Toshiyuki Arai

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.

Surgical anatomy of the bile ducts at the hepatic hilum as applied to living donor liver transplantation.

Objective:To evaluate anatomic variations of the biliary tree as applied to living donor liver transplantation. Summary Background Data:Anatomic variability is the rule rather than the exception in liver surgery. However, few studies have focused on the anatomic variations of the biliary tree in living donor liver transplantation in relation to biliary reconstruction. Methods:From November 1992 to June 2002, 165 patients underwent major hepatectomy with extrahepatic bile duct resection; right-sided hepatectomy in 110 patients and left-sided hepatectomy in 55. Confluence patterns of the intrahepatic bile ducts at the hepatic hilum in the surgical specimens were studied. Results:Confluence patterns of the right intrahepatic bile ducts were classified into 7 types. The right hepatic duct was absent in 4 of the 7 types and in 29 (26%) of the 110 livers. Confluence patterns of the left intrahepatic bile ducts were classified into 4 types. The left hepatic duct was absent in 1 of the 4 types and in 1 (2%) of the 55 livers. Conclusions:In harvesting the right liver from a donor without a right hepatic duct, 2 or more bile duct stumps will be present in the plane of transection in the graft in 3 patterns based on their relation to the portal vein. Accurate knowledge of the variations in the hepatic confluence is essential for successful living donor liver transplantation.

“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.

Kupffer cell–derived interleukin 10 is responsible for impaired bacterial clearance in bile duct–ligated mice

Extrahepatic cholestasis often evokes liver injury with hepatocyte apoptosis, aberrant cytokine production, and—most importantly—postoperative septic complications. To clarify the involvement of aberrant cytokine production and hepatocyte apoptosis in impaired resistance to bacterial infection in obstructive cholestasis, C57BL/6 mice or Fas‐mutated lpr mice were inoculated intraperitoneally with 107 colony‐forming units of Escherichia coli 5 days after bile duct ligation (BDL) or sham celiotomy. Cytokine levels in sera, liver, and immune cells were assessed via enzyme‐linked immunosorbent assay or real‐time reverse‐transcriptase polymerase chain reaction. BDL mice showed delayed clearance of E. coli in peritoneal cavity, liver, and spleen. Significantly higher levels of serum interleukin (IL) 10 with lower levels of IL‐12p40 were observed in BDL mice following E. coli infection. Interferon γ production from liver lymphocytes in BDL mice was not increased after E. coli infection either at the transcriptional or protein level. Kupffer cells from BDL mice produced low levels of IL‐12p40 and high levels of IL‐10 in vitro in response to lipopolysaccharide derived from E. coli. In vivo administration of anti–IL‐10 monoclonal antibody ameliorated the course of E. coli infection in BDL mice. Furthermore, BDL‐lpr mice did not exhibit impairment in E. coli killing in association with little hepatic injury and a small amount of IL‐10 production. In conclusion, increased IL‐10 and reciprocally suppressed IL‐12 production by Kupffer cells are responsible for deteriorated resistance to bacterial infection in BDL mice. Fas‐mediated hepatocyte apoptosis in cholestasis may be involved in the predominant IL‐10 production by Kupffer cells. (HEPATOLOGY 2004;40:414–423.)

Overexpression of Interleukin-15 Protects against Escherichia coli-Induced Shock Accompanied by Inhibition of Tumor Necrosis Factor-α-Induced Apoptosis

Interleukin (IL)-15, a potent inhibitor of tumor necrosis factor (TNF)-alpha-mediated apoptosis, causes multiple organ failure during endotoxic shock. We investigated the potential role of IL-15 in protection against Escherichia coli-induced shock by using IL-15 transgenic (Tg) mice. These mice were resistant to an otherwise lethal challenge with E. coli, although bacterial burden and serum levels of TNF-alpha were similar in non-Tg mice. Apoptosis in cells of the peritoneal cavity, liver, spleen, or lung was significantly suppressed in IL-15 Tg mice after E. coli infection. Peritoneal cells from naive IL-15 Tg mice were also resistant to TNF-alpha-induced apoptosis in vitro, and neutralization of endogenous IL-15 significantly aggravated TNF-alpha-induced apoptosis. Exogenous IL-15 prevented TNF-alpha-induced apoptosis in normal mice in vitro and improved the survival rate after E. coli challenge. These results suggest that IL-15 overexpression can prevent TNF-alpha-induced apoptosis and protect against E. coli-induced shock, indicating a possible therapeutic application of IL-15 for septic shock.

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.

Hepatectomy for Colorectal Liver Metastases with Macroscopic Intrabiliary Tumor Growth

ObjectivesWe set out to clarify the clinicopathologic characteristics of colorectal liver metastases with macroscopic intrabiliary tumor growth and to determine optimal surgical management.MethodsOver 15 years, 6 of 103 patients undergoing hepatectomy for colorectal liver metastases had macroscopic intrabiliary tumor growth and were analyzed retrospectively.ResultsWe performed 11 operations for the 6 patients, consisting of 10 hepatectomies (including 1 hepatopancreatoduodenectomy) and 1 pancreatoduodenectomy. Three patients survived more than 5 years: 1 died of pulmonary emphysema with no sign of recurrence 101 months after initial hepatectomy; the 2 others were alive with no sign of recurrence at 74 and 145 months after initial hepatectomy. Median survival time of all 6 patients was 87.5 months. Histologically, intrabiliary tumor growth had two components: intraluminal and intraepithelial extension. In the proximal direction, distance between these two components ranged from 4–10 mm.ConclusionAggressive surgical treatment can improve chances of long-term survival for patients with macroscopic intrabiliary growth of colorectal liver metastasis. Although nonanatomic limited resection is a common procedure for colorectal liver metastasis, anatomic hepatobiliary resection is recommended.

TNM classification for perihilar cholangiocarcinoma: comparison between 5th and 6th editions of the AJCC/UICC staging system

BackgroundA few investigators have evaluated the TNM classification for perihilar cholangiocarcinoma. The new sixth edition of the American Joint Committee on Cancer (AJCC)/Internal Union Against Cancer (UICC) staging system focuses on vascular invasion and regional lymph node metastasis.MethodsFor 166 patients with perihilar cholangiocarcinoma undergoing R0 resection, survival curves stratified according to TNM classifications were compared between fifth and sixth editions.ResultsThe previous T3 now is divided into T3 and T4. Most new pT4 patients had invasion of the portal bifurcation; their survival was poorer than that for new pT3 patients. The 5-, 10-, and 15-year survival rates were worse in the previous stage III than in the previous stage IVA, although the difference fell short of significance. The previous stage IVA (T3AnyNM0) is divided into new stages: IIA (T3N0M0), IIB (T1-3N1M0), and III (T4AnyNM0). All patients in stage III had invasion of the portal bifurcation. Survival was similar between stages IA, IB, and IIA, while patients with T4N0M0 tumors survived longer than those with T4N1M0 tumors and similarly to those with stage IIB tumors.ConclusionsThe sixth edition provided improved prediction of survival in patients with perihilar cholangiocarcinoma; for still better prediction, cancer invasion of the portal bifurcation and regional lymph node metastasis should be weighted equally.

DIBUTYRYL CYCLIC ADENOSINE MONOPHOSPHATE PROTECTS MICE AGAINST TUMOR NECROSIS FACTOR-ALPHA -INDUCED HEPATOCYTE APOPTOSIS ACCOMPANIED BY INCREASED HEAT SHOCK PROTEIN 70 EXPRESSION

Liver injury accompanied by apoptosis of hepatocytes was provoked in mice by an intravenous injection of recombinant tumor necrosis factor-alpha (rTNF-alpha) (1.0 microg/kg) together with an intraperitoneal injection of D-galactosamine (D-gal) (500 mg/kg). Injection of various doses of dibutyryl cAMP (DBcAMP) protected mice from TNF-alpha/D-gal-induced liver injury as assessed by serum alanine aminotransferase (ALT) levels, histological examination and DNA fragmentation. DBcAMP significantly enhanced the Hsp70 expression in the hepatocytes of D-gal/TNF-alpha-injected mice in close correlation with suppression of liver injury. DBcAMP induced Hsp70 expression in the hepatocyte in vitro. These results suggest that increase in Hsp70 expression by DBcAMP is involved in protective mechanisms by DBcAMP against TNF-alpha-induced liver injury in D-gal-sensitized mice.

A Study of the Subvesical Bile Duct (Duct of Luschka) in Resected Liver Specimens

BackgroundInjury to the duct of Luschka is associated with biliary fistula from the gallbladder bed after cholecystectomy. However, few studies have reported on the detailed anatomy. We elucidated the anatomy and frequency of the duct of LuschkaMethodsA total of 128 specimens from patients who underwent right hepatectomy or more extensive right-sided liver resection between February 1992 and December 2003 were examined. Specimens were fixed in formalin, and serial sections were prepared to trace the course of the bile ducts from the subsegmental branch level.ResultsThe duct of Luschka was observed in 6 (4.6%) specimens. The sites of confluence were as follows: right anterior inferior dorsal branch (2 patients), right anterior branch (2 patients), right hepatic duct (1 patient), and common hepatic duct (1 patient). The upstream end was located in the liver parenchyma of the right anterior inferior dorsal subsegment (5b) and connective tissue of the gallbladder bed in 4 and 2 specimens, respectively.ConclusionsThe duct of Luschka never crosses the segmental (5b) border. Therefore, its upstream region may not be injured by segmentectomy or more extensive liver resection. However, it is possible to injure the duct of Luschka at the common hepatic duct, even if right-sided hepatectomy is performed, as the sites of confluence included the common hepatic duct.