Oxidative DNA damage in human esophageal cancer: clinicopathological analysis of 8-hydroxydeoxyguanosine and its repair enzyme.

Both internal and external oxidative stresses act on DNA and can induce carcinogenesis. 8-hydroxydeoxyguanosine (8-OHdG) is an indicator of oxidative stress and it leads to transversion mutations and carcinogenesis. 8-OHdG is excision-repaired by 8-OHdG DNA glycosylase (OGG1). The purpose of this study is to clarify the effect of oxidative DNA damage and repair enzymes on esophageal carcinogenesis. The levels of 8-OHdG and OGG1 were immunohistochemically evaluated in resected specimens, including squamous cell carcinoma (SCC) in 97 patients with esophageal cancer. Higher levels of 8-OHdG in normal esophageal epithelium were associated with a higher smoking index (P = 0.0464). The 8-OHdG level was higher in cancerous areas than in normal epithelia (P = 0.0061), whereas OGG1 expression was weaker in cancerous areas than in normal epithelia (P < 0.0001). An increase of OGG1 expression in normal epithelium was observed as 8-OHdG levels increased (P = 0.0011). However, this correlation was not observed in cancerous areas. High OGG1 expression in the cytoplasm was related to deeper tumors (P = 0.0023), node metastasis (P = 0.0065) and stage (P = 0.0019). Oxidative DNA damage, which is attributable to smoking as well as disturbances in DNA repair systems, appears to be closely related to esophageal carcinogenesis and its progression.

Esophageal replacement by colon interposition with microvascular surgery for patients with thoracic esophageal cancer: the utility of superdrainage.

Replacing the thoracic esophagus with the colon is one mode of reconstruction after esophagectomy for esophageal cancer. There is, however, a high incidence of postoperative necrosis of the transposed colon. This study evaluated the outcomes of colon interposition with the routine use of superdrainage by microvascular surgery. Twenty-one patients underwent colon interposition from 2004 to 2009. The strategy for colon interposition was to: (i) use the right hemicolon; (ii) reconstruct via the subcutaneous route; (iii) perform a microvascular venous anastomosis for all patients; and (iv) perform a microvascular arterial anastomosis when the arterial blood flow was insufficient. The clinicopathologic features, surgical findings, and outcomes were investigated. The colon was used because of a previous gastrectomy in 18 patients (85.7%) and synchronous gastric cancer in three patients (14.3%). Eight patients (38.1%) underwent preoperative chemoradiotherapy including three (14.3%) treated with definitive chemoradiotherapy. Seven patients (33.3%) underwent microvascular arterial anastomosis to supplement the right colon blood supply. Pneumonia occurred in four patients (19.0%). Anastomotic leakage was observed in five patients (23.8%); however, no colon necrosis was observed. The 3-year and 5-year overall survival rates were both 50.6%. Colon interposition with superdrainage results in successful treatment outcomes. This technique is one option for colon interposition employing the right hemicolon.

Acute lung injury following an esophagectomy for esophageal cancer, with special reference to the clinical factors and cytokine levels of peripheral blood and pleural drainage fluid.

Acute lung injury (ALI) is one of most serious complications to occur after an esophagectomy for esophageal cancer. However, the pathogenesis of ALI is still unclear. The cytokine levels of pleural drainage fluid as well as peripheral blood were measured in 27 patients who had undergone an extended radical esophagectomy. Both the clinical factors and cytokine levels were compared between 11 patients with (group I) and 16 without ALI (group II). ALI occurred more frequently in patients who underwent colon interposition than in those who received a gastric tube reconstruction (86%vs 25%, P = 0.009). The operation time of group I was significantly longer than that of group II. A logistic regression analysis revealed colon interposition to be an independent factor associated with the ALI (P < 0.05). Postoperative anastomotic leakage and systemic inflammatory response syndrome (SIRS) occurred more frequently in group I than in group II (P < 0.01). Both the serum interleukin-6 (IL-6) and IL-8 levels of group I were significantly higher than those of group II. IL-1beta and tumor necrosis factor-alpha were undetectable in the peripheral blood, whereas they were detectable in the pleural effusion. The IL-1beta of pleural effusion was higher in group I than group II. In conclusion, greater surgical stress, such as a longer operative time, is thus considered to be associated with the first attack of ALI. The adverse events developing in the extra-thoracic site, such as necrosis and local infection around anastomosis may therefore be the second attack. Furthermore, ALI may cause not only SIRS but also other complications such as anastomotic leakage.

Spontaneous tumorigenesis in mice defective in the MTH1 gene encoding 8-oxo-dGTPase.

Oxygen radicals, which can be produced through normal cellular metabolism, are thought to play an important role in mutagenesis and tumorigenesis. Among various classes of oxidative DNA damage, 8-oxo-7,8-dihydroguanine (8-oxoG) is most important because of its abundance and mutagenicity. The MTH1 gene encodes an enzyme that hydrolyzes 8-oxo-dGTP to monophosphate in the nucleotide pool, thereby preventing occurrence of transversion mutations. By means of gene targeting, we have established MTH1 gene-knockout cell lines and mice. When examined 18 months after birth, a greater number of tumors were formed in the lungs, livers, and stomachs of MTH1-deficient mice, as compared with wild-type mice. The MTH1-deficient mouse will provide a useful model for investigating the role of the MTH1 protein in normal conditions and under oxidative stress.

Analysis of MTH1 gene function in mice with targeted mutagenesis.

Oxidative DNA damage is thought to contribute to carcinogenesis, ageing, and neurological degeneration. Further, the cumulative risk of cancer increases dramatically with age in humans. In general terms, cancer can be regarded as a degenerative disease of ageing. There is evidence for the accumulation of oxidative DNA damage with age based on studies mainly measuring an increase in 8-oxoguanine. 8-Oxo-7,8-dihydro-2'-deoxyguanosine 5'-triphosphate (8-oxo-dGTP) is formed in the nucleotide pool of a cell during normal cellular metabolism. When 8-oxoguanine is incorporated into DNA causes mutation. Organisms possess 8-oxo-dGTPase, an enzyme that specifically degrades 8-oxo-dGTP to 8-oxo-dGMP. To analyze the function of MTH1 with 8-oxo-dGTPase activity in vivo, we generated a mouse line carrying a mutant MTH1 allele created by targeted gene disruption. MTH1 homozygous mutant mice were found to have a physically normal appearance, but seemed to have lost 8-oxo-dGTPase activity in liver extracts. When we examined the susceptibility of the mutant mice to spontaneous tumorigenesis, no significant difference was observed in survival rate of MTH1+/+ and MTH1-/- mice. However, pathological examination revealed a statistically significant difference in the incidence of tumors. More tumors were formed in lungs, livers, and stomachs of MTH1-/- mice than in those of the wild type mice. These studies with MTH1-null mutant mice provided an important insight into the role of this nucleotide sanitization enzyme in terms of the spontaneous tumorigenesis as well as mutagenesis caused by the oxygen-induced DNA damage.

Prognostic significance of lymphocyte infiltration following preoperative chemoradiotherapy and hyperthermia for esophageal cancer.

PURPOSE: Lymphocyte infiltration (LI) around cancerous lesions is an important immune response. The purpose of this study is to evaluate the prognostic significance of LI after preoperative treatment for esophageal cancer. METHODS AND MATERIALS: Preoperative chemoradiotherapy (CR therapy), either bleomycin 30 mg or cisplatin 120 mg/m(2) plus radiation 30 Gy, was performed on 51 cases with esophageal cancer, while hyperthermo-chemoradiotherapy (HCR therapy) was also indicated in 71 cases. Using resected specimens, both the histopathologic effectiveness and degree of LI to cancerous lesions were evaluated. RESULTS: The incidences of the cases in which preoperative treatment was effective were 56% and 92.3% in LI (-) and LI (++) group (p < 0.05). The presence of LI resulted in favorable prognosis; the 5-year survival rates of LI (++) and LI (+) patients were 75.5% and 46.1%, both of which were significantly better than LI (-) (27.8%, p < 0.05 and p < 0.01, respectively). Especially among cases whose preoperative treatment was moderately effective, a multivariate analysis revealed LI to be a favorable prognostic factor independent of other clinicopathologic factors (p = 0.0171). Regarding the preoperative treatment, the incidence of LI (++) was higher in the HCR group (16.9%) than in the CR group (2.0%, p < 0.01). CONCLUSIONS: LI appears to be a prognostic predictor after preoperative CR therapy while, in addition, simultaneous hyperthermia may stimulate LI in cases with esophageal cancer.

CYFRA 21-1 determination in patients with esophageal squamous cell carcinoma: clinical utility for detection of recurrences.

BACKGROUND: While there are reports that CYFRA 21-1 is a useful tumor marker, to our knowledge the clinical utility of this marker to detect recurrences for squamous cell carcinoma of the esophagus has not been addressed. METHODS: By immunoradiometric assay, human serum levels of CYFRA 21-1, SCC antigen and CEA were measured in esophageal squamous cell carcinoma patients prior to their initial treatment. Monthly follow-ups of these tumor markers was done after surgery. RESULTS: The diagnostic sensitivity of CYFRA 21-1 was 43.9% (18 of 41), a value superior to that for SCC antigen (26.8%) and CEA (17.0%) (P < 0.05). The positive rates of CYFRA 21-1 increased with progression of the disease, 22.2% of pTNM Stage 0-IIA and 77.8% of pTNM Stage IIB/III (P = 0.013), whereas SCC antigen and CEA rates were not related to pTNM stage. Among 13 patients with clinical evidence of a recurrence, 76.9% (10 of 13) exhibited an increase in CYFRA 21-1, and this increase was evident before clinical detection of the recurrence in 9 of these 13 patients (69.2%). Consequently, postoperative elevations of serum CYFRA 21-1 levels were indicative of a tumor recurrence 1-13 months before acquisition of clinical and radiological data. CONCLUSIONS: The assay of CYFRA 21-1 is useful not only for diagnosis but also for close monitoring of patients with esophageal squamous cell carcinoma.

[Copper supplement with cocoa for copper deficiency in patients with long-term enteral nutrition].

Copper deficiency (normal serum copper level: 78-136 micrograms/dl) has been reported in patients with long-term enteral nutrition, caused by a copper deficit in enteral nutrition. Occasionally, this leads to anemia and leukopenia. We used Hershey's pure cocoa that is rich in copper (content 3.8 mg/cocoa 100 g) for copper deficiency. A total of 86 (40 men and 46 women, mean age 69 years) patients on enteral nutrition were studied. The primary diseases were cerebral vascular disease in 71 patients, neurological disease in 5 and others in 10. Those who showed serum copper levels of 20 micrograms/dl or less (N = 8) were given 30-45 g of cocoa (copper content 1.14-1.71 mg) per day for about 40 days. Among them, two patients could not continue because of vomiting and diarrhea and were excluded from this study. Mean serum copper levels increased from 8.7 +/- 6.2 to 99.0 +/- 25.4 micrograms/dl (N = 6). Those who showed serum copper levels 20-77 mg/dl (N = 31) were given 10 g of cocoa (copper content 0.38 mg) per day for about 40 days. When mean serum copper levels increased from 50.5 +/- 19.3 to 89.0 +/- 12.9 micrograms/dl with cocoa administration, anemia and neutropenia caused by copper deficiency showed a tendency to improve. After completing the study period, cocoa was reduced to 5 g (copper content 0.19 mg) per day in 23 patients. The mean serum copper levels increased from 90.7 +/- 10.4 to 100.6 +/- 17.1 micrograms/dl for about 100 days. Recently, the amount of daily copper requirement for adults has been reported to be 1.28-2.5 mg per day. We showed that 10 g of cocoa (0.6 mg total copper: 0.38 mg in cocoa and 0.22 mg in other nutrients) is sufficient to treat copper deficiency, and 5 g of cocoa (0.37 mg total copper: 0.19 mg in cocoa and 0.18 mg in other nutrients) is enough to maintain the normal level of serum copper in patients with long-term enteral nutrition.

Alcohol consumption and cigarette smoking in relation to high frequency of p53 protein accumulation in oesophageal squamous cell carcinoma in the Japanese.

We investigated levels of p53 protein expression in Japanese patients with oesophageal squamous cell carcinoma. A significantly larger proportion of heavy alcohol drinkers and cigarette smokers was evident in the p53-positive group. The combination of drinking and smoking was associated with a high frequency of p53 protein accumulation.

[Leukocytapheresis for ulcerative colitis].

Leukocytapheresis(LCAP) and Granulocytapheresis(GCAP) are classified as extracorporeal circulation therapy(ECCT). These therapies are a novel, effective way to treat patients with ulcerative colitis(UC). During 7 weeks of intensive therapy(LCAP weekly, predonisolone(PSL) 30-80 mg/day), UC patients treated with LCAP revealed significant improvements on their subjective and objective symptoms compared to patients treated with PSL intravenous administration. Moreover, LCAP has been recognized as safer than other drugs for UC. In our previous study, only 9.9% out of 1,978 LCAP sessions showed some side effects, and most were mild and temporary. Therefore, LCAP could be the first choice to treat UC patients who resist and/or reveal severe complications against ordinary drug therapies.

Esophageal carcinoma showing a long stricture due to prominent lymphatic permeation: report of a case.

Some esophageal diseases such as carcinoma, esophagitis, and collagen diseases have often been reported to show a diffusely thickened esophageal wall in the roentogenogram findings. In the current report, a preoperative upper gastrointestinal series and an endoscopic examination showed a diffusely infiltrative type carcinoma, but other examinations did not suggest any diseases such as esophagitis or collagen diseases which might cause a thickening of the esophageal wall or a constriction of the esophagus. A postoperative histological examination revealed the primary carcinoma to remain only within the mucosal layer, while a large degree of lymphatic vessel permeation reached the adventitia over a wide area. An extraordinary degree of lymphatic permeation spread through the esophageal wall, and stromal fibrosis developed as a result of such lymphatic permeation. These histological phenomena might thus have led to the macroscopic appearance of infiltrative type esophageal carcinoma.

Effect of leukocytapheresis therapy using a leukocyte removal filter in Crohn's disease.

Eighteen patients with active Crohn's disease were treated with one leukocytapheresis session per week for a five-week intensive therapy, decreasing to one leukocytapheresis session per month for five sessions of initial maintenance therapy. Nutritional indices, inflammatory reactions, flow cytometry profiles, and cytokine production were also assessed before and after the intensive and initial maintenance therapy. Nine of the patients (50%) attained remission at the end of the intensive therapy. The nine non-remission patients had exhibited longer periods of suffering and more severely affected sites prior to the therapy. In 14 of 18 patients (77.8%), the nutritional indices, Internal Organization of Inflammatory Bowel Disease (IOIBD) score and Crohn's Disease Activity Index (CDAI) improved from the pretherapy levels, but only the remission group (50%) showed improvement in C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). The remission group showed significantly higher pretherapy CD4+ CD45+ cell ratios and interleukin-2 (IL-2) production than the non-remission group, and significantly lower activated cells.

Esophageal hemangioma: a case report and review of the literature.

The patient, a 60-year-old man, was diagnosed as having a protruding lesion in the upper thoracic esophagus on a routine endoscopic examination. Endoscopy showed a polyp with a pedicle in the upper esophagus. A biopsy indicated the presence of hemangioma. Since endoscopic ultrasonography showed the tumor to be located within the mucosa and submucosa, we chose an endoscopic resection as the most appropriate treatment for the esophageal hemangioma. After endoscopic resection, the patient has remained free of any symptoms or recurrence. Although an esophageal hemangioma is a benign tumor, a risk of severe hemorrhaging does exist. We conclude that the first choice of the treatment for esophageal hemangioma should thus be an endoscopic resection if the tumor is located within the mucosal or submucosal layer. However, if it is impossible to resect endoscopically, then either endoscopic injection sclerotherapy (EIS) or a surgical resection should be considered.

[Mechanism of leukocytapheresis effect in the treatment of ulcerative colitis].

To solve adverse effects of high dose steroid administration for patients with moderately severe and severe ulcerative colitis (UC), additional use of leukocytapheresis (LCAP) was tried to settle colonic inflammation. We evaluated immunological changes in the treatment of LCAP using leukocyte removal filter for UC patients. We then assessed the clinical effectiveness of LCAP compared with that of high dose of steroid therapy. LCAP removed monocytes, granulocytes, and lymphocytes presenting CD 11 b+, CD 11 c+, and HLADR+, selectively from the patients. Proinflammatory cytokine productions measured such as TNF alpha, IL-1 beta, and IL 8 reduced and IL 10 increased immediately after LCAP compared with before perfusion. Improved rate was about 70% for LCAP group and about 40% for high dose steroid group (Refer J Gastroenterol). Selective removal of granulocyte, monocytes, and activated lymphocytes inhibits proinflammatory cytokine production and increases immune modulating cytokine productions (Refer Therapeutic Apheresis). Then quick inhibition of several inflammatory deteriorated factors simultaneously controls the activity and clinical symptoms of UC with less severe adverse effects. It can be considered one option for treatment of UC.

[Aneurysm of the membranous ventricular septum with ventricular septal defect, mitral and tricuspid insufficiency].

A seventy-year-old man was admitted at our hospital because of dyspnea. Echocardiogram and left ventriculogram showed an aneurysm formation of the membranous ventricular septum and small left-to-right shunt through ventricular septum defect and also severe mitral and tricuspid insufficiency. Operation was performed after medical therapy for congestive heart failure. During operation, mitral leaflets showed no organic lesions nor prolapse, but the annulus was dilated. The cause of mitral insufficiency, we thought, might be congenital, and the annulus dilatation was caused of mitral insufficiency, we thought, might be congenital, and the annulus dilatation was caused to produce tricuspid insufficiency secondary. The ventricular septal communication became small (diameter; 5 mm) and was associated with aneurysm formation of the remaining portion of the membranous septum. And the aneurysm, protruding to the septal leaflet of tricuspid valves, enhanced tricuspid insufficiency. It was reported by many authors that the aneurysm formation was related to spontaneous closure of ventricular septal defect. Patients with small ventricular septal defect, without any symptoms, must be followed intensively, or they might get cardiac complications, such as arrhythmia, right ventricular outflow obstruction, tricuspid insufficiency, and so on.

Clinicopathologic features of patients with oesophageal cancer obtaining a histological complete response for preoperative hyperthermo-chemo-radiotherapy.

From 1979 to 1993, 151 patients with resectable oesophageal cancer underwent preoperative hyperthermo-chemo-radiotherapy (HCR) followed by a subtotal esophagectomy. All resected specimens were histopathologically evaluated, and then were classified into two groups according to the efficacy of the preoperative HCR. Group A included 33 patients whose resected oesophagus was free of any cancer cells (grade 3). Group B included 118 patients, in which viable cancer cells remained in the resected specimens to various degrees (grade 1,2). The incidence of patients with well differentiated squamous cell carcinoma, node negative cases, or TNM stage I/II was significantly higher in group A than in group B (27.3% versus 9.3%, 72.7% versus 50.8%, 72.7% versus 50.8%, respectively). The recurrence rate was 33.3% (11/33) in group A, while it was 65.3% (77/118) in group B (p < 0.005). There was no case with any local recurrence in the former, while it was 8.5% (10/118) in the latter. The 1-, 3- and 5-year survival rates were 87.2%, 65.9% and 46.1% in group A, while they were 54.8%, 26.7% and 18.8% in group B (p < 0.005), respectively. Preoperative HCR may be expected of decreasing in the recurrence rate, including regional relapse when a grade 3 is obtained. Complete local control would further positively influence the prognosis.