Toshihiko Kohashi

Biliary Complications after Duct-to-duct Biliary Reconstruction in Living-donor Liver Transplantation: Causes and Treatment

BackgroundIn living-donor liver transplantation (LDLT), biliary complications are recognized as a significant cause of post-transplantation morbidity.MethodsEighty patients who underwent LDLT with duct-to-duct biliary reconstruction at Hiroshima University Hospital were enrolled in this study. The mean follow-up was 24 months (range, 3–72 months). Eighteen patients underwent the basiliximab-based immunosuppressive therapy, and 62 patients underwent non-basiliximab-based immunosuppressive therapy. The development of biliary complications after LDLT was retrospectively analyzed. Biliary complications were initially treated by endoscopic or radiological modalities.ResultsBiliary leakages and strictures occurred in 12 (15%) and 20 (25%) of the 80 patients, respectively. Stepwise multivariate analysis demonstrated bile leakage to be an independent risk factor for the development of biliary stricture (p = 0.001) and basiliximab-based immunosuppressive therapy to be an independent protective factor for postoperative biliary leakage (p = 0.005). The 1-week total doses of steroids were significantly lower in the basiliximab-based immunosuppressive regimes (mean dose: 573mg) than in the non-basiliximab-based ones (mean dose: 1,121mg) (p = 0.01). All patients with biliary leakage were successfully treated with endoscopic or radiological modalities, except one patient who was treated by surgical treatment. Endoscopic or radiological modalities were successful as primary treatment modalities in 12 (60%) of 20 patients with biliary strictures. Lastly, six patients were treated surgically with long-term success, except for one patient with chronic cholangitis who died after 16 months.ConclusionsSteroid-sparing basiliximab-based immunosuppressive therapy reduced the incidence of biliary leakage, and biliary leakage was the independent factor for biliary stricture. The non-surgical and surgical treatments for biliary complications were satisfactory.

Typing of hepatic nonparenchymal cells using fibulin-2 and cytoglobin/STAP as liver fibrogenesis-related markers

Fibulin-2 and cytoglobin/stellate cell activation-associated protein (Cygb/STAP) are considered to be markers of hepatic myofibroblasts (MFs) and stellate cells (HSCs), respectively. The aim of the present study was to characterize the nonparenchymal cells (NPCs) of normal rat livers and carbon tetrachloride-induced fibrotic rat livers with respect to the expression of these two proteins. NPCs in normal (Glisson’s capsules) and fibrotic (fibrotic septa) connective tissues were immunohistochemically categorized into four cell types in terms of the expression of fibulin-2 and Cygb/STAP: fibulin-2 and Cygb/STAP double-positive (Fib+/STAP+); fibulin-2-positive and Cygb/STAP-negative (Fib+/STAP−); Fib−/STAP+; and Fib−/STAP−. The Glisson’s capsules had Fib+/STAP+ and Fib−/STAP− cell occupancy rates of 45.5% and 54.5%, respectively, but did not contain Fib+/STAP− or Fib−/STAP+ cells. On the other hand, the fibrotic septa contained Fib+/STAP+, Fib−/STAP+, and Fib−/STAP− cells at occupancy rates of 35.0%, 50.5%, and 9.1%, respectively, but did not contain Fib+/STAP− cells. Thus, fibrosis is characterized by a dramatic increase in Fib−/STAP+ NPCs, and a dramatic decrease in Fib−/STAP− NPCs. Fib+/STAP+ NPCs are located uniformly in Glisson’s capsules and peripherally in fibrotic septa. The present study strongly suggests that Fib+/STAP+ and Fib−/STAP+ NPCs correspond to MFs and activated HSCs, respectively, both of which may contribute to liver fibrogenesis.

Should splenectomy be performed for hepatitis C patients undergoing living‐donor liver transplantation?

Liver cirrhosis associated with hepatitis C virus (HCV) infection has become the most common indication for liver transplantation; however, the recurrence of HCV infection is an almost universal event after liver transplantation. As a result, graft and patient survival are significantly poorer in HCV-positive recipients than in HCV-negative recipients. Although various strategies including a combination therapy of interferon and ribavirin have been used to overcome the recurrence of HCV infection after liver transplantation, the therapeutic outcome is still poor with 10–40% sustained viral response (SVR) because of adverse effects such as cytopenia. In order to overcome this problem, Kishi and colleagues performed splenectomy concurrently with liver transplantation for all HCV-positive liver transplant patients; however, the indication for splenectomy still remains controversial. Therefore, we investigated whether thrombocytopenia acts as an obstacle to the continuation of interferon therapy after living-donor liver transplantation (LDLT); we further clarified the indications for simultaneous splenectomy with LDLT. From January 2000 to August 2006, a total of 29 patients underwent elective LDLT for HCV cirrhosis in Hiroshima University Hospital. Of these, 24 patients who had undergone LDLT by February 2006 and had been followed up for 6 months were enrolled in this study. The mean age of the patients was 52 years (range, 29–69 years). All of the 24 patients were Japanese, and 16 were men. Preoperatively, all patients were sero-positive for the anti-HCV antibody. The HCV genotypes were 1b (n = 23) and 2a (n = 1). The median value of the preoperative HCV-RNA load in the 24 patients was 380 kIU/mL. The survival rate for the HCV-positive patients after LDLT was 71% at 1 year after transplantation. Necroinflammatory activity (A0–A4) and the fibrosis stage (F0–F4) were assessed using the METAVIR scoring system. The presence of recurrent hepatitis was evidenced in 14 of the 20 LDLT patients within 1 year after LDLT. The grades of the necroinflammatory activities observed in these 14 patients within 1 year were as follows: A1 in 10 patients, A2 in two patients and A3 in two patients. Significant fibrosis (F2 or more) was observed in four patients, including two patients who developed fibrosis of F4 within 1 year. Twelve patients were administered antiviral treatment for 6 months to 28 months after LDLT. The treatment protocol consisted of interferon-a2b (3–6 ¥ 10 units, three times/week) plus ribavirin (200–400 mg/ day orally) for at least 48 weeks. From June 2005, the interferon in the treatment regimen was replaced with pegylated interferon-a2b (0.5–1.0 mg/kg/week). Interferon therapy was discontinued in five of the six patients with a platelet count of <100 000/mm within 6 months because of thrombocytopenia (n = 4) and general fatigue with psychosis (n = 1). Therapy was discontinued in one of the six patients with a platelet count of >100 000/mm because of psychosis and general fatigue. The rate of cessation of the antiviral therapy was significantly higher (P = 0.02) in the patients with a platelet count of <100 000/mm prior to the administration of antiviral therapy, as compared with those having a platelet count of >100 000/mm (Fig. 1). Of the 12 patients, two patients responded to the combination therapy, and the serum HCV-RNA test remained negative 6 months after the cessation of the therapy. The other four patients have continued to receive the antiviral therapy for durations ranging from 6 to 18 months (mean 10 months). We next examined the preand post-operative course of the platelet counts in the 20 patients. In four of the nine patients with a preoperative platelet count of <60 000/mm, it exceeded beyond 100 000/mm at 2 months after LDLT. In 10 of the 11 patients with a preoperative platelet count of >60 000/mm, it exceeded 100 000/mm at 2 months after LDLT. The number of patients with a platelet count of >100 000/mm at 2 months after LDLT was significantly lower (P = 0.024) in those patients who had a preoperative platelet count of <60 000/mm, compared with those patients who had a preoperative platelet count of >60 000/mm (Fig. 2). From July 2005, based on the preliminary results, we initiated pre-emptive therapy and performed splenectomy simultaneously with liver transplantation for the patients with a preoperative platelet count of <60 000/mm. Informed consent was obtained from all patients. The platelet count of three patients who had preoperative platelet counts of <60 000/mm and underwent splenectomy with LDLT exceeded 100 000/mm (range 250 000–750 000/mm) 2 months after LDLT. Four patients have pre-emptively received antiviral therapy consisting of pegylated interferon and ribavirin that was initiated approximately 1–2 months after the operation; these patients have continued to receive the pre-emptive interferon therapy for 6–12 months without any post-operative complications, severe bacterial infection or acute rejection. Although the current standard of treatment for recurrent HCV hepatitis after liver transplantation is a combination therapy of interferon and ribavirin, its results are still poor due to a high incidence of adverse effects requiring the use of expensive adjuvant therapy or the discontinuation of the antiviral therapy. The frequency of side-effects necessitating dose reduction or the cessation of antiviral therapy for recurrent HCV hepatitis after liver transplantation has been reported to range from 45% to 85%. Cytopenias and post-operative complications including acute rejection, infections, renal dysfunction and severe debilitation limit the administration of interferon and ribavirin in the very early post-transplant period. Among the common complications of antiviral therapy, we focused on thrombocytopenia. Our results demonstrated that the rate of cessation of antiviral therapy was significantly high in the patients with a platelet count of <100 000/ mm prior to the administration of antiviral therapy. Further, we demonstrated that significantly fewer patients in the group with a preoperative platelet count of <60 000/mm had developed a platelet count of >100 000 mm by 2 months after LDLT, compared with the group with >60 000/mm. These results prompted us to perform splenectomy simultaneously with LDLT in those HCV doi:10.1111/j.1440-1746.2007.04951.x

Safety of hepatectomy for elderly patients with hepatocellular carcinoma

The number of elderly patients with hepatocellular carcinoma (HCC) has been increasing. Characteristics of elderly HCC patients are a higher proportion of females, a lower rate of positive hepatitis B surface antigen, and a higher rate of positive hepatitis C antibodies. Careful patient selection is vital for performing hepatectomy safely in elderly HCC patients. Treatment strategy should be decided by not only considering tumor stage and hepatic functional reserve, but also physiological status, including comorbid disease. Various assessment tools have been applied to predict the risk of hepatectomy. The reported mortality and morbidity rates after hepatectomy in elderly HCC patients ranged from 0% to 42.9% and from 9% to 51%, respectively. Overall survival rate after hepatectomy in elderly HCC patients at 5 years ranged from 26% to 75.9%. Both short-term and long-term results after hepatectomy for strictly selected elderly HCC patients are almost the same as those for younger patients. However, considering physiological characteristics and the high prevalence of comorbid disease in elderly patients, it is important to assess patients more meticulously and to select them strictly if scheduled to undergo major hepatectomy.

Expression of Pleiotrophin in Hepatic Nonparenchymal Cells and Preneoplastic Nodules in Carbon Tetrachloride-induced Fibrotic Rat Liver

Pleiotrophin (PTN) is a heparin-binding protein, which induces growth, angiogenesis, differentiation, and transformation of cells. The aim of this study was to examine the role of PTN in liver fibrogenesis. Rats were treated with carbon tetrachloride (CCl 4 ) for 3-9 weeks to induce liver fibrosis. The sirius-red staining of these liver tissue sections clearly showed the development of fibrosis and glutathione S-transferase placental type-positive preneoplastic nodules emerged at 7 weeks of the treatment. PTN expression was investigated in fibrotic liver tissues at the mRNA level using a real-time reverse transcription polymerase chain reaction and at the protein level by immunohistochemistry. Quantity of PTN mRNA increased 5-fold in fibrotic liver tissues at 7 weeks of CCl 4 -treatment over the control values. Immunohistochemistry localized PTN protein on hepatic nonparenchymal cells, mostly stellate cells and some of Kupffer cells, and the preneoplastic nodules in fibrotic liver tissues. PTN mRNA expression is significantly upregulated in the CCl 4 -induced chronic rat fibrotic liver tissues. We suggest that PTN might be involved in fibrogenesis and preneoplastic changes of liver.

Reconstruction of the middle hepatic vein tributaries draining segments V and VIII of a right liver graft by using the recipient’s own middle hepatic vein and vascular closure staples

A right liver graft lacking the middle hepatic vein can result in congestion of the anterior segment. We describe a method of reconstructing the middle hepatic vein tributaries by using the recipient’s own middle hepatic vein with vascular closure staples. During a living donor right liver transplantation, the middle hepatic vein tributaries draining segments V (V5) and VIII (V8) of the right lobe graft were reconstructed using the recipient’s own middle hepatic vein and secured with vascular closure staples. Computed tomography showed good venous outflow from the middle hepatic vein and no congestion or atrophy of the anterior segment of the right liver grafts. Thus, using the recipient’s own middle hepatic vein is a suitable option for reconstructing the middle hepatic vein tributaries (V8 and V5) in right-liver living donor transplantation and the application of vascular closure staples helps to accomplish this.

Hepatic venous outflow obstruction after right lateral sector living-donor liver transplantation, treated by insertion of an expandable metallic stent

Hepatic venous outflow obstruction is a relatively uncommon but important and devastating complication occurring after liver transplantation. Recently, right lateral sector liver grafts have sometimes been used in living-donor liver transplantation (LDLT), but, to our knowledge, early hepatic venous outflow obstruction has never been reported in right lateral sector LDLT. A 58-year-old woman was diagnosed with liver cirrhosis and hepatocellular carcinoma and underwent right lateral sector LDLT. Postoperatively, she developed liver dysfunction. Doppler ultrasound examination revealed flat waveforms and low-flow velocity in the right hepatic vein (RHV). A computed tomography (CT) scan revealed a ventrally distorted RHV due to hypertrophy of the liver graft. Hepatic venous obstruction was suspected and a hepatic venogram was performed. The venogram revealed stenosis of the RHV due to the distortion of the vein. We performed percutaneous transfemoral balloon dilatation, but this was not effective. We then inserted an expandable metallic stent (EMS) into the RHV. After the EMS placement, the condition of the patient improved. Venogram and CT data suggested that the obstruction of the RHV developed because of distortion of the RHV to the ventral side during liver regeneration.

Hepatocytes from fibrotic liver possess high growth potential in vivo.

Hepatocyte transplantation is effective for treating liver failure, but healthy donors as a source of hepatocytes are quite limited. The livers of patients with hepatic fibrosis could be an alternative source; however, few reports have examined the nature of hepatocytes from fibrotic livers (f-hepatocytes). In this study, we compared the growth of f-hepatocytes and hepatocytes from normal livers (n-hepatocytes). Hepatocytes were isolated from normal and CCl4-treated wild-type Fischer rats that express dipeptidyl dipeptidase IV (DPPIV) gene (DPPIV+). The n- and f-hepatocytes proliferated in culture at similar rates. Both types of hepatocytes were transplanted into DPPIV- mutant Fischer rats that had been treated with retrorsine to injure the liver and were partially hepatectomized (PHx) before transplantation. Both n- and f-DPPIV+-hepatocytes proliferated and formed colonies. The colony sizes of f-hepatocytes 21 days posttransplantation were approximately three times those of n-hepatocytes. The hepatocytes were analyzed using a fluorescence activated cell sorter (FACS). The FACS profile differed between f- and n-hepatocytes: f-hepatocytes were less granular, less autofluorescent, and smaller than n-hepatocytes. These characteristics of f-hepatocytes resembled those reported for small-sized n-hepatocytes (SHs), which are highly proliferative and preferentially express a unique set of 10 SH genes. However, f-hepatocytes preferentially expressed only five of the SH genes. The expression profile of f-hepatocytes was rather similar to that of proliferating n-hepatocytes in the regenerating liver after PHx. The f-hepatocytes were morphologically normal and did not show any preneoplastic phenotype. These normal and proliferative natures of f-hepatocytes in vivo suggest the fibrotic liver as a source of hepatocytes for transplantation.

Invasive micropapillary carcinoma component is an independent prognosticator of poorer survival in Stage III colorectal cancer patients

Background Invasive micropapillary carcinoma (IMPC) is an aggressive variant of adenocarcinoma found in several organs. Recent studies showed that IMPC in colorectal cancer leads to poorer prognosis than conventional colorectal cancer; however, the influence of IMPC on outcomes remains unclear. The present study aimed to identify the clinicopathological characteristics of colorectal cancers with IMPCs, and to evaluate the prognostic significance of IMPCs per se. Methods We retrospectively analyzed data from 837 patients with colorectal cancer who underwent surgical treatment. We compared the clinicopathological characteristics and survival outcomes of colorectal cancer patients with IMPCs to those without. Results Among 837 patients, 130 (16%) had an IMPC component, including 0 (0%) of 18, 9 (4.2%) of 215, 34 (13%) of 254, 59 (24%) of 249 and 28 (27%) of 101 patients with TNM Stages 0, I, II, III and IV, respectively. The 3-year disease-free survival (DFS) rates were significantly worse for Stage III patients with IMPC than for those without (55.3% vs. 78.7% respectively, P < 0.001), but not in patients with other stages. Multivariate analyses of patients with Stage III colorectal cancer found IMPC to be associated with significantly worse DFS (P = 0.026), as were high CEA levels, tumor budding and TNM staging. IMPC was only significantly associated with tumor invasion (P = 0.045) and venous invasion (P = 0.045) in Stage III tumors. Conclusions Identifying IMPC components in Stage III colorectal cancer is crucial, as their presence is significantly associated with poorer survival.

Single-incision laparoscopic excision of a chylous mesenteric cyst: A case report

Highlights • Single-incision laparoscopic surgery has been performed for resection of benign and malignant gastrointestinal tumors in recent years; however, its safety and feasibility is still controversial, and there have been no reports of its use in resecting mesenteric cysts.• This report deals with the first case of a mesenteric chylous cyst successfully treated by single-incision laparoscopic surgery.