Hepsin as a potential therapeutic target for alleviating acetaminophen-induced hepatotoxicity via gap-junction regulation and oxidative stress modulation.

Acetaminophen (APAP) overdose is a leading cause of drug-induced liver damage, highlighting the limitations of current emergency treatments that primarily involve administering the glutathione precursor N-acetylcysteine and supportive therapy. This study highlights the essential protective role of the type II transmembrane serine protease (TTSP), hepsin, in mitigating acetaminophen-induced liver injury, particularly through its regulation of gap junction (GJ) abundance in response to reactive oxygen stress in the liver. We previously reported that reduced levels of activated hepatocyte growth factor and the c-Met receptor tyrosine kinase-both of which are vital for maintaining cellular redox balance-combined with increased expression of GJ proteins in hepsin-deficient mice. Here, we show that hepsin deficiency in mice exacerbates acetaminophen toxicity compared to wild-type mice, leading to more severe liver pathology, elevated oxidative stress, and greater mortality within 6 h after exposure. Administering hepsin had a protective effect in both mouse models, reducing hepatotoxicity by modulating GJ abundance. Additionally, transcriptome analysis and a functional GJ inhibitor have highlighted hepsin's mechanism for managing oxidative stress. Combining hepsin with relatively low doses of N-acetylcysteine had a synergistic effect that was more efficacious than high-dose N-acetylcysteine alone. Our results illustrate the crucial role of hepsin in modulating the abundance of hepatic GJs and reducing oxidative stress, thereby offering early protection against acetaminophen-induced hepatotoxicity and a new, combination approach. Emerging as a promising therapeutic target, hepsin holds potential for combination therapy with N-acetylcysteine, paving the way for novel approaches in managing drug-induced liver injury.

Cryptococcosis in wait-listed liver transplant candidates: Prevalence, manifestations, and risk factors.

BACKGROUND: Liver cirrhosis compromises immunity against cryptococcosis, and liver transplant recipients tend to develop the disease earlier after transplantation, possibly due to unrecognized pretransplant infection. We assessed the prevalence and characteristics of cryptococcosis among liver transplant candidates and whether pre-transplant cryptococcal antigen (CrAg) can detect the disease before transplantation. METHODS: We retrospectively included liver transplant candidates in a tertiary hospital during 2017-2022. Serum CrAg and pulmonary computed tomography were incorporated in routine transplant evaluation. Other investigations were done if indicated. Cryptococcosis was diagnosed by positive culture or CrAg. Risk factors for cryptococcosis were also assessed. RESULTS: Of the 377 candidates with a median MELD-Na score of 18, 84.4% had hepatitis B virus (HBV) infection. Cryptococcosis was diagnosed in 10 (2.6%) candidates, by CrAg in 6, culture in 2, or both in 2. Only 3 had fever, and 3 were asymptomatic; 7 had pulmonary cryptococcosis. Of the 10 candidates with cryptococcosis, one underwent transplantation after 143-day antifungals. Of the 87 candidates undergoing liver transplantation, one (1.2%) recipient developed cryptococcosis 14 days post-transplant with negative CrAg three weeks before transplantation. HBsAg-positive chronic HBV infection with HBV DNA loads <2000 IU/mL was significantly associated with cryptococcosis (odds ratio 4.4, 95% confidence interval 1.2-16.5, p = 0.03) after the adjustment of MELD-Na score. CONCLUSIONS: The prevalence of cryptococcosis was 2.6% among our liver transplant candidates and CrAg detected 80% of the cases. Disease presentation was mild and pulmonary disease predominated. HBsAg-positive chronic HBV infection with HBV DNA loads <2000 IU/mL was significantly associated with cryptococcosis.

Robotic living donor hepatectomy is associated with superior outcomes for both the donor and the recipient compared with laparoscopic or open - A single-center prospective registry study of 3448 cases.

Minimally invasive donor hepatectomy is an emerging surgical technique in living donor liver transplantation (LDLT). We examined outcomes across open, laparoscopic, and robotic LDLT using a prospective registry. We analyzed 3448 cases (1724 donor-recipient pairs) from January 2011 to March 2023 (NCT06062706). Among donors, 520 (30%) were female. Adult-to-adult LDLT comprised 1061 (62%) cases. A total of 646 (37%) of the donors underwent open, 165 (10%) laparoscopic, and 913 (53%) robotic hepatectomies. Primary outcomes: donor overall morbidity was 4% (35/903) for robotic, 8% (13/165) laparoscopic, and 16% (106/646) open (P < .001) procedures. Pediatric and adult recipient mortality was similar among the 3 donor hepatectomy approaches: robotic 1.5% and 7.0%, compared with 2.3% and 8.3% laparoscopic, and 1.6% and 5.5% for open donor surgery, respectively (P = .802, P = .564). Secondary outcomes: pediatric and adult recipients major morbidity after robotic hepatectomy was 15% and 23%, compared with 25% and 44% for laparoscopic surgery and 19% and 31% for open surgery, respectively (P = .033, P < .001). Graft and recipient 5-year survival were 90% and 93% for pediatrics and 79% and 80% for adults, respectively. In conclusion, robotic LDLT was associated with superior outcomes when compared with the laparoscopic and open approaches. Both donors and, for the first time reported, recipients benefitted from lower morbidity rates in robotic surgery, emphasizing its potential for further advancing this field.

Longitudinal analysis of liver transplant candidates for hepatocellular carcinoma in a single center.

BACKGROUND: Wailitst lost is an critical issue and we investigated the long-term effect of insufficient liver functional reserve at liver transplantation evaluation on waitlist outcomes in patients with hepatocellular carcinoma (HCC). METHODS: Clinical data of patients with HCC waitlisted for liver transplantation were retrospectively collected from a single hospital cohort during the period from 2014 to 2021. Parameters of liver reserve, including cirrhosis, Child-Pugh grade, and Model for End-Stage Liver Disease (MELD) scores, were analyzed for patient survival, after adjustment for tumor factors. RESULTS: Of 292 eligible patients, 94.2% had cirrhosis, 55.8% had Child-Pugh grade B or C, and the median MELD score was 13.2. The median follow-up time was 2.2 years, with a dropout rate of 62.7%. Eighty-nine candidates (30.5%) eventually received liver transplant, including 67 from live donors. The estimated 1-year mortality rate reached 40.6% in 203 patients who remained on the waitlist without receiving a transplant, of whom 143 died. Most deaths were attributed to liver failure (37.1%) and cancer death (35.7%). After we adjusted for tumor confounders, including alpha fetoprotein, primary HCC stage, tumor number at evaluation, and sequential cancer treatment before and while waiting, hazard ratios (HRs) for patient survival were 1.69 (95% confidence interval, 1.18-2.41) for cirrhotic stage B or C, 1.07 (1.04-1.10) for MELD scores, and 1.14 (1.04-1.25) for tumor size at transplant evaluation. Transplantation was a protective disease modifier with adjusted HR 0.22 (0.14-0.33). CONCLUSION: Insufficient liver functional reserve poses more risk than expected to liver transplant waitlist outcomes with HCC.

Risk factors, patterns, and outcome predictors of late recurrence in patients with hepatocellular carcinoma after curative resection: A large cohort study with long-term follow-up results.

BACKGROUND: Late recurrence of hepatocellular carcinoma after curative resection significantly influences long-term patient survival outcomes, and yet it remains understudied. This study aims to explore the risk factors and patterns of late recurrence and predictors of subsequent outcome. METHODS: This single-center retrospective study analyzed 1,701 consecutive patients who achieved a disease-free survival period exceeding 2 years after curative resection for hepatocellular carcinoma between 2001 and 2018. Univariate and multivariate analyses of factors associated with late recurrence and death after recurrence were conducted using Cox's models. RESULTS: The mean age of patients was 60.2 years, with 76.8% being male. During a median follow-up of 8.1 years, 653 patients (38.4%) experienced late recurrence, with median time to recurrence being 4.0 years (interquartile range, 2.7-6.0). Factors such as age >60, chronic hepatitis C, cirrhosis, high albumin-bilirubin grade, absence of family history, multiple tumors, satellite nodules, alpha-fetoprotein levels <400 ng/mL, and minor hepatic resection were identified as risk factors for late recurrence. Among patients with late recurrence, 131 (20.1%) underwent surgical treatment, 272 (41.7%) received radiofrequency ablation, and 27 (4.1%) exhibited extrahepatic lesions. A higher-high albumin-bilirubin grade, recurrent tumor >3 cm, and nonsurgical treatment emerged as predictors of death after late recurrence. CONCLUSION: Over one-third of patients who remain disease-free for more than 2 years postresection will experience late recurrence during subsequent follow-up. For 2-year disease-free survivors, risk factors for late recurrence differ from early recurrence. Treating underlying hepatitis is of paramount importance, given its association with both the risk of late recurrence and survival outcomes post-recurrence.

Robotic and laparoscopic right lobe living donation compared to the open approach: A multicenter study on 1194 donor hepatectomies.

Due to the success of minimally invasive liver surgery, laparoscopic and robotic minimally invasive donor hepatectomies (MIDH) are increasingly performed worldwide. We conducted a retrospective, multicentre, propensity score-matched analysis on right lobe MIDH by comparing the robotic, laparoscopic, and open approaches to assess the feasibility, safety, and early outcomes of MIDHs. From January 2016 until December 2020, 1194 donors underwent a right donor hepatectomy performed with a robotic (n = 92), laparoscopic (n = 306), and open approach (n = 796) at 6 high-volume centers. Donor and recipients were matched for different variables using propensity score matching (1:1:2). Donor outcomes were recorded, and postoperative pain was measured through a visual analog scale. Recipients' outcomes were also analyzed. Ninety-two donors undergoing robotic surgery were matched and compared to 92 and 184 donors undergoing laparoscopic and open surgery, respectively. Conversions to open surgery occurred during 1 (1.1%) robotic and 2 (2.2%) laparoscopic procedures. Robotic procedures had a longer operative time (493 ± 96 min) compared to laparoscopic and open procedures (347 ± 120 and 358 ± 95 min; p < 0.001) but were associated with reduced donor blood losses ( p < 0.001). No differences were observed in overall and major complications (≥ IIIa). Robotic hepatectomy donors had significantly less pain compared to the 2 other groups ( p < 0.001). Fifty recipients of robotic-procured grafts were matched to 50 and 100 recipients of laparoscopic and open surgery procured grafts, respectively. No differences were observed in terms of postoperative complications, and recipients' survival was similar ( p =0.455). In very few high-volume centers, robotic right lobe procurement has shown to be a safe procedure. Despite an increased operative and the first warm ischemia times, this approach is associated with reduced intraoperative blood losses and pain compared to the laparoscopic and open approaches. Further data are needed to confirm it as a valuable option for the laparoscopic approach in MIDH.

Diagnostic performance of ultrasound in acute cholecystitis: a systematic review and meta-analysis.

BACKGROUND: An updated overview of ultrasound (US) for diagnosis of acute cholecystitis (AC) remains lacking. This systematic review was conducted to evaluate the diagnostic performance of US for AC. METHODS: A systematic review was conducted following PRISMA guidelines. We meticulously screened articles from MEDLINE, Embase, and the Cochrane Library, spanning from inception to August 2023. We employed the search strategy combining the keywords "bedside US", "emergency US" or "point-of-care US" with "AC". Two reviewers independently screened the titles and abstracts of the retrieved articles to identify suitable studies. The inclusion criteria encompassed articles investigating the diagnostic performance of US for AC. Data regarding diagnostic performance, sonographers, and sonographic findings including the presence of gallstone, gallbladder (GB) wall thickness, peri-GB fluid, or sonographic Murphy sign were extracted, and a meta-analysis was executed. Case reports, editorials, and review articles were excluded, as well as studies focused on acalculous cholecystitis. The study quality was assessed with the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool. RESULTS: Forty studies with 8,652 patients were included. The majority of studies had a low risk of bias and applicability concerns. US had a pooled sensitivity of 71% (95% CI, 69-72%), a specificity of 85% (95% CI, 84-86%), and an accuracy of 0.83 (95% CI, 0.82-0.83) for the diagnosis of AC. The pooled sensitivity and specificity were 71% (95% CI, 67-74%) and 92% (95% CI, 90-93%) performed by emergency physicians (EPs), 79% (95% CI, 71-85%) and 76% (95% CI, 69-81%) performed by surgeons, and 68% (95% CI 66-71%) and 87% (95% CI, 86-88%) performed by radiologists, respectively. There were no statistically significant differences among the three groups. CONCLUSION: US is a good imaging modality for the diagnosis of AC. EP-performed US has a similar diagnostic performance to radiologist-performed US. Further investigations would be needed to investigate the impact of US on expediting the management process and improving patient-centered outcomes.

Decreased B4GALT1 promotes hepatocellular carcinoma cell invasiveness by regulating the laminin-integrin pathway.

Beta1,4-galactosyltransferases (B4GALTs) play a crucial role in several diseases, including cancer. B4GALT1 is highly expressed in the liver, and patients with mutations in B4GALT1 exhibit hepatopathy. However, the role of B4GALT1 in liver cancer remains unclear. Here, we found that B4GALT1 was significantly downregulated in hepatocellular carcinoma (HCC) tissue compared with the adjacent liver tissue, and low B4GALT1 expression was associated with vascular invasion and poor overall survival in patients with HCC. Additionally, silencing or loss of B4GALT1 enhanced HCC cell migration and invasion in vitro and promoted lung metastasis of HCC in NOD/SCID mice. Moreover, B4GALT1 knockdown or knockout increased cell adhesion to laminin, whereas B4GALT1 overexpression decreased the adhesion. Through a mass spectrometry-based approach and Griffonia simplicifolia lectin II (GSL-II) pull-down assays, we identified integrins α6 and ß1 as the main protein substrates of B4GALT1 and their N-glycans were modified by B4GALT1. Further, the increased cell migration and invasion induced by B4GALT1 knockdown or knockout were significantly reversed using a blocking antibody against integrin α6 or integrin ß1. These results suggest that B4GALT1 downregulation alters N-glycosylation and enhances the laminin-binding activity of integrin α6 and integrin ß1 to promote invasiveness of HCC cells. Our findings provide novel insights into the role of B4GALT1 in HCC metastasis and highlight targeting the laminin-integrin axis as a potential therapeutic strategy for HCC with low B4GALT1 expression.

Hepatitis C treatment and long-term outcome of patients with hepatocellular carcinoma after resection.

BACKGROUND AND AIM: This study aimed to investigate the survival outcomes of antiviral agents (direct-acting antivirals [DAAs] or interferon [IFN]) in patients with hepatitis C virus who underwent liver resection for primary hepatocellular carcinoma. METHODS: This retrospective single-center study included 247 patients, between 2013 and 2020, being treated with DAAs (n = 93), IFN (n = 73), or no treatment (n = 81). Overall survival (OS), recurrence-free survival (RFS), and risk factors were analyzed. RESULTS: After a median follow-up time of 50.4 months, the rates of 5-year OS and RFS in the IFN, DAA, and no treatment groups were 91.5% and 55.4%, 87.2% and 39.8%, and 60.9% and 26.7%, respectively. One hundred and twenty-eight (51.6%) patients developed recurrence; recurrence was mostly (86.7%) intrahepatic, and 58 (23.4%) developed early recurrence, most of which received no antiviral treatment. The OS and RFS were similar between patients who received antiviral treatment before (50.0%) and after surgery, but longer survival was observed in patients achieving sustained virologic response. In multivariate analysis, antiviral treatment was protective for OS (hazard ratio [HR] 0.475, 95% confidence interval [CI]: 0.242-0.933) with significance but not RFS, in contrast to microvascular invasion (OS HR 3.389, 95% CI: 1.637-7.017; RFS HR 2.594, 95% CI: 1.520-4.008). In competing risk analysis, DAAs (subdistribution HR 0.086, 95% CI: 0.007-0.991) were protective against hepatic decompensation events but not recurrence events. CONCLUSION: In patients with hepatitis C virus, antiviral treatment suggested OS benefit for primary hepatocellular carcinoma after resection, and DAAs might be protective against hepatic decompensation. Following adjustment for oncological factors, IFN and DAA treatment was not significantly advantageous relative to the other.

Membrane translocation process revealed by in situ structures of type II secretion system secretins.

The GspD secretin is the outer membrane channel of the bacterial type II secretion system (T2SS) which secrets diverse toxins that cause severe diseases such as diarrhea and cholera. GspD needs to translocate from the inner to the outer membrane to exert its function, and this process is an essential step for T2SS to assemble. Here, we investigate two types of secretins discovered so far in Escherichia coli, GspDα, and GspDß. By electron cryotomography subtomogram averaging, we determine in situ structures of key intermediate states of GspDα and GspDß in the translocation process, with resolution ranging from 9 Å to 19 Å. In our results, GspDα and GspDß present entirely different membrane interaction patterns and ways of transitioning the peptidoglycan layer. From this, we hypothesize two distinct models for the membrane translocation of GspDα and GspDß, providing a comprehensive perspective on the inner to outer membrane biogenesis of T2SS secretins.

Viral Status and Treatment Efficacy in Recurrent Hepatocellular Carcinoma After Primary Resection.

BACKGROUND: The impact of viral background on long-term effectiveness of different treatment modalities for recurrent hepatocellular carcinoma (HCC) was not fully analyzed. METHOD: Consecutive 726 patients who developed intrahepatic recurrence after primary hepatectomy for HCC between 2008 and 2015 were retrospectively studied. Post-recurrence survival (PRS) and rerecurrence-free survival (R-RFS) and risk factors were analyzed. RESULTS: After a median follow-up period of 56 months, the 5-year PRS rates of the patients who underwent rehepatectomy, radiofrequency ablation (RFA), and transarterial chemoembolization (TACE) were 79.4%, 83.0%, and 54.6%, respectively. The treatment benefit for PRS was consistently observed in patients with hepatitis B virus (HBV) and non-B, non-C subgroups, but not hepatitis C virus (HCV). For patients with late recurrence of HCC, R-RFS was superior in HBV subgroup and HCV subgroup which received antiviral treatment (compared to naïve HCV subgroup). Survival difference triaged by viral status was lost in the counterpart with early recurrence. Overall, RFA improved PRS and R-RFS in patients receiving antiviral treatment. CONCLUSION: To achieve long-term survival after HCC recurrence, rehepatectomy and RFA were comparably effective, particularly among those with HBV. Antiviral treatment complemented survivals of patients with HCV after RFA, particularly in late first recurrence.

Pre-operative gamma-glutamyl transferase levels predict outcomes in hepatitis B-related hepatocellular carcinoma after curative resection.

BACKGROUND: Surgical resection is a curative therapy for early-stage hepatocellular carcinoma (HCC); however, HCC recurrence is not uncommon. Identifying outcome predictors helps to manage the disease. Gamma-glutamyl transferase (GGT) may predict the development of HCC, but its role to predict the outcomes after surgical resection of HCC was unclear. This study aimed to investigate pre-operative GGT levels for outcome prediction in patients with hepatitis B virus (HBV)-related HCC. METHODS: We conducted a retrospective cohort study to include patients with HBV-related HCC receiving surgical resection. Clinical information, HCC characteristics and usage of antiviral therapy were collected. A time-dependent Cox proportional hazard regression analysis were used to predict HCC recurrence and survival. RESULTS: A total of 699 consecutive patients with HBV-related HCC who received surgical resection with curative intent between 2004 and 2013 were included. After a median of 4.4 years, 266 (38%) patients had HCC recurrence. Pre-operative GGT positively correlated with cirrhosis, tumor burden and significantly increased in patients to develop HCC recurrence. Multivariable analysis demonstrated that pre-operative GGT ≥38 U/L increased 57% risk (hazard ratio [HR]: 1.57, 95% confidence interval [CI]: 1.20-2.06) of recurrent HCC after adjustment for confounding factors. Specifically, pre-operative GGT ≥38 U/L predicted early (<2 years) HCC recurrence (HR: 1.94, 95% CI: 1.30-2.89). Moreover, pre-operative GGT ≥38 U/L predicted all-cause mortality (HR: 1.73, 95% CI: 1.06-2.84) after surgery. CONCLUSION: Pre-operative GGT levels ≥38 U/L independently predict high risks of HCC recurrence and all-cause mortality in HBV-related HCC patients receiving surgical resection.

Synergistic efficacy of telomerase-specific oncolytic adenoviral therapy and histone deacetylase inhibition in human hepatocellular carcinoma.

The telomerase-specific oncolytic adenovirus Telomelysin and the histone deacetylase inhibitor AR42 have demonstrated anticancer effects in preclinical models of human hepatocellular carcinoma (HCC). However, the clinical development of Telomelysin may be hindered by human antiviral immunity and tumor resistance. Combining oncolytic and epigenetic therapies is a viable approach for treating various cancers. This study investigated the potential synergism of Telomelysin and AR42 and the relevant underlying mechanisms. Telomelysin and AR42 exhibited synergistic antiproliferative effects in human HCC models in vitro and in vivo. Apoptosis induced by Telomelysin was significantly enhanced by AR42 in both PLC5 and Hep3B HCC cells. AR42 treatment unexpectedly attenuated the expression of the coxsackievirus and adenovirus receptor and the mRNA levels of human telomerase reverse transcriptase, which may be positively associated with the cytotoxicity of Telomelysin. Meanwhile, the cellular antiviral interferon response was not altered by AR42 treatment. Further, we found that Telomelysin enhanced Akt phosphorylation in HCC cells. AR42 reduced Telomelysin-induced phospho-Akt activation and enhanced Telomelysin-induced apoptosis. The correlation of Akt phosphorylation with drug-induced apoptosis was validated in HCC cells with upregulated or downregulated Akt signaling. Combination therapy with Telomelysin and AR42 demonstrated synergistic anti-HCC efficacy. Clinical trials investigating this new combination regimen are warranted.

Longitudinal analysis of transplant candidates with primary sclerosing cholangitis in an Asian liver transplant center.

BACKGROUND: Primary sclerosing cholangitis (PSC) is a rare disease in Asia, and few studies have investigated the disease in this ethnicity, particularly in wait-listed patients for liver transplantation (LT). We aimed to investigate the prognostic factors and outcomes of wait-listed patients with PSC in an Asian transplant center. METHODS: Survival was retrospectively analyzed. RESULTS: Eighteen (10 male and 8 female) wait-listed patients with PSC, with a median age at diagnosis of 44.5 years, were included. Compared with men, women had significantly higher aspartate aminotransferase to platelet ratio index scores (3.28 vs. 1.13; P = 0.012) and bilirubin levels (7.68 vs. 4.03 mg/dl; P = 0.043) and more often presented with decompensating events, including ascites [5 (63%) vs. 1 (10%); P = 0.043] and splenomegaly [8 (100%) vs. 4 (40%); P = 0.013]. Compared with the non-LT group, the LT group exhibited a superior survival rate for women ( P = 0.004) but not for men. In the univariable analysis, significant risk factors associated with overall survival included malignancies with a hazard ratio (95% confidence interval) of 5.53 (1.00-30.51) and esophageal varices (EV) [4.18 (1.05-16.61)], whereas female gender [25.00 (1.49-500.00)], LT [0.09 (0.01-0.80)] and EV [39.03 (2.92-521.96)] were indicated in the multivariable analysis. CONCLUSIONS: For Asian wait-listed patients with PSC, EV and female gender were the risk factors related to overall survival, and LT was the protective factor. Our experiences suggested that LT brings more benefits in female patients. Strategies are needed to provide equivalent transplant benefits.

In situ structures of secretins from bacterial type II secretion system reveal their membrane interactions and translocation process.

The GspD secretin is the outer membrane channel of the bacterial type II secretion system (T2SS) which secrets diverse effector proteins or toxins that cause severe diseases such as diarrhea and cholera. GspD needs to translocate from the inner to the outer membrane to exert its function, and this process is an essential step for T2SS to assemble. Here, we investigate two types of secretins discovered so far in Escherichia coli , GspD α and GspD ß , respectively. By electron cryotomography subtomogram averaging, we determine in situ structures of all the key intermediate states of GspD α and GspD ß in the translocation process, with resolution ranging from 9 Å to 19 Å. In our results, GspD α and GspD ß present entirely different membrane interaction patterns and ways of going across the peptidoglycan layer. We propose two distinct models for the membrane translocation of GspD α and GspD ß , providing a comprehensive perspective on the inner to outer membrane biogenesis of T2SS secretins.

Therapeutic Effects of Anti-PD1 Immunotherapy on Hepatocellular Carcinoma Under Administration of Tacrolimus.

BACKGROUND: Liver transplantation (LT) is the treatment of choice for patients with hepatocellular carcinoma (HCC). Recurrence of HCC after LT occurs in 10% to 20% of cases. Preclinical studies to evaluate immune checkpoint inhibitors in conjunction with immunosuppressant treatment in transplant recipients have been lacking. Here, we evaluated the efficacy, safety, and mechanism of programmed cell death-1 (PD1) blockade under tacrolimus treatment in transplant recipients. METHODS: We used a murine allogeneic skin transplantation model and murine syngeneic subcutaneous and orthotopic HCC models and measured the tumor volume and the change in tumor-infiltrating lymphocytes under PD1 blockade and tacrolimus treatment. RESULTS: Tacrolimus treatment prolonged allograft survival in the allogeneic transplantation model and enhanced tumor growth in both subcutaneous and orthotopic HCC models. PD1 blockade suppressed tumor growth and lung metastasis in correlation with the number of infiltrating CD8 + T cells. Under tacrolimus treatment, PD1 blockade still resulted in an antitumor effect accompanied by a significant increase in tumor-infiltrating CD8 + T cells, natural killer cells, dendritic cells, and natural killer T cells. Tacrolimus treatment rescued the acceleration of transplant rejection induced by PD1 blockade in the allogeneic transplantation model. CONCLUSIONS: Our data suggest that treatment with high-dose tacrolimus in conjunction with PD1 blockade has an antitumor effect and reduces transplant rejection in mouse models of allograft skin transplantation and HCC. Thus, these results suggest that a clinical trial of PD1 inhibitors for HCC in LT merits consideration.

Interval dynamics of transplantability for hepatocellular carcinoma after primary curative resection: risk factors for nontransplantable recurrence.

BACKGROUND: To investigate the changes in transplantability between primary and recurrent Hepatocellular carcinoma (HCC) after hepatic resection (HR) and the risk factors for nontransplantable recurrence (NTR). METHODS: Consecutive 3122 patients who received HR for primary HCC between 2001 and 2019 were analyzed for changes in transplantability. Predictors of survival and NTR were evaluated using a competing risk analysis. RESULTS: After a median follow-up of 78.3 months, the 5-year overall survival rate was 82.6%. Also, 58.2% of them developed recurrence after a median of 45.6 months. Recurrence occurred in 1205 and 611 patients with primary transplantable and nontransplantable HCC, respectively, of whom 26.1% and 63.2%, respectively, had NTR. Tumor diameter >3 cm [subdistribution hazard ratios (95% CI), 2.00 (1.62-2.48)], major resection [1.20 (1.00-1.43)], pathological grade >2 [1.28 (1.07-1.52)], microvascular invasion [1.74 (1.45-2.08)], and early recurrence (<1 year) [9.22 (7.83-10.87)] were associated with NTR. The overall transplantable pool increased from 72.3% to 77.5%. CONCLUSION: Microvascular invasion and early recurrence were risk factors for NTR. Nonetheless, the transplantable pool increased after HR, 41.8% of the patients had no recurrence and may not require liver transplantation. If the patient's liver function is acceptable, HR should be considered the treatment of choice for HCC.

Delayed Hepatocellular Carcinoma Recurrence After Liver Transplantation: Comprehensive Clinical Characterization of Case Series.

Purpose: Liver transplantation (LT) is the definite curative treatment for hepatocellular carcinoma (HCC), but recurrence can occur even under stringent criteria. "Delayed" HCC recurrence (>3 years after LT) is not common. Here, we present the clinical features of patients who developed delayed HCC recurrence after LT. Patients and Methods: We reviewed the data of eligible patients from February 1999 to December 2020 from medical records. Results: From among 195 (17%) HCC patients who received LT, 34 experienced HCC recurrence, with 5 (15%) delayed recurrence. These five explant tumors were staged T1b-T2, graded II-III, with two vascular invasion and four beyond the Milan criteria. The median time to recurrence was 6.1 years, with the longest interval being nearly 18 years. Recurrence patterns included two extrahepatic, one intrahepatic, and two mixed extrahepatic and intrahepatic recurrences. A drastic increase in serum alpha-fetoprotein levels was observed in four cases 1 year before recurrence. Management of recurrence included locoregional (surgssical resection in three, radiotherapy in three, transarterial chemoembolization in one, radiofrequency ablation in one) and systemic sorafenib use in three. Two patients died within 12-18 months, one died within 18-24 months, and two are still alive until the end of the study, with respective 13.5- and 16.5-month survival. Conclusion: Delayed HCC recurrence could occur over 10 years. Therefore, continual surveillance for recurrence is justified, but biomarkers and intervals or intensities specific for delayed recurrence are not validated, which warrants further validation to facilitate personalized medical care.

Noninvasive assessment of liver function reserve with fluorescent dosimetry of indocyanine green.

Using in vivo multiphoton fluorescent dosimetry, we demonstrate that the clearance dynamics of Indocyanine Green (ICG) in the blood can quickly reveal liver function reserve. In normal rats, the ICG retention rate was below 10% at the 15-minute post-administration; While in the rat with severe hepatocellular carcinoma (HCC), the 15-minute retention rate is over 40% due to poor liver metabolism. With a 785 nm CW laser, the fluorescence dosimeter can evaluate the liver function reserve at a 1/10 clinical dosage of ICG without any blood sampling. In the future, this low-dosage ICG 15-minute retention dosimetry can be applied for the preoperative assessment of hepatectomy or timely perioperative examination.