Treatment of local recurrences of giant cell tumour in long bones after curettage and cementing. A Scandinavian Sarcoma Group study.

We retrospectively studied local recurrence of giant cell tumour in long bones following treatment with curettage and cementing in 137 patients. The median follow-up time was 60 months (3 to 166). A total of 19 patients (14%) had at least one local recurrence, the first was diagnosed at a median of 17 months (3 to 29) after treatment of the primary tumour. There were 13 patients with a total of 15 local recurrences who were successfully treated by further curettage and cementing. Two patients with a second local recurrence were consequently treated twice. At the last follow-up, at a median of 53 months (3 to 128) after the most recent operation, all patients were free from disease and had good function. We concluded that local recurrence of giant cell tumour after curettage and cementing in long bones can generally be successfully treated with further curettage and cementing, with only a minor risk of increased morbidity. This suggests that more extensive surgery for the primary tumour in an attempt to obtain wide margins is not the method of choice, since it leaves the patient with higher morbidity with no significant gain with respect to cure of the disease.

Lower limb amputations in Southern Finland in 2000 and trends up to 2001.

OBJECTIVES: To assess the current incidence of major lower limb amputations in Southern Finland and epidemiological trends during the last 17 years. MATERIALS AND METHODS: In a retrospective survey for the year 2000 patient data was gathered from hospital records in the eight surgical hospitals in the area studied. Follow-up was 1 year. Amputation data for years 1984-1995 was gathered from reports done before at the same area and amputation figures for years 1990-2001 also from the National Research and Development Centre for Welfare and Health. RESULTS: In year 2000, the incidence of major amputations was 154/million inhabitants. The reason for major amputation was chronic critical lower limb ischaemia in 71.8% and acute ischaemia in 16.5% of the cases. The below-knee (BK)/above-knee (AK) ratio was 0.76. After 1 year only 48% of the patients were alive. From 1984 to 2000 amputation incidence showed a decrease of 41%. The decline in age-adjusted amputation incidence from 1990 to 2000 was 30% and by 2001 as much as 40%. There was a significant inverse correlation both between incidence of infrainguinal bypass and amputation (r=-0.682, p=0.021) and between infrapopliteal bypass and amputation (r=-0.682, p=0.021). CONCLUSIONS: There was a reduction in the number of amputations in Southern Finland during the past 17 years. This occurred synchronously with the increase in vascular reconstructions. Our data suggests that vascular surgery saves patients from BK-amputations and therefore relative amount of AK-amputations inevitably rises.

Allergic sensitization among adults in Tallinn, Estonia.

BACKGROUND: The prevalence of allergic sensitization has increased worldwide during recent years. OBJECTIVE: The aim of the study was to estimate the prevalence of allergic sensitization and to evaluate the influence of age, gender, number of siblings, pet keeping in childhood, and residential area before the age of five on allergic sensitization among adolescents and adults aged 17-66 years in the capital of Estonia, Tallinn. A cross-sectional study was carried out between March 1997 and December 1998. METHODS: The sensitization to 15 inhalant allergens was assessed. The associations between sensitization based on skin prick tests (SPTs), symptoms based on a structured interview, and possible risk factors were estimated. A random sample of 516 subjects was included in the study analysis. RESULTS: The prevalence of allergic sensitization was 34.5%, while it was 39.3% in subjects aged 20-44 years. The most prevalent sensitization was against the German cockroach, 15.5%, and it was particularly high among adolescents. It was followed by mugwort, dog, two storage mites species, and cat dander. Subjects with wheezing during the last 12 months, attacks of shortness of breath, wheezing due to furred animals, and allergic rhinitis or conjunctivitis had a significantly higher prevalence of positive SPT. CONCLUSION: We found a surprisingly high prevalence of allergic sensitization among adults in Tallinn. Our results suggest that the cockroach allergen should be included in the investigation panel in order to reach a true prevalence of allergic sensitization in Estonia. Further, the pattern of allergic sensitization in Estonia appears to be different from published data about allergic sensitization in Scandinavia.

Scandinavian Sarcoma Group Osteosarcoma Study SSG VIII: prognostic factors for outcome and the role of replacement salvage chemotherapy for poor histological responders.

From 1990 to 1997, 113 eligible patients with classical osteosarcoma received neo-adjuvant chemotherapy consisting of high-dose methotrexate, cisplatin and doxorubicin. Good histological responders continued to receive the same therapy postoperatively, while poor responders received salvage therapy with an etoposide/ifosfamide combination. With a median follow-up of 83 months, the projected metastasis-free and overall survival rates at 5 years are 63 and 74%, respectively. Independent favourable prognostic factors for outcome were tumour volume < 190 ml, 24-h serum methotrexate > 4.5 microM and female gender. The etoposide/ifosfamide replacement combination did not improve outcome in the poor histological responders. In conclusion, this intensive multi-agent chemotherapy results in > 70% of patients with classical osteosarcoma surviving for 5 years. The data obtained from this non-randomised study do not support discontinuation and exchange of all drugs used preoperatively in histological poor responders. As observed in previous Scandinavian osteosarcoma studies, female gender appears to be a strong predictor of a favourable outcome.

Intubation and survival in severe paediatric blunt head injury.

The majority of severe childhood injuries are due to head injuries. We studied the impact of emergency intubation in a cohort of children suffering severe blunt head trauma. A 10-year retrospective case note analysis was performed on 176 children (age < 16 years) with severe blunt head trauma (abbreviated injury scale > or =4) in Southern Finland, who required intensive care in a level 1 trauma centre, or who died despite initiation of life supporting measures at the scene. Children in whom emergency intubation was performed either at the scene, or in the emergency room (ER) were analysed. Of the 59 children who fulfilled the study criteria, 20 had an isolated head injury. Most injuries (56/59) were caused by road traffic accidents. Field-intubation was performed in 24 children, and emergency intubation in the ERs of regional hospitals or the level 1 trauma centre, in 13 and 22 children respectively. Mortality was 54.2% (32/59), and was highest in children intubated in regional hospital ERs or in the field. Children intubated at the scene or in the ER of regional hospitals, had significantly worse AIS (head/neck), injury severity score (ISS), and Glasgow coma (GCS) scores than those children intubated in the ER of the level 1 trauma centre. Survival was better in field-intubated children compared with those intubated in regional hospital ERs, despite similar trauma scores (p = 0.05). It is concluded that although children with severe (AIS > or =4) head injury who require emergency intubation have a high overall mortality, field-intubation may improve survival, compared with 'scoop and run' with BLS airway management and deferred emergency intubation.

Chondrosarcoma in a family with multiple hereditary exostoses.

Multiple hereditary exostoses is an autosomal dominant skeletal disorder in which there are numerous cartilage-capped excrescences in areas of actively growing bone. The condition is genetically heterogeneous, and at least three genes, ext1, ext2 and ext3 are involved. The reported risk for malignant transformation to chondrosarcoma has been from 0.6% to 2.8%. We have reviewed six generations of a family with 114 living adult members, 46 of them with multiple exostoses. Four have had operations for chondrosarcoma, giving the risk for malignant transformation as 8.3% in this family. Clinical and radiological examination revealed two additional patients with a suspicion of malignancy, but in whom the histological findings were benign. Reported elsewhere in detail, genetic linkage analysis mapped the causative gene to chromosome 11 and molecular studies revealed a guanine-to-thymine transversion in the ext2 gene. Patients with multiple hereditary exostoses carry a relatively high risk of malignant transformation. They should be informed of this possibility and regularly reviewed.

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.

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.

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.

Severe and fatal childhood trauma.

We wanted to study epidemiology and the outcome of severe childhood trauma. A retrospective study was carried out of 347 severely injured children under 16 years of age, who required intensive care or died during a 10-year period in southern Finland. Of the severely injured children, 65.4 per cent were male. Blunt injuries were the most common (83.0 per cent) followed by penetrating injuries (4.9 per cent), burns (4.6 per cent) and others (7.5 per cent). Of the patients with blunt or penetrating trauma, 85.6 per cent had head injury alone, or combined with other injuries. The majority of all injuries (58.2 per cent) and deaths (59.3 per cent) in children were caused by road traffic accidents. Of this patient population, 64 died at the scene, 54 died in hospital and 229 survived. Most of the deceased trauma patients (77.1 per cent) died within the first 6 h following the incident and all the deaths occurred within 9 days. The annual incidence of severe trauma was 14.1 per 100,000 children, and the annual mortality was 4.8 per 100,000. All the trauma deaths occurred immediately or within a few days of the accident. Late trauma deaths due to sepsis or multiple organ failure were not seen in children.

Prehospital care and survival of pediatric patients with blunt trauma.

BACKGROUND: The aim of this study was to compare the outcome of severe blunt trauma in children receiving prehospital care from either physician-staffed advanced life support (ALS) units, or from basic life support (BLS) units staffed by emergency medical technicians. METHODS: The records of 288 children with severe blunt trauma who required intensive care in the regional level 1 trauma center or who died from their injuries were analyzed retrospectively. Patients were excluded if resuscitation at the scene was not attempted, if the level of prehospital care was unspecified, or if arrival at the level 1 trauma center was delayed beyond 150 minutes. Seventy-two patients met the inclusion criteria of BLS-, and 49 the criteria of ALS-prehospital care. RESULTS: A reduced mortality rate (22.4% v 31.9%) was seen in the ALS group, which was more apparent in a "salvageable but high-risk" subgroup, characterized by Glasgow Coma of Scale 4 through 8, Pediatric Trauma Score of 0 through 5, and Injury Severity Score (ISS) of 25 through 49. However, a statistically significant difference was only seen when trauma severity was evaluated by the ISS. CONCLUSION: An improved outcome in children with severe blunt trauma has been demonstrated when prehospital care is provided by physician-staffed ALS units compared with BLS units.

Comparative genomic hybridization of low-grade central osteosarcoma.

Very little is known concerning the cytogenetic and molecular genetic changes of low-grade central osteosarcoma, a rare form of osteosarcoma. In the present study, we used comparative genomic hybridization (CGH) to screen for DNA sequence copy number aberrations in 10 samples from 6 patients: 7 typical low-grade central osteosarcomas, one low-grade (Grade II) central osteosarcoma, and two high-grade (III and IV) local recurrences of a low-grade central osteosarcoma Nine samples had aberrations. Six typical low-grade central osteosarcoma samples had a single DNA sequence copy number change per tumor. Three samples from more advanced tumors (a Grade II low-grade central osteosarcoma and local recurrences of Grade III and IV) had a mean of five changes per tumor. Recurrent changes affected these minimal common regions: +12q13-q14 (three tumors), +12p (two tumors), and +6p21.1-p21.3 (two tumors). Nine samples were analyzed for CDK4 and MDM2 expression and SAS amplification. One sample with a gain of chromosome 12 had a very strong expression of MDM2, strong expression of CDK4, and amplification of SAS. One sample with a gain of 12q13-q14 had strong expression of CDK4 and MDM2. Strong expression of CDK4 was found in two additional tumors; one had a gain of 12q13-q21, and the other had no changes in chromosome 12 by CGH. No alterations were detected in the CDK4, MDM2, and SAS panel in three other samples with no changes in chromosome 12 by CGH. In conclusion, the low number of DNA sequence copy number alterations reflects the relatively low malignancy of low-grade central osteosarcoma. This simplicity differs from the complex aberrations seen in conventional high-grade osteosarcomas.

Efficacy of cardiopulmonary resuscitation in pulseless paediatric trauma patients.

BACKGROUND: A study was designed to determine which paediatric trauma patients with no detectable vital signs are likely to benefit from cardiopulmonary resuscitation (CPR). METHODS: A 10-year retrospective study of all pulseless patients under 16 years of age with trauma in whom CPR was initiated in a prehospital or in-hospital setting in Southern Finland. RESULTS: Forty-one patients, 25 male and 16 female, were included in this study. The mean age was 7.8 years (range 0.1-15.9 years). Twenty three patients had blunt injuries and three patients had penetrating injuries. The mean Injury Severity Score was 51 (range 25-75). In 15 patients, the arrest was secondary to smoke inhalation, strangulation or electric shock. Resuscitation was initiated at the scene or en route in 28 patients and in 13 patients at the hospital. Five patients received open-chest CPR and 36 patients closed-chest CPR. Spontaneous circulation was restored in four patients with open-chest CPR and in six patients with closed-chest CPR. Two patients had intact survival and one patient survived with moderate disability. The mechanism of traumatic cardiac arrest, initial cardiac rhythm or location of arrest did not seem to affect outcome of CPR. CONCLUSIONS: The overall survival rate of paediatric patients with cardiac arrest secondary to trauma is poor. Trauma patients in whom cardiac arrest is caused by respiratory arrest or by thoracoabdominal trauma in the hospital setting may have a chance of survival if a spontaneous circulation is rapidly restored with effective resuscitative measures.

A novel splice site mutation of the EXT2 gene in a Finnish hereditary multiple exostoses family. Mutations in brief no. 197. Online.

Hereditary multiple exostoses is a dominantly inherited disease characterized by multiple benign osteochondromas. The affected individuals have an increased risk of developing sarcoma. A large Finnish family with hereditary multiple exostosis was analyzed to find the disease-causing mutation. Blood samples were obtained from 35 family members, including 21 affected and 14 unaffected individuals. Using 2-point linkage analysis the EXT phenotype was shown to be linked to the recently cloned EXT2 gene on chromosome 11p11. The coding region of the gene was sequenced and a previously unreported splice site mutation found. This G to T transversion within a 5-prime splice donor site following exon 6 was shown to cause aberrant splicing of RNA. The described change is considered to be a novel disease-causing mutation in the EXT2 gene.

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.

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.

Comparison of cytogenetics, interphase cytogenetics, and DNA flow cytometry in bone tumors.

Twenty-three samples of benign and malignant bone tumors were studied with cytogenetic analysis, interphase cytogenetics (IC) using in situ hybridization with (peri)centromeric probes for chromosomes 1, 7, and/or 8, and DNA flow cytometry (FCM). Our aim was to compare these methods in the detection of numerical chromosome aberrations (NCA) and aneuploidy. IC detected aneuploidy in 91%, FCM in 73%, and cytogenetics in 27% of the malignant tumors. In benign tumors IC detected aneuploid by in 4(33%), FCM in 2(17%), and cytogenetic analysis in 1. All of the benign tumors aneuploid by IC, two of which were also aneuploid by FCM, were histologically potentially aggressive. The clonal aberrations detected with cytogenetics usually agreed with the IC and FCM findings. All malignant tumors which had a normal karyotype were aneuploid either by IC or FCM or by both. In conclusion, IC was the most sensitive method in the detection of NCA and aneuploidy even though it was usually performed with only two (peri)centromeric probes. Aneuploidy was detected by cytogenetic analysis alone in 4 samples (17%), by cytogenetic analysis and/or FCM in 11 samples (48%), and by cytogenetic analysis, FCM, and/or IC in 16 samples (70%). Thus, the combined use of all three methods increased the sensitivity of aneuploidy detection.

No evidence of microsatellite instability in bone tumours.

Microsatellite instability has recently been reported in sporadic and familial colorectal tumours and can be due to defects in DNA mismatch repair genes. Such instability has subsequently been detected in several other types of sporadic tumours. We studied 29 specimens of bone tumours with different histopathological diagnoses and found no evidence of microsatellite instability. Our results suggest that mismatch repair defects are unlikely to play a significant part in the tumorigenesis of bone neoplasms. Loss of heterozygosity with at least one marker was detected in 11, i.e. in 38% of the tumour samples, most frequently with markers D2S136 at 2p (eight of 28 informative specimens, 29%) and D11S904 at 11p (four of 21 informative specimens, 19%).