Gains and losses of DNA sequences in osteosarcomas by comparative genomic hybridization.

Our aim was to identify chromosomal regions that are likely to harbor previously unknown genes with an important role in the genesis of osteosarcoma. Comparative genomic hybridization was used to screen for losses and gains of DNA sequences along all chromosome arms in 11 tumors. Extensive genetic aberrations, with an average of 11 changes/tumor (range, 1-20), were found in 10 of the 11 specimens. High level amplifications of small chromosomal regions were detected in eight tumors. These involved the 12q12-q13 region (known to contain the SAS-MDM2 locus) and several previously unreported amplification sites such as 17p11-p12, 3q26, and Xq12. When all DNA sequence gains were evaluated, the gains at 8q and Xp were most common (45%). The most common losses of DNA sequences were seen at 2q, 6q, 8p, and 10p (36%). In conclusion, despite the very complex pattern of genetic changes in osteosarcomas, certain chromosomal regions appear to be affected more often than others. Most of these regions have not previously been reported to be implicated in osteosarcomas and may thus highlight locations of novel genes with an important role in the development and progression of these tumors.

Surgical treatment of myeloma of bone.

33 patients treated operatively for plasma cell disease were analysed. There were 21 men and 12 women with an average age of 54 years. There was an undefined bone tumour in 23 cases, and a pathologic fracture in 10 cases. In only 6 cases was the diagnosis known before the operation. The primary tumour localisations were: vertebral column in 13, pelvis in 7, femur in 6, humerus in 2, rib in 1, tibia in 1, fibula in 1, scapula in 1 and olecranon in 1 case. 16 diagnostic biopsies were taken. Vertebral tumours were mainly evacuated or decompressed, combined with a stabilising procedure in 8 cases. A total of six endoprostheses, five to the femur and one to the humerus were performed. Two primarily wide resections, to the fibula and to the scapula were done. There were no locally recurring tumours during a mean follow-up time of 4 years and 2 months, and we conclude that operative and oncologic treatment is successful in providing the patient with a stable, pain-free locomotive system.

Clinical significance of genetic imbalances revealed by comparative genomic hybridization in chondrosarcomas.

DNA copy number changes were studied by comparative genomic hybridization (CGH) in 50 chondrosarcoma samples from 45 patients. Mean number of genetic aberrations in primary tumors was 4.8 +/- 1.8. The most frequently gained regions were 20q12-qter (37%), 20q (32%), 8q24.1-qter (27%), 20p (24%), and 14q24-qter (24%). Losses were 5.5 times less frequent than gains and observed mainly at Xcen-q21, 6cen-q22, and 18cen-q11.2 (11% each). Recurrent and metastatic tumors showed a mean of 4.0 +/- 2.2 aberrations per sample. The most frequently gained regions were chromosome 7 (4 cases), 5q14-q32 (4 cases), 6p (3 cases), and 12q (3 cases). Losses of DNA sequences were 3.4 times less frequent than gains. Histological tumor grade was significantly associated with metastasis-free survival (P = .002) and overall survival (P = .003), being the strongest prognostic factor tested. A statistically significant correlation was found between gain at 8q24.1-qter and shorter overall survival (P = .01) but not with local recurrence or metastasis-free survival. Gain at 14q24-qter was associated with a trend to shorter overall survival (P = .05) but neither with an increased risk for local recurrence nor with metastasis-free survival. In a multivariate analysis, only the tumor grade associated with overall survival (P = .02). In a multivariate analysis together with the tumor grade, gain at 8q24.1-qter did not retain its significance (P = .44), indicating that this imbalance is not an independent prognostic factor.

No DNA copy number changes in osteochondromas: a comparative genomic hybridization study.

Cytogenetic changes in osteochondroma samples were studied by comparative genomic hybridization and by chromosome banding. No DNA copy number changes (15 patients) or chromosomal aberrations (9 patients) were observed in any of the patients.

Is the treatment of the most severe multiply injured patients worth the effort? A follow-up examination 5 to 20 years after severe multiple injury.

Ninety-two most severely injured patients--with injuries to at least four body regions with a mean ISS of 39--were examined at the outpatient clinic 5 to 20 years after the trauma. In addition, nine patients were interviewed by phone, thus 92.6% of the patients still alive were contacted. Of those who were not retired before the injury 59 of 82 (72%) had been able to return to work and most of them were still working at the time of the followup. The main reasons for inability to work were brain and spinal cord injuries, blindness, and 'failure in re-education.' Most complaints arose from sequelae of brain, pelvic, and upper and lower extremity injuries. Only seven patients needed constant medication because of their injuries. We conclude that the treatment of even the most severely injured patients with multiple injuries is certainly worth the effort.

Among numerous DNA copy number changes, losses of chromosome 13 are highly recurrent in plasmacytoma.

Chromosomal imbalances were studied by comparative genomic hybridization (CGH) on 27 specimens from 24 patients with plasmacytoma. All the specimens exhibited DNA copy number changes (mean, 7.7 aberrations/tumor; range, 2-15). The most recurrent change involved losses at 13q, found in 19 out of 24 patients. Other frequent losses were at 1p (42%), 14q (33%), X (33%), 8p (25%), and 6q (25%). Gains were frequent at 19p (58%), 9q (58%), 1q (58%), 7p (42%), 11q (38%), 15 (33%), 6p (25%), 8q (25%), and 5p (21%). High-level copy number increases were found at 1q, 5, 7, 8q, 9q, 11q, 15, and 19. The findings of highly recurrent chromosomal imbalances in plasmacytomas confirm the analytical power of CGH to detect chromosomal abnormalities in malignancies characterized by low mitotic activity. Our most striking finding, the losses in chromosome 13, provides a basis to investigate the role of the 13q loss in the tumorigenesis and progression of plasmacytoma and to evaluate the prognostic significance of this loss.

Characteristics of patients with multiple injuries treated in an intensive care unit with favorable results.

A series of 1,169 consecutive patients with multiple injuries was analyzed. A strict criterion for multiple injury was used, the average Injury Sum (sum of the severities of regional injuries) was 7.6, the average time of treatment in the intensive care unit was 11 days and the mean duration of hospital treatment was 51 days. Road traffic accidents were the most common cause of injury (75%) and the regions most commonly injured were the lower extremity (68%), brain (62%) and chest (58%). 46% required ventilation. Mortality was 11.3% during intensive care and the total hospital mortality was 13.1%. The factors most relevant to patients who were able to return home from the hospital were: no need for respirator treatment, no renal complications, no previous mental disturbance or alcoholism, young age, less severe brain or thoracolumbar spine injuries, few initial blood transfusions, few complications during treatment and prompt operative intervention if required.

DNA sequence copy number increase at 8q: a potential new prognostic marker in high-grade osteosarcoma.

Histologic response to chemotherapy is currently the best prognostic parameter in high-grade osteosarcoma but it can be evaluated only after several weeks of chemotherapy. Thus a prognostic parameter known at the time of diagnosis would be of great clinical benefit. In the present study, we present the results of 31 primary high-grade osteosarcomas analyzed by comparative genomic hybridization (CGH). CGH allows for genome-wide screening of a tumor by detecting alterations in DNA sequence copy number. The most frequent aberrations were copy number increases at 1q21 in 58% of the tumors and at 8q (8q21.3-q22 in 52% and 8cen-q13 in 45%), followed by copy number increases at 14q24-qter (35%) and Xp11.2-p21 (35%). The most common losses were detected at 6q16 (32%) and 6q21-q22 (32%). Patients with a copy number increase at 8q21.3-q22 and/or at 8cen-q13 had a statistically significant poor distant disease-free survival (p = 0.003) and showed a trend toward short overall survival (p = 0.04). Patients with a copy number increase at 1q21 showed a trend toward short overall survival (p = 0.04). Thus, specific genetic aberrations detected at the time of the diagnosis could be used in prognostic evaluation of high-grade osteosarcoma.

Blunt injury patients benefiting from intensive care.

The files of 2,002 trauma patients admitted to our intensive care unit between 1966 and 1984 were analyzed. 74% of the patients were admitted because of the trauma after primary care and 26% later. The main reasons for later admissions were respiratory distress in 11% and postoperative follow-up in 8% of the cases. The series consists of blunt injury patients with a mean age of 39 years for those who survived and 52 years for those who died. 65% of the patients were injured in road traffic accidents. Injuries to the lower extremity were the most frequent (60%) and injuries to the cervical spine the least frequent (11%). The injury Sum (= sum of injuries) ranged from 1 to 18 with an average of 5.6 in the whole series. Two thirds of the patients were multiply injured. A statistical analysis showed that the most important determinants between the dead and those who survived were resuscitation, need for respirator treatment, age of the patient, amount of primary blood transfusions, brain and renal complications. The ICU mortality was 9.0% and the total hospital mortality was 11.9%.

Gains, losses, and amplifications of DNA sequences evaluated by comparative genomic hybridization in chondrosarcomas.

Comparative genomic hybridization was used to search for previously unknown gains and losses of DNA sequences along all chromosome arms in 29 chondrosarcoma specimens obtained from 23 patients. Extensive genetic aberrations, with a mean of 6 changes per tumor (range, 1 to 24), were detected in 21 of the 29 samples analyzed (72%). The majority of these changes were gains of whole chromosomes or whole chromosome arms. Gains of DNA sequence copy number were most frequent at 20q (38%), 17p (38%), 20p (31%), 1cen-q24 (28%), and 14q23-qter (28%). High-level amplifications of small chromosome regions were sporadic, detected in only 17% of the samples. The only recurrent high-level amplification, seen in two tumors (7%), affected the minimal common region 12cen-q15. Other amplifications, each encountered only once, involved 1p33-p35, 2p23-pter, 4p, 6p22-pter, 18q12-q22, 19p13.2, 19q13.2, and 20q13.1. Losses of DNA sequences were rare and were most commonly observed at 6cen-q22 (17%) and 9p (17%).

Recurrent gains of 1q, 8 and 12 in the Ewing family of tumours by comparative genomic hybridization.

Comparative genomic hybridization (CGH) was used to detect copy number changes of DNA sequences in the Ewing family of tumours (ET). We analysed 20 samples from 17 patients. Fifteen tumours (75%) showed copy number changes. Gains of DNA sequences were much more frequent than losses, the majority of the gains affecting whole chromosomes or whole chromosome arms. Recurrent findings included copy number increases for chromosomes 8 (seven out of 20 samples; 35%), 1q (five samples; 25%) and 12 (five samples; 25%). The minimal common regions of these gains were the whole chromosomes 8 and 12, and 1q21-22. High-level amplifications affected 8q13-24, 1q and 1q21-22, each once. Southern blot analysis of the specimen with high-level amplification at 1q21-22 showed an amplification of FLG and SPRR3, both mapped to this region. All cases with a gain of chromosome 12 simultaneously showed a gain of chromosome 8. Comparison of CGH findings with cytogenetic analysis of the same tumours and previous cytogenetic reports of ET showed, in general, concordant results. In conclusion, our findings confirm that secondary changes, which may have prognostic significance in ET, are trisomy 8, trisomy 12 and a gain of DNA sequences in 1q.