Yuji Nimura

Two hundred forty consecutive portal vein embolizations before extended hepatectomy for biliary cancer: surgical outcome and long-term follow-up.

Objective:To assess clinical benefit of portal vein embolization (PVE) before extended, complex hepatectomy for biliary cancer. Summary Background Data:Many investigators have addressed clinical utility of PVE before simple hepatectomy for metastatic liver cancer or hepatocellular carcinoma, but few have reported PVE before hepatectomy for biliary cancer due to the limited number of surgical cases. Methods:This study involved 240 consecutive patients with biliary cancer (150 cholangiocarcinomas and 90 gallbladder cancers) who underwent PVE before an extended hepatectomy (right or left trisectionectomy or right hepatectomy). All PVEs were performed by the “ipsilateral approach” 2 to 3 weeks before surgery. Hepatic volume and function changes after PVE were analyzed, and the outcome also was reviewed. Results:There were no procedure-related complications requiring blood transfusion or interventions. Of the 240 patients, 47 (19.6%) did not undergo subsequent hepatectomy. The incidence of unresectability was higher in gallbladder cancer than in cholangiocarcinoma (32.2% versus 12.0%, P < 0.005). The remaining 193 patients (132 cholangiocarcinomas and 61 gallbladder cancers) underwent hepatectomy with resection of the caudate lobe and extrahepatic bile duct (n = 187), pancreatoduodenectomy (n = 42), and/or portal vein resection (n = 63). Seventeen (8.8%) patients died of postoperative complications: mortality was higher in gallbladder cancer than in cholangiocarcinoma (18.0% versus 4.5%, P < 0.05); and it was also higher in patients whose indocyanine green clearance (KICG) of the future liver remnant after PVE was <0.05 than those whose index was ≥0.05 (28.6% versus 5.5%, P < 0.001). The 3- and 5-year survival after hepatectomy was 41.7% and 26.8% in cholangiocarcinoma and 25.3% and 17.1% in gallbladder cancer, respectively (P = 0.011). In 136 other patients with cholangiocarcinoma who underwent a less than 50% resection of the liver without PVE, a mortality of 3.7% and a 5-year survival of 27.6% were observed, which was similar to the 132 patients with cholangiocarcinoma who underwent extended hepatectomy after PVE. Conclusions:PVE has the potential benefit for patients with advanced biliary cancer who are to undergo extended, complex hepatectomy. Along with the use of PVE, further improvements in surgical techniques and refinements in perioperative management are necessary to make difficult hepatobiliary resections safer.

Apoptosis induction by antisense oligonucleotides against miR-17-5p and miR-20a in lung cancers overexpressing miR-17-92.

Amplification and overexpression of the miR-17-92 microRNAs (miRNA) cluster at 13q31.3 has recently reported, with pointers to functional involvement in the development of B-cell lymphomas and lung cancers. In the present study, we show that inhibition of miR-17-5p and miR-20a with antisense oligonucleotides (ONs) can induce apoptosis selectively in lung cancer cells overexpressing miR-17-92, suggesting the possibility of ‘OncomiR addiction’ to expression of these miRNAs in a subset of lung cancers. In marked contrast, antisense ONs against miR-18a and miR-19a did not exhibit such inhibitory effects, whereas inhibition of miR-92-1 resulted in only modest reduction of cell growth, showing significant distinctions among miRNAs of the miR-17-92 cluster in terms of their roles in cancer cell growth. During the course of this study, we also found that enforced expression of a genomic region, termed C2, residing 3′ to miR-17-92 in the intron 3 of C13orf25 led to marked growth inhibition in association with double stranded RNA-dependent protein kinase activation. Finally, this study also revealed that the vast majority of C13orf25 transcripts are detected as Drosha-processed cleavage products on Northern blot analysis and that a novel polyadenylation site is present 3′ to the miR-17-92 cluster and 5′ to the C2 region. Taken together, the present findings contribute towards better understanding of the oncogenic roles of miR-17-92, which might ultimately lead to the future translation into clinical applications.

Perioperative Synbiotic Treatment to Prevent Postoperative Infectious Complications in Biliary Cancer Surgery A Randomized Controlled Trial

Summary Background Data:Use of synbiotics has been reported to benefit human health, but clinical value in surgical patients remains unclear. Objective:To investigate the effect of perioperative oral administration of synbiotics upon intestinal barrier function, immune responses, systemic inflammatory responses, microflora, and surgical outcome in patients undergoing high-risk hepatobiliary resection. Methods:Patients with biliary cancer involving the hepatic hilus (n = 101) were randomized before hepatectomy, into a group receiving postoperative enteral feeding with synbiotics (group A); or another receiving preoperative plus postoperative synbiotics (group B). Lactulose-mannitol (L/M) ratio, serum diamine oxidase (DAO) activity, natural killer (NK) cell activity, interleukin-6 (IL-6), fecal microflora, and fecal organic acid concentrations were determined before and after hepatectomy. Postoperative infectious complications were recorded. Results:Of 101 patients, 81 completed the trial. Preoperative and postoperative changes in L/M ratio and DAO activity were similar between groups. Preoperatively in group B, NK activity, and lymphocyte counts increased, while IL-6 decreased significantly (P < 0.05). Postoperative serum IL-6, white blood cell counts, and C-reactive protein in group B were significantly lower than in group A (P < 0.05). During the preoperative period, numbers of Bifidobacterium colonies cultured from and total organic acid concentrations measured in feces increased significantly in group B (P < 0.05). Postoperative concentrations of total organic acids and acetic acid in feces were significantly higher in group B than in group A (P < 0.05). Incidence of postoperative infectious complications was 30.0% (12 of 40) in group A and 12.1% (5 of 41) in group B (P < 0.05). Conclusions:Preoperative oral administration of synbiotics can enhance immune responses, attenuate systemic postoperative inflammatory responses, and improve intestinal microbial environment. These beneficial effects likely reduce postoperative infectious complications after hepatobiliary resection for biliary tract cancer.

“Anatomic” Right Hepatic Trisectionectomy (Extended Right Hepatectomy) With Caudate Lobectomy for Hilar Cholangiocarcinoma

Background:The techniques of right hepatic trisectionectomy are now standardized in patients with hepatocellular or metastatic carcinoma, but not in those with hilar cholangiocarcinoma. Methods:Under preoperative diagnosis of hilar cholangiocarcinoma, 8 patients underwent “anatomic” right hepatic trisectionectomy with en bloc resection of the caudate lobe and the extrahepatic bile duct, in which the bile ducts of the left lateral section were divided at the left side of the umbilical fissure following complete dissection of the umbilical plate. Results:Liver resection was successfully performed, and all patients were discharged from the hospital in good condition, giving a mortality of 0%. All patients were histologically diagnosed as having cholangiocarcinoma. The proximal resection margins were cancer-negative in 7 patients and cancer-positive in 1 patient. Four patients with multiple lymph node metastases died of cancer recurrence within 3 years after hepatectomy. One patient died of liver failure without recurrence 42 months after hepatectomy. The remaining 3 patients without lymph node metastasis are now alive after more than 5 years. Conclusions:Anatomic right hepatic trisectionectomy with caudate lobectomy can produce a longer proximal resection margin and can offer a better chance of long-term survival in some selected patients with advanced hilar cholangiocarcinoma.

Nek2 as an Effective Target for Inhibition of Tumorigenic Growth and Peritoneal Dissemination of Cholangiocarcinoma

We investigated the role of Nek2, a member of the serine/threonine kinase family, Nek, in the tumorigenic growth of cholangiocarcinoma cells. Expression of Nek2 is elevated in cholangiocarcinoma in a tumor-specific manner as compared with that of normal fibroblast cells. Expression of exogenous Nek2 did not perturb the growth of cholangiocarcinoma cells, whereas suppression of the Nek2 expression with siRNA resulted in the inhibition of cell proliferation and induced cell death. In xenograft-nude mouse model, s.c. injection of Nek2 siRNA around the tumor nodules resulted in reduction of tumor size as compared with those of control siRNA injection. In peritoneal dissemination model, Nek2 siRNA-treated mice showed statistically longer survival periods in comparison with those of the control siRNA-treated mice. Taken together, our data indicate a pivotal role of Nek2 in tumorigenic growth of cholangiocarcinoma.

Methods and timing of biliary drainage for acute cholangitis: Tokyo Guidelines

Biliary drainage is a radical method to relieve cholestasis, a cause of acute cholangitis, and takes a central part in the treatment of acute cholangitis. Emergent drainage is essential for severe cases, whereas patients with moderate and mild disease should also receive drainage as soon as possible if they do not respond to conservative treatment, and their condition has not improved. Biliary drainage can be achieved via three different routes/procedures: endoscopic, percutaneous transhepatic, and open methods. The clinical value of both endoscopic and percutaneous transhepatic drainage is well known. Endoscopic drainage is associated with a low morbidity rate and shorter duration of hospitalization; therefore, this approach is advocated whenever it is applicable. In endoscopic drainage, either endoscopic nasobiliary drainage (ENBD) or tube stent placement can be used. There is no significant difference in the success rate, effectiveness, and morbidity between the two procedures. The decision to perform endoscopic sphincterotomy (EST) is made based on the patient’s condition and the number and diameter of common bile duct stones. Open drainage, on the other hand, should be applied only in patients for whom endoscopic or percutaneous transhepatic drainage is contraindicated or has not been successfully performed. Cholecystectomy is recommended in patients with gallbladder stones, following the resolution of acute cholangitis with medical treatment, unless the patient has poor operative risk factors or declines surgery.

Intrahepatic cholangiojejunostomy following hepatobiliary resection.

Although intrahepatic cholangiojejunostomy is technically difficult, with recent improvements in surgery it should be possible to perform the anastomosis safely. The aim of this study was to evaluate the incidence of anastomotic leak after intrahepatic cholangiojejunostomy and to identify risk factors for such leakage.

Immunohistochemically Demonstrated Lymph Node Micrometastasis and Prognosis in Patients With Gallbladder Carcinoma

Objective:To investigate whether immunohistochemically demonstrated lymph node micrometastasis has a survival impact in patients with advanced gallbladder carcinoma (pT2–4 tumors). Summary Background Data:The clinical significance of immunohistochemically detected lymph node micrometastasis recently has been evaluated in various tumors. However, few reports have addressed this issue with regard to gallbladder carcinoma. Methods:A total of 1476 lymph nodes from 67 patients with gallbladder carcinoma (pN0, n = 40; pN1, n = 27) who underwent curative resection were immunostained with monoclonal antibody against cytokeratins 8 and 18. The results were correlated with clinical and pathologic features and with patient survival. Results:Lymph node micrometastases were detected immunohistochemically in 23 (34.3%) of the 67 patients and in 37 (2.5%) of the 1476 nodes examined. Of the 37 nodal micrometastases, 21 (56.8%) were single-cell events, and the remaining 16 were clusters. Five micrometastases were detected in the paraaortic nodes. Clinicopathologic features showed no significant associations with the presence of lymph node micrometastases. Survival was worse in the 27 patients with pN1 disease than in the 40 with pN0 disease (5-year survival; 22.2% vs. 52.6%, P = 0.0038). Similarly, survival was worse in the 23 patients with micrometastasis than in the 44 without micrometastasis (5-year survival; 17.4% vs. 52.7%, P = 0.0027). Twenty-eight patients without any lymph node involvement had the best prognosis, whereas survival for the 11 patients with both types of metastasis was dismal. The grade of micrometastasis (single-cell or cluster) had no effect on survival. The Cox proportional hazard model identified perineural invasion, lymph node micrometastasis, and microscopic venous invasion as significant independent prognostic factors. Conclusions:Lymph node micrometastasis has a significant survival impact in patients with pN0 or pN1 gallbladder carcinoma who underwent macroscopically curative resection. Extensive lymph node sectioning with keratin immunostaining is recommended for accurate prognostic evaluation for patients with gallbladder carcinoma.

Value of Multidetector-row Computed Tomography in Diagnosis of Portal Vein Invasion by Perihilar Cholangiocarcinoma

BackgroundAlthough knowledge of cancer invasion of the portal bifurcation is vitally important in planning an operation for perihilar cholangiocarcinoma, the diagnostic capability of multidetector-row computed tomography (MDCT) for this purpose has not been assessed. We evaluated how well MDCT could identify cancer invasion of the portal bifurcation by perihilar cholangiocarcinoma.MethodsBetween April 2003 and June 2005, perihilar cholangiocarcinoma was resected in 87 patients, 83 of whom underwent MDCT within 1xa0month before the surgery. Three-dimensional volume-rendered (3DVR) and multiplanar reformation (MPR) images were examined for evidence of portal vein invasion. Agreement with intraoperative and pathologic findings was assessed. Portal bifurcation findings by 3DVR and MPR were classified into no portal vein stenosis, unilateral stenosis, or more extensive stenosis, and also into tumor contact with the bifurcation in no, one of two, or two projections.ResultsFor macroscopic portal vein invasion, sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy were 81.5, 91.1, 81.5, 91.1, and 88.0% in 3D portography and 96.3, 92.6, 86.7, 98.1, and 94.0% in MPR, respectively. Findings by both 3DVR and MPR were significantly correlated with depth of cancer invasion (pxa0<xa00.001).ConclusionMDCT is useful in assessing cancer invasion of the portal vein bifurcation by perihilar cholangiocarcinoma.

Pancreatic and duodenal invasion in distal bile duct cancer: paradox in the tumor classification of the American Joint Committee on Cancer.

BackgroundDistal bile duct cancer often invades the pancreas and/or duodenum. Invasion of the pancreas is defined as a T3 and that of the duodenum as a T4 tumor in the T classification of the American Joint Committee on Cancer (AJCC). The aim of this study was to assess whether this T classification is rational from the viewpoint of prognostic power.MethodNinety-five patients with distal bile duct cancer were retrospectively analyzed according to the current T classification of the AJCC.ResultsThe main determinant of pT3 (n = 32) and pT4 (n = 30) was pancreatic and duodenal invasion, respectively, and the survival rates for patients with pT3 and pT4 are similar (p = 0.595). Duodenal invasion was present in 39% of the patients with pancreatic invasion, whereas pancreatic invasion was observed in 86% of those with duodenal invasion. The survival for patients with pancreatic invasion was not significantly different (p = 0.283) whether or not there was concomitant duodenal invasion (n = 19 and n = 37, respectively). Multivariate analysis identified venous invasion, distant metastasis, histologic grade, and pancreatic invasion as independent prognostic factors.ConclusionAlthough duodenal invasion usually occurs after pancreatic invasion, it is not a significant prognostic factor while pancreatic invasion is. The current T classification should be revised since it expresses tumor extension but does not reflect a survival in distal bile duct cancer.