Comparative toxicity study of 3-aminophenol in newborn and young rats

Repeated dose toxicity of 3-aminophenol was examined on oral administration to newborn and young rats, and susceptibility was analyzed in terms of the no observed adverse effect level (NOAEL) and the unequivocally toxic level. In the 18-day newborn rat study, starting at day 4 after birth, tremors and depression of body weight gain were observed, as well as hypertrophy of thyroid follicular epithelial cells and increases of relative liver and kidney weights at 240 mg/kg. Increase of relative liver weights in males and decrease of blood sugar in females without any histopathological changes at 80 mg/kg were not considered to be adverse effects. No chemical-related changes were observed at 24 mg/kg. Abnormalities of external development and reflex ontogeny in the newborn were not observed. In the 28-day study, starting at 5 weeks of age, depression of body weight gain, tremors, anemia, and liver, kidney and thyroid toxicity were observed at 720 mg/kg. Although slight pigmentation in the renal proximal tubular epithelium was observed in females at 240 mg/kg, this was not considered to be an adverse effect because of the lack of changes in related toxicological parameters. It was concluded that the NOAEL is 80 mg/kg/day in newborn rats and 240 mg/kg/day in young rats, with unequivocally toxic levels of 240 mg/kg/day and 720 mg/kg/day, respectively. Based on these two endpoints, the susceptibility of newborn rats to the chemical was approx. 3 times higher than that of young rats, consistent with our previous results for 4-nitrophenol and 2,4-dinitrophenol.     

Role of kinin and prostaglandin in cutaneous thermal nociception

Involvements of kinin and prostaglandin and their interaction in noxious thermal stimuli were investigated in noninflamed and inflamed rats. The nociceptive response was evaluated from the escape latency of foot withdrawal to the thermal stimuli with a beam of light. The escape latency in kininogens-deficient Brown Norway (B/N-) Katholiek rats was significantly longer than that in the normal strain, B/N-Kitasato rats. The latency in B/N-Kitasato rat was prolonged by administration of a bradykinin (BK) B2 receptor antagonist, FR173657 (30 mg/kg, p.o.), whereas it was shortened by pretreatment with a kininase II inhibitor, captopril (10 mg/kg, i.p.). Both agents did not affect the latency in B/N-Katholiek rats. In normal Sprague-Dawley (SD) rat, administration of indomethacin did not change the escape latency against the thermal stimuli. In contrast, administration of indomethacin or a relatively cyclooxygenase-1-selective inhibitor, mofezolac (10 mg/kg, p.o.) significantly reduced numbers of writhing reaction in mice induced by acetic acid solution. Injection of lipopolysaccharide (1 mg/kg, i.v.) resulted in shortening escape latency at 8 h after the injection in B/N-Kitasato rats. This hyperalgesia could be reversed by pretreatment of the rats with indomethacin, a cyclooxygenase-2-selective inhibitor JTE-522 (10 mg/kg, p.o.), or FR173657, but not with mofezolac. The hyperalgesia was not seen in B/N-Katholiek rats. These results indicate that kinin has major participation in peripheral skin thermal nociception under noninflamed condition, although cyclooxygenases may have little participation. Prostaglandins produced by cyclooxygenase-2 could coordinate with BK to elicit hyperalgesia during inflammation induced by lipopolysaccharide.     

Contribution of the combination of (201)Tl SPECT and (99m)T(c)O(4)(-) SPECT to the differential diagnosis of brain tumors and tumor-like lesions. A preliminary report

This study was undertaken to assess the contribution of the combination of (201)Tl SPECT and (99m)TcO(4)(-)SPECT to the differential diagnosis of brain tumors and tumor-like lesions. In the 8 patients selected for this study, both (201)Tl SPECT and (99m)TcO(4)(-) SPECT were performed because of clinical or radiological suspicion of brain tumor, no therapy was initiated before either SPECTs, diagnosis was based on biopsy, and MRI findings were stable in the interval between SPECTs. Histological diagnoses consisted of low grade glioma (n=1), high grade glioma (n=2), lymphoma (n=1), metastasis (n=1), multiple sclerosis (n=2) and cavernous angioma (n=1). Two high grade astrocytomas, one malignant lymphoma and one metastatic tumor showed (201)Tl accumulation and were diagnosed as tumor. The combination of (201)Tl and (99m)TcO(4)(-) did not change the diagnosis. One cavernous angioma showed no (201)Tl accumulation and was diagnosed as non-tumor. The combination of (201)Tl and (99m)TcO(4)(-) did not change the diagnosis. One low grade astrocytoma showed faint (201)Tl accumulation and was diagnosed as non-tumor. As (201)Tl uptake was higher than (99m)TcO(4)(-) uptake, the combination of (201)Tl and (99m)TcO(4)(-) changed the diagnosis to tumor. Two multiple sclerosis showed (201)Tl accumulation and were diagnosed as tumor. As (99m)TcO(4)(-) uptake was higher than (201)Tl uptake, the combination of (201)Tl and (99m)TcO(4)(-) changed the diagnosis to non-tumor. In three of the eight patients (38%), the combination of (201)Tl SPECT and (99m)TcO(4)(-) SPECT altered the diagnosis made by (201)Tl SPECT alone. In all of these three cases, the diagnosis made by the combination of (201)Tl SPECT and (99m)TcO(4)(-) SPECT was correct.     

An outbreak of gastroenteritis in Osaka,Japan due to Escherichia coli serogroup O166:H15 that had a coding gene for enteroaggregative E. coli heat-stable enterotoxin 1 (EAST1)

In an outbreak of gastroenteritis on 23 July 1996, in Osaka, Japan, 54 of 91 persons who had attended a meeting the previous day became ill. Escherichia coli O166:H15 was isolated from stool specimens of patients (29/33, 88%). Laboratory tests for other bacterial pathogens and viruses were negative. The E. coli 0166 organisms did not adhere to HEp-2 cells in a localized, diffuse, or enteroaggregative manner. The organisms did not express known enterotoxigenic E. coli (ETEC) colonization factors. In polymerase chain reaction tests, the bacteria did not have coding genes for shigatoxin of enterohemorrhagic E. coli (EHEC), heat-labile, or heat-stable enterotoxin of ETEC, attachment and effacement (eaeA) of EPEC, or invasion (invE) of enteroinvasive E. coli (EIEC). Consequently, they could not be assigned to any of the recognized diarrhoeagenic groups of E. coli: EPEC, ETEC, EHEC, EIEC, enteroaggregative E. coli (EAggEC), or diffusely adhering E. coli. However, the organisms possessed the EAggEC heat-stable enterotoxin (EAST1) gene. To our knowledge, this is the first report of an outbreak caused by E. coli that did not have well-characterized virulence genes other than EAST1. The isolates showed the same DNA banding pattern in pulsed-field gel electrophoresis after digestion with the restriction enzymes XbaI or NotI. Three O166:H15 strains isolated from two sporadic cases and another outbreak during 1997-8 were distinct, indicating that multiple clones have spread already. We propose that diarrhoeal specimens should be examined for E. coli possessing the EAST1 gene.     

Phase I study of combination chemotherapy with 5-fluorouracil (5-FU) and nedaplatin (NDP): adverse effects and eecommended dose of NDP administered after 5-FU

When nedaplatin (NDP) was used as a single agent in the phase I study, the dose-limiting toxicity (DLT) was thrombocytopenia and the recommended dose (RD) was 100 mg/m2. However, the DLT, maximum tolerated dose (MTD) and RD of NDP used in combination with 5-fluorouracil remained unknown. Therefore, we performed this study to assess the DLT and RD of NDP administered after 5-fluorouracil (5-FU). In this study, 5-FU was administered to 38 patients at a fixed dose (700 mg/m2/d on days 1-5) and NDP administered on day 6 at an initial dose of 80 mg/m2, which was subsequently increased to 100, 120, 130, 140, 150, and 160 mg/m2. The DLT of NDP was leukopenia and its MTD and RD were 160 and 150 mg/m2, respectively. Concerning impairment of renal function, only two patients had a grade I increase in serum creatinine. There were 19 responders (50%, 19/38) achieving partial response or complete response in the evaluation of antitumor effect. The result of this study is notable in that administration of 5-FU before NDP allows the dose of NDP to be substantially increased.     

Complete response of Sister Mary Joseph Nodule from gastric adenocarcinoma treated with combination chemotherapy of low-dose S-1 and cisplatin

A case of an unresected, advanced gastric cancer with Sister Mary Joseph nodule was presented. It was treated with new combination chemotherapy of low-dose S-1 and cisplatin producing complete response of periumbilical metastasis. Few treatments are efficacious for umbilical invasion of peritoneal dissemination. A complete response for Sister Mary Joseph nodule from gastric adenocarcinoma has not been ever reported.     

Brain metastases from esophageal carcinoma: natural history, prognostic factors, and outcome

BACKGROUND: Brain metastases from esophageal carcinoma are extremely rare, and information regarding the natural history, results of treatment, and possible prognostic factors in these patients is limited. METHODS: The records of 36 patients with brain metastases from esophageal carcinoma who were treated between 1986 and 2000 were reviewed. For brain metastases, 12 patients (33%) were treated with surgical resection followed by radiation therapy (S+RT), and the remaining 24 patients were treated with radiation therapy alone. RESULTS: At the initial diagnosis of esophageal carcinoma, the median primary tumor length was 8 cm (range, 2-19 cm), and 26 of 32 available patients (81%) had clinical Stage III-IV tumors according to the International Union Against Cancer 1997 criteria. At time brain metastases appeared, lung metastases were not demonstrated in 25 of 36 patients (69%) who were assessed by chest computed tomography (CT) scans. The overall median survival for all patients was 3.9 months (range, 0.6-36.8 months), and the actuarial survival rates at 12 months and 24 months were 14% and 3%, respectively. In univariate analysis, treatment modality, Karnofsky performance status (KPS), and extracranial disease status each had a statistically significant impact on survival, and, in multivariate analysis, treatment modality and KPS were statistically significant prognostic factors for survival. Five patients (14%) survived more than 1 year, all of whom were treated with S+RT. These five patients had inactive extracranial disease and, four of five patients (80%) had a 90-100% KPS. CONCLUSIONS: Brain metastases from esophageal carcinoma tended to occur in patients with a large primary tumors and/or disease in advanced clinical stages. With the appearance of brain metastases, an absence of lung metastasis frequently was observed on chest CT scans. The prognoses for these patients were generally poor, although selected patients may survive longer with intensive brain tumor treatment.     

Development of human renal cell carcinoma (RCC)--the responsible genes for the development of hereditary and sporadic human RCCs

Renal Cell Carcinoma (RCC) is classified into six cell pathological types by the Thoenes classification (5). Deletion of DNA (loss of heterozeigosity: LOH) is seen with a high frequency in human RCC of all 6 types at chromosome 3p 14-25. The presence of at least three tumor suppressor genes at this domain has been pointed out. The VHL gene, one of the tumor suppressor genes (TSG), was identified in 1993 at chromosome 3p25-26 as the gene responsible for VHL disease. As a consequence, it was demonstrated that inactivation of the von Hippel-Lindau (VHL) gene is responsible for sporadic clear cell RCC. Activating mutations of c-Met receptor type tyrosine kinase has been demonstrated in papillary renal cell carcinoma families. Possible involvement of the FHIT tumor suppressor gene, located at the fragile site (FRA3B) of chromosome 3p14, has been detected in sporadic RCC. Recently, methylation of RASSF1A at chromosome 3p21.3 was pointed out in sporadic RCC. Thus, it has become apparent that chromosome 3p14-25 3 has possible TSGs for RCC. Furthermore, it was pointed out in April that germline mutation of fumarate hydratase, a Krebs cycle enzyme (FH), is present in multiple cutaneous and uterine leiomyomatosis families that develop papillary RCC. The functional significance in these genes for the development of RCC is still not apparent, except for the VHL gene. Thus, there is still a long way to go before we find all responsible TSGs in all pathological subtypes in sporadic RCC.     

A case of vulval extramammary Paget's disease associated with pancreatic cancer that was successfully treated with chemotherapy

We report the case of an 84-year-old woman with vulval extramammary Paget's disease associated with pancreatic cancer who was successfully treated. At first, biweekly low-dose FP (cisplatin 10 mg/body, 5-fluorouracil 250 mg/body) was administered by intravenous infusion. Next, we attempted a regimen of gemcitabine (1,000 mg/body) was administered weekly by intravenous infusion. As a result, the size of the pruritic lesion of the vulva was reduced more than 50%, and the serum level of CA19-9 decreased clearly. These treatments would be a valid option in certain cases of pancreas cancer and extramammary Paget's disease.