Histopathological Analysis of the Degree of Tendinosis in Failed Anterior Cruciate Ligament Grafts. / Histopathologische Analyse des Tendinosegrades nach Transplantatversagen vorderer Kreuzbandplastiken.

INTRODUCTION: After reconstruction of the anterior cruciate ligament, the modification processes in the transplanted tendon tissue directly influence the biomechanical properties of the knee. The histopathological alterations in failed grafts have hardly been studied. OBJECTIVE: Our study focused on examining the presence and extent of tendinosis (low or high grade) in the tendon tissue of failed anterior cruciate ligament reconstructions. We considered its relationship to the type of transplant, the symptoms, the arthroscopic appearance, the mode of trauma, and the timing of the failure. MATERIALS AND METHODS: The tendon tissue of failed anterior cruciate ligament reconstructions in 30 patients was gathered during revision surgery and its histopathology was analysed for the occurrence of structural alterations. The classification of the tendinosis as low or high grade was semiquantitative based on five qualities. We used a standardised questionnaire to collect patient data and we used the Marburg Arthroscopy Score for the intraoperative evaluation of the graft. RESULTS: We found histological vitality and, except for two samples, structural alterations consistent with tendinosis, predominantly high grade, in all failed anterior cruciate ligament grafts. No direct link could be proved between the degree of tendinosis and the type of graft used, the symptoms (except for instability) or the timing of the graft failure, the mode of trauma, or the arthroscopic appearance of the failed plasty. However, the accumulation of high-grade tendinosis in patients with hamstring tendons, subjective instability, and graft failure between 1 to 5 years postoperatively was noteworthy. CONCLUSION: Structural alterations consistent with tendinosis could be detected, with different expressions, in the vital tendon tissue of anterior cruciate ligament reconstructions. This indicates that the graft is subject to repetitive microtrauma. However, it is still unclear how tendinosis influences the failure of anterior cruciate ligament reconstructions.

Association of vascular endothelial growth factor--a gene polymorphisms and haplotypes with breast cancer metastases.

BACKGROUND: Vascular endothelial growth factor (VEGF-A) is a key regulator of tumor-induced angiogenesis and essential for tumor growth and distant tumor spread. The aim of the present study was to evaluate the role of VEGF-A polymorphisms and haplotypes for metastatic progression in breast cancer patients. MATERIAL AND METHODS: We performed a prospective study including 801 breast cancer patients. Occurrence of metastases was examined in regular follow-up investigations. Seven VEGF-A polymorphisms were selected and determined by 5'-nuclease assays (TaqMan). The selection of VEGF-A variants was based upon their location (promoter or UTR) as well as a minor allele frequency of at least 0.10. Haplotypes and linkage disequilibrium were determined using the Haploview program. RESULTS: Within a median follow-up time of 84 months, 165 (21%) patients developed distant metastases. In univariate analysis, carriers of the CCCCC haplotype formed by five polymorphisms upstream the coding region were at decreased risk of distant metastases [hazard ratio (HR)=0.743; 95% CI 0.579-0.953; p=0.019]. Univariate analysis also revealed a decreased risk of distant metastases for postmenopausal patients carrying the -634G>C polymorphism (HR 0.704; 95% CI 0.514-0.965; p=0.029) and the CCCCC haplotype (HR=0.645; 95% CI 0.464-0.898; p=0.009). After adjustment for other co-variates, the HR for distant metastases was 0.651 (95% CI 0.447-0.948) for postmenopausal carriers of the -634G>C polymorphism (p=0.025; corrected p-value=0.262), and 0.586 (95% CI 0.393-0.873) for postmenopausal patients with the CCCCC haplotype (p=0.009, corrected p-value=0.189). CONCLUSION: The results from univariate and multivariate analyses suggest an influence of VEGF-A gene variants on the development of distant metastases in breast cancer patients. However, none of the observed associations reached statistical significance after correction for the effects of multiple testing. Additional prospective and sufficiently powered studies are essential before firm conclusions about the role of VEGF-A gene variants for distant progression in breast cancer can be drawn.

Novel biomarkers to detect infection in revision hip and knee arthroplasties.

BACKGROUND: A periprosthetic joint infection is one of the most challenging complications associated with THA and TKA. In the diagnostic process for detecting a periprosthetic joint infection, one of the most important steps is analysis of laboratory infection biomarkers. QUESTIONS/PURPOSES: We investigated the sensitivity and specificity of the biomarkers procalcitonin, interleukin 6 (IL-6), and interferon α (IFN-α) as compared with conventional biomarkers (C-reactive protein [CRP], leukocyte level) for a periprosthetic joint infection associated with revision arthroplasties. METHODS: We prospectively included and analyzed 84 patients (124 revision arthroplasties). The blood parameters of interest were procalcitonin, IL-6, IFN-α, leukocyte level, and CRP. Samples were taken preoperatively and on the first, third, and seventh postoperative days. The sensitivity and specificity of these biomarkers then were calculated. RESULTS: Considering the preoperative values of 84 patients (124 operations), procalcitonin, IL-6, CRP, and leukocyte level correlated with periprosthetic joint infection, whereas IFN-α did not. A procalcitonin cut-off level of 0.35 ng/mL revealed a sensitivity of 80% and specificity of 37%. An IL-6 cut-off level of 2.55 pg/mL had a sensitivity of 92% and specificity of 59%. CONCLUSIONS: In this study procalcitonin and IL-6 were helpful for detecting periprosthetic joint infections in revision arthroplasties, although CRP generally was superior. Procalcitonin and IL-6 may be considered adjuvant tests when the diagnosis of a periprosthetic joint infection is in doubt. This study showed, in addition to conventional biomarkers such as CRP and leukocyte level, procalcitonin and IL-6 were helpful for detecting infections associated with revision arthroplasties.

IL-7, IL-18, MCP-1, MIP1-ß, and OPG as biomarkers for pain treatment response in patients with cancer.

BACKGROUND: Pain is one of the most common symptoms in patients suffering from advanced cancer and receiving palliative care and is often responsible for a poor quality of life. To date, there exists no published correlation between biological, measurable biomarkers and pain intensity. OBJECTIVES: The primary objective was to search and identify pain-associated cytokines (biomarkers) correlating with changes in numeric rating scale (NRS) pain scores in patients with cancer before and after pain treatment. The secondary objectives were to assess cytokine serum level differences between patients and healthy controls and to evaluate possible relationships between pain entities, pain intensity (in NRS), gender, location of primary tumor, and the patients' cytokine baseline concentrations. STUDY DESIGN: Controlled, prospective study. SETTING: University medical center. METHODS: Eligible patients with exacerbated cancer-related pain (NRS = 5) and healthy controls with no pain were included. Serum level changes of 19 cytokines were analyzed before and during opioid treatment. RESULTS: Of 19 analyzed biomarkers, 5 (IL-7, IL-18, MCP-1, MIP-1α, MIP-1ß and OPG) turned out to correlate significantly with pain relief. In healthy controls, all analyzed cytokines showed no significant differences. In the secondary analysis, only one significant correlation was detected between OPG and pain entities. Furthermore, IL-4, IL-7, IFN-γ and OPG appeared to account for the ability to predict a patient's gender. LIMITATIONS: Our findings should be considered as preliminary and need to be confirmed in further studies. CONCLUSION: Our results provide preliminary evidence of a significant correlation of pain relief in patients with cancer and at least 5 cytokines. These biomarkers may serve as the basis for development of diagnostic tools for pain assessment and could serve as potential new targets for pain control.

Impact of VEGF gene polymorphisms and haplotypes on radiation-induced late toxicity in prostate cancer patients.

BACKGROUND AND PURPOSE: Vascular endothelial growth factor (VEGF) is an important determinant of microvascular permeability and angiogenesis and has been shown to be up-regulated during the late phase of radiation injury. The present prospective study was performed to evaluate the role of VEGF gene polymorphisms and haplotypes in the development of radiation-induced late side effects in prostate cancer patients. PATIENTS AND METHODS: The association of VEGF gene polymorphisms and haplotypes with high-grade late rectal or urinary toxicity (defined as late toxicity EORTC/RTOG ≥ 2) was analyzed using 493 prostate cancer patients from the Austrian PROCAGENE study treated with definitive radiotherapy. Seven candidate polymorphisms in the VEGF gene were selected and determined by 5'-nuclease (TaqMan) assays. RESULTS: Within a median follow-up time of 48 months, 42 patients (8.6%) developed high-grade late rectal and 47 patients (9.6%) urinary toxicity, respectively. In a Kaplan-Meier analysis, carriers of the VEGF -7C > T polymorphism were at increased risk of high-grade late rectal toxicity (p = 0.003) and in a multivariate analysis including clinical and dosimetric parameters as potential confounders the VEGF -7C > T polymorphism remained a significant predictor (HR = 2.8, 95% CI 1.349-5.813; p = 0.006). Furthermore, the ATTGT haplotype formed by five polymorphisms upstream of the coding sequence demonstrated a significant association with late rectal toxicity grade ≥ 2 (p = 0.001). No significant associations were found for the remaining polymorphisms and haplotypes. CONCLUSION: We conclude that genetic variants in the VEGF gene may influence the risk of high-grade late rectal toxicity after definitive radiotherapy for prostate cancer.

Single nucleotide polymorphisms of integrin alpha-2 and beta-3 genes are not associated with relapse-free and overall survival in colorectal cancer patients.

BACKGROUND: Integrins influence tumourigenesis, tumor progression and development of metastases. The impact of polymorphisms in integrin genes on relapse-free survival (RFS) and overall survival (OS) for 433 Caucasian patients with colorectal cancer was analysed in this retrospective study. PATIENTS AND METHODS: A Cox regression model including integrin genotype, age, grading, tumour size, number of lymph nodes examined, number of metastatic lymph nodes, stage and application of fluorouracil-based adjuvant chemotherapy was used to estimate their effect. RESULTS: After a median follow-up of 41 months for RFS and 55 months for OS, no significant correlation between the ITGA2 1648A allele (RFS p=0.618, OS p=0.604), the ITGA2 807T allele (RFS p=0.603, OS p=0.807) and the ITGB3 176C allele (RFS p=0.719, OS p=0.261) and survival was detectable. CONCLUSION: The investigated integrin polymorphisms are not associated with RFS or OS in colorectal cancer patients.

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.

Association between single nucleotide polymorphisms in the gene for XRCC1 and radiation-induced late toxicity in prostate cancer patients.

BACKGROUND AND PURPOSE: Polymorphisms in genes responsible for DNA damage signaling and repair might modulate DNA repair capacity and, therefore, affect cell and tissue response to radiation and influence individual radiosensitivity. The purpose of the present prospective investigation was to evaluate the association of single nucleotide polymorphisms in XRCC1 with radiation-induced late side effects in prostate cancer patients treated with radiotherapy. MATERIAL AND METHODS: To analyze the role of XRCC1 polymorphisms for late toxicity 603 participants from the Austrian PROCAGENE study treated with three-dimensional conformal radiotherapy were included in the present investigation. Three non-synonymous candidate polymorphisms in the X-ray repair cross-complementing group 1 (XRCC1) gene (Arg194Trp; Arg280His; Arg399Gln) were selected and determined by 5´-nuclease (TaqMan) assays. RESULTS: Within a median follow-up time of 35 months, 91 patients (15.7%) developed high-grade late toxicities (defined as late bladder and/or rectal toxicity RTOG≥2). In a Kaplan-Meier analysis, carriers of the XRCC1 Arg280His polymorphism were at decreased risk of high-grade late toxicity (p=0.022), in multivariate analysis including clinical and dosimetric parameters as potential confounders the XRCC1 Arg280His polymorphism remained a significant predictor for high-grade late toxicity (HR=0.221, 95% CI 0.051-0.956; p=0.043). No significant associations were found for the remaining polymorphisms. CONCLUSIONS: We conclude that the XRCC1 Arg280His polymorphism may be protective against the development of high-grade late toxicity after radiotherapy in prostate cancer patients.

Paraneoplastic limbic encephalitis in a patient with extragonadal choriocarcinoma--significance of onconeural antibodies.

BACKGROUND: Paraneoplastic limbic or brainstem encephalitis is considered to be an autoimmune-mediated disorder of the nervous system associated with different types of cancer including germ cell tumors. CASE REPORT: We report on a 31-year-old patient presenting with eye motility dysfunction, dysarthrophonia, lethargy, depression, slow mentation, disorientation, dysgraphia, and retarded motion sequence. Neurologic tests, brain imaging, and blood chemistry tests failed to determine the cause of the symptoms. Further examinations including ultrasound of the abdomen led to the detection of a retroperitoneal mass. The biopsy of this mass showed fractions of a choriocarcinoma. The patient underwent curative chemotherapy, but although the cancer therapy was successful, the neurologic disorders did not improve. Concurrent examination for anti-Ma2 antibodies in the serum was positive and confirmed the paraneoplastic origin of these symptoms. CONCLUSIONS: Patients with symptoms of limbic or brainstem encephalitis, especially young men, should be tested for anti-Ma2 antibodies in the serum to elucidate their origin. The detection of these antibodies supports the diagnosis of a paraneoplastic syndrome, and may lead to the earlier identification of an otherwise hidden extragonadal germ cell tumor.

Association of hypoxia-inducible factor 1-alpha gene polymorphisms and colorectal cancer prognosis.

BACKGROUND: Hypoxia inducible factor-1 (HIF-1) is the key regulator of cellular responses to hypoxia and plays a central role in tumour growth. Recently, two single nucleotide polymorphisms (SNPs) in the HIF-1 alpha gene, C1772T and G1790A, were shown to cause significantly higher transcriptional activity than did the wild-type. This study aimed to investigate the effect of these SNPs on the prognosis of colorectal cancer (CRC). PATIENTS AND METHODS: DNA from 336 CRC patients was genotyped. Genotypes of each polymorphism were tested for association with disease-free survival (DFS) using univariate and multivariate Cox-regression analysis. RESULTS: Genotype frequencies were: CC 75.6%, CT 18.8% and TT 1.8% for HIF1A1 C1772T and GG 93.2%, GA 2.7% and AA 0% for G1790A. A statistically significant association between DFS and clinicopathological features was observed. However, no association was found between HIF1A1 C1772T (p=0.44; risk ratio of recurrence, RR=1.19, 95% confidence interval, CI=0.77 to 1.83) and G1790A (p=0.89; RR=0.92, 95% CI=0.29 to 2.90) polymorphisms and DFS in univariate and multivariate Cox-regression analysis. CONCLUSION: These results suggest that HIF1A1 C1772T and G1790A polymorphisms are not involved in the progression or metastasis of CRC.

Single nucleotide polymorphisms in the hypoxia-inducible factor-1 gene and colorectal cancer risk.

With an incidence of about 300 000 new cases colorectal cancer (CRC) is the second leading cause of cancer-related death in Europe and the United States. Environmental and genetic factors influence CRC risk. Hypoxia-inducible factor-1 (HIF-1), a heterodimeric protein composed of two subunits, HIF-1 alpha and HIF-1 beta, plays a critical role in oxygen homeostasis and is involved in angiogenesis and cell proliferation. The gene for the HIF-1 alpha subunit (HIF1A) carries two common missense mutations-P582S (rs11549465) and A588T (rs11549467)-which both have been related to increased trans-activation capacity of HIF1A. In our case-control study we investigated the association between these polymorphisms and CRC risk. We investigated 381 patients with histologically confirmed CRC and 2156 control subjects. HIF1A genotypes were determined by exonuclease (TaqMan) assays. For determination of microvessel density (MVD) tumor sections were stained using a mouse monoclonal antibody recognizing the pan-endothelial marker CD31. In a multivariate logistic regression analysis including age and sex neither the HIF1A 582S allele (Odds ratio: 1.204; 95% confidence interval 0.911-1.592; P = 0.193) nor the 588T allele was significantly associated with CRC (Odds ratio: 0.851; 95% confidence interval 0.444-1.631; P = 0.626). However, in an exploratory analysis, the HIF1A 588T allele was associated with tumor localization (P = 0.016) and tumor size (P = 0.003). MVD was similar in tumors of patients carrying HIF1A 588T allele and patients without this rare allele. We conclude that functional polymorphisms in the HIF1A gene do not modify CRC risk but maybe associated with clinic-pathological features of the disease.

Analysis of common germline polymorphisms as prognostic factors in patients with lymph node-positive breast cancer.

PURPOSE: Women with breast cancer that initially involves local lymph nodes have a higher risk for local recurrence or developing metastases. Recent data suggest that germline polymorphism is a significant, previously unrecognized factor in breast cancer progression and metastasis. We assessed the influence of 16 selected common germline polymorphisms in disease-free survival and overall survival among 216 women diagnosed with lymph node-positive breast cancer. RESULTS: The rare allele of FAS 1377G>A was significantly associated with prolonged disease-free survival (P = 0.012, risk ratio of recurrence (RR) = 0.557, 95% confidence interval (CI) = 0.353-0.878) in univariate analysis. After adjusting for known breast cancer prognostic factors the association remained significant (P = 0.050, RR = 0.500, CI = 0.309-0.809). In overall survival analysis we found a significant association of the FAS 1377G>A (P = 0.040, RR = 0.451, CI = 0.496-1.188) and IL10 592C>A polymorphisms (P = 0.020, RR = 1.707, CI = 1.087-2.680) in the univariate Cox regression. The effect remained statistically significant in the multivariate analysis for the IL10 592C>A polymorphism (P = 0.013, RR 1.841, CI 1.140-2.973). No association was found for MTHFR 677C>T, VEGF 936C>T, CCND1 870G>A, TGFB1 29T>C, FASLG 844C>T, FAS 670A>G, GPB3 825C>T, ITGA2 807C>T, ITGA2 1648G>A, ITGB3 176T>C, MMP1 -1607 1G/2G, MMP3 5A/6A, PTGS2 8473T>C, IL10 592C>A and SULT1A1 638G>A polymorphisms and disease-free survival or overall survival. CONCLUSIONS: Our data suggest that the FAS 1377G>A and IL10 592C>A polymorphisms could modify disease-free and overall survival in women with lymph node-positive breast cancer.

Association of interleukin-10 gene variation with breast cancer prognosis.

Genetic polymorphisms are responsible for inter-individual variation and diversity and have been recently considered as the main genetic elements involved in the development and progression of cancer. We examined associations between common germline genetic variants in 7 genes involved in folate metabolism, cell proliferation and apoptosis, prostaglandin synthesis, detoxification of compounds and inflammation, and disease-free survival among women diagnosed with invasive breast cancer. DNA from up to 432 women was genotyped for 8 polymorphisms. The genotypes of each polymorphism were tested for association with disease-free survival using univariate and multivariate Cox regression analysis. The model was adjusted for known breast cancer prognostic factors. The rare allele of the IL-10 592C>A polymorphism was significantly associated with reduced disease-free survival (P = 0.018, risk ratio of recurrence (RR) = 1.45, 95% confidence interval (CI) = 1.06-1.98), which was not attenuated after adjusting for age at diagnosis, tumor size, lymph node status, clinical stage, histological grade, estrogen receptor status, progesterone receptor status, and treatment modalities (P = 0.019, RR = 1.48, 95% CI = 1.066-2.044). No association was found between MTHFR 677C>T, TGFB1 29T>C, FASLG 844C>T, FAS 1377G>A, FAS 670A>G, PTGS2 8473T>C and SULT1A1 638G>A polymorphisms and disease-free survival. Our data suggest that the rare allele of IL-10 592C>A may be a potential prognostic marker in breast cancer for disease-free survival.

Radiation- and reference base-free navigation procedure for placement of instruments and implants: application to retrograde drilling of osteochondral lesions of the knee joint.

OBJECTIVE: A novel, radiation- and reference base-free procedure for placement of navigated instruments and implants was developed and its practicability and precision in retrograde drillings evaluated in an experimental setting. MATERIALS AND METHODS: Two different guidance techniques were used: One experimental group was operated on using the radiation- and reference base-free navigation technique (Fluoro Free), and the control group was operated on using standard fluoroscopy for guidance. For each group, 12 core decompressions were simulated by retrograde drillings in different artificial femurs following arthroscopic determination of the osteochondral lesions. The final guide-wire position was evaluated by postoperative CT analysis using vector calculation. RESULTS: High precision was achieved in both groups, but operating time was significantly reduced in the navigated group as compared to the control group. This was due to a 100% first-pass accuracy of drilling in the navigated group; in the control group a mean of 2.5 correction maneuvers per drilling were necessary. Additionally, the procedure was free of radiation in the navigated group, whereas 17.2 seconds of radiation exposure time were measured in the fluoroscopy-guided group. CONCLUSION: The developed Fluoro Free procedure is a promising and simplified approach to navigating different instruments as well as implants in relation to visually or tactilely placed pointers or objects without the need for radiation exposure or invasive fixation of a dynamic reference base in the bone.

Integrin alpha-2 and beta-3 gene polymorphisms and colorectal cancer risk.

BACKGROUND AND AIMS: Integrins such as alpha(2)beta(1), alpha(IIb)beta(3), and alpha(v)beta(3) have been suggested as key players for cancer development and progression. Several polymorphisms affecting these molecules, two in integrin alpha(2) (ITGA2 807C>T and 1648G>A) and one in beta(3) (ITGB3 176T>C), influence their levels, structure, and possibly their function. To analyze the role of ITGA2 and ITGB3 polymorphisms for colorectal cancer risk and clinical presentation, we performed a case-control study. MATERIALS AND METHODS: Four hundred thirty-three colorectal cancer patients and 433 healthy sex- and age-matched control subjects were investigated. ITGA2 and ITGB3 polymorphisms were determined by 5'-nuclease assays. RESULTS/FINDINGS: The ITGA2 807C>T polymorphism was associated with reduced colorectal cancer risk. In a codominant model, the odds ratio for each additional 807-T allele for colorectal cancer was 0.77 (95% confidence interval 0.64-0.94; p = 0.011). The ITGA2 1648G> and the ITGB3 176T>C polymorphism were not associated with colorectal cancer. None of the three polymorphisms investigated was associated with tumor size, histological grade, presence of primary lymph node metastases, tumor stage, or age at diagnosis. INTERPRETATION/CONCLUSION: We conclude that the ITGA2 807C>T polymorphism may be associated with reduced colorectal cancer risk.

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

BACKGROUND: 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. METHODS: We carried out a prospective study including 702 prostate cancer patients from the Austrian PROCAGENE (Prostate Cancer Genetics) study. Development of metastases was examined in regular follow-up investigations. TNFRSF10A genotypes were determined by a 5'-nuclease assay (TaqMan). RESULTS: Within a median follow-up time of 10 months (range 0-60 months), 24 (3.4%) patients developed metastases. In a Cox regression model including age at diagnosis and risk group as potential confounders, carriage of an 228Ala allele was associated with a relative risk of 2.47 (95% CI 1.10-5.54; P=0.028) for metastases. TNFRSF10A genotypes were not associated with tumor stage, grade, risk group or age at diagnosis. CONCLUSION: We conclude that the TNFRSF10A Glu228Ala polymorphism may be a novel independent risk factor for prostate cancer metastases after radiation therapy.

Genetic polymorphisms in the vascular endothelial growth factor gene and breast cancer risk. The Austrian "tumor of breast tissue: incidence, genetics, and environmental risk factors" study.

PURPOSE: Vascular endothelial growth factor (VEGF) is a key regulator of tumor-induced angiogenesis and is required for growth of tumors. We tested the hypothesis that VEGF gene polymorphisms may be associated with breast cancer. EXPERIMENTAL DESIGN: We performed a case-control study including 804 female incident breast cancer patients and 804 female age-matched healthy control subjects. We selected seven VEGF candidate polymorphisms and determined genotypes by 5'-nuclease (TaqMan) assays. Furthermore, VEGF plasma levels and genotypes were analyzed in a group of 81 healthy volunteers (64 men and 17 women). RESULTS: Haplotype analysis showed two separate blocks of high-linkage disequilibrium, formed by five polymorphisms upstream of the coding sequence (promoter and 5' untranslated region) and two polymorphisms downstream of the coding sequence. None of the single polymorphisms or haplotypes was significantly associated with the presence of breast cancer. After Bonferroni correction for multiple testing, only one statistical signifcant association between VEGF genotypes and haplotypes and tumor characteristics was observed (-634C allele and small tumor size; p < 0.001). In a multivariate regression analysis including sex, age, VEGF genotypes, and haplotypes as covariates and VEGF plasma level as dependent variable, none of the VEGF polymorphism or haplotypes was a significant predictor of VEGF plasma levels. CONCLUSIONS: Our findings do not support the hypothesis that VEGF polymorphisms are associated with breast cancer risk. The association of the VEGF -634C allele with small tumor size is in clear contrast to a previous publication and should be interpreted with caution until replicated by additional studies.

The predictive value of EGFR and HER-2/neu in tumor tissue and serum for response to anthracycline-based neoadjuvant chemotherapy of breast cancer.

We investigated the predictive value of HER-2/neu and epidermal growth factor receptor (EGFR) in tumor tissue and prechemotherapy serum for histopathologic response in 108 patients with breast cancer undergoing neoadjuvant anthracycline-based chemotherapy. Response to chemotherapy, assessed by histopathologic classification of regression (grade 0 [no therapy effect] to 4 [no residual tumor]), correlated significantly with prechemotherapy serum HER-2/neu levels. Median prechemotherapy serum HER-2/neu levels were significantly higher in patients with regression grades 1 through 4 compared with those in patients with regression grade 0 (9.6 vs 8.55 ng/mL; P = .011; 95% confidence interval [CI], .009-.014). Median pretreatment serum HER-2/neu levels of patients with complete pathologic response (pCR) were significantly higher than in patients with moderate or no treatment response (10.95 vs 9.1 ng/mL; P = .041; 95% CI, .036-.046). Receiver operating characteristic curve analysis revealed a serum HER-2/neu value of more than 10.3 ng/mL to predict a pCR with 80% sensitivity and 69.4% specificity. There was no significant correlation of response with HER-2/neu and EGFR scores in tumor tissue or with serum EGFR levels. Results demonstrate prechemotherapy serum HER-2/neu to be a significant predictor of response to neoadjuvant anthracycline-based chemotherapy for breast cancer.

Global quality of life and its potential predictors in breast cancer patients: an exploratory study.

GOALS OF WORK: This study reflects variables being depicted as predictors of global quality of life in current research. The evaluation was conducted at the Division of Clinical Oncology at the Medical University in Graz, Austria. PATIENTS AND METHODS: A sample of 210 breast cancer patients between ages 30 and 80 years was assessed 1-5 years after initial diagnosis in a tumor-free stage. Besides the socio-demographic and medical variables, the Brief Symptom Inventory (BSI), Impact of Event Scale (IES), Mental Adjustment to Cancer (MAC), and the Perceived Family Support (PFS) were used. To identify variables related to quality of life, stepwise multiple regression analyses were calculated. MAIN RESULTS: In a regression analysis, the general severity index (BSI) was identified as the most important and helplessness/hopelessness (MAC) as the second important variable related to QoL. Including the BSI-subscales as predictors, the depression-subscale (BSI) explained 25% of the variance; in addition, somatization (BSI), helplessness/hopelessness (MAC), and having financial problems (semi-structured interview) were significantly related to global quality of life, but the medical variables showed no associations to the measured quality of life. Depression itself is associated with negative the impact of cancer, the number of stressful life events, being uncomfortable with the body, having financial problems and anxious preoccupation (MAC). CONCLUSIONS: The awareness of the role of multi-factorial and associated variables could provide patients, family, and medical staff with appropriate and adequate tools to treat specific symptoms.

A multigenic approach to predict breast cancer risk.

In the biology of complex disorders, such as breast cancer, interactions among genetic factors may play an important role and theoretical considerations suggest that gene-gene interactions are quite common in such diseases. In this case-control study with 500 breast cancer patients and 500 population-based healthy sex- and age-matched control subjects, we applied a multigenic approach to examine the associations with breast cancer risk of a comprehensive panel of 16 selected polymorphisms in a variety of pathways using classification tree analysis (CART). Overall, 79.6% of all breast cancer patients and 80.6% of all control subjects were correctly classified on the basis of their individual genetic profile by the classification procedure. CART analysis of the data identified the heterozygous vascular endothelial growth factor (VEGF) and matrix metalloproteinase 3 (MMP3) genotype and homozygous cyclooxygenase-2 (PTGS2) mutant as the initial splits, indicating that these genotypes exert the greatest impact on the classification process. Breast cancer patients were primarily indicated by 30 distinct genetic profiles. The odds ratio of these genetic risk profiles for breast cancer was 16.12 (95% confidence interval 11.09-23.49). Five genetic profiles formed homogenous breast cancer subgroups and represented highest risk genetic profiles. This is the first comprehensive study to use a multigenic analysis for breast cancer and the data suggest that individuals with distinct genetic profiles are at an increased risk for breast cancer, confirming the importance of taking a multigenic approach for risk assessment.