Hepatectomy preserving drainage veins of the posterior section for liver malignancy invading the right hepatic vein: an alternative to right hepatectomy.

BACKGROUND: Although a right hepatectomy (RH) traditionally has been performed for liver tumors infiltrating the main trunk of the right hepatic vein (RHV), the presence of drainage veins of the posterior section (DVPS) beside the RHV provides a chance to preserve their draining area even if the main trunk of the RHV is removed. METHODS: Since 2005, we systematically have performed DVPS-preserving hepatectomies whenever possible. In the present study, we describe our experience treating 12 consecutive patients who underwent this procedure. RESULTS: We performed the following types of liver resections concomitant with the main trunk of the RHV without packed red cell transfusion, liver failure, or 90-day mortality: extended right anterior sectionectomy in 2 patients, extended segmentectomy 7 in 3, extended segmentectomy 8 in 2, and partial resection of segment 7 in 2 and segment 8 in 3. Postoperative morbidity was observed in 4 (33%) cases, all of which had pleural effusion requiring a tap. A free resection margin was obtained in all patients. CONCLUSIONS: This procedure could be a useful alternative to RH, providing a chance for radical liver resection with minimal parenchymal sacrifice in selected patients with DVPS.

Role of bone marrow cells in the development of pancreatic fibrosis in a rat model of pancreatitis induced by a choline-deficient/ethionine-supplemented diet.

Bone marrow cell (BMC)-derived myofibroblast-like cells have been reported in various organs, including the pancreas. However, the contribution of these cells to pancreatic fibrosis has not been fully discussed. The present study examined the possible involvement of pancreatic stellate cells (PSCs) originating from BMCs in the development of pancreatic fibrosis in a clinically relevant rat model of acute pancreatitis induced by a choline-deficient/ethionine-supplemented (CDE) diet. BMCs from female transgenic mice ubiquitously expressing green fluorescent protein (GFP) were transplanted into lethally irradiated male rats. Once chimerism was established, acute pancreatitis was induced by a CDE diet. Chronological changes in the number of PSCs originating from the donor BMCs were examined using double immunofluorescence for GFP and markers for PSCs, such as desmin and alpha smooth muscle actin (αSMA), 1, 3 and 8 weeks after the initiation of CDE feeding. We also used immunohistochemical staining to evaluate whether the PSCs from the BMCs produce growth factors, such as platelet-derived growth factor (PDGF) and transforming growth factor (TGF) ß1. The percentage of BMC-derived activated PSCs increased significantly, peaking after 1 week of CDE treatment (accounting for 23.3±0.9% of the total population of activated PSCs) and then decreasing. These cells produced both PDGF and TGFß1 during the early stage of pancreatic fibrosis. Our results suggest that PSCs originating from BMCs contribute mainly to the early stage of pancreatic injury, at least in part, by producing growth factors in a rat CDE diet-induced pancreatitis model.

A case report of follicular lymphoma arising from the extrahepatic bile duct: interesting contrast-enhanced ultrasonographic findings.

We report a case of follicular lymphoma of the extrahepatic bile duct and the associated characteristic findings of contrast-enhanced ultrasonography (CEUS). A 60-year-old man with jaundice was scheduled to undergo surgical treatment because of a suspected diagnosis of biliary adenocarcinoma. CEUS in the high-resolution power Doppler mode showed early pulsatile enhancement of the inner layer of the thickened bile duct wall. Thereafter, gradual weak enhancement was detected in the outer layer. Extrahepatic bile duct resection was performed, and the resected specimen was diagnosed as a follicular lymphoma. On microscopic examination, the fibromuscular and deeper layers of the specimen were found to be infiltrated by follicle-forming tumor cells. The mucosal epithelium of the bile duct was almost normal. Although this is the fourth report of this condition in the English-language literature, it is the first to discuss the possibility of a preoperative diagnosis by CEUS.

Isolation and characterization of portal branch ligation-stimulated Hmga2-positive bipotent hepatic progenitor cells.

Hepatic stem/progenitor cells are one of several cell sources that show promise for restoration of liver mass and function. Although hepatic progenitor cells (HPCs), including oval cells, are induced by administration of certain hepatotoxins in experimental animals, such a strategy would be inappropriate in a clinical setting. Here, we investigated the possibility of isolating HPCs in a portal branch-ligated liver model without administration of any chemical agents. A non-parenchymal cell fraction was prepared from the portal branch-ligated or non-ligated lobe, and seeded onto plates coated with laminin. Most of the cells died, but a small number were able to proliferate. These proliferating cells were cloned as portal branch ligation-stimulated hepatic cells (PBLHCs) by the limiting dilution method. The PBLHCs expressed cytokeratin19, albumin, and Hmga2. The PBLHCs exhibited metabolic functions such as detoxification of ammonium ions and synthesis of urea on Matrigel-coated plates in the presence of oncostatin M. In Matrigel mixed with type I collagen, the PBLHCs became rearranged into cystic and tubular structures. Immunohistochemical staining demonstrated the presence of Hmga2-positive cells around the interlobular bile ducts in the portal branch-ligated liver lobes. In conclusion, successful isolation of bipotent hepatic progenitor cell clones, PBLHCs, from the portal branch-ligated liver lobes of mice provides the possibility of future clinical application of portal vein ligation to induce hepatic progenitor cells.

Potential feasibility of early bone marrow cell injection into the spleen for creating functional hepatocytes.

BACKGROUND: Bone marrow cells (BMCs) are believed to have the ability to generate functional hepatocytes and have some merits as a therapeutic modality for metabolic liver diseases. However, the appearance of BMC-derived hepatocytes (BMDHs) is low. We hypothesized that early BMC injection would be feasible for creating BMDHs for two main reasons: (1) the liver is a hematopoietic organ in neonatal rats and (2) it may allow sufficient time to generate more BMDHs before severe liver injury occurs. METHODS: We used Long Evans Cinnamon (LEC) rats as recipients, a model of (1) Wilson disease and (2) liver carcinogenesis. Green fluorescent protein-expressing BMCs were injected into newborn LEC rats through the spleen. The oxidative activity of ceruloplasmin, which is low in LEC rats, was measured to evaluate the treatment. In addition, we performed fluorescence in situ hybridization to clarify the origin of the BMDHs and immunohistochemical analysis to confirm whether these BMDHs had malignant potential. RESULTS: At 18 months after injection, we found some green fluorescent protein-expressing areas macroscopically in the liver of treated LEC rats. The oxidative activity of ceruloplasmin increased in treated LEC rats (n=7) and were much higher than that in untreated LEC rats (P=0.015). Moreover, we confirmed that the BMDHs were generated by cell fusion and was not detected in any of the neoplastic lesions or cholngiofibrotic regions. CONCLUSION: Our results suggest that this novel strategy for creating BMDHs is effective and safe.

Efficacy of preoperative endoscopic nasobiliary drainage for hilar cholangiocarcinoma.

BACKGROUND/PURPOSE: Although percutaneous transhepatic biliary drainage has previously been recommended as a primary preoperative step, endoscopic nasobiliary drainage (ENBD) is prevalent as an alternative procedure. Few reports assess the efficacy and safety of ENBD in a substantial patient cohort. METHODS: Of 116 patients with hilar cholangiocarcinoma who underwent surgery, 62 (43 men and 19 women, median age 69 years) underwent preoperative ENBD. After classification of lesions according to Bismuth-Corlette (B-C) criteria, we evaluated efficacy and safety with respect to B-C type. RESULTS: Patients were classified as B-C types I (n = 5), II (n = 21), IIIa (n = 23), IIIb (n = 5), and IV (n = 8). Preoperative single ENBD was effective in 46/62 patients (74%) including 5/5 (100%) B-C type I, 20/21 (94%) type II, 16/23 (70%) type IIIa, 4/5 (80%) type IIIb, and 1/8 (13%) type IV. Sixteen cases (26%) required additional drainages with ENBD or endoscopic biliary stenting (EBS) in 8/16 (50%), and with PTBD in 8/16 (50%). Mild acute pancreatitis (n = 1, 2%), segmental cholangitis (n = 2, 3%), and acute cholangitis with catheter obstruction (n = 7, 11%) occurred with ENBD. CONCLUSIONS: Preoperative single ENBD in the future remnant lobe is effective treatment for B-C type I-III hilar cholangiocarcinoma. Preoperative ENBD was rarely complicated with segmental cholangitis.

Clinical and pathological features of primary carcinoma of the cystic duct.

BACKGROUND: According to Farrar's criteria, a tumor restricted to the cystic duct is defined as cystic duct carcinoma, but this definition excludes advanced carcinoma originating from the cystic duct. PATIENTS AND METHODS: For the purpose of this study, primary cystic duct carcinoma was defined as a tumor originating from the cystic duct. We investigated the clinicopathological features of 15 cystic duct carcinomas, including 13 that did not fit Farrar's criteria, and compared them with those of 52 cases of gallbladder carcinoma and 161 cases of extrahepatic bile duct carcinoma. RESULTS: The incidence of primary cystic duct carcinoma was 6.6% among all malignant biliary tumors. The main symptom was jaundice in 67% of cases. The operative procedures employed ranged from cholecystectomy to hepatopancreatoduodenectomy. The cases of cystic duct carcinoma and bile duct carcinoma showed a high frequency of perineural infiltration. The overall 5-year survival rate of the 15 patients was 40%. CONCLUSION: Patients with advanced cystic duct carcinoma show a high frequency of jaundice and perineural infiltration. Our data suggest that cystic duct carcinoma may be considered a distinct subgroup of gallbladder carcinoma. Radical surgery is necessary for potentially curative resection in patients with advanced cystic duct carcinoma.

Prognostic impact of anatomical resection on early and late intrahepatic recurrence in patients with hepatocellular carcinoma.

BACKGROUND/PURPOSE: Little has been addressed regarding the impact of the type of resection, which can be anatomical or nonanatomical, for patients with hepatocellular carcinoma (HCC), from the viewpoint of early (< or =2-year) and late (>2-year) intrahepatic recurrence. The aim of the present study was to investigate this issue. METHODS: Between 1990 and 2004, we performed 365 potentially curative liver resections. Among these, 233 patients with a solitary tumor were the subjects of this study. They were classified into two groups: anatomical resection (n = 106) and nonanatomical resection (n = 127). We evaluated the following outcomes: (1) early and late recurrence rates; (2) topography of the recurrent tumors; and (3) risk factors for early recurrence. RESULTS: The early recurrence rate after anatomical resection was significantly lower than that after nonanatomical resection: recurrence rates at 1 and 2 years were 13.8% and 29.8%, respectively, in the former group; while they were 22.6% and 46.3%, respectively, in the latter group (P = 0.01; log-rank test). However, late recurrence rates were similar in the two groups (P = 0.36). Local recurrence was observed in 25 of the 89 patients with intrahepatic recurrence after nonanatomical resection (28%), whereas it was observed in 3 of the 64 patients with intrahepatic recurrence after anatomical resection (5%), showing a significantly lower local recurrence rate in the anatomical resection group (P = 0.0002). Cox multivariate analysis identified the type of resection employed as one of the variables contributing to early HCC recurrence (nonanatomical resection: hazard ratio, 1.84; 95% confidence interval [CI], 1.01-3.37). CONCLUSIONS: Anatomical resection would be a more appropriate strategy than nonanatomical resection for preventing early intrahepatic recurrence in patients with solitary HCC. However, the type of resection has no significant influence on late recurrence.

Identification of genes associated with multiple nodules in hepatocellular carcinoma using cDNA microarray: multicentric occurrence or intrahepatic metastasis?

BACKGROUND/AIMS: The prognosis of hepatocellular carcinoma (HCC) is poor because of frequent intrahepatic metastasis (IM) or multicentric carcinogenesis (MC). This study compared the effectiveness of microarray analysis in the diagnosis of these 2 forms with that of conventional histopathological diagnosis. The aim was to identify IM- or MC-associated genes through delineation of the clonality of multinodular liver cancer. METHODOLOGY: The clonal relationship of 23 tumor foci obtained from 11 surgically resected liver specimens was investigated by genome-wide expression profiling via an in-house cDNA microarray consisting of 4,608 genes. RESULTS: The gene expression signature of primary HCCs with IM was very similar to that of their corresponding IMs, implying that genes favoring progression of metastasis were initiated in the primary tumors. In comparison, different gene expression was observed in multicentric HCCs. The gene for adrenomedullin, which has been identified as a lead gene in the gene expression signature, was overexpressed in HCCs with IM, as confirmed by real time-PCR and immunohistochemistry. CONCLUSIONS: Analysis of expression profiles by microarray could provide a reliable method of delineating the clonal relationship of multiple nodules of liver cancer and identifying metastasis-associated genes. Adrenomedullin is a factor associated with progression of IM in human HCC.

Primary liver carcinoma exhibiting dual hepatocellular-biliary epithelial differentiations associated with citrin deficiency: a case report.

We report a 50-year-old male patient with primary liver carcinoma exhibiting dual hepatocellular and biliary epithelial differentiations associated with citrin deficiency (asymptomatic adult-onset type II citrullinemia, CTLN2). Although so far 14 CTLN2 patients with hepatocellular carcinoma have been reported, this report describes a unique case of liver carcinoma showing the features of both hepatocellular and cholangiocellular carcinoma. In addition to the clinical data of the 14 patients reported previously, the findings in our patient suggest that the citrin deficiency might be one of the key disorders causing hepatocellular carcinoma especially at younger ages and can also play an important role in hepatocarcinogenesis of the hepatic progenitor cells, which have the bipotential to differentiate into both hepatocytes and cholangiocytes.

Radical surgery for advanced squamous cell carcinoma of the gallbladder: a report of three cases, including a 10-year survivor.

We report three patients who underwent radical resections for advanced squamous cell carcinoma of the gallbladder, two of whom are still alive without recurrence 10 and 9 years after surgery. The other patient, who had lymph node involvement, suffered recurrence of the disease and died 9 months after surgery. Our experience indicates that radical surgery can sometimes provide a chance for long-term survival in patients with this neoplasm. Lymph node metastasis, albeit a rare event, might be a poor prognostic factor in patients with this type of gallbladder carcinoma.

Is major hepatectomy with pancreatoduodenectomy justified for advanced biliary malignancy?

BACKGROUND/PURPOSE: Major hepatectomy with concomitant pancreatoduodenectomy (M-HPD) is usually indicated for the resection of diffuse bile duct cancer or advanced gallbladder cancer. This is the only procedure that can potentially cure such advanced cancers, so both a low mortality rate and long-term survival could potentially justify performing this procedure. METHODS: Between 1990 and 2005, the morbidity, mortality, and long-term survival of 26 patients with advanced biliary tract carcinoma 14 with diffuse bile duct cancer, 9 with advanced gallbladder cancer, and 3 with hilar bile duct cancer, who underwent hepatopancreatoduodectomy (HPD) were reviewed and analyzed. RESULTS: The overall morbidity and mortality rates were 30.8% and 0%, respectively. Postoperative infectious complications occurred in 6 patients (23.0%). The 5-year survival rate of the 14 patients with diffuse bile duct cancer who underwent HPD was 51.9%, while the 5-year survival rate in the 12 of these patients who underwent M-HPD was 61.4%. Patients with diffuse bile duct cancer without residual tumor and those without lymph node metastasis had 5-year survival rates of 68.6% and 80%, respectively. Thirty-three percent (2 of 6) of the patients who underwent M-HPD for advanced gallbladder cancer survived for more than 5 years. CONCLUSIONS: Preoperative biliary drainage, portal embolization, complete external drainage of pancreatic juice, reduction of intraoperative bleeding, and prevention of bacterial colonization of bile may enable the incidence of mortality and hepatic failure to approach zero in patients who undergo HPD. Surgeons should strive for complete clearance of the tumor with a negative surgical margin to achieve long-term survival when performing M-HPD.

Impact of tumor spread to the cystic duct on the prognosis of patients with gallbladder carcinoma.

INTRODUCTION: The importance of gallbladder carcinoma spread to the cystic duct has not yet been described. Although the cystic duct is contiguous with the gallbladder, it is located in the hepatoduodenal ligament and differs in structure from the gallbladder. The incidence and prognostic significance of cancer spread to the cystic duct in patients with gallbladder cancer is unclear. METHODS: Surgical specimens from 42 patients who underwent resection for advanced gallbladder carcinoma were examined retrospectively. RESULTS: Altogether, 13 (31%) of the patients had cancer spread to the cystic duct. The incidences of perineural invasion, lymph node metastasis, and venous invasion were significantly higher in these patients than in the other 29 patients without cancer spread to the cystic duct (P = 0.027, 0.034, and 0.034, respectively). The 3- and 5-year survival rates of these 13 patients were significantly lower than those of the other 29 patients (15.4% vs. 51.0% and 7.7% vs. 46.6%, respectively, P < 0.0001 each). Multivariate analysis using the Cox proportional hazard model identified positive cancer spread to the cystic duct and depth of invasion (beyond serosa) as significant independent indicators of a poor prognosis. CONCLUSIONS: Cancer spread to the cystic duct is an indicator of poor prognosis in patients with gallbladder carcinoma. This may be due to the high incidence of concomitant perineural invasion and lymph node metastasis associated with cancer spread.

Predictive factors for intrahepatic cholangiocarcinoma recurrence in the liver following surgery.

BACKGROUND: We performed hepatectomy without lymph node (LN) dissection for intrahepatic cholangiocarcinoma (ICC) limited to the peripheral region of the liver, and hepatectomy with extrahepatic bile duct resection and regional LN dissection for any types of ICC extending to the hepatic hilum. Surgical outcomes were evaluated to elucidate the prognostic factors that influence patient survival with respect to intrahepatic recurrence. METHODS: Forty-one patients underwent resection of ICC with no macroscopic evidence of residual cancer. RESULTS: Significant risk factors for poorer survival included preoperative jaundice (P = 0.0115), serum CA19-9 levels >37 U/ml (P = 0.0089), tumor diameter >4.5 cm (P = 0.017), ICC extending to the hepatic hilum (P = 0.0065), mass-forming with periductal-infiltrating type (P = 0.003), poorly differentiated adenocarcinoma, portal vein involvement (P = 0.0785), LN metastasis at initial hepatectomy (P < 0.0001), and positive surgical margin (P = 0.023). Intrahepatic recurrence, which was the predominant manner of recurrence, was detected in 20 patients (74.1%). Patients with intrahepatic recurrence had a significantly high incidence of high serum CA19-9 levels (>37 U/ml; P = 0.0006), preoperative jaundice (P = 0.0262), ICC extended to the hepatic hilum (P = 0.0349), large tumors (>4.5 cm; P = 0.0351), portal vein involvement (P = 0.0423), and LN metastasis at initial hepatectomy (P = 0.009) compared with disease-free patients. The multiple logistic regression analysis revealed that preoperative CA19-9 elevation and obstructive jaundice influenced intrahepatic recurrence of ICC. CONCLUSIONS: Although LN metastasis is a significant prognostic factor, the most obvious recurrence pattern after surgery was intrahepatic recurrence, which could be predicted preoperatively by a combination of elevated serum CA19-9 levels and manifestation of obstructive jaundice.

Neurilemoma originating from the left recurrent nerve in the superior mediastinum: report of a case.

We report a rare case of neurilemoma originating from the left recurrent nerve in the superior mediastinum.

[Complete disappearance with oral UFT administration of recurrent hepatocellular carcinoma of the remnant liver and multiple lung metastasis after hepatic resection].

UFT is an anti-cancer drug which combines uracil with tegafur at a mole rate of 1:4, and shows a high anti-tumor effect by raising the 5-FU level in a tumor. A 55-year-old man with hypochondriac pain was admitted to Shinshu University Hospital. The preoperative diagnosis was giant hepatocellular carcinoma (HCC) of the right hepatic anterior region, and extended anterior segmentectomy of the liver was performed. Three months later, serum alpha-fetoprotein (AFP) and PIVKA-II were elevated markedly, and computed tomography (CT) and magnetic resonance imaging (MRI) revealed a recurrence in the remnant liver and multiple lung metastasis. Chemotherapy with oral UFT (300 mg/day) administration alone was started for the unresectable HCC. Three months later, CT and MRI showed complete disappearance of the recurrent HCC and multiple lung metastasis. Also, the titers of AFP and PIVKA-II were reduced to normal levels. This case suggests that oral UFT administration is a safe and effective therapy for postoperative HCC, even with lung metastasis.