Allelotype analysis of adult T-cell leukemia

Allelotype analysis of adult T-cell leukemia (ATL) was undertaken for the first time to identify chromosomal loci relevant to the development of acute/lymphomatous ATL. Loss of heterozygosity (LOH) was screened using 94 highly polymorphic microsatellite markers, distributed among all nonacrocentric, autosomal chromosomes. In each of the 22 cases, DNA obtained from their leukemic cells in acute/lymphomatous phase was compared with their constitutional DNA from mononuclear cells in chronic or remission phase. Allelic losses of at least on one chromosome arm occurred in 91% of the cases (20 individuals). Among 39 chromosome arms, allelic losses were observed on 31 arms at least for one sample. A high frequency of allelic loss (>30%) was seen on chromosome arms 6q (41%) and 17p (48%). The mean fractional allelic loss (FAL) was 0.109. These findings suggest that a novel tumor suppressor gene on chromosome arm 6q, as well as the p53 gene on chromosome arm 17p, probably have an important role in the development of acute/lymphomatous ATL.     

Allelotype and replication error phenotype of small cell lung carcinoma

Allelotype and replication error (RER) phenotype analyses were performed to clarify the pathogenetic significance of inactivation of tumor suppressor genes and genomic instability in the genesis and progression of small cell lung carcinoma (SCLC). We examined 37 cases of SCLC for loss of heterozygosity (LOH) and microsatellite instability at 49 loci on all 39 nonacrocentric chromosomal arms. LOH was frequently (>70%) detected on chromosomes 3p (29/32, 90.6%), 5q (15/21, 71.4%), 13q (25/26, 96.2%), 17p (22/25, 88.0%), and 22q (24/33, 72.7%). Frequent LOH (>70%) on these loci was observed even among seven cases of stage I tumors. The incidence of LOH on all 39 nonacrocentric chromosomal arms was not significantly different between primary tumors and metastases. These results suggest that inactivation of multiple tumor suppressor genes accumulates relatively early during progression of SCLC and it may be responsible for clinically and biologically aggressive phenotype of SCLC. RER was observed in 6/37 (16.2%) of SCLC, however, RER at multiple loci was observed only in two cases. Therefore, it was indicated that genomic instability is uncommon, but might play a role in the genesis of a small subset of SCLC.     

Chest wall rhabdomyosarcoma

BACKGROUND: Rhabdomyosarcoma is the most common soft tissue sarcoma in the pediatric age group. The primary tumor site is an important prognostic determinant. Axial lesions are associated with decreased survival and provide a clinical challenge. METHODS: A retrospective analysis of the authors' institutional experience between 1972 and 1996 was performed. Patients were from a data base of 302 consecutive cases. RESULTS: Fifteen consecutive patients with chest wall rhabdomyosarcoma were identified. The median age was 16 years (range, 6 months-25 years). Median follow-up was 6.6 years (range, 10 months-18.5 years). Nine patients presented with a mass, six with pain, two with respiratory distress, and one with ulnar neuropathy. The median lesion size was 7 cm (range, 3-16 cm). A surgical procedure was the initial therapy for 13 of 15 patients. Fourteen patients received radiation therapy with a median dose of 4400 cGy. All but one were included in institutional-based trials using multiagent chemotherapy. At last follow-up, 10 patients were alive and disease free, with a median survival of 123 months (range, 51-221 months). Seven of ten survivors underwent a complete resection as their initial therapy. There was no surgical mortality, and only two patients had treatment-related complications. Of the five patients who died, two underwent complete resection as their initial therapy. All five patients had invasive tumors. Four were > 10 cm, 3 were of alveolar subtype, and 2 were embryonal. CONCLUSIONS: Complete resection of chest wall rhabdomyosarcoma is recommended. However, survival is possible for patients with microscopically positive surgical margins with the addition of chemotherapy and radiation.     

Allelotype analysis of oesophageal adenocarcinoma: loss of heterozygosity occurs at multiple sites

Deletions of tumour-suppressor genes can be detected by loss of heterozygosity (LOH) studies, which were performed on 23 cases of adenocarcinoma of the oesophagus, using 120 microsatellite primers covering all non-acrocentric autosomal chromosome arms. The chromosomal arms most frequently demonstrating LOH were 3p (64% of tumours), 5q (45%), 9p (52%), 11p (61%), 13q (50%), 17p (96%), 17q (55%) and 18q (70%). LOH on 3p, 9p, 13q, 17p and 18q occurred mainly within the loci of the VHL, CDKN2, Rb, TP53 and DCC tumour-suppressor genes respectively. LOH on 5q occurred at the sites of the MSH3 mismatch repair gene and the APC tumour-suppressor gene. 11p15.5 and 17q25-qter represented areas of greatest LOH on chromosomes 11p and 17q, and are putative sites of novel tumour-suppressor genes. LOH on 9p was significantly associated with LOH on 5q, and tumours demonstrating LOH at both the CDKN2 (9p21) and MSH3 (5q11-q12) genes had a significantly higher fractional allele loss than those retaining heterozygosity at these sites. Six of nine carcinomas displaying microsatellite alterations also demonstrated LOH at CDKN2, which may be associated with widespread genomic instability. Overall, there are nine sites of LOH associated with oesophageal adenocarcinoma.     

Allelotype influence at glutathione S-transferase M1 locus on breast cancer susceptibility

PURPOSE: To compare development of visual acuity and binocular vision in preterm and full-term infants in a prospective study that used testers masked to subject's gestational age. METHODS: Seventy-nine healthy full-term infants, mean gestational age 40 weeks, and 18 low-risk preterm infants, mean gestational age 33 weeks, were examined biweekly between the 44th and 54th weeks of postmenstrual age. Ocular alignment, convergence, fusion, grating acuity, and onset of optokinetic nystagmus (OKN) were assessed at each examination. RESULTS: The mean postnatal ages of onset of ocular alignment, convergence, fusion, grating acuity to 1.6 cycles per degree, and OKN from temporal to nasal and nasal to temporal were, respectively, 5, 7, 7, 11, 6, and 9 weeks for the full-term and 12, 13, 14, 18, 13, and 16 weeks for the preterm infants. The mean postmenstrual ages of onset for the corresponding parameters were 46, 48, 48, 51, 46, and 50 weeks for full-term and 46, 47, 48, 52, 47, and 49 weeks for preterm infants. The onset of all parameters was earlier in full-term infants than in preterm infants of the same postnatal age (P < or = 0.0001). However, no differences were found when the parameters were compared at postmenstrual ages. CONCLUSIONS: Additional visual experience of preterm infants does not influence development of visual acuity or binocular vision during the first months of life as measured from the time of conception.     

Epidermal nevus and rhabdomyosarcoma

A child with an epidermal nevus was diagnosed at the age of 15 months as having an embryonal rhabdomyosarcoma of the bladder. This child also had pigmentary abnormalities characteristic of the epidermal nevus syndrome. The question is again asked whether patients with epidermal nevi have an increased incidence of tumors. It is suggested that the thorough evaluation of these patients as recommended by Solomon should also include an alertness for the development of earlier-than-anticipated neoplasms.     

The radiological manifestations of intracranial rhabdomyosarcoma

Two cases of rhabdomyosarcoma, one arising in the parotid gland and the other within the middle ear cavity, are presented. Both cases developed neurological signs of intracranial extension, which, in one, were non-localizing. The angiographic characteristics of these two cases as well as those reported in the literature are discussed. Angiography delineated the extent of tumor involvement and influenced the treatment ports. Isolated reports of long term survivals and some promising preliminary results from more aggressive therapy warrant delineation of tumor extent. To this end angiography is helpful.     

Cytologic diagnosis and subtyping of rhabdomyosarcoma

Ornithine transcarbamylase (OTC) deficiency is an X-linked disorder of urea synthesis. Among females who carry a mutant OTC allele, there is a wide range of phenotypic variability, ranging from apparent normality to a severe onset and the resulting profound neurologic impairment observed in hemizygous males. This study was designed to define the phenotypic variability of OTC deficiency in ostensibly healthy carrier females and to compare them to noncarrier females from their own and other families. One hundred seventy-five women from 89 families participated in this study. Each completed a mailed questionnaire, allopurinol testing, and fasting plasma amino acid determinations. OTC carrier status was determined by pedigree analysis, allopurinol test results, and/or DNA mutation analysis. Overall, 79 women were identified as carriers of a mutant OTC allele (60 proband mothers, 19 relatives), and 96 women (32 proband mothers, 64 female relatives) were determined to be noncarriers. Comparison of biochemical phenotypes indicated that carriers and noncarriers do not differ in daily urinary creatinine excretion, but that carriers excrete significantly less urea nitrogen and total nitrogen, reflecting their significantly lower historically reported daily protein intake. Carriers had significantly higher levels of fasting plasma glutamine and alanine, and significantly lower levels of citrulline and arginine compared with noncarriers. Carriers and noncarriers reported similar demographic characteristics, anthropometric measurements, level of education, and medical and pregnancy histories. There was no indication of increased incidence of migraine headaches among carriers. Thus, we found no evidence that asymptomatic adult female OTC heterozygotes are at increased risk for previously unidentified health problems apart from an unknown risk for hyperammonemic encephalopathy as occurred in 3 of the carriers in this study. Because these episodes appear to be related to physiologic stress (fracture, parturition), it would seem medically prudent for carriers to be aware of this risk.     

Alveolar rhabdomyosarcoma of the uterine cervix

Porphyria cutanea tarda is characterized by severe connective tissue damage in sun-exposed skin. The regulated synthesis and degradation of the extracellular matrix by various matrix metalloproteinases (MMPs) determine its amount and composition within the skin. In this study, we therefore asked whether long-wave ultraviolet irradiation (340-450 nm) in conjunction with uroporphyrin I could modulate the synthesis of MMPs with substrate specificities for dermal (collagens I, III, V; proteoglycans) and basement membrane components (collagens IV, VII; fibronectin; laminin) and whether synthesis of the counteracting tissue inhibitor of metalloproteinases is also affected. After irradiation of uroporphyrin-pretreated fibroblasts, specific mRNAs of MMP-1 and MMP-3 increased concomitantly up to 2.7-fold compared with ultraviolet-irradiated cells and up to 10-fold compared with mock-irradiated or uroporphyrin I-treated controls. In contrast, mRNA levels of tissue inhibitor of metalloproteinases remained unaltered. Similar results were obtained by immunoprecipitation. Gelatin and casein zymography revealed increased proteolytic activity of MMP-2 and MMP-3 in blister fluids of patients with porphyria cutanea tarda, indicating that similar events may occur in vivo. Using deuterium oxide as enhancer and sodium azide as quencher of singlet oxygen, we could increase or reduce MMP synthesis, suggesting that singlet oxygen is the major intermediate in the upregulation of MMPs after irradiation of uroporphyrin-pretreated fibroblasts. Taken together, our results show that ultraviolet irradiation alone, and to a greater extent in conjunction with uroporphyrin I, results in an unbalanced synthesis of MMPs that may contribute to the destruction of the dermis and basement membrane, leading to blistering and accelerated photoaging in porphyria cutanea tarda patients.     

Treatment results for rhabdomyosarcoma in children

The results of treatment in 45 children with rhabdomyosarcoma was presented. Two-years survival was achieved in 63% and five-year in 45%. The importance of location and group of clinical progression discussed was importance prognostic factors in rhabdomyosarcoma.     

Pediatric rhabdomyosarcoma of the head and neck

PURPOSE: Survival for pediatric rhabdomyosarcoma has improved with the use of multidrug chemotherapy and external beam radiotherapy. This study was performed to determine survival in a cohort of patients treated on one of three multidrug treatment protocols for head and neck rhabdomyosarcoma and to identify factors that place patients at risk for treatment failure. METHODS: Pertinent prognostic variables including age, sex, subsite of origin, resectability, and TNM stage were analyzed by the Kaplan-Meier methods with comparisons between variables performed using the Prentice-Wilcoxon test statistic. RESULTS: Overall 5-year survival was 74% (95% confidence interval 64% to 84%). Local failure accounted for the cause of death in 10 patients, and 8 died of disseminated disease. On univariate analysis, each variable contributing to the TNM staging system was significant in determining survival; invasiveness (P = 0.01), size (P = 0.02), nodal metastases (P <0.01), and distant disease (P <0.01). CONCLUSION: Survival has improved for head and neck rhabdomyosarcoma treated with multimodality therapy. Patients with advanced-stage disease are at greatest risk for treatment failure and require the most aggressive therapy.     

Interventional radiology in children with hepatobiliary rhabdomyosarcoma

A patient presented with severe bactrim-induced neutropenia with a reversed CD4+/CD8+ lymphocyte ratio. R-metHUG-CSF at 300 micrograms daily produced a dramatic neutrophil response and the therapy was discontinued after 2 weeks.