Management of high-grade bone sarcomas over two decades: the Norwegian Radium Hospital experience.

All cases of high-grade osteosarcoma (OS) (n = 196) and Ewing's sarcoma of bone (ES) (n = 56) treated at the Norwegian Radium Hospital in the period 1980-1999 were analyzed retrospectively. They were allocated to consecutive ten-year periods by their time of diagnosis. Patient and tumour characteristics have been relatively stable. Eighty percent of all patients received surgical treatment and the amputation rate decreased from 64% to 23%. The percentage of patients receiving chemotherapy has remained around 80%. The use of radiotherapy in primary treatment decreased gradually from 33% to 18%. Sarcoma specific survival (SSS) at five years for all patients increased significantly from 39% to 53%. Similar trends for improvement were seen for both OS and ES. In multivariate analysis, independent prognostic factors for improved SSS were non-metastatic disease at diagnosis, age under 40, extremity tumours, small tumours and treatment from 1995 onwards. No major new treatment options have emerged over these 20 years. The improved outcome appears partly to be due to refinements in the use of existing modalities and improved quality and integration of multidisciplinary approaches. Improved formalized organisation of the sarcoma group and annual audited reports of its patient and research activity may also have contributed to improved focus and performance.

Alterations of the fragile histidine triad gene, FHIT, and its encoded products contribute to testicular germ cell tumorigenesis.

The fragile histidine triad (FHIT) gene, located within chromosome arm 3p, is a potential target for testicular tumorigenesis. In the present study, 62 primary testicular germ cell tumors were analyzed for allelic imbalance (AI) at 10 loci mapping to chromosome bands 3p14.1-21.1. Twenty-seven tumors (44%) showed AI at one or more 3p loci. The chromosome 3 copy number was evaluated by fluorescence in situ hybridization with centromere and p-telomere probes onto interphase nuclei from 22 of the tumors. Sixteen of these (73%) presented three or more signals of each probe in at least one-third of the nuclei. The combined fluorescence in situ hybridization and AI results indicated that tumors with AI at all loci, in most cases (five of six), reflected an increased chromosome copy number, whereas tumors presenting AI only at some loci reflected interstitial chromosomal changes. A smallest region of overlapping changes could be delineated from tumors showing interstitial chromosomal changes (n = 16). The smallest region of overlapping changes was flanked by D3S1312 and D3S1234 and included parts of FHIT. In the second part of this study, expression analyses of FHIT were performed. Transcripts of aberrant lengths were found in 7 of 17 (41%) analyzed tumors and were identified by sequencing as splice variants. Three different types of transcripts were found, and all lacked exon 3. Immunohistochemical staining showed reduced Fhit protein expression, compared with normal testicular tissue, in 62% (40 of 65) of the testicular germ cell tumors. Although we found a significant association between FHIT mRNA alterations and AI (P = 0.006), altered protein expression did not correlate with AI. The nonepithelial components of teratomas showed strong association with reduced Fhit protein compared with the epithelial component (P < 0.001). Interestingly, reduced Fhit expression seems to be associated with metastasis in the patient at the time of diagnosis, although the association was not statistically significant.