Living donor liver transplantation for adult patients with hepatocellular carcinoma: experience in Japan

OBJECTIVE: We sought to determine the outcome of living donor liver transplantation (LDLTx) in 316 adult patients with hepatocellular carcinoma (HCC). SUMMARY BACKGROUND DATA: LDLTx has increasingly been performed worldwide, but the impact of the procedure on HCC has not been evaluated in a large series. METHODS: Between October 1989 and December 2003, 1389 adults underwent LDLTx at 49 centers in Japan. In 316 (22.8%) who received LDLTx for HCC (70 females, 22%, median age 57 years; and 246 males, 88%, median age, 54 years), we analyzed pretransplant clinical status, imaging diagnosis, transplant procedure, pathologic study of explanted liver, and outcome. In 232 patients (73.4%), various surgical and nonsurgical therapies had been employed prior to LDLTx. The median follow-up period was 16 months (range, 2.5-72.0) RESULTS: Currently, 236 (74.7%) of the patients are living. One- and 3-year patient survivals were 78.1% and 69.0%, respectively. Model end-stage liver disease score and preoperative serum alpha-fetoprotein level were independent risk factors for patient survival. Forty patients (12.7%) developed HCC recurrence. Alpha-fetoprotein level, tumor size, vascular invasion, and bilobar distribution were independent risk factors for HCC recurrence. Grade of histologic differentiation of HCC showed close correlation with tumor characteristics and recurrence. One- and 3-year recurrence-free survivals were 72.7% and 64.7%, respectively. When the Milan criteria were applied, patient survival and disease-free survival at 3 years were 78.7% and 79.1%, respectively, in patients who met the criteria, and 60.4% and 52.6%, respectively, in those who did not. CONCLUSION: LDLTx can achieve acceptable survival in HCC patients, even when liver function is markedly impaired, or HCC is uncontrollable by conventional antitumor treatments.     

Liver regeneration in living-donor liver transplantation

Liver regeneration in living-donor liver transplantation is summarized from the authors' data. In donors, liver function tests recovered to within the normal range 2 weeks after surgery regardless of graft type. At 2 weeks, the volumetric recovery of the remnant liver was 65% and 80% of the original volume in right and left lobe donors, respectively. These results suggest that functional recovery occurs earlier than morphologic restoration in donors. In recipients, the factor that affected the regeneration rate in size 4 weeks after transplantation was only implanted graft size; the rate was greater in patients in whom smaller grafts were implanted. In recipients with a rate of two or more, however, high portal vein pressure and flow were observed. Further, persistent low platelet counts and hyperbilirubinemia were seen in those patients. These results indicate that size enlargement may be caused by engorgement, and functional recovery is not achieved concurrently with morphologic restoration, especially in patients with smaller grafts. In patients with fulminant hepatic failure who receive auxiliary partial orthotopic liver transplantation, sequential histopathologic observations of the diseased liver revealed that liver regeneration initiates from cytokeratin 17-positive ductules and at least 1 year is necessary for complete recovery.     

Peripheral anatomic evaluation using 3D CT hepatic venography in donors: significance of peripheral venous visualization in living-donor liver transplantation

OBJECTIVE: The purpose of this study was to determine clinical roles for 3D CT hepatic venography in the evaluation of peripheral hepatic venous anatomy during living-donor liver transplantation. MATERIALS AND METHODS: Subjects comprised 54 donors (age range, 20-60 years) who had undergone surgery to donate a liver for transplantation. Visualization of each hepatic venous branch and total visualization using 3D CT hepatic venography were evaluated. Maximum venous branch order visualized was graded as nil, first branch, second branch, or third branch or more. The distance between the hepatic surface and the tip of each hepatic venous branch was classified as 0-5 mm, 6-10 mm, 11-15 mm, 16-20 mm, or 21-25 mm. Quality of total 3D CT hepatic venography was evaluated subjectively as poor, good, fair, or excellent. Dominance of large hepatic veins in the right lobe, peripheral branching pattern of the middle hepatic vein, and branching pattern of the vein draining segment IVb were also assessed. RESULTS: Most hepatic venous branches (96.2% [275/286]) were visualized up to at least the second-order branches, and 93.7% (268/286) of branches were within 10 mm of the hepatic surface. As for total visualization, 98% (53/54) of cases were regarded as excellent. The dominant vein in the right lobe was the right hepatic vein in 27 cases, inferior hepatic vein in 25, and middle hepatic vein in one. The branching pattern of the middle hepatic vein was type 1 in 36 cases, type 2 in nine, and type 3 in eight. Segment IVb vein branched from the middle hepatic vein in 20 patients, and from the left hepatic vein in 34. CONCLUSION: Because 3D CT hepatic venography visualizes peripheral hepatic venous branches in detail, the technique is useful for determining operative indications in living-donor liver transplantation.     

Gene therapy-mediated CD40L and CD28 co-stimulatory signaling blockade plus transient anti-xenograft antibody suppression induces long-term acceptance of cardiac xenografts

BACKGROUND: The authors have previously demonstrated that inhibition of CD28 and CD40 ligand (CD40L) co-stimulatory signals by adenovirus-mediated cytotoxic T-lymphocyte-associated (CTL) antigen 4 (A4) immunoglobulin (Ig) and CD40Ig gene therapies induces tolerance or long-term acceptance in rat liver and heart allograft transplantation. In this study, the authors examined whether co-stimulation blockade with a brief course treatment of FK779, a novel leflunomide derivative, would be an ideal strategy for controlling xenograft rejection. METHODS: Hamster hearts were transplanted into Lewis rats. Adenovirus vector coding (Ad) CD40Ig, CTLA4Ig, or LacZ gene (1 x 10(9) plaque-forming units) was administered intravenously to recipient rats 2 days before or immediately after xenografting. FK779 (10 mg/kg/day) was administered orally to recipients for 7 days beginning on day -1. Graft survival, graft histology, and xenoreactive antibodies were examined. RESULTS.: Both untreated and AdLacZ-treated control rats rejected cardiac xenografts, with a median survival time (MST) of 3 days. Co-stimulatory blockade alone by AdCTLA4Ig, AdCD40Ig, or both could not overcome such delayed xenograft rejection (DXR) (MST, 3-4 days). Under a short-course FK779 treatment that suppressed T-cell-independent xenoreactive antibodies, administration of AdCD40Ig (MST, 30.5 days) but not AdCTLA4Ig (MST, 9 days) significantly prolonged xenograft survival as compared with the FK779 monotherapy (MST, 7 days). In contrast, DXR and cellular rejection were controlled successfully and all xenografts were accepted for over 100 days when AdCTLA4Ig and AdCD40Ig were administered under FK779 induction therapy. However, chronic rejection was present in all long-term surviving xenografts. CONCLUSIONS.: Gene therapy-based co-stimulation blockade with FK779 induction treatment seems to be an attractive strategy with which to control xenograft rejection.     

Optimum pain relief with continuous epidural infusion of local anesthetics shortens the duration of zoster-associated pain

OBJECTIVE: To investigate effects of continuous epidural infusion (CEI) of 0.5% bupivacaine added to intermittent epidural boluses (IEB) on the duration of zoster-associated pain (ZAP), as compared with continuous infusion of normal saline placebo added to IEB. DESIGN: A prospective, double-blind, randomized, placebo-controlled study. SETTING: A university hospital and an affiliated clinic in Japan from 1996 through 1999. PATIENTS: 56 immunocompetent herpes zoster (HZ) patients, 50 years or older, within 10 days of rash onset and with severe pain and eruption. INTERVENTIONS: Patients were hospitalized and randomly allocated into 2 groups. CEI group given CEI of 0.5% bupivacaine (0.5-1.0 mL/h) plus IEB of 0.5% bupivacaine 4 times daily (n = 29). IEB group given normal saline infusion plus IEB of 0.5% bupivacaine 4 times daily (n = 27). All patients received oral acyclovir 800 mg, 5 times daily, for 7 days. OUTCOME MEASURES: The number of days required for complete cessation of ZAP and the proportion of subjects with allodynia beyond 30 days. RESULTS: The median time to cessation of ZAP was significantly shorter in the CEI group than in the IEB group (29 days vs. 40 days, P = 0.002). The number of patients whose allodynia persisted beyond 30 days of treatment was significantly lower in the CEI group than in the IEB group (10% vs. 37%, P = 0.027). CONCLUSIONS: CEI of 0.5% bupivacaine plus IEB was associated with a shorter duration of ZAP and fewer patients with allodynia beyond 30 days, compared with IEB plus normal saline infusion. Patients at high risk for developing postherpetic neuralgia (PHN) can be managed with intensive therapies at the early stage of disease, such as CEI, which maintains effective analgesia and may reduce the burden of PHN.     

In vitro chemosensitivity test for hepatocellular carcinoma using collagen-gel droplet embedded cultures

This study evaluated an in vitro assay for chemosensitivity test using a collagen-gel droplet-embedded culture drug sensitivity test (CD-DST) for hepatocellular carcinoma (HCC). In 25 patients with HCC, in vitro chemosensitivity to 5-fluorouracil (5-FU), epirubicin (EPI), and cisplatin (CDDP) was examined by CD-DST, and 5-FU, EPI, and paclitaxel (PTX) were examined in 38 patients with breast cancer. Successful rates of chemosensitive evaluation by CD-DST were 64% for HCC and 79% for breast cancers. Although chemosensitivities of breast cancer were 5-FU 23.1%, EPI 83.3%, and PTX 67.7%, only one HCC sample was sensitive to EPI. Growth rates of HCC for 7 days of culture were significantly lower than those of breast cancers (1.04 vs 3.61). The culture methods for HCC in CD-DST should be improved to estimate accurate results.     

Vascular change of hippocampal capillary is associated with vascular change of retinal capillary in aging

Vascular deficiency, such as deleterious change of endothelial cells, becomes the prominent feature of hippocampal microvessels during the processes of aging in rodents and it seems to be associated with deficiency of intellectual behavior in aged subjects. The hippocampal microvessels and hippocampal pyramidal neurons form and accumulate intermediates of advanced Maillard reaction (glycation) end products, specifically N()-carboxymethyl lysine (CML) and CML in rodents during the processes of aging. CML facilitates proliferation of endothelial cells in culture. However, further conjugation of CML with the substance(s) seems to occur in the microvessels and pyramidal neurons of hippocampus and it brings about deleterious change of endothelial cells and pyramidal neuron death. This would cause deficiency of recognition and reference memory in rodents during the processes of aging. In man in Alzheimer's disease (AD), one might speculate that formation and accumulation of CML in the hippocampal microvessels initiate the accumulation of amyloid to produce cerebral amyloid angiopathy and it brings about hypoglycemia and hypoxia in the hippocampal pyramidal neurons. Furthermore, formation and accumulation of CML in the hippocampal pyramidal neurons initiate the deposition of neurofibrillary tangles and senile plaques which cause neuronal death. In this way, vascular deficiency of hippocampal microvessels seems to be associated with the demented disease, the atrophic process of the brain and accumulation of amyloid in the brain in man. In terms of vascular deficiency concerns, the vascular change of the retinal capillaries becomes also a prominent feature during the processes of aging and it has a positive correlation with the vascular change of hippocampal capillary. In man during senescence, one might also speculate that vascular change of eye capillaries would become the early market for diagnosis of dementia in AD.     

Significance and usefulness of corticospinal motor evoked potential monitoring for lesions adjacent to primary motor cortex]

This study evaluated the usefulness of intraoperative corticospinal motor evoked potential (MEP) monitoring in preventing postoperative motor deficits, and whether this procedure contributed to surgery on intrinsic brain lesions in the vicinity of the motor area. The subjects were 45 patients with brain tumors located in and around the primary motor area. MEP was recorded through the cervical epidural electrodes in response to stimulation of the motor cortex. The amplitude of D-response of MEP was compared at the beginning and at the end of surgery. Then MEP changes were divided into five groups; "increase", "no change", "diminish", "decrease" and "disappear". We used the DeJong classification for qualitative analysis of motor function, and reviewed these findings in relation to the change in MEP. It was possible to record MEP when the preoperative motor weakness was DeJong 3 or better. There was no postoperative motor deficit when the MEP amplitude was preserved at better than 50% of a control amplitude. If the amplitude decreased to less than 50%, motor deficits were encoutered. When MEP amplitude increased during the surgery, preoperative motor weakness was improved after the surgery. It is concluded that there is little possibility of causing motor deficits even if tumor removal is aggressively pursued, as long as the amplitude of D-response remains at 50% or more of the baseline. This monitoring procedure is expected to improve the overall surgical results in patients with intrinsic brain tumors around the motor area.     

Overproduction of N(epsilon)-(carboxymethyl)lysine-induced neovascularization in cultured choroidal explant of streptozotocin-diabetic rat

Action of N(epsilon)-(carboxymethyl)lysine (CML) adduct, an advanced glycation end product, was investigated on neovascularization of cultured choroidal explants in streptozotocin (STZ)-diabetic rat. The choroidal explants of early (4 weeks after an injection of 60 mg/kg STZ) and advanced (8 months after the STZ injection) diabetic rats, and age-matched normal rats were cultured in fibrin gel with Dulbecco's modified Eagle medium containing fetal bovine serum. The number of budded microvessel-like structures was counted and used as an index of in vitro neovascularization. Choroidal explants in the early diabetic stage released vascular endothelial growth factor (VEGF) and tended to increase tumor necrosis factor (TNF) alpha and platelet-derived growth factor (PDGF)-B, and concomitantly facilitated growth of sprout and buds, compared to the normal control. When choroidal explants were stimulated with CML-human serum albumin (HSA), its releasing effect was in the order VEGF>TNFalpha>PDGF-B. CML-HSA and CML-bovine serum albumin augmented the neovascularization in the cultured diabetic explant and their actions did not virtually differ. A monoclonal anti-CML antibody (6D12) inhibited the neovascularization in the advanced diabetes greater than that in the early diabetes. Inhibitory actions of anti-VEGF and anti-TNFalpha antibodies on the neovascularization were similar to that of the anti-CML antibody in the diabetes. In conclusion, CML adducts were accumulated and over-produced the actions of VEGF, TNFalpha and PDGF-B in the choroidal explant during diabetes in an age-dependent manner. TNFalpha and VEGF are likely to play a predominant role for the CML-induced choroidal neovascularization.     

Biological features of sporadic colorectal carcinoma with high-frequency microsatellite instability: special reference to tumor proliferation and apoptosis

Background We evaluated the relationship between biological behavior and microsatellite instability (MSI) status, with or without p53 status, in sporadic colorectal carcinoma.Methods MSI was analyzed with regard to biological features such as cellular proliferation and apoptotic cell death, in addition to clinicopathological features, in 87 patients with sporadic colorectal carcinoma.Results Fourteen (16.1%) of 87 tumors showed instability at two or more of the five loci examined (high-frequency MSI [MSI-H]). Four demonstrated instability at one locus (low-frequency MSI [MSI-L]), and 69 showed no instability (microsatellite-stable [MSS]). The MSI-H tumors tended to be located in the proximal colon and more often were mucinous carcinoma. The MSI-H tumors also tended to be in patients with multiple colorectal carcinomas and to demonstrate, rarely, an infiltrating growth pattern or venous invasion. The incidence of p53 protein overexpression in the MSI-H tumors was significantly lower than that in the MSI-L/MSS tumors (21% vs 54%). There was no significant difference in the proliferating-cell nuclear antigen (PCNA) labeling index (PI) or apoptotic index (AI) between the MSI-H and MSI-L/MSS tumors. The AI in the MSI-H tumors with p53 overexpression was significantly lower than that in the MSI-H tumors without p53 overexpression, and was also significantly lower than that in the MSI-L/MSS tumors with p53 overexpression. In the MSI-H tumors with p53 overexpression, no expression of BAX protein was found, and there was high expression of bcl-2 protein, resulting in a low BAX/bcl-2 ratio.Conclusion In sporadic colorectal carcinoma, an MSI-H tumor with p53 protein overexpression may display aggressive biological features.