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Introduction:This study aimed to compare the prognostic impact of laparoscopic left hepatectomy (LLH) with that of open left hepatectomy (OLH) on patient survival after resection of left hepatocellular carcinoma (HCC). Methods:Among the 953 patients who received initial treatment for primary HCC that was resectable by either LLH or OLH from 2013 to 2017 in Japan and Korea, 146 patients underwent LLH and 807 underwent OLH. The inverse probability of treatment weighting approach based on propensity scoring was used to address the potential selection bias inherent in the recurrence and survival outcomes between the LLH and OLH groups. Results:The occurrence rate of postoperative complications and hepatic decompensation was significantly lower in the LLH group than in the OLH group. Recurrence-free survival (RFS) was better in the LLH group than in the OLH group (hazard ratio, 1.33; 95% confidence interval, 1.03–1.71; p= 0.029), whereas overall survival (OS) was not significantly different. Subgroup analyses of RFS and OS revealed an almost consistent trend in favor of LLH over OLH. In patients with tumor sizes of ≥4.0 cm or those with single tumors, both RFS and OS were significantly better in the LLH group than in the OLH group. Conclusions:LLH decreases the risk of tumor recurrence and improves OS in patients with primary HCC located in the left liver.

ABSTRACTBackgroundThe technique to analyze circulating tumor DNA (ctDNA) in body fluid (so-called “liquid biopsy”) is recently developed.AimsOur aim was to assess the utility of liquid biopsy for predicting progression of pancreatic ductal adenocarcinoma (PDAC) after surgical resection or chemotherapy.MethodsA total of 72 patients with PDAC were retrospectively enrolled for this study, 33 treated surgically and 39 given chemotherapy, either FOLFIRINOX (oxaliplatin/irinotecan/fluorouracil/leucovorin) or gemcitabine plus nab-paclitaxel. Prior to treatment, patients were screened for the presence of KRAS mutations (G12D and G12V) in plasma using droplet digital polymerase chain reaction, and outcomes were compared.ResultsKRAS mutations were identified in plasma samples of 12 patients (36%) underwent surgical resection. Patients with plasma KRAS mutations had significantly shorter disease-free survival (DFS) and overall survival (p< .01 and p= .01, respectively). Of 10 clinical variables analyzed, plasma KRAS mutation was the factor predictive of DFS in multivariate analysis (RR = 3.58, 95% CI: 1.36–9.60; p= .01). Although 12 patients (31%) given chemotherapy tested positive for plasma KRAS mutations, there was no demonstrable relation between plasma KRAS mutations and progression-free survival (PFS) or overall survival (OS) (p= .35 and p= .68, respectively).ConclusionsIn patients with PDAC, detection of KRAS mutations in plasma proved independently predictive of early recurrence after surgical resection but did not correlate with PFS following chemotherapy.

The excess mortality of COVID-19 solid organ transplant recipients (SOTRs) throughout the pandemic remains unclear. This prospective cohort study based on the Japanese nationwide registry included 1,632 SOTRs diagnosed with COVID-19 between February 1, 2020, and July 31, 2022, categorized based on dominant phases of variants of concern (VOC): Waves 1–3 (Beta), 4 (Alpha), 5 (Delta), 6 (Omicron BA.1/BA.2), and 7 (Omicron BA.5). Excess mortality of COVID-19-affected SOTRs was analyzed by calculating standardized mortality ratios (SMRs). Overall, 1,632 COVID-19-confirmed SOTRs included 1,170 kidney, 408 liver, 25 lung, 20 heart, 1 small-intestine, and 8 multiorgan recipients. Although disease severity and all-cause mortality decreased as VOC transitioned, SMRs of SOTRs were consistently higher than those of the general population throughout the pandemic, showing a U-shaped gap that peaked toward the Omicron BA.5 phase; SMR (95% CI): 6.2 (3.1–12.5), 4.0 (1.5–10.6), 3.0 (1.3–6.7), 8.8 (5.3–14.5), and 21.9 (5.5–87.6) for Waves 1–3 (Beta), Wave 4 (Alpha), Wave 5 (Delta), Wave 6 (Omicron BA.1/2), and Wave 7 (Omicron BA.5), respectively. In conclusion, COVID-19 SOTRs had greater SMRs than the general population across the pandemic. Vaccine boosters, immunosuppression optimization, and other protective measures, particularly for older SOTRs, are paramount.

Introduction:Radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) is considered a safe and minimally invasive procedure. We previously reported that the mortality and complication rates for RFA were 0.038% (5/13,283 patients) and 3.54% (579 complications/16,346 procedures), respectively, from 1999 to 2010 (previous period). In this study, we investigated the clinical criteria for RFA and the mortality and complication rates from 2011 to 2015 (recent period). Methods:Data were collected from 25 centers by using a questionnaire developed by the Chugoku-Shikoku Society for Local Ablation Therapy of HCC. The criteria for RFA, RFA modification, use of image-guidance modalities, mortality, and complications during the previous and recent periods were compared. Results:We evaluated 11,298 procedures for 9,411 patients, including those that involved new devices (bipolar RFA and internally adjustable electrode system). The criterion of hepatic function for RFA increased from a Child-Pugh score ≤8 during the previous period to ≤9 during the recent period. The criteria regarding the tumor location and other risk factors have been expanded recently because of the increased use of several modifications of the RFA procedure and image-guidance modalities. The mortality rate was 0.064% (6/9,411 patients), and the complication rate was 2.92% (330 complications/11,298 procedures). There was no difference in mortality rates between the 2 periods (p= 0.38), but the complication rates was significantly lower during the recent period (p= 0.038). Discussion and Conclusions:Our findings confirmed that RFA, including the use of new devices, is a low-risk procedure for HCC, despite the expansion of the criteria for RFA during the recent period.

Objective:Keratin 19 (K19) expression is a potential predictor of poor prognosis in patients with hepatocellular carcinoma (HCC). To clarify the feature of K19-proficient HCC, we traced epigenetic footprints in cultured cells and clinical materials. Patients and Methods:In vitro, KRT19promoter methylation was analyzed and 5-aza-2’-deoxycytidine with trichostatin A (TSA) treatment was performed. Among 564 surgically resected HCCs, the clinicopathological relevance of K19-proficent HCCs was performed in comparison with hepatocytic (HepPar-1 and arginase-1), epithelial-mesenchymal transition (E-cadherin and vimentin), biliary differentiation-associated (K7 and NOTCH-1) markers, and epigenetic markers (KRT19promoter/long interspersed nucleotide element-1 [LINE-1] methylation status). Results:KRT19promoter methylation was clearly associated with K19 deficiency and 5-aza-2’-deoxycytidine with TSA treatment-stimulated K19 re-expression, implicating DNA methylation as a potential epigenetic process for K19 expression. After excluding HCCs with recurrence, TNM stage as IIIB or greater, preoperative therapy, transplantation, and combined hepatocellular cholangiocarcinoma, we assessed 125 of 564 HCC cases. In this cohort, K19 expression was found in 29 HCCs (23.2%) and corresponded with poor survival following surgery (p= 0.025) and extrahepatic recurrence-free survival (p= 0.017). Compared with K19-deficient HCCs, lower KRT19promoter methylation level was observed in K19-proficient HCCs (p< 0.0001). Conversely, HCC with genome-wide LINE-1hypermethylation was frequently observed in K19-proficient HCCs (p= 0.0079). Additionally, K19 proficiency was associated with K7 proficiency (p= 0.043), and reduced E-cadherin and HepPar-1 expression (p= 0.043 and p< 0.0001, respectively). Conclusions:K19-proficient HCC exhibited poor prognosis owing to extrahepatic recurrence, with molecular signatures differing from those in conventional cancer stem cells, providing novel insights of the heterogeneity underlying tumor development.

Post orthotopic liver transplantation (OLT) viral hepatitis is an immunological condition where immune cells induce hepatitis during conditions of immune-suppression. The immune-regulatory programmed death-1 (PD-1)PD-ligand 1 system is acknowledged to play important roles in immune-mediated diseases. However, the PD-1PD-L2 interaction is not well characterized, with PD-L2 also exhibiting an immunostimulatory function. We hypothesized that this atypical molecule could affect the recurrence of post-OLT hepatitis. To test this hypothesis, we conducted immunohistochemical staining analysis and in vitro analysis of PD-L2.

Posttransplant diabetes mellitus is a frequent complication among transplant recipients. Ligation of advanced glycation end products (AGEs) with their receptor on monocytes/macrophages plays a role in diabetes complications. The enhancement of adhesion molecule expression on monocytes/macrophages activates T cells, reducing allograft survival. In previous work, we found that toxic AGEs, AGE-2 and AGE-3, induced the expression of intracellular adhesion molecule-1, B7.1, B7.2, and CD40 on monocytes, production of interferon-gamma and tumor necrosis factor alpha, and lymphocyte proliferation during human mixed lymphocyte reaction. AGE-induced up-regulation of adhesion molecule expression was involved in cytokine production and lymphocyte proliferation. Prostaglandin E2 (PGE2) concentration-dependently inhibited the actions of AGE-2 and AGE-3. The effects of PGE2 were mimicked by an EP2 receptor agonist, ONO-AE1-259-01 (11,15-O-dimethyl PGE2), and an EP4 receptor agonist, ONO-AE1-329 [16-(3-methoxymethyl)phenyl-omega-tetranor-3,7dithia PGE1]. An EP2 receptor antagonist, AH6809 (6-isopropoxy-9-oxaxanthene-2-carboxylic acid), and an EP4 receptor antagonist, AH23848 [(4Z)-7-[(rel-1S,2S,5R)-5-((1,1'-biphenyl-4-yl)methoxy)-2-(4-morpholinyl)-3-oxocyclopentyl]-4-heptenoic acid], inhibited the actions of PGE2. The stimulation of EP2 and EP4 receptors is reported to increase cAMP levels. The effects of PGE2 were reversed by protein kinase A (PKA) inhibitors and mimicked by dibutyryl cAMP and an adenylate cyclase activator, forskolin. These results as a whole indicate that PGE2 inhibited the actions of AGE-2 and AGE-3 via EP2/EP4 receptors and the cAMP/PKA pathway.

Living-donor liver transplantation (LDLT) has been widely performed in patients with end-stage liver disease and hepatocellular carcinoma in Japan. Although extrahepatic cancer survey for LDLT candidates is absolutely required, few reports have indicated the optimal surveillance method for colorectal cancer. The aim of this study is to investigate the feasibility and findings of colonoscopy before LDLT.

The small-for-size (SFS) syndrome is caused by excessive portal inflow into a small-sized liver graft. Various approaches for portal decompression have been used, but details of their impact on liver regeneration in SFS graft remain unclear. We examined the effect of prophylactic splenic artery modulation (SAM).

The negative effects of increased donor age on liver transplantation became evident in deceased donor liver transplantation. In living donor liver transplantation (LDLT), the details remain unclear.

A 79-year-old woman presented with epigastralgia, and computed tomography showed a 3-cm multiloculated mass with a mural nodule in the head of the pancreas. Arteriography showed stenosis of the celiac artery and a saccular aneurysm, arising from the first jejunal artery. We made a preoperative diagnosis of intraductal papillary adenocarcinoma of the pancreatic head and performed a laparotomy. Transection of the median arcuate ligament failed to restore adequate hepatic blood flow, necessitating construction of celiac vascularization, achieved by a gastroduodenal to jejunal artery anastomosis. After ligation of the jejunal artery aneurysm, we performed a pylorus-preserving pancreaticoduodenectomy. Microscopically, the tumor had papillary intracystic growth, and was lined by plump cells with abundant eosinophilic cytoplasm, consistent with a diagnosis of intraductal oncocytic papillary neoplasm. We discuss this recently recognized entity of papillary neoplasm of the pancreas, and the importance of managing hepatic blood flow during pancreaticoduodenectomy in celiac artery compression syndrome.

The plasma interleukin (IL)-18 level is elevated in acute rejection after organ transplantation. Although 2-adrenergic receptor (AR) agonists suppress the rejection of organ and tissue transplants, little is known about their action mechanisms. We examined the effects of endogenous catecholamines and 2-AR agonists on the expression of intercellular adhesion molecule (ICAM)-1, B7.1, B7.2, CD40, and CD40 ligand (CD40L) in human mixed lymphocyte reaction (MLR) and in an in vitro model of acute rejection in the presence or absence of IL-18.

The elevation of plasma interleukin (IL)-18 levels and the expression of intercellular adhesion molecule (ICAM)-1 and B7 on monocytes are involved in acute rejection. Prostaglandin (PG) E2 suppresses the rejection in animal transplantation models; however, little is known about its action mechanism. We examined the effect of PGE2 on the expression of ICAM-1 and B7 in the human mixed leukocyte reaction (MLR) in the presence or absence of IL-18.

Th1 cell activation and cytokine production shift the balance between Th1 and Th2, favoring the upregulation of proinflammatory activity that leads to destruction of allogeneic hepatocytes following transplantation. Th2-type cytokines, such as IL-10, have immune regulatory function. The aim of this study was to determine the antirejection efficacy of allogeneic hepatocytes with spheroidal shape (spheroids) genetically modified with viral IL-10 (vIL-10). Allogeneic hepatocyte spheroids, transferred vIL-10 gene by using adenovirus as the vector, were transplanted into the spleen of Nagase's analbuminemic rats (NAR). NAR transplanted with vIL-10-transfected hepatocytes showed an abrupt rise in serum albumin levels that peaked on day 7 and remained at high levels up to day 21 after transplantation. The peak level of albumin on day 7 in vIL-10-transfected NAR was eminently higher than that in nontransfected NAR. Histopathological analysis revealed that in nontransfected NAR hepatocyte spheroids were more or less rejected on day 4, and, in contrast, vIL-10-transfected spheroids were still not rejected on day 14. This protective effect correlated with sustained high vIL-10 level in the splenic vein in NAR transplanted with vIL-10-transfected hepatocyte spheroids, suggesting that vIL-10 secreted from the transplanted hepatocytes induced an active suppression of allogeneic response. This study provides evidence to support the possibility of using vIL-10 gene therapy to prevent allogeneic response in hepatocyte transplantation.

Interleukin (IL)-18 was identified as an interferon (IFN)-–inducing factor and was demonstrated to up-regulate the expression of intercellular adhesion molecule (ICAM)-1 on human monocytes. In organ transplantation, elevation of plasma IL-18 levels has been reported during acute rejection. In the present study, we examined the effect of IL-18 on human mixed lymphocyte reaction (MLR), an in vitro model of acute rejection after organ transplantation. We also investigated the modulatory effects of histamine on IL-18 action because histamine has been demonstrated to be a modulator of IL-18 effect and a mediator of inflammation.

The in vitro mixed lymphocyte reaction (MLR) is a useful model to study alloresponsiveness to histocompatibility antigens. Secretion of different cytokine proteins in the supernatant of allo-MLR cultures has been reported in a few studies. We studied the levels of the cytokines interferon gamma (IFN- gamma ) and interleukin-6 (IL-6), IL-10, IL-12, and IL-18 in the supernatant in allo-MLR by ELISA assay. Supernatant levels of IFN- gamma , IL-6, IL-10, and IL-18 were detected at 12 h after MLR and markedly increased thereafter. In contrast, secretion of IL-12 was detected after 48-72 h. These results suggested that IFN-gamma production depended on IL-18 in the early phase of MLR and depended on both IL-18 and IL-12 in the late phase. An antibody (Ab) neutralizing test was also performed. The levels of IFN- gamma were significantly downregulated after the addition of anti-IL18 Ab, anti-IL-12 Ab, or anti-IFN- gamma Ab, and the levels of IL-12 were significantly downregulated after the addition of anti-IL-12 Ab and anti-IL-18 Ab. Treatment with these Ab did not suppress IL-6 production at all. The two-way MLR showed the same tendency as the one-way MLR. These results suggest the importance of IL-18 and IL-12 in allogeneic cell interactions and also suggest the usefullness of these Ab as regulators of alloresponsiveness.

Various cryopreservation techniques have been investigated to elongate preservation time, however, most have failed to be clinically induced because of damage due to ice crystal formation. Subzero nonfreezing conditions could theoretically reduce organ metabolism without damage due to ice crystal formation. We evaluated the superiority of subzero nonfreezing storage compared with conventional hypothermic storage using isolated rat hepatocytes stored in University of Wisconsin (UW) solution without cryoprotectants.

It has been shown that the nutritional state of the donor may affect the outcome of liver transplantation. However, many donors staying in the intensive care unit for a long period are in a reduced nutritional state. In this study, we investigated the effects of various methods of nutritional repletion on the outcome of liver transplantation in pigs. Donor pigs were divided into three groups according to the nutritional pretreatment given for 7 days before harvesting: group I were fasted and received intravenous administration of saline; group II were fed orally; group III were fasted, but given 20 glucose intravenously. Donor livers were stored for 4 hr in cold Euro-Collins' solution and transplanted. The serum AST level 24 hr after reperfusion remained at a lower level in group III compared with those in groups I and II. Bile production of the liver after transplantation was also well recovered in group III. The glycogen content of the liver at harvesting, which was completely consumed in group 1, was well preserved in groups II and III. These storages in both groups were rapidly consumed 1 hr after reperfusion. On the other hand, ATP content of the liver in groups I, II, and III, which were at a similar level at harvesting, were markedly decreased 4 hr after cold preservation and, 1 hr after reperfusion, recovered to 26, 48, and 73 of that before preservation, respectively. The mean survival time in group III was 37.2 days, significantly longer than 5.8±0.7 and

Hepatitis B immunoglobulin (HBIg) and lamivudine combination has been accepted as the best way to control hepatitis B recurrence after liver transplantation. However, the optimal dose of HBIg and the target titer of hepatitis B surface antibody (HBsAb) remain unclear. We report our satisfactory experience with high-dose HBIg in the early period followed by low-dose HBIg with lamivudine. Subjects comprised five patients with fulminant hepatitis (FH) and 18 patients with liver cirrhosis (LC) who underwent liver transplantation. HBIg at a dosage of 200 IU/kg per day was administered for one week postoperatively. Thereafter, HBIg was administered only for HBsAb titer <100 IU/L. After six months, HBIg was withdrawn in FH and administered in LC only for HBsAb titer <10 IU/L. Lamivudine was administered to two FH and all LC cases. Although two patients with LC showed transient hepatitis B surface antigen (HBsAg) recurrence, all patients remained HBsAg-negative at the final follow-up date. This method allows reliable and cost-effective control of hepatitis B recurrence.

Hereditary haemorrhagic telangiectasia or Rendu-Osler-Weber syndrome is a systemic vascular disease with autosomal dominant inheritance, mucocutaneous telangiectasia, and repeated nasal bleeding due to vascular abnormalities. Hereditary haemorrhagic telangiectasia may occasionally lead to complications, including arteriovenous malformations and pulmonary hypertension. We present a case of a 52-year-old female patient with hereditary haemorrhagic telangiectasia who was referred to our hospital for treatment of pulmonary hypertension. She had been diagnosed with hereditary haemorrhagic telangiectasia during adolescence and was being followed up. Six months prior to presentation, she had undergone coil embolization for pulmonary haemorrhage due to pulmonary arteriovenous malformations. She was in World Health Organization functional class IV, with a mean of pulmonary arterial pressure of 38 mmHg, a pulmonary capillary wedge pressure of 10 mmHg, and a right atrial pressure of 22 mmHg. A contrast-enhanced computed tomography angiography showed large arteriovenous malformations in the liver. Right heart catheterization revealed an increase in oxygen saturation in the inferior vena cava between the supra- and infra-hepatic veins, low pulmonary vascular resistance, and high right atrial pressure. Hence, she was diagnosed with hereditary haemorrhagic telangiectasia with pulmonary hypertension due to major arteriovenous shunt resulting from arteriovenous malformations in the liver. Therefore, we considered liver transplantation as an essential treatment option. She underwent cadaveric liver transplantation after a year resulting in dramatic haemodynamic improvement to World Health Organization functional class I. Liver transplantation is a promising treatment in patients with hereditary haemorrhagic telangiectasia and pulmonary hypertension resulting from arteriovenous shunt caused by arteriovenous malformations in the liver.