Yasuhiro Murata

Gemcitabine-based chemoradiotherapy followed by surgery for borderline resectable and locally unresectable pancreatic ductal adenocarcinoma: significance of the CA19-9 reduction rate and intratumoral human equilibrative nucleoside transporter 1 expression.

Objectives This study aimed to evaluate the efficacy of gemcitabine-based chemoradiotherapy followed by surgery (gem-CRTS) for pancreatic ductal adenocarcinoma (PDAC) for borderline resectable (BR) and locally unresectable (UR) tumors. Methods One hundred patients with PDAC who underwent the gem-CRTS protocol were classified into 3 groups, namely, resectable (R; 14), BR (44), and UR (42). After chemoradiotherapy, the patients were reassessed for curative-intent resection. Results At reassessment, distant metastases became apparent in 27% of R patients, in 12% of BR patients, and in 18% of UR patients. The multivariate analysis of preoperative factors indicated that the CA19-9 reduction rate was an independent prognostic factor in the BR group. Among reassessed patients, the resection rate was 63.6% in R, 83.7% in BR, and 50.0% in UR patients. In 63 patients that underwent curative-intent resection, the 3-year survival rate was 83.3% in R, 33.0% in BR, and 7.8% in UR patients. Using multivariate analysis, the independent prognostic factor was found to be the surgical margin in BR patients and human equilibrative nucleoside transporter 1 expression in UR patients. Conclusions We consider that our gem-CRTS protocol, even for locally UR PDAC, allows for the identification of candidates for aggressive resection at the time of reassessment and improved prognosis in the patients with positive human equilibrative nucleoside transporter 1 expression.

Impact of histological response after neoadjuvant chemoradiotherapy on recurrence-free survival in UICC-T3 pancreatic adenocarcinoma but not in UICC-T4.

Objectives Although the prognostic benefit of neoadjuvant chemoradiotherapy (NCRT) against pancreatic cancer has been indicated by several reports, it is controversial whether histological response is associated with prognosis. The objective was to explore the relationship between histological response and prognosis in T3 and T4 pancreatic adenocarcinoma. Methods We histologically examined the resected specimens obtained from 58 patients (T3, n = 40; and T4, n = 18) for whom we performed curative-intent resection after NCRT. Histological response was evaluated according to Evans’s criteria to determine whether it influenced survival. Results In T3 tumors, 13 (32.5%) belonged to high responders (tumor destruction of >50%) (R0, n = 13) and 27 (67.5%) belonged to low responders (tumor destruction of ⩽50%) (R0, n = 22, R1, n = 3, R2, n = 2). Recurrence-free survival rate was significantly higher in high responders than in low responders (3-year recurrence-free survival rates: 71.3% vs 13.1%, P = 0.0095). In T4 tumors, however, only 1 (5.6%) was a high responder, and R0 resection was obtained only in 5 patients (27.8%). Conclusions In T3 tumors, histological response is considered a significant prognostic indicator, securing the surgical margin, whereas in T4 tumors, NCRT did not provide beneficial histological response, not securing the surgical margin.

Human Equilibrative Nucleoside Transporter 1 Expression in Endoscopic Ultrasonography-Guided Fine-Needle Aspiration Biopsy Samples Is a Strong Predictor of Clinical Response and Survival in the Patients With Pancreatic Ductal Adenocarcinoma Undergoing Gemcitabine-Based Chemoradiotherapy.

ObjectivesThis study aimed to clarify whether pretreatment human equilibrative nucleoside transporter (hENT1) expressions in endoscopic ultrasonography-guided fine-needle aspiration biopsy (EUS-FNAB) specimens obtained from resectable, borderline resectable, and locally advanced unresectable pancreatic ductal adenocarcinoma (PDAC) are concordant with those in the resected specimen after gemcitabine-based chemoradiotherapy (Gem-CRT) and to validate the utility of hENT1 expression using EUS-FNAB samples as a prognostic marker. MethodsWe evaluated the relationship between hENT1 expressions assessed by immunohistochemical staining and clinical outcomes in 51 of 76 patients with PDAC who were diagnosed by EUS-FNAB and received preoperative Gem-CRT. ResultsThe concordance rate of hENT1 expressions was 89.2% (K = 0.681). Median survival time (month) in the 51 whole patients and 37 patients with resection was significantly longer in hENT1 positive than in hENT1 negative: 25.0 and 30.0 versus 9.0 and 9.0, respectively. A multivariate analysis confirmed that hENT1 expression was an independent prognostic factor in both whole patients and those with resection. Regardless of T3 and T4, hENT1-positive patients with resection had significantly better prognosis than hENT1-negative patients, whose prognosis was similar to those without resection. ConclusionsThe assessment of hENT1 expression using EUS-FNAB samples before Gem-CRT provides important information on patients with PDAC who can benefit from curative-intent resection.

A New Surgical Technique of Pancreaticoduodenectomy with Splenic Artery Resection for Ductal Adenocarcinoma of the Pancreatic Head and/or Body Invading Splenic Artery: Impact of the Balance between Surgical Radicality and QOL to Avoid Total Pancreatectomy

For pancreatic ductal adenocarcinoma (PDAC) of the head and/or body invading the splenic artery (SA), we developed a new surgical technique of proximal subtotal pancreatectomy with splenic artery and vein resection, so-called pancreaticoduodenectomy with splenic artery resection (PD-SAR). We retrospectively reviewed a total of 84 patients with curative intent pancreaticoduodenectomy (PD) for PDAC of the head and/or body. These 84 patients were classified into the two groups: conventional PD (n = 66) and PD-SAR (n = 18). Most patients were treated by preoperative chemoradiotherapy (CRT). Postoperative MDCT clearly demonstrated enhancement of the remnant pancreas at 1 and 6 months in all patients examined. Overall survival rates were very similar between PD and PD-SAR (3-year OS: 23.7% versus 23.1%, P = 0.538), despite the fact that the tumor size and the percentages of UICC-T4 determined before treatment were higher in PD-SAR. Total daily insulin dose was significantly higher in PD-SAR than in PD at 1 month, while showing no significant differences between the two groups thereafter. PD-SAR with preoperative CRT seems to be promising surgical strategy for PDAC of head and/or body with invasion of the splenic artery, in regard to the balance between operative radicality and postoperative QOL.

Living Donor Liver Transplantation for the Patients With Portal Vein Thrombosis: Use of an Interpositional Venous Graft Passed Posteriorly to the Pancreatic Parenchyma Without Using Jump Graft

BACKGROUND It is difficult to reconstruct the portal vein (PV) using a long interpositional venous graft in living donor liver transplant (LDLT) patients with portal vein thrombosis (PVT), which involves the confluence of the superior mesenteric vein (SMV) and splenic vein (SV). We successfully performed LDLT for three patients with PVT using an interpositional vascular conduit passing posterior to the pancreas without a jump graft. METHODS Three of 130 patients who underwent LDLT in our hospital between March 2002 and June 2011 required this technique. After indentifying the location of the SMV, SV and gastrocolic trunk, we ligated and cut the posterior superior pancreaticoduodenal vein and other short branches from the PV. The PV was drawn inferiorly to the pancreas and transected at the confluence of SMV and SV. The external iliac vein or internal jugular vein was sacrificed as a graft for anastomosis to the cut end of the SMV using 6-0 polypropylene running sutures. Then the venous graft was drawn superiorly to the pancreas by passing it posterior to the pancreas parenchyma for anastomosis to the liver graft PV. The interpositional vein was placed posterior to the pancreas where the PV used to be. RESULTS All three patients displayed favorable postoperative courses with the Doppler ultrasound demonstrating good portal flow perioperatively. The postoperative portogram demonstrated patency of the vascular graft. CONCLUSION This method is easy and helpful to treat portal vein thrombosis, by providing the shortest route between the PV of the donor and the SMV of the recipient.

Clinicopathological factors affecting survival and recurrence after initial hepatectomy in non-B non-C hepatocellular carcinoma patients with comparison to hepatitis B or C virus.

We evaluated clinicopathological factors affecting survival and recurrence after initial hepatectomy in non-B non-C (NBNC) hepatocellular carcinoma (HCC) patients with comparison to hepatitis B or C virus, paying attention to relationship between alcohol consumption and histopathological findings. The medical records on the 201HCC patients who underwent initial hepatectomy between January 2000 and April 2013 were retrospectively reviewed. NBNC patients had higher prevalence of hypertension (47.4%), diabetes mellitus (35.5%), alcohol consumption (>20 g/day) (61.8%), and preserved liver function than hepatitis B or C patients. The 5-year survival rate of NBNC patients (74.1%) was significantly better than hepatitis B (49.1%) or C (65.0%) patients (NBNC versus B, P = 0.031). Among the NBNC patients, there was no relationship between alcohol consumption and clinicopathological findings including nonalcoholic fatty liver disease activity score (NAS). However, the 5-year OS and RFS rates in the alcohol-unrelated NBNC patients tend to be better than in the alcohol-related. By multivariate analysis, independent factors for OS in NBNC patients were Child-Pugh B/C, intrahepatic metastasis (im), and extrahepatic recurrence. NBNC patients, who were highly associated with lifestyle-related disease and preserved liver function, had significantly better prognosis compared to hepatitis B/C patients; however, there was no association between alcohol consumption and histopathological findings.

Comparative Study on the Cytoprotective Effects of Activated Protein C Treatment in Nonsteatotic and Steatotic Livers under Ischemia-Reperfusion Injury

Activated protein C (APC) has cytoprotective effects on liver ischemia-reperfusion injury (IRI). However, it is unclear whether APC is beneficial in steatotic liver IRI. We compared the cytoprotective effects of APC in nonsteatotic and steatotic liver IRI. Methods. Mice fed either normal diets (ND mice) or high fat diets (HF mice), were treated with APC or saline (control) and were performed 60 min partial IRI. Moreover, primary steatotic hepatocytes were either untreated or treated with APC and then incubated with H2O2. Results. APC significantly reduced serum transaminase levels and the inflammatory cells infiltration compared with control at 4 h in ND mice and at 24 h in HF mice. APC inhibited sinusoidal endothelial injury in ND mice, but not in HF mice. In contrast, APC activated adenosine monophosphate-activated protein kinase (AMPK) phosphorylation in HF mice, but not in ND mice. In the in vitro study, APC significantly increased AMPK phosphorylation, ATP concentration, and survival rates of hepatocytes compared with control. Conclusion. During IRI in normal liver, APC attenuated initial damage by inhibiting inflammatory cell infiltration and sinusoidal endothelial injury, but not in steatotic liver. However, in steatotic liver, APC might attenuate late damage via activation of AMPK.

Long-Term Influence of CYP3A5 Gene Polymorphism on Pharmacokinetics of Tacrolimus and Patient Outcome After Living Donor Liver Transplantation.

BACKGROUND We investigated a long-term association between donor/recipient CYP3A5 polymorphisms, pharmacokinetics of tacrolimus, and recipient outcomes in settings of living donor liver transplantation (LDLT). METHODS From February 2002 to November 2009, 67 couples of donor/recipients with tacrolimus administration, who could be genotyped for CYP3A5*3 and *1, were eligible in this study. We compared the dose-adjusted trough levels (C/D ratio) and dose/weight ratio of tacrolimus at 1 to 36 months postoperatively and recipient prognosis according to donor/recipient CYP3A5 polymorphisms; *1*1 in 7, *1*3 in 15, and *3*3 in 45, based on recipient genotype, and *1*1 in 1, *1*3 in 28, and *3*3 in 38, based on donor genotype. RESULTS On the basis of the data from C/D ratio and dose/weight ratio of tacrolimus, the recipients who had *1 allele and/or whose donor had *1allele required significantly high doses of tacrolimus with, compared with those without, all through 3 years after transplantation. These data allowed us to show the importance of not only recipient CYP3A5 polymorphisms but also donor polymorphisms to obtain the target tacrolimus blood concentration. The overall survival rates of the recipients with *1*1 (5-year survival rate: 28.6%) were significantly unfavorable, which might have been caused by over-immunosuppression, compared with those with *1*3 (5-year survival rate: 78.8%) and *3*3 genotype (5-year survival rate: 84.3%). CONCLUSIONS Immune suppressive therapy with the use of tacrolimus should be tailored on the basis of CYP3A5 genotype, which may reduce the adverse effects and improve graft outcome.

A Novel Predictor of Posttransplant Portal Hypertension in Adult-To-Adult Living Donor Liver Transplantation: Increased Estimated Spleen/Graft Volume Ratio.

Background In adult living donor liver transplantation (ALDLT), graft-to-recipient weight ratio of less than 0.8 is incomplete for predicting portal hypertension (>20 mm Hg) after reperfusion. We aimed to identify preoperative factors contributing to portal venous pressure (PVP) after reperfusion and to predict portal hypertension, focusing on spleen volume-to-graft volume ratio (SVGVR). Methods In 73 recipients with ALDLT between 2002 and 2013, first we analyzed survival according to PVP of 20 mm Hg as the threshold, evaluating the efficacy of splenectomy. Second, we evaluated various preoperative factors contributing to portal hypertension after reperfusion. Results All of the recipients with PVP greater than 20 mm Hg (n = 19) underwent PVP modulation by splenectomy, and their overall survival was favorable compared with 54 recipients who did not need splenectomy (PVP ⩽ 20 mm Hg). Graft-to-recipient weight ratio had no correlation with PVP. Multivariate analysis revealed that estimated graft and spleen volume were significant factors contributing to PVP after reperfusion (P < 0.0001 and P < 0.0001, respectively). Furthermore, estimated SVGVR showed a significant negative correlation to PVP after reperfusion (R = 0.652), and the best cutoff value for portal hypertension was 0.95. Conclusions In ALDLT, preoperative assessment of SVGVR is a good predictor of portal hypertension after reperfusion can be used to indicate the need for splenectomy before reperfusion.

Platelet Activation Assessed by Glycoprotein VI/Platelet Ratio Is Associated With Portal Vein Thrombosis After Hepatectomy and Splenectomy in Patients With Liver Cirrhosis

Portal vein thrombosis (PVT) is a serious complication after hepatobiliary-pancreatic surgery. Portal vein thrombosis often develops in patients with liver cirrhosis (LC) postoperatively, although they have low platelet counts. Platelet activation is one of the causes of thrombosis formation, and soluble form of glycoprotein VI (sGPVI) has received attention as a platelet activation marker. We had prospectively enrolled the 81 consecutive patients who underwent splenectomy (Sx) and/or hepatectomy: these patients were divided as Sx (n = 38) and hepatectomy (Hx, n = 46) groups. The 3 patients who underwent both procedures were added to both groups. Each group was subdivided into patients with non-LC and LC: non-LC-Sx (n = 22) and LC-Sx (n = 16), non-LC-Hx (n = 40) and LC-Hx (n = 6). The presence of PVT was diagnosed by using enhanced computed tomography (CT) scan. Platelet counts were significantly lower in LC-Sx than in non-LC-Sx, and incidence of PVT was significantly higher in LC-Sx than in non-LC-Sx (68.8% vs 31.8%, P = .024). Soluble form of glycoprotein VI /platelet ratios on preoperative day and postoperative day 1 were significantly higher in LC-Sx than in non-LC-Sx. Incidence of PVT was significantly higher in LC-Hx than in non-LC-Hx (50.0% vs 7.5%, P < .01). Soluble form of glycoprotein VI /platelet ratios were significantly higher in LC-Hx before and after Hx, compared to non-LC-Hx. Patients with LC stay in hypercoagulable state together with platelet activation before and after surgery. Under this circumstance, alteration of portal venous blood flow after Sx or Hx is likely to cause PVT in patients with LC.