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.

The Halofixator for the Treatment of Unstable Fractures of the Upper Cervical Spine - Our Own Experience and Narrative Review. / Der Halofixateur zur Therapie von instabilen Frakturen der oberen Halswirbelsäule ­ eigene Erfahrungen und narratives Review.

INTRODUCTION: In the treatment of upper cervical spine injuries, the semiconservative procedure of the halofixator is now of only secondary importance. Older studies from the 2000 s showed unsatisfactory rates of consolidation as well as high rates of complications. However, due to current data on therapy effectiveness, the literature is inconsistent. The aim of this work is to compare our own experiences and results of treatment with the current literature and to help to clarify the role of the halofixator. MATERIAL AND METHODS: In a monocentric retrospective cohort study, patients with unstable injuries of the axial cervical spine who were to be treated in the halofixator were investigated. Individual variables (sex, age, concomitant diseases, Charlson Comorbidity Index) and treatment characteristics (duration of treatment, consolidation status, complications) were recorded using the electronic medical record. Injuries were classified based on CT data at the time of the accident and at the end of treatment, using common classification systems, and assessed with respect to the rate of consolidation. Possible factors influencing bony consolidation as well as complications were statistically analysed. RESULTS: A total of 54 patients met the inclusion criteria. The median duration of treatment was 83 days. The most common injuries were isolated atlas fracture type III (7; 13%) and isolated dens fracture type III (24; 44%). Bony consolidation was demonstrated in 34 cases (63%) and tight pseudarthrosis in 13 cases (24%). Secondary surgical stabilisation was performed in 6 cases (11%). Isolated type III atlas fractures and type III dens fractures had very high consolidation rates of 86% and 92%, respectively. In the subgroups of patients older than 65 years or with a CCI ≥ 4, unstable pseudarthroses were found more frequently. Complications included pin infection (6%), pin dislocation (9%), and pressure ulceration from the halo vest (6%). Cardiopulmonary complications did not occur. No patient died. DISCUSSION: Good rates of bony consolidation were seen for atlas fractures type III as well as dens fractures type III, which correlate with data in the literature. Dens fractures type II (isolated and combined) and atlas fractures type III in combination with dens fractures showed a worse radiological outcome, which is also unsatisfactory compared to the literature. The rates for procedure-specific complications were relatively low. In particular, work from recent years has demonstrated very good rates for bony consolidation and low complication rates for the treatment of atlas and/or dens fractures with the halofixator, which are confirmed by our results. In contrast, however, a significantly higher cardiac/respiratory complication rate has been reported than occurred in our own patient population.

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.

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.

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.

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.

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.

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.

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 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.

Comparison of two methods for enumerating circulating tumor cells in carcinoma patients.

BACKGROUND: Monitoring of circulating tumor cells (CTCs) in blood of carcinoma patients treated with novel compounds may be a measurement of treatment effectiveness. Before it can be used clinically, a reliably method is needed to enumerate CTCs. We compared two methods for CTC enumeration, OnkoQuick and the CellSearch system. METHODS: We drew 22.5 ml of blood into three CellSave tubes from 15 healthy donors and 61 patients with metastatic carcinoma. After pooling, 15 ml was processed with OncoQuick and 7.5 ml with CellSearch. RESULTS: With both methods no CTCs were found in healthy donors. At least one CTC was detected in 14 of 61 patients (23%) with OncoQuick and 33 of 61 patients (54%) with CellSearch (P < 0.0001). The number of CTCs detected was larger for CellSearch (mean 20 CTCs/7.5 ml of blood) than for OncoQuick (3 CTCs/7.5 ml; P < 0.0001). CONCLUSION: The CellSearch system is a more accurate and sensitive method to enumerate CTCs. Further studies are warranted to evaluate CTC enumeration by the CellSearch system as a monitoring tool for the evaluation of the efficacy of novel anticancer agents.

Association of disease progression and poor overall survival with detection of circulating tumor cells in peripheral blood of patients with metastatic breast cancer.

The aim of this study was to define the frequency and clinical relevance of cytokeratin positive metastatic tumor cells in the peripheral circulation of patients with stage IV breast cancer. Peripheral blood was collected from 32 consecutive patients with metastatic breast cancer and 23 healthy donors. Tumor cells were enriched using positive selection with anti-HEA125-microbeads and cytospins were prepared of the positive selection eluate. Slides were incubated with a Fab2 fragment of the pancytokeratin antibody A45-B/B3 conjugated with alkaline phosphatase (AKP) and a CAM5.2-AKP monoclonal antibody and developed with an alkaline phosphatase anti-alkaline phosphate reaction (APAAP). All samples were evaluated using light microscopy and an automated image analysis system. In 8/32 (25%) patients cytokeratin positive (CK+) cells could be detected after anti-HEA125 enrichment in the peripheral blood whereas in none out of 23 healthy donors. One to 1000 (median 5) positive cells per patient sample were observed and cluster of tumor cells in one patient. Automated image analysis was as powerful in detecting micrometastases as conventional light microscopy. All patients with CK+ cells in the peripheral circulation (8/8, 100%) showed progressive disease at the time-point of blood draw whilst only 9/24 (37.5%) showed disease progression without detection of positive cells. The median overall survival of CK+ patients was 4+/-2 months compared to 13+/-7 months of CK- patients (p<0.001). CK+ cells are detectable in the peripheral circulation of 25% of patients with metastatic breast cancer after positive selection with anti-HEA125. Detection of tumor cells in the peripheral circulation might be correlated with progression of disease and shorter overall survival.

The course of serum HER-2/neu levels as an independent prognostic factor for survival in metastatic breast cancer.

The purpose of this study was to determine the impact of serum HER-2/neu level dynamics during the course of disease and treatment on the prognosis of patients with metastatic breast cancer. Two thousand and thirty-eight serum samples collected sequentially after disease relapse in 286 patients with metastatic breast cancer were measured by Bayer Immuno 1 trade mark assay retrospectively for serum HER-2/neu (cut-off level 15 ng/ml). One hundred and five patients (37%) presented with serum HER-2/neu continuously

Stability of a transdermal salmon calcitonin formulation.

This study was designed to monitor the stability of salmon calcitonin during storage conditions, under the electric fields generated during iontophoresis and electroporation, in contact with transdermal glass diffusion cells, and during transport through skin. The formulation in a citrate buffer (pH 4.0) was stable in storage for short-term studies but degraded significantly on extended storage. Albumin was able to minimize adsorption in contact with glass surfaces, and aprotinin was able to minimize proteolytic degradation in contact with skin. The formulation was stable under electric field, but there was a loss due to adsorption if salt bridges were used.

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.

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.

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.

Diurnal IOP-lowering efficacy and safety of travoprost 0.004% compared with tafluprost 0.0015% in patients with primary open-angle glaucoma or ocular hypertension.

PURPOSE: To compare the diurnal intraocular pressure (IOP)-lowering efficacy and safety of travoprost 0.004% and tafluprost 0.0015% administered to patients with primary open-angle glaucoma or ocular hypertension. METHODS: This was a randomized, double-masked, active-controlled, crossover design trial, in which patients were randomized to either travoprost or tafluprost monotherapy administered once daily in the evening for six weeks and then crossed over to the alternative treatment for another six weeks. Diurnal IOP was measured (8 am to 8 pm, every two hours) and a solicited symptom survey was administered at the end of both six-week periods, as was conjunctival hyperemia and visual acuity assessment, slit-lamp biomicroscopy, and adverse event solicitation. RESULTS: Fifty-one patients were randomized and 48 patients completed the study. The 12-hour mean diurnal IOP was significantly lower with travoprost therapy than with tafluprost therapy (P = 0.01), and a significantly lower IOP was also reported for travoprost at five of the seven individual time points (P < 0.05). Neither therapy produced a significant increase from baseline in any of the individual patient-reported symptom scores, except for hyperemia (P ≤ 0.01), which was increased with both treatments. Investigator-observed hyperemia was also increased from baseline with both therapies (P < 0.01), although the increase with travoprost therapy was significantly smaller than with tafluprost (P < 0.01). No additional safety concerns were noted from slit-lamp biomicroscopy or visual acuity results, and no difference was noted in patient-reported tolerability of the two medications. CONCLUSION: Travoprost 0.004% monotherapy produced lower diurnal IOP than tafluprost 0.0015% in patients with primary open-angle glaucoma or ocular hypertension and exhibited a similar safety profile.