Search

Reduced systolic and diastolic calcium levels in cardiomyocytes from NKA-α2 transgenic mice minimize the desensitization of the β-adrenergic signaling system. These effects result in an improved β-adrenergic reserve and prevent functional deterioration and cardiac remodeling.

There is evidence suggesting that pre-treatment clinical parameters can predict the probability of sphincter-preserving surgery in rectal cancer, however, to date, data on the predictive role of inflammatory parameters on the sphincter-preservation rate are not available. The aim of the present cohort study was to investigate the association between inflammation-based parameters and the sphincter-preserving surgery rate in patients with low-lying locally advanced rectal cancer (LARC). A total of 848 patients with LARC undergoing radiotherapy from 2004 to 2019 were retrospectively reviewed in order to identify patients with rectal cancer localized ≤6 cm from the anal verge, treated with neo-adjuvant radiochemotherapy (nRCT) and subsequent surgery. Univariable and multivariable analyses were used to investigate the role of pre-treatment inflammatory parameters, including the C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) for the prediction of sphincter preservation. A total of 363 patients met the inclusion criteria, among them, 210 patients (57.9%) underwent sphincter-preserving surgery, and in 153 patients (42.1%), an abdominoperineal rectum resection was performed. Univariable analysis showed a significant association of the pre-treatment CRP value (OR = 2.548, 95% CI: 1.584–4.097, p &lt, 0.001) with sphincter preservation, whereas the pre-treatment NLR (OR = 1.098, 95% CI: 0.976–1.235, p = 0.120) and PLR (OR = 1.002, 95% CI: 1.000–1.005, p = 0.062) were not significantly associated with the type of surgery. In multivariable analysis, the pre-treatment CRP value (OR = 2.544, 95% CI: 1.314–4.926, p = 0.006) was identified as an independent predictive factor for sphincter-preserving surgery. The findings of the present study suggest that the pre-treatment CRP value represents an independent parameter predicting the probability of sphincter-preserving surgery in patients with low-lying LARC.

Background: Erythropoietin has a pivotal role in erythropoiesis and angiogenesis. A common polymorphism (rs1617640, A &gt, C) in the promoter of the erythropoietin gene (EPO) has been associated with erythropoietin expression and microvascular complications of diabetes. We aimed to analyze the potential role of this polymorphism in the pathogenesis of peripheral arterial disease (PAD). Methods: EPO genotypes and laboratory markers for erythropoiesis were determined in 945 patients with PAD. Results: The minor EPO rs1617640 C-allele was associated in an allele-dose-dependent manner with hemoglobin levels (p = 0.006), hematocrit (p = 0.029), and red blood cell count (p = 0.003). In a multivariate linear regression analysis including conventional risk factors diabetes, sex, and smoking, EPO genotypes were furthermore associated with age at onset of PAD symptoms (p = 0.009). Conclusions: The EPO rs1617640 gene polymorphism affects erythropoiesis, leads to an earlier onset of PAD, and is a potential biomarker for the pathogenesis of this disease.

Background There is considerable evidence that platelets contribute to cancer growth and metastatic dissemination. In recent studies, altered mean platelet volume (MPV) has been associated with prognosis in different types of cancer. However, the prognostic role of the MPV in head and neck squamous cell cancer (HNSCC) is currently discussed controversially. The present study was performed to analyze and further elucidate the prognostic significance of the MPV in HNSCC. Methods A total of 319 oropharyngeal squamous cell cancer (OPSCC) patients treated with radiotherapy at a tertiary academic center were enrolled in the present study. Kaplan–Meier method as well as uni- and multivariate Cox proportional hazards were used to evaluate the impact of MPV on cancer-specific survival (CSS), locoregional control (LC) and recurrence-free survival (RFS). Results The median MPV was 10.30 fL (mean 10.26 ± 1.17fL). Univariate analyses showed a significant association of the MPV with CSS (HR 0.85, 95% CI 0.74–0.98, p = 0.025), LC (HR 0.86, 95% CI 0.74–0.99, p = 0.034) and RFS (HR 0.87, 95% CI 0.76–0.996; p = 0.043). In multivariate analysis, the MPV remained an independent prognostic factor for CSS (HR 0.77, 95% CI 0.63–0.93, p = 0.008), LC (HR 0.80, 95% CI 0.65–0.98, p = 0.030), and RFS (HR 0.83, 95% CI 0.685–0.999, p = 0.049). Conclusions Our findings indicate that the MPV is a prognostic marker in OPSCC patients and may contribute to future individual risk assessment.

The aim of the present study was to investigate the association of the pre-treatment C-reactive protein (CRP) plasma level with survival outcomes in a cohort of 423 consecutive patients with locally advanced rectal cancer treated with neo-adjuvant radiochemotherapy followed by surgical resection. To evaluate the prognostic value of the CRP level for clinical endpoints recurrence-free survival (RFS), local-regional control (LC), metastases-free survival (MFS), and overall survival (OS), uni- and multivariate Cox regression analyses were applied, and survival rates were calculated using Kaplan&ndash, Meier analysis. The median follow-up time was 73 months. In univariate analyses, the pre-treatment CRP level was a significant predictor of RFS (hazard ratio (HR) 1.015, 95% CI 1.006&ndash, 1.023, p &lt, 0.001), LC (HR 1.015, 95% CI 1.004&ndash, 1.027, p = 0.009), MFS (HR 1.014, 95% CI 1.004&ndash, p = 0.004), and OS (HR 1.016, 95% CI 1.007&ndash, 1.024, 0.001). Additionally, univariate analysis identified the MRI circumferential resection margin (mrCRM) and pre-treatment carcinoembryonic antigen (CEA) as significant predictor of RFS (HR 2.082, 95% CI 1.106&ndash, 3.919, p = 0.023 and HR 1.005, 95% CI 1.002&ndash, 1.008, 0.001). Univariate analysis also revealed a significant association of the mrCRM (HR 2.089, 95% CI 1.052&ndash, 4.147, p = 0.035) and CEA (HR 1.006, 95% CI 1.003&ndash, 0.001) with MFS. Age and CEA were prognostic factors for OS (HR 1.039, 95% CI 1.013&ndash, 1.066, p = 0.003 and HR 1.005, 95% CI 1.002&ndash, 0.001). In multivariate analysis that included parameters with a p-level &lt, 0.20 in univariate analysis, the pre-treatment CRP remained a significant prognostic factor for RFS (HR 1.013, 95%CI 1.001&ndash, 1.025, p = 0.036), LC (HR 1.014, 95% CI 1.001&ndash, p = 0.031), and MFS (HR 1.013, 95% CI 1.000&ndash, p = 0.046). The results support the hypothesis that an elevated pre-treatment CRP level is a predictor of poor outcome. If confirmed by additional studies, this easily measurable biomarker could contribute to the identification of patients who might be candidates for more aggressive local or systemic treatment approaches or the administration of anti-inflammatory drugs.

Background/Aim: Carboplatin-containing treatment regimens demonstrate moderate efficacy in metastatic castration-resistant prostate cancer (mCRPC). In this study, we retrospectively analyzed the efficacy of carboplatin in relation to blood-based parameters. Patients and Methods: A retrospective chart review was performed for 20 patients with mCRPC who received carboplatin in a single center. Results: Median overall survival was 3.8 months (95%CI=1.5-7.1), median progression-free survival was 1.7 months. We observed two partial remissions (PR, 10%), four stable diseases (SD, 20%) and 14 disease progressions (PD, 70%), resulting in a clinical benefit rate of 30%. A doubling of NSE (neurone specific enolase) values was associated with a 19% absolute higher response rate (95%CI=14-23, p=0.027). All other laboratory parameters failed as predictive markers of response to carboplatin. In univariate Cox regression analysis, only NSE was significantly associated with impaired PFS (HR=0.7, 95%CI=0.56-0.96, p=0.030). Conclusion: Carboplatin showed moderate efficacy against mCRPC in this unselected population of patients and NSE levels may help to predict the success of this treatment.

Prostate cancer is a common malignancy in men worldwide and it is known that oxidative stress is a risk factor for cancer development. A common functional haptoglobin (Hp) polymorphism, originating from a duplication of a gene segment spanning over two exons, results in three distinct phenotypes with different anti-oxidative capacities: Hp1-1, Hp1-2, and Hp2-2. The aim of the study was to investigate the relationship between this Hp polymorphism and prostate cancer mortality. The study was performed on 690 patients with histologically confirmed prostate cancer, recruited between January 2004 and January 2007. Hp genotypes were determined by a TaqMan fluorogenic 5′-exonuclease assay. Hp1-1 was present in 76 (11%), Hp1-2 in 314 (45.5%), and Hp2-2 in 300 (43.5%) patients. During a median follow-up of 149 months, 251 (35.3%) patients died. Hp genotypes were not significantly associated with higher overall mortality (HR 1.10; 95% CI 0.91–1.33; p = 0.34). This remained similar in a multivariate analysis including age at diagnosis, androgen deprivation therapy, and risk group based on PSA level, GS, and T stage (HR 1.11; 95% CI 0.91–1.34; p = 0.30). We conclude that the common Hp polymorphism does not seem to be associated with overall mortality in prostate cancer patients.

Background Although controversial, there are data suggesting that clinical parameters can predict the probability of sphincter preserving procedures in rectal cancer. The purpose of this study was to investigate the association between clinical parameters and the sphincter-preserving surgery rate in patients who had undergone neoadjuvant combination therapy for advanced low rectal cancer. Methods In this single center study, the charts of 540 patients with locally advanced rectal cancer who had been treated with induction chemotherapy-and/or neoadjuvant concomitant radiochemotherapy (nRCT) over an 11-year period were reviewed in order to identify patients with rectal cancer ≤6 cm from the anal verge, who had received the prescribed nRCT only. Univariate and multivariate analyses were used to identify pretreatment patient- and tumor associated parameters correlating with sphincter preservation. Survival rates were calculated using Kaplan-Meier analyses. Results Two hundred eighty of the 540 patients met the selection criteria. Of the 280 patients included in the study, 158 (56.4%) underwent sphincter-preserving surgery. One hundred sixty-four of 280 patients (58.6%) had a downsizing of the primary tumor (ypT p = 0.003), relative lymphocyte value (HR = 0.94, CI95%: 0.89–0.99, p = 0.029), and interval between nRCT and surgery (HR = 2.39, CI95%: 1.17–4.88, p = 0.016) remained as independent predictive parameters. Conclusions These clinical parameters can be considered in the prognostication of sphincter-preserving surgery in case of low rectal adenocarcinoma. More future research is required in this area.

The purpose of the present study was to evaluate the prognostic significance of the pre- treatment C-reactive protein (CRP) level in a cohort of 503 patients with oral and oropharyngeal cancer treated at a tertiary academic center between 2000 and 2017. Cancer-specific survival (CSS), overall survival (OS) and loco-regional control (LC) were calculated using Kaplan-Meier analysis. To evaluate the prognostic value of the CRP level for the clinical endpoints, univariate and multivariate Cox regression models were applied. The median follow-up period was 61 months. Patients were divided into elevated CRP (&ge, 5 mg/L) and normal CRP groups, according to pre-treatment plasma levels. An increased CRP level was significantly associated with shorter CSS (p &lt, 0.001, log-rank test), as well as with shorter OS (p &lt, 0.001, log-rank test) and loco-regional control (p = 0.001, log-rank test). In addition, multivariate analysis identified CRP as an independent predictor for CSS (hazard ratio (HR) 1.59, 95% confidence interval (CI) 1.08&ndash, 2.35, p = 0.020) as well as for OS (HR 1.62, 95%CI 1.17&ndash, 2.24, p = 0.004) and LC (HR 1.50, 95%CI 1.06&ndash, 2.14, p = 0.023). In subgroup analysis, Kaplan Meier curves revealed that an elevated pre-treatment CRP level was a consistent prognostic factor for poor CSS (p = 0.003, log-rank test), OS (p = 0.001, log-rank test), and LC (p = 0.028, log-rank test) in patients treated with definitive (chemo-) radiotherapy, whereas a significant association in patients undergoing surgery and postoperative radiotherapy was not detected. The pre-treatment CRP level seems to represent a prognostic factor for CSS, OS, and LC in patients with oral and oropharyngeal cancer, particularly in those treated with definitive (chemo-) radiotherapy. Additional large-scale prospective studies are warranted to confirm and extend our findings.

Purpose The antiapoptotic B‑cell lymphoma 2 (BCL2) gene is a key player in cancer development and progression. A functional single-nucleotide polymorphism (c.-938C>A, rs2279115) in the inhibitory P2 BCL2 gene promoter has been associated with clinical outcomes in various types of cancer. Aim of the present study was to analyze the role of BCL2-938C>A genotypes in prostate cancer mortality. Methods The association between BCL2-938C>A (rs2279115) genotypes and prostate cancer outcome was studied within the prospective PROCAGENE study comprising 702 prostate cancer patients. Results During a median follow-up time of 92 months, 120 (17.1%) patients died. A univariate Cox regression model showed a significant association of the CC genotype with reduced cancer-specific survival (CSS; hazard ratio, HR, 2.13, 95% confidence interval, CI, 1.10–4.12; p = 0.024) and overall survival (OS; HR 2.34, 95% CI 1.58–3.47; p < 0.001). In a multivariate Cox regression model including age at diagnosis, risk group, and androgen deprivation therapy, the CC genotype remained a significant predictor of poor CSS (HR 2.05, 95% CI 1.05–3.99; p = 0.034) and OS (HR 2.25, 95% CI 1.51–3.36; p < 0.001). Conclusion This study provides evidence that the homozygous BCL2-938 CC genotype is associated with OS and C in prostate cancer patients.

Telomeres are essential for the maintenance of chromosomal integrity and telomere length has been associated with cancer risk and development. Aim of the present study was to analyze the prognostic value of leukocyte relative telomere (RTL) length in long-term prostate cancer (PCa) mortality. Blood samples of PCa patients were obtained before initiation of radiotherapy. RTL of peripheral blood leukocytes was determined by a quantitative polymerase chain reaction method in 533 patients with PCa. Main outcome was overall mortality. During a median follow-up time of 149 months, 188 (35.3%) patients died. In a univariate Cox regression analysis, RTL quartiles (longer RTL) were significantly associated with higher overall mortality (hazard ration (HR) = 1.20; 95% confidence interval (CI): 1.05–1.36; p = 0.006). In a multivariate Cox regression model including age at diagnosis, androgen deprivation therapy, and risk group (based on PSA level, GS, and T stage), RTL quartiles remained a significant predictor of higher overall mortality (HR = 1.22; 95% CI: 1.07–1.39; p = 0.003). Longer leukocyte RTL predicts higher overall mortality in patients with PCa.

Purpose Decreased vitamin D levels have been associated with prostate cancer, but it is unclear whether this association is causal. A functional single-nucleotide polymorphism (SNP) in the group-specific component (GC) gene (T > G, rs2282679) has been associated with 25-hydroxy (25-OH) vitamin D and 1.25 dihydroxy (1.25-OH2) vitamin D levels.

Fibrinogen plays an important role in the pathophysiology of tumour cell invasion and metastases. In recent studies, an elevated plasma fibrinogen level has been associated with poor prognosis in different types of cancer. The present study was performed to analyse the prognostic impact of an elevated fibrinogen level in prostate cancer patients. We evaluated data from 268 prostate cancer patients who underwent 3D conformal radiotherapy between 1999 and 2006 at a single tertiary academic center. Cancer-specific survival (CSS), overall survival (OS), and clinical disease-free survival (DFS) were assessed using the Kaplan–Meier method. Univariable and multivariable Cox regression models were performed for each endpoint. Applying receiver operating characteristics (ROC) curve analysis, the optimal cut-off level for the plasma fibrinogen level was 530 mg dl−1, respectively. Univariable (HR 3.638, 95 % CI 1.15–11.47, p = 0.027) and multivariable analyses (HR 3.964, 95 % CI 1.06–14.87, p = 0.041) revealed a significant correlation between increased plasma fibrinogen and CSS. Univariable analysis also showed a significant association between the elevated plasma fibrinogen level and decreased OS (HR 3.242, 95 % CI 1.53–6.89, p = 0.002), that remained significant in multivariable analysis (HR 3.215, 95 % CI 1.44–7.19, p = 0.004). No significant associations were found for clinical DFS. Although our data show a significant association between an elevated plasma fibrinogen level and poor prostate cancer prognosis, they have to be interpreted cautiously. Limitations of the present study are caused by its retrospective design, the limited accuracy obtained using ROC curve analysis, and potential confounding factors like cardiovascular disease and inflammatory diseases that have not been accounted for.

Enumeration and especially molecular characterization of circulating tumour cells (CTCs) holds great promise for cancer management. We tested a modified type of an in vivo enrichment device (Catch&Release) for its ability to bind and detach cancer cells for the purpose of single-cell molecular downstream analysis in vitro. The evaluation showed that single–cell analysis using array comparative genome hybridization (array-CGH) and next generation sequencing (NGS) is feasible. We found array-CGH to be less noisy when whole genome amplification (WGA) was performed with Ampli1 as compared to GenomePlex (DLRS values 0.65 vs. 1.39). Moreover, Ampli1-processed cells allowed detection of smaller aberrations (median 14.0 vs. 49.9 Mb). Single-cell NGS data obtained from Ampli1-processed samples showed the expected non-synonymous mutations (deletion/SNP) according to bulk DNA. We conclude that clinical application of this refined in vivo enrichment device allows CTC enumeration and characterization, thus, representing a promising tool for personalized medicine.

High-risk non-metastatic prostate cancer (PCa) has the potential to progress into lethal disease. Treatment options are manifold but, given a lack of surrogate biomarkers, it remains unclear which treatment offers the best results. Several studies have reported circulating tumor cells (CTCs) to be a prognostic biomarker in metastatic PCa. However, few reports on CTCs in high-risk non-metastatic PCa are available. Herein, we evaluated CTC detection in high-risk non-metastatic PCa patients using the in vivo CellCollector CANCER01 (DC01) and CellSearch system. CTC counts were analyzed and compared before and after radiotherapy (two sampling time points) in 51 high-risk non-metastatic PCa patients and were further compared according to isolation technique, further, CTC counts were correlated to clinical features. Use of DC01 resulted in a significantly higher percentage of CTC-positive samples compared to CellSearch (33.7% vs. 18.6%, p = 0.024) and yielded significantly higher CTC numbers (range: 0&ndash, 15 vs. 0&ndash, 5, p = 0.006). Matched pair analysis of samples between two sampling time points showed no difference in CTC counts determined by both techniques. CTC counts were not correlated with clinicopathological features. In vivo enrichment using DC01 has the potential to detect CTC at a higher efficiency compared to CellSearch, suggesting that CTC is a suitable biomarker in high-risk non-metastatic PCa.

Low concentrations of 25-hydroxyvitamin D3 (25(OH)D) have been associated with increased risk and poor prognosis of various cancer types, including colon cancer. Common genetic variants in genes that influence circulating 25(OH)D levels may affect vitamin D concentrations and risk of vitamin D insufficiency. In the present study, we investigated the association of three functional gene variants in GC (rs2282679 T>G), DHCR7 (rs12785878 G>T) and CYP2R1 (rs10741657 A>G) with time to recurrence (TTR) in patients with stages II and III colon cancer. Two hundred and sixty-four patients were included in this retrospective study. Genomic DNA was genotyped for GC rs2282679 T>G, DHCR7 rs12785878 G>T and CYP2R1 rs10741657 A>G by 5′-exonuclease (TaqMan™) technology. In the univariate analysis, GC rs2282679 GG was significantly associated with decreased TTR (HR = 3.30, 95 % CI 1.09–9.97, p = 0.034) in patients with surgery alone and remained significantly associated in multivariate analysis including lymph node involvement and clinical stage (HR = 3.64, 95 % CI 1.16–11.46, p = 0.027). In patients with adjuvant chemotherapy, GC rs2282679 T>G was not significantly associated with TTR (HR = 1.02, 95 % CI 0.44–2.37, p = 0.964). Furthermore, we observed a trend toward decreased TTR in patients harboring the CYP2R1 rs10741657 A>G gene variant including all patients (HR = 1.50, 95 % CI 0.98–2.28, p = 0.060). No association was found between DHCR7 rs12785878 G>T and TTR in our study cohort. In conclusion, our results may indicate a prognostic effect of GC rs2282679 in stages II and III colon cancer patients with surgery alone. Larger studies have to be performed to validate our findings.

Angiogenesis and cell cycle control play critical roles in breast cancer susceptibility and clinical outcome and are mainly controlled by vascular endothelial growth factor (VEGF) and cyclin-dependent kinases, respectively. Functional germline polymorphisms in these genes alter the function, thereby causing inter-individual differences in breast cancer risk and clinical outcome. In this study, we investigated the influence of the functional polymorphisms VEGF-A rs3025039 C > T and CCND1 rs9344 G > A on risk and clinical outcome in early-stage breast cancer. DNA of 539 female patients with histologically confirmed early-stage breast cancer and 804 control subjects was genotyped for these polymorphisms. Genotypes were tested for associations with breast cancer risk and clinical outcome. There was no significant association between the polymorphisms and breast cancer risk. However, the minor allele of VEGF-A rs3025039 C > T was significantly associated with decreased recurrence-free survival (HR 1.845; 95% confidence interval [CI] 1.035-3.290; P = 0.038) and remained significant in multivariate analysis (HR 1.880; 95% CI 1.020-3.465; P = 0.043). Patients carrying at least one A-allele in CCND1 rs9344 G > A showed a trend towards decreased recurrence-free survival in univariate analysis (HR 2.379; 95% CI 0.841-6.728; P = 0.068). This study provides evidence that the functional VEGF-A rs3025039 C > T polymorphism influences recurrence-free survival in early-stage breast cancer.

Recent evidence suggests that PLS3 (T-Plastin), an important member of the actin filamentous network, significantly influences cell invasion and metastasis. Germline polymorphisms within the PLS3 gene may impact the gene’s function, resulting in inter-individual differences in tumor recurrence capacity. In the present study, we investigated the association of germline polymorphisms in PLS3 to predict time to recurrence (TTR) in patients with stage II and III colon cancer. A total of 264 patients with histologically confirmed colon cancer were included in this retrospective study. Germline DNA was genotyped for rs871773 C>T, rs757124 C>G, rs1557770 G>T, rs6643869 G>A, and rs2522188 C>T in the PLS3 gene by 5′-exonuclease (TaqMan™) technology. As the PLS3 gene is located on the X chromosome, a gender-specific statistical analysis was performed. In univariate analysis, the minor allele of PLS3 rs871773 C>T was significantly associated with decreased TTR in women (hazard ratio (HR) = 5.02; 95 % confidence interval (CI) = 1.251–20.114; p = 0.023) and remained significantly associated in multivariate analysis (HR = 6.165; 95 % CI = 1.538–24.716; p = 0.010). Female patients carrying the C/T genotype in PLS3 rs871773 showed a median TTR of 69 months. In contrast, female patients with homozygous C/C had a median TTR of 112 months. There were no significant associations between PLS3 rs871773 C>T and TTR in male and between the other polymorphisms and TTR in male or female colon cancer patients. In conclusion, we identified a common gene variant in PLS3 as an independent prognostic marker in female patients with stage II and III colon cancer. Larger prospective trials are warranted to confirm these findings.

Aim of the present study was to investigate survival rates of unselected patients with glioblastoma after multimodal treatment and estimation of prognostic factors. Data of 189 patients (118 men; 71 women; median age: 59 years) with histologically confirmed glioblastoma treated from 1999 to 2009 were analyzed retrospectively. Complete tumor resection was performed in 99 patients (52%), subtotal excision in 65 patients (34%), and stereotactic biopsy in 25 patients (13%). In 135 patients (71%), residual tumors were detectable in post-surgical imaging. All patients underwent three-dimensional conformal radiotherapy of the tumor region in shrinking-field technique to a total dose of 60 Gy. Beginning in 2002, 124 patients (66%) received concomitant temozolomide (TMZ) treatment, 76 patients among them were additionally treated with adjuvant TMZ. After disease progression, 74 patients underwent salvage therapy (salvage chemotherapy, n=61; local therapy, n=30). Actuarial 1- and 2- year progression-free survival (PFS) rates were 32% and 7%, overall survival (OS) rates were 54% and 22%, respectively. Without TMZ, 1- and 2- year OS rates were 47% and 11%, with concomitant TMZ 57% and 28%, and with concomitant and adjuvant TMZ 72% and 44%. In multivariate Cox proportional hazards regression models, age (p

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. 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. 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. 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.

Aim of this analysis was to assess the current status of prostate cancer radiotherapy in Austria and compare these numbers to patients treated with surgery. A questionnaire was sent to all 14 Austrian departments asking about numbers of prostate cancer patients treated and indication of treatment (primary, postoperative), as well as the treatment technique used (3D-CRT, IMRT, brachytherapy), treatment volumes (with/without pelvic irradiation), dose applied, and differences in treatment concepts. Data investigated were based on the year 2007. Of the 14 departments (65%), 9 departments decided to participate. A total of 1,191 prostate cancer patients were treated (847 primary, 344 postoperative). Primary patients were treated by external beam technique (91%) and permanent interstitial brachytherapy (9%). All postoperative patients were treated by 3D-CRT. Dose ranged from 70–78 Gy for primary pa-tients and from 60–72 Gy for postoperative patients. A risk-adapted dose prescription was performed in 5 centers. Additional pelvic lymph node irradiation was based on signs of positive nodes in 4 departments and based on Roach formula/Partin table in 5 departments. About 25% of prostate cancer patients receive primary radiotherapy. This number reflects a high potential to conduct national studies. Treatment technique and dose applied was in all centers investigated in accordance with the German S3 guidelines.

To assess local control and survival rates in patients with muscle-invasive bladder cancer treated with external-beam radiotherapy and to investigate prognostic factors. Between 1997 and 2007, 75 patients (male, n = 58; female, n = 17, median age, 74.2 years) with localized transitional cell carcinoma of the bladder (T2, n = 34; T3, n = 32; T4, n = 9) not suitable for radical surgery due to advanced age, comorbidity or inoperability underwent external-beam radiotherapy without simultaneous chemotherapy at the University Clinic of Therapeutic Radiology and Oncology, Medical University of Graz, Austria. A conformal four-field technique was used in all patients to treat the tumor and regional lymph nodes with single daily fractions of 1.8–2 Gy to a total dose of 50–50.4 Gy, followed by a cone-down to encompass the empty bladder which was boosted to 70–70.4 Gy. All patients had undergone transurethral tumor resection prior to radiotherapy which was macroscopically incomplete in 62 patients. Complete response was achieved in 65% of patients. Actuarial 3-year local control and metastases-free survival rates were 52.5% and 63.7%, 3-year local recurrence-free survival rate in complete responders was 71%. In univariate analysis, hydronephrosis, lymph vessel invasion, and macroscopic residual tumor were significantly predictive of disease progression. Hydronephrosis and lymph vessel invasion were also associated with a higher risk of local recurrence. The actuarial 3-year progression-free and overall survival rates were 40.1% and 56.9%, respectively. Radiotherapy is an effective treatment option in terms of local control and survival even in elderly patients with locally advanced bladder cancer not suitable for cystectomy.

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.The rare allele of FAS 1377GA 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 1377GA (P = 0.040, RR = 0.451, CI = 0.496-1.188) and IL10 592CA 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 592CA polymorphism (P = 0.013, RR 1.841, CI 1.140-2.973). No association was found for MTHFR 677CT, VEGF 936CT, CCND1 870GA, TGFB1 29TC, FASLG 844CT, FAS 670AG, GPB3 825CT, ITGA2 807CT, ITGA2 1648GA, ITGB3 176TC, MMP1 -1607 1G/2G, MMP3 5A/6A, PTGS2 8473TC, IL10 592CA and SULT1A1 638GA polymorphisms and disease-free survival or overall survival.Our data suggest that the FAS 1377GA and IL10 592CA polymorphisms could modify disease-free and overall survival in women with lymph node-positive breast cancer.

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.

To retrospectively assess the outcome in patients treated with adjuvant radiotherapy for penile cancer. Between 1987 and 2006, 24 patients (median age, 62.7 years; range, 35.5–90.4 years) with squamous cell carcinoma of the penis (T1, n = 10; T2, n = 11; T3, n = 3) received megavoltage external radiotherapy (n = 22) or 192Ir high-dose-rate brachytherapy (n = 2) following total penectomy (n = 7), partial penectomy (n = 10), or local excision (n = 7); lymphadenectomy was performed in eight patients. In 14 patients, radiotherapy was delivered after incomplete tumor resection, and in 20 patients the planning target volume included the regional lymph nodes. Median total dose of external radiotherapy was 56 Gy/1.8–2 Gy (range, 50–60 Gy). Brachytherapy was given with a total dose of 45 Gy/3 Gy. During a median follow-up of 58.4 months, penile or perineal recurrence was found in four patients giving a 5-year local control rate of 74.8%. Regional failure occurred in two patients. 5-year metastases-free survival and progression-free survival rates were 86.7% and 64.5%, respectively. Four patients died due to tumor progression. The actuarial 5-year cause-specific and overall survival rates were 84.3 and 56.6%, respectively. Radiation therapy is a successful method of treatment for penile cancer in terms of local control and organ preservation after microscopically incomplete surgery. Radiotherapy of the regional lymph nodes might also be effective in preventing regional recurrence and can be considered in case of high-risk features and following excision of extensive lymph node involvement.

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. Prostate 68: 264–268, 2008. © Wiley-Liss, Inc.

Tumor growth requires the formation of new blood vessels, a phenomenon known as angiogenesis. The most important regulator of angiogenesis is vascular endothelial growth factor (VEGF). Several common polymorphisms in the VEGF-gene have been associated with different VEGF expression, production and plasma levels according to allele status, and influence the risk of developing different types of cancer. Therefore, these variants might be risk factors for colorectal cancer (CRC).In the present case-control study, VEGF genotypes of the +936 CT, -2578 CA and -634 GC polymorphisms were determined in 427 patients with histologically verified CRC and 427 age and sex-matched healthy control subjects. Genotypes were analyzed by a fluorogenic exonuclease assay (TaqMan). P-value for age at diagnosis was analyzed by student's t test, P-values for tumor characteristics were determined by Pearson's Chi-square test. Threshold for significance was P0.05.At the time of diagnoses, patients were between 29 and 83 years of age, with a mean age of 61+/-10.9 years. VEGF -2578 CA and VEGF -634 GC genotype frequencies were similar among patients and controls. Carriers of the 936T-allele were found slightly more frequent among controls (27.2%) than among patients (22.5%), but this difference did not reach statistical significance (P=0.07). Furthermore, no correlation was found between all these variants and tumor characteristics like size, histological grading, positive regional lymph node metastases or tumor stage.We conclude that the investigated polymorphisms are not associated with individual susceptibility to colorectal cancer.

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.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).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; p0.001). 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.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.

Background Radiotherapy (RT) is one of the major treatment options in cancer management. The process of RT is complex and incorporates the use of highly specialized technical equipment. Therefore quality assurance (QA) procedures have always been an inclusive part of RT. Due to the rapidly increasing complexity during the last years, comprehensive QA has become even more of an issue, including treatment planning software, information handling and treatment delivery. Obviously methods from clinical risk management (RM) can be well adapted and adopted for use in radiotherapy. In this paper we aim to discuss currently available guidelines on RM in radiotherapy and to present risk assessment and process evaluation activities involved in the RM-implementation process at our department.

Existing preclinical and clinical data suggest that the presence of a systemic inflammatory response plays a critical role in the progression of several solid tumors. The derived neutrophil-to-lymphocyte ratio (dNLR) represents an easily determinable marker of systemic inflammation and has been proposed as a potential prognostic marker. The present study was performed to validate and further clarify the prognostic relevance of an elevated pre-treatment dNLR in a large cohort of European breast cancer patients. Data from 762 consecutive female breast cancer patients treated from 1999 to 2004 were evaluated. Disease-free survival (DFS) and overall survival (OS) were assessed using the Kaplan–Meier method. To evaluate the prognostic relevance, univariate and multivariate Cox regression models were performed for each endpoint. Applying receiver operating characteristics (ROC) analysis, the optimal cutoff level for the dNLR was 3. In univariate analysis, a dNLR ≥3 was associated with poor DFS (hazard ratio (HR) 1.87, 95 % confidence interval (CI) 1.28–2.73, p = 0.001) and OS (HR 1.67, 95 % CI 1.07–2.63, p = 0.025). Multivariate analysis revealed a significant association between the elevated dNLR and poor DFS (hazard ratio (HR) 1.70, 95 % CI 1.09–2.65, p = 0.018) but did not show a significant association between the dNLR and OS (HR 1.54, 95 % CI 0.91–2.59, p = 0.106). The present study shows that the pre-treatment dNLR is an independent prognostic factor that could be useful for future individual risk assessment in breast cancer patients.

Recent studies have expanded the concept that the systemic inflammatory response has an important role in the progression of several solid tumors. The neutrophil-to-lymphocyte ratio (NLR), an easily determinable marker of systemic inflammation, has been associated with clinical outcome in various cancer entities. In the present study, we validated the prognostic relevance of an elevated NLR in a cohort of European prostate cancer patients.Data from 415 consecutive prostate cancer patients treated with 3D conformal radiotherapy at a single tertiary academic center from 1999 to 2007 were included in this retrospective study. Clinical progression-free survival (PFS), distant metastases-free survival (DMFS), and overall survival (OS) were assessed using the Kaplan-Meier method. To evaluate the prognostic relevance, univariate and multivariate Cox regression models were performed for each end point.Based on previously published studies, an NLR ≥ 5 was selected as cutoff value for external validation. Multivariate analysis identified an increased NLR as an independent prognostic factor for clinical PFS [hazard ratio (HR) 3.09, 95 % CI 1.64-5.82, p0.001], DMFS (HR 3.51, 95 % CI 1.80-6.85, p0.001), and OS (HR 2.16, 95 % CI 1.17-3.99, p = 0.013).The NLR seems to represent an independent prognostic marker and should be considered for future individual risk assessment in patients with prostate cancer.

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.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.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 -634GC 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 -634GC 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).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.

C-reactive protein (CRP) is a sensitive marker of inflammation that has been linked with prognosis in various solid tumours. In the present study, we analysed the prognostic relevance of elevated plasma CRP levels in prostate cancer patients treated with radiotherapy.A total of 261 prostate cancer patients treated with 3D-conformal radiotherapy were evaluated retrospectively. Cancer specific survival (CSS), overall survival (OS) and clinical disease-free survival (DFS) were assessed using Kaplan-Meier analysis. To evaluate the independent prognostic significance of CRP plasma levels, multivariate Cox regression models were applied.The median follow-time was 80months. Applying receiver operating characteristics (ROC) analysis, the optimal cut-off level for the plasma CRP was 8.6mgl(-1). An elevated CRP level was associated with decreased CSS in univariate (hazard ratio (HR) 3.36, 95% confidence interval (CI) 1.42-7.91; p=0.006) and multivariate analysis (HR 4.31, 95% CI 1.22-15.1; p=0.023). Furthermore, a significant association with OS was detected in univariate (HR 2.69, 95% CI 1.57-4.59; p0.001) and multivariate analyses (HR 3.24, 95% CI 1.84-5.71, p0.001). Multivariate analysis also showed a significant association between plasma CRP and clinical DFS (HR 2.07, 95% CI 1.02-4.17; p=0.043).In the present study, an elevated plasma CRP (⩾8.6mgl(-1)) has been identified as a prognostic factor for poor CSS, OS and DFS in prostate cancer patients undergoing radiotherapy. The association between elevated CRP levels and poor prognosis was independent of other measures of prognosis such as tumour stage, Gleason grading and prostate specific antigen (PSA) level at diagnosis. If confirmed by additional studies, our findings may contribute to future individual risk assessment in prostate cancer patients.

Background: The elevation of the platelet-to-lymphocyte ratio (PLR), an easily applicable blood test based on platelet and lymphocyte counts has been associated with poor prognosis in patients with different types of cancer. The present study was aimed to investigate the prognostic significance of the preoperative PLR in a large cohort of breast cancer patients. Methods: Data from 793 consecutive non-metastatic breast cancer patients, treated between 1999 and 2004, were evaluated retrospectively. The optimal cutoff values for the PLR were calculated using receiver operating curve analysis. Cancer-specific survival (CSS), overall survival (OS) as well as distant metastasis-free survival (DMFS) were assessed using the Kaplan–Meier method. To evaluate the independent prognostic significance of PLR, multivariable Cox regression models were applied for all three different end points. Results: Univariable analysis revealed a significant association between the elevated preoperative PLR and CSS (hazard ratio (HR): 2.75, 95% confidence interval (CI): 1.57–4.83, P

The Transient Receptor Potential Channel Subunit 4 (TRPC4) has been considered as a crucial Ca\(^{2+}\) component in cardiomyocytes promoting structural and functional remodeling in the course of pathological cardiac hypertrophy. TRPC4 assembles as homo or hetero-tetramer in the plasma membrane, allowing a non-selective Na\(^{+}\) and Ca\(^{2+}\) influx. Gαq protein-coupled receptor (GPCR) stimulation is known to increase TRPC4 channel activity and a TRPC4-mediated Ca\(^{2+}\) influx which has been regarded as ideal Ca\(^{2+}\) source for calcineurin and subsequent nuclear factor of activated T-cells (NFAT) activation. Functional properties of TRPC4 are also based on the expression of the TRPC4 splice variants TRPC4α and TRPC4β. Aim of the present study was to analyze cytosolic Ca\(^{2+}\) signals, signaling, hypertrophy and vitality of cardiomyocytes in dependence on the expression level of either TRPC4α or TRPC4β. The analysis of Ca\(^{2+}\) transients in neonatal rat cardiomyocytes (NRCs) showed that TRPC4α and TRPC4β affected Ca\(^{2+}\) cycling in beating cardiomyocytes with both splice variants inducing an elevation of the Ca\(^{2+}\) transient amplitude at baseline and TRPC4β increasing the Ca\(^{2+}\) peak during angiotensin II (Ang II) stimulation. NRCs infected with TRPC4β (Ad-C4β) also responded with a sustained Ca\(^{2+}\) influx when treated with Ang II under non-pacing conditions. Consistent with the Ca\(^{2+}\) data, NRCs infected with TRPC4α (Ad-C4α) showed an elevated calcineurin/NFAT activity and a baseline hypertrophic phenotype but did not further develop hypertrophy during chronic Ang II/phenylephrine stimulation. Down-regulation of endogenous TRPC4α reversed these effects, resulting in less hypertrophy of NRCs at baseline but a markedly increased hypertrophic enlargement after chronic agonist stimulation. Ad-C4β NRCs did not exhibit baseline calcineurin/NFAT activity or hypertrophy but responded with an increased calcineurin/NFAT activity after GPCR stimulation. However, this effect was not translated into an increased propensity towards hypertrophy but rather less hypertrophy during GPCR stimulation. Further analyses revealed that, although hypertrophy was preserved in Ad-C4α NRCs and even attenuated in Ad-C4β NRCs, cardiomyocytes had an increased apoptosis rate and thus were less viable after chronic GPCR stimulation. These findings suggest that TRPC4α and TRPC4β differentially affect Ca\(^{2+}\) signals, calcineurin/NFAT signaling and hypertrophy but similarly impair cardiomyocyte viability during GPCR stimulation.

To the editorThe most common skeletal complication of breast can-cer is bone metastasis, which occurs in 80% of patientswith advanced disease [1, 2].The maintenance of skeletal integrity in a healthyindividual requires a balanced bone remodeling. Osteo-clast-mediated bone resorption is a common factor in thepathogenesis of osteoporosis and metastatic bone disease[3, 4]. Evidence is given, that tumor mediated osteoclastactivation disrupts the normal equilibrium of boneremodeling, allowing tumor cells to survive and grow inthis microenvironment [4, 5].A functional dimorphism, 13910 C/T (LCT) which isassociated with adult lactose intolerance, has been sug-gested as a possible risk factor for osteoporosis and bonefractures, particularly in postmenopausal women [6].In the present study, we investigated the impact of the13910 C/T LCT polymorphism on the risk of bonemetastasis in 500 breast cancer patients. Patient charac-teristics have been described previously [7]. The study wasperformed according to the Austrian Gene Technology Actand had been approved by the local ethics committee.Written informed consent was obtained from all subjects.LCT -13910 genotypes were determined as describedpreviously [7]. SPSS 14.0 for Windows was used for sta-tistical analysis. Continuous values were analyzed byStudent’s t-test, and proportions of groups compared by the