Expression of 8-hydroxydeoxyguanosine in the gastric remnant after distal gastrectomy.

BACKGROUND/AIMS: The correlation between remnant gastritis after distal gastrectomy for gastric cancer and expression of 8-hydroxydeoxyguanosine (8-OHdG) and inducible oxide synthase (iNOS) as a marker of oxidative DNA damage was investigated. METHODOLOGY: Ninety-seven patients who had undergone curative distal gastrectomy for gastric cancer were studied. Reconstructive procedures included Billroth I, Billroth II, and Roux-Y reconstruction in 42, 27, and 28 patients, respectively. Histologic and immunohistochemical analyses were performed on biopsy specimens of the gastric mucosa obtained endoscopically within 2 weeks before and 12 weeks after surgery. The grades of remnant gastritis were evaluated according to the updated Sydney System. 8-OHdG and iNOS expression levels, detected immunohistochemically, were graded. RESULTS: Neutrophil infiltration correlated with expression of 8-OHdG (p = 0.02). Expression of iNOS also correlated with 8-OHdG (p = 0.02). The ratio of postoperative to preoperative infiltration of neutrophils was less in patients who underwent Roux-Y reconstruction than in others (p = 0.04). CONCLUSIONS: These results suggest that remnant gastritis possibly causes DNA damage. Excess production of reactive oxygen species correlates with carcinogenic DNA changes. Roux-Y reconstruction may reduce carcinogenesis in the gastric remnant.

Intracorporeal Billroth 1 reconstruction by triangulating stapling technique after laparoscopic distal gastrectomy for gastric cancer.

As the laparoscopic operations for gastric cancer have increased, the intracorporeal reconstruction of the digestive tract has received attention because the procedure offers a good visual field regardless of the patient's figure. We performed laparoscopic gastrectomies with regional lymph node dissection on 586 gastric cancer patients between March 1998 and June 2006: 465 distal gastrectomies, 42 proximal gastrectomies, and 79 total gastrectomies. Intracorporeal anastomosis was carried out in 303, 36, and 69 of the above cases, respectively. The intracorporeal Billroth 1 reconstruction was performed in 226 out of the 303 cases who underwent distal gastrectomy and intracorporeal anastomosis. The "triangulating stapling technique" (TST) that uses laparoscopic linear stapling devices was adopted for 196 of these 226 cases; in the remaining 30, circular stapling devices for conventional open gastrectomy (CEEA) were used. In the initial 115 cases of distal gastrectomy, hand-assisted laparoscopic surgery (HALS) was used, and then we shifted to totally laparoscopic distal gastrectomy (TLDG) without HALS. In this paper, we concentrated on the techniques and results of intracorporeal Billroth 1 reconstruction by TST. Reducing postoperative wounds was possible TLDG by TST, compared with HALS and the extracorporeal anastomosis, that is, laparoscopy-assisted distal gastrectomy. Complications from anastomosis resulted in leakage in 2 HALS-TST patients and in 1 TLDG-TST patient, and anastomotic stenosis and bleeding were observed in each 1 case of reconstruction that used CEEA. Intracorporeal Billroth 1 reconstruction by TST is a safe procedure that provides a good visual field regardless of the patient's figure and a feasible technique for reconstruction after laparoscopic distal gastrectomies.

N-acetylcysteine and S-methylcysteine inhibit MeIQx rat hepatocarcinogenesis in the post-initiation stage.

N-acetylcysteine (NAC) and S-methylcysteine (SMC), water soluble organosulfur compounds contained in garlic, were evaluated for chemoprevention of hepatocarcinogenesis after 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) initiation in rats. Intergastric treatment with NAC or SMC five times a week resulted in decreased numbers and areas of preneoplastic, glutathione S-transferase placental form (GST-P) positive foci of the liver in a dose-dependent manner. Moreover, cell proliferation was reduced in GST-P positive foci by NAC and SMC. Insulin-like growth factor I (IGF-I) and inducible nitric oxide synthase (iNOS) mRNA expressions were found downregulated in the liver by NAC. The studies indicate that NAC can serve as a chemopreventive agent for rat hepatocarcinogenesis induced by MeIQx by reducing cell proliferation, which may involve IGF-I and iNOS downregulation.

Thoracoscopic esophagectomy for intrathoracic esophageal cancer.

Thoracoscopic approaches for esophageal cancer are still disparate. Complete scopic technique is feasible for esophagectomy. Mini-thoracotomy is effective for excellent exposure of the mediastinum for lymph node dissection. The magnifying effect of a video, by keeping the camera in close proximity to the dissection is essential to perform the same quality of dissection as open surgery. The benefit, for respiratory morbidity, remains to be studied in a large number of patients. Minimizing the chest wall injury contributed, to the reduction of constrictive pulmonary damage. Survival after the thoracoscopic approach was favorably compared with open surgery, when extensive lymphadenectomy was performed. Because the efficacy improves with the surgeon's experience, satisfactory outcome will only be obtained in a center performing a sufficient volume of esophageal surgery to provide the surgeon with opportunities to refine his necessary skills. Improvements in technique and instrumentation should make the procedure more accessible and steepen the learning curve.

[Pathologic complete response of thoracic esophageal cancer developing after gastrectomy to neoadjuvant low-dose nedaplatin (CDGP), 5-fluorouracil and radiotherapy].

We treated a 69-year-old man who had developed esophageal cancer following gastrectomy. Pathologic complete response (pCR) was obtained by neoadjvant chemoradiotherapy using low-dose nedaplatin (CDGP) and 5-fluorouracil. The cancer located in the middle of the thoracic esophagus, had invaded the trachea and metastasized to cervical lymph nodes according to computed tomography. Preoperative chemoradiotherapy combining a low-dose of CDGP with 5-FU was administered together with radiotherapy. Adverse effects included grade 2 stomatitis and leukocytopenia. The esophageal cancer was found by endoscopy to have diminished significantly after completion of neoadjuvant therapy, An endoscopic biopsy specimen was found to contain no malignant cells. The tumor also was smaller by CT, where cervical lymph nodes no longer showed involvement. Partial response was diagnosed based on imaging, and radical resection of the esophageal cancer was performed via right thoracotomy and laparotomy. Operative staging findings indicated Ch x R-T 3 N 0 M 0, Stage II R 0 D 2 Cur A. Pedicled jejunum was used to reconstruct the esophagus through a mediastinal route. Pathologic examination of resected specimens disclosed no viable cancer cells in the esophagus or metastasis to dissected lymph nodes. Neoadjuvant chemoradiotherapy using low-dose CDGP/5-FU is an effective treatment for esophageal cancer.

[A patient with multiple bone metastases from gastric cancer after an 8-year disease-free interval following gastrectomy].

We present a patient with multiple bone metastases who was treated successfully using only TS-1. Metastasis was diagnosed 8 years after distal gastrectomy for early gastric cancer in a woman now 61 years old. Surgery was performed on February 13, 1995. The primary tumor was located in the midportion of the gastric body, and had invaded the submucosa with metastasis to lymph nodes in the area of the lesser curvature and the left gastric artery. She was discharged from our hospital 41 days after surgery. After the 8 years of follow-up, elevation of alkaline phosphatase (ALP: 1,029 IU/l) was noted. Bone scintigraphy disclosed scattered areas of uptake in systemic bones. The biopsy specimen from the pubic bone contained metastatic adenocarcinoma, and the bone lesions were diagnosed as multiple bone metastases from gastric cancer. Chemotherapy was started with oral administration of TS-1 alone at 80 mg/day for 2 weeks, followed by 2 weeks of rest. The patient did not experience any side effects, and treatment was repeated on an outpatient basis. At 4 month after initiation of therapy, decreases in ALP and number of foci of abnormal bone uptake in scintigrams were noted. She has survived for an additional 16 months after starting TS-1, without major complications.

High susceptibility of p53 knockout mice to esophageal and urinary bladder carcinogenesis induced by N, N-dibutylnitrosamine.

In human cancer, alterations in the p53 tumor suppressor gene are the most common genetic alterations. The aim of the present study was to detect sensitivity of the p53 (+/-) mice and their littermates p53 (+/+) mice to N, N-dibutylnitrosamine (DBN) carcinogenicity. In experiment 1, 6-7-week-old p53 (+/-) and p53 (+/+) mice were treated with 0, 0.025 and 0.05% DBN, respectively, in drinking water for 20 weeks. Esophageal squamous cell and urinary bladder transitional cell carcinomas (TCCs) and fibrosarcomas were found to be significantly increased in p53 (+/-) mice treated with doses of DBN compared to p53 (+/+) mice administered similar doses. In experiment 2, 6-7-week-old p53 (+/-) and p53 (+/+) mice were administered 0 or 0.05 % DBN in drinking water for 8 weeks. Immunohistochemical staining revealed a significant increase in numbers of p53 and bromodeoxyuridine (BrdU) positive cells in the esophageal and urinary bladder epithelia of DBN-treated p53 (+/-) mice compared to p53 (+/+) mice administered DBN. Molecular analysis revealed point mutations in the residual p53 allele in four of eight (50%) esophageal mucosa of DBN-treated p53 (+/-) mice, and in three of eight (38%) of treated p53 (+/+) mice. The results show that p53 (+/-) mice were sensitive to DBN treatment with respect to esophageal and bladder tumor development, with a mechanism that could be confined to early mutations of the residual p53 allele and increased cellular proliferation in the target organs.

Enhancement of lung carcinogenesis by nonylphenol and genistein in a F344 rat multiorgan carcinogenesis model.

The modifying effects of nonylphenol and genistein on cancer induction were assessed in a multi-organ carcinogenesis model in male F344 rats initially treated with five different carcinogens. In experiment 1 rats received 250 or 25 ppm nonylphenol, or 250 or 25 ppm genistein in their diet for 28 weeks. The total incidences of adenomas and carcinomas in the lungs of animals treated with nonylphenol and genistein were significantly higher than in the control group. 5-Bromo-2'-deoxyuridine labeling indices, reflecting cell proliferation, were also significantly elevated in the lungs of rats given 250 and 25 ppm nonylphenol and 250 ppm genistein. In experiment 2, rats were treated with nonylphenol or genistein at concentrations of 250 ppm after DHPN initiation. In the lung, formation of 8-hydroxy-2'-deoxyguanosine, a marker of oxygen radical-mediated DNA damage, was significantly increased. These results indicate that nonylphenol and genistein have the potential to promote rat lung carcinogenesis, possibly via a mechanism involving stimulation of cell proliferation and DNA damage caused by oxygen radicals.

Different genetic alterations in rat forestomach tumors induced by genotoxic and non-genotoxic carcinogens.

Human beings are exposed to a multitude of carcinogens in their environment, and most cancers are considered to be chemically induced. Here we examined differences in genetic alterations in rat forestomach tumors induced by repeated exposure to a genotoxic carcinogen, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) or N-methylnitrosourethane (MNUR), and chronic treatment with a non-genotoxic carcinogen, butylated hydroxyanisole (BHA) or caffeic acid (CA). A total of 132, 6-week-old male F344 rats were employed. Forty rats were treated with MNNG by intragastric administration at a dose of 20 mg/kg body wt once a week for 32 weeks, and 20 rats received 20 p.p.m. MNUR in their drinking water for 48 weeks. Further groups of 20 animals were administered 2% BHA or 2% CA in the diet for 104 weeks. The remaining rats were maintained without any supplement as controls. Multiple forestomach tumors were observed in all rats of the MNNG-, MNUR-, BHA- and CA-treated groups. Histopathologically, MNUR- and CA-treated groups showed almost the same pattern. On polymerase chain reaction-single strand conformation polymorphism analysis, H-ras and p53 gene mutations were observed at high and relatively low frequencies, respectively, in forestomach tumors induced by MNNG and MNUR. Most H-ras gene mutations were G-->A transitions in codons 7 and 12 of exon 1. On the other hand, forestomach tumors due to the non-genotoxic carcinogens, BHA and CA, had almost no mutations of the H-ras and p53 genes. Moreover, relative overexpression of cyclin D1 and p53 was detected in forestomach tumors induced by the genotoxic carcinogens, while their non-genotoxic counterparts had a tendency to show low expression of those molecules. Mutations of the beta-catenin gene were not detected in any group. The present study demonstrates that rat forestomach tumors induced by genotoxic and non-genotoxic carcinogens have different underlying genetic alterations, even if their pathological features are similar.

Weak enhancing effects of simultaneous ethanol administration on chemically induced rat esophageal tumorigenesis.

Excessive alcohol consumption is associated epidemiologically with an elevated risk of esophageal cancer. In this study, we examined the effects of simultaneous administration of ethanol on N-nitrosomethylbenzylamine (NMBA)-induced rat esophageal tumorigenesis. Groups 1-3 were treated with NMBA at a dose of 0.5 mg/kg body weight (high dose), and groups 4-6 received a dose of 0.1 mg/kg body weight (low dose), by s.c.-injection, 3 times per week for the first 5 weeks. Groups 1 and 4 were given ethanol free water as controls. Groups 2 and 5 were treated with 10% ethanol in their drinking water only at the time of NMBA treatment, while groups 3 and 6 were administrated the supplement continuously up to the end of the experiment. Macroscopically, with high dose NMBA-initiation, simultaneous 5-week and continuous 24-week ethanol administration demonstrated a tendency to increase the incidence and multiplicity of tumors, and also microscopically the multiplicity of papillary hyperplasias. In low dose groups, the incidence of esophageal papillary hyperplasias was significantly increased by continuous 24-week ethanol administration. Immunohistochemistry, proliferating cell nuclear antigen (PCNA) positive indices tended to be increased in tumors by simultaneous 5-week and continuous 24-week ethanol administration, but cyclin D1 expression was not affected. These data suggest that simultaneous ethanol administration have weak enhancing effects, and also promoting effects in post-initiation phase is present on NMBA-induced rat tumorigenesis.

Promoting effects of monomethylarsonic acid, dimethylarsinic acid and trimethylarsine oxide on induction of rat liver preneoplastic glutathione S-transferase placental form positive foci: a possible reactive oxygen species mechanism.

Dimethylarsinic acid (DMA) is a major metabolite of inorganic arsenicals, which are epidemiologically significant chemicals in relation to liver cancer in mammals. The present study was conducted to determine the promoting effects of organic arsenicals related to DMA [monomethylarsonic acid (MMA) and trimethylarsine oxide (TMAO)] on rat liver carcinogenesis using a liver medium-term bioassay (the Ito test). Male, 10-week-old, F344 rats were given a single i.p. injection of diethylnitrosamine at a dose of 200 mg/kg b.w. as an initiator. Starting 2 weeks thereafter they received 100 ppm of MMA, DMA or TMAO in their drinking water, or no supplement as a control, for 6 weeks. All animals underwent 2/3 partial hepatectomy in week 3 after initiation. Quantification of glutathione S-transferase placental form (GST-P)-positive foci as preneoplastic lesions in liver sections revealed significantly increased numbers and areas in all 3 treated groups compared with controls. Hepatic microsome cytochrome P-450 content was markedly increased with all 3 arsenic treatments. Markedly elevated CYP 2B1 protein levels and CYP 2B1/2 mRNA levels were thus observed in all cases. The potency of promotion was similar for MMA, DMA and TMAO. Since hydroxyradicals were found to be generated in the relatively early phase while methylated arsenicals were metabolized in liver, the resultant oxidative stress might have promoted lesion development.

Detailed low-dose study of 1,1-bis(p-chlorophenyl)-2,2,2- trichloroethane carcinogenesis suggests the possibility of a hormetic effect.

To obtain information on the effects of nongenotoxic carcinogens at low doses for human cancer risk assessment, the carcinogenic potential of the organochlorine insecticide, 1,1-bis(p-chlorophenyl)-2,2,2-trichloroethane (DDT), in the liver was assessed in F344 rats. In experiment 1, 240 male animals, 21 days old, were administered 0, 0.5, 1.0, 2.0, 5.0, 20, 100 and 500 ppm DDT in the diet for 16 weeks. Experiment 2 was conducted to elucidate the carcinogenic potential of DDT at lower levels using 180 rats given doses of 0, 0.005, 0.01, 0.1, 0.2 and 0.5 ppm. The livers of all animals were immunohistochemically examined for expression of glutathione S-transferase placental form (GST-P), putative preneoplastic lesions. Quantitative values for GST-P-positive foci in the liver were increased dose-dependently in rats given 20 ppm DDT and above with statistical significance as compared with the concurrent control value. In contrast, doses of 0.005 and 0.01 ppm were associated with a tendency for decrease below the control value, although not significantly. Western blotting analysis show that cytochrome P-450 3A2 (CYP3A2) protein expression tended to decrease at 0.005 and 0.01 ppm, a good correlation being observed with the change in the number of GST-P-positive foci. These findings suggest that a DDT hepatocarcinogenicity may show nonlinear response, that is, hormetic response at low doses. Furthermore, since CYP3A2 protein expression appears to be important for the effects of phenobarbital and the alpha-isomer of benzene hexachloride, mRNAs for IL-1 receptor type 1 (IL-1R1) and TNF-alpha receptor type 1 (TNFR1) whose ligands have roles not only in downregulating CYP3A2 expression but also in inducing antiproliferative effect or apoptosis in hepatocyte were examined. Increase was observed at low doses of DDT. Oxidative stress in liver DNA, assessed in terms of 8-hydroxydeoxyguanosine as a marker, was also decreased. These findings suggest that the possible hormetic effect that was observed in our detailed low-dose study of DDT carcinogenesis, although not statistically significant, may be linked to levels of oxidative stress and proinflammatory cytokines.

Lack of promoting effect due to oral administration of dimethylarsinic acid on rat lung carcinogenesis initiated with N-bis(2-hydroxypropyl)nitrosamine.

Dimethylarsinic acid (DMA), a major metabolite of inorganic arsenics, and arsenic exposure is associated with tumor development in a wide variety of human tissues. In the present study, we examined whether DMA has tumor-promoting activity on rat lung carcinogenesis initiated with N-bis(2-hydroxypropyl)nitrosamine (DHPN). Male, 8-week-old, F344 rats were treated with DHPN at a concentration of 0.1% in drinking water for 1 week, and starting 1 week thereafter, DMA was administered at concentrations of 0, 100, 200 or 400 ppm in the drinking water for 30 weeks. Induction of epithelial lesions, classified as alveolar epithelial hyperplasia, adenoma, and adenocarcinoma was evident in the lungs of DHPN-initiated animals, but no significant differences were found between DMA-treated groups and control groups. Furthermore, no significant differences in 5-bromo-2'-deoxyuridine labeling indices, as a marker of cell proliferation were observed among the groups. An additional group treated with DMA at concentrations of 200 ppm alone, without prior DHPN initiation was found to develop no epithelial lesions in the lung. There was no significant gain in 8-hydroxydeoxyguanosine formation, as a marker of oxidative stress, in the lungs of rats treated with DMA in their drinking water. In conclusion, oral-administered DMA does not exert promoting effects on rat lung carcinogenesis initiated with DHPN.