[POEMS syndrome: imaging of skeletal manifestations, a study of 8 cases]. / Imagerie des localisations osseuses du POEMS syndrome: à propos de 8 cas.

PURPOSE: To describe the imaging features of POEMS, and to compare our experience of 8 cases to a review of literature. MATERIALS AND METHODS: This retrospective study included 8 patients (6 men, 2 women) with POEMS. Plain radiographs (8 patients), CT (6), MR (2) were performed. RESULTS: Topographic localizations of POEMS were pelvis (7 cases), spine (5), femur (1), humerus (1), rib cage (1). Focal bone lesions, multiple (5 cases) or solitary (3 cases), were sclerotic in 4 cases, mixed lytic-sclerotic (lytic center and sclerotic rim) in 3 cases and one patient had an osteolytic lesion with sclerotic margins associated with many osteosclerotic lesions. Profilerative osseous changes were seen in 4 cases (pelvis, spine, tibia). MR imaging was performed in 2 patients: in one patient MR imaging revealed areas of low signal intensity on spin echo T1- and T2-weighted images in vertebral bodies, the other showed a lesion of low signal intensity on spin echo T1-weighted and high signal intensity on T2-weighted images in the ilium and adjacent soft tissue. CONCLUSION: The imaging features commonly observed in POEMS syndrome are sclerotic and mixed lytic-sclerotic lesions, particularly in the pelvis and spine. Proliferative new bone formation is detected in 50%. MR imaging correlates with ostesclerotic or mixed lytic-sclerotic appearance.

Presence of genetic alterations in microdissected stroma of human colon and breast cancers.

BACKGROUND: Human carcinomas not only consist of neoplastic epithelial cells but also of tumor stroma, which may play an important role in tumor-progression. Whereas the tumor surrounding stroma is generally believed to represent a reactive component induced by tumor cell derived factors, a contribution of neoplastic cells to stroma formation via epithelium-mesenchyme transition during tumor invasion has become a novel concept in recent years. MATERIALS, METHODS AND RESULTS: We here show, by laser-assisted microdissection, that frequent genetic alterations in non-hereditary invasive human colon and breast cancers (loss of heterozygosity and TP53 mutations) occur not only in the neoplastic epithelial cells, but also in the adjacent fibroblastic stroma and that both components can share clonal features. CONCLUSION: Tumor cell-mesenchyme transitions are among the possible explanations for these findings and could actually occur during tumor invasion in vivo.

Presence of genetic alterations in microdissected stroma of human colon and breast cancers.

We show by laser-assisted microdissection that frequent genetic alterations in non-hereditary invasive human colon and breast cancers (loss of heterozygosity and TP53 mutations) occur not only in the neoplastic epithelial cells, but also in the adjacent fibroblastic tumor stroma and that both components can share clonal features. Tumor cell-mesenchyme transitions are among the possible explanations for these findings.

Expression of the Ets-1 transcription factor in human astrocytomas is associated with Fms-like tyrosine kinase-1 (Flt-1)/vascular endothelial growth factor receptor-1 synthesis and neoangiogenesis.

Marked neovascularization and vascular endothelial proliferation are characteristic features of malignant gliomas. Vascular endothelial growth factor (VEGF), an angiogenic protein secreted by glioma cells, appears to play a crucial role for induction of neoangiogenesis. The VEGF receptors fms-like tyrosine kinase-1 (Flt-1)/VEGFR-1 and kinase insert domain-containing receptor (KDR)/ VEGFR-2 are up-regulated on the surface of endothelial cells (ECs) in gliomas. Both receptor genes contain an Ets-responsible element in their promoters. The proto-oncogene ets-1 encodes a transcription factor that has been associated with blood vessel formation in vivo under physiological and pathophysiological conditions including tumor neovascularization. Ets-1 is induced by VEGF in cultured ECs. In vitro data also point to a role of Ets-1 as a transcriptional activator of Flt-1. These properties prompted us to investigate Ets-1 expression in 32 human astroglial tumors of WHO grades I-IV and to correlate the data with the expression pattern of VEGF, Flt-1, and KDR. By in situ hybridization, high ets-1 mRNA levels were found in the glioma microvasculature with particularly prominent signals in glomeruloid vascular endothelial proliferations of glioblastomas (WHO grade IV). Semiquantitative reverse transcription-PCR identified the full-length ets-1 transcript but none of three known splice variants encoding isoforms with different functional domains. Immunohistochemical staining demonstrated Ets-1 protein preferentially in the nucleus of those ECs with an epithelioid morphology consistent with an activated state, whereas quiescent flat-shaped ECs predominantly displayed cytosolic immunoreactivity. This observation proposes nuclear translocation of Ets-1 during neoangiogenesis. VEGF synthesis by glioma cells was accompanied by Ets-1 expression in adjacent microvascular ECs. Furthermore, a highly significant correlation was observed between Ets-1 and Flt-1 (but not KDR) expression in ECs of the glioma microvasculature. Our data suggest that VEGF secreted by glioma cells induces Ets-1 in adjacent microvascular ECs, which subsequently transactivates the VEGF receptor Flt-1. This cascade may crucially promote neoangiogenesis in human gliomas.

Inhibition of Angiogenesis In Vivo by ets-1 Antisense Oligonucleotides-Inhibition of Ets-1 Transcription Factor Expression by the Antibiotic Fumagillin.

The inhibition of angiogenesis in vivo as a result of the inhibition of Ets-1 transcription factor expression by the ets-1 phosphorothioate antisense oligodeoxynucleotide 5'-AGATCGACGGCCGCCTTCAT-3' has been proven by experiments with chicken embryos. Thus, participation of the Ets-1 transcription factor in the formation of new blood vessels in vivo has been demonstrated. Furthermore, it is shown that the angiostatic effect of the fungal metabolite and angiogenesis inhibitor fumagillin is mainly a result of its ability to inhibit Ets-1 expression.

Loss of heterozygosity (LOH), malignancy grade and clonality in microdissected prostate cancer.

The aim of the present study was to find out whether increasing malignancy of prostate carcinoma correlates with an overall increase of loss of heterozygosity (LOH), and whether LOH typing of microdissected tumour areas can help to distinguish between multifocal or clonal tumour development. In 47 carcinomas analysed at 25 chromosomal loci, the overall LOH rate was found to be significantly lower in grade 1 areas (2.2%) compared with grade 2 (9.4%) and grade 3 areas (8.3%, P = 0.007). A similar tendency was found for the mean fractional allele loss (FAL, 0.043 for grade 1, 0.2 for grade 2 and 0.23 for grade 3, P = 0.0004). Of 20 tumours (65%) with LOH in several microdissected areas, 13 had identical losses at 1-4 loci within two or three areas, suggesting clonal development of these areas. Markers near RB, DCC, BBC1, TP53 and at D13S325 (13q21-22) showed higher loss rates in grades 2 and 3 (between 25% and 44.4%) compared with grade 1 (0-6.6%). Tumour-suppressor genes (TSGs) near these loci might, thus, be important for tumour progression. TP53 mutations were detected in 27%, but BBC1 mutations in only 7%, of samples with LOH. Evaluation of all 25 loci in every tumour made evident that each prostate cancer has its own pattern of allelic losses.

[Inhibition of angiogenesis on the chicken chorioallantoic membrane by Ets 1 antisense oligodeoxyribonucleotides]. / Hemmung der Angiogenese auf der Chorioallantoismembran des Hühnchens durch Ets 1 Antisenseoligodesoxynukleotide.

The Ets 1 transcription factor, the founder of the ets gene family of transcriptional regulators, has strongly been supposed to play a role in angiogenesis under both physiological and pathological conditions including tumor vascularization. An in vivo role has nevertheless not yet been proven. We therefore investigated whether an Ets 1 antisense oligodesoxynucleotide (ODN) blockade effectively inhibits in vivo angiogenesis in the chicken chorioallantois membrane-assay. We used a 20-mer phosphorothioate directed against the AUG initiation codon and a short 3' sequence of the c-ets 1 mRNA (5'-AGATCGACGGCCGCCTTCAT-3') in order to block Ets 1 expression. Three quantities of either antisense or negative control sense ODNs were directly applied on the chorioallantois membrane on day five of development and results evaluated on day seven. No effect on angiogenesis was seen in the antisense group treated with 2.5 micrograms ODN/egg compared to the sense control group. In contrast chorioallantoic blood vessel numbers and diameters were considerably reduced after application of 5 micrograms antisense ODN. 10 micrograms of either antisense or sense ODNs turned out to be toxic: all 6 embryos had died on day seven. Our results are the first proof that the Ets 1 transcription factor is actually necessary for the regulation of in vivo angiogenesis. Its role is probably not restricted to development but also concerns new blood vessel formation during chronic inflammation and tumor vascularization.

[Genetic alterations in the fibroblastic stroma of invasive colon and breast carcinomas]. / Genetische Veränderungen im fibroblastischen Stroma invasiver Kolon- und Mammakarzinome.

While the neoplastic cells have always been in the center of interest in cancer research in recent years, more and more attention has been paid also to the tumor stroma which is today known to play an important role for tumor progression. In early days of histology the interpretation of stroma as either neoplastic or reactive was still a matter of discussion. Today's generally held view is clearly in favor of a secondary induction by tumor cell derived factors. Recent findings of epithelium-mesenchymal transitions of cultured tumor cells now put again a doubt on this exclusive interpretation. In the present work we show for the first time that genetic alterations (allelic losses, microsatellite instabilities and p53 mutations) are not restricted to tumor cells but also occur within the fibroblastic stroma of non-hereditary invasive human colon and breast cancers. In view of the clonality of epithelial and stromal components in the same cases (loss of same alleles and identical MSI patterns) epithelium-mesenchymal transitions are among possible explanations for these findings which could shed a new light on the true nature of tumor stroma.

Pathological aspects of prostate cancer and benign nodular hyperplasia.

The aim of the study was to investigate tumor suppressor genes (TSGs) which play a role in the pathogenesis of prostate cancer. Additionally, different prostate tumors were immunohistochemically related to their potential precursor cells, the basal cells and the glandular secretory epithelium, which differ in their hormone responsiveness. By PCR-amplification of microsatellite-DNA we found allelic losses of chromosomal loci near known or putative TSGs to increase with the malignancy grade of prostate carcinoma. When investigated for numerous markers common and endometrioid carcinoma were immunohistochemically related to the secretory epithelium while the rare basal cell tumor, containing the estrogen receptor, squamous cell carcinoma and urothelial carcinoma showed features of the basal cells. In histopathological differential diagnosis high molecular weight basal cell keratins, prostatic acid phosphatase and prostate specific antigen may be of value. Stromal type nodular hyperplasia and the fetal prostate mesenchyme had common immunohistochemical features which might reflect analogous development.

Cytogenetic investigations from lymphocyte cultures of patients with probable Alzheimer's disease.

Chromosome investigations were carried out on lymphocyte cultures of 21 patients with probable Alzheimer's disease in comparison to an age-matched control group of 11 healthy subjects. Different cytogenetic parameters were analyzed: sister chromatid exchanges, polyploid mitoses, mitotic activity and secondary chromosomal aberrations such as gaps, breaks and exchanges. Only the average rate of sister chromatic exchanges was slightly decreased in patients (8.4 +/- 1.7; control group: 10.4 +/- 2.1). There were interindividual differences of values for each of the cytogenetic parameters analyzed, but these were not related to the onset, duration or severity of dementia.