Katsuhiko Uesaka

Hepatectomy with portal vein resection for hilar cholangiocarcinoma: audit of 52 consecutive cases.

Objective: To better determine the role of portal vein resection and its effect on survival, as well as to appreciate the impact of portal vein invasion on prognosis in hilar cholangiocarcinoma. Summary Background Data: Hepatectomy with portal vein resection is sometimes performed for locally advanced hilar cholangiocarcinoma. However, the significance of microscopic invasion of the portal vein has not been determined. Methods: Medical records of 160 patients with hilar cholangiocarcinoma who underwent macroscopically curative hepatectomy with (n = 52) or without portal vein resection (n = 108) were reviewed. Invasion of the portal vein was assessed histologically on the surgical specimen, and results were correlated with clinicopathologic features and survival. Results: Surgical mortality, including all hospital deaths, was similar in patients who did and did not undergo portal vein resection (9.6% vs. 9.3%), but the primary tumor was more advanced in patients who underwent portal vein resection. Histologically, no invasion was found in 16 (30.8%) of resected portal veins. However, dense fibrosis adjacent to the portal vein was common, and the mean distance between the leading edge of cancer cells and the adventitia of the portal vein was 437 ± 431 &mgr;m. The prognosis was worse in patients with than without portal vein resection (5-year survival, 9.9% vs. 36.8%; P < 0.0001). The presence or absence of microscopic invasion of the resected portal vein did not influence survival (16.6 months in patients with microscopic invasion vs. 19.4 months in those without; P = 0.1506). Multivariate analysis identified histologic differentiation, lymph node metastasis, and macroscopic portal vein invasion as independent prognostic factors. Conclusions: Microscopic invasion of the portal vein may be misdiagnosed clinically in patients with hilar cholangiocarcinoma. However, the distance between tumor and adventitia is so narrow that curative resection without portal vein resection is unlikely to be possible. Gross portal vein invasion has a negative impact on survival, and hepatectomy with portal vein resection can offer long-term survival in some patients with advanced hilar cholangiocarcinoma.

Lymph Node Metastasis from Hilar Cholangiocarcinoma: Audit of 110 Patients Who Underwent Regional and Paraaortic Node Dissection

ObjectiveTo assess the status of the regional and paraaortic lymph nodes in hilar cholangiocarcinoma and to clarify the efficacy of systematic extended lymphadenectomy. Summary Background DataThere have been no studies in which regional and paraaortic lymphadenectomies for hilar cholangiocarcinoma have been routinely performed. Therefore, the metastasis rates to the regional and paraaortic nodes, the mode of lymphatic spread, and the effect of extended lymph node dissection on survival remain unknown. MethodsThis study involved 110 patients who underwent surgical resection for hilar cholangiocarcinoma with lymph node dissection including both the regional and paraaortic nodes. A total of 2,652 nodes retrieved from the surgical specimens were examined microscopically. ResultsOf the 110 patients, 52 (47.3%) had no involved nodes, 39 (35.5%) had regional lymph node metastases, and 19 (17.3%) had regional and paraaortic node metastases. The incidence of positive nodes was significantly higher in the patients with pT3 disease than in those with pT2 disease. The pericholedochal nodes were most commonly involved (42.7%), followed by the periportal nodes (30.9%), the common hepatic nodes (27.3%), and the posterior pancreaticoduodenal nodes (14.5%). The celiac and superior mesenteric nodes were rarely involved. The 3-year and 5-year survival rates were 55.4% and 30.5% for the 52 patients without involved nodes, 31.8% and 14.7% for the 39 patients with regional node metastases, and 12.3% and 12.3% for the 19 patients with paraaortic node metastases, respectively. Of the 19 patients with positive paraaortic nodes, 7 had no macroscopic evidence of paraaortic disease on intraoperative inspection. The survival in this group was significantly better than in the remaining 12 patients. ConclusionThe paraaortic nodes and the regional nodes are frequently involved in advanced hilar cholangiocarcinoma. Whether extended lymph node dissection provides a survival benefit requires further study. However, the fact that long-term survival is possible despite pN2 or pM1 disease encourages the authors to perform an aggressive surgical procedure with extended lymph node dissection in selected patients with hilar cholangiocarcinoma.

Management of Hilar Cholangiocarcinoma: Comparison of an American and a Japanese Experience

ObjectiveTo compare the experience and outcome in the management of hilar cholangiocarcinoma at one American and one Japanese medical center. Summary Background DataControversies surround the issues of extent of resection for hilar cholangiocarcinoma and whether the histopathology of such cancers are similar between patients treated in America and in Japan. MethodsRecords were reviewed of 100 patients treated between 1980 and 1995 at the Lahey Clinic in the United States, and of 155 patients treated between 1977 and 1995 at Nagoya University Hospital in Japan. Selected pathologic slides of resected cancers were exchanged between the two institutions and reviewed for diagnostic concordance. ResultsIn the Lahey cohort, there were 25 resections, 53 cases of surgical exploration with biliary bypass or intubation, and 22 cases of percutaneous transhepatic biliary drainage or endoscopic biliary drainage without surgery. In the Nagoya cohort, the respective figures were 122, 10, and 23. The overall 5-year survival rate of all patients treated (surgical and nonsurgical) during the study periods was 7% in the Lahey cohort and 16% in the Nagoya cohort. The overall 10-year survival rates were 0% and 12%, respectively. In patients who underwent resection with negative margins, the 5- and 10-year survival rates were 43% and 0% for the Lahey cohort and 25% and 18% for the Nagoya cohort. The surgical death rate for patients undergoing resection was 4% for Lahey patients and 8% for Nagoya patients. Of the patients who underwent resection, en bloc caudate lobectomy was performed in 8% of the Lahey patients and 89% of the Nagoya patients. Histopathologic examination of resected cancers showed that the Nagoya patients had a higher stage of disease than the Lahey patients. ConclusionsIn both Lahey and Nagoya patients, survival was most favorable when resection of hilar cholangiocarcinoma was accomplished with margin-negative resections. Combined bile duct and liver resection with caudate lobectomy contributed to a higher margin-negative resection rate in the Nagoya cohort.

The pattern of infiltration at the proximal border of hilar bile duct carcinoma. A histologic analysis of 62 resected cases

OBJECTIVE To clarify the importance of different patterns of infiltration at the proximal border of hilar bile duct carcinomas. SUMMARY BACKGROUND DATA There are few detailed pathologic studies on the proximal resection margins in patients with hilar bile duct carcinoma. METHODS Serial sections of 62 specimens of resected hilar bile duct carcinoma were examined histologically to determine the involved layers and routes of invasion at the proximal border. The degree of cancer extension was determined, and the relation between the length of the tumor-free resection margin and postoperative anastomotic recurrences was analyzed. RESULTS Mucosal extension was predominant in papillary and nodular tumors, but submucosal extension was predominant in diffusely infiltrating and nodular-infiltrating tumors. Submucosal extension usually consisted of direct or lymphatic invasion. The mean length of submucosal extension was 6.0 mm. Superficial spread of cancer, defined as mucosal extension of more than 20 mm from the main lesion, was seen in 8 specimens. No patient had an anastomotic recurrence when the tumor-free resection margin was greater than 5 mm. CONCLUSIONS The pattern of infiltration at the proximal border of resected hilar bile duct carcinomas is closely related to the gross tumor type. The length of submucosal extension is usually less than 10 mm. Superficial spread of cancer is seen in more than 10% of cases. A tumor-free proximal resection margin of 5 mm appears to be adequate in hilar bile duct carcinoma.

Right or left trisegment portal vein embolization before hepatic trisegmentectomy for hilar bile duct carcinoma.

BACKGROUND Percutaneous transhepatic embolization of the right portal vein plus the left medial portal branch (R3-PE) and the left portal vein plus the right anterior portal branch (L3-PE) is not well described. METHODS Four patients with far advanced carcinoma of the hepatic hilus underwent R3-PE (n = 1) or L3-PE (n = 3) as preoperative management for right hepatic trisegmentectomy or left hepatic trisegmentectomy. The portal vein embolization was performed with the ipsilateral approach through the right anterior portal branch. RESULTS In all patients the embolizations were successful without complications. Volumetric study with computed tomography showed sufficient hypertrophy of the nonembolized hepatic segments. Three of the four patients eventually underwent trisegmentectomy. The postoperative courses in two of the patients were uneventful. The remaining patient suffered from posthepatectomy liver failure but recovered. CONCLUSIONS R3-PE or L3-PE is advisable as preoperative management for trisegmentectomy and appears effective for increasing the safety of the operation. This embolization is achievable only through the ipsilateral approach.

Changes in hepatic lobar function after right portal vein embolization. An appraisal by biliary indocyanine green excretion.

OBJECTIVE The changes in the functional capacity of the hepatic lobe after right portal vein embolization (RPE) were investigated in patients with complete obstruction of the hepatic hilus who had undergone multiple percutaneous transhepatic biliary drainage catheterizations. METHODS After injection of 0.5 mg/kg of indocyanine green (ICG), bile draining from each hepatic lobe was collected separately for 6 hours. Biliary ICG excretion in each hepatic lobe was estimated and compared with hepatic lobar volume measured by computed tomographic volumetry before and an average of 11 days after RPE. RESULTS Right portal vein embolization produced a significant increase in bile volume and biliary ICG concentration in the left lobe, resulting in a significant increase in ICG excretion in the left lobe. The percentage of ICG excretion in the left lobe to the whole-liver excretion showed a mean increase of 20.1%, which was statistically significant. In contrast, the percentage of left lobar volume to the total liver volume increased by only 8.3%. CONCLUSIONS Measurement of biliary ICG excretion is useful for estimating changes of hepatic lobar function and has revealed that within 11 days RPE enhances functional capacity in the left lobe compared with volume gain without affecting total liver function.

Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: a phase 3, open-label, randomised, non-inferiority trial (JASPAC 01)

BACKGROUND Although adjuvant chemotherapy with gemcitabine is standard care for resected pancreatic cancer, S-1 has shown non-inferiority to gemcitabine for advanced disease. We aimed to investigate the non-inferiority of S-1 to gemcitabine as adjuvant chemotherapy for pancreatic cancer in terms of overall survival. METHODS We did a randomised, open-label, multicentre, non-inferiority phase 3 trial undertaken at 33 hospitals in Japan. Patients who had histologically proven invasive ductal carcinoma of the pancreas, pathologically documented stage I-III, and no local residual or microscopic residual tumour, and were aged 20 years or older were eligible. Patients with resected pancreatic cancer were randomly assigned (in a 1:1 ratio) to receive gemcitabine (1000 mg/m(2), intravenously administered on days 1, 8, and 15, every 4 weeks [one cycle], for up to six cycles) or S-1 (40 mg, 50 mg, or 60 mg according to body-surface area, orally administered twice a day for 28 days followed by a 14 day rest, every 6 weeks [one cycle], for up to four cycles) at the data centre by a modified minimisation method, balancing residual tumour status, nodal status, and institutions. The primary outcome was overall survival in the two treatment groups, assessed in the per-protocol population, excluding ineligible patients and those not receiving the allocated treatment. The protocol prespecified that the superiority of S-1 with respect to overall survival was also to be assessed in the per-protocol population by a log-rank test, if the non-inferiority of S-1 was verified. We estimated overall and relapse-free survival using the Kaplan-Meier methods, and assessed non-inferiority of S-1 to gemcitabine using the Cox proportional hazard model. The expected hazard ratio (HR) for mortality was 0.87 with a non-inferiority margin of 1.25 (power 80%; one-sided type I error 2.5%). This trial is registered at UMIN CTR (UMIN000000655). FINDINGS 385 patients were randomly assigned to treatment between April 11, 2007, and June 29, 2010 (193 to the gemcitabine group and 192 to the S-1 group). Of these, three were exlcuded because of ineligibility and five did not receive chemotherapy. The per-protocol population therefore consisted of 190 patients in the gemcitabine group and 187 patients in the S-1 group. On Sept 15, 2012, following the recommendation from the independent data and safety monitoring committee, this study was discontinued because the prespecified criteria for early discontinuation were met at the interim analysis for efficacy, when all the protocol treatments had been finished. Analysis with the follow-up data on Jan 15, 2016, showed HR of mortality was 0.57 (95% CI 0.44-0.72, pnon-inferiority<0.0001, p<0.0001 for superiority), associated with 5-year overall survival of 24.4% (18.6-30.8) in the gemcitabine group and 44.1% (36.9-51.1) in the S-1 group. Grade 3 or 4 leucopenia, neutropenia, aspartate aminotransferase, and alanine aminotransferase were observed more frequently in the gemcitabine group, whereas stomatitis and diarrhoea were more frequently experienced in the S-1 group. INTERPRETATION Adjuvant chemotherapy with S-1 can be a new standard care for resected pancreatic cancer in Japanese patients. These results should be assessed in non-Asian patients. FUNDING Pharma Valley Center, Shizuoka Industrial Foundation, Taiho Pharmaceutical.

Phase I Trial of a Glypican-3–Derived Peptide Vaccine for Advanced Hepatocellular Carcinoma: Immunologic Evidence and Potential for Improving Overall Survival

Purpose: The carcinoembryonic antigen glypican-3 (GPC3) is an ideal target of anticancer immunotherapy against hepatocellular carcinoma (HCC). In this nonrandomized, open-label, phase I clinical trial, we analyzed the safety and efficacy of GPC3 peptide vaccination in patients with advanced HCC. Experimental Design: Thirty-three patients with advanced HCC underwent GPC3 peptide vaccination (intradermal injections on days 1, 15, and 29 with dose escalation). The primary endpoint was the safety of GPC3 peptide vaccination. The secondary endpoints were immune response, as measured by IFN-γ ELISPOT assay, and the clinical outcomes tumor response, time to tumor progression, and overall survival (OS). Results: GPC3 vaccination was well-tolerated. One patient showed a partial response, and 19 patients showed stable disease 2 months after initiation of treatment. Four of the 19 patients with stable disease had tumor necrosis or regression that did not meet the criteria for a partial response. Levels of the tumor markers α-fetoprotein and/or des-γ-carboxy prothrombin temporarily decreased in nine patients. The GPC3 peptide vaccine induced a GPC3-specific CTL response in 30 patients. Furthermore, GPC3-specific CTL frequency after vaccination correlated with OS. OS was significantly longer in patients with high GPC3-specific CTL frequencies (N = 15) than in those with low frequencies (N = 18; P = 0.033). Conclusions: GPC3-derived peptide vaccination was well-tolerated, and measurable immune responses and antitumor efficacy were noted. This is the first study to show that peptide-specific CTL frequency can be a predictive marker of OS in patients with HCC receiving peptide vaccination. Clin Cancer Res; 18(13); 3686–96. ©2012 AACR.

Complications of Hepatectomy for Hilar Cholangiocarcinoma

Abstract. We retrospectively reviewed postoperative complications in 105 patients with hilar cholangiocarcinoma who underwent hepatectomy at Nagoya University Hospital from January 1990 through March 1999. Of the 105 subjects, 97 (92.4%) underwent resection of two or more Healeys segments of the liver. Combined portal vein resection was performed in 33 (31.4%) patients and pancreatoduodenectomy in 10 (9.5%). Twenty (19.0%) patients had no postoperative complications, another 39 (37.1%) patients had minor complication(s) only, and the remaining 46 (43.8%) developed major complication(s). The morbidity rate reached as high as 81.0%. Major complications required relaparotomy in 11 (10.5%) patients. Of the 46 patients with major complication(s) 36 recovered; the remaining 10 patients died of liver failure with other organ failure(s) or of intraabdominal bleeding 12, 14, 18, 21, 57, 75, 75, 87, 93, or 134 days after surgery. Thus the 30-day mortality was 3.8% and the overall mortality 9.5%. Pleural effusion was the most frequent complication found in 66 (62.9%) patients, followed by wound sepsis in 39 (37.1%), and then liver failure in 29 (27.6%). Liver failure developed in 16.7% of 48 patients with less than 50% liver resection and in 36.8% of 57 patients with 50% or more resection (P < 0.05). Other organ failures, including renal, respiratory, gastrointestinal, and hematologic failures, developed as a sign of multiple organ failure following liver failure in most patients or preceding liver failure in a few patients. None of the six patients with four or more organ failures survived. Hepatectomy for hilar cholangiocarcinoma is risky owing to impaired hepatic functional reserve in jaundiced patients and the technical difficulty associated with hepatobiliary resection. Our goal is to reduce mortality to less than 5% while keeping a high resectability rate (above 80%).

A new macroscopic classification predicts prognosis for patient with liver metastases from colorectal cancer.

OBJECTIVE The authors defined a new macroscopic classification of liver metastases from colorectal cancer. SUMMARY BACKGROUND DATA There were different prognostic results after the same operative procedure for liver metastases with similar background factors. METHODS Eighty-one resected liver metastases were classified into simple nodular (SN) or confluent nodular (CN) types according to the characteristics of the cut surface of the tumor. RESULTS The 5-year survival rates after hepatectomy were 41.7% for the SN lesions (n = 39) and 23.1% for the CN lesions (n = 42). The difference between the survival curves was statistically significant (p = 0.0307). Multivariate analysis using Coxs proportional hazards model revealed that the macroscopic type (p = 0.023), the tumor diameter (p = 0.0001), and the presence of lymph node metastases (p = 0.0016) were statistically significant independent prognostic factors. CONCLUSION The new macroscopic classification may be valuable as a prognostic factor reflecting the biologic behavior of liver metastases.