Antithrombotic Revascularization Strategy of Bioengineered Liver Using a Biomimetic Polymer.

A bioengineered liver has the potential to save patients with end-stage liver disease, and a three-dimensional decellularized scaffold is a promising approach for practical use. The main challenge in bioengineered liver transplantation is thrombogenicity during blood perfusion. We aimed to apply a novel antithrombotic polymer to revascularize liver scaffolds and evaluate the thrombogenicity and biosafety of the polymer-treated scaffolds. A biomimetic polymer, 2-metacryloyloxyethyl phosphorylcholine (MPC) was prepared for modification of the extracellular matrix in liver scaffolds. The polymer was injected into the rat liver scaffolds' portal vein and could extensively react to the vessel walls. In an ex vivo blood perfusion experiment, we demonstrated significantly less platelet deposition in the polymer-treated scaffolds than nontreated or re-endothelialized scaffolds with human umbilical vein endothelial cells. In the heterotopic transplantation model, liver volume was better maintained in the polymer-treated groups, and platelet deposition was suppressed in these groups. Additionally, the polymer-treated liver scaffolds maintained the metabolic function of the recellularized rat primary hepatocytes during perfusion culture. The MPC polymer treatment efficiently suppressed thrombus formation during blood perfusion in liver scaffolds and maintained the function of recellularized hepatocytes. Revascularizing liver scaffolds using this polymer is a promising approach for bioengineered liver transplantation.

Combination of risk alleles of PNPLA3, TM6SF2, and HSD17B13 of donors can predict recurrence of steatotic liver disease after liver transplantation.

AIMS: This study aimed to identify the genetic risk factors from donors or recipients that contribute to postliver transplantation (LT) steatotic liver disease (SLD), focusing on the genetic risk score (GRS) based on single nucleotide polymorphisms (SNPs) in SLD patients. METHODS: This retrospective study included 55 Japanese SLD recipients and their respective donors. Genotyping of PNPLA3, TM6SF2, and HSD17B13 was undertaken, and the combined GRS was calculated. The relationship between the GRS and the incidence of posttransplant SLD was also evaluated. RESULTS: The SLD recipients had a high prevalence of post-LT graft steatosis/steatohepatitis (76.4% and 58.2%, respectively). Although the recipients had a high frequency of risk alleles, there was no relationship between the number of risk alleles for each SNP and the incidence of posttransplant SLD. In contrast, an increased number of risk alleles for any SNP in the donor was correlated with high incidence rates of both post-LT steatosis and steatohepatitis. A multivariable analysis showed that a high donor GRS was an independent risk factor for graft steatosis (odds ratio 8.77; 95% CI, 1.94-52.94; p = 0.009). Similarly, a high donor GRS was an independent risk factor (odds ratio 6.76; 95% CI, 1.84-30.78; p = 0.007) for post-LT graft steatohepatitis. CONCLUSIONS: Donor risk alleles of PNPLA3, TM6SF2, and HSD17B13, rather than recipient risk alleles, have been implicated in the development of posttransplant SLD. The combination of these donor risk alleles into a GRS could predict the development of posttransplant SLD.

Integrated analyses of the genetic and clinicopathological features of cholangiolocarcinoma: cholangiolocarcinoma may be characterized by mismatch-repair deficiency.

Cholangiolocarcinoma (CLC) is a primary liver carcinoma that resembles the canals of Hering and that has been reported to be associated with stem cell features. Due to its rarity, the nature of CLC remains unclear, and its pathological classification remains controversial. To clarify the positioning of CLC in primary liver cancers and identify characteristics that could distinguish CLC from other liver cancers, we performed integrated analyses using whole-exome sequencing (WES), immunohistochemistry, and a retrospective review of clinical information on eight CLC cases and two cases of recurrent CLC. WES demonstrated that CLC includes IDH1 and BAP1 mutations, which are characteristic of intrahepatic cholangiocarcinoma (iCCA). A mutational signature analysis showed a pattern similar to that of iCCA, which was different from that of hepatocellular carcinoma (HCC). CLC cells, including CK7, CK19, and EpCAM, were positive for cholangiocytic differentiation markers. However, the hepatocytic differentiation marker AFP and stem cell marker SALL4 were completely negative. The immunostaining patterns of CLC with CD56 and epithelial membrane antigen were similar to those of the noncancerous bile ductules. In contrast, mutational signature cluster analyses revealed that CLC formed a cluster associated with mismatch-repair deficiency (dMMR), which was separate from iCCA. Therefore, to evaluate MMR status, we performed immunostaining of four MMR proteins (PMS2, MSH6, MLH1, and MSH2) and detected dMMR in almost all CLCs. In conclusion, CLC had highly similar characteristics to iCCA but not to HCC. CLC can be categorized as a subtype of iCCA. In contrast, CLC has characteristics of dMMR tumors that are not found in iCCA, suggesting that it should be treated distinctly from iCCA. © 2024 The Pathological Society of Great Britain and Ireland.

Trends in long-term outcomes of patients with HCV-associated hepatocellular carcinoma after hepatectomy: A comparison before and after introduction of direct-acting antivirus therapy.

Backgrounds: The success of direct-acting antiviral (DAA) therapy provides a cure for patients chronically infected with hepatitis C virus (HCV); however, outcomes after hepatectomy for HCV-associated hepatocellular carcinoma (HCC) before and after DAA introduction remain poorly studied. Methods: Patients who underwent R0/R1 hepatectomy for HCV-associated HCC were retrospectively analyzed. Two time periods were defined: Pre-DAA (2007-2011, December 2013 was defined as the end of follow-up) and Post-DAA groups (2014-2018, December 2020 was defined as the end of follow-up). Propensity score matching (PSM) analyses were performed to highlight the effect of DAA therapy. Results: A total of 155 patients with HCV-associated HCC were included in this study (Pre-DAA group, n = 103 and post-DAA group, n = 52). In the Post-DAA group, DAA therapy was performed in 26 patients (50.0%), and all of these patients achieved sustained virologic response (SVR) (preoperative SVR, n = 7; postoperative SVR, n = 19). There was no significant difference between the two groups regarding surgical settings and tumor pathology. There was no significant difference in the 5-year overall survival (OS) rate (61.1% and 64.8%, pre- and post-DAA group, respectively, p = 0.441); meanwhile, the 5-year recurrence-free survival (RFS) rate in the post-DAA group was better than the pre-DAA group (21.1% and 40.2%, p = 0.073) with a trend toward significance. After PSM except for the postoperative SVR status, there were no significant differences in OS (p = 0.586) and RFS (p = 0.888). Conclusions: This study showed that survival outcomes were not changed in hepatectomized cases of HCV-associated HCC before and after the introduction of DAA therapy.

Factors associated with early postoperative exercise tolerance after living-donor liver transplantation.

BACKGROUND: Physical dysfunction, including exercise intolerance, is a major factor for delayed societal reintegration for patients who underwent living-donor liver transplantation (LDLT). However, what may contribute to early postoperative physical function is not well known. The purpose of this study is to elucidate the perioperative factors affecting early posttransplant exercise intolerance. METHODS: 103 consecutive patients who underwent LDLT were enrolled, and 68 patients were retrospectively analyzed. We examined the relationship between postoperative exercise tolerance evaluated by a 6-minute walking distance (6MWD) at discharge after surgery and demographic data, surgical information, preoperative physical function, clinical course, and the postoperative decline in physical function with univariate and multivariate analyses. RESULTS: Almost all patients were discharged within 3 months after surgery. The postoperative 6MWD was 408 ± 94 m (68 [61-84]% of the predicted value), and patients who had a low %6MWD at discharge had significantly lower preoperative physical function than patients who had a high %6MWD at discharge (grip strength: 29.8 ± 8.9 kgf vs. 23.0 ± 8.8 kgf, P < .01, knee extensor strength: 138.9 ± 59.4 Nm vs. 95.2 ± 42.1 Nm, P < .01). Multivariate analysis revealed that preoperative knee extensor strength (standardized ß = 0.35, P < .01) and first postoperative walking day (standardized ß = -0.22, P = .04) were independently associated with the postoperative %6MWD. CONCLUSION: These results suggest that maintaining preoperative muscle strength and allowing for early postoperative mobilization might help to enhance the recovery of physical function and facilitate the patient's social reintegration after LDLT.

Mesh shrinkage is the potential pathogenesis of chronic somatic pain following transabdominal preperitoneal repair: Report of two cases.

Although mesh-related pain, termed "somatic pain," is a well-known pain syndrome following Lichtenstein repair, few reports are available on somatic pain following transabdominal preperitoneal repair (TAPP) and its pathogenesis remains unclear. We report on two patients with refractory somatic chronic pain following TAPP. In the present two cases, both mesh fixation with rigid permanent metal tackers and mesh shrinkage resulting in contractile forces on the groin musculature could be considered as potential mechanisms in the etiology of chronic somatic pain following TAPP. The lessons learned from these two cases are: (a) mesh shrinkage resulting in contractile forces on the groin musculature could be considered as potential mechanisms in the etiology of chronic somatic pain following TAPP; (b) partial mesh removal would be an effective alternative to total mesh removal in those patients for remedial surgery.