Comprehensive geriatric assessment predicts radiation-induced acute toxicity in prostate cancer patients.

PURPOSE: The purpose of the present prospective study was to evaluate the significance of geriatric conditions measured by a comprehensive geriatric assessment (GA) for the prediction of the risk of high-grade acute radiation-induced toxicity. METHODS: A total of 314 prostate cancer patients (age ≥ 65 years) undergoing definitive radiotherapy at a tertiary academic center were included. Prior to treatment, patients underwent a GA. High-grade toxicity was defined as acute toxicity grade ≥ 2 according to standard RTOG/EORTC criteria. To analyze the predictive value of the GA, univariable and multivariable logistic regression models were applied. RESULTS: A total of 40 patients (12.7%) developed acute toxicity grade ≥ 2; high grade genitourinary was found in 37 patients (11.8%) and rectal toxicity in 8 patients (2.5%), respectively. Multivariable analysis revealed a significant association of comorbidities with overall toxicity grade ≥ 2 (odds ratio [OR] 2.633, 95% confidence interval [CI] 1.260-5.502; p = 0.010) as well as with high-grade genitourinary and rectal toxicity (OR 2.169, 95%CI1.017-4.625; p = 0.045 and OR 7.220, 95%CI 1.227-42.473; p = 0.029, respectively). Furthermore, the Activities of Daily Living score (OR 0.054, 95%CI 0.004-0.651; p = 0.022), social status (OR 0.159, 95%CI 0.028-0.891; p = 0.036), and polypharmacy (OR 4.618, 95%CI 1.045-20.405; p = 0.044) were identified as independent predictors of rectal toxicity grade ≥ 2. CONCLUSION: Geriatric conditions seem to be predictive of the development of high-grade radiation-induced toxicity in prostate cancer patients treated with definitive radiotherapy.

The Pre-Treatment Platelet-to-Lymphocyte Ratio as a Prognostic Factor for Loco-Regional Control in Locally Advanced Rectal Cancer.

Chronic inflammatory reactions have been proven to represent relevant mechanisms for the development and progression of cancer in numerous tumor entities. There is evidence that the platelet-to-lymphocyte ratio (PLR) is associated with the prognostic outcome. In rectal cancer, the prognostic role of this parameter has not yet been conclusively clarified. The aim of this study was to further clarify the prognostic significance of the pre-treatment PLR in patients with locally advanced rectal cancer (LARC). In the present study, 603 patients with LARC, who were treated with neoadjuvant chemoradiotherapy (nCRT) and subsequent surgical resection between 2004 and 2019, were retrospectively evaluated. The influence of clinico-pathological and laboratory factors on locoregional control (LC), metastasis-free survival (MFS) and overall survival (OS) was investigated. In univariate analyses, high PLR was significantly associated with worse LC (p = 0.017) and OS (p = 0.008). In multivariate analyses, the PLR remained an independent parameter for the LC (HR = 1.005, 95% CI: 1.000-1.009, p = 0.050). Pre-treatment lactate dehydrogenase (LDH) (HR: 1.005 95% CI:1.002-1.008; p = 0.001) and carcinoembryonic antigen (CEA) (HR: 1.006, 95% CI:1.003-1.009; p < 0.001) were independent predictors for MFS; additionally, age (HR: 1.052, 95% CI:1.023-1.081; p < 0.001), LDH (HR: 1.003, 95% CI:1.000-1.007; p = 0.029) and CEA (HR: 1.006, 95% CI:1.003-1.009; p < 0.001) independently predicted OS. Pre-treatment PLR before nCRT is an independent prognostic factor for LC in LARC, which could be used to further individualize tumor treatment.

The α2-isoform of the Na+/K+-ATPase protects against pathological remodeling and ß-adrenergic desensitization after myocardial infarction.

The role of the Na+/K+-ATPase (NKA) in heart failure associated with myocardial infarction (MI) is poorly understood. The elucidation of its precise function is hampered by the existence of two catalytic NKA isoforms (NKA-α1 and NKA-α2). Our aim was to analyze the effects of an increased NKA-α2 expression on functional deterioration and remodeling during long-term MI treatment in mice and its impact on Ca2+ handling and inotropy of the failing heart. Wild-type (WT) and NKA-α2 transgenic (TG) mice (TG-α2) with a cardiac-specific overexpression of NKA-α2 were subjected to MI injury for 8 wk. As examined by echocardiography, gravimetry, and histology, TG-α2 mice were protected from functional deterioration and adverse cardiac remodeling. Contractility and Ca2+ transients (Fura 2-AM) in cardiomyocytes from MI-treated TG-α2 animals showed reduced Ca2+ amplitudes during pacing or after caffeine application. Ca2+ efflux in cardiomyocytes from TG-α2 mice was accelerated and diastolic Ca2+ levels were decreased. Based on these alterations, sarcomeres exhibited an enhanced sensitization and thus increased contractility. After the acute stimulation with the ß-adrenergic agonist isoproterenol (ISO), cardiomyocytes from MI-treated TG-α2 mice responded with increased sarcomere shortenings and Ca2+ peak amplitudes. This positive inotropic response was absent in cardiomyocytes from WT-MI animals. Cardiomyocytes with NKA-α2 as predominant isoform minimize Ca2+ cycling but respond to ß-adrenergic stimulation more efficiently during chronic cardiac stress. These mechanisms might improve the ß-adrenergic reserve and contribute to functional preservation in heart failure.NEW & NOTEWORTHY Reduced systolic and diastolic calcium levels in cardiomyocytes from NKA-α2 transgenic mice minimize the desensitization of the ß-adrenergic signaling system. These effects result in an improved ß-adrenergic reserve and prevent functional deterioration and cardiac remodeling.

Can Pre-Treatment Inflammatory Parameters Predict the Probability of Sphincter-Preserving Surgery in Patients with Locally Advanced Low-Lying Rectal Cancer?

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 < 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.

The AST/ALT (De Ritis) Ratio Predicts Survival in Patients with Oral and Oropharyngeal Cancer.

Aminotransaminases, including aspartate aminotransaminase (AST) and alanine aminotransaminase (ALT), are strongly involved in cancer cell metabolism and have been associated with prognosis in different types of cancer. The purpose of the present study was to evaluate the prognostic significance of the pre-treatment AST/ALT ratio in a large European cohort of patients with oral and oropharyngeal squamous cell cancer (OOSCC). Data from 515 patients treated for OOSCC at a tertiary academic center from 2000-2017 were retrospectively analyzed. Levels of AST and ALT were measured prior to the start of treatment. Uni- and multivariate Cox regression analyses were applied to evaluate the prognostic value of the AST/ALT ratio for cancer-specific survival (CSS) and overall survival (OS), survival rates were calculated. Univariate analyses showed a significant association of the AST/ALT ratio with CSS (hazard ratio (HR) 1.71, 95% confidence interval (CI) 1.38-2.12; p < 0.001) and OS (HR 1.69, 95% CI 1.41-2.02; p < 0.001). In multivariate analysis, the AST/ALT ratio remained an independent prognostic factor for CSS and OS (HR 1.45, 95% CI 1.12-1.88, p = 0.005 and HR 1.42, 95% CI 1.14-1.77, p = 0.002). Applying receiver operating characteristics (ROC) curve analysis, the optimal cut-off level for the AST/ALT ratio was 1.44, respectively. In multivariate analysis, an AST/ALT ratio > 1.44 was an independent prognostic factor for poor CSS and OS (HR 1.64, 95% CI 1.10-2.43, p = 0.014 and HR 1.55, 95% CI 1.12-2.15; p = 0.008). We conclude that the AST/ALT ratio is a prognostic marker for survival in OOSCC patients and could contribute to a better risk stratification and improved oncological therapy decisions.

The Erythropoetin rs1617640 Gene Polymorphism Associates with Hemoglobin Levels, Hematocrit and Red Blood Cell Count in Patients with Peripheral Arterial Disease.

BACKGROUND: Erythropoietin has a pivotal role in erythropoiesis and angiogenesis. A common polymorphism (rs1617640, A > 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.

The decreased mean platelet volume is associated with poor prognosis in patients with oropharyngeal cancer treated with radiotherapy.

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.

Evaluation of Blood-based Biomarkers for Prediction of Response in Carboplatin-treated Metastatic Castration-resistant Prostate Cancer Patients.

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.

The Elevated Pre-Treatment C-Reactive Protein Predicts Poor Prognosis in Patients with Locally Advanced Rectal Cancer Treated with Neo-Adjuvant Radiochemotherapy.

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-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 1.006-1.023; p < 0.001), LC (HR 1.015, 95% CI 1.004-1.027; p = 0.009), MFS (HR 1.014, 95% CI 1.004-1.023; p = 0.004), and OS (HR 1.016, 95% CI 1.007-1.024; p < 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 1.106-3.919; p = 0.023 and HR 1.005, 95% CI 1.002-1.008; p < 0.001). Univariate analysis also revealed a significant association of the mrCRM (HR 2.089, 95% CI 1.052-4.147; p = 0.035) and CEA (HR 1.006, 95% CI 1.003-1.008; p < 0.001) with MFS. Age and CEA were prognostic factors for OS (HR 1.039, 95% CI 1.013-1.066; p = 0.003 and HR 1.005, 95% CI 1.002-1.008; p < 0.001). In multivariate analysis that included parameters with a p-level < 0.20 in univariate analysis, the pre-treatment CRP remained a significant prognostic factor for RFS (HR 1.013, 95%CI 1.001-1.025; p = 0.036), LC (HR 1.014, 95% CI 1.001-1.027; p = 0.031), and MFS (HR 1.013, 95% CI 1.000-1.027; 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.

Haptoglobin polymorphism and prostate cancer mortality.

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.

Clinical parameters predictive for sphincter-preserving surgery and prognostic outcome in patients with locally advanced low rectal cancer.

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 < cT) and 39 (23.8%) of these showed a complete histopathological response (ypT0 ypN0). In univariate analysis, age prior to treatment, Karnofsky performance status, clinical T-size, relative lymphocyte value, CRP value, and interval between nRCT and surgery, were significantly associated with sphincter-preserving surgery. In multivariate analysis, age (hazard ratio (HR) = 1.05, CI95%: 1.02-1.09, 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 Pre-Treatment C-Reactive Protein Represents a Prognostic Factor in Patients with Oral and Oropharyngeal Cancer Treated with Radiotherapy.

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 (≥5 mg/L) and normal CRP groups, according to pre-treatment plasma levels. An increased CRP level was significantly associated with shorter CSS (p < 0.001, log-rank test), as well as with shorter OS (p < 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) 1.08-2.35; p = 0.020) as well as for OS (HR 1.62, 95%CI 1.17-2.24; p = 0.004) and LC (HR 1.50, 95%CI 1.06-2.14; 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.

In Vivo Detection of Circulating Tumor Cells in High-Risk Non-Metastatic Prostate Cancer Patients Undergoing Radiotherapy.

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: 0-15 vs. 0-5; 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.

Relative telomere length and prostate cancer mortality.

PURPOSE: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: Longer leukocyte RTL predicts higher overall mortality in patients with PCa.

BCL2 genotypes and prostate cancer survival.

PURPOSE: The antiapoptotic B­cell 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.

Catch and Release: rare cell analysis from a functionalised medical wire.

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.

TRPC4α and TRPC4ß Similarly Affect Neonatal Cardiomyocyte Survival during Chronic GPCR Stimulation.

The Transient Receptor Potential Channel Subunit 4 (TRPC4) has been considered as a crucial Ca2+ 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 Ca2+ influx. Gαq protein-coupled receptor (GPCR) stimulation is known to increase TRPC4 channel activity and a TRPC4-mediated Ca2+ influx which has been regarded as ideal Ca2+ 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 TRPC4ß. Aim of the present study was to analyze cytosolic Ca2+ signals, signaling, hypertrophy and vitality of cardiomyocytes in dependence on the expression level of either TRPC4α or TRPC4ß. The analysis of Ca2+ transients in neonatal rat cardiomyocytes (NRCs) showed that TRPC4α and TRPC4ß affected Ca2+ cycling in beating cardiomyocytes with both splice variants inducing an elevation of the Ca2+ transient amplitude at baseline and TRPC4ß increasing the Ca2+ peak during angiotensin II (Ang II) stimulation. NRCs infected with TRPC4ß (Ad-C4ß) also responded with a sustained Ca2+ influx when treated with Ang II under non-pacing conditions. Consistent with the Ca2+ 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-C4ß 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-C4ß NRCs, cardiomyocytes had an increased apoptosis rate and thus were less viable after chronic GPCR stimulation. These findings suggest that TRPC4α and TRPC4ß differentially affect Ca2+ signals, calcineurin/NFAT signaling and hypertrophy but similarly impair cardiomyocyte viability during GPCR stimulation.

Vitamin D and prostate cancer prognosis: a Mendelian randomization study.

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. METHODS: To examine the hypothesized inverse relationship between vitamin D status and prostate cancer, we studied the association between this SNP and prostate cancer outcome in the prospective PROCAGENE study comprising 702 prostate cancer patients with a median follow-up of 82 months. RESULTS: GC rs2282679 genotypes were not associated with biochemical recurrence [hazard ratios (HR) 0.91, 95 % confidence interval (CI) 0.73-1.12; p = 0.36], development of metastases (HR 1.20, 95 % CI 0.88-1.63; p = 0.25) or overall survival (HR 1.10; 95 % CI 0.84-1.43; p = 0.50). CONCLUSIONS: A causal role of vitamin D status, as reflected by GC rs2282679 genotype, in disease progression and mortality in prostate cancer patients is unlikely.