Dysbiosis and Depletion of Fecal Organic Acids Correlate With the Severity of Rejection After Rat Liver Transplantation.

The impact of T cell-mediated rejection (TCMR) after liver transplantation (LT) on the alterations in the gut microbiota (GM) and associated intestinal environment represented by fecal organic acids (OAs) require further elucidation. A rat allogeneic LT model was prepared without immunosuppressants or antibiotics, and a syngeneic model was used as a control. Qualitative and quantitative analyses of fecal samples at fixed time points were performed. Correlation analyses were also performed between liver function and GMs and OA levels. In the allogeneic TCMR group, the number of predominant obligate anaerobes decreased as liver function declined. Clostridioides difficile, Enterobacteriaceae, Enterococcus, Streptococcus, and Staphylococcus were significantly increased. Regarding fecal OA concentration, short-chain fatty acid (SCFA) concentrations were depleted as liver function declined. In contrast, in the syngeneic group, GM and OAs exhibited only slight, transient, and reversible disturbances. In addition, alanine aminotransferase and total bilirubin were positively correlated with the number of Enterobacteriaceae and Enterococcus, and negatively correlated with the fecal concentration of SCFAs. The allogeneic TCMR model demonstrated distinct dysbiosis and depletion of fecal OAs as TCMR progressed after LT. The degree of graft injury was closely related to the number of specific bacterial strains and the concentrations of fecal SCFAs.

Perioperative Oral ß-Hydroxy-ß-Methylbutyrate Supplementation Ameliorates Sarcopenia in Rats Undergoing Major Hepatectomy.

ß-Hydroxy-ß-methylbutyrate (HMB), a metabolite of leucine, is known to increase muscle mass and strength. However, the effect of perioperative HMB supplementation in liver surgery is unclear. Moreover, the impact of HMB on the skeletal muscle fiber type also remains unclear. We investigated the impact of HMB on the body composition and skeletal muscle fiber type in sarcopenic rats undergoing major hepatectomy. Nine-week-old male F344/NSlc rats were maintained in hindlimb suspension (HLS) and were forcedly supplemented with HMB calcium salt (HMB-Ca, 0.58 g/kg×2 times) or distilled water in addition to free feeding. After 2 wk of HLS, the rats underwent 70% hepatectomy and were sacrificed 3 d after surgery. Body composition factors and the proportion of slow-twitch fibers in hindlimb muscles were evaluated. HMB maintained the body composition and hindlimb force and acted against their deterioration in sarcopenic rats, exerting a particular effect on lean mass weight, which was significant. In the histological study, HMB significantly increased the proportion of slow-twitch fibers in the soleus (p=0.044) and plantaris (p=0.001) of sarcopenic rats. HMB ameliorated deterioration of the body composition and increased the proportion of slow-twitch fibers in sarcopenic rats undergoing major hepatectomy.

Muscularity Defined by the Combination of Muscle Quantity and Quality is Closely Related to Both Liver Hypertrophy and Postoperative Outcomes Following Portal Vein Embolization in Cancer Patients.

BACKGROUND: Portal vein embolization (PVE) is a common procedure for preventing hepatic insufficiency after major hepatectomy. While evaluating the body composition of surgical patients is common, the impact of muscularity defined by both muscle quantity and quality on liver hypertrophy after PVE and associated outcomes after major hepatectomy in patients with hepatobiliary cancer remain unclear. METHODS: This retrospective review included 126 patients who had undergone hepatobiliary cancer resection after PVE. Muscularity was measured on preoperative computed tomography images by combining the skeletal mass index and intramuscular adipose content. Various factors including the degree of hypertrophy (DH) of the future liver remnant and post-hepatectomy outcomes were compared according to muscularity. RESULTS: DH did not differ by malignancy type. Patients with high muscularity had better DH after PVE (P = 0.028), and low muscularity was an independent predictor for poor liver hypertrophy after PVE [odds ratio (OR), 3.418; 95% confidence interval (CI), 1.129-10.352; P = 0.030]. In subgroup analyses in which patients were stratified into groups based on primary hepatobiliary tumors and metastases, low muscularity was associated with higher incidence of post-hepatectomy liver failure (PHLF) ≥ grade B (P = 0.018) and was identified as an independent predictor for high-grade PHLF (OR 3.931; 95% CI 1.113-13.885; P = 0.034) among the primary tumor group. In contrast, muscularity did not affect surgical outcomes in patients with metastases. CONCLUSIONS: Low muscularity leads to poor liver hypertrophy after PVE and is also a predictor of PHLF, particularly in primary hepatobiliary cancer.

Visceral adiposity is an independent risk factor for high intra-operative blood loss during living-donor liver transplantation; could preoperative rehabilitation and nutritional therapy mitigate that risk?

BACKGROUND & AIMS: Blood loss during liver transplantation (LT) is one of the major concerns of the transplant team, given the potential negative post-transplant outcomes related to it. Blood loss was reported to be higher in certain body compositions, such as obese patients, undergoing LT. Therefore, we aimed to study the risk factors for high blood loss (HBL) during adult living donor liver transplant (ALDLT) including the body composition markers; visceral-to-subcutaneous adipose tissue area ratio (VSR), skeletal muscle index and intramuscular adipose tissue content. In June 2015, an aggressive perioperative rehabilitation and nutritional therapy (APRNT) program was prescribed in our institute for the patients with abnormal body composition. METHODS: We retrospectively analyzed 394 patients who had undergone their first ALDLT between 2006 and 2019. Risk factors for HBL were analyzed in the total cohort. Differences in blood loss and risk factors were analyzed in relation to the APRNT. RESULTS: Multivariate risk factor analysis in the total cohort showed that a high VSR (odds ratio (OR): 1.98, 95% confidence interval (CI): 1.19-3.29, P = 0.009), was an independent risk factor for HBL during ALDLT, as well as a history of upper abdominal surgery, simultaneous splenectomy and the presence of a large amount of ascites. After the introduction of the APRNT, a significantly lower blood loss was observed during the ALDLT recipient operation (P = 0.003). Moreover, the significant difference in blood loss observed between normal and high VSR groups before the application of the APRNT (P < 0.001), was not observed with the APRNT (P = 0.85). Likewise, before the APRNT, only high VSR was a risk factor for HBL by multivariate analysis (OR: 2.34, CI: 1.33-4.09, P = 0.003). Whereas with the APRNT, high VSR was no longer a significant risk factor for HBL even by univariate analysis (OR: 0.89, CI: 0.26-3.12, P = 0.86). CONCLUSION: Increased visceral adiposity was an independent risk factor for high intraoperative blood loss during ALDLT recipient operation. With APRNT, high VSR was not associated with high blood loss. Therefore, APRNT might have mitigated the risk of high blood loss related to high visceral adiposity.

Donor-dominant one-way matching of human leukocyte antigen-A/B/DR alleles predicts graft-versus-host disease following living donor liver transplantation.

AIM: Graft-versus-host disease (GVHD) following liver transplantation is rare but fatal. Therefore, it is important to identify possible risk factors before transplantation. Although it has been suggested that donor-dominant one-way human leukocyte antigen (HLA) matching of three loci (HLA-A/B/DR) is associated with the occurrence of GVHD, the precise significance of HLA matching including HLA-C/DQ/DP remains unclear. METHODS: We retrospectively analyzed the impact of donor-dominant one-way HLA matching at six HLA loci at the allele level on GVHD using clinical registry data from 1759 cases who underwent living donor liver transplantation between June 1990 and June 2019. We extracted cases with donor-dominant one-way HLA matching at the antigen level and reconfirmed them at the allele level using preserved DNA samples. RESULTS: Three of four cases (75%) who developed GVHD showed donor-dominant one-way HLA matching at three HLA-A/B/DR loci. These cases also showed donor-dominant one-way HLA matching at HLA-C/DQ/DP. Three of six cases (50%) with donor-dominant one-way HLA matching at three loci of HLA-A/B/DR developed GVHD. Notably, none of the cases with donor-dominant one-way HLA matching at one or two HLA-A/B/DR loci developed GVHD, irrespective of matching status at HLA-C/DQ/DP. The HLA matching status at the antigen level was revised in 22 of 56 cases, following reconfirmation at the allele level. CONCLUSIONS: Pairing of donors and recipients with donor-dominant one-way HLA matching at three HLA-A/B/DR loci should be avoided to prevent GVHD. No impact of HLA-C/DQ/DP on GVHD was identified. For liver transplantation, HLA genotypes should be determined at the allele level.

Liver transplantation in patients with portal vein thrombosis: A strategic road map throughout management.

BACKGROUND: Liver transplantation in the setting of portal vein thrombosis is an intricate issue that occasionally necessitates extraordinary procedures for portal flow restoration. However, to date, there is no consensus on a persistent management strategy, particularly with extensive forms. This work aims to introduce our experience-based surgical management algorithm for portal vein thrombosis during liver transplantation and to clarify some of the debatable circumstances associated with this problematic issue. METHODS: Between 2006 and 2019, 494 adults underwent liver transplantation at our institute. Ninety patients had preoperative portal vein thrombosis, and 79 patients underwent living donor liver transplantation. Our algorithm trichotomized the management plan into 3 pathways based on portal vein thrombosis grade. The surgical procedures implemented included thrombectomy, interposition vein grafts, jump grafts from the superior mesenteric vein, jump grafts from a collateral and renoportal anastomosis in 56, 13, 11, 4, and 2 patients, respectively. Four patients with mural thrombi did not require any special intervention. RESULTS: Thirteen patients experienced posttransplant portal vein complications. They all proved to have a patent portal vein by the end of follow-up regardless of the management modality. No significant survival difference was observed between cohorts with versus without portal vein thrombosis. The early graft loss rate was significantly higher with advanced grades (P = .048) as well as technically demanding procedures (P = .032). CONCLUSION: A stepwise broad-minded strategy should always be adopted when approaching advanced portal vein thrombosis during liver transplantation. An industrious preoperative evaluation should always be carried out to locate the ideal reliable source for portal flow restoration.

Diagnostic potential of presepsin in bacterial infection following hepato-biliary-pancreatic surgery: A prospective observational study.

BACKGROUND/PURPOSE: The aim in the present study was to elucidate the diagnostic ability of presepsin for postoperative infectious complications following major hepato-biliary-pancreatic (HBP) surgery. METHODS: Between 2017 and 2019, 50 patients with major hepatectomy and 55 patients with pancreatoduodenectomy were enrolled. Presepsin, the neutrophil-to-lymphocyte ratio (NLR), C-reactive protein (CRP), and procalcitonin (PCT) were prospectively measured for the first 2 weeks after surgery. The diagnostic abilities of these biomarkers were compared multidirectionally. RESULTS: All biomarkers returned to normal ranges within 2 weeks after surgery. However, presepsin, unlike the other biomarkers, showed less nonspecific elevation in response to the invasiveness of the surgical procedure immediately after surgery. Receiver operating characteristic curve analysis revealed that presepsin (area under the curve (AUC), 0.959) had a greater ability to discriminate bacterial infection than PCT (AUC, 0.723), CRP (AUC, 0.800), and the NLR (AUC, 0.804). A very high sensitivity of 93.3% and a specificity of 89.2% were achieved at the cutoff value of 620 pg/mL. Multivariable analysis revealed that presepsin on day 3 (P = .013) independently predicted bacterial infection after HBP surgery. CONCLUSIONS: Presepsin may have a better predictive ability than existing biomarkers for infection following major HBP surgery, which may help us achieve faster and more accurate detection of bacterial infections.

Etiology of Liver Steatosis Influences the Severity of Ischemia/Reperfusion Injury and Survival After Liver Transplantation in Rats.

Liver steatosis is a leading cause of graft disposal in liver transplantation, though the degree of steatosis is often the single factor determining acceptability of the graft. We investigated how the cause of liver steatosis affects graft function in rat orthotopic liver transplantation (OLT). OLT was performed using 2 types of steatotic liver grafts: the fasting and hyperalimentation (FHA) model and the methionine- and choline-deficient diet models. The FHA and 4-week feeding of a methionine- and choline-deficient diet (MCDD4wk) groups showed similar liver triglyceride levels without signs of steatohepatitis. Therefore, the 2 groups were compared in the following experiment. With 6-hour cold storage, the 7-day survival rate after OLT was far worse in the FHA than in the MCDD4wk group (0% versus 100%, P = 0.002). With 1-hour cold storage, the FHA group showed higher aspartate aminotransferase and alanine aminotransferase levels and histological injury scores in zones 1 and 2 at 24 hours after reperfusion than the normal liver and MCDD4wk groups. Intrahepatic microcirculation and tissue adenosine triphosphate levels were significantly lower in the FHA group after reperfusion. Hepatocyte necrosis, sinusoidal endothelial cell injury, and abnormal swelling of the mitochondria were also found in the FHA group after reperfusion. Tissue malondialdehyde levels were higher in the MCDD4wk group before and after reperfusion. However, the grafts up-regulated several antioxidant enzymes soon after reperfusion. Even though the degree of steatosis was equivalent, the 2 liver steatosis models possessed quite unique basal characteristics and showed completely different responses against ischemia/reperfusion injury and survival after transplantation. Our results demonstrate that the degree of fat accumulation is not a single determinant for the usability of steatotic liver grafts.

Preoperative abnormal body composition is closely related to bacteremia after living donor liver transplantation.

OBJECTIVE: Infection is the most critical cause of early death after liver transplantation (LT). However, the effect of preoperative body composition on bacteremia after LT is unclear. The aim of this study was to examine the effects of preoperative body composition on bacteremia after living donor LT (LDLT). METHODS: The study comprised 277 patients who underwent LDLT at Kyoto University, Kyoto, Japan, between January 2008 and June 2016. We evaluated body composition parameters including skeletal muscle mass index (SMI), intramuscular adipose tissue content (IMAC), and visceral-to-subcutaneous adipose tissue area ratio (VSR) using preoperative plain computed tomography at the L3 level. We compared the incidence of bacteremia, species, period of antibiotic administration, mortality due to bacteremia, and survival rates according to the number of abnormal body composition factors (low SMI, high IMAC, and high VSR). Moreover, risk factors for post-transplant bacteremia were examined. RESULTS: Incidence of bacteremia was significantly higher in patients with three abnormal factors (47.1%), two factors (42%), or a single factor (37%) than in patients with no factors (22.5%; P = 0.027). Species of bacteremia did not differ significantly among the four groups. The period of antibiotic administration was significantly shorter (P = 0.039) and mortality of patients with bacteremia and survival rates were significantly better (P < 0.001, each) in patients with no factors. Multivariate analysis identified ABO incompatibility (P = 0.002) and low SMI (P = 0.045) as independent risk factors for bacteremia after LT. CONCLUSION: Preoperative abnormal body composition was closely related to bacteremia after LDLT.

The combination of a male donor's high muscle mass and quality is an independent protective factor for graft loss after living donor liver transplantation.

We evaluated the hypothesis that grafts from donors with high muscle mass and quality may have a better outcome after living-donor-liver-transplantation (LDLT) than those from usual donors. A total of 376 primary adult-to-adult LDLT cases were enrolled in this study. Donor skeletal muscle mass index (SMI) and intramuscular adipose tissue content (IMAC) were used as markers of muscle mass and quality. In male donor cases (n = 198), those with higher SMI and lower IMAC than age-adjusted values were defined as the "high muscularity donors" (n = 38) and the others were defined as the "control" (n = 160). The high muscularity donor showed better 1-year (97% vs 82%, P = .020) and overall graft survival rate (88% vs 67%, P = .024) than the control group after LDLT. Contrastingly, the influence of the muscularity was not observed in female donor cases. Multivariable analysis including donor age confirmed that a high muscularity donor was an independent protective factor for overall graft survival after LDLT (hazard ratio, 0.337; 95% CI: 0.101-0.838; P = .017). Our study first confirmed that high muscle mass and quality of a male donor is a protective factor of allograft loss after LDLT, independently from donor age.

Impact of the preoperative bone mineral density on the outcomes after resection of pancreatic cancer.

PURPOSE: The aim of this study is to evaluate the correlation between bone mineral density (BMD) and other body composition markers, as well as, the impact of preoperative BMD on the surgical outcomes after resection of pancreatic cancer. METHODS: This retrospective study included 275 patients who underwent surgical resection of pancreatic cancer in our institute between 2003 and 2016. Patients were divided according to BMD into low and normal groups and their postoperative outcomes were compared. Risk factors for mortality and tumor recurrence were also evaluated. RESULTS: Patients with low BMD were older (P < 0.001), had a higher intramuscular adipose tissue content (P = 0.011) and higher visceral fat area (P = 0.003). The incidence of postoperative pancreatic fistula (POPF) (grade ≥ B) was higher in the low BMD group. No significant difference was observed between the two groups regarding overall survival and recurrence-free survival and low BMD was not a risk factor for mortality or tumor recurrence after resection of pancreatic cancer. CONCLUSION: A low preoperative BMD was not found to be a risk factor for mortality or tumor recurrence after resection of pancreatic cancer; however, it was associated with a higher incidence of clinically relevant POPF.

Impact of imbalanced graft-to-spleen volume ratio on outcomes following living donor liver transplantation in an era when simultaneous splenectomy is not typically indicated.

The impact of an imbalanced graft-to-spleen volume ratio (GSVR) on posttransplant outcomes other than postreperfusion portal hypertension remains unknown. The importance of GSVR might vary according to whether simultaneous splenectomy (SPX) is performed. This retrospective study divided 349 living donor liver transplantation (LDLT) recipients from 2006 to 2017 into 2 groups: low GSVR (≤0.70 g/mL) and normal GSVR (>0.70 g/mL). The cutoff value of GSVR was set based on the first quartile of the distributed data. Graft survival and associations with various clinical factors were investigated between the groups according to whether SPX was performed. Low GSVR did not affect outcomes when SPX was performed. In contrast, it was associated with an increased incidence of early graft loss (EGL) and poor graft survival by presenting posttransplant thrombocytopenia, cholestasis, coagulopathy, and massive ascites when the spleen was preserved. Among patients with a preserved spleen, the multivariable analysis results revealed that older donor age and low GSVR were independent risk factors for graft loss. In conclusion, low GSVR was an independent predictor of graft loss after LDLT when the spleen was preserved. Preserved spleen with extremely low GSVR may be related to persistent hypersplenism, impaired graft function, and consequent EGL.

Risk-benefit point of the Model for End-stage Liver Disease score in patients waiting for deceased-donor liver transplantation: A single-center experience.

AIM: To clarify the risk-benefit point of the Model for End-stage Liver Disease (MELD) score in patients waiting for deceased-donor liver transplantation (DDLT). METHODS: The present study retrospectively investigated 213 patients registered on the waiting list at Kyoto University (Kyoto, Japan) between 2005 and 2016. Patients were stratified by MELD score (6-9/10-14/15-20/21-30/31-40) and classified into two groups: the DDLT group (30 patients) and the waiting group (183 patients). Their post-registration mortality risk and long-term survival were compared. RESULTS: For all MELD categories, the mortality risk was lower in the DDLT group than in the waiting group. The hazard ratio of post-registration mortality decreased in the DDLT group compared to the waiting group as the MELD score increased (0.36/0.12/0.06/0.042/0.004). Survival was significantly better among patients in the DDLT group with a MELD score of 15 or more than among patients in the waiting group. CONCLUSION: For all MELD categories, DDLT reduced the mortality risk of patients on the waiting list.

Bone mineral density correlates with survival after resection of extrahepatic biliary malignancies.

BACKGROUND & AIMS: Osteopenia is a condition in which bone mineral density (BMD) is lower than normal, and it is an important determinant of bone fragility. However, the utility of osteopenia in assessing the risks of surgery is unclear. This study investigated the impact of preoperative low BMD on the outcomes in patients undergoing resection of extrahepatic biliary cancers. METHODS: A retrospective analysis was performed with 181 patients who underwent resections of extrahepatic biliary cancers between 2005 and 2015. Their BMD was measured on preoperative computed tomography images. Overall survival (OS) and recurrence-free survival (RFS) rates were compared according to BMD (normal vs. low), and the prognostic factors after surgery were assessed. Propensity score matching was used to minimize the bias in patient background. RESULTS: Older age and female were strongly associated with low BMD. These factors were used to construct the propensity score model, which yielded a matched cohort of 52 legs in each group. The OS (21.2% vs. 53.9% at 5 years, p < .001) and RFS (21.8% vs. 64.6% at 5 years, p < .001) rates were significantly lower in patients with low BMD (osteopenia) than in those with normal BMD (non-osteopenia). Multivariable analyses showed that low BMD was an independent factor predictive of poor OS (hazard ratio [HR]: 2.343, 95% confidence interval [CI]: 1.362-4.129, p = .002) and poor RFS (HR: 3.648, 95% CI: 1.986-6.990, p=<.001). CONCLUSIONS: Preoperative low BMD is closely related to mortality and cancer recurrence after the resection of extrahepatic biliary cancers. BMD screening in patients with cancer should be further highlighted in the oncology field.

Etiologies, risk factors, and outcomes of bacterial cholangitis after living donor liver transplantation.

The interpretation of bacterial cholangitis after liver transplantation (LT) remains vague, because the presence of bacteria in bile, namely bacteriobilia, does not necessarily indicate an active infection. We investigated the association between post-LT bacterial cholangitis and a variety of short- and long-term outcomes. Two-hundred-seventy-four primary adult-to-adult living donor LT recipients from 2008 to 2016 were divided into three groups according the presence or absence of bacteriobilia and clinical symptoms: (1) no bacteriobilia (N group), (2) asymptomatic bacteriobilia (B group), and (3) cholangitis (C group). The number of patients was by group: N, 161; B, 64; and C, 49. Donor age ≥ 45 years (p = 0.012), choledochojejunostomy (p < 0.001), and post-LT portal hypertension (p = 0.023) were independent risk factors for developing cholangitis. Survival analysis revealed that the C group had significantly worse short- and long-term graft survival. The C group was associated with an increased incidence of early graft loss (EGL) (p < 0.001). While the frequency of readmission for recurrent cholangitis was significantly higher in both the B and C groups (p < 0.001), late graft loss (LGL) due to chronic cholangitis was only commonly observed in the C group (p = 0.002). Post-LT cholangitis could result in not only EGL but also chronic cholangitis and associated LGL.

Fistula Formation Secondary to Mucinous Appendiceal Adenocarcinoma May Be Related to a Favorable Prognosis: A Case Report and Literature Review.

A 90-year-old man was referred to our hospital because of a positive fecal occult blood test. Colonoscopy revealed a lesion with multiple nodules covered with abundant mucus at the hepatic flexure. Computed tomography showed a dilated appendix attached distally to the hepatic flexure. Right hemicolectomy was performed, and the pathological examination revealed a mucinous appendiceal adenocarcinoma infiltrating the hepatic flexure without pseudomyxoma peritonei. The patient is doing well without recurrence 12 months postoperatively. Extraperitoneal drainage of the malignant ascites caused by the fistula may allow for an early diagnosis, while also making it possible to successfully resect the lesion, thus resulting in a favorable outcome.

Laparoscopic appendectomy during the third trimester: Case presentation and literature review.

Acute appendicitis is the most common general surgical problem encountered during pregnancy. Laparoscopic appendectomy (LA) is widely accepted as a minimally invasive procedure for acute appendicitis. However, LA during the third trimester is associated with problems, including technical difficulty, risk of preterm delivery, and fetal loss. We successfully managed three cases of LA during the third trimester between 2011 and 2016. None of the cases required conversion to an open procedure, and none of the patients had postoperative complications and/or fetal loss. We reviewed the literature using the PubMED database from 2007 to 2016 to acquire further evidence and identified 6 reports and 17 cases. The conversion rate was 11.8% (2 cases), the complication rate was 6.67% (1 case), and the preterm delivery rate was 20% (3 cases); no fetal loss was observed. Our study and literature review highlights the role of LA as a potentially feasible treatment approach for appendicitis during the third trimester.

[Hepatic resection for local recurrence after radiofrequency ablation therapy for colorectal liver metastases].

Patients who underwent hepatic resection of locally recurrent tumors after radiofrequency ablation(RFA)for colorectal liver metastases (CRLM) were retrospectively investigated. Among 12 patients who underwent RFA as first-line treatment for CRLM, 7 experienced local recurrence, 5 of whom (6 nodules) underwent hepatic resection. The mean diameter (range) of the tumors was 9.5(5-16) mm, and they were located at S2, S7 (adjacent to the right hepatic vein), S5/6 (between the root of the anterior and the posterior Glisson's pedicle), S1r (right paracaval portion), S6, and S3. No local recurrence was observed after hepatic resection. In conclusion, hepatic resection must be the initial therapeutic strategy for CRLM, and the indication for RFA must be considered carefully.