Yasutsugu Takada

Randomized, multicenter trial comparing tacrolimus plus mycophenolate mofetil to tacrolimus plus steroids in hepatitis C virus–positive recipients of living donor liver transplantation

The purpose of this prospective, randomized, multicenter trial was to evaluate the effects of a steroid‐avoiding immunosuppression protocol on hepatitis C virus (HCV)–positive recipients of living donor liver transplantation (LDLT). Seventy‐five HCV‐positive LDLT recipients were included in this study, and they were randomized to receive tacrolimus (TAC) plus a corticosteroid (ST; n = 35) or TAC plus mycophenolate mofetil (MMF; n = 40). Biopsy‐proven acute rejection (BPAR) was treated with steroid pulse therapy in both groups. Protocol biopsy was performed 3, 6, and 12 months after LDLT and annually thereafter. Histological recurrence of HCV (fibrosis stage ≥ F1 according to the METAVIR score), BPAR resistant to 2 sets of steroid pulse therapy, hepatocellular carcinoma (HCC) recurrence, retransplantation, and patient death were defined as events, and the primary endpoint was event‐free survival. The median follow‐up was 55 months. The event‐free survival rates at 1, 3, and 5 years were 38.2%, 11.8%, and 5.9%, respectively, for the ST group and 25.0%, 17.5%, and 14.6%, respectively, for the MMF group (P = 0.45). The overall 5‐year patient survival rates were similar for the ST group (82.7%) and the MMF group (81.0%, P = 0.28). Steroid‐resistant BPAR occurred in only 1 patient from the MMF group. HCC recurrence occurred for 1 patient from the ST group and 2 patients from the MMF group. HCV recurrence rates with a fibrosis stage ≥ F1 1 and 3 years after LDLT were 59.4% and 85.9%, respectively, for the ST group and 74.2% and 81.9%, respectively, for the MMF group (P = 0.57). In conclusion, our steroid‐avoidance regimen had no apparent impact on LDLT outcomes for HCV‐positive recipients. Liver Transpl 19:896‐906, 2013.

Usefulness of the Kyoto criteria as selection criteria for living donor liver transplantation for hepatocellular carcinoma

With the advent of the Milan criteria (MC) for patient selection, deceased donor liver transplantation (DDLT) has been performed a large number of times, with excellent results, in Western transplantation centers for patients with hepatocellular carcinoma (HCC). In Eastern countries, the high incidence of HCC and the critical shortage of deceased organ donation have led to the rapid development of living donor liver transplantation (LDLT) for HCC patients. In both Western and Eastern transplantation centers, some expanded criteria based on tumor morphology have been proposed because the MC may be too restrictive. However, expansion of the criteria naturally carries a risk of increased posttransplant recurrence. Therefore, expanded criteria can be justified only if the criteria show acceptably low recurrence rates. In a retrospective analysis of 136 HCC patients who underwent LDLT at our institute between February 1999 and December 2006, we recently proposed new selection criteria (the Kyoto criteria) for LDLT in patients with HCC using a combination of the tumor number, the tumor size (based on pretransplant imaging using contrast-enhanced multidetector computed tomography), and a tumor marker: a tumor number 10, all tumors 5 cm in size, and a protein induced by vitamin K absence or antagonist-II (PIVKA-II) level 400 mAU/mL. The Kyoto criteria are a combination of 3 independent significant risk factors of recurrence, including a specific tumor marker of HCC. Patients with a PIVKA-II level > 400 mAU/mL showed a significantly higher incidence of positive microvascular invasion and a markedly higher incidence of poorly differentiated grade in comparison with patients with a PIVKA-II level 400 mAU/mL. Consequently, the Kyoto criteria could effectively exclude patients with biologically aggressive tumors before liver transplantation (LT) and promote an extremely low recurrence rate. However, the superiority of the Kyoto criteria to other expanded criteria is unclear. We therefore compared the overall survival and recurrence rates of the 136 HCC patients stratified by 6 representative selection criteria, including ours, to examine the usefulness of the Kyoto criteria. Table 1 shows the overall survival rates and recurrence rates after LT and the inclusion rates stratified by the respective criteria: the MC (a single tumor 5 cm in size or 3 or fewer tumors, each 3 cm in size), the Tokyo criteria (tumor number 5 and all tumors 5 cm in size), the Kyushu criteria (all tumors < 5 cm in size or PIVKA-II < 300 mAU/mL), the Up to 7 criteria (sum of the size of the largest tumor in centimeters and the number of tumors 7), and the University of California San Francisco criteria (a solitary tumor 6.5 cm in size or 3 or fewer nodules with the largest lesion 4.5 cm in size and a total tumor diameter 8 cm). The 1-, 3-, and 5-year overall survival rates and recurrence rates of patients who met the Kyoto criteria were superior to those of patients treated under other criteria. Similarly, those rates for patients beyond the Kyoto criteria were the worst in comparison with those of patients treated under other criteria, except for those of patients treated under the Kyushu criteria. In fact, the inclusion rate under the Kyoto criteria was 65.7%, whereas that under the Kyushu criteria was 95.6% (nearly 100%). In other words, the Kyoto criteria could most significantly stratify patient survival as well as recurrence rates with an appropriate inclusion rate. Because of the risks to the live donor as well as the higher perioperative morbidity and mortality of the recipient in LT in comparison with those in other treatment modalities for HCC, at least an 80% overall survival rate at 5 years after LDLT would be desirable. The findings of an 85.2% 5-year survival rate and a 2.9% 5-year recurrence rate in patients who met the Kyoto criteria demonstrate that the Kyoto criteria are excellent and acceptable new expanded criteria for LDLT for HCC. To investigate the validity of the expanded criteria in comparison with the MC, the prognosis of HCC patients beyond the MC should also be examined.

Impact of psoas muscle index on short-term outcome after living donor liver transplantation.

BACKGROUND/AIMSnLiving donor liver transplantation is an operation with high morbidity and mortality rates. The purpose of this study was to examine factors affecting the short-term outcome after living donor liver transplantation.nnnMATERIALS AND METHODSnForty-seven adult patients who underwent living donor liver transplantation from September 2001 to December 2014 were included. Short-term post-transplant outcomes were evaluated in terms of the onset of postoperative complications of grade 3a and above (Clavien-Dindo classification) and postoperative 120-day mortality. Univariate and multivariate analyses were used to determine possible predictive factors among perioperative variables such as preoperative psoas muscle index (PMI), blood laboratory test results, perioperative nutritional therapy, and operative factors.nnnRESULTSnLower PMI (lower than the first quartile of PMI of donors), higher blood urea nitrogen level (≥14 mg/dL), and blood type incompatibility were independent risk factors for the development of postoperative complications. The 120-day survival rates were significantly lower for the lower PMI group (n=30, 66.7%) than for the higher PMI group (n=17, 94.1%, p=0.034).nnnCONCLUSIONnA significant correlation was observed between preoperative PMI and short-term postoperative outcomes. Sarcopenia estimated by PMI may serve as a measure of patient frailty and a target for risk stratification.

Pathologic Assessment of Pancreatic Fibrosis for Objective Prediction of Pancreatic Fistula and Management of Prophylactic Drain Removal After Pancreaticoduodenectomy

BackgroundSoft pancreatic texture is a commonly accepted risk factor associated with pancreatic fistula (PF) after pancreaticoduodenectomy (PD). However, its evaluation is subjective and its predictive value is limited. The present study was performed to establish intraoperative PF prediction parameter: the pathological assessment of pancreatic fibrosis, which was an objective evaluation that was strongly related to pancreatic consistency.MethodsBased on the results of a retrospective investigation on grades of pancreatic fibrosis and PF occurrence in 51 consecutive patients, an algorithm for intraoperative selection of early prophylactic drain removal was established. Prophylactic drains of patients with pancreatic fibrosisxa0≥30xa0% in the frozen section of pancreatic stump were removed on postoperative day (POD) 4. As CRPxa0≥10xa0mg/dL on POD 4 was a strong risk factor for PF in patients with fibrosisxa0<30xa0%, the drains of these patients were maintained.ResultsThe algorithm was applied to 26 consecutive patients. Prophylactic drains were removed in 14 patients and retained in 12 patients on POD 4. No PF was observed in patients with pancreatic fibrosisxa0≥30xa0% (nxa0=xa08). Among six patients with fibrosisxa0<30xa0%, CRPxa0<10xa0mg/dL, and without infection in the drain fluid, only two developed grade A PF. All nine patients with pancreatic fibrosisxa0<30xa0% and CRPxa0≥10xa0mg/dL developed grade B PF. No grade C PF was observed in any group.ConclusionsThe pathological evaluation of pancreatic fibrosis could objectively predict PF occurrence. Intraoperative assessment of pancreatic fibrosis could be applied to tailor postoperative drain management after PD.

Significance of preoperative fluorodeoxyglucose-positron emission tomography in prediction of tumor recurrence after liver transplantation for hepatocellular carcinoma patients: a Japanese multicenter study

In the present study, we conducted a multicenter nationwide survey to investigate the effects of preoperative fluorine‐18‐fluorodeoxyglucose (FDG) positron emission tomography (PET) on the prediction of hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT).

A Truncated form of CD200 (CD200S) Expressed on Glioma Cells Prolonged Survival in a Rat Glioma Model by Induction of a Dendritic Cell-Like Phenotype in Tumor-Associated Macrophages.

CD200 induces immunosuppression in myeloid cells expressing its receptor CD200R, which may have consequences for tumor immunity. We found that human carcinoma tissues express not only full-length CD200 (CD200L) but also its truncated form, CD200S. Although CD200S is reported to antagonize the immunosuppressive actions of CD200L, the role of CD200S in tumor immunity has never been investigated. We established rat C6 glioma cell lines that expressed either CD200L or CD200S; the original C6 cell line did not express CD200 molecules. The cell lines showed no significant differences in growth. Upon transplantation into the neonatal Wistar rat forebrain parenchyma, rats transplanted with C6-CD200S cells survived for a significantly longer period than those transplanted with the original C6 and C6-CD200L cells. The C6-CD200S tumors were smaller than the C6-CD200L or C6-original tumors, and many apoptotic cells were found in the tumor cell aggregates. Tumor-associated macrophages (TAMs) in C6-CD200S tumors displayed dendritic cell (DC)-like morphology with multiple processes and CD86 expression. Furthermore, CD3+, CD4+ or CD8+ cells were more frequently found in C6-CD200S tumors, and the expression of DC markers, granzyme, and perforin was increased in C6-CD200S tumors. Isolated TAMs from original C6 tumors were co-cultured with C6-CD200S cells and showed increased expression of DC markers. These results suggest that CD200S activates TAMs to become DC-like antigen presenting cells, leading to the activation of CD8+ cytotoxic T lymphocytes, which induce apoptotic elimination of tumor cells. The findings on CD200S action may provide a novel therapeutic modality for the treatment of carcinomas.

Impact of human T-cell leukemia virus type 1 on living donor liver transplantation: a multi-center study in Japan

The natural history of human T‐cell leukemia virus type 1 (HTLV‐1), which causes adult T‐cell leukemia (ATL) or HTLV‐1 associated myelopathy, after liver transplantation is unclear.

Recovery After Critical Illness Polyneuropathy in a Patient With Orthotopic Liver Transplantation: A Case Report

After liver transplantation, some patients show neuromuscular abnormalities. A 43-year-old man with liver cirrhosis due to hepatitis C virus underwent living-donor liver transplantation. He developed severe neuromuscular dysfunction after sepsis, and acute respiratory distress syndrome. After the inflammatory reaction gradually improved, we observed bilateral weakness of the extremities and foot drop. Electrophysiological studies indicated primary axonal degeneration of peripheral motor and sensory fibers without inflammation. Critical illness polyneuropathy was diagnosed. During follow-up, complaints gradually recovered with rehabilitation by approximately 1 year later. Based on this case, we suggest that paralysis should be evaluated for critical illness polyneuropathy in patients with unexplained muscle weakness.

Living vs. deceased-donor liver transplantation for patients with hepatocellular carcinoma.

With the scarcity of deceased donor liver grafts, living donor liver transplantation (LDLT) is gaining popularity as an alternative to deceased donor liver transplantation (DDLT) for patients with hepatocellular carcinoma (HCC). However, as the evidence of cases of LDLT accumulates, several authors have reported higher HCC recurrence rates after LDLT. The suggested reasons for the higher recurrence rates following LDLT are related to the small-for-size graft in LDLT, surgical procedures that are specific to LDLT, and the fast-track to LDLT. Fast-tracking to LDLT may not allow sufficient time for evaluation of the biological aggressiveness of tumors, which may result in high recurrence rates due to inclusion of patients with more inherently aggressive tumors. Actually, some studies that reported higher recurrence rates with LDLT included a larger number of cases of HCC with microvascular invasion or poorly differentiated HCC. In order to exclude biologically aggressive HCC preoperatively, selection criteria incorporating tumor markers, such as alpha-fetoprotein (AFP) and des-gamma-carboxyprothrombin (DCP), as well as morphological tumor number and size have been proposed. With more reliable selection criteria incorporating biological markers to eliminate biologically aggressive HCC, LDLT can be a viable treatment option for patients with HCC, providing similar recurrence rates as those achieved with DDLT.

Localized 18F-fluorodeoxyglucose uptake at the pancreatic head during remission phase of autoimmune pancreatitis: A case report

Autoimmune pancreatitis (AIP) is a unique form of pancreatitis, histopathologically characterized by dense lymphoplasmacytic infiltration and fibrosis of the pancreas with obliterative phlebitis. AIP is associated with a good response to steroid therapy. Differentiation between AIP and pancreatic cancer to determine a preoperative diagnosis is often challenging, despite the use of various diagnostic modalities, including computed tomography (CT), magnetic resonance imaging and endoscopic retrograde cholangiopancreatography. It has been reported that 18F-fluorodeoxyglucose (18F-FDG)-positron emission tomography (PET)/CT may be a useful tool for distinguishing between the two diseases. In the present case report, a 71-year-old male patient presented with a well-circumscribed, solitary, nodular and homogenous 18F-FDG uptake at the pancreatic head, while receiving maintenance steroid therapy in the remission phase of AIP; preoperatively, the patient had been strongly suspected of having pancreatic cancer. Pathological examination revealed post-treatment relapse of AIP. The present case highlights the diagnostic and management difficulties with AIP in the remission phase. In certain cases, it remains challenging to differentiate the two diseases, even using the latest modalities.