Ken Hoshino

Intraportal infusion therapy as a novel approach to adult ABO-incompatible liver transplantation

Background. ABO-incompatible liver transplantation is associated with an extremely complicated postoperative course, especially when the recipients are adults. Methods. Two adult patients underwent living-donor liver transplantation from ABO-incompatible donors. The antirejection therapy included multiple perioperative plasmapheresis, splenectomy, systemic triple immunosuppressive regimen with tacrolimus, methylprednisolone, and cyclophophamide, or azathioprine. In addition to these conventional approaches, we performed intraportal infusion therapy after transplantation with methylprednisolone, prostaglandin E1, and gabexate mesilate. Results. With our protocol, antidonor blood group antibody titers in both cases remained low without any evidence of rejection or vascular complications throughout the postoperative course. Biliary complications were transient and resolved completely. The patients have now survived 30 and 12 months posttransplantation and have regained normal life activity with good liver function. Conclusions. Our experience has shown the feasibility of controlling rejection and other complications in adult ABO-incompatible liver transplantation under intraportal infusion therapy.

Contrasting action of IL-12 and IL-18 in the development of dextran sodium sulphate colitis in mice

Background: Interleukin (IL)-12 and IL-18 are major interferon (IFN)- % -inducing factors that collaborate with each other. The present study was conducted to determine the distinct roles of IL-12 and IL-18 in the development of dextran sulphate sodium (DSS) colitis in mice. Methods: Colitis was induced in IL-12p35 m / m , IL-18 m / m , IL-18 receptor m / m and control mice with DSS. Clinical and histopathological analysis was conducted using survival rate, weight loss score, diarrhoea score, bloody stool score and histological score. In addition, cytokine production by lamina propria mononuclear cells (LPMCs) was examined using the specific enzyme-linked immunoassay. Results: IL-12p35 m / m mice developed only a mild disease associated with no lethality and few histopathological abnormalities. In contrast, IL-18 m / m and IL-18R m / m mice developed more severe colitis associated with high lethality and more histopathological abnormalities compared with control mice. LPMCs from DSS-fed IL-18 m / m mice produced significantly higher amounts of IFN- % , while LPMCs from DSS-fed IL-12 m / m mice produced lower amounts of IFN- % and tumour necrosis factor (TNF)- ! compared with control mice. Conclusion: These results suggest that IL-18 might function with manners different from IL-12 at some pathological conditions in the development of colitis.BACKGROUND Interleukin (IL)-12 and IL-18 are major interferon (IFN)-gamma-inducing factors that collaborate with each other. The present study was conducted to determine the distinct roles of IL-12 and IL-18 in the development of dextran sulphate sodium (DSS) colitis in mice. METHODS Colitis was induced in IL-12p35(-/-), IL-18(-/-), IL-18 receptor(-/-) and control mice with DSS. Clinical and histopathological analysis was conducted using survival rate, weight loss score, diarrhoea score, bloody stool score and histological score. In addition, cytokine production by lamina propria mononuclear cells (LPMCs) was examined using the specific enzyme-linked immunoassay. RESULTS IL-12p35(-/-) mice developed only a mild disease associated with no lethality and few histopathological abnormalities. In contrast, IL-18(-/-) and IL-18R(-/-) mice developed more severe colitis associated with high lethality and more histopathological abnormalities compared with control mice. LPMCs from DSS-fed IL-18(-/-) mice produced significantly higher amounts of IFN-gamma, while LPMCs from DSS-fed IL-12(-/-) mice produced lower amounts of IFN-gamma and tumour necrosis factor (TNF)-alpha compared with control mice. CONCLUSION These results suggest that IL-18 might function with manners different from IL-12 at some pathological conditions in the development of colitis.

Liver regeneration in donors and adult recipients after living donor liver transplantation

In living donor liver transplantation, the safety of the donor operation is the highest priority. The introduction of the right lobe graft was late because of concerns about donor safety. We investigated donor liver regeneration by the types of resected segments as well as recipients to assess that appropriate regeneration was occurring. Eighty‐seven donors were classified into 3 groups: left lateral section donors, left lobe donors, and right lobe donors. Forty‐seven adult recipients were classified as either left or right lobe grafted recipients. Volumetry was retrospectively performed at 1 week, 1, 2, 3, and 6 months, and 1 year after the operation. In the right lobe donor group, the remnant liver volume was 45.4%, and it rapidly increased to 68.9% at 1 month and 89.8% at 6 months. At 6 months, the regeneration ratios were almost the same in all donor groups. The recipient liver volume increased rapidly until 2 months, exceeding the standard liver volume, and then gradually decreased to 90% of the standard liver volume. Livers of the right lobe donor group regenerated fastest in the donor groups, and the recipient liver regenerated faster than the donor liver. Analyzing liver regeneration many times with a large number of donors enabled us to understand the normal liver regeneration pattern. Although the donor livers did not reach their initial volume, the donors showed normal liver function at 1 year. The donors have returned to their normal daily activities. Donor hepatectomy, even right hepatectomy, can be safely performed with accurate preoperative volumetry and careful decision‐making concerning graft‐type selection. Liver Transpl 14:1718–1724, 2008.

Effective and safe immunizations with live-attenuated vaccines for children after living donor liver transplantation.

Immunizations using live-attenuated vaccines are not recommended for post-liver transplant children due to its theoretical risks. However, they will encounter vaccine-preventable viral diseases upon returning to real-life situations. We performed a total of 70 immunizations with four individual live-attenuated vaccines to 18 pediatric post-living donor liver transplant (LDLT) recipients who fulfilled a clinical criteria including humoral and cell-mediated immunity. The seroconversion rates at the first dose for measles (strain AIK-C), rubella (strain TO-336), varicella (strain Oka), and mumps (strains Hoshino) were 100% (15/15), 100% (15/15), 82% (9/11), and 82% (9/11), respectively. During observed period (-5 years 11 months), a few cases with waning immunity (antibodies were once produced but the levels fell over time) were seen except after rubella immunization. Clinical diseases after seroconversion or definite serious adverse effects due to immunization were not observed. Immunizations using selected live-attenuated vaccines were safe and effective for post-LDLT children who were not severely immunosuppressed.

colorectal Motility Induction by Sacral Nerve Electrostimulation in a Canine Model : implications for Colonic Pacing

AbstractPURPOSE: This study investigated the role of the sacral nerves in the mechanism of defecation using adult mongrel dogs. The possibility of designing a colonic pacemaker as a new therapeutic device to treat defecation disturbances, such as fecal incontinence and severe constipation, is also discussed. METHODS: Colorectal motility during spontaneous defecation was monitored with force strain-gauge transducers implanted in the proximal, distal, and sigmoid colon, rectum, and internal anal sphincter. Under general anesthesia, the sacral nerve was stimulated electrically, and the colorectal motility response was examined. RESULTS: During spontaneous defecation, three characteristic motility patterns were observed: 1) giant migrating contractions of the colon were propagated to the rectum or anus; 2) the rectum relaxed before the giant migrating contractions were propagated; and 3) the internal anal sphincter was relaxed during the propagation of the giant migrating contraction. Sacral nerve stimulation elicited the following three unique responses: 1) contractile movements were propagated from the distal colon to the rectum; 2) a relaxation response was noted in the rectum; and 3) the internal anal sphincter exhibited a relaxation response. The duration and propagation velocity of the contractile responses and the duration of relaxation responses elicited by electrical stimulation of the sacral nerve were similar to those that occurred during spontaneous defecation, but their amplitudes were smaller. CONCLUSION: The coordinated processes of the colon and anorectum during defecation were affected by the sacral nerves. This suggests that it is possible to design a colonic pacemaker to control lower colonic and rectal movements.

Clinical characteristics of thrombotic microangiopathy following ABO incompatible living donor liver transplantation

Thrombotic microangiopathy (TMA) may develop after living donor liver transplantation (LDLT), but the mechanism is not fully understood. We retrospectively analyzed all patients undergoing LDLT at our center, including TMA patients, to elucidate the clinical characteristics and presentation and to determine which patients have a higher risk of occurrence of TMA. In all, 57 adult patients were reviewed after LDLT at our institution. TMA was diagnosed by sudden and severe thrombocytopenia, followed by hemolytic anemia with fractionated erythrocytes in the blood smear. Clinical features were compared between the TMA group and the non‐TMA group. Of the 57 patients, 4 were diagnosed with posttransplantation TMA. ABO blood group (ABO)‐incompatibility, cyclophosphamide (CPA), and recipient blood group (type O) were closely correlated with the occurrence of TMA. Thrombocytopenia appeared 1 to 5 days before hemolytic anemia. Coagulative function markers stayed at the same level after TMA, while marked elevation was shown in fibrinolytic function markers such as plasminogen activator inhibitor type 1 (PAI‐1). TMA occurred at a higher prevalence in ABO‐incompatible graft recipients. Additional factors associated with ABO‐incompatible transplantation, such as an overdose of immunosuppressants, may affect the likelihood of TMA. Sudden and severe thrombocytopenia presented before hemolytic anemia and the serum levels of PAI‐1 correlated well with the clinical course of TMA. In conclusion, early recognition of thrombocytopenia and elevation of PAI‐1 is crucial to diagnose TMA especially in ABO‐incompatible LDLT. Liver Transpl 13:1455–1462, 2007.

Chronic rejection in lung allografts: immunohistological analysis of fibrogenesis

Abstract  In ongoing chronic rejection after lung transplantation, alveolar interstitial fibrosis develops. However, little is known about the mechanisms involved. In order to investigate these mechanisms, expression of extracellular matrix molecules (ECM) (undulin, decorin, tenascin, laminin, and fibronectin) and cytokines [transforming growth factor(TGF)‐β1, TGF‐β3, platelet‐derived growth factor(PDGF), and PDGF receptor] were semiquantita‐tively evaluated in chronically rejected lung allografts, using standard immunohistochemical techniques. Additionally, the presence of mac‐rophages was analysed. The present study demonstrates an increased infiltration of macrophages with a concomitant upregulation of cytokines (TGF‐β1, TGF‐β3, and PDGF) and an increased deposition of ECM in chronic lung rejection. These cytokines have an important role in the stimulation of fibroblasts which are a major source of ECM. Upregulated expression of ECM in the alveolar interstitial space leads to alveolar malfunction by thickening of the wall and, thus, is one of the causative factors of respiratory dysfunction in chronic lung graft rejection.

Critical infantile hepatic hemangioma: results of a nationwide survey by the Japanese Infantile Hepatic Hemangioma Study Group

BACKGROUND The current survey aimed to describe the clinical features of critical infantile hepatic hemangioma (IHH) and the implications of recent treatments. MATERIALS AND METHODS A nationwide survey of critical IHH patients treated between 2005 and 2010 was performed in all 117 registered pediatric surgical hospitals in Japan. As a result, 19 patients were identified and reviewed using a statistical analysis. RESULTS Abdominal distention (47.4%), high-output cardiac failure (47.4%), coagulopathy (42.1%), and respiratory distress (31.6%) were the major symptoms. Three patients died (1 of coagulopathy, 1 of cardiac failure, and 1 of both). An accompanying portovenous shunt was also highlighted. Infantile hepatic hemangioma was totally insensitive to steroid treatment in 3 (23.1%) of the 13 patients, and 9 (47.4%) of the 19 patients required other treatments. Surgical resection and β-blocker improved the hematologic data, whereas hepatic arterial ligation and embolization seemed to produce a limited effect. Among the dead patients, several hematologic parameters were significantly worse: the thrombocyte count (pretherapeutic: 73,000 vs 300,000/mm(3), dead vs survivor, respectively [P < .03]; posttherapeutic: 66,000 vs 388,700/mm(3) [P < .003]) and the prothrombin time (posttherapeutic, 35.0 vs 12.1 seconds [P < .0001], dead vs survivor, respectively). CONCLUSION For critical IHH cases with steroid-insensitive hematologic disorders, alternative treatments including β-blocker therapy, surgery, and liver transplantation should be considered.

Imatinib Blocks Spontaneous Mechanical Activities in the Adult Mouse Small Intestine: Possible Inhibition of c-Kit Signaling

Interstitial cells of Cajal (ICCs) are postulated to serve as pacemakers that physiologically generate electrical slow waves in the gastrointestinal tract. Imatinib is a novel and potent inhibitor of c-Kit tyrosine kinase and a new therapeutic agent for gastrointestinal stromal tumors (GIST) which presumably arise from ICCs. The effects of imatinib on the basal rhythmic mechanical activities of small intestinal circular muscles were investigated in ring preparations of the gut. The small intestinal rings of BALB/c mice exhibited spontaneous contractile activity at a rate of 40.8 ± 4.9 contractions/min. Imatinib (1– 81 µmol/l) dose-dependently abolished spontaneous contractile activity in the 9- to 27-µmol/l concentration range. Contraction was restored by washing imatinib out with a fresh buffer. High K+-induced contraction was not affected by imatinib, suggesting that the drug does not have nonspecific inhibitory actions on the smooth muscles. The small intestinal rings of adult W/Wvmice, which lack a functional c-Kit activity,exhibited only small and irregular spontaneous contractions. These results demonstrate that imatinib affects bowel contractions, and suggest that the c-Kit signaling of ICCs plays an essential role in the spontaneous movements in circular muscles of the mouse small intestine.

Extra-anal mucosectomy: Laparoscopic-assisted endorectal pull-through using a prolapsing technique

BACKGROUND/PURPOSE The mucosectomy of the aganglionic rectal mucosa has been performed transabdominally in the Soave procedure. Recently, mucosectomy with transanal approach was reported both in the laparoscopic and the open surgical procedure. However, the operative view and working field are restricted because the dissection has to be done in the anal canal. The authors report an innovative approach, an extra-anal mucosectomy, to perform mucosectomy in the Soave procedure for Hirschspungs disease in combination with the laparoscopic-assisted prolapsing technique. METHODS Four patients underwent laparoscopic surgery for Hirschsprungs disease with extra-anal mucosectomy between 1995 and 1997. One 10-mm and 5-mm ports were used throughout the operation. The rectum was pulled out through the anal canal to create a rectal prolapse and was divided outside the anal canal. The mucosectomy was performed in the everted rectal mucosa outside the anal canal to the level of dentate line. The colon was sutured to the anal mucosa 2 mm above the dentate line. Mean operative time was 3 hours. RESULTS The present technique made the whole mucosectomy possible under direct observation. CONCLUSION The extra-anal mucosectomy in conjunction with a laparoscopic-assisted prolapsing technique seems to be a safe and reliable modality in the surgical treatment of Hirschsprungs disease.