Expression of ADAMTS4 in Ewing's sarcoma.

Ewing's sarcoma (EWS) is a malignant bone tumor that frequently occurs in teenagers. Genetic mutations which cause EWS have been investigated, and the most frequent one proved to be a fusion gene between EWS gene of chromosome 22 and the FLI1 gene of chromosome 11. However, a limited numbers of useful biological markers for diagnosis of EWS are available. In this study, we identified ADAMTS4 (a disintegrin and metalloproteinase with thrombospondin motifs) as a possible tumor marker for EWS using the retrovirus-mediated signal sequence trap method. ADAMTS4 is a secreted protein of 837 amino acids with a predicted molecular mass of 98-100 kDa. It is a member of metalloprotease family, is expressed mainly in cartilage and brain, and regulates the degradation of aggrecans. ADAMTS4 has been suggested to be involved in arthritic diseases and gliomas. Herein, we show that ADAMTS4 mRNA was expressed in all primary EWS samples and all EWS-derived cell lines examined, while its expression was detected only in small subpopulations of other solid tumors. Furthermore, ADAMTS4 expression was found to be regulated by EWS-FLI1 fusion gene-dependent manner. We also demonstrated that ADAMTS4 protein was highly expressed in tumor samples of the patients with EWS by using immunohistochemistry. These results suggest that ADAMTS4 is a novel tumor marker for EWS.

Loss of heterozygosity at 3p24-p25 as a prognostic factor in breast cancer.

Differences in clinical course and biological characteristics among breast cancers will probably be explained ultimately by variations in the pattern of genetic alterations among the many genes that can play roles in carcinogenesis. Loss of heterozygosity (LOH) of a particular chromosomal region in a tumor, which presumably indicates loss of a growth-regulating 'tumor-suppressor' gene in that region, may represent a useful marker for postoperative prognosis. In earlier work we observed LOH at chromosomal regions 3p14-p21 and/or 3p24-p25 in a large proportion of breast cancers. To examine whether allelic losses in either of those regions might correlate with postoperative survival, we tested tumors from a cohort of 504 breast cancer patients for allelic losses of microsatellite markers in the relevant portions of chromosome 3p. Five years postoperatively, patients whose tumors had undergone LOH at 3p24-p25 were found to have borne significantly higher risks of mortality than women whose tumors retained both alleles at that locus; i.e. the 5-year mortality rate was 22% among patients with losses at 3p24-p25 vs. 9% with retentions of heterozygosity at that locus (P=0.0014). These data indicate that LOH at 3p24-p25 is a significant predictive factor for postoperative survival of patients who have undergone surgery for breast cancer.

Two target regions of allelic loss on chromosome 9 in urinary-bladder cancer.

Allelic losses on chromosome 9 are common in a wide variety of human tumors; moreover, two predisposing loci for some inherited cancer syndromes, i.e., familial malignant melanoma and Gorlin syndrome, have been identified on this chromosome. To define the location of putative tumor suppressor genes involved in cancer of the urinary bladder, 85 bladder cancers were examined for allelic loss at 18 microsatellite loci on chromosome 9. Correlations were also sought between loss of heterozygosity on chromosome 9 and several clinicopathological parameters. Allelic loss was observed in 54 of the tumors (64%) and deletion mapping identified two target regions; one at an interval on 9p21 flanked by D9S736 and D9S165, and the other at an interval on 9q31-34 flanked by D9S58 and D9S61. No subtle mutation was detected in the PTCH gene which lies in the latter interval. Allelic loss on chromosome 9 was observed frequently in low grade and non-invasive tumors as well as in tumors of more advanced phenotype. Inactivation of tumor suppressor genes lying in either of two regions of common deletion identified on chromosome 9 might affect carcinogenic mechanisms at an early stage of tumor development in the urinary bladder.

Allelic loss at 1p34, 13q12, 17p13.3, and 17q21.1 correlates with poor postoperative prognosis in breast cancer.

Allelic losses of tumor suppressor genes (TSGs), or the chromosomal regions harboring them, in tumor DNA may become useful postoperative prognostic indicators. To examine whether specific allelic losses might correlate with postoperative survival in a 5-year prospective follow-up, we tested tumors from a cohort of 264 breast cancer patients for allelic losses of 18 microsatellite markers representing either a known TSG or a region where genetic alterations are frequent in breast tumors. Patients whose tumors had lost an allele at 1p34, 13q12, 17p13.3, or 17q21.1 had significantly higher risks of postoperative mortality than those whose tumors retained both alleles at those loci (at 1p34, a 5-year mortality rate of 29% among patients with losses vs. 7% with retentions, P = 0. 0008; at 13q12, 31% vs. 10%, P = 0.0062; at 17p13.3, 24% vs. 13%, P = 0.026; and at 17q21.1, 31% vs. 13%, P = 0.0047). Furthermore, combined losses at 13q12 and 17p13.3 increased the predicted postoperative mortality risks by a factor of 9.6 (5-year mortality rate of 42% vs. 5% with retentions, P = 0.0001), and combined losses at 1p34 and 17p13.3 raised the predicted postoperative mortality risks by a factor of 8.6 (27% vs. 3%, P = 0.0064). We conclude that allelic losses at these loci can serve as negative prognostic indicators to guide postoperative management of patients. Genes Chromosomes Cancer 26:134-141, 1999.

Somatic mutation of the PTEN/MMAC1 gene in breast cancers with microsatellite instability.

The extent to which microsatellite instability (MI) contributes to the etiology of breast cancer has not been established in any large-scale studies. We examined 528 samples of tumor DNA from patients with primary breast cancer for MI, using 14 polymorphic CA-repeat markers. The frequency of MI in these tumors was unexpectedly low (10/528, 1.9%). The ten MI+ tumors were analyzed for mutations in five potential target genes that contain simple repeat sequences (TGFBIIR, IGF2R, hMSH6, BAX and PTEN/MMAC1). A somatic insertion of an extra adenine in the (A)6 region at codon 321-323 (exon 8) of the PTEN/MMAC1 gene, leading to a frame-shift, was identified in one tumor. This observation represented the first documented instance of PTEN/MMAC1 alteration in a MI+ primary breast cancer.

Ret/PTC3 is the most frequent form of gene rearrangement in papillary thyroid carcinomas in Japan.

Rearrangements of the RET and TRK proto-oncogenes, which generate fusion oncogenes, are frequent in papillary thyroid carcinomas in Caucasian populations. To determine the spectrum of gene rearrangements in Japanese patients, we systematically examined 40 papillary thyroid carcinomas for all possible types of gene fusion events involving RET or TRK genes. RET rearrangements were found in ten tumors (25%): ret/PTC1 had occurred in two tumors, ret/PTC2 in one, ret/PTC3 in six, and a novel RET rearrangement in the remaining patient. In this last patient, the 5' novel sequence was fused in-frame to the RET amino acid sequence; thus, the fusion gene may encode a protein with a RET kinase domain at the carboxy terminus. The RET gene was fused to 5' donor sequences at the beginning of exon 12 in all ten tumors. No rearrangements involving the TRK gene were found in this panel of carcinomas. Our results indicated that constitutive activation of the RET by gene rearrangement is a frequent mechanism of papillary thyroid carcinogenesis in Japanese adults.

Correlation of Allelic Loss with Poor Postoperative Survival in Breast Cancer.

BACKGROUND: Allelic losses of tumor suppressor genes or the chromosomal regions harboring them in the DNA of tumor cells may become useful postoperative prognostic indicators. METHODS: To examine whether specific allelic losses correlate with postoperative survival in a five-year prospective follow-up, we tested tumors from a cohort of 504 breast cancer patients for allelic loss of 18 microsatellite markers representing either known tumor suppressor genes or regions where genetic alterations are frequent in breast tumors. RESULTS: Patients with allelic loss at 1p34, 3p25, 8p22, 13q12, 17p13.3, or 17q21.1 had a significantly higher risks of postoperative mortality compared withthose whose tumors retained both alleles at those loci (at 1p34, the 5-year mortality rate was 23% among patients with loss vs 10% with retention, p 0.0100; at 3p25, 22% vs 9%, p =0.0014; at 8p22, 24% vs 7%, p =0.0177; at 13q12, 19%vs 8%, p=0.0093; at 17p13.3, 19% vs 9%, p=0.0078; and at 17q21.1, 17% vs 10%, p =0.0475). CONCLUSION: Allelic losses at these loci can serve as negative prognostic indicators to guide post-operative management, especially in the selection of thosewho will benefit from intensive adjuvant therapies.

Allelic loss on chromosome 9q is associated with lymph node metastasis of primary breast cancer.

Frequent allelic losses on chromosome 9 are seen in a wide variety of human tumors; moreover, two genes (P16 and PTC) whose mutant alleles confer predispositions to some inherited cancer syndromes have been identified on this chromosome. Using 15 highly polymorphic microsatellite markers distributed on both arms of chromosome 9, we tested 96 primary breast carcinomas for allelic loss in order to define the locations of genes that might be involved in this type of tumor. Allelic loss was observed in 37 of the tumors (39%) and detailed deletion mapping identified target regions at 9p21, 9q22.3 and 9q33. Losses at 9q22.3 and 9q33 were correlated with the presence of lymph node metastasis, and allelic loss at 9q22.3 was observed more frequently in scirrhous tumors than in less aggressive histologic types. Therefore, inactivation of tumor suppressor genes in 9q22.3 and 9q33 regions might play a role in progression of breast cancers, especially in metastasis to lymph nodes and in development of scirrhous tumors.

[Effects of neoadjuvant intra-arterial infusion chemotherapy in patients with stage III breast carcinoma].

From 1991 to 1996, we performed neoadjuvant intra-arterial infusion chemotherapy in 5 eligible patients among 21 patients with Stage III breast carcinoma. The treatment regimen for neoadjuvant chemotherapy was intra-arterial Epirubicin (EPR) on Day 1, 3, 5, 7 combined with endocrine therapy (MPA 1,200 mg). The effects of the treatment were compared among 8 patients given adjuvant intravenous chemotherapy. The clinical response rate was 100% with all partial response and metastatic lymph nodes were disappeared histologically in 2 cases. The median disease-free interval and overall survivals are 44 months (range 28-64) and 48 months (range 28-64), respectively. Neoadjuvant (intra-arterial) group had a longer disease-free interval than the adjuvant (intravenous) group. We are applying this treatment for down staging, and it is possible to use minimal invasive surgery for cure of stage III breast carcinoma.

[Neoadjuvant intra-arterial infusion chemotherapy in over stage III and inflammatory carcinoma of the breast].

From 1991 to 1996, 11 eligible patients (median age 50.4 years, range 33-71 years) with over Stage III and inflammatory breast carcinoma have been treated with neoadjuvant intra-arterial infusion chemotherapy. There were three Stage III a, one III b, three IV and four inflammatory carcinoma. Patients were treated with Epirubicin (10) and Doxorubicin (1), with a total amount of 120-190 mg. Three cases were combined with endocrine therapy (MPA 1,200 mg). In terms of morphological efficacy, 10 of 11 achieved PR, and three of those with endocrine therapy had over Grade 2 in histological efficacy. Carcinoma cells were especially deceased in one inflammatory carcinoma with MPA. Three of 11 died of liver metastasis, the others are still alive (median 24.5 months, range 7-51 months). Combined endocrine therapy should be considered applicable for the treatment strategy of the breast carcinoma.

Prevalencia de vida de trastornos mentales de Independencia (Lima, Perú) / Lifetime prevalence of mental disorders of Independence (Lima, Peru)

Se presentan los resultados de la segunda fase del estudio epidemiológico psiquiátrico realizado en Independencia, distrito urbano marginal de Lima. Se determinó la Prevalencia de Vida (P. V) de trastornos mentales utilizando el Diagnostic Interview Schedule (DIS), administrado por entrevistadores especialmente adiestrados y supervisados por psiquiatras. La muestra fue de 816 adultos mayores de 18 años, seleccionados aleatoriamente. Los datos se recolectaron en el segundo semestre de 1983. El porcentaje de rechazo fue el 1.3%. La P. V. global fue de 32%. Los trastornos mentales fueron significativamente mayores en hombre, 48%, que en mujeres, 40%. Los diagnósticos más prevalentes fueron abuso/dependencia del alcohol, 18.6%, episodio depresivo mayor, 9.7%, fobia 8.5% y personalidad antisocial, 7.1%. El primero y último diagnóstico predominaron significativamente en hombres, mientras que el episodio depresivo mayor y distimia en mujeres. Al grupo de 25-44 años correspondieron las tasas más altas para la mayor parte de los trastornos mentales investigados.

The authors report the findings corresponding to the second wave of the psychiatric epidemiological study in Independencia, a marginal-urban district of Lima City. The data was obtained by standardized layman interview through the Diagnostic Interview Schedule, evaluated by psychiatrists; the rate of interview rejection by the population was 1.3%. Lifetime prevalence rates are presented for 14 DSM-III psychiatric diagnoses. Any DIS disorder covered was 32%. It was significantly higher in men, 48%, than in women, 40%. The most common diagnoses were alcohol abuse/dependence, 18.6%; major depressive episode, 9.7%; phobia, 8.5%; and antisocial personality, 7.1%. Disorders that most clearly predominated in men were alcohol abuse/dependence and antisocial personality. In women were major depressive episode and dysthymia. The age group with highest rates most mental disorders was found to be young adults aged 25-44.