Taketoshi Suehiro

Accurate preoperative estimation of liver-graft volumetry using three-dimensional computed tomography

Background. The aim of this study was to clarify the value of three-dimensional computed-tomography (3D-CT) volumetry for size matching in living-donor liver transplantation (LDLT). Methods. 3D-CT volumetry was applied to 25 donors who underwent hepatectomy for a living relative needing an orthotopic liver transplantation. Fifteen patients underwent extended left lobectomy, one patient an extended left lateral lobectomy, and nine patients right lobectomy. 3D-CT imaging was performed with the workstation ZIO M900 (Zio Software Inc., Tokyo, Japan). The estimated volume of the grafts in two-dimensional (2D) and 3D images were compared, and an error ratio was calculated. Results. 3D-CT imaging revealed the anatomy of the hepatic vein bifurcation and the shape of the graft. The error ratio was 12.8±2.3% in 3D, compared with 19.4±2.5% in 2D. As such, 3D-CT volumetry appears to be more exact than conventional 2D-CT volumetry, but volumetry by 3D-CT still produces an error ratio of approximately 13%. The weight transition of the rats’ livers under preservation in University of Wisconsin (UW) solution indicated that the graft volume seems to decrease during perfusion with UW solution. Mismatch of the cutting line and volume reduction by dehydration (approximately 5% reduction 1 hour after perfusion) seems to cause the error in 3D-CT volumetry. Conclusions. Three-dimensional CT volumetry is useful for size matching in cases of living-related orthotopic liver transplantation.

Use of steatotic graft in living-donor liver transplantation.

Background. The degree of fatty infiltration in hepatic grafts is known to be an important risk factor for primary graft nonfunction in cadaveric liver transplantation. However, the effect of hepatic steatosis in living-donor liver transplantation (LDLT) has not yet been well defined. In this study, we evaluated the impact that the degree of hepatic graft steatosis has on the outcome of LDLT. Methods. Sixty consecutive donors and recipients who underwent LDLT between October 1996 and August 2001 at Kyushu University Hospital were the subjects of this study. The pathologic findings of the prereperfusion biopsy of the graft were classified into the following three groups according to the degree of macrovesicular steatosis: None (n=23), 0% steatosis; Mild (n=23), 0% to 20% steatosis; and Moderate (n=6), 20% to 50% steatosis. Liver function tests including total bilirubin (at postoperative day [POD] 7), the peak alanine aminotransferase (ALT) and prothrombin time (at POD 3), and both patient and graft survival were compared among the groups. Furthermore, we also compared the donor parameters including the peak ALT and total bilirubin (at POD 3) and the operative time, blood loss, and length of hospital stay after surgery. Results. The 1-year patient and graft survival were comparable among the groups. The peak ALT was significantly higher in the Moderate group (606±641 IU/L) than in the None (290±190 IU/L) and Mild (376±296 IU/L) groups. Total bilirubin (POD 7) and prothrombin time (POD 3) were comparable among the groups. The donor parameters were comparable among the groups except for the fact that the donor body weight of the Mild and Moderate groups were significantly heavier (P <0.0001) than that of the None group. Conclusions. In conclusion, the use of a fatty liver graft up to the moderate level can be justified in LDLT, even though ischemia-reperfusion injury tends to be severe in such grafts.

Feasibility of duct-to-duct biliary reconstruction in left-lobe adult-living-donor liver transplantation.

A Roux-en-Y choledochojejunostomy (CDJ) has been the sole method of choice for the reconstruction of the bile duct in living-donor liver transplantation (LDLT) using left-lobe grafts. In this study, we evaluated the feasibility of duct-to-duct (DD) biliary reconstruction in adult-to-adult LDLT using left-lobe grafts. Between October 1996 and October 2001, 46 adult-to-adult LDLTs using the left lobe were performed at our institution. The DD biliary reconstruction (hepaticocholedochostomy) over a T-tube was performed for seven of the last nine recipients (DD group, n=7), whereas the conventional Roux-en-Y CDJ was used for the remaining cases (CDJ group, n=39). The technical problems and the incidence of biliary complications were compared between the groups. Bile leakage developed in only 1 of 7 (14%) in the DD group (leakage from a T-tube exit site), whereas it occurred in 8 of 39 (20%) in the CDJ group. Up to now, no patients from the DD group developed anastomotic stricture, whereas twelve (30.7%) patients from the CDJ group did. Other complications included bleeding from the Roux-en-Y jejunojejunostomy (n=1) and anastomotic occlusion caused by an internal stent (n=1), and both complications were associated with CDJ. In conclusion, DD anastomosis is a simple and viable option for biliary reconstruction in left-lobe LDLTs. A long-term follow-up, especially regarding the incidence of biliary stricture, is thus warranted in such patients.

IL-12 Gene Therapy Is an Effective Therapeutic Strategy for Hepatocellular Carcinoma in Immunosuppressed Mice

Immunosuppressive therapy for organ transplantation is essential for controlling rejection. When liver transplantation is performed as a therapy for hepatocellular carcinoma (HCC), recurrent HCC is one of the most fatal complications. In this study, we show that intratumoral murine IL-12 (mIL-12) gene therapy has the potential to be an effective treatment for malignancies under immunosuppression. C3H mice (H-2k), injected with FK506 (3 mg/kg) i.p., were s.c. implanted with 2.5 × 106 MH134 cells (H-2k) and we treated the established HCC with electroporation-mediated gene therapy using mIL-12 plasmid DNA. Intratumoral gene transfer of mIL-12 elevated intratumoral mIL-12, IFN-γ, and IFN-γ-inducible protein-10, significantly reduced the number of microvessels and inhibited the growth of HCC, compared with HCC-transferred control pCAGGS plasmid. The inhibition of tumor growth in immunosuppressed mice was comparable with that of mIL-12 gene therapy in immunocompetent mice. Intratumoral mIL-12 gene therapy enhanced lymphocytic infiltration into the tumor and elicited the MH134-specific CTL response even under FK506. The dose of FK506 was sufficient to prevent the rejection of distant allogenic skin grafts (BALB/c mice, H-2d) and tumors, B7-p815 (H-2d) used as transplants, during mIL-12 gene therapy against MH134. Ab-mediated depletion studies suggested that the inhibition of tumor growth, neovascularization, and spontaneous lung metastasis by mIL-12 was dependent almost entirely on NK cells and partially on T cells. These results suggest that intratumoral mIL-12 gene therapy is a potent effective strategy not only to treat recurrences of HCC in liver transplantation, but also to treat solid malignant tumors in immunosuppressed patients with transplanted organ.

Graft‐versus‐host disease following living donor liver transplantation

Graft‐versus‐host disease (GVHD) is the most common and well‐known cause of morbidity and mortality following allogeneic bone marrow transplantation. Sporadic cases have been reported after cadaveric donor liver transplantation with usually fatal outcomes, however, the actual incidence and the characteristics of GVHD after living donor liver transplantation (LDLT) remain unknown. We herein report a person who developed fatal GVHD following LDLT and discuss the applicability of an HLA‐homozygous donor to an HLA‐haploidentical recipient. A 48‐year‐old male underwent LDLT for unresectable hepatocellular carcinoma with alcoholic liver cirrhosis. The donor was his 20‐year‐old son whose pretransplant HLA typing was homozygous at all loci. GVHD occurred 35 days after LDLT and was characterized by fever, diarrhea, maculopapular rash, and leukopenia, which led to the development of fatal pneumonia. We identified 4 cases of GVHD after LDLT in Japan and 1 in the United States, all associated with the use of an HLA‐homozygous donor. The use of an HLA homozygous donor which results in a complete 1‐way donor‐recipient HLA match carries an extremely high risk of developing GVHD after LDLT. Therefore, it is possible that LDLT should be ruled out for such donors. A pretransplant work‐up of the HLA type in both the donors and recipients is therefore imperative before determining the indications for LDLT. (Liver Transpl 2004;10:460–464.)

Des-gamma-carboxy prothrombin and proliferative activity of hepatocellular carcinoma.

BACKGROUND Des-gamma-carboxy prothrombin (DCP) is a useful marker for the prognosis of hepatocellular carcinoma (HCC). In this report we investigated the relationship between the positivity of DCP and proliferative activity of HCC and discuss the cause of poor prognosis of DCP-positive HCC. METHODS Immunohistochemical and clinicopathologic study was done in 114 patients with resected HCC measuring less than 6 cm in diameter by using monoclonal antibody for proliferating cell nuclear antigen (PCNA). RESULTS PCNA labeling index (PCNA-LI) was significantly higher in the patients with DCP-positive HCC than in those with DCP-negative HCC; also a positive correlation was noted between the PCNA-LI and the DCP level. We divided patients into two groups according to the PCNA-LI. In the high PCNA-LI group the patients with DCP-positive HCC exhibited a higher PCNA-LI than did the patients with DCP-negative HCC. As for pathologic prognostic factors, the DCP-positive high PCNA-LI group showed the highest incidence of tumor thrombus of the portal vein and intrahepatic metastasis while also exhibiting the lowest recurrence-freedom rate. From multivariate analysis we find that DCP, as well as PCNA-LI, is one of the risk factors for recurrence of HCC after hepatectomy. CONCLUSIONS Our results thus suggest that DCP-positive HCC showed high PCNA-LI, and this might be the main cause for early intrahepatic spread and poor prognosis of DCP-positive HCC.

Effect of intraportal infusion to improve small for size graft injury in living donor adult liver transplantation

The most important problem in the living donor adult liver transplantation (LDALT) is a small for size graft. Although a right lobe graft is used in many cases in order to avoid small for size graft, for a donor, the risk has few in left lobe graft. We evaluate the effect of an intraportal infusion treatment to the small for size graft. One hundred and twelve patients who underwent LDALT were studied. The graft weight recipient standard liver volume ratio (GV/SLV) of these patients were 50% or less. We divided the patients into following two groups; infusion group (n = 53) and control group (n = 59). For the infusion group, 16 G double lumen catheter was inserted into portal vein and nafamostat mesilate (protease inhibitor which stabilize coagulofibrinolytic state; 200 mg/day), prostaglandin E1 (vasodilator and hepatoprotective effect; 500 μg/day) and thromboxane A2 synthetase inhibitor (vasodilator and anticoagulant effect; 160 mg/day) were administrated continuously for 7 days. Small‐for‐size graft syndrome was defined as bilirubin >10 mg/dl and ascites >1000 cc on postoperative day (POD) 14. Comparison examination of a background factors and postoperative bilirubin and amount of ascites was carried out. The mean GV/SLV did not have the difference at 39.1% of infusion group, and 38.3% of control group (P = 0.58). By the control group, 15 patients (25.4%) were small‐for‐size graft syndrome, however, there was only two (3.8%) small‐for‐size graft syndrome in infusion group (P = 0.04). The bilirubin levels of infusion and control group on 7 and 14 POD were 9.9 and 7.8 vs. 9.5 and 10.5 mg/dl, respectively. The amount of ascites of infusion group on 7 and 14 POD were 870 and 430 cc, respectively. On the contrary, in control group, the amount of ascites on 7 and 14 POD were 1290 and 1070 cc, respectively. Bilirubin levels and the amount of ascites on 7 and 14 POD were lower in the patients with infusion group then those with control group. There were no differences between infusion group and control group in age, sex and Childs classification. The intraportal infusion had an effect in prevention of hyperbilirubinemia and loss in quality of excessive ascites in the patients with small for size graft. This was suggested to be what is depended on the improvement of the microcirculation insufficiency considered one of the causes of small‐for‐size graft syndrome.

Hepatocellular carcinoma producing a granulocyte colony‐stimulating factor: report of a resected case with a literature review

A complete resection of a hepatocellular carcinoma (HCC) producing the granulocyte colony‐stimulating factor (G‐CSF) was performed and is reported here. The patient had a few general symptoms and complications, such as the paraneoplastic syndrome. He had marked granulocytosis, and his serum levels of G‐CSF and interleukin‐6 were elevated. The pathological findings of the resected specimen revealed poorly differentiated HCC with sarcomatous change and showed, immunohistochemically, staining of G‐CSF. Only a few cases of G‐CSF‐producing HCC have been reported, and they resulted in rapid tumour growth and poor prognosis. The case presented here may be the first complete resection ever performed, but the patients prognosis was similar to that observed in typical cases.

Clinicopathologic features and prognosis of resected hepatocellular carcinomas of varied sizes with special reference to proliferating cell nuclear antigen

Background. Proliferating cell nuclear antigen (PCNA) is an intranuclear protein that is linked closely to the cell cycle. An immunohistochemical study was performed on the expression of PCNA in various sized hepatocellular carcinomas (HCCs) to determine the relation between the proliferative activity of cancer cells and prognosis.

Impact of graft hepatic vein inferior vena cava reconstruction with graft venoplasty and inferior vena cava cavoplasty in living donor adult liver transplantation using a left lobe graft.

Background. Hepatic venous reconstruction is critical in living donor adult liver transplantation (LDALT) because outflow obstruction in small for size graft may lead to graft dysfunction or loss. We describe the usefulness of venoplasties of the graft hepatic vein (HV) and graft HV-recipient inferior vena cava (IVC) reconstruction in LDALT using a left lobe graft. Methods. Sixty patients who underwent LDALT were studied. We divided the patients into following two groups: venoplasty group (n=30) and control group (n=30). For the patients with venoplasty group, venoplasty of the graft and recipient IVC cavoplasty was made to widen the orifice. Comparison examination of a background factors and postoperative bilirubin and the ascites was carried out. Results. The mean graft volume standard liver volume ratio (GV/SLV) did not have the difference at 41.7% of venoplasty group, and 42.1% of control group (p=NS). The diameter of the hepatic vein in control and venoplasty group before and after venoplasty is 26.9±5.5, 28.2±2.9, and 34.1±3.9 mm, respectively. The diameter of the hepatic vein after venoplasty is larger than that of before venoplasty and of control (P<0.05). Mean total bilirubin level on postoperative day (POD) 7 is 13.8±9.3 mg/dl in control group and 7.0±3.3 mg/dl in venoplasty group (P<0.05). Mean amount of ascites on POD 7 and 14 are 1576±1113 and 1397±1661 cc in control group, and 736±416 and 550±385 cc in venoplasty group, respectively (P<0.05). Two-year survival rate is 75.2 % in control group and 86.6 % in venoplasty group (P<0.05). Conclusions. We conclude that in LDALT using left lobe graft, HV-IVC reconstruction with graft venoplasty and IVC cavoplasty is useful not only to prevent outflow block but also to improve graft function.