Tetsuo Sumi

Clinical significance of interleukin-6 (IL-6) in the spread of gastric cancer: role of IL-6 as a prognostic factor.

BackgroundIt is becoming clear that various cytokines are associated with the spread of cancer cells. The purpose of this study was to compare interleukin (IL)-6 levels in patients with gastric cancer to elucidate the role of IL-6 in predicting the spread of tumors.MethodsIn 60 patients, we assessed the correlation of serum IL-6 (pg/ml) with stage, histological findings, hepatic metastasis, and related factors (hepatocyte growth factor [HGF], IL-1β, tumor necrosis factor [TNF]-α, and transforming growth factor [TGF]-β1). We also investigated the diagnostic significance of the IL-6 level for advanced gastric cancer and lymph node metastasis, as well as the association between IL-6 elevation and outcome. Finally, we examined the expression of IL-6 in tumor tissue.ResultsSignificant relationships were seen between serum IL-6 and stage, depth of tumor invasion (pT), lymphatic invasion (ly), venons invasion (v)*, lymph node metastasis (pN), hepatic metastasis (cH), and HGF (P < 0.01; *P < 0.05). With regard to the diagnostic significance of the IL-6 level for advanced gastric cancer and lymph node metastasis, when the cutoff value of IL-6 was set at 1.97 pg/ml, the sensitivity was 81.8% and 87.5%; specificity was 66.7% and 58.3%; and accuracy was 77.1% and 72.9%, respectively. The 1- and 3-year cumulative survival rates for patients with an IL-6 value of more than 1.97 pg/ml (69.0% and 43.4%, respectively) were significantly lower than those for patients with an IL-6 value of 1.97 pg/ml or less (94.4% and 87.2%, respectively; P < 0.05). Immunohistochemical staining was positive for IL-6 in the cytoplasm of cancer cells.ConclusionWe suspect that IL-6 is involved in cancer invasion and lymph node and/or hepatic metastasis. Our results indicate that IL-6 could be used as a prognostic factor for survival.

Calcium-induced generation of reactive oxygen species in brain mitochondria is mediated by permeability transition.

Mitochondrial uptake of calcium in excitotoxicity is associated with subsequent increase in reactive oxygen species (ROS) generation and delayed cellular calcium deregulation in ischemic and neurodegenerative insults. The mechanisms linking mitochondrial calcium uptake and ROS production remain unknown but activation of the mitochondrial permeability transition (mPT) may be one such mechanism. In the present study, calcium increased ROS generation in isolated rodent brain and human liver mitochondria undergoing mPT despite an associated loss of membrane potential, NADH and respiration. Unspecific permeabilization of the inner mitochondrial membrane by alamethicin likewise increased ROS independently of calcium, and the ROS increase was further potentiated if NAD(H) was added to the system. Importantly, calcium per se did not induce a ROS increase unless mPT was triggered. Twenty-one cyclosporin A analogs were evaluated for inhibition of calcium-induced ROS and their efficacy clearly paralleled their potency of inhibiting mPT-mediated mitochondrial swelling. We conclude that while intact respiring mitochondria possess powerful antioxidant capability, mPT induces a dysregulated oxidative state with loss of GSH- and NADPH-dependent ROS detoxification. We propose that mPT is a significant cause of pathological ROS generation in excitotoxic cell death.

Detection and evaluation of epithelial cells in the blood of colon cancer patients using RT-PCR.

BackgroundAs a mode of colorectal cancer recurrence, liver metastasis plays an important role. One of the factors reported to predict liver metastasis is the detection of trace amounts of tumor cells in the blood. For this purpose, cancer cell-induced cytokeratins (CKs) are generally identified, using the reverse transcriptase-polymerase chain reaction (RT-PCR). In the present study, we aimed to detect trace amounts of tumor cells, based on CK20, in the circulating venous blood, and we examined pathological factors, liver metastasis, and prognosis.MethodsThe subjects were 57 colorectal cancer patients who had undergone operation. We examined the cancer-induced marker (CK20) in circulating venous blood by RT-PCR and investigated the relationships between this marker, pathological factors, and prognosis.ResultsDetection ratio of CK20 mRNA was 42.1%, and CK20 was significantly correlated with the pathological factor of lymph node metastasis(P = 0.037). The 5-year survival rate for CK20-positive patients was 62.5% and that for the CK20-negative patients was 87.5%; there was a significant difference(P = 0.048) between the two groups. Recurrence was recognized in six patients; two were positive for CK20 and four were negative for CK20.ConclusionsThese findings indicate that CK20 is strongly related to lymph node metastasis and prognosis, suggesting its usefulness for the diagnosis of colorectal cancer recurrence. However, CK20 did not predict liver metastasis.

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

BackgroundWe investigated the influence of genes on the apoptosis of colorectal tumor cells, based on DNA and mRNA kinetics.MethodsIn 30 colorectal cancer patients, we examined the mRNA expression of p53, bax, bcl-2, and p21WAF1, and we also investigated the development of tumor cell apoptosis, using a terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick-end labeling (TUNEL) method.ResultsTUNEL-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.ConclusionsThe 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.

Analysis of Autonomic Nerve Preservation and Pouch Reconstruction Influencing Fragmentation of Defecation after Sphincter-Preserving Surgery for Rectal Cancer

Our questionnaire survey on defecation disorders after rectal cancer surgery revealed that 66.7% of postoperative patients were most annoyed with fragmentation of defecation. Therefore, we performed a change-over-time analysis on the relationship of fragmentation and factors including location of rectal cancer, surgical technique, anastomosis method, pouch reconstruction, extent of lymph node dissection, and degree of pelvic and colonic nerve preservation surrounding the superior mesenteric artery. The fragmentation decreased over time at the postoperative time points of 6 months, 2 and 5 years. A statistical analysis of factors influencing fragmentation revealed that location of cancer, reconstruction technique, anastomosis method and degree of pelvic nerve preservation were significant factors for the entire patient population and that colonic nerve preservation was a significant factor 5 years after surgery. Analysis of patients with lower rectal cancer only showed that in addition to surgical technique and anastomosis method, pouch reconstruction was effective and autonomic nerve preservation was effective 5 years after surgery. As a result, when the anastomotic site was closer to the anus, the frequency of fragmentation increased; we concluded that pouch reconstruction was an effective surgical technique and colonic nerve preservation was effective in the longer term.

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

Abstract. 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.

Correlations of Clinicopathological Factors with Protein Expression Levels of Thymidylate Synthase, Dihydropyrimidine Dehydrogenase and Orotate Phosphoribosyltransferase in Colorectal Cancer

Background: Expression levels of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), and orotate phosphoribosyltransferase (OPRT) have been reported to be associated with tumor response to 5-fluorouracil (5-FU). Method: We investigated correlations of clinicopathological factors with protein expression levels of TS, DPD, OPRT in colorectal cancer (CRC). The subjects were 202 patients who had undergone CRC resection. Result: There was a negative correlation between DPD and OPRT protein levels, but no correlation of TS levels with either OPRT or DPD levels. The DPD levels in women was significantly lower than that in men. The DPD level was significantly lower in colonic tumors than in rectal tumors, while the OPRT level was significantly higher in colonic tumors than in rectal tumors. The TS level did not correlate with any clinicopathological factors. Conclusion: DPD and OPRT protein levels in CRC suggest that female gender and colonic tumors are positive prognostic factors in patients who receive chemotherapy with 5-FU.

Examination of prognostic factors in patients undergoing surgery for colorectal perforation: A case controlled study

OBJECTIVE To determine if the POSSUM, SOFA, MPI, and SAS scores provide a better measure of severity for patients with prognostic factors undergoing surgery for colorectal perforation. SUBJECTS Fifty-nine patients who underwent surgery between 1996 and 2012. METHODS We retrospectively reviewed background factors, blood and physiological test results, and intraoperative findings of patients who survived and those who died. We also compared the POSSUM, SOFA, MPI, and SAS scores. Multivariate analysis was performed for factors that were significant by univariate analysis, and selected factors were used to produce a predictive prognostic model. RESULTS Univariate analysis revealed significant differences in age, anticoagulant/steroid administration, serum creatinine level, PF ratio, base excess (BE), chest radiography, pulse rate, and severity of peritoneal soiling. Age, serum creatinine level, pulse rate, and severity of peritoneal soiling were selected for multivariate analysis; only pulse rate was significantly different. There were significant differences between the two groups in POSSUM PS, OSS, SOFA, and MPI scores, and a comparison in terms of the ROC curve showed that our model had the highest peak; the area under the curve was 94.8% compared with 70-80% for the other systems, suggesting that our model is better than those systems. CONCLUSIONS POSSUM and SOFA are valid methods of evaluating risk from colorectal perforation, but our study revealed addition risk factors: (1) the PF ratio and BE, which are not included in POSSUM; (2) the pulse rate and severity of peritonitis, which are not included in SOFA; and (3) anticoagulant/steroid hormone administration.

Oxaliplatin for Metastatic Colon Cancer in a Patient with Renal Failure

Objective Oxaliplatin, a key part of the standard regimen for colorectal cancer in Western countries, has become available in Japan. In a hemodialysis patient with cecal cancer, we investigated the efficacy, safety, pharmacokinetics, and dialysability of oxaliplatin. Methods A 65-year-old man who had cecal cancer was treated with oxaliplatin (40 mg/m2) and l-leucovorin(l-LV) (200 mg/m2), which were administered simultaneously over 120 min via the side and main arms of a Y-tube, respectively. Then 5-FU (400 mg/m2) was administered rapidly via the side tube, followed by 5-FU (2,000 mg/m2) over 46 hours via the main tube. The patient had chronic renal failure due to diabetic nephropathy and hemodialysis was performed 3 times a week. Blood samples were collected from the dialyzer before and after each hemodialysis session to examine platinum clearance. Results The patient received 3 courses of oxaliplatin before he died of cancer. During hemodialysis, the platinum level fell from 0.32 μg/mL to 0.15 μg/mL. Conclusion Since patients with renal failure have various associated disorders and oxaliplatin has a long half-life, it is necessary to obtain more pharmacokinetic data to investigate its accumulation and dialysability during long-term treatment. Such data will assist in treating the rapidly increasing number of hemodialysis patients with colorectal cancer.

A case of a gastrointestinal stromal tumor with skeinoid fibers of the sigmoid colon.

An 80-year-old man was diagnosed with rectal cancer and underwent Hartmanns procedure. Although no tumors were identified during the preoperative examination, gross examination of the resected specimen incidentally revealed a submucosal tumor that was 9 mm in diameter at the oral side and located in the proximal stump of the specimen from the sigmoid colon. We suspected a concurrent gastrointestinal stromal tumor (GIST) and performed a histopathological examination. An L-shaped nodular lesion measuring 9 × 6 mm was histologically composed of a patternless proliferation of spindle cells intermingled with eosinophilic globules. Cellular atypia, prominent mitotic figures and necrotic foci were not observed in the nodule. The spindle cells were positive for CD34, CD117 and vimentin, but negative for CD56, smooth muscle actin and S-100 protein. MIB-1 positivity was estimated to be as low as approximately 1-2%. Electron microscopy showed a bundle of wool-like fibers with a periodicity of approximately 40 nm. We therefore considered the lesion to be a low-risk GIST with skeinoid fibers in the large intestine. Although numerous previous reports have reported skeinoid fibers in the stomach and small intestines, there have been only 9 cases (including the present case) of skeinoid fibers in the large intestine.