Impact of Portal Flow on the Prognosis of Children With Congenital Portosystemic Shunt: A Multicentric Observation Study in Japan.

BACKGROUND: Although congenital portosystemic shunts (CPSSs) are increasingly being recognized, the optimal treatment strategies and natural prognosis remain unclear, as individual CPSSs show different phenotypes. METHODS: The medical records of 122 patients who were diagnosed with CPSSs at 15 participating hospitals in Japan between 2000 and 2019 were collected for a retrospective analysis based on the state of portal vein (PV) visualization on imaging. RESULTS: Among the 122 patients, 75 (61.5%) showed PV on imaging. The median age at the diagnosis was 5 months. The main complications related to CPSS were hyperammonemia (85.2%), liver masses (25.4%), hepatopulmonary shunts (13.9%), and pulmonary hypertension (11.5%). The prevalence of complications was significantly higher in patients without PV visualization than in those with PV visualization (P < 0.001). Overall, 91 patients (74.6%) received treatment, including shunt closure by surgery or interventional radiology (n = 82) and liver transplantation (LT) or liver resection (n = 9). Over the past 20 years, there has been a decrease in the number of patients undergoing LT. Although most patients showed improvement or reduced progression of symptoms, liver masses and pulmonary hypertension were less likely to improve after shunt closure. Complications related to shunt closure were more likely to occur in patients without PV visualization (P = 0.001). In 25 patients (20.5%) without treatment, those without PV visualization were significantly more likely to develop complications related to CPSS than those with PV visualization (P = 0.011). CONCLUSION: Patients without PV visualization develop CPSS-related complications and, early treatment using prophylactic approaches should be considered, even if they are asymptomatic. LEVEL OF EVIDENCE: Level III.

The new definition of dominant stricture in primary sclerosing cholangitis: Prevalence and clinical significance.

BACKGROUND AND AIMS: A new definition of dominant stricture (NDS) has recently been defined for patients with primary sclerosing cholangitis (PSC). Prevalence and clinical features of this, compared to traditional dominant stricture (TDS), have not been reported. METHODS: In this single-centre longitudinal prospective cohort study, all PSC patients who underwent endoscopic retrograde cholangiopancreatography (ERCP) between October 2021 and 2022 were recruited. Symptoms of cholestasis, laboratory values (P-alkaline phosphatase, P-Bilirubin), Helsinki PSC-score, brush cytology findings and need for endoscopic therapy (i.e. dilation, stenting) were prospectively collected. RESULTS: Overall, 228 patients with PSC underwent 248 ERCPs. NDS was detected in 43 (17%; 36 patients) and TDS without NDS (TDS group) was detected in 62 (25%; 58 patients) ERCPs, respectively; in the remaining 143 ERCPs, neither TDS nor NDS was seen (no dominant stricture [NoDS] group). PSC duration (median 8 years) and patient's age did not differ between the three groups; males presented more often with NDS. Patients with NDS were more often symptomatic, had higher cholestatic liver enzymes, advanced bile duct disease and markers of biliary inflammation (p < .001). Patients with NDS needed dilation (81%) and stenting (21%) more often than the TDS group (60% and 5%, respectively). Dysplasia in brush cytology was more common in TDS (5%) and NDS (9%) than in NoDS (3%) groups (p = .04), but did not differ between TDS and NDS groups. CONCLUSIONS: Dominant stricture according to the new definition developed in 17% of PSC patients in our cohort and identifies patients with more advanced disease, biliary inflammation and need of endo-therapy.

Chronological alterations in de novo malignancies after living-donor liver transplantation: A cohort study of 1781 recipients using annual comparisons of standardized incidence ratios.

BACKGROUND: De novo malignancies (DNMs) are a major adverse event after solid organ transplantation; however, their characteristics and recent trends after living-donor liver transplantation (LDLT) remain unclear. METHODS: We retrospectively reviewed 1781 primary LDLT recipients (1990-2020) and annually calculated standardized incidence ratios (SIRs) of DNMs compared to the age-adjusted Japanese general population. RESULTS: After 21 845 person-years follow-up, 153 DNM lesions (8.6%) were identified in 131 patients (7.4%). The incidence was 0.007 person-years. DNMs included 81 post-transplant lymphoproliferative disorders (PTLDs), 14 colorectal, 12 lung, and 12 gastric cancers, and so on. Comorbid DNMs significantly worsened recipient survival than those without (p < .001). The 5- and 10-year recipient survival after DNM diagnosis were 65% and 58%, respectively. Notably, SIR1993-1995: 8.12 (95% CI: 3.71-15.4, p < .001) and SIR1996-1998: 3.11 (1.34-6.12, p = .01) were significantly high, but had decreased time-dependently to SIR2005-2007: 1.31 (0.68-2.29, p = .42) and SIR2008-2010: 1.34 (0.75-2.20, p = .33), indicating no longer significant difference in DNMs development. Currently, however, SIR2014-2016: 2.27 (1.54-3.22, p < .001) and SIR2017-2019: 2.07 (1.40-2.96, p < .001) have become significantly higher again, reflecting recent aging of recipients (>50 years) and resultant increases in non-PTLD DNMs. Furthermore, characteristically in LDLT, the fewer the donor-recipient HLA-mismatches, the less the post-transplant DNMs development. CONCLUSION: DNM development after LDLT was significantly higher than in the general population due to higher PTLD incidence (1993-1998), but once became equivalent (2005-2013), then significantly increased again (2014-2019) due to recent recipient aging and resultant increase in solid cancers.

Hepatic manifestations of hereditary haemorrhagic telangiectasia.

Hereditary haemorrhagic telangiectasia is a genetic condition of abnormal blood vessel formation resulting from an imbalance of pro- and anti-angiogenic products of the transforming growth factor ß/bone morphogenetic protein signalling pathway which contributes to vascular remodelling and maintenance. Hepatic vascular malformations are common although less frequently symptomatic, but may result in high-output cardiac failure, portal hypertension and biliary ischaemia. Whilst the understanding of the genetic and cell signalling pathways that are the hallmark of hereditary haemorrhagic telangiectasia have been clarified, there remain challenges in therapy for these patients. Only patients with symptomatic hepatic vascular malformations require treatment, with most (63%) responding to first-line medical therapy. For non-responders, bevacizumab is effective in reducing cardiac output in those with heart failure secondary to hepatic vascular malformations as well as other manifestations of the disease. Although liver transplantation is the only curative option, optimal timing is critical. Novel anti-angiogenetic drugs and those that target aberrant cell signalling pathway are being explored.

The role of living donor liver transplantation in treating intrahepatic cholangiocarcinoma.

Introduction: Intrahepatic cholangiocarcinoma (iCC) is the liver's second most common neoplasm. Until now, surgery is the only curative option, but only 35% of the cases are considered resectable at the diagnosis, with a post-resection survival of around 30%. Advancements in surgical techniques and perioperative care related to liver transplantation (LT) have facilitated the expansion of indications for hepatic neoplasms. Method: This study is a comprehensive review of the global experience in living donor LT (LDLT) for treating iCC and describes our first case of LDLT for an unresectable iCC. Results: While exploring LT for intrahepatic cholangiocarcinoma dates to the 1990s, the initial outcomes were discouraging, marked by poor survival and high recurrence rates. Nevertheless, contemporary perspectives underscore a reinvigorated emphasis on extending the frontiers of LT indications within the context of the "oncologic era." The insights gleaned from examining explants, wherein incidental iCC was categorized as hepatocellular carcinoma in the preoperative period, have demonstrated comparable survival rates to small hepatocellular carcinoma. These findings substantiate the potential viability of LT as a curative alternative for iCC. Another investigated scenario pertains to "unresectable tumors with favorable biological behavior," LT presents a theoretical advantage by providing free margins without the concern of a small future liver remnant. The constraint of organ shortage persists, particularly in nations with low donation rates. LDLT emerges as a viable and secure alternative for treating iCC. Conclusion: LDLT is an excellent option for augmenting the graft pool, particularly in carefully selected patients.

Minimizing Incision in Living Donor Liver Transplantation: Initial Experience and Comparative Analysis of Upper Midline Incision in 115 Recipients.

Living donor liver transplantation (LDLT) needs "Mercedes Benz" or "J-shaped" incision, causing short and long-term complications. An upper midline incision (UMI) is less invasive alternative but technically challenging. Reporting UMI for recipients in LDLT vs. conventional J-shaped incision. Retrospective analysis, July 2021 to December 2022. Peri-operative details and post-transplant outcomes of 115 consecutive adult LDLT recipients transplanted with UMI compared with 140 recipients with J-shaped incision. Cohorts had similar preoperative and intraoperative variables. The UMI group had significant shorter time to ambulation (3 ± 1.6 vs. 3.6 ± 1.3 days, p = 0.001), ICU stay (3.8 ± 1.3 vs. 4.4 ± 1.5 days, p = 0.001), but a similar hospital stay (15.6±7.6 vs. 16.1±10.9 days, p = 0.677), lower incidence of pleural effusion (11.3% vs. 27.1% p = 0.002), and post-operative ileus (1.7% vs. 9.3% p = 0.011). The rates of graft dysfunction (4.3% vs. 8.5% p = 0.412), biliary complications (6.1% vs. 12.1% p = 0.099), 90-day mortality (7.8% vs. 12.1% p = 0.598) were similar. UMI-LDLT afforded benefits such as reduced pleuropulmonary complications, better early post-operative recovery and reduction in scar-related complaints in the medium-term. This is a safe, non-inferior and reproducible technique for LDLT.

Deep learning-based pathway-centric approach to characterize recurrent hepatocellular carcinoma after liver transplantation.

BACKGROUND: Liver transplantation (LT) is offered as a cure for Hepatocellular carcinoma (HCC), however 15-20% develop recurrence post-transplant which tends to be aggressive. In this study, we examined the transcriptome profiles of patients with recurrent HCC to identify differentially expressed genes (DEGs), the involved pathways, biological functions, and potential gene signatures of recurrent HCC post-transplant using deep machine learning (ML) methodology. MATERIALS AND METHODS: We analyzed the transcriptomic profiles of primary and recurrent tumor samples from 7 pairs of patients who underwent LT. Following differential gene expression analysis, we performed pathway enrichment, gene ontology (GO) analyses and protein-protein interactions (PPIs) with top 10 hub gene networks. We also predicted the landscape of infiltrating immune cells using Cibersortx. We next develop pathway and GO term-based deep learning models leveraging primary tissue gene expression data from The Cancer Genome Atlas (TCGA) to identify gene signatures in recurrent HCC. RESULTS: The PI3K/Akt signaling pathway and cytokine-mediated signaling pathway were particularly activated in HCC recurrence. The recurrent tumors exhibited upregulation of an immune-escape related gene, CD274, in the top 10 hub gene analysis. Significantly higher infiltration of monocytes and lower M1 macrophages were found in recurrent HCC tumors. Our deep learning approach identified a 20-gene signature in recurrent HCC. Amongst the 20 genes, through multiple analysis, IL6 was found to be significantly associated with HCC recurrence. CONCLUSION: Our deep learning approach identified PI3K/Akt signaling as potentially regulating cytokine-mediated functions and the expression of immune escape genes, leading to alterations in the pattern of immune cell infiltration. In conclusion, IL6 was identified to play an important role in HCC recurrence.

A Clinical Course of Repeated Supratherapeutic Ingestion of Acetaminophen.

Acute liver failure (ALF) exemplifies a rapid decline in liver function among individuals with previously healthy livers, often manifesting through symptoms such as jaundice, confusion, and potentially life-threatening complications. Timely medical intervention, and, in severe instances, liver transplantation, are essential for enhancing outcomes and averting further deterioration. While the causes of ALF are multifaceted, in developed nations, it predominantly arises from drug-induced liver injury. Treatment primarily revolves around supportive measures, with severe cases necessitating liver transplantation. In instances where acute overdose with acetaminophen serves as the instigating factor, N-acetylcysteine (NAC) emerges as a pivotal component of management, as indicated by the Rumack-Matthew nomogram. The Rumack-Matthew nomogram guides treatment for acetaminophen overdose by correlating serum levels with the risk of liver damage. If levels exceed a set threshold, NAC is administered to prevent toxicity by replenishing glutathione. The decision to administer NAC is typically guided by this clinical tool, which aids healthcare providers in determining the appropriate course of action. NAC assumes a critical role in ameliorating the detrimental effects of acetaminophen overdose, particularly in averting liver damage, thus holding significant importance in patient care and recovery. While chronic acetaminophen overdose cases leading to ALF may also benefit from NAC, the supporting evidence remains weak. In this context, we present a case of ALF stemming from chronic acetaminophen ingestion, managed with NAC when liver transplantation was not a viable option.

Correlation Between NLR Combined with PLR Score and Prognosis of Hepatocellular Carcinoma After Liver Transplantation.

Background: This investigation evaluated the prognostic significance of the neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR), and introduced a combined NLR-PLR score to evaluate the correlation between NLR-PLR score and hepatocellular carcinoma (HCC) recurrence. Material/Methods: We enrolled 110 patients who underwent orthotopic liver transplantation (LT) for HCC. The neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) were assessed, and appropriate cut-off values were established. The NLR-PLR score ranged from 0 to 2 as follows: score of 2, high NLR (≥3.37) and high PLR (≥105.96); score of 1, either high NLR or high PLR; score of 0, neither high NLR nor high PLR. Results: The median overall survival (OS) of patients with NLR-PLR score of 0, 1 and 2 was 27, 26.5, and 6 months, respectively. The median OS of patients with NLR-PLR score of 2 was shorter than those with 0 (P < 0.001) and 1 (P < 0.001). The median disease-free survival (DFS) time of patients with NLR-PLR score of 0, 1 and 2 was 24.5, 24, and 6 months, The median DFS of patients with NLR-PLR score of 2 was shorter than those with 0 (P = 0.001) and 1 (P = 0.015). Multivariate analysis showed that NLR-PLR score was an independent risk factor for prognosis and survival. Conclusion: NLR, PLR and NLR-PLR score can predict the long-term survival of patients, and NLR-PLR score, having more predictive value than NLR and PLR alone is an independent risk factor for patient survival. more predictive value than NLR and PLR alone.

Successful liver transplantation as rescue therapy in a patient with metastases from a vasoactive intestinal peptide producing neuroendocrine tumor.

This case report presents a 40-year-old patient with a vasoactive intestinal peptide (VIP) secreting high grade (Ki-67 39%) neuroendocrine tumor (NET) from the pancreas, for whom successful liver transplantation (LT) was carried out 8 years after resection of the primary tumor due to massive liver metastases. The transplantation was done as rescue therapy due to rapid progression and a devastating clinical condition requiring intravenous supplementation for 20 hours daily. The latest imaging carried out 18 months after transplantation is without signs of recurrence, and the patient is in good health with undetectable levels of VIP. According to the guidelines, LT is only recommended if Ki-67 is <20% and if there has been tumor control for more than 6 months prior to transplantation. Our case illustrates that LT is an option that should be considered for selected NET patients without extrahepatic involvement regardless of tumor grade and clinical condition.

Comparison of prophylaxis and preemptive strategy as cytomegalovirus prevention in liver transplant recipients.

OBJECTIVES: Prophylaxis (P) or pre-emptive strategy (PS) in high-risk liver transplant recipients (LTRs) are either recommended. We compared the results of each strategy. METHODS: Two groups of LTR transplanted during two consecutive periods were compared. Only cytomegalovirus (CMV)-mismatched LTR (Donor +/ Recipient -) were included. The primary endpoints were: the onset of polymerase chain reaction-based DNAemia and the proportion of patients with CMV disease. A number of episodes of CMV infection, antiviral therapy, ganciclovir resistance, infectious or immunological complications, cost of both strategies, and survival (1, 5, and 10 years) were also compared. RESULTS: Forty-eight and 60 patients were respectively included in the P and PS groups. Eighteen (38%) in the P group and 56 (93%) in the PS group had CMV DNAemia (p <.0001) with a similar CMV disease rate (16.7% and 15%). Duration of curative therapy was longer in the PS group: 91 days versus 16 (p <.0001). Acute rejection was less frequent (p = .04) and more patients experienced a ganciclovir-resistant CMV infection in the PS group (10% vs. 0, p = .03). The drug-associated cost of PS was higher (10 004 vs. 4804€) and the median number of rehospitalization days tended to be higher (6 vs. 4, p = .06). Survival at any time was similar. CONCLUSION: We reported more CMV DNAemias and ganciclovir-resistant CMV events with PS. The cost of the PS strategy was higher.

Combined transarterial chemoembolization and thermal ablation in candidates to liver transplantation with hepatocellular carcinoma: pathological findings and post-transplant outcome.

OBJECTIVES: Evaluating the pathological response and the survival outcomes of combined thermal ablation (TA) and transarterial chemoembolization (TACE) as a bridge or downstaging for liver transplantation (LT) in patients with hepatocellular carcinoma (HCC) > 3 cm. MATERIALS AND METHODS: A retrospective review encompassed 36 consecutive patients who underwent combined TA-TACE as bridging or downstaging before LT. Primary objectives included necrosis of the target lesion at explant pathology, post-LT overall survival (OS) and post-LT recurrence-free survival (RFS). For OS and RFS, a comparison with 170 patients subjected to TA alone for nodules <3 cm in size was also made. RESULTS: Out of the 36 patients, 63.9% underwent TA-TACE as bridging, while 36.1% required downstaging. The average node size was 4.25 cm. All cases were discussed in a multidisciplinary tumor board to assess the best treatment for each patient. Half received radiofrequency (RF), and the other half underwent microwave (MW). All nodes underwent drug-eluting beads (DEB) TACE with epirubicin. The mean necrosis percentage was 65.9% in the RF+TACE group and 83.3% in the MW+TACE group (p-value = 0.099). OS was 100% at 1 year, 100% at 3 years and 94.7% at 5 years. RFS was 97.2% at 1 year, 94.4% at 3 years and 90% at 5 years. Despite the different sizes of the lesions, OS and RFS did not show significant differences with the cohort of patients subjected to TA alone. CONCLUSIONS: The study highlights the effectiveness of combined TA-TACE for HCC>3 cm, particularly for bridging and downstaging to LT, achieving OS and RFS rates significantly exceeding 80% at 1, 3 and 5 years.

Assessment of Mitochondrial Respiration During Hypothermic Storage of Liver Biopsies Following Normothermic Machine Perfusion.

Organ quality can be assessed prior to transplantation, during normothermic machine perfusion (NMP) of the liver. Evaluation of mitochondrial function by high-resolution respirometry (HRR) may serve as a viability assessment concept in this setting. Freshly collected tissue is considered as optimal sample for HRR, but due to technical and personnel requirements, more flexible and schedulable measurements are needed. However, the impact of cold storage following NMP before processing biopsy samples for mitochondrial analysis remains unknown. We aimed at establishing an appropriate storage protocol of liver biopsies for HRR. Wedge biopsies of 5 human livers during NMP were obtained and assessed by HRR. Analysis was performed after 0, 4, 8, and 12 h of hypothermic storage (HTS) in HTK organ preservation solution at 4°C. With HTS up to 4 h, mitochondrial performance did not decrease in HTS samples compared with 0 h (OXPHOS, 44.62 [34.75-60.15] pmol·s-1·mg wet mass-1 vs. 43.73 [40.69-57.71], median [IQR], p > 0.999). However, at HTS beyond 4 h, mitochondrial respiration decreased. We conclude that HTS can be safely applied for extending the biopsy measurement window for up to 4 h to determine organ quality, but also that human liver respiration degrades beyond 4 h HTS following NMP.

Survival of propionic acidemia patients with liver transplant.

Propionic acidemia (PA) is a rare metabolic disorder affecting amino acid metabolism. Liver transplantation improves some outcomes, but the impact on long-term survival remains unclear. A systematic literature review and survival analysis, identifying 94 PA patients who underwent transplantation, revealed a survival probability of 62% at age 33; while median survival was estimated at 40 years. These findings highlight a substantial survival deficit of PA patients compared to the general population despite liver transplantation.

A 29-mRNA host-response classifier identifies bacterial infections following liver transplantation - a pilot study.

PURPOSE: Infections are common complications in patients following liver transplantation (LTX). The early diagnosis and prognosis of these infections is an unmet medical need even when using routine biomarkers such as C-reactive protein (CRP) and procalcitonin (PCT). Therefore, new approaches are necessary. METHODS: In a prospective, observational pilot study, we monitored 30 consecutive patients daily between days 0 and 13 following LTX using the 29-mRNA host classifier IMX-BVN-3b that determine the likelihood of bacterial infections and viral infections. True infection status was determined using clinical adjudication. Results were compared to the accuracy of CRP and PCT for patients with and without bacterial infection due to clinical adjudication. RESULTS: Clinical adjudication confirmed bacterial infections in 10 and fungal infections in 2 patients. 20 patients stayed non-infected until day 13 post-LTX. IMX-BVN-3b bacterial scores were increased directly following LTX and decreased until day four in all patients. Bacterial IMX-BVN-3b scores detected bacterial infections in 9 out of 10 patients. PCT concentrations did not differ between patients with or without bacterial, whereas CRP was elevated in all patients with significantly higher levels in patients with bacterial infections. CONCLUSION: The 29-mRNA host classifier IMX-BVN-3b identified bacterial infections in post-LTX patients and did so earlier than routine biomarkers. While our pilot study holds promise future studies will determine whether these classifiers may help to identify post-LTX infections earlier and improve patient management. CLINICAL TRIAL NOTATION: German Clinical Trials Register: DRKS00023236, Registered 07 October 2020, https://drks.de/search/en/trial/DRKS00023236.

Multi-omics analysis reveals a crosstalk between ferroptosis and peroxisomes on steatotic graft failure after liver transplantation.

To identify the mechanism underlying macrosteatosis (MaS)-related graft failure (GF) in liver transplantation (LT) by multi-omics network analysis. The transcriptome and metabolome were assayed in graft and recipient plasma in discovery (n = 68) and validation (n = 89) cohorts. Differentially expressed molecules were identified by MaS and GF status. Transcriptional regulatory networks were generated to explore the mechanism for MaS-related inferior post-transplant prognosis. The differentially expressed molecules associated with MaS and GF were enriched in ferroptosis and peroxisome-related pathways. Core features of MaS-related GF were presented on decreased transferrin and impaired anti-oxidative capacity dependent upon dysregulation of transcription factors hepatocyte nuclear factor 4A (HNF4A) and hypoxia-inducible factor 1A (HIF1A). Furthermore, miR-362-3p and miR-299-5p inhibited transferrin and HIF1A expression, respectively. Lower M2 macrophages but higher memory CD4 T cells were observed in MaS-related GF cases. These results were validated in clinical specimens and cellular models. Systemic analysis of multi-omics data depicted a panorama of biological pathways deregulated in MaS-related GF. Transcriptional regulatory networks centered on transferrin and anti-oxidant responses were associated with poor MaS graft quality, qualifying as potential targets to improve prognosis of patients after LT.

A Case of Metastatic Melanoma Post Orthotopic Liver Transplantation.

With the rising prevalence of organ transplantation, clinicians must be aware of the many potential complications that may arise. One such complication is post-transplantation melanoma. Herein, we present a case of advanced metastatic melanoma following orthotopic liver transplantation (OLT).  This is a 54-year-old cirrhotic male who underwent OLT that was complicated by metastatic melanoma. Despite adherence to yearly screening guidelines and timely radiation and immunotherapy, the disease course was rapidly progressive and fatal. This case aims to highlight the risk of post-transplantation melanoma and the potential need for screening modifications to identify melanoma earlier in its development.  The association between organ transplantation and melanoma is well-reported, but the underlying risks and mechanisms remain incompletely understood. One potential risk factor is post-transplant immunosuppressive therapy, which may result in fatally aggressive melanoma. Understanding the potential mortality risks in transplant patients, modifications to peri-transplant screening guidelines, and immunosuppressive therapy may be lifesaving.