Electroporation and use of hepatitis B virus envelope L proteins as bionanocapsules.

Hepatitis B virus (HBV) envelope L proteins, when synthesized in yeast cells, form a hollow bionanocapsule (BNC) in which genes (including large plasmids up to 40 kbp), small interfering RNA (siRNA), drugs, and proteins can be enclosed by electroporation. BNCs made from L proteins have several advantages as a delivery system: Because they display a human liver-specific receptor (the pre-S region of the L protein) on their surface, BNCs can efficiently and specifically deliver their contents to human liver-derived cells and tissues ex vivo (in cell culture) and in vivo (in a mouse xenograft model). Retargeting can be achieved simply by substituting other biorecognition molecules such as antibodies, ligands, receptors, and homing peptides for the pre-S region. In addition, BNCs have already been proven to be safe for use in humans during their development as an immunogen of hepatitis B vaccine. This protocol describes the loading of BNCs and their use in cell culture and in vivo.

Cancer-testis antigen BORIS is a novel prognostic marker for patients with esophageal cancer.

Esophageal squamous cell cancer (ESCC) is one of the most common lethal tumors in the world, and development of new diagnostic and therapeutic methods is needed. In this study, cancer-testis antigen, BORIS, was isolated by functional cDNA expression cloning using screening technique with serum IgG Abs from ESCC patients. BORIS was previously reported to show cancer-testis antigen like expression, but its immunogenicity has remained unclear in cancer patients. BORIS was considered to be an immunogenic antigen capable of inducing IgG Abs in patients with various cancers, including four of 11 ESCC patients. Immunohistochemical study showed that the BORIS protein was expressed in 28 of 50 (56%) ESCC tissues. The BORIS expression was significantly associated with lymph node metastasis in ESCC patients with pT1 disease (P = 0.036). Furthermore, the patients with BORIS-positive tumors had a poor overall survival (5-year survival rate: BORIS-negative 70.0% vs BORIS-positive 29.9%, log-rank P = 0.028) in Kaplan-Meier survival analysis and log-rank test. Multivariate Cox proportional hazard model demonstrated that BORIS expression was an independent poor prognostic factor (hazard ratio = 4.158 [95% confidence interval 1.494-11.57], P = 0.006). Downregulation of BORIS with specific siRNAs resulted in decreased cell proliferation and invasion ability of ESCC cell lines. BORIS may be a useful biomarker for prognostic diagnosis of ESCC patients and a potential target for treatment including by BORIS-specific immunotherapy and molecular target therapy.

Sentinel node mapping with thermoresponsive magnetic nanoparticles in rats.

BACKGROUND: In this study, we investigated the ability of magnetic resonance imaging (MRI) after interstitial administration of thermoresponsive magnetic nanoparticles to detect the sentinel lymph node (SLN). MATERIALS AND METHODS: Postcontrast MRI scans were acquired following subcutaneous injection of thermoresponsive magnetic nanoparticles into the thoracic wall of rats. The signal-to-noise ratio of axillary lymph nodes was calculated to assess whether the SLN could be detected by MRI. In a second experiment, after injecting thermoresponsive magnetic nanoparticles, i.e., Therma-Max 36, Therma-Max 42, Therma-Max 55, and Ferridex, into the subserosa of the cecum of rats, the injection sites, the SLNs, and the distant lymph nodes were resected and examined histologically in order to determine which nanoparticles, if any, were specifically retained in the SLN. RESULTS: MRI showed that the signal-to-noise ratio of axillary SLNs was significantly lower 24 h after injection of Therma-Max 42 than on the precontrast images (P < 0.05). Histologic evaluation revealed that Therma-Max 36 aggregated at body temperature and did not migrate to the SLN. Therma-Max 42, on the other hand, aggregated, and the particles became large enough to be retained in the SLNs. Therma-Max 55 and Ferridex did not aggregate, and they both migrated to the SLNs and the distant lymph nodes. CONCLUSIONS: The results of this study showed that thermoresponsive magnetic nanoparticles could be targeted to the SLN by adjusting the temperature at which they aggregate, and that they could be used as a contrast agent for SLN mapping by MRI.

Photodynamic therapy using an anti-EGF receptor antibody complexed with verteporfin nanoparticles: a proof of concept study.

Photodynamic therapy (PDT) is a noninvasive optical treatment method in which the topical or systemic delivery of photosensitizing drugs is followed by irradiation with broadband red light. Coupling photosensitizers with a specific antibody may allow this approach to target specific cancers. This study determines the antitumor efficacy of coupling verteporfin (Visudyne(®)), a hydrophobic polyporphryin oligomer, with an antiepidermal growth factor receptor (anti-EGFR) antibody. Poly[2-methacryloyloxyethyl phosphorylcholine-co-n-butyl methacrylate-co-p-nitrophenylcarbonyloxyethyl methacrylate] (PMBN) was conjugated with an anti-EGFR antibody and mixed with verteporfin (verteporfin-PMBN-antibody complex). Tumor-bearing mice were intravenously injected with the verteporfin-PMBN-antibody complex or verteporfin plus PMBN without the antibody. Irradiation was conducted at 640 nm with a dose of 75 J/cm(2). The fluorescence intensity in A431 cells in vitro was threefold higher after exposure to verteporfin-PMBN-antibody complex than after exposure to verteporfin-PMBN. In A431 tumor-bearing mice, the intratumor concentration of verteporfin was 9.4 times higher than that of the skin, following administration of the verteporfin-PMBN-antibody complex. Tumor size significantly decreased within 8 days in mice treated with verteporfin-PMBN-antibody complex compared with those treated with verteporfin-PMBN. PDT using a PMBN-verteporfin-antibody complex offers a promising anticancer therapy.

Human liver-specific nanocarrier in a novel mouse xenograft model bearing noncancerous human liver tissue.

For the targeted delivery of genes and drugs to the human liver, hepatitis B virus (HBV) envelope L particles, which form hollow nanoparticles and display a peptide that is indispensable for liver-specific infection by HBV in humans, should be a useful tool. To test the efficacy of these particles in vivo, in the present study we generated a small animal model harboring a functional human liver tissue xenograft. An anti-asialo GM1 antibody was administered to SCID mice to induce the depletion of natural-killer-cell-dependent immune responsibility and then the mice underwent transplantation of a noncancerous liver tissue originating in humans into the kidney capsule. Interestingly, human liver tissues were engrafted in 58% of the animals at least for 14 days shown by a human hepatocyte-specific antibody. The engineered HBV nanoparticles which contained fluorescent chemicals could selectively bind to the xenograft in these immune-deficient mice when they were administered systemically. These results suggested that the model animal was usable to demonstrate the efficacy of the nanoparticles that could deliver chemicals specific to the normal human liver tissue by systemic administration, which will facilitate the study of human liver cell biology, drug metabolism and infections with hepatotropic viruses.

Radiation-sensitizing effect of low-concentration docetaxel on human esophageal squamous cell carcinoma cell lines.

Esophageal squamous cell carcinoma (ESCC) is more sensitive to radiation and chemotherapy than other cancers of the digestive system, and combined modality therapy may represent a promising treatment method. The radiation-sensitizing effect of docetaxel on ESCC cell lines was investigated. A colony formation assay was performed in which ESCC cell lines (TE2, TE3) and A431 were exposed to docetaxel (from 1.0×10(-11) to 10(-7) M) for 3 h to determine the concentration of docetaxel that was not able to kill individual cells (i.e., the non-cytocidal concentration). Individual cell lines were then exposed to the non-cytocidal concentration of docetaxel prior to, during, and after irradiation to determine whether the timing of docetaxel administration affected cell survival. In addition, flow-cytometry was performed, and the cell cycle was examined prior to and after docetaxel exposure to assess the mechanism of docetaxel as a radiation sensitizer. Docetaxel exhibited a concentration-dependent cytocidal effect, with a different IC(50) for each cell type. Almost no cytocidal effect was observed at the following docetaxel concentrations: A431, ≤1.0×10(-10) M; TE-2 and TE-3, ≤1.0×10(-9) M. Concurrent treatment with docetaxel and radiation tended to decrease cell survival in all the cell lines compared with docetaxel or radiation alone. Cell survival was lowest when the cells were treated using X-ray irradiation after docetaxel exposure (p<0.05). Flow cytometry revealed that in all three cell lines, docetaxel exposure increased the G2/M cell fraction with a higher increase in the cell line that exhibited the highest radiosensitivity. This study demonstrated that the administration of docetaxel at a non-cytocidal concentration prior to radiotherapy produced a synergistic cell-killing effect in SCC cell lines.

Molecular diagnosis and translymphatic chemotherapy targeting sentinel lymph nodes of patients with early gastrointestinal cancers.

The sentinel lymph node (SLN) is defined as the lymph node(s) that first receives lymphatic drainage from the site of the primary tumor. Recent progress in molecular techniques has demonstrated the presence of micrometastatic tumor cells in SLNs. Quantitative real-time RT-PCR assay, which enables rapid analysis, is currently being undertaken for intraoperative molecular diagnosis of SLNs. We developed an intraoperative real-time RT-PCR assay to detect micrometastasis in SLNs for early gastric cancer. All SLNs and randomly selected non-SLNs in 96 cT1 or cT2 gastric cancer patients were biopsied intraoperatively and examined by routine hematoxylin and eosin staining, immunohistochemistry with anticytokeratin antibody (AE1/AE3), and multimarker real-time RT-PCR assay including cytokeratin (CK) 19, CK20, and carcinoembryonic antigen. All patients with histopathologically verified metastasis in their SLNs demonstrated positive results by RT-PCR assay. Forty percent of patients with histopathologically negative SLNs showed positive SLNs by RT-PCR assay. RT-PCR assay revealed that 4 patients (4%) with negative SLNs had positive non-SLNs; however, these positive non-SLNs were identified within each SLN basin. We recently developed a new drug delivery system targeting SLNs with a phospholipid polymer, using 2-methacryloyloxyethyl phosphorylcholine conjugated with paclitaxel. Our preliminary data suggest that this novel drug delivery system may be feasible for translymphatic chemotherapy targeting SLNs of patients with cN0 early gastrointestinal cancer, who have the potential for occult metastasis in SLNs. Endoscopic resection of the primary tumor followed by translymphatic chemotherapy targeting SLNs may become a promising minimally invasive multidisciplinary therapy.

Reduced transforming growth factor-beta receptor II expression in hepatocellular carcinoma correlates with intrahepatic metastasis.

Hepatocellular carcinoma (HCC) occurs mainly in the liver associated with chronic hepatitis and hepatic cirrhosis as a result of prolonged viral infection. Transforming growth factor-beta (TGF-beta) induces the fibrosis in hepatic cirrhosis, although it is also an inhibitor of hepatocyte proliferation. To understand the role of TGF-beta signaling in HCC progression, we analyzed gene expression in HCC cells in relation to TGF-beta signaling using a two-way clustering algorithm. By the analysis, five HCC cell lines were classified into two groups according to their metastatic capacity. TGF-beta receptor II (TGFBR2) was downregulated in metastatic cells, which did not show a response to TGF-beta. Immunohistochemistry demonstrated clear membrane distribution of TGFBR2 in noncancerous hepatocytes, whereas reduced TGFBR2 expression was observed in 34 of 136 HCCs. In clinical cases, reduced TGFBR2 expression correlated with larger tumor size (P<0.001), poor differentiation (P<0.001), portal vein invasion (P=0.002), intrahepatic metastasis (IM) (P<0.001), and shorter recurrence-free survival (P=0.022). In conclusion, reduced TGFBR2 expression was associated with aggressive features of HCC such as IM, and may represent an immunohistochemical biomarker to detect aggressive HCC.

Beneficial effects of 5-Fluorouracil and heparin-based portal infusion chemotherapy combined with mitomycin C and cisplatin after curative resection of pancreatic cancer.

AIMS: We retrospectively assessed the benefits of 5-fluorouracil (5-FU)- and heparin-based portal infusion chemotherapy combined with systemic administration of mitomycin C (MMC) and cisplatin (CDDP) for 4 weeks following surgery (PI4W). The goal was to determine if this treatment prevented liver metastasis and improved survival for patients with potentially curative resection of pancreatic cancer. METHODS: 68 patients who underwent pancreatectomy from January 1995 to August 2007 were treated. Of these cases, 22 patients received portal infusion with 5-FU (250 mg/day) for 2 weeks (PI2W) following surgery, while 25 patients received PI4W therapy (250 mg/day of 5-FU with 2,000 IU/day of heparin everyday for 4 weeks, 4 mg MMC on days 6, 13, 20, 27, and 10 mg CDDP on days 7, 14, 21, 28). The remaining 21 patients were treated without adjuvant therapy during the perioperative period. RESULTS: All patients except one completed the portal infusion chemotherapy without toxicity. The cumulative liver metastasis-free survival rate in the PI4W group was significantly higher than those in the other two groups. Furthermore, in the PI4W group, 3-year survival was 82.9% and 5-year survival was 63.8%, rates which were significantly better than those observed in the other two groups. CONCLUSION: PI4W therapy after surgery is feasible and could become a promising adjuvant therapy in patients with potentially curative resection of pancreatic cancer. and IAP.

Castleman's disease arising from the gallbladder neck causing difficulty in the differential diagnosis.

We report a patient with Castleman's disease arising from the gallbladder neck, which caused difficulty in making the differential diagnosis against gallbladder malignancies. A 50-year-old woman presented to our institution with epigastric pain. An abdominal computed tomography scan (CT) and magnetic resonance cholangiopancreatography (MRCP) study showed a 20-mm tumor located in the gallbladder neck for which malignancy could not be completely ruled out. For the definitive diagnosis and treatment, cholecystectomy was performed. In the operation, the main tumor and resection margins of the cystic duct were submitted for frozen section. The tumor was composed of a proliferation of lymphoid tissue with no signs of dysplasia. The ductal margin was free of tumor. The final histopathological diagnosis was unicentric Castleman's disease, a hyaline vascular variant that developed in the gallbladder. The patient is currently in good condition without any signs of recurrence 28 months after the operation. This is the first detailed report of Castleman's disease of the gallbladder. Making a correct diagnosis was very difficult before the operation, and only a surgical approach enabled confirmation of the diagnosis for this patient.

Bouveret's syndrome with a concomitant incidental T1 gallbladder cancer.

Bouveret's syndrome, which is a gastric outlet obstruction caused by a gallstone in the duodenum, is a rare complication of gallstone disease. We report a case of Bouveret's syndrome in an 81-year-old woman who also exhibited incidental gallbladder cancer. She was admitted to our hospital complaining of upper abdominal pain and vomiting. A computed tomography examination showed a cholecystoduodenal fistula, a large impacted stone at the gastric outlet, and a dilated stomach. She was diagnosed as having Bouveret's syndrome. The patient underwent an upper gastrointestinal endoscopy and a mechanical lithotripsy was successfully performed for the stone. She then underwent a cholecystectomy with primary closure of the duodenal fistula. An intra-operative histopathology examination revealed severe cholecystitis with an adenocarcinoma in part of the gallbladder. Gallbladder bed resection and regional lymph node dissection were also performed. To the best of our knowledge, this is the first published report of a case in which Bouveret's syndrome and gallbladder cancer co-existed.

Increase in E-selectin expression in umbilical vein endothelial cells by anticancer drugs and inhibition by cimetidine.

E-selectin is expressed on the surfaces of stimulated vascular endothelial cells and is sometimes involved in cancer cell metastasis. The H2-receptor antagonist cimetidine inhibits the increase in E-selectin expression on vascular endothelial cells that is induced by interleukin-1beta (IL-1beta) and cimetidine. It also inhibits the adhesion of sialyl-Lewis-antigen-positive cancer cells to vascular endothelial cells, ultimately inhibiting hematogenous metastasis. Anticancer drugs are essential to cancer therapy, but whether they can alter the expression of E-selectin in vascular endothelial cells remains unclear. Whether cimetidine inhibits the expression of E-selectin in the same manner in the presence or absence of anticancer drugs also remains unknown. Human umbilical vein endothelial cells were cultured with 5-fluorouracil (5-FU), doxorubicin (DXR), cisplatin (CDDP), or IL-1beta and with or without cimetidine. The expression of E-selectin at the mRNA and protein levels was then determined using quantitative reverse transcription-polymerase chain reaction and immunohistochemical staining, respectively. The E-selectin mRNA level increased in cells exposed to 5-FU, DXR, or CDDP, but the addition of cimetidine had no effect on the E-selectin mRNA level. The expression of E-selectin protein was also significantly higher after the addition of 5-FU, DXR, or CDDP, compared with that of a negative control. However, when cimetidine was added prior to the addition of 5-FU, DXR, or CDDP, the expression of E-selectin was significantly suppressed. Thus, cimetidine significantly inhibited the expression of E-selectin at the protein level without affecting its expression at the mRNA level in cells treated with anticancer drugs. In conclusion, anticancer drugs increased the expression of E-selectin and this increase was inhibited by cimetidine. These findings suggest that the administration of cimetidine during treatment with anticancer drugs might be useful for preventing metastasis.

Development of targeted therapy with paclitaxel incorporated into EGF-conjugated nanoparticles.

BACKGROUND: 2-Methacryloyloxyethyl phosphorylcholine (MPC) polymer is a suitable vehicle for paclitaxel (PTX) delivery. A new targeted therapy has been developed by conjugating epidermal growth factor (EGF) to MPC polymer and its growth inhibitory and antitumor effects on cancer cells overexpressing EGF receptors (EGFR) has been investigated. MATERIALS AND METHODS: EGF was conjugated to poly [MPC-co-n-butyl methacrylate-co-p-nitrophenyloxycarbonyl poly (ethylene glycol) methacrylate] (PMBN) and mixed with PTX. The cytotoxicity of the resulting PTX incorporated into EGF-conjugated PMBN (EGF-PMBN-PTX) on EGFR-overexpressing and EGFR-deficient cell lines was compared with PTX incorporated into PMBN alone (PMBN-PTX) and PTX alone. Suspensions of the cells were injected into nude mice subcutaneously. EGF-PMBN-PTX, PMBN-PTX, PTX or NaCl solution was injected intraperitoneally. RESULTS: The cytotoxicity and antitumor effect of EGF-PMBN-PTX were significantly greater than those of PMBN-PTX for EGFR-overexpressing cells but not for an EGFR-deficient line. CONCLUSION: These results suggest that EGF-PMBN-PTX may represent a more potent targeted therapy for tumors overexpressing EGFR.

Selective targeting by preS1 domain of hepatitis B surface antigen conjugated with phosphorylcholine-based amphiphilic block copolymer micelles as a biocompatible, drug delivery carrier for treatment of human hepatocellular carcinoma with paclitaxel.

Using dithioester-capped 2-methacryloyloxyethyl phosphorylcholine (MPC) as a macro chain transfer agent, a diblock copolymer was synthesized with n-butyl methacrylate (BMA) as hydrophobic core-forming blocks. The MPC-BMA unit was copolymerized with an immobilizable unit, p-nitrophenylcarbonyloxyethyl methacrylate (NPMA). The NPMA moiety then was modified by the addition of preS1 domain of hepatitis B surface antigen (HBsAg). This micelle-forming nanoparticle, the poly (MPC-co-BMA-co-NPMA) (PMBN) conjugated with preS1 enables solubilization of paclitaxel (PTX) with increased hepatotropism. The 50% inhibitory concentration (IC(50)) values of PTX and PTX/PMBN-preS1 against the human hepatocellular carcinoma cell line, HepG2, were 1,008 and 131 nM, respectively (p < 0.05). Conjugation of preS1 to PMBN enhanced strongly the synergistic inhibitory effect of paclitaxel on HepG2 cells in vitro, whereas such a change in IC(50) was not detected against the human squamous cell carcinoma cell line, A431. Tumor growth rates of a HepG2 xenograft in Balb/c nude mice after intraperitoneal injection of PTX, PTX/PMBN and PTX/PMBN-preS1 were +97.9%, -74.3% and -96.2%*, respectively (*p < 0.05 versus PTX). The local paclitaxel levels after administration of the PMBN-preS1 conjugate were determined in the xenografts by high-performance liquid chromatography and were 8 times higher than that after administration of paclitaxel alone. No side effects attributable to PMBN-preS1 were observed histologically in vital organs, and body weight loss was significantly less in the PTX/PMBN-preS1 group. These studies demonstrate that PMBN-preS1 may be used as a human hepatocyte-specific drug delivery carrier without serious adverse effects.

Surgical site infection risk factors identified by multivariate analysis for patient undergoing laparoscopic, open colon, and gastric surgery.

BACKGROUND: Surgical site infection (SSI) is an important clinical indicator of quality of patient care and infection control; therefore, we aimed to assess risk factors SSI in colon and gastric surgeries. METHODS: SSI was assessed according to the National Nosocomial Infection Surveillance (NNIS) system (1999). Risk factors examined included operative approach, operative procedure, duration of operation, diabetes mellitus (DM), body mass index (BMI), age, and sex. RESULTS: Among 3152 operated patients, 1675 patients were included in the study. The univariate analysis showed that male sex, high BMI, and long duration of operation were significant risk factors for colon surgery and that advanced age, presence of DM and long duration of operation were significant risk factors for gastric surgery. The multivariate analysis indicated that significant risk factors for SSI were BMI of 25 or above, open surgery, and long duration of operation for colon surgery and open surgery for gastric surgery. The SSI rate of laparoscopic colon surgery was 40%, less than that of open colon surgery, and that of laparoscopic gastric surgery was 75%, less than that of open gastric surgery. CONCLUSION: The risk factors for SSI depend on whether the operation is laparoscopic or open and duration of operation. In addition, BMI (25 or above) and age (70 years or above) are risk factors for colon and gastric surgery, respectively.

Establishment of combined immuno-chemotherapy with systemically administered gemcitabine and intra-portal administration of interleukin-2 in murine models of liver metastases of pancreatic cancer.

Despite attempts to use multiple drug combinations that include gemcitabine (GEM), there is very little evidence that these combination regimens are superior to the single use of this agent. We therefore investigated the suppressive effect of the combination of systemically administered GEM and locally administered interleukin-2 (IL-2) on liver metastasis in pancreatic cancer. Tumor-bearing mice were randomly divided into four groups: a control group, an IL-2 intrasplenic (is) administration group, a GEM intraperitoneal (ip) administration group, and a GEM ip+IL-2 is group. Liver weight, liver metastases, and tumor diameter (as assessed by the Winn assay) were compared among groups. Liver weight was significantly lower in the GEM+IL-2 group than in the control and IL-2 groups. The number of liver metastases was significantly reduced in the GEM+IL-2 group compared with all other groups. Splenocyte production of interferon-gamma increased significantly in the GEM+IL-2 group after stimulation with Concanavalin A. Furthermore, tumor diameter was significantly reduced in the GEM+IL-2 group in the Winn assay when compared to that of the control group. These findings suggest that a combined regimen of GEM and portally administrated IL-2 might prevent liver metastasis in pancreatic cancer patients more effectively than current approaches and could prove useful as a postsurgical adjuvant therapeutic.

Clinicopathological features and surgical outcome of isolated metastasis of renal cell carcinoma.

BACKGROUND/AIMS: The benefit of pancreatic resection for metastatic renal cell carcinoma (RCC) is poorly defined. Here, we investigate the clinicopathological features and surgical outcome of patients with pancreatic metastasis from RCC. METHODOLOGY: Among a total of 131 patients who underwent pancreatic resection at our center between November 2000 and November 2005, four patients (three men, one woman) with a median age of 57 years (range: 52-80 years) at the time of pancreatic tumor presentation, had histologically confirmed metastatic RCC to the pancreas. The medical records, imaging data, surgical records, and pathology findings of these patients were reviewed retrospectively. RESULTS: All patients underwent radical nephrectomy for primary RCC. The pathologic stage was TNM stage T2N0M0 (n = 1) or T3aN0M0 (n = 2) (no data were available on one patient). RCCs developed in the right (n = 2) or left (n = 2) kidney. The median interval between nephrectomy and detection of pancreatic metastasis was 84 months (range: 0-285 months). All patients were asymptomatic, and the pancreatic masses with a median tumor diameter of 2.0 cm (range: 1.5-4.0 cm) were detected during routine follow-up or screening examinations. All pancreatic tumors were smooth, well-demarcated, and hypervascular on imaging studies. None of them showed evidence of associated extrapancreatic disease. Complete resection with an adequate margin of safety was achieved by distal pancreatectomy (n = 3) or pylorus-preserving pancreatoduodenectomy (n = 1). Within a median follow-up period of 39 months (range: 4-41 months) after the surgery, three patients were alive with no evidence of recurrence, and one patient was alive with evidence of recurrence. The median survival from nephrectomy was 103 months (range: 40-326 months). CONCLUSIONS: RCCs may demonstrate very late metastasis to the pancreas, thus the possibility of pancreatic metastasis should be considered when a patient with a pancreatic tumor has a history of RCC, despite the interval since nephrectomy. The experience gained in this study suggests that pancreatic metastasectomy should be attempted for RCC patients without extrapancreatic disease.

Intrahepatic cholangiocarcinoma with old infestation of Schistosoma japonicum: report of a case.

We report a rare case of intrahepatic cholangiocarcinoma associated with old infestation of Schistosoma japonicum. The patient was a 76-year-old Japanese man who had lived his childhood in an endemic area of this parasite. He presented with jaundice and computed tomography showed a 4-cm, hypodense tumor in segment VIII of the liver. Microscopically, the resected mass was composed of well-differentiated adenocarcinoma cells. Fibrosis and inflammation were seen around the dilated peripheral portal veins embolized with dead S. japonicum eggs. Our search of the literature found only one other case of cholangiocarcinoma coincident with S. japonicum, suggesting that it is not a risk factor for cholangiocarcinoma, although the inflammation and fibrosis caused by the S. japonicum eggshells may predispose to carcinogenesis. However, there is no evidence supporting this hypothesis. More data are necessary to evaluate the differences in clinicopathological findings between cholangiocarcinoma concomitant with S. japonicum and the usual type of cholangiocarcinoma.