Usefulness of endoscope guided transabdominal ultrasonography in T staging of colorectal cancer.

BACKGROUND/AIMS: We investigated the efficacy of endoscope guided transabdominal ultrasonography (EGTUS) for the evaluating the depth of colorectal cancer invasion. METHODOLOGY: The subjects were 52 patients with colon cancer and 30 patients with rectal cancer who underwent transabdominal US and curative surgery. During endoscopy, we applied transabdominal US by filling the area around the tumor with de-gassed water. The accuracy of depth invasion assessment using EGTUS was compared with that using endoscopic, computed tomography (CT), surgical or histological findings. RESULTS: The tumor detection rate was 75.6% (62/82), 88.5% (46/52) for colon cancer and 53.3% (16/30) for rectal cancer. The diagnostic accuracies of EGTUS, endoscopic, CT and surgical findings were 87.1% (54/62), 73.2% (60/82), 66.7% (46/69), 65.9% (54/82), respectively. The diagnostic accuracy of EGTUS was 100% (2/2), 66.7% (4/6), and 90.0% (44/49) for T1, T2 and T3 cancer, respectively. CONCLUSION: The results suggest that EGTUS is useful for evaluating preoperative T staging of colorectal cancer.

Long-term quality of life of donors after living donor liver transplantation.

The aims of this study were to investigate the long-term effects of living donor liver transplantation (LDLT) on the health-related quality of life (HRQOL) of donors with the Short Form 36 health survey and to determine the risk factors for poor outcomes. Between June 1990 and June 2004, LDLT was performed 1000 times at Kyoto University Hospital. In July 2005, 997 of the 1000 donors were contacted by mail so that data on their HRQOL could be collected. In all, 578 donors responded (ie, there was a 58.0% response rate). The norm-based HRQOL scores for donors were better than the scores for Japanese norms across all time periods. All scores were similar for left lobe donors (n = 367) and right lobe donors (n = 211). For all donors, a multivariate logistic regression analysis revealed that age, the number of months until recovery to the preoperative health status, hospital visits due to donation-related symptoms, rest from work related to donation in the past month, and the existence of 2 or more comorbidities were significantly associated with decreased HRQOL scores. Postoperative complications and recipient mortality were not predictors of poor HRQOL. In conclusion, HRQOL was better for both right lobe donors and left lobe donors versus the Japanese norm population in the long term (mean postdonation period = 6.8 years). However, the prolongation of symptoms or sequelae related to donation lowered mental health or social functioning. The emergence of comorbidities after donation also significantly affected HRQOL in the long term. Careful follow-up and sustained counseling are required for donors with risk factors for lower HRQOL.

Progressive familial intrahepatic cholestasis: a single-center experience of living-donor liver transplantation during two decades in Japan.

BACKGROUND: Progressive familial intrahepatic cholestasis (PFIC) results in liver cirrhosis. Therefore, some PFIC patients require liver transplantation (LT). Although three types of PFIC have been identified, their etiologies include unknown mechanisms. PATIENTS: A total of 717 recipients who underwent living-donor LT (LDLT) at <20 yr old were enrolled in this study. Among these recipients, 14 PFIC recipients comprising 11 PFIC type 1 (PFIC1) and three PFIC type 2 (PFIC2) were evaluated. RESULTS: Three of 11 PFIC1 recipients died, while all three PFIC2 recipients survived. Eight of 11 PFIC1 recipients showed steatosis after LDLT. Among the eight steatosis-positive PFIC1 recipients, seven showed severe steatosis and seven were complicated with steatohepatitis. Nine of 11 PFIC1 recipients showed fibrosis after LDLT, and eight of the nine fibrosis-positive PFIC1 recipients showed severe fibrosis. In contrast to the PFIC1 recipients, the PFIC2 recipients did not show any steatosis or fibrosis after LDLT. CONCLUSIONS: The clinical courses and outcomes of PFIC1 recipients after LDLT are still not sufficient owing to steatosis/fibrosis, unlike the case for PFIC2 recipients. As PFIC1 patients will require LT during the long-term progression of the disease, further strategy improvements are required for PFIC1 patients.

Pediatric orthotopic living-donor liver transplantation cures pulmonary hypertension caused by Abernethy malformation type Ib.

A 3.3-yr-old boy was diagnosed with PH caused by a PSS of Abernethy malformation type Ib. After control of PH, he underwent OLDLT at 4.9 yr. His PV flowed directly into the confluence of the CCLMHV and the IVC. To shorten the anhepatic phase, hepatic arterial flow was partially maintained. Removal of the native liver began simultaneously with the graft harvest. The proximal PV was cut at the optimal point for reconstruction. The distal PV was cut at the concrescence of the PV and the CCLMHV. After IVC-plasty, the LHV of the graft was attached with an anterior patch by venous grafting and was then anastomosed to the IVC. Although the mPAP temporarily increased above the mean arterial pressure, mPAP was stable during OLDLT. FNH and steatosis were confirmed histopathologically. In summary, pediatric OLDLT was performed successfully in PH caused by PSS.

Posttransplant bacteremia in adult living donor liver transplant recipients.

Infectious complications such as bacteremia after living donor liver transplantation (LDLT) are associated with significant morbidity and mortality. We retrospectively analyzed the frequency and characteristics of posttransplant bacteremia in 181 adult LDLT recipients between April 2006 and November 2009, and we evaluated the risk factors for posttransplant bacteremia. One hundred seventeen episodes of bacteremia occurred in 62 of 181 recipients (34.3%) within 12 days (median) after transplantation (range = 1-71 days). The most frequently isolated pathogens were Pseudomonasaeruginosa (26 episodes), methicillin-resistant coagulase-negative staphylococci (22 episodes), and Enterococcus sp. (11 episodes). The overall survival rate at 1 year for patients with bacteremia (n = 62) was significantly lower than the rate for patients without bacteremia (n = 119; 69.6% versus 92.3%, respectively, P < 0.0001). Multivariate analysis showed that Child-Pugh class C (P = 0.0002), preoperative massive pleural effusion or ascites requiring drainage (P = 0.0384), postoperative cytomegalovirus infection (P = 0.0014), ABO incompatibility (P = 0.0188), and older donor age (P = 0.015) were independent risk factors for postoperative bacteremia. In conclusion, bacteremia occurred at a high rate after adult LDLT and induced a higher mortality rate in those who developed it. Infection control may play a pivotal role in improving early outcomes after LDLT.

Portal pressure <15 mm Hg is a key for successful adult living donor liver transplantation utilizing smaller grafts than before.

To prevent small-for-size syndrome in adult-to-adult living donor liver transplantation (A-LDLT), larger grafts (ie, right lobe grafts) have been selected in many transplant centers. However, some centers are investigating the benefits of portal pressure modulation. Five hundred sixty-six A-LDLT procedures using right or left lobe grafts were performed between 1998 and 2008. In 2006, we introduced intentional portal pressure control, and we changed the graft selection criteria to include a graft/recipient weight ratio >0.7% instead of the original value of >0.8%. All recipients were divided into period I (1998-2006, the era of unintentional portal pressure control; n = 432) and period II (2006-2008, the era of intentional portal pressure control; n = 134). The selection of small-for-size grafts increased from 7.8% to 23.9%, and the selection of left lobe grafts increased from 4.9% to 32.1%. Despite the increase in the number of smaller grafts in period II, 1-year patient survival was significantly improved (87.9% versus 76.2%). In 129 recipients in period II, portal pressure was monitored. Patients with a portal pressure <15 mm Hg demonstrated better 2-year survival (n = 86, 93.0%) than patients with a portal pressure >or=15 mm Hg (n = 43, 66.3%). The recovery from hyperbilirubinemia and coagulopathy after transplantation was significantly better in patients with a portal pressure <15 mm Hg. In conclusion, our strategy for A-LDLT has changed from larger graft-based A-LDLT to controlled portal pressure-based A-LDLT with smaller grafts. A portal pressure <15 mm Hg seems to be a key for successful A-LDLT.

Liver transplantation for congenital biliary dilatation: a single-center experience.

BACKGROUND: Congenital biliary dilatation is a rare disease. Although the possibility of refractory cholangitis and/or the frequency of malignant tumors legitimize hepatobiliary surgery, repeated cholangitis and biliary obstruction result in secondary liver cirrhosis even after polysurgery. There are no definitive guidelines on liver transplantation for congenital biliary dilatation. PATIENTS: A total of 1,101 liver transplantation recipients were enrolled in this study. Eleven patients with congenital biliary dilatation including 5 patients with Caroli's disease were retrospectively analyzed in detail. RESULTS: Nine of 11 patients underwent initial operations before liver transplantation while 2 patients with Caroli's disease received liver transplantation as initial surgery, with good outcomes. All patients had intractable symptoms caused by liver cirrhosis, and growth delay was considerable in patients aged <20 years. Histopathological analysis of the native liver revealed hepatic fibrosis (≥F2). One patient with ABO incompatibility died. One patient with Caroli's disease accompanied with intrahepatic carcinoma survives 11.8 years after liver transplantation without any recurrences. CONCLUSIONS: Patients with congenital biliary dilatation with refractory symptoms and complications secondary to liver failure are appropriate candidates for liver transplantation. We suggest that liver transplantation is an effective therapeutic option for patients with congenital biliary dilatation with due consideration to many accompanying factors, such as clinical course, growth delay, image findings and histopathological analysis.

Impact of pretransplant nutritional status in patients undergoing liver transplantation.

BACKGROUND/AIMS: Protein-energy malnutrition is common in patients with end-stage liver disease requiring liver transplantation and is a risk factor for posttransplant morbidity including sepsis. We therefore investigated the relationship between preoperative nutritional status and postoperative clinical course, and the risk factors for postoperative sepsis in patients undergoing living donor liver transplantation (LDLT), focusing on nutritional parameters. METHODOLOGY: We preoperatively measured body cell mass (BCM) using a body composition analyzer and various nutritional parameters including prealbumin, branched-chain amino acids (BCAA)/tyrosine ratio, and zinc in 50 consecutive recipients undergoing LDLT between February 2008 and February 2009. Risk factors for post-transplant sepsis were analyzed. RESULTS: The incidence of postoperative severe infection and in-hospital death was significantly higher in patients with preoperative low BCM than in patients with normal or high BCM. Multivariate predictors of posttransplant sepsis included preoperative low BCM (p = 0.016), absence of preoperative supplementation with BCAA-enriched nutrient mixture (p = 0.028), and a Model for End-stage Liver Disease score of 20 or above (p = 0.040). CONCLUSIONS: Preoperative BCM level was closely related to the postoperative clinical course in patients undergoing LDLT. Pretransplant nutritional status and supplementation with BCAA-enriched nutrient mixture have potent impacts on the incidence of postoperative sepsis.

Impact of intestinal CYP2C19 genotypes on the interaction between tacrolimus and omeprazole, but not lansoprazole, in adult living-donor liver transplant patients.

To assess the effects of intestinal cytochrome P450 2C19 on the interaction between tacrolimus and proton pump inhibitors, we examined the concentration/dose ratio [(ng/ml)/(mg/day)] of tacrolimus coadministered with omeprazole (20 mg) or lansoprazole (30 mg) to 89 adult living-donor liver transplant patients on postoperative days 22 to 28, considering the CYP2C19 genotypes of the native intestine and the graft liver, separately. The concentration/dose ratio of tacrolimus coadministered with omeprazole was significantly higher in patients with two variants (*2 or *3) for intestinal CYP2C19 (median, 6.38; range, 1.55-22.9) than intestinal wild-type homozygotes (median, 2.11; range, 1.04-2.54) and heterozygotes (median, 2.11; range, 0.52-4.33) (P = 0.010), but the extent of the increase was attenuated by carrying the wild-type allele in the graft liver even when patients were CYP3A5*1 noncarriers. Conversely, the CYP2C19 polymorphisms both in the native intestine and in the graft liver little influenced the interaction between tacrolimus and lansoprazole, but CYP3A5*1 noncarriers showed higher tacrolimus concentration/dose ratio than CYP3A5*1 carriers. Furthermore, our experiments in vitro revealed that lansoprazole had a stronger inhibitory effect on the CYP3A5-mediated metabolism of tacrolimus than omeprazole, although not significantly (IC(50) = 19.9 +/- 13.8 microM for lansoprazole, 53.7 +/- 6.1 microM for omeprazole). Our findings suggest that intestinal and graft liver CYP2C19 plays a relatively greater role in the metabolism of omeprazole than it does for lansoprazole, so that the effects of CYP3A5 on the metabolism of tacrolimus might be masked by the interaction with omeprazole associated with the CYP2C19 genotype.

MDR1 haplotypes conferring an increased expression of intestinal CYP3A4 rather than MDR1 in female living-donor liver transplant patients.

PURPOSE: This study investigated whether haplotypes in the multidrug resistance 1 (MDR1) gene had effects on mRNA expression levels of MDR1 and cytochrome P450 (CYP) 3A4, and on the pharmacokinetics of tacrolimus in living-donor liver transplant (LDLT) patients, considering the gender difference. METHODS: Haplotype analysis of MDR1 with G2677T/A and C3435T was performed in 63 de novo Japanese LDLT patients (17 to 55 years; 44.4% women). The expression levels of MDR1 and CYP3A4 mRNAs in jejunal biopsy specimens were quantified by real-time PCR. RESULTS: Intestinal CYP3A4 mRNA expression levels (amol/microg total RNA) showed significantly higher values in women carrying the 2677TT-3435TT haplotype (median, 10.7; range, 5.92-15.2) than those with 2677GG-3435CC (3.03; range 1.38-4.68) and 2677GT-3435CT (median, 4.31; range, 0.07-9.42) (P = 0.022), but not in men (P = 0.81). However, MDR1 haplotype did not influence mRNA expression levels of MDR1 nor the concentration/dose ratio [(ng/mL)/(mg/day)] of oral tacrolimus for the postoperative 7 days, irrespective of gender. CONCLUSION: MDR1 haplotype may have a minor association with the tacrolimus pharmacokinetics after LDLT, but could be a good predictor of the inter-individual variation of intestinal expression of CYP3A4 in women.

Mesorenal shunt using inferior mesenteric vein and left renal vein in a case of LDLT.

Adult-to-adult living donor liver transplantation (LDLT) has become an established treatment option around the world. However, small-for-size graft syndrome remains one of the most serious complications affecting transplant outcomes. Excessive portal hypertension and overperfusion have been shown to play a causative role in this graft injury. Recently, portal hypertension per se has been considered detrimental to graft function, and thus to be avoided for successful outcomes after LDLT. We constructed a mesorenal shunt with anastomosis of the inferior mesenteric vein and left renal vein in the case of an LDLT recipient who showed high portal vein pressure after graft reperfusion. The inferior mesenteric vein is close to the left renal vein, and the anastomosis was obtained with relative ease. The shunt was effective in decreasing portal vein pressure, and postoperative graft function was satisfactory. This new method represents an option for attenuating portal hypertension when elevated portal vein pressure is observed in adult LDLT after graft reperfusion.

Successful stent placement for hepatic venous outflow obstruction in pediatric living donor liver transplantation, including a case series review.

HVOO may lead to graft dysfunction in LDLT. Balloon angioplasty is the first treatment for HVOO. However, some cases with recurrent HVOO need multiple interventions and require stent placement. The authors describe a pediatric case with recurrent HVOO requiring multiple stent placements. Her symptoms related to HVOO finally disappeared after the third stenting. A year later, follow-up liver biopsy did not show any dramatic change in perivenular fibrosis. From a review of our pediatric cases with HVOO requiring stent placement, the majority of them lost the grafts, because the timing of stent placement was too late to prevent the progression of fibrosis. In conclusion, stent placement should be considered in select cases of HVOO. Serial liver biopsies evaluating the degree of fibrosis are essential in determining the timing of stent placement.

Impact of preexisting circulating effector T cells on the outcome of ABO-incompatible adult LDLT.

Our aim was to clarify the significance of phenotype of circulating CD8 T(+) cells on the outcome of ABO-incompatible (ABO-I) living donor liver transplantation (LDLT). Twenty-six recipients undergoing ABO-I LDLT and 92 undergoing ABO-compatible (ABO-C) LDLT were classified into three groups according to preoperative proportion of CD8 T(+) cells: naive-dominant (group I), effector memory-dominant (group II), and effector-dominant (group III) recipients. The clinical courses were analyzed. The results showed that in ABO-C groups I and II and in ABO-I group I, effector cells remained above the pretransplant levels after tacrolimus administration. However, in ABO-C group III and ABO-I groups II and III, effector cells were down-regulated for a prolonged period, along with markedly decreased perforin expression and frequent life-threatening complications. ABO-I group II and group III recipients had higher infection rates. It was concluded that recipients with preexisting high effector CD8 T(+) cells are unfavorable candidates for ABO-I LDLT.

Relation between mRNA expression level of multidrug resistance 1/ABCB1 in blood cells and required level of tacrolimus in pediatric living-donor liver transplantation.

It has been difficult to set an individualized therapeutic window of tacrolimus after organ transplantation, because of wide interindividual variation of responsiveness to immunosuppressive therapy. In this study, we examined the significance of multidrug resistance 1 (MDR1) in the peripheral blood cells by comparing the trough concentration of tacrolimus with the occurrence of acute cellular rejection (ACR) in retrospectively collected pediatric living-donor liver transplant patients, who were enrolled after obtaining written informed consent. No significant difference in the intraindividual variation in MDR1 mRNA expression in the peripheral blood cells was observed between postoperative days 3 and 7. The average trough concentration of tacrolimus during the 15-day postoperative period was significantly higher in the event-free patients than in those who experienced ACR (21 of 44 cases), and they had higher levels of blood MDR1 mRNA. In addition, the average trough concentration of tacrolimus significantly correlated with the logarithmically transformed MDR1 mRNA data from the blood cells in patients of both the event-free (r = 0.5406; P = 0.0077) and ACR (r = 0.4772; P = 0.0284). The cellular accumulation of [(14)C]tacrolimus in the peripheral blood mononuclear cells was 2-fold higher in mdr1a/1b-knockout mice than in wild-type mice (P = 0.0182). These results suggest that MDR1 in blood cells decreases the leukocytic concentration of tacrolimus, and it could be a useful marker to establish an individualized target concentration of tacrolimus to prevent ACR in pediatric patients after liver transplantation.

The technical pitfalls of duct-to-duct biliary reconstruction in pediatric living-donor left-lobe liver transplantation: the impact of stent placement.

The feasibility of D-D biliary reconstruction in pediatric LDLT using a left-lobe graft is still controversial. The medical records of 19 pediatric patients (age: four months to 16 yr) were reviewed. The biliary reconstruction was performed in an end-to-end fashion using absorbable sutures. An external biliary tube was placed into the bile duct through the anastomotic site (n = 10) and not through the anastomotic site (n = 4). An external tube was not used in five patients. The median follow-up was 4.7 yr. Nine patients had 11 biliary complications (leakage, n = 2; stricture, n = 7; stricture with leakage, n = 2). Due to biliary complications, conversion to an R-Y was required in five patients, and four patients required radiological or endoscopic management. The patients younger than one yr of age required conversion to R-Y within one wk after LDLT. The analysis of factors related to biliary complications revealed that the use of a trans-anastomotic biliary tube was the only significant factor to avoid biliary complications. In conclusion, D-D biliary reconstruction in LDLT using a left-lobe graft is feasible in selected cases, though it remains challenging. The use of a trans-anastomotic biliary tube is important to avoid biliary complications.

Nonalcoholic steatohepatitis in donors for living donor liver transplantation.

BACKGROUND: In 2003, we encountered the first donor death for living donor liver transplantation in Japan, which was related to nonalcoholic steatohepatitis (NASH). The aim of this study was to retrospectively investigate the prevalence of NASH among a living donor liver transplantation donor population and to analyze the postoperative course for both donors and recipients of NASH grafts to minimize risk for donors. METHODS: The study population comprised 263 donors who donated the right lobe of the liver between February 1998 and April 2003. Their zero-hour biopsy specimens were screened retrospectively. Regarding severe steatosis or NASH, long-term follow-up results for laboratory data from donors were investigated along with changes in graft histologic findings in recipients. RESULTS: NASH was diagnosed histopathologically in three cases (1.1%). Pathologic examination showed that a donor who died in 2003 had the most severe NASH among the three cases. The remaining two NASH donors had uneventful postoperative courses without complications. All grafts showed improvement with respect to the steatosis and histologic findings of NASH. CONCLUSIONS: Donor safety is a top priority in living donor liver transplantation. To exclude patients with NASH from potential donor lists, careful evaluation, including selective preoperative liver biopsy, should be carried out.

Impact of age older than 60 years in living donor liver transplantation.

BACKGROUND: Living donor liver transplantation (LDLT) was extended to adults in recent years and more recently to older patients. The impact of donor age, analysis of preoperative risk factors for older LDLT recipients, and comparison of the complication rate between older and younger recipients were analyzed. METHODS: Subjects included patients who underwent LDLT at Kyoto University Hospital from October 1996 to December 2005. Twenty-three donors were 60 years of age or older, and 411 were younger than 60 years of age. Fifty-two recipients were 60 years of age or older and 410 were younger than 60 years of age. RESULTS: Postoperative recovery of liver function for donors and recipient/graft survival were not influenced by donor age. Hospital stay was longer in the donors 60 years of age or older than those younger than 60 years of age (P=0.02). The 5-year survival rates were 78.7% in recipients 60 years of age or older and 69.3% in younger recipients (P=0.26). Among preoperative risk factors for recipient survival rate, fulminant hepatic failure and preoperative status in the intensive care unit were significant (P<0.05). There were no significant differences in the incidence of postoperative complications for recipients. CONCLUSIONS: Selected right lobe donors from individuals who were 60 years of age or older showed a similar postoperative course compared with younger donors. Moreover, LDLT is feasible for patients 60 years of age or older who do not require care in the intensive care unit or do not have fulminant hepatic failure.

Living donor liver transplantation with reduced monosegments for neonates and small infants.

BACKGROUND: In pediatric living donor liver transplantation, left lateral segment or monosegmental graft is used to overcome size discrepancies between adult donors and pediatric recipients. For neonates and extremely small infants, however, problems related to large-for-size graft are sometimes encountered even when using such grafts. The reduced monosegmental graft, in which the caudal part of the monosegmental graft is resected, has been introduced to address this problem. METHODS: Of 566 children who underwent transplant between June 1990 and September 2004, reduced monosegment living donor liver transplants were used for nine patients (median age, 144 days; median weight, 4.1 kg). This technique was used for infants with estimated graft-to-recipient weight ratio (GRWR) > or =4.0% when using the left lateral segment. RESULTS: Graft and patient survival was 66.7%. GRWR was reduced from 7.45+/-2.70% to 3.39+/-0.89% using this modification. Transaminase levels at days 1 and 2 after transplantation were significantly higher in reduced monosegmental transplantation than in left lateral segmental transplantation. Hepatic artery thrombosis and portal vein thrombosis were observed in one case each. CONCLUSION: Reduced monosegmental living donor liver transplantation represents a feasible option for neonates and extremely small infants with liver failure.

Living donor liver transplantation for patients with HCC exceeding the Milan criteria: a proposal of expanded criteria.

BACKGROUND: Optimal indications for living donor liver transplantation (LDLT) for patients with hepatocellular carcinoma (HCC) have yet not been established. The aim of the present study was to determine optimal criteria including categories outside the Milan criteria (MC) and still with a predictably good outcome. PATIENTS AND METHODS: Between February 1999 and December 2007, 136 patients with HCC underwent LDLT. Based on preoperative imaging studies, 74 patients met the MC and 62 did not. RESULTS: Overall patient survival rate at 5 years was 70%. Patients who exceeded MC but presented with

Prospective registry for laparoscopic liver resection.

INTRODUCTION: Laparoscopic liver resection (LLR) has been widely performed throughout the world. Although prospective registry studies to clarify the safety of LLR have been feasible, no prior multicenter prospective study has addressed this issue. We have conducted a multicenter prospective cohort study to reveal the current status of LLR in Japan. METHODS: From April 2015 to March 2016, candidates for LLR were preoperatively enrolled at 12 institutions. The primary end-point was surgical safety, which was evaluated based on surgical factors and on short-term and midterm outcomes. RESULTS: A total of 102 patients were enrolled. Planned laparoscopic procedures included 96 pure laparoscopies, 1 hand-assisted laparoscopy, and 5 hybrid techniques. Non-anatomical partial resection or left lateral sectionectomy were performed in almost all cases. The median duration of surgery was 221 min. The median blood loss was 80.5 mL. Conversion was required for four patients (3.9%). The 90-day postoperative morbidities with grades more severe than II in the Clavien-Dindo classification were observed in six patients (5.9%). The median postoperative hospital stay was 9.5 days. No cases involved reoperation or mortality. CONCLUSION: Minor resection of LLR has been performed safely. To ensure the safe dissemination of LLR, including for major resection, a larger multicenter prospective study is required.