Endometrial carcinoma: multisection dynamic MR imaging using a three-dimensional FLASH technique during breath holding.

PURPOSE: Our aim was to investigate the usefulness of multisection dynamic MR imaging using a 3D FLASH technique during breath holding in assessing myometrial invasion by endometrial carcinoma. MATERIALS AND METHODS: Twenty-eight endometrial carcinomas were evaluated with pathologic correlation. Dynamic MR imaging was performed using the 3D FLASH technique during breath holding. We compared accuracy in the assessment of myometrial invasion by endometrial carcinoma between T2-weighted images, contrast-enhanced T1-weighted images, and dynamic MR images. RESULTS: The accuracy rates in estimating myometrial invasion with T2-weighted images, contrast-enhanced T1-weighted images, and dynamic MR images were 64.3%, 67.8%, and 85.7%, respectively. Statistically significant differences were seen between dynamic MR images and both T2-weighted images and contrast-enhanced T1-weighted images. CONCLUSION: Multisection dynamic MR imaging using the 3D FLASH technique during breath holding is useful for the evaluation of myometrial invasion by endometrial carcinoma with polypoid growth or an unclear junctional zone on T2-weighted images.     

Consensus recommendations for the diagnosis,treatment and follow-up of inherited methylation disorders

Inherited methylation disorders are a group of rarely reported, probably largely underdiagnosed disorders affecting transmethylation processes in the metabolic pathway between methionine and homocysteine. These are methionine adenosyltransferase I/III, glycine N-methyltransferase, S-adenosylhomocysteine hydrolase and adenosine kinase deficiencies. This paper provides the first consensus recommendations for the diagnosis and management of methylation disorders. Following search of the literature and evaluation according to the SIGN-methodology of all reported patients with methylation defects, graded recommendations are provided in a structured way comprising diagnosis (clinical presentation, biochemical abnormalities, differential diagnosis, newborn screening, prenatal diagnosis), therapy and follow-up. Methylation disorders predominantly affect the liver, central nervous system and muscles, but clinical presentation can vary considerably between and within disorders. Although isolated hypermethioninemia is the biochemical hallmark of this group of disorders, it is not always present, especially in early infancy. Plasma S-adenosylmethionine and S-adenosylhomocysteine are key metabolites for the biochemical clarification of isolated hypermethioninemia. Mild hyperhomocysteinemia can be present in all methylation disorders. Methylation disorders do not qualify as primary targets of newborn screening. A low-methionine diet can be beneficial in patients with methionine adenosyltransferase I/III deficiency if plasma methionine concentrations exceed 800 μmol/L. There is some evidence that this diet may also be beneficial in patients with S-adenosylhomocysteine hydrolase and adenosine kinase deficiencies. S-adenosylmethionine supplementation may be useful in patients with methionine adenosyltransferase I/III deficiency. Recommendations given in this article are based on general principles and in practice should be adjusted individually according to patient’s age, severity of the disease, clinical and laboratory findings.     

The role of ARX in cortical development

The ARX protein (encoded by the aristaless-related homeobox gene) is a member of the paired class of homeoproteins. More precisely, it is a member of the Aristaless subclass of proteins with a glutamine residue (Q) at the critical position 50 of the homeodomain (Q50). Through identification of diverse inherited or de novo mutations, genetic investigations of X-linked mental retardation conditions have demonstrated the implication of ARX in a wide spectrum of disorders extending from phenotypes with severe neuronal migration defects, such as lissencephaly, to mild forms of X-linked mental retardation without apparent brain abnormalities. These investigations have recently directed attention to the role of this gene in brain development. Analysis of its spatiotemporal localization profile have revealed expression mainly in telencephalic structures at all stages of development. Interestingly, in adult, ARX expression becomes restricted to a population of GABAergic neurons. Although the identification of the target genes regulated by ARX remains a crucial step to better understanding its role during brain development, studies of the role of ARX orthologs in different models have indicated that it is essential for important developmental processes such as proliferation, cell differentiation and neuronal migration.     

Verapamil results in increased blood levels of oncolytic adenovirus in treatment of patients with advanced cancer

Calcium channel blockers including verapamil have been proposed to enhance release and antitumor efficacy of oncolytic adenoviruses in preclinical studies but this has not been studied in humans before. Here, we studied if verapamil leads to increased replication of oncolytic adenovirus in cancer patients, as measured by release of virions from tumor cells into the systemic circulation. The study was conducted as a matched case-control study of advanced cancer patients treated with oncolytic adenoviruses with or without verapamil. We observed that verapamil increased mean virus titers present in blood after treatment (P < 0.05). The frequency or severity of adverse events was not increased, nor were cytokine responses or neutralizing antibody levels different between groups. Signs of possible treatment-related clinical benefits were observed in both groups, but there was no significant difference in responses or survival. Thus, our data suggests that the combination of verapamil with oncolytic adenoviruses is safe and well tolerated. Moreover, verapamil treatment seems to result in higher virus titers in blood, indicating enhanced overall replication in tumors. A randomized trial is needed to confirm these findings and to study if enhanced replication results in benefits to patients.     

Treatment of Cancer Patients With a Serotype 5/3 Chimeric Oncolytic Adenovirus Expressing GMCSF

Augmenting antitumor immunity is a promising way to enhance the potency of oncolytic adenoviral therapy. Granulocyte–macrophage colony–stimulating factor (GMCSF) can mediate antitumor effects by recruiting natural killer cells and by induction of tumor-specific CD8⁺ cytotoxic T-lymphocytes. Serotype 5 adenoviruses (Ad5) are commonly used in cancer gene therapy. However, expression of the coxsackie-adenovirus receptor is variable in many advanced tumors and preclinical data have demonstrated an advantage for replacing the Ad5 knob with the Ad3 knob. Here, a 5/3 capsid chimeric and p16-Rb pathway selective oncolytic adenovirus coding for GMCSF was engineered and tested preclinically. A total of 21 patients with advanced solid tumors refractory to standard therapies were then treated intratumorally and intravenously with Ad5/3-D24-GMCSF, which was combined with low-dose metronomic cyclophosphamide to reduce regulatory T cells. No severe adverse events occurred. Analysis of pretreatment samples of malignant pleural effusion and ascites confirmed the efficacy of Ad5/3-D24-GMCSF in transduction and cell killing. Evidence of biological activity of the virus was seen in 13/21 patients and 8/12 showed objective clinical benefit as evaluated by radiology with Response Evaluation Criteria In Solid Tumors (RECIST) criteria. Antiadenoviral and antitumoral immune responses were elicited after treatment. Thus, Ad5/3-D24-GMCSF seems safe in treating cancer patients and promising signs of efficacy were seen.     

Comparative studies of antimicrobial agents against causative organisms isolated from urinary tract infections (1984). II. Background of patients

Groups of bacteria were isolated from patients with infections of urinary tracts, and backgrounds of these isolates and patients have been studied in terms of the sexual distribution, and distributions of sexes versus age of the patients relationships between bacterial types and sexual and age distribution of the patients from whom the isolates were obtained correlation ages of patients and types of infections, the association of certain types of bacteria with certain infections and the effect of antibacterial treatments on these types of bacteria, approximately 20% of simple infections of urinary tracts occurred in males and approximately 80% in females on average from 1981 to 1984. This ratio showed hardly any changes during this period. Likewise, male patients comprised approximately 60-70% of all the cases with complicated infections of urinary tracts regardless of indwelling or without indwelling of catheters. In terms of age, the ratio of urinary tract infections was almost universally observed, e.g., for patients in 40's: 10.0% in 1981, 11.0% in 1984, while in those in 70's: 25.5% and 21.2%, respectively. Consequently, background factors of the cases with infections of urinary tracts, such as sexes, age, or simple or complicated, remained almost stable, whereas bacteria involved showed considerable variations. In 1982 and 1983, the frequency of isolations of Enterococcus spp. was approximately 8% in both males and females. However, in 1984, the frequency of isolation of Enterococcus spp. was 22.5% in the males 17.9% in the females. The frequency of isolation of Enterococcus spp. increased in all age groups, but the frequency was not particularly high among the aged. A study on variations and isolation frequencies of bacteria before the administration of antibiotic agents revealed that isolation frequencies of Enterococcus spp. sharply increased in 1983, and this high frequency remained in 1984. The frequency of isolation of E. coli tended to decrease year after year. This finding represents that the frequency of isolations of E. coli from materials of cases with simple infections of urinary tracts has decreased, showing that pathogenic bacteria from simple infections of urinary tracts were becoming similar to that of the complicated infections of urinary tracts. These findings seem to be worth mentioning here. In cases receiving administrations of antibacterial and antibiotic agents for more than 8 days. Frequencies of isolation from cases without catheter retention and from those with catheter retention were similar.(ABSTRACT TRUNCATED AT 400 WORDS)     

A recurrent gastric carcinoma found by metastasis to the scrotum

Reported is a case of 67-year-old man with a recurrent gastric carcinoma that was associated with a possible lymphatic metastasis to the scrotum. Seven years earlier (October, 1980), since an adenocarcinoma of the stomach was present, a subtotal gastrectomy was performed. At that time, a IIc-like advanced tumor with a ul-III, measuring 32 x 28 mm in size, was noted on the anterior wall of the corpus near the greater curvature of the stomach, on macroscopical examination of the resected specimen. Microscopic findings showed a poorly differentiated adenocarcinoma with an involvement of the serosa but without a lymph node metastasis (H0, P0, n0, se, stage III). In July 1987, a tumor in the right scrotum was found and the patient underwent surgery. The resected specimen revealed a histologically cancerous involvement of the testis, the epididymis, the tunica vaginalis testis, and the spermatic cord. The cancerous cells showed the same poorly differentiated adenocarcinoma which had been observed in the primary locus of the stomach. Judging from these findings, this case was diagnosed as a recurrent gastric carcinoma with a lymphatic metastasis to the scrotum.     

Comparative histochemical investigation of the glutathione S-transferase placental form and {gamma}-glutamyltranspeptidase during N-nitrosobis(2-hydroxypropyl)amine-induced lung carcinogenesis in rats

Immunohistochemical staining using anti-rat glutathione S-transferaseplacental form (GST-P) rabbit antibody and enzyme histochemicalstaining for -glutamyltranspeptidase (-GT) were investigatedin lesions appearing during lung carcinogenesis induced by N-nitrosobis(2-hydroxypropyl)amine(BHP) in rats. Rats were given BHP at a concentration of 2000p.p.m. in drinking water, and were killed after 12 weeks ofBHP intake, after 12 weeks of BHP intake followed by 12 weeksof tap water intake or after 20 weeks of continuous BHP intake.It was found that bronchiolo-alveolar hyperplasias, adenomas,adenocarcinomas, squamous metaplasias and squamous cell carcinomashad been induced by BHP. All of the squamous metaplasias andsquamous cell carcinomas were shown to stain with GST-P butnot with -GT. On the other hand, the hyperplasias, adenomasand adenocarcinomas stained with -GT to various degrees andin different areas, but did not stain with GST-P. The incidenceof -GT phenotype and the average percentage of -GT positiveareas in hyperplasias and adenomas suggested that adenocarcinomasmight develop from hyperplasias and adenomas. These resultssuggest that GST-P is a marker for squamous lesions while -GTis a marker for adenomatous lesionsin rat lung carcinogenesis.Furthermore, squamous metaplasias appear to be preneoplasticlesions of squamous cell carcinomas while -GT-positive hyperplasiasor adenomas are preneoplastic lesions of peripheral adenocarcinomas.