Heimo Clar

Survival analysis of 254 patients after manifestation of spinal metastases: evaluation of seven preoperative scoring systems.

Study Design. Retrospective study. Objective. This study analyzed the predictive value of the scoring systems of Bauer, Bauer modified, Tokuhashi, Tokuhashi revised, Tomita, van der Linden, and Sioutos as well as the parameters included in these systems. Summary of Background Data. Metastases of the spinal column are a common manifestation of advanced cancer. Severe pain, pathologic fracture, and neurologic deficit due to spinal metastases need adequate treatment. Besides oncologic aspects and quality of life, treatment decisions should also include the survival prognosis. Methods. Two hundred fifty-four patients with confirmed spinal metastases were investigated retrospectively (treatment 1998–2006; 62 underwent surgery and 192 had conservative treatment only). Factors related to survival, such as primary tumor, general condition (Karnofsky Performance Status Scale), neurologic deficit, number of spinal and extraspinal bone metastases, visceral metastases, and pathologic fracture, were analyzed. The survival period was calculated from date of diagnosis of the spinal metastases to date of death or last follow-up (minimum follow-up: 12 months). For statistical analysis, univariate and stepwise multivariate Cox regression analyses were performed. Results. Median overall survival for all patients was 10.6 months. The following factors showed significant influence on survival in multivariate analysis: primary tumor (P < 0.0001), status of visceral metastases (P < 0.0001), and systemic therapy (P < 0.0001). Using the recommended group assignment for each system, only Bauer and Bauer modified showed significant results for the distinction between good, moderate, and poor prognosis. The other systems failed to distinguish significantly between good and moderate prognosis. The hazard ratio of the absolute score of all analyzed systems was, however, statistically significant, with a better score leading to lower risk of death. Conclusion. According to this analysis, the Bauer and the Bauer modified scores are the most reliable systems for predicting survival. Since the Bauer modified score furthermore consists of only four positive prognostic factors, we emphasize its impact and simplicity.

Integrin alpha-2 and beta-3 gene polymorphisms and breast cancer risk

SummaryIntegrins are cell surface receptors, which mediate cell-to-cell and cell-to-extracellular matrix adhesion. Some of them, e.g. αVβ3, αIIbβ3 and α2β1, have been suggested as key players for cancer development and tumor metastasis. Two polymorphisms in the gene for the α2 component, ITGA2 807C>T and 1648G>A, have been associated with the cell-surface density of integrin α2β1. The 176T>C polymorphism in the ITGB3 gene, encoding the β3 subunit of integrins αIIbβ3 and αVβ3, modifies a variety of traits of β3 expressing cells. To analyze the role of ITGA2 and ITGB3 polymorphisms for breast cancer risk and prognosis, we performed a case-control study including 500 female breast cancer patients and 500 healthy female age-matched control subjects. All study participants were of Caucasian origin (Austria, Middle-Europe). The ITGA2 1648_AA genotype was significantly associated with breast cancer (odds ratio 3.12; 95% confidence interval 1.11–8.77). Carriers of the most common ITGA2 haplotype (807C_1648G, ‘wildtype’) were at decreased risk for breast cancer (odds ratio 0.72; 95% confidence interval 0.53–0.98). A histological grade of 3 or 4 was found more often in ITGA2 807TT subjects (p=0.039 compared to CC+CT genotypes) and carriers of an ITGA2 1648A allele (p=0.017 compared to GG genotype). Carriers of the ITGA2 807C_1648G haplotype were less likely to have a histological grade 3 or 4 compared to non-carriers (p=0.003). The ITGB3 176T>C polymorphisms was not associated with breast cancer susceptibility. In a Cox-regression analysis, carriers of the homozygous ITGB3 176-CC genotype had a higher risk for metastasis (relative risk 2.3; 95% CI 1.3–4.2; p=0.005). We conclude that functional polymorphisms in integrin genes ITGA2 and ITGB3 influence the development and progression of breast cancer, respectively. The precise mechanism remains to be determined, but likely involves dysregulated signaling pathways.

Measurement of the acromiohumeral interval on standardized anteroposterior radiographs: a prospective study of observer variability.

BACKGROUND An acromiohumeral interval narrower than 6 mm has been considered pathologic and strongly indicative for rotator cuff tears by numerous authors. This prospective study assessed interobserver and intraobserver variability in the radiographic measurement of the acromiohumeral interval. MATERIAL AND METHODS Five board-certified orthopedic surgeons independently reviewed 58 blinded, standardized anteroposterior shoulder radiographs. The acromiohumeral interval was measured in millimeters. The 5 investigators classified each image a second time in random order. RESULTS After the same 58 radiographs had been evaluated by the 5 investigators at both examination time points, no significant differences were noted in the interobserver and intraobserver measurements (P < .05). The respective maximum interobserver and intraobserver differences were 4 and 3 mm (range, 0-4 mm). CONCLUSION The assessment of the acromiohumeral interval using standardized anteroposterior radiographs is a reliable and reproducible method of measurement. LEVEL OF EVIDENCE Level 1; Investigating a diagnostic test.

The Glu228Ala polymorphism in the ligand binding domain of death receptor 4 is associated with increased risk for prostate cancer metastases.

Death receptor 4, encoded by the TNFRSF10A gene, is an important mediator of apoptosis and its dysfunction may be related to cancer development and distant tumor spread. A single nucleotide polymorphism in TNFRSF10A (Glu228Ala, rs20576) within a conserved region of the extracellular cysteine‐rich domain of death receptor 4 has been associated with an increased risk for a variety of tumor entities. Aim of the present study was to evaluate the role of the TNFRSF10A polymorphism in metastatic progression of prostate cancer after radiation therapy.

Mesothelioma mortality in Europe: impact of asbestos consumption and simian virus 40

BackgroundIt is well established that asbestos is the most important cause of mesothelioma. The role of simian virus 40 (SV40) in mesothelioma development, on the other hand, remains controversial. This potential human oncogene has been introduced into various populations through contaminated polio vaccines. The aim of this study was to investigate whether the possible presence of SV40 in various European countries, as indicated either by molecular genetic evidence or previous exposure to SV40-contaminated vaccines, had any effect on pleural cancer rates in the respective countries.MethodsWe conducted a Medline search that covered the period from January 1969 to August 2005 for reports on the detection of SV40 DNA in human tissue samples. In addition, we collected all available information about the types of polio vaccines that had been used in these European countries and their SV40 contamination status.ResultsOur ecological analysis confirms that pleural cancer mortality in males, but not in females, correlates with the extent of asbestos exposure 25 – 30 years earlier. In contrast, neither the presence of SV40 DNA in tumor samples nor a previous vaccination exposure had any detectable influence on the cancer mortality rate in neither in males (asbestos-corrected rates) nor in females.ConclusionUsing the currently existing data on SV40 prevalence, no association between SV40 prevalence and asbestos-corrected male pleural cancer can be demonstrated.

Surgical treatment of pathologic fractures of the humerus and femur

The life expectancy of patients with malignant tumours and the incidence of osseous metastases have increased over the last decades. Operations for skeletal metastases of the extremities represent the most frequent surgery in orthopaedic oncology. The purpose of this study was to evaluate and compare the different operative treatment options for patients with pathologic fractures of the humerus and femur in terms of complications, postoperative recovery, and survival.From 2000 to 2005, 109 patients were surgically treated for pathologic fractures of the humerus (n=19) or femur (n=90). The study group consisted of 60 women and 43 men, with a mean age of 67 years (13-88). Breast carcinoma (36%) was the most common primary tumour, followed by kidney (17%) and bronchial (16%) carcinoma. Of all patients, 75 (73%) had numerous skeletal metastases, and 38 (37%) had visceral metastases.Wide or marginal resection was performed in seven fractures of the humerus and 14 fractures of the femur; intralesional resection was done in seven humeral and 73 femoral fractures; and stabilisation alone was done in five fractures of the humerus and three fractures of the femur. The median survival time for all patients was 6 months (0-102). The survival rate at 1 year was 25% (25% for both humeral and femoral fractures), 15% at 2 years (17% for humeral and 15% for femoral fractures), and 8% at 3 years (16% for humeral and 7% for femoral fractures). The overall complication rate was 11%, and revision surgeries were performed in seven patients (6.4%). The majority of patients (n=65; 60%), especially those with fractures close to the articular joint, were successfully treated with endoprosthetic replacement. Patients with fractures stabilised by intramedullary nails had shorter operating times, a shorter hospital stay, and fewer complications than patients treated with plating systems. Therefore, we recommend intralesional resection of the metastasis and stabilisation with intramedullary devices, supported by bone cement, as the treatment of choice for pathologic fractures of the diaphysis and metaphysis of the humerus and femur. Wide resection should be reserved for selected cases, such as solitary bone metastasis of kidney carcinoma.

Operative Versorgung von pathologischen Humerus- und Femurfrakturen

The life expectancy of patients with malignant tumours and the incidence of osseous metastases have increased over the last decades. Operations for skeletal metastases of the extremities represent the most frequent surgery in orthopaedic oncology. The purpose of this study was to evaluate and compare the different operative treatment options for patients with pathologic fractures of the humerus and femur in terms of complications, postoperative recovery, and survival.From 2000 to 2005, 109 patients were surgically treated for pathologic fractures of the humerus (n=19) or femur (n=90). The study group consisted of 60 women and 43 men, with a mean age of 67 years (13-88). Breast carcinoma (36%) was the most common primary tumour, followed by kidney (17%) and bronchial (16%) carcinoma. Of all patients, 75 (73%) had numerous skeletal metastases, and 38 (37%) had visceral metastases.Wide or marginal resection was performed in seven fractures of the humerus and 14 fractures of the femur; intralesional resection was done in seven humeral and 73 femoral fractures; and stabilisation alone was done in five fractures of the humerus and three fractures of the femur. The median survival time for all patients was 6 months (0-102). The survival rate at 1 year was 25% (25% for both humeral and femoral fractures), 15% at 2 years (17% for humeral and 15% for femoral fractures), and 8% at 3 years (16% for humeral and 7% for femoral fractures). The overall complication rate was 11%, and revision surgeries were performed in seven patients (6.4%). The majority of patients (n=65; 60%), especially those with fractures close to the articular joint, were successfully treated with endoprosthetic replacement. Patients with fractures stabilised by intramedullary nails had shorter operating times, a shorter hospital stay, and fewer complications than patients treated with plating systems. Therefore, we recommend intralesional resection of the metastasis and stabilisation with intramedullary devices, supported by bone cement, as the treatment of choice for pathologic fractures of the diaphysis and metaphysis of the humerus and femur. Wide resection should be reserved for selected cases, such as solitary bone metastasis of kidney carcinoma.

Association of polymorphisms of angiogenesis genes with breast cancer.

To the Editor With great interest we have read the recent publication by Schneider et al. [1] about the association between polymorphisms of angiogenesis genes and breast cancer. The authors described an association of the VEGF-2578A and 1498C allele with increased breast cancer risk. These results are in contrast to our recent findings that VEGF polymorphisms are not associated with breast cancer risk [2]. Interestingly, Schneider and colleagues also investigated the influence of VEGF polymorphisms on metastatic disease progression and found no significant association. Encouraged by that report, we have retrieved data on metastasis of the 839 breast cancer patients from our study and performed an analysis of the association between metastases and VEGF polymorphisms. VEGF genotypes (-2578C[A, -2489C[T, 1498C[T, -634G[C, -7C[T, -936C[T, -1612G[A) were determined using 50-nuclease assays (TaqMan). Reaction conditions were as described previously [2]. The study was performed according to the Austrian Gene Technology Act and has been approved by the local Ethical Committee. Written informed consent was obtained from all patients. According to breast cancer staging, patients were divided in three groups, representing patients without metastases (n = 708), those with metastases other than bone (n = 69), and those with bone metastases (n = 62). SPSS 14.0 for Windows was used for statistical analysis. Continuous values were analyzed by Student’s t-test, and proportions of groups compared by the v test. Odds ratio (OR) and the 95% confidence interval (CI) were calculated to estimate the risk of bone metastasis. The level of significance was set at P \ 0.05. The frequency of the VEGF 1498 CC genotype was significantly lower among patients with bone metastases (6.5%) than among patients with metastases other than bone (23.2%; P = 0.005) or patients without metastases (23.4%; P = 0.002, Table 1). Odds ratio of the CC genotype for bone metastases was 0.22 (95% CI 0.08–0.61; P = 0.004). Genotype distribution of the other investigated VEGF polymorphisms did not show a significant association with metastases. VEGF plays a critical role in tumor progression and distant tumor spread [3]. The present results suggest that the homozygous VEGF 1498 CC genotype might decrease the risk of bone metastases in breast cancer patients. However, further large prospective population based studies will be necessary before firm conclusions on the role of genetic risk factors for breast cancer metastases can be drawn. H. Clar R. Windhager Department of Orthopedic Surgery, Medical University of Graz, Graz, Austria

Cyclin D1 Genotype and Breast Cancer Metastasis1

To the Editors: We have reported previously that the 870G > A polymorphism in the Cyclin D1 gene ( CCND1 ) is not associated with breast cancer risk ([1][1]). This has been confirmed in a recent larger study work by Shu et al. ([2][2]). Interestingly, the authors described a favorable outcome for

A common hereditary single‐nucleotide polymorphism in the gene of FAS and colorectal cancer survival

Apoptosis plays an important role in embryogenesis, autoimmunity and tumourigenesis. Cell surface death receptors such as TNFRSF6 (FAS) confer a major apoptotic effect. A single‐nucleotide polymorphism in the FAS promoter gene, −670A/G, modulates apoptotic signalling and has been related to susceptibility and progression of a variety of cancers. The present study aimed to evaluate the role of this polymorphism for survival of patients with colorectal cancer. We performed a retrospective analysis including 433 patients with histologically confirmed colorectal cancer. A Cox regression model including FAS ‐670 genotypes, age at diagnosis, tumour grading, primary tumour size, number of lymph nodes examined, number of metastatic lymph nodes, tumour stage and application of fluorouracil‐based adjuvant chemotherapy was used to estimate the effect of the FAS genotype on survival. FAS −670A/G genotype frequencies were 24.2% (AA), 46.3% (AG) and 29.5% (GG). Forty‐nine patients were excluded from the Cox regression analysis because of missing values. Out of the remaining 384 patients, 69 (18%) died during a follow‐up of maximum 10 years. Mean follow‐up time was 58 ± 34 months (median 55 months). Carriers of the homozygous FAS ‐670GG genotype had a significantly lower survival rate compared with AA/AG genotype carriers (relative risk 1.76, 95% confidence interval 1.08–2.87; P= 0.023). The FAS −670A/G polymorphism may be associated with overall survival time of patients with colorectal cancer.