Lack of a dose-response relationship for carcinogenicity in the rat liver with low doses of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline or N-nitrosodiethylamine.

For a long period, it has been generally considered that carcinogens, particularly genotoxic ones, have no threshold in exerting their potential for cancer induction. However, the non-threshold theory can be challenged with regard to assessment of cancer risk to humans. Here we show that a food-derived, genotoxic hepatocarcinogen, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, forms DNA adducts at low doses, but does not induce glutathione S-transferase placental form (GST-P)-positive foci (considered to be preneoplastic lesions) or 8-hydroxy-2'-deoxyguanosine in rat liver. Moreover a N-nitroso compound, N-nitrosodiethylamine, at low doses was also found not to induce GST-P-positive foci in rat liver. These results imply that there is a no-observed effect level for hepatocarcinogenesis by these genotoxic carcinogens.     

Anti-tumor Effect of Chemically Synthesized Sulfolipids Based on Sea Urchin's Natural Sulfonoquinovosylmonoacylglycerols

We recently reported that 3'-sulfonoquinovosyl-1'-monoacylglycerol (designatedA-5) extracted from sea urchin intestine was effective in suppressing the growth of solid tumors. Although the major fatty acid component of A-5 was a saturated C₁₆ acid, there were five other fatty acids, 14:0, 18:0, 14:1, 16:1, and 18:1, which constitute minor components of A-5. Therefore, it remains unclear as to which of these six fatty acid components of A-5 has the anti-tumor effect. In this study, we synthesized sulfolipids each containing only one of these six fatty acids and tested their cytotoxicity against tumor cells and in vivo anti-tumor effects on nude-mice bearing solid tumors of human lung adenocarcinoma cell line A-549. The IC₅₀ values of all products against tumor cells were more than 10^-5 M , suggesting weak cytotoxic activity compared with other chemotherapeutic compounds for cancer. On the other hand, in vivo anti-tumor assay showed that sulfoquinovosyl-monoacylglycerols (SQMG) composed of 14:1 and 18:1 (designated SQMG(14:1) and SQMG(18:1), respectively) were significantly effective in suppressing the growth of solid tumors. Our data suggested that these two SQMGs had a substantial anti-tumor effect in vivo , and they are of interest as candidate drugs for anti-cancer treatment.     

Is arterial surgery advisable for patients over 80 years of age?

BACKGROUND: Recently life expectancy has become longer and longer. The purpose of this study was to analyse whether arterial surgery for patients over 80 years of age is advisable. METHODS: During the last 14 years, 527 patients, 50 of whom were over 80 and 477 of whom were under 80 years of age, received graft replacement or bypass surgery. They suffered from ruptured abdominal aortic aneurysm (R-AAA, n=21), non-ruptured abdominal aortic aneurysm (N-R AAA, n=133) or arteriosclerosis obliterans (ASO, n=373). Complications such as cerebrovascular disease, ischemic heart disease, respiratory and kidney dysfunction, and risk factors for ASO were also checked. RESULTS: All of the patients over 80 with R-AAA (n=3/3) and 50% of the patients under 80 with R-AAA (n=9/18) died during their stay in the hospital. However, none of the N-R AAA patients over 80 (n=0/7) and only one of the 126 N-R AAA patients (0.8%) under 80 died. For the patients over 80 with ASO, the graft patency rate was better than the patients survival rate. There were no age-specific factors that should condemn arterial surgery for patients over 80 years of age. CONCLUSIONS: Arterial surgery should not be ruled out on the basis of age alone.     

N-Myc induction stimulated by insulin-like growth factor I through mitogen-activated protein kinase signaling pathway in human neuroblastoma cells

Insulin-like growth factor I (IGF-I) stimulates proliferation, survival, and differentiation in many cell types, including pediatric neuroblastomas. The effect is mediated via the type I IGF-I receptor (IGF-IR), which is essential for growth in these cells. Several lines of evidence indicate that IGF-IR function may be particularly important in the pathogenesis of neuroblastoma. Amplification of the N-myc oncogene or overexpression of N-Myc oncoprotein has been reported to be associated with resistance to therapy and poor prognosis of neuroblastomas. It was therefore of interest to analyze whether IGF-I signaling regulated expression of N-myc in KP-N-RT human neuroblastoma cells as an experimental model that has amplified N-myc. We found that IGF-I induces N-myc mRNA and protein in the KP-N-RT with maximums of four and six times more than the basal level at 2 and 3 h after stimulation, respectively. These effects of IGF-I were blocked by a neutralizing antibody against IGF-IR (alpha-IR3). Exogenous IGF-I induced phosphorylation and activation of extracellular signal-regulated kinases p44/42 (ERK1 and ERK2), with a maximal level 30 min after the stimulation. The MEK1 inhibitor PD98059 reduced IGF-I-mediated p44/42 MAPKs phosphorylation and produced a parallel reduction of IGF-I-stimulated N-Myc induction. Furthermore, both alpha-IR3 and PD98059 inhibited G1-S cell cycle progression stimulated by IGF-I. Our results demonstrate that IGF-I induces N-Myc in the KP-N-RT neuroblastoma cell line at the RNA level and establishes a clear correlation between N-Myc induction and activation of p44/42 MAPK signaling.     

Arterial infusion chemotherapy for liver metastases from colorectal cancer--therapeutic effects of different protocols

The therapeutic effects of different protocols for arterial infusion chemotherapy were compared in patients with multiple liver metastases from colorectal cancer. A total of 49 patients with colorectal multiple liver metastases treated in our hospital since 1988 were the subjects. In order to compare the therapeutic effects on the regression of cancer and the survival rate, the subjects were assigned into Groups A-D, which were treated using different protocols. Group A received ADR, EPI, CDDP or 5-FU alone at first. If this drug was not effective, it was replaced with another of those mentioned here, and so on. Group B received CDDP 50 mg on day 1, 5-FU 500 mg/day from day 2 to day 7 and 5-FU 500 mg/day for 2 weeks thereafter (FP treatment). Group C received CDDP 50 mg at the time of reservoir insertion and 5-FU 1,000 mg for 5 hours thereafter (WHF treatment). Group D received 5-FU 1,000 mg for 24 hours on day 1, day 3, and day 5 of every week with combination of CDDP 5-10 mg/day from day 1 to day 5 and none on day 6 and day 7 (intermittent F + low-dose P treatment) for 3 weeks. The response rate was 33% for Group A (n = 18), 46% for Group B (n = 13), 25% for Group C (n = 8) and 80% for Group D (n = 10), showing significant differences between Group D and other groups. The 1-year survival rate was 50% for Group A, 46% for Group B, 29% for Group C and 89% for Group D. Significant differences in survival rate were found between Group B and D, and Group C and D.     

Papillary eccrine adenoma: Immunohistochemicai study and literature review

A case of papillary eccrine adenoma on the right forearm of a 78-year-old Japanese woman is reported. The tumor was 1.3 cm in diameter, occupying the whole thickness of the dermis. Histologically, the tumor was composed of dilated tubules of various sizes with intraluminal papillary projections, and was surrounded by a fibrous stroma. An immunohistochemical study revealed that the proliferating tubules were composed of a single outermost layer of α-smooth muscle actin-and keratin 14-positive myoepithelial cells, and keratin 8-positive inner cells. This antigen expression pattern was comparable to that of the normal eccrine secretory coil, which indicates that the tumor differentiated toward the secretory coil of an eccrine sweat gland.     

Relationship between hepatic hemodynamics and biliary pressure in dogs: Its significance in clinical shock following biliary decompression

The changes in the hepatic hemodynamics were promptly reflected in the biliary pressure in dogs. Both wedged hepatic venous pressure and portal venous pressure increased in response to the elevated biliary pressure, and conversely decreased following rapid biliary decompression, suggesting that the changes in the biliary pressure might affect the hepatic hemodynamics post-sinusoidally. It was supposed that too rapid biliary decompression might trigger the following consequences; 1) decrease in sinusoidal pressure, 2) increase in sinusoidal inflow, and 3) extravasation of intravascular fluid in the perivascular space. When these were not sufficiently compensated, they could trigger shock in the jaundiced patients.     

A case of small cell carcinoma of the stomach

We report a rare case of small cell carcinoma of the stomach with metastasis to the liver and invasion of the pancreas, which was associated with acute peritonitis due to perforation of the stomach. CPT-11/CDDP chemotherapy achieved a partial response. A 60-year-old man suddenly developed abdominal pain and visited the emergency room. We diagnosed acute peritonitis due to perforation of the digestive tract because CT scan showed free air in the abdominal cavity. An emergency operation was performed with an omental patch for closing the perforated hole in the stomach. Excisional biopsy was performed to the small liver nodule. Histological findings showed that the liver nodule was metastasis from small cell carcinoma. There was no finding from the thoracic CT scan, but gastroscopy revealed a giant tumor, which was diagnosed as small cell carcinoma in histology. Therefore, we diagnosed small cell carcinoma of the stomach with liver metastasis and invasion of the pancreas. After operation, one course of FP chemotherapy was performed, but the liver metastasis increased in size. Then we changed to CPT-11/CDDP chemotherapy as second-line therapy, and achieved partial remission (PR) of both the liver metastasis and gastric tumor.