCC within conventional Milan criteria, respectively, and 92.1% and 92.7% of patients in each group had a Child-Pugh score of A or B. ABO-incompatible and -compatible LDLT groups were followed up for 48.0 and 48.7 months, respectively, with both groups showing comparable recurrence-free survival rates (hazard ratio [HR] 1.14; 95% CI 0.68-1.90; p = 0.630) and overall patient-survival outcomes (HR 1.10; 95% CI 0.60-2.00; p = 0.763). CONCLUSIONS: These findings suggested that ABO-incompatible liver transplantation is a feasible option for patients with HCC, especially for those with compensated cirrhosis with HCC within conventional Milan criteria. LAY SUMMARY: Despite hypothetical immunological concerns that the desensitization protocol for breaking through the ABO blood group barrier might have a negative impact on the recurrence of hepatocellular carcinoma, our experience demonstrated no significant differences in the long-term overall survival and recurrence-free survival rates between patients receiving ABO-compatible or ABO-incompatible liver transplantation. In conclusion, results from our institution indicated that ABO-incompatible living-donor liver transplantation constitutes a potentially feasible option for patients with hepatocellular carcinoma, especially those with compensated cirrhosis with hepatocellular carcinoma within conventional Milan criteria.

Antitumor effect of sorafenib and mammalian target of rapamycin inhibitor in liver transplantation recipients with hepatocellular carcinoma recurrence.

Both sorafenib and mammalian target of rapamycin inhibitor (mTORi) have antitumor effects. This study aimed to evaluate their antitumor effects in liver transplantation (LT) recipients with hepatocellular carcinoma (HCC) recurrence. We performed a laboratory study using sorafenib and mTORi and subsequently validated their survival benefit in a clinical LT setting. In the laboratory study, the HepG2.2.15 liver tumor cell line and 5 patient-derived graft HCC cell lines were used for in vitro cytotoxic studies. After treatment with everolimus and sorafenib, cell viability and apoptosis assays revealed noticeable cytotoxic effects with individual agents and augmented effects by combination therapy. An in vivo mouse study also demonstrated similar cytotoxic outcomes. In the clinical study including 232 LT recipients with HCC recurrence, the 3-month medication drop-out rate was 35.6% for sorafenib administration and 23.5% for mTORi administration. Postrecurrence survival rates were not different according to sorafenib administration (P = 0.17) but were significantly improved following mTORi administration (P < 0.001). In mTORi subgroups with and without sorafenib, there was no difference in the overall postrecurrence patient survival period (P = 0.26), indicating an absence of synergistic or additional antitumor effect from sorafenib. The median progression-free and overall survival period was 6.4 and 11.8 months, respectively, after sorafenib administration. Time of tumor recurrence and use of mTORi were independent risk factors. In conclusion, our laboratory study demonstrated synergistic antitumor effects of sorafenib and mTORi, but this was not reproduced in our clinical LT study. Our clinical result of mTORi administration showed improved postrecurrence survival, thus administering mTORi in LT recipients with HCC recurrence appears worthwhile. However, the antitumor effect of sorafenib on posttransplant recurrence was not determined in this retrospective study, thus requiring further studies with early start of sorafenib administration. Liver Transplantation 24 932-945 2018. © 2018 AASLD.

Survival Outcomes in Split Compared With Whole Liver Transplantation.

Split-liver transplantation (SLT) should be cautiously considered because the right trisection (RTS) graft can be a marginal graft in adult recipients. Herein, we analyzed the outcomes of RTS-SLT in Korea, where >75% of adult liver transplantations are performed with living donor liver transplantation. Among 2462 patients who underwent deceased donor liver transplantations (DDLTs) from 2005 to 2014, we retrospectively reviewed 86 (3.5%) adult patients who received a RTS graft (RTS-SLT group). The outcomes of the RTS-SLT group were compared with those of 303 recipients of whole liver (WL; WL-DDLT group). Recipient age, laboratory Model for End-Stage-Liver Disease (L-MELD) score, ischemia time, and donor-to-recipient weight ratio (DRWR) were not different between the 2 groups (P > 0.05). However, malignancy was uncommon (4.7% versus 36.3%), and the donor was younger (25.2 versus 42.7 years) in the RST-SLT group than in the WL-DDLT group (P < 0.05). The technical complication rates and the 5-year graft survival rates (89.0% versus 92.8%) were not different between the 2 groups (P > 0.05). The 5-year overall survival (OS) rate (63.1%) and graft-failure-free survival rate (63.1%) of the RTS-SLT group were worse than that of the WL-DDLT group (79.3% and 79.3%; P < 0.05). The factors affecting graft survival rates were not definite. However, the factors affecting OS in the RTS-SLT group were L-MELD score >30 and DRWR ≤1.0. In the subgroup analysis, OS was not different between the 2 groups if the DRWR was >1.0, regardless of the L-MELD score (P > 0.05). In conclusion, a sufficient volume of the graft estimated from DRWR-matching could lead to better outcomes of adult SLTs with a RTS graft, even in patients with high L-MELD scores.

Preemptive pyloroplasty for iatrogenic vagus nerve injury in intrahepatic cholangiocarcinoma patients undergoing extensive left-sided lymph node dissection: a retrospective observational study.

BACKGRUOUND: Intrahepatic cholangiocarcinoma (ICC) of the left liver often shows left-sided lymph node (LN) metastasis. If gastric lesser curvature is extensively dissected, it can induce an iatrogenic injury to the extragastric vagus nerve branches that control motility of the pyloric sphincter and lead to gastric stasis. To cope with such LN dissection-associated gastric stasis, we performed pyloroplasty preemptively. The objective of this study was to analyze our 20-year experience of preemptive pyloroplasty performed in 10 patients. METHODS: We investigated clinical sequences of 10 patients with ICC who underwent preemptive pyloroplasty following left hepatectomy and extended left-sided LN dissection. Incidence of gastric stasis and oncological survival outcomes were analyzed. RESULTS: All 10 patients were classified as stage IIIB due to T1-3N1M0 stage according to the 8th edition of American Joint Committee on Cancer staging system. The overall patient survival rate was 51.9% at 1 year, 25.9% at 2 years, and 0% at 3 years. Seven patients showed uneventful postoperative recovery after surgery. Two patients suffered from gastric stasis, which was successfully managed with supportive care. One patient suffered from overt gastric paresis, which was successfully managed with azithromycin administration for 1 month. CONCLUSION: We believe that preemptive pyloroplasty is an effective surgical option to prevent gastric stasis in patients undergoing extensive left-sided LN dissection. Azithromycin appears to be a potent prokinetic agent in gastroparesis.

Feasibility of Dual Living Donor Liver Transplantation From Donors With Complex Portal Vein Variations.

Living donor liver transplantation (LDLT) from donors with complex portal vein anomalies has been considered a challenging procedure because vasculobiliary variations of the donor's liver may lead to significant increases in donor and recipient complications. The use of donors with anatomic variations may be considered under the accurate preoperative planning if a more suitable donor is not available. We report a successful dual LDLT for 2 donors with portal vein anomaly to overcome the small-for-size graft syndrome and secure donor safety. A 62-year-old man was referred to our institution for liver transplant because of hepatitis B-related liver cirrhosis with hepatocellular carcinoma. The only available donors were his son and his daughter-in-law, one with type IV portal venous anatomic variation and the other with type III variation. Neither of the 2 available donors were suitable as a single donor because of the complexity of the portal vein reconstruction and the donor's safety. Therefore, the decision was made to perform LDLT using dual graft, and we planned to harvest the right posterior sector graph from the first donor together with the left lobe graft of the second donor. Donor hepatectomy and recipient total hepatectomy were performed in the usual manner. He has recovered well with normal graft function, and there has been no tumor recurrence after dual LDLT. Dual graft LDLT using right posterior sector and left lobe graft could be undertaken successfully to overcome the small-for-size graft syndrome and secure the safety of donors in cases with the complex portal vein anomalies.

Comparison of hepatic artery reconstruction using surgical loupe and operating microscope during living donor liver transplantation focusing on the beginner's point.

BACKGROUNDS/AIMS: Hepatic artery (HA) reconstruction during living donor liver transplantation (LDLT) has been performed by experienced microsurgeons with operative microscope in most centers. However, it takes long time to learn the skills and so, to simplify this procedure, transplant surgeons recently performed this procedure using surgical loupe. METHODS: This study retrospectively reviewed outcomes of 237 LDLTs at our institution from January 2012 to October 2016. In group I, HA reconstruction was performed under operative microscope by an experienced microsurgeon and in group II, it was performed using surgical loupe by a transplant surgeon with little experience for arterial anastomosis. RESULTS: There was no difference in most perioperative outcomes between two groups except mean time required for HA reconstruction (24.2±4.3 vs. 20.9±6.9 minutes, p=0.001). Multivariable regression modeling to adjust for baseline differences showed that the use of surgical loupe was not associated with either HA thrombosis or intraoperative HA revision rate. CONCLUSIONS: HA reconstruction under surgical loupe can be performed simply and yields results as good as with operative microscopy, even when the transplant surgeon has less experience with HA anastomosis.

Clinicopathological features and post-resection outcomes of biliary cystadenoma and cystadenocarcinoma of the liver.

BACKGROUNDS/AIMS: Biliary cystadenoma (BCA) and biliary cystadenocarcinoma (BCAC) account for 5%-10% of liver cystic diseases. In this study, we analysed the clinical presentation and surgical management of patients with BCA and BCAC. METHODS: We retrospectively analysed the medical records of 23 BCA and 7 BCAC cases diagnosed between January 2007 and December 2013. RESULTS: There was a statistically significant difference in age (p=0.044) and sex (p=0.048) between BCA and BCAC groups. In the BCA group, 17 patients showed no symptoms (74%), 5 had abdominal pain (22%) and 1 showed abdominal distension (4%). In the BCAC group, two patients were without any symptoms (29%), three had abdominal pain (43%), one showed abdominal distension (14%) and one had fever and chills (14%). The cystic lesion size was widely variable; thus, there was no statistical difference (p=0.84). Complete resection was performed in all patients with BCA and BCAC. No tumour recurrence developed in patients with BCA. In patients with BCAC, 1-, 3- and 5-year disease-free survival rates were 100%, 85.7% and 57.1%, respectively, and 1-, 3- and 5-year overall patient survival rates were 100%, 100% and 75.0%, respectively. CONCLUSIONS: It is difficult to distinguish between BCA and BCAC via clinical manifestations and diagnostic imaging findings. Surgical resection is the treatment of choice for BCA and BCAC, and patient prognosis after complete resection was very favourable.

Extended pancreatic transection for secure pancreatic reconstruction during pancreaticoduodenectomy.

BACKGROUNDS/AIMS: Pancreaticoduodenectomy (PD) is associated with various surgical complications including healing failure of the pancreaticojejunostomy (PJ). This study intended to ensure blood supply to the pancreatic stump through extended pancreatic transection (EPT). METHODS: This study assessed whether EPT reduces PJ-associated complications and whether EPT is harmful on the remnant pancreatic function. The EPT group included 19 patients undergoing PD, pylorus-preserving PD (PPPD) or hepatopancreaticoduodenectomy. The propensity score matched control group included 45 patients who had undergone PPPD. Pancreatic transection was performed at the level of the celiac axis in the EPT group, by which the pancreatic body was additionally removed by 3 cm in length comparing with the conventional pancreatic transection. RESULTS: A small invagination fissure suspected as the embryonic fusion site was identified at the ventro-caudal edge of the pancreatic body in all patients undergoing EPT. A sizable fissure permitting easy separation of the pancreatic parenchyma was identified in 15 of 19 patients (78.9%). The incidence of significant postoperative pancreatic fistula was significantly lower in the EPT group than in the control group (p=0.047). There was no significant increase in the postoperative de novo diabetes mellitus in EPT group (p=0.60). CONCLUSIONS: The EPT technique contributes to the prevention of major pancreatic fistula without impairing remnant pancreatic function. EPT is feasible for routine clinical application or at least in patients with any known risk of PJ leak.