[A Case of Consciousness Disorder Due to Hyperammonemia Induced by Modified FOLFOX6 for Multiple Liver Metastasis from Rectal Cancer].

A 74-year-old man underwent laparoscopic-assisted high anterior resection with D3 lymph node dissection for rectal cancer, which was simultaneously accompanied by multiple liver metastases. The patient received mFOLFOX6 therapy for liver metastases 1 month after the surgery. Anorexia, nausea, and vomiting appeared on the second day of treatment. On the third day of treatment, impaired consciousness(JCS Ⅱ-20)and flapping tremors appeared. Blood tests revealed hyperammonemia, and the patient was diagnosed with impaired consciousness due to hyperammonemia, which was inferred to be caused by 5-fluorouracil(5-FU). Intravenous infusion and branched-chain amino acids were administered, and the patient recovered. The underlying disease of renal dysfunction, constipation, and dehydration due to chemotherapy might have induced the hyperammonemia. It is important to note that hyperammonemia can lead to a disturbance of consciousness during chemotherapy including 5-FU.

Laparoscopic Training for Gastrointestinal Surgery Using Japanese Traditional Papercraft Origami.

PURPOSE: The aim of this study is to show the experience and results of laparoscopic training using origami, a Japanese traditional papercraft, and to discuss its usefulness in gastrointestinal surgery. MATERIALS AND METHODS: A laparoscopic training dry box was used. An origami paper crane was folded using laparoscopic instruments. The time to complete the origami crane was measured. RESULTS: Two trainees participated in this study; the total number of origami cranes folded by these trainees was 2000 and 700, respectively. The learning curve gradually improved. According to our experience, this training strengthened mental faculties and was associated with the improvement of hand-eye and left-right coordination, reduction of tremor, acquisition of delicate technique, the ability to distinguish subtle differences in color, ability to respond to trouble. CONCLUSIONS: Laparoscopic training for gastrointestinal surgery using origami may have the potential to improve the technical skills in laparoscopic surgery.

A case of unclassified multicystic biliary tumor with biliary adenofibroma features.

A 40-year-old Japanese man was admitted to our hospital for evaluation of upper abdominal pain. Abdominal computed tomography (CT) revealed a well-circumscribed multicystic mass measuring approximately 7 × 6 cm. The mass contained a solid lesion measuring 3 × 2 cm. Biopsy of a swollen cervical lymph node led to a diagnosis of diffuse large B-cell lymphoma. After initial chemotherapy for lymphoma, the multicystic mass was surgically resected. The tumor was composed of a multicystic lesion and a solid lesion. Histopathologic examination of the multicystic lesion revealed that the locules were lined by biliary epithelium, demonstrating various degrees of cytological atypia. The stroma was fibrous, and the tumor showed marked apocrine snouts. Part of the tumor showed papillary growth with strong cytological atypia. The solid lesion showed tubulocystic proliferation of tumor cells, with prominent apocrine snouts, embedded in dense and partially hyalinized fibrous stroma. The morphology of the solid part was quite similar to that of reported biliary adenofibroma. Despite lengthy discussion, an appropriate pathological diagnosis could not be found among the current classifications of biliary tumor. The tumor was finally diagnosed as unclassified multicystic biliary tumor with adenofibroma features.

Tumor budding and dedifferentiation in gallbladder carcinoma: potential for the prognostic factors in T2 lesions.

Dedifferentiation (DD) is often encountered in gallbladder carcinoma (GBC) and poor prognosis with budding (BD) has been reported for other malignancies. However, the features of DD and BD in GBC remain unclear. The purpose of this study was to clarify the features and prognostic potential of DD and BD in GBC. A total of 80 patients with GBC (excluding intramucosal cancer) were enrolled. DD was histopathologically evaluated as tumors in which the grade of the invasive front is higher than the grade at the surface. BD was defined as an isolated single cancer cell or a cluster of fewer than five cancer cells at the invasive front. Of the 80 patients, 47 (58.8%) were positive for BD and 33 (41.2%) were positive for DD. Both BD and DD correlated significantly with disease-specific survival in univariate analysis (P < 0.0001 and P = 0.0013, respectively), but they were not identified as independent prognostic factors by multivariate analysis. In univariate analysis according to T stage, both BD and DD correlated significantly with survival in patients with T2 (n = 32) tumor (P = 0.0011 and P = 0.0018, respectively), whereas no prognostic impact in patients with T1b (n = 8), T3 (n = 34), or T4 (n = 6) tumor. Both DD and BD are frequently observed in GBC and reflect prognosis, particularly for T2 lesions. Therefore, the status of BD and DD should be taken into consideration in pathological reports on GBC.

Outcomes of patients with spontaneous rupture of hepatocellular carcinoma.

BACKGROUND/AIMS: The prognosis of ruptured hepatocellular carcinoma (HCC) has been reported to be poor, but some studies have reported better survival with staged hepatectomy. The aim of this study was to elucidate the clinical features of ruptured HCC. METHODOLOGY: Among 305 patients with HCC who underwent hepatic resection between 1990 and 2008 in our institution, 10 patients had ruptured HCC. Ruptured group (Group R; n=10)were compared with those of patients with unruptured HCC group (Group UR; n=295), concerning hepatic reserve, tumor extent and outcome. RESULTS: Rupturedgroup had extremely large tumor than unruptured group (94 + 43 mm vs. 45 +/- 32 mm, p < 0.001). The proportions of multiple nodules and poorly tumor grade were significantly higher in Group R than in Group UR. The populations of extrahepatic recurrence and early mortality (<1 year) were significant higher in Group R than Group NR. The median survival time of Group R was shorter than Group NR. The tumor rupture was independent prognostic factors that had the most serious effect on the survival of patients with HCC among the patients with HCC underwent hepatic resection. CONCLUSIONS: The patients with spontaneously ruptured HCC had advanced disease, and poor prognosis. Hepatic resection might improve the survival, but a new therapeutic strategy is necessary for the long-term survival of patients with ruptured HCC.

Ribonucleotide reductase subunit M1 assessed by quantitative double-fluorescence immunohistochemistry predicts the efficacy of gemcitabine in biliary tract carcinoma.

Gemcitabine is a commonly used chemotherapeutic agent for advanced biliary tract carcinoma (BTC), although its efficacy is insufficient. Therefore, it is essential to establish new diagnostic methods, which can predict responders before the treatment. The aim of this study is to identify the most reliable chemoresistance marker to gemcitabine in BTC among the 4 molecules (hENT1, dCK, RRM1 and RRM2) involved in gemcitabine metabolism. The expression of 4 molecules were investigated in 5 BTC cell lines, and correlated with gemcitabine sensitivity. RRM1 protein was also assessed by quantitative double-fluorescence immunohistochemistry (qDFIHC) in 10 patients with unresectable or recurrent BTC who received gemcitabine-based chemotherapy. RRM1 and RRM2 protein strongly correlated with the IC(50) value for gemcitabine in BTC cell lines (R=0.935, 0.771, respectively). In addition, patients with low RRM1 were significantly more sensitive to gemcitabine (p=0.033), and their survival was significantly better than patients with high RRM1 (p=0.001). In conclusion, RRM1 particularly in protein level is a reliable marker for gemcitabine resistance in BTC. Furthermore, qDFIHC is a useful method for the assessment of RRM1 protein, in order to design a tailor-made chemotherapeutic regimen for BTC patients.

Rational therapeutic strategy for T2 gallbladder carcinoma based on tumor spread.

AIM: To evaluate the adequacy of surgical treatment of T2 gallbladder carcinoma (GBCa) according to tumor spread in the subserosal layer. METHODS: A series of 84 patients with GBCa were treated at Saga University Hospital, Japan between April 1989 and October 2008. The tumor stage was graded according to the TNM staging for GBCa from the American Joint Committee on Cancer Manual 6th edition. Tumor staging revealed 30 patients with T2 tumors. T2 GBCa was divided into three groups histologically by the extent of tumor spread in the subserosal layer, using a score of ss minimum (ss min), ss medium (ss med) or ss massive (ss mas). RESULTS: For ss min GBCa, there was no positive pathological factor and patient survival was satisfactory with simple cholecystectomy, with or without extra-hepatic bile duct resection. For ss med GBCa, some pathological factors, h-inf (hepatic infiltration), ly (lymphatic invasion) and n (lymph node metastasis), were positive. For ss mas GBCa, there was a high incidence of positive pathological factors. The patient group with extra-hepatic bile duct resection with D2 lymph node dissection (BDR with D2) and those with S4a5 hepatectomy had significantly better survival rates. CONCLUSION: We suggest that radical surgery is not necessary for ss min GBCa, and partial hepatectomy and BDR are necessary for both ss med and ss mas GBCa.

Gallbladder carcinoma with a large monolocular cystic cancerous component.

The monolocular cystic formation associated with gallbladder carcinoma is an extremely rare condition. A 79-year-old female suffering from upper abdominal pain and distention was admitted to our hospital. Ultrasonography and computed tomography revealed a monolocular cyst with an irregular wall thickness of 15 cm in diameter concomitant with a solid mass of 8 cm in diameter around the gallbladder bed. During celiotomy, the tumor was found to have a large pale gray cystic component at the fundus of the gallbladder, and disseminated nodules were observed in the peritoneum. We diagnosed the patient with gallbladder carcinoma and performed a simple cholecystectomy that included the tumor without systematic lymphadenectomy. On the cut face of the gallbladder, the lumen was occupied by a solid neoplasm. The cyst included a large amount of serous fluid and protruded continuously from the body of the gallbladder, but it did not communicate with the gallbladder lumen. Although the mechanism responsible for the development of cyst-forming papillary carcinoma of the gallbladder remains unknown, the present case is crucial for understanding the mechanism of cystogenesis in gallbladder carcinoma.

[A case of unresectable hilar bile duct cancer responding to chemo-radiotherapy by gemcitabine].

A 66-year-old woman was admitted to our hospital because of general fatigue and icterus. PTC findings showed irregular stenosis of hilar bile duct. Abdominal CT scan showed a dilatation of the intra-hepatic bile duct and a tumor around hilar bile duct. We diagnosed it as hilar bile duct carcinoma, and although we operated it was unresectable because of the metastasis of a para-aorta lymph node and duodenal invasion. We started chemo-radiotherapy with a total dose of 45 Gy and gemcitabine. The tumor and para-aorta lymph node were remarkably decreased, and tumor marker CA 19-9 was also decreased to within the normal range. The patient had a peritoneal dissemination 10 months after the chemo-radiotherapy and survived 20 months.

Efficacy of major hepatectomy for large hepatocellular carcinoma.

BACKGROUND/AIMS: Large hepatocellular carcinomas (HCC) with diameter >10 cm reportedly displays poor prognosis. The role of hepatic resection in the treatment of large HCC remains controversial. We evaluated the efficacy of hepatic resection, particularly major hepatectomy, for large HCC. METHODOLOGY: From January 1987 to December 2004, a total of 252 patients with primary HCC underwent hepatic resection in our institution. The 22 patients with HCC > or =10 cm (Group A) were compared with the 230 patients with HCC <10 cm (Group B) in terms of clinicopathological factors and prognosis. RESULTS: Serum alpha-fetoprotein level was significantly higher in Group A than in Group B (p=0.004) and populations of patients with portal vein invasion, hepatic vein invasion and satellite nodules were significantly higher in Group A than in Group B (p<0.001; p<0.001; p=0.034. The 5-year survival rate was worse for Group A (45.2%; median survival, 25 months) than for Group B (67.8%; median survival, 48.2 months). Major hepatic resection (>2 segments) was the only prognostic factor for overall survival in patients with large HCC (p=0.024). Five-year survival rate was significantly better for patients with major hepatectomy (58.3%; median survival, 30.0 months) than for patients with minor hepatic resection (16.7%; median survival, 7.1 months). Liver cirrhosis and early recurrence were significantly less frequent in the major hepatectomy group than in the minor hepatectomy group (p=0.026; p=0.005). Hepatic resection for large HCC could be performed with zero mortality. CONCLUSIONS: Major hepatectomy can improve prognosis while preserving liver function for patients with large HCC.

Improvement of glucose metabolism after a pancreatoduodenectomy.

OBJECTIVES: The aim of this study was to investigate the mechanisms of the change in glucose metabolism after a pancreatoduodenectomy (PD). METHODS: Oral glucose tolerance tests were performed in 17 patients before and 1 month after a PD. The changes in plasma glucose and insulin concentrations, homeostasis model of insulin resistance, and insulinogenic index (beta-cell function) were analyzed. Two additional factors, gastric emptying function and plasma glucagon-like peptide-1 (GLP-1) concentration, that possibly affect perioperative glucose metabolism were also assessed. RESULTS: The plasma glucose and insulin concentrations were significantly lower after the operation, especially in preoperative diabetic patients. beta-Cell function did not change after the operation. On the other hand, insulin resistance became normal 1 month after the operation. The value of gastric emptying function after the operation was not statistically different in comparison with that before the operation. Postoperative plasma GLP-1 concentration was significantly higher than the preoperative value. CONCLUSIONS: beta-Cell function is maintained after a PD, whereas the improvement of insulin resistance may cause a short-term transient improvement of the glucose metabolism after the operation. The significance of increased postoperative GLP-1 concentration remains an unsolved issue.

A long-time survivor of alpha-fetoprotein-producing gastric cancer successfully treated by fluoropyrimidine-based chemotherapy: a case study.

A 67-year-old male with advanced gastric cancer and lymph node metastasis as well as a tumor embolus in the portal vein was treated by S-1/cisplatin therapy. The serum alpha-fetoprotein levels were elevated to 836 ng/ml at the first visit. After one course of chemotherapy, the patient showed stable disease; the serum level of alpha-fetoprotein also decreased to 626 ng/ml after a transient increase, and therefore reduction surgery was performed. A total gastrectomy with a distal pancreatectomy, splenectomy, and regional lymph node dissection was performed. The resected specimen was diagnosed to be alpha-fetoprotein-producing gastric cancer. There were no metastatic foci in the resected lymph nodes, presumably due to the preoperative chemotherapy. S-1/cisplatin therapy was continued after the operation to treat the remaining tumor embolus in the portal vein. After one course of this therapy, the tumor embolus disappeared. However, a lymph node measuring 1.5 cm in diameter appeared in the hepatoduodenal ligament. Therefore, the chemotherapy was changed to paclitaxel monotherapy. After 2 courses of paclitaxel monotherapy, the lymph node swelled, and thus 5'-deoxy-5-fluorouridine was added to the paclitaxel regimen. After 5 courses of this regimen, the lymph node swelling disappeared without any other new lesions and a total of 21 courses were performed. The patient remained stable for over 8 years without recurrence. The expression of chemoresistance-related proteins was retrospectively analyzed by immunohistochemistry to evaluate the chemoresistance. The ortate phosphoribosyltransferase expression was strongly positive, and the good outcome in this case may have been associated with this result.

Percutaneous transhepatic portal embolization for persistent bile leakage after hepatic resection: report of a case.

Bile leakage is a relatively common complication after hepatic resection. We report a case of intractable bile leakage after hepatectomy, which was successfully treated by percutaneous transhepatic portal embolization (PTPE). A 58-year-old Japanese man underwent anterior resection of the rectum followed by central bisegmentectomy of the liver (S4 + S5 + S8) for rectal cancer with liver metastasis. Bile leakage from the cut surface of the posterior segment developed on postoperative day 2. Conservative management with simple drainage and ethanol injections into the fistula proved ineffective. Thus, we performed PTPE in the posterior portal branch to eliminate the production of bile from the posterior segment and to block the enterohepatic circulation to that segment. His post-treatment course was uneventful and the bile leakage resolved immediately.

Ribonucleotide reductase subunit M1 is a possible chemoresistance marker to gemcitabine in biliary tract carcinoma.

Biliary tract carcinoma is a relatively rare tumor with a poor prognosis. Surgical resection is the only potential cure. However, the efficacy of chemotherapeutic agents is disappointing in advanced or recurrent cases. Gemcitabine (GEM) appears to be one of the most promising chemotherapeutic agents in biliary tract carcinoma, and ribonucleotide reductase subunit M1 (RRM1) plays an important role in GEM resistance. The aim of this study was to evaluate the correlation between the expression of RRM1 and the response to GEM in biliary tract carcinoma in vitro and in vivo. The drug sensitivity to GEM was assessed by MTT assay. The expression of RRM1 was evaluated by quantitative RT-PCR, a Western blot analysis and immunohistochemistry. RNAi assay was used to investigate the down-regulation of the expression of RRM1. After the RRM1-specific RNAi transfection, a cell growth assay was performed to evaluate the drug sensitivity to GEM, and flow cytometry and TUNEL assay were performed to evaluate apoptosis. The results showed that in 6 biliary tract carcinoma cell lines, a tendency for a positive correlation between the expression of RRM1 and IC50 for GEM exists (R=0.620, p=0.19). The transfection of the RRM1-specific RNAi suppressed the expression level of RRM1 in a dose-dependent manner. After the transfection of RRM1-specific RNAi into G-415, the drug sensitivity to GEM markedly increased (p<0.001), and apoptosis was highly induced according to flow cytometry and the TUNEL assay. In an analysis of cancer tissue specimens obtained from the 12 patients treated with GEM for biliary tract cancer, RRM1 immunostaining was strongly positive in all of the PD cases (3/3), while weakly positive in all of the PR cases except for one (4/5). In conclusion, RRM1 may be one of the key marker molecules for GEM chemotherapy that overcomes advanced and recurrent biliary tract carcinoma.

Hepatectomy of segment 4a and 5 combined with extra-hepatic bile duct resection for T2 and T3 gallbladder carcinoma.

BACKGROUND: The prognosis of advanced gallbladder carcinoma (GBCa) remains unfortunate. However, the prognostic factors and the efficacy of extended resection remain unclear. The adequacy for extended resection for T2 and T3 GB Ca, according to the characteristics of either the clinicopathological factors or the prognostic factors, was evaluated. METHODS: A series of 73 patients with GBCa were treated after 1989. Tumor staging from the AJCC revealed 23 patients with T2 tumors, and 29 patients with T3 tumors, respectively. RESULTS: For T2 GB Ca, the patient group of extra-hepatic bile duct resection (BDR) and the patient group of S4a + 5 hepatectomy S4a + 5 had significantly better survival rates. For T3 GB Ca, the patient group of BDR and S4a + 5 tend to have better survival rates. For both T2 and T3 GB Ca, either pancreatoduodenectomy (PD) or pylorus-preserving pancreatoduodenectomy (PpPD) showed no significant difference in survival. CONCLUSION: S4a + 5 combined with BDR and D2 lymph node dissection is a highly recommended operation for the treatment of T2 and T3 GB Ca. Further extension of the operation, such as the addition of PD (PpPD) or an extended hepatectomy, should be carefully modified for each individual according to the cancer spread mode.

Phase I/II study of combination therapy with S-1 and CPT-11 for metastatic colorectal cancer.

We conducted a Phase I/II study of combination therapy using CPT-11 and S-1 as a first-line treatment for metastatic colorectal cancer. The 28-day treatment cycle consisted of S-1 administered orally from day 1 to 21 and CPT-11 administered intravenously on days 1 and 15. In the Phase I portion, the dose of S-1 was fixed at 80 mg/m2/day, while CPT-11 was administered at a starting dose of 60 mg/m2 then stepped up in 20 mg/m2 increments. The maximum-tolerated dose was achieved at 80 mg/m2 of CPT-11, and the recommended dose was determined to be 60 mg/m2 of CPT-11. In the Phase II portion, this therapy exhibited a response rate of 58%, a median progression-free survival of 8.4 months, and a median overall survival of 18.7 months. Toxicity was generally mild and manageable. No patient showed grade 4 toxicity, and grade 3 toxicity was observed in only 18% of patients. The most frequently observed grade 3 toxicity was diarrhea, at a rate of 6%. The mean relative dose intensity of CPT-11 and S-1 was as high as 98 and 97%, respectively. In conclusion, combination therapy with CPT-11 and S-1 according to our treatment schedule is effective, safe and highly feasible for metastatic colorectal cancer patients. These data suggest that assessing this combination therapy in a Phase III study would be worthwhile.

CPT-11 (SN-38) chemotherapy may be selectively applicable to biliary tract cancer with low hMLH1 expression.

Biliary tract cancer is of highly malignancy with a poor 5-year survival. However, established chemotherapeutic regimens have not yet been established. Previously, we have reported that hMLH1, a mismatch repair (MMR) gene was frequently (57%) found to be lacking in surgically resected biliary tract carcinomas and the patients lacking the expression of hMLH1 revealed a poorer prognosis than those patients who possessed it. The MMR gene has been considered to be associated with sensitivity to various chemotherapeutic agents that act on DNA. A loss of MMR expression has been reported to increase sensitivity to topoisomerase inhibitors such as etoposide (ETP) or camptothecins (CPT). In the present study, whether or not hMLH1 deficiency resulted in a higher sensitivity to irinotecan (CPT-11) active form (SN-38) was investigated using a short interfering (Si)RNA system. A quantitative reverse transcription-polymerase chain reaction (RT-PCR) was conducted to measure the levels of hMLH1 expression in seven cancer cell lines, and this was compared with the drug sensitivity (IC50) to SN-38. The hMLH1 expression was correlated with the IC50 for SN-38, although the relationship was not statistically significant (R = 0.717, p = 0.0715). SiRNA double strand RNA (dsRNA) was transiently transfected into KMG-C (gallbladder cancer) cells. hMLH1 mRNA expression was repressed by hMLH1 dsRNA in a dose-dependent manner in comparison to the control dsRNA. The cell growth of the hMLH1 dsRNA transfected group was decreased by approximately 50% by SN-38 exposure. Flow cytometry was also carried out to examine the effect of the SN-38 treatment on the cell cycle. Following hMLH1 dsRNA transfection, the subG1 fraction was increased in comparison with the control in a dose-dependent manner. In conclusion, a low expression of hMLH1 in biliary tract cancer may aid in predicting its responsiveness to CPT-11 (SN38).

Aberrant promoter hypermethylation in biliary tract carcinoma.

Biliary tract carcinoma is a relatively rare tumor with a poor survival rate. The molecular biological mechanisms underlying the development of biliary tract carcinomas are not well understood. Promoter methylation is an important epigenetic mechanism for suppressing tumor-suppressor gene activity. There is limited information regarding the abnormal methylation of cancer-related genes in biliary tract carcinoma; however, a few insights have been obtained into the role of epigenetic silencing in the progression of biliary tract carcinoma. In this review, we summarize recent data on gene silencing by promoter hypermethylation, and we discuss the implications for biliary tract carcinomas.

FAT10/diubiquitin-like protein-deficient mice exhibit minimal phenotypic differences.

The FAT10 gene encodes a diubiquitin-like protein containing two tandem head-to-tail ubiquitin-like domains. There is a high degree of similarity between murine and human FAT10 sequences at both the mRNA and protein levels. In various cell lines, FAT10 expression was shown to be induced by gamma interferon or by tumor necrosis factor alpha. In addition, FAT10 expression was found to be up-regulated in some Epstein-Barr virus-infected B-cell lines, in activated dendritic cells, and in several epithelial tumors. However, forced expression of FAT10 in cultured cells was also found to produce apoptotic cell death. Overall, these findings suggest that FAT10 may modulate cellular growth or cellular viability. Here we describe the steps to generate, by genetic targeting, a FAT10 gene knockout mouse model. The FAT10 knockout homozygous mice are viable and fertile. No gross lesions or obvious histological differences were found in these mutated mice. Examination of lymphocyte populations from spleen, thymus, and bone marrow did not reveal any abnormalities. However, flow cytometry analysis demonstrated that the lymphocytes of FAT10 knockout mice were, on average, more prone to spontaneous apoptotic death. Physiologically, these mice demonstrated a high level of sensitivity toward endotoxin challenge. These findings indicate that FAT10 may function as a survival factor.