[A case of liver failure associated with liver damage due to mFOLFOX 6 after resection for multiple liver metastases from colorectal cancer].

A case of colorectal cancer in a 60-year-old man became resectable after downstaging was achieved with mFOLFOX 6 for multiple liver metastases from colorectal cancer. The patient received 8 cycles of mFOLFOX 6 on the basis of a diagnosis of multiple liver metastases in the right and left lobes and a single metastasis in the right lung. After chemotherapy, the liver metastases showed partial response, and the lung metastasis stable disease. Because the lung metastasis was controlled and radical cure of the liver metastases was thought possible by resection, we performed right lobectomy of the liver. Postoperative progress was good, and we then planned a staged partial resection of the lung. However,on postoperative day 28, the patient was hospitalized again with liver dysfunction, which evolved into liver failure, in spite of conservative treatment. The patient died on postoperative day 95. The needle biopsy specimens of the liver taken on readmission showed bile duct occlusion, portal hypertension, and perisinusoidal fibrosis, and histopathology of the surgical non-tumoral liver specimen showed the same findings. We think that liver failure was triggered by resection of the liver which had been damaged by mFOLFOX 6. Recently, liver damage due to oxaliplatin was reported, and evaluation of liver injury is considered important before liver resection for colorectal liver metastases with neoadjuvant FOLFOX.

Primary omental-mesenteric myxoid hamartoma of the mesoappendix incidentally detected after abdominal trauma in a child: report of a case.

A 14-year-old boy was brought to our hospital with abdominal pain and nausea after suffering a blow to the abdomen. A mass was felt in the right hypogastrium, and the patient was hospitalized for possible hematoma resulting from the abdominal trauma. Initially, we treated him conservatively and observed his course, but on the 20th day after trauma, enhanced computed tomography showed that the area of strong enhancement in the tumor was unchanged. Superior mesenteric angiography showed findings indicative of a pseudoaneurysm caused by the trauma, and surgery was performed 26 days after the injury. Laparotomy revealed a tumor with a clear boundary, thought to originate in the mesoappendix, without any sign of pseudoaneurysm. Histopathological examination confirmed that the tumor was an omental-mesenteric myxoid hamartoma. The patient had an uneventful postoperative course and was discharged from hospital on the 12th day after surgery. More than 5 years have elapsed since the operation and no sign of recurrence or metastasis has been recognized.

Traumatic rupture of choledochal cyst in a child.

Traumatic rupture of choledochal cyst is an extremely rare disorder. The current patient is a 4-year-old boy who fell in a bathroom and suffered a blow to the abdomen. Percutaneous transhepatic cholangiography revealed pancreaticobiliary maljunction. Inflammation of the peritoneal cavity was moderate. At first look, the choledochal cyst was excised and hepaticojejunostomy was performed. At this time, a rupture approximately 2 mm in diameter was recognized at the rear surface of the inferior part of the common bile duct.

[Three-dimentional volumetric interpolated breath-hold magnetic resonance imaging for the diagnosis of breast tumors].

PURPOSE: Three dimensional volumetric interpolated breath-hold examination magnetic resonance imaging(3D-VIBE MRI) has the advantage of improving z-axis resolution, which makes it possible to obtain high quality multi-planar reconstruction (MPR) and 3-D reconstruction images. Using these capabilities of 3D-VIBE MRI, we have attempted to diagnose and evaluate breast tumors for preoperative planning. MATERIALS AND METHODS: One hundred patients with breast cancer and 5 patients with benign breast tumors were scanned by 1.5-T MR imaging, and the findings were compared with pathological findings. Triple-phase contrast-enhanced 3D-VIBE MRI was performed at 20 seconds (early arterial phase), 50 seconds (late arterial phase) and 180 seconds (equilibrium phase) after the beginning of injection of contrast material. Dynamic imaging was performed with 20 ml Gd-DOTA injected at a rate of 3.0 ml/sec. We also attempted to diagnose breast tumor for the detection of the primary lesion, estimation of histologic type, prediction of extensive intraductal components (EIC) and axillary lymph node metastases from breast cancer. RESULTS: (1) The diagnostic accuracy for breast cancer was 96.0% and it was 100.0% for benign disease. (2) The accuracy of the histologic estimation for breast cancer was 56.4%, and it was 83.3% for benign disease. (3) The accuracy of evaluation of ductal spread of breast cancer was 52.4%. (4) The accuracy was 72.4% for lymph node metastasis from breast cancer. CONCLUSION: This method provides useful information about the location of the primary tumor and lymph nodes. 3D-VIBE method is considered especially important for the preoperative evaluation of axillary lymph node status.

Synergistic antitumor effect by coexpression of chemokine CCL21/SLC and costimulatory molecule LIGHT.

To establish a more efficient treatment for immunotherapy against solid tumors, we have evaluated the antitumor effect by coexpression of a chemokine CCL21/secondary lymphoid tissue chemokine and a costimulatory molecule LIGHT in colon carcinoma C26. C26 cells expressing either CCL21 or LIGHT exhibited a significantly reduced tumor growth in vivo, and mice inoculated with these cells showed a prolonged survival, but eventually all these mice died. In contrast, C26 cells expressing both CCL21 and LIGHT exhibited a minimal tumor growth in vivo, and all these mice survived healthily with a tumor remission and consequently acquired a strong protective immunity. A markedly increased infiltration of mature dendritic cells (DCs), and CD8(+) T cells was observed in the tumor mass, and their spleen cells showed a greatly enhanced cytotoxic T lymphocyte (CTL) activity against C26 tumor and interferon (IFN)-gamma production. Neutralization of IFN-gamma or depletion of CD8(+) or CD4(+) T cells significantly reduced the antitumor activity. These results suggest that the combined treatment with CCL21 and LIGHT is able to induce a synergistic antitumor effect to eradicate tumor completely by greatly enhancing tumor-infiltration of lymphocytes including mature DCs and CD8(+) T cells, resulting in markedly augmented CTL activity and IFN-gamma production.

Potent antitumor activity of interleukin-27.

Although much promising data that interleukin (IL)-12 could be a powerful therapeutic agent against cancer were reported in animal models, its excessive toxicity has become a problem for its clinical application. IL-27 is a novel IL-12 family member that plays a role in the early regulation of T helper cell 1 initiation, including induction of T-bet and IL-12 receptor beta 2 expression. In the present study, we have evaluated the antitumor activity of IL-27 against a murine tumor model of colon carcinoma C26. C26 cells, which were transduced with the single-chain IL-27 cDNA and became secreting IL-27 (C26-IL-27), exhibited minimal tumor growth in vivo, and all of the mice inoculated with these cells survived healthily with complete tumor remission. Inoculation of mice with C26-IL-27 induced enhanced IFN-gamma production and cytotoxic T-lymphocyte activity against C26 tumor in spleen cells. Recovered mice from the inoculation showed a tumor-specific protective immunity to the following challenge with parental C26 tumor. The antitumor activity of IL-27 was almost diminished in nude mice, and depletion of CD8(+) T cells and neutralization of IFN-gamma in immunocompetent mice reduced greatly the antitumor activity. Moreover, the antitumor activity was abolished in T-bet-deficient mice, whereas it was observed unexpectedly in mice deficient of signal transducer and activator of transcription (STAT) 4. These results suggest that IL-27 has potent abilities to induce tumor-specific antitumor activity and protective immunity and that the antitumor activity is mediated mainly through CD8(+) T cells, IFN-gamma, and T-bet but not through STAT4.

Induction of apoptosis by p53, bax, bcl-2, and p21 expressed in colorectal cancer.

BACKGROUND: We investigated the influence of genes on the apoptosis of colorectal tumor cells, based on DNA and mRNA kinetics. METHODS: In 30 colorectal cancer patients, we examined the mRNA expression of p53, bax, bcl-2, and p21(WAF1), and we also investigated the development of tumor cell apoptosis, using a terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick-end labeling (TUNEL) method. RESULTS: TUNEL-positive cells showed a positive correlation with bax (P = 0.010) and a negative correlation with p21 (P = 0.04). We also investigated the relationship between p53 point mutation, p21 immunostaining degree, and apoptosis, based on DNA ladder expression. A remarkable correlation (P = 0.0090) was found between p21 and apoptosis. CONCLUSIONS: The present study findings suggest that tumor cell apoptosis is (1) strongly inhibited by p21, (2) induced by bax, and (3) influenced by bcl-2, which, presumably, inhibits tumor cell apoptosis.

Carcinogenetic process in gallbladder mucosa with pancreaticobiliary maljunction (Review).

Pancreaticobiliary maljunction (PBM) is a congenital anomaly with a high incidence of biliary tract carcinoma. Pathological findings strongly suggest that there is a hyperplasia-dysplasia-carcinoma sequence in carcinogenesis of PBM. A molecular biological analysis revealed high incidence of cellular proliferation activating factors such as TGF-alpha, COX-2 from the hyperplasia stage. In addition, cellular proliferative activity including BrdU, AgNOR, PCNA, and Ki-67 was significantly higher in regular gallbladder mucosa without PBM. Furthermore, a high incidence of K-ras gene mutation could be seen in hyperplasia (13-63%) and microsatellite instability could be observed in 60% of all cases in dysplasia. In cancerous lesions, a high rate of overexpression of cyclin D1, beta-catenin, p53, as well as p53 gene mutation has been recognized. These results suggest that a multistep carcinogenetic process contributes to the carcinogenesis of PBM, similar to that of other cancers. In addition, after preventive operation with resection of the extrahepatic bile duct is performed, carcinogenesis in the remnant biliary tract or pancreatic duct is rarely found. Whether the carcinogenesis is a result of the accumulation of genetic alteration from shortly after birth, or a result of regurgitation of gastrointestinal juice due to hepaticoenterostomy, remains unknown. Since a high frequency of COX-2 is positive in PBM, COX-2 inhibitors such as NSAIDs may play an important role in preventing carcinogenesis.

Standardization of ischemic hepatic failure in pigs as a model for bioartificial liver assessment.

PURPOSE: A standard protocol of ischemic liver failure in pigs was examined to establish a system for assessing the efficacy of a bioartificial liver, based on clinical practice. METHODS: The portal blood flow was extracorporeally bypassed into the cervical jugular vein, using a centrifugal blood pump. The portal vein and hepatic artery were then ligated. RESULTS: The maintenance protocol was established as follows: (1) the concentration of the inhaled anesthetic was decreased by 0.2% when the systolic blood pressure was <100 mmHg; (2) the volume of an infusion containing 5% glucose was increased to 10 ml/kg per hour when central venous pressure was <5 mmHg; (3) 20 ml of 50% glucose was injected intravenously when the blood glucose was <50 mg/dl; (4) 2000 units of heparin was injected intravenously when the activated clotting time was <150 s; (5) sodium bicarbonate was given when the blood pH was <7.3; (6) tidal volume was increased by 1 ml/kg when the pCO(2) was >80 mmHg; (7) oxygen was increased by 25% when the pO(2) was <100 mmHg. No vasopressors were used in the experiment. CONCLUSION: Our protocol reduced the operating time and minimized the risk of data deviation that can arise from variations in operating techniques and individual animal conditions. This experimental model is also easy to use as a bridge to transplantation.

High risk of bile duct carcinogenesis after primary resection of a congenital biliary dilatation.

Congenital biliary dilatation (CBD) is a relatively rare disease and highly associated with hepatobiliary malignancies due to pancreaticobiliary maljunction. For the treatment of CBD, the standard surgical method is the excision of the entire extrahepatic duct with a hepaticoenterostomy. However, in recent years, there has been an increase in reports of cancer developing in the biliary or pancreatic duct after hepaticoenterostomy. In this report, we describe the postoperative complications and carcinogenesis in 50 CBD patients according to the method of reconstruction of the bile duct. Hepaticojejunostomy (HJ) was performed in 34 patients and hepaticoduodenostomy (HD) in 16. In the HJ group, there were 7 cases of ascending cholangitis (20.6%), 3 cases of choledocholithiasis (8.8%), 4 cases of anastomotic stricture (11.8%) and 1 case of cholangiocarcinoma (2.9%). In the patient with cholangiocarcinoma, all complications including ascending cholangitis, choledocholithiasis, and anastomotic stricture were present. In the HD group, however, 2 cases of ascending cholangitis (5.9%) were recognized although choledocholithiasis, anastomotic stricture or cholangiocarcinoma were not observed. No significant differences were found in incidences of these complications between HJ and HD. It is unclear which method of reconstruction has a higher risk of carcinogenesis, however, it can be stated that hepaticoenterostomy itself is indeed one of the risk factors for biliary tract carcinoma. In any event, as several researchers have pointed out, since the incidence of bile duct carcinoma after the resection of the extrahepatic bile duct in CBD patients is very high compared to natural control, a long-term follow-up of the patient is necessary.

Rectal malignant melanoma diagnosed by N-isopropyl- p-123I-iodoamphetamine single photon emission computed tomography and 5-S-cysteinyl dopa: report of a case.

Malignant melanoma in the anorectal region is a rare disease associated with a very poor prognosis. Taking a biopsy of malignant melanoma is generally contraindicated because of the high risk of inducing metastasis. Although clinical examination and imaging findings are important for the preoperative diagnosis, conventional imaging techniques sometimes fail to provide information from which an accurate diagnosis can be made. We recently treated an 84-year-old woman with rectal malignant melanoma, in whom magnetic resonance imaging showed atypical findings. On the other hand, N-isopropyl- p-(123)I-iodoamphetamine single photon emission computed tomography and 5- S-cysteinyl dopa in blood serum, as a tumor marker of malignant melanoma, proved very effective for establishing the preoperative diagnosis. Despite radical abdominoperineal resection, the patient died of multiple liver and lung metastases about 5 months after surgery.

Clinical effects of combination therapy with mitoxantrone, vincristine, and prednisolone in breast cancer.

PURPOSE: We assessed the clinical efficacy and safety of mitoxantrone hydrochloride which has been used as an anticancer drug in our hospital to treat breast cancer patients since 1993. METHODS: A group of 23 patients with breast cancer were given one course of the following regimen every 3 weeks: mitoxantrone hydrochloride (8 mg/m(2) i.v. day 1), vincristine sulfate (1.2 mg/m(2) i.v. day 1), and prednisolone (30 mg orally days 1-7). RESULTS: The response rate was 52.2% including a complete response in four patients, and a partial response in eight patients. Adverse drug reactions included leukocytopenia (78.3%, 18/23 patients), alopecia (30.8%, 7/23), and peripheral neuropathy and generalized fatigue (26.1%, 6/23). In patients responding to the drug regimen, 50% survival was 29 months, and in those not responding it was 12 months. CONCLUSION: Combination treatment with mitoxantrone hydrochloride, vincristine sulfate and prednisolone is an effective treatment for breast cancer.

Subphrenic bronchopulmonary foregut malformation with pulmonary-sequestration-like features.

A retroperitoneal bronchopulmonary foregut malformation in a 62-year-old man is reported. The lesion was composed of mature lung tissue with randomly distributed bronchial structures and ciliated epithelium-lined cysts, some of which were lined with gastric mucosa. The histological features of this lesion were of both pulmonary sequestration and a bronchogenic, or foregut, cyst, and thus were a unique example of bronchopulmonary foregut malformation with pulmonary differentiation. This case is important in understanding the pathogenesis of foregut anomalies (i.e. bronchopulmonary foregut malformations), which range from pulmonary sequestrations to bronchogenic cysts and foregut duplication cysts.

Liver metastasis of pancreatic cancer managed by intra-arterial infusion chemotherapy combined with degradable starch microspheres.

A patient with liver metastasis of pancreatic cancer received chemotherapy using mitomycin C and degradable starch microspheres. The patient was a 52-year-old woman who had undergone surgery for cancer of the head of the pancreas in October 1996. She had stage III disease and was followed up as an outpatient on oral therapy with a combined uracil and tegafur preparation. In October 2000, abdominal computed tomography (CT) scans detected multiple liver metastases. Three courses of intra-arterial infusion of mitomycin C and microspheres (1000 mg) resulted in regression of her tumor and a decrease of tumor marker levels. After three more courses of this therapy, the patient developed bile duct necrosis and died of disseminated intravascular coagulation. As her metastases were controlled for about 7 months, hepatic arterial infusion of mitomycin C and degradable starch microspheres appears to be useful for treating liver metastasis of pancreatic cancer, but careful attention should be paid to the risk of severe complications such as bile duct necrosis.

Correlation between clinicopathologic factors and kinetics of metabolic enzymes for 5-fluorouracil given to patients with colon carcinoma by two different dosage regimens.

PURPOSE: Using tumor tissue specimens from colon carcinoma patients given 5-fluorouracil (5-FU) by two different administration methods, we investigated the degree of correlation between clinicopathologic factors and the kinetics of metabolic enzymes for 5-FU. METHODS: Group A patients received 500 mg/day of 5-FU as a rapid infusion over 2 h for 3 days preoperatively, and group B patients received 500 mg/day of 5-FU as a continuous infusion for 3 days preoperatively. The activities of orotate phosphoribosyl transferase (OPRT), thymidine phosphorylase (TP), uridine phosphorylase (UP), and dihydropyrimidine dehydrogenase (DPD) were measured by separation on ion-exchange filter paper, by high-performance liquid chromatography (HPLC) with UV detection and by HPLC with radioactive flow monitoring, respectively, and the [(3)H]-5-fluorodeoxyuridine monophosphate binding site in thymidylate synthetase (TS) was determined as an index of the amount of TS using a radiobinding assay. The TS inhibition rate (TSIR) was calculated from the formula: 1-(TS(free)/TS(total))x100. Finally, 5-FU incorporation into RNA (FRNA) was measured by capillary gas chromatography-mass spectrometry. RESULTS: In group A patients, FRNA showed a positive correlation only with OPRT, and TSIR showed positive correlations with OPRT and TP, but a negative correlation with TS. In group B patients, FRNA showed a negative correlation with DPD, and TSIR showed a negative correlation with TS. No difference in TSIR levels was seen between groups A and B. FRNA was higher in group A than in group B, but the difference was not statistically significant. CONCLUSION: The method of administration may influence 5-FU metabolism in colon carcinoma patients.

Efficient gene transfer to hepatoblastoma cells through asialoglycoprotein receptor and expression under the control of the cyclin A promoter.

Specific gene delivery into hepatoma cells by liposomes and specific gene expression under the control of the cyclin A promoter were examined in HepG2 cells, a hepatoblastoma cell line that overexpresses cyclin A. A plasmid carrying the luciferase gene under the cyclin A promoter sequence was condensed with poly-L-lysine and encapsulated into anionic asialofetuin-labeled liposomes (AF-liposomes), which were preferentially taken up by hepatocytes through the action of the asialoglycoprotein receptor (AgpR). AF-liposomes delivered plasmids to the hepatoma cells by receptor-mediated endocytosis through the AgpR, and transgene expression could be achieved under the control of the cyclin A promoter. Furthermore, a fusogenic lipid, DOPE, as a liposomal component was required for the enhancement of transfection efficiency of AF-liposomes.

Immunohistochemical analysis of cyclooxygenase-2 and vascular endothelial growth factor in pancreaticobiliary maljunction.

Recent studies have elucidated that cyclooxygenase (COX)-2 is strongly related to cancer progression or development by means of its anti-apoptotic effect, enhancement of angiogenesis or decrease of cell-to-cell adhesive activity. However, there is no report on the relationship between COX-2 expression and angiogenesis in pancreaticobiliary maljunction (PBM). We examined the correlation between the overexpression of COX-2 and vascular endothelial growth factor (VEGF) in 65 lesions from 30 patients with PBM immunohistochemically. The positive expression of COX-2 was found in 20% of regenerative epithelium, 11.1% of hyperplasia without atypia, 86.4% of hyperplasia with mild atypia, 75% of dysplasia, and 75% of cancerous lesions. VEGF was highly expressed in 80% of regenerative epithelium, 27.8% of hyperplasia without atypia, 86.4% of hyperplasia with mild atypia, 66.7% of dysplasia, and 75% of cancerous lesions. The positive rate of both COX-2 and VEFG expression was significantly higher in hyperplasia with atypia, dysplasia and cancerous lesions than that in hyperplasia without atypia. In addition, there was a statistically significant correlation between COX-2 and VEGF overexpression among all lesions. In 6 of 8 patients of various histological types, both COX-2 and VEGF were stained in almost exactly the same locations. In addition, there were no significant differences between the degree of inflammatory cell infiltration in the surrounding stroma and the expression of COX-2 and VEGF, respectively. These results demonstrated a strong relationship between COX-2 and VEGF overexpression in PBM. Therefore, chemoprevention via the suppression of angiogenesis by means of COX-2 inhibitor may be effective in PBM.

Immunohistochemical analysis of transforming growth factor beta in gallbladder cancer.

TGF-beta is highly expressed in various cancer cells, yet its mechanism suppressing the cell cycle fails and cell proliferation accelerates, resulting in carcinogenesis. However, there are only a very few reports on animal experiments or clinical specimens with regard to the TGF-beta in gallbladder cancer. We performed immunohistochemical analysis of TGF-beta expression with regard to cell proliferation, angiogenesis, and tumor cell infiltration in clinical specimens of gallbladder cancer. TGF-beta immunoreactivity was significantly higher in advanced cancer than in early cancer. With regard to Ki-67 labeling index, there was no significant difference between early cancer and advanced one. There was no statistically significant difference of the density of pre-existing blood vessels (CD34) between TGF-beta-positive group and negative one. The density of angiogenic vessels (CD105) was significantly greater in the TGF-beta-positive group than in the negative one. Tumor-associated macrophage infiltration was significantly higher in the TGF-beta-positive group than in the negative one. No statistically significant differences in cumulative survival rate were noted between patients in the TGF-beta-positive and TGF-beta-negative groups. In conclusion, our study revealed that in patients with gallbladder cancer, expression of TGF-beta increases according to cancer progression and strongly influences angiogenesis and macrophage infiltration, which contributes to tumor proliferation, but acts weakly on cancer cells by itself.

Measurement of serum thymidine phosphorylase levels by highly sensitive enzyme-linked immunosorbent assay in gastric cancer.

Thymidine phosphorylase (TP) is an enzyme that converts 5'-DFUR to 5-FU and also acts as an angiogenic factor. Measurement of serum TP levels has recently become possible by highly sensitive enzyme-linked immunosorbent assay (ELISA). We examined 38 patients with gastric adenocarcinoma to measure serum TP levels by highly sensitive ELISA method and tissue TP levels by conventional ELISA. In addition, immunohistochemical staining of normal and cancer tissues was also performed. Serum TP levels in patients with stages III and IV and inoperable or recurrent cancer were significantly higher than those in healthy controls. A high correlation was found between serum TP levels and tumor TP levels (r=0.65, p<0.0001). Moreover, serum TP levels were about 1/2500 of tumor TP levels. Tissue TP values in tumor were significantly higher than those in normal tissue. On the other hand, no significant differences among the cancer stages were found in either serum or tumor tissue. In conclusion, we demonstrate that serum TP levels strongly reflect tumor TP levels, and it may predict clinicopathological factors, prognosis, or sensitivity of anti-cancer drugs.