Seven-year survivor with malignant melanoma of the anus without radical surgery

We report a case of a long-term survivor with malignant melanoma of the anus who did not undergo radical surgery. A 71-year-old woman who presented with anal bleeding and anal tumor underwent an excisional biopsy in September 1985. The biopsy specimen was a lobulated, polypoid, pigmented mass 2 cm in diameter, that had been located on the anterior wall of the anus. A satellite nodule 7 mm in diameter was found on the left wall of the anus at the level of the dentate line. Both tumors were histologically diagnosed as malignant melanoma. The primary tumor was 6 mm thick. Melanoma cells were present microscopically at the cut end of the rectum. Because of her history of ischemic heart disease, the patient rejected our recommendation that she undergo radical surgery, and received 10 courses of carboplatin 20 mg intramuscularly and OK-432 10 K.E. (Klinische Einheit) intradermally every week. A single, pigmented metastatic inguinal lymph node developed and was excised in June 1987. A recurrent tumor was detected in the rectum in October 1992, so again we recommended radical surgery. The patient rejected radical surgery again, and received 12 courses of carboplatin 10 mg intramuscularly every 2 weeks. She died of disease at home in July 1993 after surviving for 7 years and 10 months. An autopsy was not performed. This case shows that local excision of the primary lesion may be appropriate to preserve the quality of life of patients with early-stage malignant melanoma of the anus.     

Induction of apoptosis in multi-drug resistant (MDR) human glioblastoma cells by SN-38, a metabolite of the camptothecin derivative CPT-11

 The overexpression of the multidrug resistance (mdr1) gene and its product, P-glycoprotein (P-gp), is thought to limit the successful chemotherapy of human tumors. Recent studies demonstrate that SN-38, a metabolite of the camptothecin (CPT) derivative CPT-11, has antitumor effects on several tumors, but the mechanisms responsible for its cytotoxicity remain unclear. We therefore determined whether SN-38 has cytotoxic effects on MDR human glioblastoma GB-1 cells and non-MDR human glioblastoma U87-MG cells. Furthermore, we determined what role SN-38 plays in the induction of cytotoxicity in these tumor cells. In this study, we demonstrated that SN-38 had significantly stronger antitumor effects on GB-1 and U-87MG cells than did CPT (P<0.01 and P<0.05, respectively). In addition, findings obtained using a DNA fragmentation assay, Hoechst 33258 staining, in situ end-labeling and cell cycle analysis demonstrated that SN-38 induced apoptosis in these tumors. Our results suggest that SN-38 has a stronger antitumor effect on malignant glioma cells regardless of MDR expression than does CPT, and therefore can be considered a new chemotherapeutic agent potentially effective in the treatment of human primary or recurrent malignant gliomas resistant to chemotherapy. Received: 6 October 1995/Accepted 29 June 1996     

Genetic instability and p53 mutations in metastatic foci of mouse urinary bladder carcinomas induced by N-butyl-N-(4- hydroxybutyl)nitrosamine

In a variety of human malignancies, alteration of the p53 tumour suppressor gene is known as a significant indicator of late progression events including invasion and metastasis, with a possible close relationship to genetic instability. Mutational analysis of the p53 and H-ras genes was performed for 10 pairs of N-butyl-N-(4- hydroxybutyl)nitrosamine-induced invasive mouse urinary bladder carcinomas and metastatic foci. p53 Mutations were found in nine of 10 (90%) primary carcinomas and seven of 10 (70%) metastatic foci. A total of eight p53 mutations in primary carcinomas were common in metastatic foci in six pairs. Additional p53 or H-ras mutations which were not identified in the primary carcinomas were found in three metastatic foci. Evaluation of the allelic distribution of the p53 mutations using RT-PCR, PCR and subcloning, further indicated possible intra-tumour genomic heterogeneity or excess copy numbers of the p53 gene due to genetic instability. Overall, p53 alterations were frequent in mouse urinary bladder carcinomas demonstrating progression. The results suggest that genetic instability might underlie generation of additional genetic alterations in this animal model.      

Genetic Alterations of Mixed Hyperplastic Adenomatous Polyps in the Colon and Rectum

Some mixed hyperplastic adenomatous polyps (MHAPs) contain dysplastic lesions or even carcinomas. These polyps are considered to be different from ordinary hyperplastic polyps and may have a preneoplastic potential. We investigated APC and K- ras mutations in MHAPs of the colon and rectum, and also in colorectal adenomas and hyperplastic polyps to identify molecular differences between MHAPs, adenomas and hyperplastic polyps, using direct sequencing of mutation cluster regions (MCR) in APC and K- ras . No APC mutations were identified in 12 MHAPs and 8 hyperplastic polyps, whereas 10 of 27 (37.0%) adenomas showed somatic mutations. K- ras mutations were identified in one of 12 (8.3%) MHAPs, one of 8 (12.5%) hyperplastic polyps, and 10 of 27 (37.0%) adenomas. p53 mutation was found in a carcinoma arising in an MHAP. Mutations other than APC mutations may play a role in the development of MHAPs.     

Infrequent Mutations of the hOGG1 Gene, That Is Involved in the Excision of 8-Hydroxyguanine in Damaged DNA, in Human Gastric Cancer

DNA glycosylase, encoded by the hOGG1 gene, repairs 8-hydroxyguanine (oh⁸Gua), which is an oxidatively damaged mutagenic base. To clarify whether the DNA repair activity of hOGG1 protein is involved in gastric carcinogenesis, we examined 9 gastric cancer cell lines and 35 primary gastric cancers for mutations and genetic polymorphisms of the hOGG1 gene by polymerase chain reaction-single strand conformation polymorphism analysis. A G-to-A transition was detected in a gastric cancer cell line, MKN1. This nucleotide change caused the conversion of the amino acid from Arg to His at codon 154, which is located in a domain highly conserved among human, mouse, and yeast OGG1 proteins. No mutation was detected in primary gastric cancers. We compared the distribution of the polymorphic alleles associated with enzymatic activity (hOGG1-Ser³²⁶ vs. hOGG1-Cys³²⁶) between 35 gastric cancer patients and 42 healthy individuals. Although the frequency of the Cys³²⁶ allele, associated with low enzymatic activity, in gastric cancer patients was a little higher than that in healthy individuals, the difference did not reach statistical significance. These results suggest that low hOGG1 activity due to mutations and genetic polymorphisms is involved in the development of only a small subset of gastric cancers.     

Application of an electronic nose system for evaluation of unpleasant odor in coated tablets.

The purpose of this study was to apply an electronic nose system for evaluation of unpleasant odor in tablets containing L-cysteine, an unpleasant odor drug, and demonstrate the odor masking ability of thin-layer sugarless coated tablets, which we have newly developed, by both electronic nose system and sensory evaluations. We demonstrated the qualitative evaluation of the unpleasant odor using air as a reference indicator and the quantitative evaluation of the unpleasant odor using the distances between air and samples in the electronic nose system evaluation. The electronic nose system evaluation was positively and well-correlated with the sensory evaluation by volunteers. We suggest that the electronic nose system evaluation is appropriate as an alternative or a support method for sensory evaluation by volunteers. As the results of both electronic nose system and sensory evaluations, we demonstrated that the thin-layer sugarless coated tablets have excellent masking ability of the unpleasant odor, equivalent to that of sugar-coated tablets due to the dense coating layers.     

Choledochal cyst associated with duodenal obstruction

The association between congenital duodenal obstruction and concomitant choledochal cyst has not been reported, although duodenal obstruction is known to be associated with many other anomalies. The authors describe 2 patients with choledochal cyst with duodenal obstruction. In 1 patient, a diverticulum type of choledochal cyst was found within an annular pancreas. Cyst excision, choledochojejunostomy, and side-to-side duodeno-duodenostomy were performed. The other patient showed separated duodenal atresia and other multiple anomalies including imperforate anus. A choledochal cyst was noted at the time of duodeno-duodenostomy and sigmoid colostomy. Cyst-enterostomy was performed at the age of 8 months, but the patient died of multiple anomalies. Intraoperative cholangiography indicated an anomalous pancreatobiliary ductal junction (APBDJ). In both patients the bile in the cyst contained high levels of amylase, suggesting the presence of an APBDJ. An APBDJ is considered to play an etiologic role in the development of the choledochal cysts associated with duodenal obstruction.     

Free‐wall perforation of the left ventricle after acute myocardial infarction complicated with pericardial tamponade that mimicked ascending aortic dissection: A case report

Life‐threatening cardiac events may be misdiagnosed as acute aortic dissection because of notable symptom mimicry. We report the case of a 72‐year‐old male patient with presentations presumed to be of aortic origin. However, surgery revealed posterior free‐wall perforation in the left ventricle caused by the occlusion of an obtuse marginal branch.     

Involvement of central opioid systems in human interferon-alpha induced immobility in the mouse forced swimming test

1. We investigated the mechanism by which human interferon-alpha (IFN-alpha) increases the immobility time in a forced swimming test, an animal model of depression. 2. Central administration of IFN-alpha (0.05 - 50 IU per mouse, i.cist.) increased the immobility time in the forced swimming test in mice in a dose-dependent manner. 3. Neither IFN-beta nor -gamma possessed any effect under the same experimental conditions. 4. Pre-treatment with an opioid receptor antagonist, naloxone (1 mg kg(-1), s.c.) inhibited the prolonged immobility time induced by IFN-alpha (60 KIU kg(-1), i.v. or 50 IU per mouse. i.cist. ). 5. Peripheral administration of naloxone methiodide (1 mg kg(-1), s. c.), which does not pass the blood - brain barrier, failed to block the effect of IFN-alpha, while intracisternal administration of naloxone methiodide (1 nmol per mouse) completely blocked. 6. The effect of IFN-alpha was inhibited by a mu(1)-specific opioid receptor antagonist, naloxonazine (35 mg kg(-1), s.c.) and a mu(1)/mu(2) receptor antagonist, beta-FNA (40 mg kg(-1), s.c.). A selective delta-opioid receptor antagonist, naltrindole (3 mg kg(-1), s.c.) and a kappa-opioid receptor antagonist, nor-binaltorphimine (20 mg kg(-1), s.c.), both failed to inhibit the increasing effect of IFN-alpha. 7. These results suggest that the activator of the central opioid receptors of the mu(1)-subtype might be related to the prolonged immobility time of IFN-alpha, but delta and kappa-opioid receptors most likely are not involved.