Classification of clear-cell sarcoma as a subtype of melanoma by genomic profiling.

PURPOSE: To develop a genome-based classification scheme for clear-cell sarcoma (CCS), also known as melanoma of soft parts (MSP), which would have implications for diagnosis and treatment. This tumor displays characteristic features of soft tissue sarcoma (STS), including deep soft tissue primary location and a characteristic translocation, t(12;22)(q13;q12), involving EWS and ATF1 genes. CCS/MSP also has typical melanoma features, including immunoreactivity for S100 and HMB45, pigmentation, MITF-M expression, and a propensity for regional lymph node metastases. MATERIALS AND METHODS: RNA samples from 21 cell lines and 60 pathologically confirmed cases of STS, melanoma, and CCS/MSP were examined using the U95A GeneChip (Affymetrix, Santa Clara, CA). Hierarchical cluster analysis, principal component analysis, and support vector machine (SVM) analysis exploited genomic correlations within the data to classify CCS/MSP. RESULTS: Unsupervised analyses demonstrated a clear distinction between STS and melanoma and, furthermore, showed that CCS/MSP cluster with the melanomas as a distinct group. A supervised SVM learning approach further validated this finding and provided a user-independent approach to diagnosis. Genes of interest that discriminate CCS/MSP included those encoding melanocyte differentiation antigens, MITF, SOX10, ERBB3, and FGFR1. CONCLUSION: Gene expression profiles support the classification of CCS/MSP as a distinct genomic subtype of melanoma. Analysis of these gene profiles using the SVM may be an important diagnostic tool. Genomic analysis identified potential targets for the development of therapeutic strategies in the treatment of this disease.     

Pulmonary thrombo-embolism in nephrotic syndrome treated with tissue plasminogen activator

We describe the case of a boy with steroid sensitive nephrotic syndrome and left pulmonary artery thrombo-embolism. Clinical presentation initially suggested sepsis and respiratory signs were minor. Treatment with tissue plasminogen activator infused into the pulmonary artery was successful. Conclusion Pulmonary thrombo-embolism should be considered in unwell children with nephrotic syndrome. Received: 6 September 1996 / Accepted: 17 December 1996     

Efficacy of Zoladex LA (goserelin) in the treatment of girls with central precocious or early puberty

OBJECTIVE: To assess the efficacy of a longer acting preparation of the gonadotrophin releasing hormone (GnRH) analogue goserelin (Zoladex LA, 10.8 mg) in 12 girls with central precocious or early puberty. METHODS: Two girls started treatment de novo; the remainder had been on suppressive treatment for a median duration of 1.5 (range, 0.2-5.6) years. Assessment comprising auxology, pubertal staging, and pelvic ultrasound examination was carried out at weeks 0, 4, 8, 10, and 12 (first cycle) and weeks 8, 10, and 12 (second cycle) to evaluate the required injection frequency. Thereafter, assessment was performed on the day of injection. Zoladex LA was given every 12 weeks unless pubertal progression occurred. RESULTS: Satisfactory control was achieved in eight patients using this regimen, and three patients required more frequent injections. One girl was removed from the study because of clinical progression and extreme mood swings. No serious adverse effects occurred. Mean height velocity during the study period was 4.5 cm/year (range, 3.1-6.6) compared with 6.5 cm/year (range, 3.8-9.6) before treatment in nine patients for whom data were available. CONCLUSIONS: Zoladex LA was effective in controlling precocious puberty in girls when given at intervals of 9-12 weeks and it is recommended that an initial assessment is made eight weeks after beginning treatment.     

Beta2 integrin/ICAM-1 adhesion molecule interactions in cutaneous inflammation and tumor promotion

The beta2 integrin (CD 18/CD 11 a, b, c) family of proteins mediate adherence of leukocytes to vascular endothelium and the associated ligand, intercellular adhesion molecule-1 (ICAM-1; CD 54), interacts with beta2 integrin proteins to allow transendothelial migration of leukocytes into sites of inflammation. The present study examines the function of these proteins in a murine model of acute cutaneous inflammation induced following topical application of 12-O- tetradecanoylphorbol-13-acetate (TPA) to the dorsal epidermis of SENCAR mice and in a model of skin multistage carcinogenesis. At 24 h following topical application of TPA to the dorsal epidermis of mice, dermal leukocytes expressed higher levels of beta2 integrin protein compared with the lower levels of beta2 integrin protein expression by peripheral blood leukocytes. ICAM-1 protein was localized to epidermal keratinocytes and vascular endothelium in TPA-treated skin and to proliferating papilloma cells. Intravenous (i.v.) injection of either 50 microg anti-beta2 integrin antibody alone or in combination with anti-ICAM-1 antibody significantly inhibited both TPA-stimulated neutrophil infiltration into the dermis (P < 0.001) and myeloperoxidase (MPO) activity (P < 0.03 anti-beta2 integrin antibody; P < 0.01 anti- beta2 integrin + ICAM-1 adhesion molecule antibodies), but had no effect on TPA-induced epidermal hyperplasia. In addition, injection of either anti-ICAM-1 adhesion molecule antibody alone (P < 0.004) or in combination with anti-beta2 integrin antibody (P < 0.001) significantly inhibited TPA-induced production of 7,8-dihydroxy-2'-deoxyguanosine (8- OHdG) immunoreactive proteins by epidermal keratinocytes. Beta2 integrin/ICAM-1 adhesion molecules work in concert to regulate migration, retention and functional activation of leukocytes within the dermis during TPA-induced skin inflammation and within stromal tissue of papillomas that form during multi-stage carcinogenesis. Agents that inhibit these receptor/ligand interactions may be useful in defining the roles of specific cell populations in cutaneous inflammation and multistage carcinogenesis and may also have potential as anti-promoting and anti-progression agents.      

Haptoglobin-related protein as a serum marker in malignant lymphoma

A novel serum 21 kDa haptoglobin-related protein (Hpr) was investigated in patients with malignant lymphoma, to evaluate its correlation with clinical and histologic features at presentation and its possible role as a tumor marker for patient outcome. One hundred fifty eight serum samples were taken from 88 patients with non-Hodgkin’s lymphoma (n=58) and Hodgkin’s disease (n=30) at presentation and in the course of follow-up. Sera from 61 healthy volunteers served as normal controls. Serum Hpr levels in the lymphoma patients (median 430xl0³ u/ml, range 0-4000xl0³) were significantly higher than in the control group (median 68xl0³ u/ml, range 0-180xl0³) (p=0.0001). Higher median Hpr values were detected in patients with advanced disease (p=0.013), “B” symptoms (p=0.029) and in males (p=0.053). There was also a significant correlation between Hpr and erythrocyte sedimentation rate (p=0.028). Serial determinations showed a significant decrease of the initial Hpr values obtained after treatment in 41 patients, 38 of whom achieved complete remission. In the follow-up period additional Hpr measurements were taken from 17 patients. Three of them eventually relapsed, and showed increased Hpr levels at the time of relapse. Hpr levels remained low in 11 of 14 patients who maintained complete remission, and increased in three. In conclusion, serum Hpr is a new serum tumor marker of potential use in the clinical setting of lymphoma. This work is dedicated to the memory of Dr. Arie H. Bartal, a dedicated oncologist and friend. This work was supported by Chemotech Thechnologies Ltd., by grant no. 3676 from the Chief Scientist’s Office of the Ministry of Health, Israel, and by the Fund for Promotion of Research in the Technion.     

Mutation of the p53 tumor suppressor gene in spontaneously occurring osteosarcomas of the dog

Inactivation of the p53 tumor suppressor gene has been implicated in the pathogenesis of numerous human cancers, including osteosarcomas. Appendicular osteosarcomas of the dog appear to be a good model for their human equivalent with regard to biologic behavior, epidemiology and histopathology. We individually screened exons 5-8 of the p53 gene for mutations in 15 canine appendicular osteosarcomas using 'Cold' SSCP to compare the role of this gene in human and canine osteosarcoma tumorigenesis. Seven of the tumors (47%) exhibited point mutations, with one tumor possessing two mutations within different exons. Of these, seven were missense mutations and the eighth was a 'silent' mutation potentially affecting the exon 6-7 splicing region. Five of the missense mutations were located in highly conserved regions IV and V, while another corresponded with the highly conserved codon 220 mutational hotspot located outside the conserved domains. The locations and types of mutations were nearly identical to those reported in human cancer. These findings provide strong evidence of the involvement of p53 mutations in the development of canine appendicular osteosarcomas. Canine osteosarcomas appear to be a promising model for their human equivalent on a clinical, pathologic, and molecular level.      

SOMATIC NEUROPATHY IN DIABETES MELLITUS

One hundred patients of Diabetes Mellitus (70 with and 30 without clinical somatic neuropathy) were studied to correlate clinical severity with the magnitude of nerve conduction abnormalities. Age range was 10-79 years (mean 49) with equal number of males and females. Incidence of neuropathy was more in patients over 40 years of age (60 out of 70 patients) with duration of disease over two years (78.33%). The grades of severity were mild in 22 (31.33%), moderate in 25 (35.71%) and severe in 23 (32.86%) patients. Nerve conduction studies were carried out in 48 (27 with and 21 without clinical neuropathy) patients, using the apparatus Dantec (Cantata TM). The nerves (median, peroneal and sural) were stimulated at two points and the recording of latency; amplitude (micro V) and motor and sensory nerve conduction velocities (m/s) were done under identical environmental conditions. Sensory nerve conduction velocity was more affected than motor velocity. In the 21 patients without clinical neuropathy, 14 showed abnormalities indicating early involvement of peripheral nerves. Reduction of motor nerve conduction velocity was more in patients with moderate and severe grades. The reduction was more in lower than in upper limbs. Nerve conduction abnormality helps in diagnosis in diabetic neuropathy even in preclinical state and correlates with severity, in clinical neuropathy.KEY WORDS: Diabetic neuropathy, Nerve conduction abnormality, Peripheral neuropathy     

Endometrial cancer in patients undergoing diagnostic curettage

We made a retrospective review of in 2769 patients in whom curettage was performed. Of 1468 women under 50 years of age, only one (0.08%) had endometrial cancer. Of 834 patients presenting with postmenopausal bleeding 31, (3.7%) had endometrial cancer. Received: 24 June 1997 / Accepted: 24 September 1997