Motoshige Nabeshima

Vascular complications in living related liver transplantation detected with intraoperative and postoperative Doppler US

BACKGROUND/AIMS The purpose of this study was to clarify changes in the graft hemodynamics induced by vascular complications in living related liver transplantation. METHODS This study included 46 pediatric recipients who underwent partial liver transplantation from living related donors. The blood flow was evaluated in the portal system, the hepatic artery and the hepatic vein with serial intra- and post-operative Doppler ultrasound (US). RESULTS In 12 patients, intraoperative Doppler US showed a decrease in portal venous inflow (< 9 ml.min-1.kg-1) toward the liver graft and could act as a guide for ligation of collaterals in seven patients, portal re-construction in two, thrombectomy in one and relief of hepatic venous outflow obstruction in two for increasing the portal venous inflow. In five patients, intraoperative Doppler US showed poor arterial inflow, i.e. dampened arterial waveforms which involved both low pulsatility index (< 0.90) and low peak-systolic velocity (< 31 cm/s). In three of them, the waveform was more pulsatile after re-anastomosis or relief from stretching of the hepatic artery. The remaining two patients developed hepatic artery thrombosis. Most of the hepatic venous outflow obstruction (four of five patients) had flat waveforms, low flow velocity (< 10 cm/s) of the hepatic vein, and poor portal inflow (flow velocity < 14 cm/s). Postoperative Doppler US showed hepatic venous outflow obstruction in three patients, hepatic artery thrombosis in three (twice in one patient), portal vein stenosis in two and portal vein thrombosis in one. These complications were successfully managed with surgical procedures in three patients, transhepatic angioplasty in three and conservative treatments in four. Six patients died of non-vascular complications. CONCLUSIONS Serial intra- and post-operative Doppler US was a useful technique for making an early diagnosis of abnormal hemodynamics of the graft circulation. Furthermore, intraoperative Doppler US could assess reconstructed vessels objectively and would reduce the incidence of vascular complications following transplantation.

Liver targeting of human interferon-β with pullulan based on metal coordination

Abstract Although interferon (IFN)-β is widely used for the elimination of hepatitis C virus in patients with chronic liver disease, its clinical efficacy is unsatisfactory. Targeting IFN-β to the liver might enhance its efficacy without increasing its side effects. The objective of the present study was to target IFN-β to the liver to enhance its biological activity and reduce its side effects. A chelating residue, diethylenetriaminepentaacetic acid (DTPA), was introduced to pullulan, a water-soluble polysaccharide with a high affinity to the liver (DTPA-pullulan) and natural human IFN-β was coordinately conjugated with the DTPA-pullulan by mixing in an aqueous solution containing zinc ions (Zn 2+ ). Intravenous injection of the IFN-β-DTPA-pullulan conjugate with Zn 2+ coordination into mice enhanced induction of an antiviral enzyme, 2′,5′-oligoadenylate synthetase (2-5AS), specifically in the liver to a significantly greater extent than free natural IFN-β. The enhanced 2-5AS level in the liver depended on the molar mixing ratio of IFN-β, DTPA residue of the DTPA-pullulan, and Zn 2+ . Moreover, the duration of the liver 2-5AS induction by the IFN-β-DTPA-pullulan conjugate was longer than that by free natural IFN-β. Thus, human IFN-β-DTPA-pullulan conjugate appears to be applicable for clinical use, which is promising for treatment of patients with chronic hepatitis C.

Clinical outcomes of living donor liver transplantation for hepatitis C virus (HCV)-positive patients

Background. Whether hepatitis C virus recurrence occurs earlier and with greater severity for living donor liver transplantation (LDLT) than for deceased donor liver transplantation (DDLT) has recently become a subject of debate. Methods. We retrospectively evaluated clinical outcomes for a cohort of 91 HCV-positive patients who underwent LDLT at Kyoto University with a median follow-up period of 25 months. Results. Overall 5-year patient survival for HCV patients was similar to that for non-HCV patients (n=209) who underwent right-lobe LDLT at our institute (69% vs. 71%). Survival rate of patients without HCC (n=34) tended to be better than that of patients with HCC (n=57) (82% vs. 60%, P=0.069). According to annual liver biopsy, rate of fibrosis progression to stage 2 or more (representing significant fibrosis) was 39% at 2 years after LDLT. Univariate analysis showed that female recipient and male donor represented significant risk factors for significant fibrosis. Progression to severe recurrence (defined as the presence of liver cirrhosis (F4) in a liver biopsy and/or the development of clinical decompensation) was observed in five patients. Conclusions. Postoperative patient survival was similar for HCV-positive and -negative recipients in our adult LDLT series. Rates of progression to severe disease due to HCV recurrence seemed comparable between our LDLT recipients and DDLT recipients described in the literature. Although longer-term follow-up is required, our results suggest that LDLT can produce acceptable outcomes also for patients suffering from HCV-related cirrhosis.

Identification of novel defective HCV clones in liver transplant recipients with recurrent HCV infection

Summary.  Patients with recurrent hepatitis C after liver transplantation usually have a high viral load and are generally resistant to interferon (IFN)‐α2b plus ribavirin (RBV) therapy. However, it remains unclear whether pretreatment viral titre determines the effectiveness of combination therapy, especially in patients with a high viral load. The aim of this study was to identify the viral factors associated with a sustained virological response (SVR) to antiviral therapy in patients with recurrent hepatitis C after living‐donor liver transplantation. Twenty‐three patients with recurrent hepatitis C received combination therapy of IFN‐α2b plus RBV. SVR was achieved in 7 of the 23 patients (30.4%). Predictive factors for SVR included a 2 log10 decline in Hepatitis C virus (HCV) RNA at 2 weeks after the start of therapy and disappearance of HCV RNA at 4 or 24 weeks after the start of therapy. As the pretreatment high viral load showed no association with SVR, we asked whether other viral factor was associated with the response to the combination therapy in transplant recipients. We found the several novel defective HCV clones in 4 of 12 recipients’ sera. All defective HCV clones had deletions in the envelope region. Interestingly, no patients with defective clones showed a prompt decrease in HCV RNA after the start of IFN‐α2b plus RBV therapy. Thus, early decline in serum HCV RNA after treatment was closely associated with SVR. The circulating defective HCV clones are present and might be associated with the response to the combination therapy in patients with recurrent hepatitis after liver transplantation.

Limited benefit of biochemical response to combination therapy for patients with recurrent hepatitis C after living-donor liver transplantation.

Background. Effective management of patients with recurrent hepatitis C after liver transplantation has not been established. In this study, we tested the significance of biochemical response (BR) as well as sustained virological response (SVR) to combination therapy with interferon alpha-2b and ribavirin for recurrent hepatitis C after living-donor liver transplantation. Methods. Forty patients received therapy and formed 3 groups by response: SVR (n=14, 35%) and BR (n=14, 35%), defined when serum alanine aminotransferase normalized during therapy in non-SVR patients, and no response (NR; n=12, 30%). Histological changes of these groups after the combination therapy were investigated. Results. Activity grade of liver histology improved significantly in patients with an SVR at 1 and at 2–4 years after the initiation of treatment, showing difference from the BR and NR groups in which the activity was not improved by interferon therapy. Fibrosis deteriorated significantly in both the BR and the NR groups at two to four years. The rates of patients whose fibrosis stage deteriorated to stage F2 or more were significantly greater in the BR and NR groups than in the SVR group. Fibrosis decreased or remained stable in five of eight patients (63%) with an SVR at two to four years, whereas it increased in 12 of 15 patients (80%) with a BR or NR. Conclusions. Patients with an SVR showed histological improvement, but the benefit of a BR for non-SVR patients to improve the activity grade or to inhibit the progression of fibrosis was limited.

Photodynamic therapy using pheophorbide-a and Q-switched Nd:YAG laser on implanted human hepatocellular carcinoma.

SummaryTo evaluate whether administration of pheophorbide-a, a new photosensitizer, followed by use of Q-switched Nd:YAG Laser produces a photodynamic reaction, we administered pheophorbide-a to female nude mice (BALB/c-nu) that had been implanted with human hepatocellular carcinoma. Intra-tumoral concentrations of pheophorbide-a were measured by high-performance liquid chromatography. 3 hours after peroral administration of 1 mg/kg body weight, the intra-tumoral concentration was too low to reveal photodynamic effects. Peroral administration of 250 mg/kg body weight, intra-peritoneal administraion of 5 mg/kg body weight, and intra-tumoral injection of 200 μg yielded 0.24 μg/g, 0.83 μg/g and 3.68-108 μg/g tumor concentrations, respectively. All tumors were irradiated interstitially using a Q-switched Nd:YAG Laser at 1064 nm. Only tumors that had been intra-tumorally injected had areas of necrosis larger than those in control tumors. The results suggest that the injection of pheophorbide-a followed by interstitial irradiation using a Q-switched Nd: YAG Laser does not induce sufficient photodynamic reaction if the intratumoral pheophorbide-a concentration is less than 0.83 μglg tumor tissue, and that photodynamic therapy may be useful if the pheophorbide-a tumor concentration is within the range of 0.83-108 μg/g.

Lens culinaris agglutinin-A-reactive alpha-fetoprotein as a marker for liver atrophy in fulminant hepatic failure.

Liver atrophy is frequently found at autopsy of patients with fulminant hepatic failure (FHF). Imaging studies in patients with FHF demonstrate that estimation of total liver volume correlates with prognosis. In this study, in order to determine serum markers for evaluating liver atrophy, we measured the weight of whole livers resected from 31 transplant recipients with FHF, and assessed the relation between the liver weights and several prognostic markers. The level of liver atrophy was evaluated by calculating the ratio of the removed whole liver weight to the body weight of each recipient, and 16 major variables including several serological markers were analyzed among those recipients. We found that the serum Lens culinaris agglutinin-A-reactive alpha-fetoprotein (AFP-L3) levels were significantly higher in patients with FHF than in those with other liver diseases. In FHF patients, the serum AFP-L3 level at the onset of encephalopathy was significantly higher in cases with mild atrophy than in those with severe atrophy (P<0.05). Notably, the residual liver volume was significantly correlated with the serum AFP-L3 level (Pearsons correlation coefficient=0.63), but not with AFP. In conclusion, AFP-L3 is a possible serum marker for evaluating liver atrophy and/or liver regeneration in patients with FHF.

Refractory enterovesical and duodenocolic fistulas in Crohn's disease successfully managed with tacrolimus.

the present patient, the area showing a hepatoid appearance was immunohistochemically negative for PIVKA-II. To our knowledge, only five cases of PIVKA-II-producing gastric cancer, including the present case, have been reported in the English-language literature.2–5 The result of immunohistochemical staining for PIVKA-II was poor in two patients, partially positive in two patients, and positive in one patient. Four (80%) out of the five patients were positive for hepatic metastasis, causing death within 6 months. PIVKA-II is a putative tumor marker of HCC; however, when tumors are found in the stomach and liver, and the serum PIVKA-II level is abnormally high, the possibility of PIVKA-II-producing gastric cancer with liver metastasis should be considered.

Spontaneous Regression of Hepatocellular Carcinoma due to Disruption of the Feeding Artery

We present an unusual case of spontaneous regression of hepatocellular carcinoma (HCC). A 77-year-old man with alcoholic liver cirrhosis presented with a 50-mm tumor in the Couinauds segment 8 (S8) of the liver, a 15-mm tumor in the S8-7 and 10-mm tumors in the other segments (S4, S6). The tumors were diagnosed as HCC by typical imaging findings and elevated serum alpha-fetoprotein (AFP, 1,825.0 ng/ml) and protein induced by vitamin K absence II (PIVKA II, 3,043 mAU/ml). One month later, AFP and PIVKA II decreased to 51.1 ng/ml and 411 mAU/ml, respectively, and the 50-mm tumor in the S8 became small and completely necrotic on angiography and computed tomography arteriography without any treatment. On the other hand, the 15-mm tumor in the S8-7 decreased in size to 10 mm and received blood supply from the right posterior superior arteries (A7). The other 10-mm tumors remained. Ischemia of the tumors due to disruption of the feeding artery (A8) might have induced tumor regression in the present case.

Adenomyoma of the minor duodenal papilla

apy. Bueno et al. described a combined antegrade/ retrograde dilation procedure to surmount the difficulties encountered in the treatment of complex strictures. Complete esophageal obstruction, however, is even more challenging. For our patient, who could not have tolerated another surgical procedure, however, a decision was made to modify the approach of Bueno et al. to reestablish esophageal patency. The most critical element in the effort to avoid perforation is meticulous alignment of both the proximal and the distal endoscopes by using fluoroscopy and diaphanoscopy before careful penetration of the obstruction. Endoscopic rendezvous recanalization of nonmalignant radiotherapy-induced esophageal stricture may be considered in patients who are unable to tolerate surgical reconstruction. REFERENCES