T. Jäger

The GNAS1 T393C Polymorphism Predicts Survival in Patients with Clear Cell Renal Cell Carcinoma

Purpose: G proteins mediate signaling from cell surface receptors to specific intracellular proteins. In vitro cancer cell line studies revealed a link between the Gαs protein and proapoptotic processes. We have recently shown that TT genotypes of the GNAS1 T393C polymorphism display increased transcription of Gαs and a more favorable clinical course in bladder and colorectal cancer patients compared both with TC or CC genotypes. Experimental Design: In the present study, 150 patients with clear cell renal cell carcinoma surgically treated by nephrectomy with curative intent were retrospectively genotyped to elucidate a potential association between T393C genotypes and clinical outcome. Results: The C-allele frequency in the renal cell carcinoma patient group was 0.51, which is not significantly different from that of a healthy blood donor group. Kaplan-Meier curves for tumor progression, development of metastasis, and tumor-related death showed a significant association of the T393C polymorphism with outcome (5-year cancer-specific survival rates: TT, 91%; TC, 81%; CC, 69%; P = 0.015). Multivariate Cox proportional analysis of a 10-year follow-up confirmed the T393C polymorphism as an independent prognostic factor in clear cell renal cell carcinoma. Homozygous CC patients were at highest risk for progression (hazard ratio, 2.48; P = 0.009) or tumor-related death (hazard ratio, 3.15; P = 0.018) compared with T-allele carriers. Conclusion: Our results show that besides tumor stage, lymph node status, and tumor grade, the GNAS1 T393C status is a novel independent host factor for disease progression in patients with clear cell renal cell carcinoma and provides further evidence for the T393C polymorphism as a general prognostic tumor marker.

Angiogenic Switch of Angiopietins-Tie2 System and Its Prognostic Value in Bladder Cancer

Purpose: Vascular endothelial growth factor (VEGF), angiopoietins (Ang-1 and Ang-2), and their receptor Tie2 are critically involved in both normal and pathologic angiogenesis. The aim of this study was to explore the role of Ang-1, Ang-2, VEGF, and Tie2 in the development and progression of bladder cancer as well as to examine their prognostic value in this tumor type. Experimental Design: Tumor samples of 113 bladder cancer patients, normal bladder epithelium of 5 noncancer patients, and two low-grade (UMUC3 and RT4) and two high-grade (J82 and T24) bladder cancer cell lines were analyzed by quantitative real-time PCR. The expression data were analyzed performing Wilcoxon rank-sum and Kaplan-Meier log-rank tests as well as univariate Cox analyses and Cox proportional hazards regression model. Results: In tissues of noninvasive bladder tumors, Ang-1 expression was significantly lower (P < 0.001), whereas VEGF expression was significantly higher (P = 0.031) than in normal bladder tissue. These findings were also confirmed at the protein level by immunohistochemistry. In contrast, Tie2 and Ang-2 abundance in tumor did not differ significantly from that in normal bladder tissue. Multivariate analysis identified Ang-2 as a strong and independent predictor of tumor recurrence [hazard ratio (HR), 10.18; 95% confidence interval (95% CI), 2.69-38.49; P < 0.001] and Tie2 expression as an independent favorable prognostic factor for both metastasis (HR, 0.31; 95% CI, 0.11-0.89; P = 0.029) and disease-specific survival (HR, 0.25; 95% CI, 0.10-0.62; P = 0.003). Conclusions: These data show the strongest change in expression of VEGF and Ang-1 in superficial bladder cancer in comparison with normal bladder epithelium and the invasive tumor stages. The prognostic significance of Ang-2 and Tie2 underlines the essential role of angiopoietins-Tie2 system in progression of bladder cancer.

Serum Levels of Angiogenic Factors and their Prognostic Relevance in Bladder Cancer

Angiogenesis plays a critical role in tumor growth. VEGF, angiopoietins (Ang-1, Ang-2) and their tyrosine kinase receptor Tie2 are major regulators of angiogenesis. The aim of this study was to evaluate the prognostic value of the serum levels of these factors in bladder cancer. We analyzed the serum samples of 117 bladder cancer patients and 64 healthy volunteers by enzyme linked immunosorbent assay (ELISA) for Ang-1, Ang-2, VEGF and the extracellular domain of Tie2. The statistical evaluation of the obtained data was performed via Kaplan–Meier log-rank test, univariate Cox analyses as well as Cox proportional hazards regression model. Serum Ang-1 levels of bladder cancer patients were significantly higher (p < 0.001), while soluble Ang-2 and Tie2 levels were significantly lower (p = 0.016 and p = 0.001 respectively) in patients than those in controls. Cox univariate analysis revealed high sTie2 serum level as a risk factor for metastasis and as a borderline significant risk factor for disease related death (p = 0.022 and p = 0.081 respectively). These correlations were independent from tumor stage and grade in a Cox multivariate model (p = 0.016 and p = 0.069). These data indicate that the serum levels of analyzed angiogenic factors do change characteristically in bladder cancer. The soluble extracellular serum level of Tie2 may provide a stage and grade independent diagnostic tool to select a high risk group of bladder cancer patients.

Validation of Circulating MMP-7 Level as an Independent Prognostic Marker of Poor Survival in Urinary Bladder Cancer

Molecular marker analyses aiming a more accurate disease characterization and risk stratification of cancer patients provided several promising marker candidates in the last few years. However, recent reviews underlined the paramount importance of validation, since many of the initially promising results could not be confirmed in independent patient cohorts. If serum or plasma is a more appropriate sample to test for prognostic markers is a matter of debate. We recently found serum MMP-7 levels to correlate with poor patients’ prognosis in urinary bladder cancer. In this study, we examined associations of the MMP-7 plasma levels with clinical follow-up data in an independent cohort of bladder cancer patients to validate our former results and to assess if plasma is also suitable for MMP-7 analysis. Plasma levels of 97 patients and 22 controls were analyzed, using enzyme-linked immunosorbent assay. Associations between MMP-7 plasma concentrations and clinical data were assessed applying both univariate and multivariate analysis. Plasma MMP-7 levels were significantly higher in patients than in controls. Similarly to our former findings in sera, high MMP-7 plasma levels proved to be significant and independent predictors of both overall and disease-specific survival. In addition, we observed a metastasis-specific difference in MMP-7 levels between serum and plasma. In summary, we confirmed the prognostic relevance of circulating MMP-7 levels in an independent cohort of patients and concluded that circulating MMP-7 levels may help to identify bladder cancer patients at high-risk of disease progression who could benefit from an adjuvant chemotherapy or from an extended lymph node dissection.

Urinary matrix metalloproteinase-7 level is associated with the presence of metastasis in bladder cancer

Study Type – Therapy (case series)
Level of Evidence 4

Does cigarette smoking influence the survival of patients with prostate cancer

ZusammenfassungDas Prostatakarzinom hat sich in den vergangenen Jahren weltweit zu einer der häufigsten Todesursachen entwickelt. Daher ist es wichtig, mögliche Risikofaktoren für diese maligne Tumorerkrankung zu ermitteln. Neben den Risikofaktoren, die zu einem erhöhten Erkrankungsrisiko führen, sollte das Augenmerk auch auf Faktoren gerichtet werden, die den Erkrankungsverlauf beeinflussen können. In unserer Untersuchung konnten wir einen signifikant schlechteren Erkrankungsverlauf für das Prostatakarzinom bei Patienten nachweisen, die zum Zeitpunkt der Erstdiagnose ihrer Tumorerkrankung Zigaretten rauchten. Trotz gleicher Ausgangsbedingungen bezüglich Staging, Grading und Ausgangs-PSA-Wert, haben die Raucher der untersuchten Gruppe ein 3fach erhöhtes Risiko, tumorbedingt zu versterben. Dieser Effekt ist möglicherweise auf durch das Rauchen ausgelöste Stoffwechselveränderungen zurückzuführen, die sowohl das Tumorwachstum als auch die Metastasenbildung begünstigen.AbstractIn the last few years, prostate cancer has become one of the most common causes of mortality worldwide. It is therefore important to detect possible risk factors for this malignant disease. Besides risk factors which increase incidence, attention should be paid to factors which have a possible influence on the course of the disease. In our analysis, we demonstrate a worse course for the disease in patients with prostate cancer who smoked cigarettes at the time of first diagnosis. In spite of comparable staging, grading and PSA values at the time of primary diagnosis, individuals who smoked had a threefold higher risk of dying from prostate cancer. This effect is probably caused by metabolic changes which are activated by cigarette smoking and promote tumor growth and the development of metastases.

Expression of splicing variants of the inhibitor of apoptosis livin in testicular germ cell tumors.

The inhibitor of apoptosis family member livin is expressed in several neoplasms but is absent in most benign tissues. Livin has therefore been evaluated as a diagnostic and prognostic marker and recently gained much attention as a target for tumor therapy. We evaluated the expression of livin splicing variants in 131 testicular germ cell tumors (TGCT) compared to 20 normal testicular tissue samples using dual-color real-time RT-PCR and Western blot analysis. Expression of livin β was detected in 51.9% and expression of the α-variant in 28.2% of the TGCT specimens. None of the splicing variants could be detected in normal testicular tissue. Livin α was only expressed in combination with the β-isoform, the respective expression levels being highly intercorrelated (Spearman’s correlation coefficient: ρ = 0.854). Livin expression was strongly related to TGCT differentiation but not to clinical tumor stage and patient age. The β-variant was expressed in 67.5% of seminomas but only in 27.1% of nonseminomatous germ cell tumors (NSGCT). Expression of the α-variant was detected in 38.5% of seminomas and in 10.4% of NSGCT. Among NSGCT, livin expression was confined to embryonal carcinomas (EC) and mixed NSGCT exclusively consisting of EC and seminoma elements. Our findings suggest livin to be implicated in testicular tumorigenesis and to be related to the histological TGCT subtype. Considering that livin expression is restricted to malignant testicular tissue, it appears reasonable to conduct further investigations regarding its targeted inhibition in TGCT.

Beeinflusst Rauchen das Überleben von Prostatakarzinompatienten

ZusammenfassungDas Prostatakarzinom hat sich in den vergangenen Jahren weltweit zu einer der häufigsten Todesursachen entwickelt. Daher ist es wichtig, mögliche Risikofaktoren für diese maligne Tumorerkrankung zu ermitteln. Neben den Risikofaktoren, die zu einem erhöhten Erkrankungsrisiko führen, sollte das Augenmerk auch auf Faktoren gerichtet werden, die den Erkrankungsverlauf beeinflussen können. In unserer Untersuchung konnten wir einen signifikant schlechteren Erkrankungsverlauf für das Prostatakarzinom bei Patienten nachweisen, die zum Zeitpunkt der Erstdiagnose ihrer Tumorerkrankung Zigaretten rauchten. Trotz gleicher Ausgangsbedingungen bezüglich Staging, Grading und Ausgangs-PSA-Wert, haben die Raucher der untersuchten Gruppe ein 3fach erhöhtes Risiko, tumorbedingt zu versterben. Dieser Effekt ist möglicherweise auf durch das Rauchen ausgelöste Stoffwechselveränderungen zurückzuführen, die sowohl das Tumorwachstum als auch die Metastasenbildung begünstigen.AbstractIn the last few years, prostate cancer has become one of the most common causes of mortality worldwide. It is therefore important to detect possible risk factors for this malignant disease. Besides risk factors which increase incidence, attention should be paid to factors which have a possible influence on the course of the disease. In our analysis, we demonstrate a worse course for the disease in patients with prostate cancer who smoked cigarettes at the time of first diagnosis. In spite of comparable staging, grading and PSA values at the time of primary diagnosis, individuals who smoked had a threefold higher risk of dying from prostate cancer. This effect is probably caused by metabolic changes which are activated by cigarette smoking and promote tumor growth and the development of metastases.

MMP-7-Bestimmung im Urin basierend auf Siliziumchiptechnologie

BACKGROUND Early detection of metastases in muscle-invasive bladder cancer is crucial. Current imaging techniques provide only limited sensitivity for the detection of low volume metastases. Molecular markers and new rapid analysis techniques are therefore needed to improve metastasis detection sensitivity. High urinary matrix metalloproteinase 7 (MMP 7) levels were previously shown to be correlated with the presence of lymph node metastases. In the present study we applied a new innovative antibody-based electrical biochip technology for the quantitative detection of urinary MMP 7. MATERIALS AND METHODS Preoperative urine samples were acquired from 30 bladder cancer patients (15xN0 and 15xN1-2) who underwent cystectomy because of muscle-invasive bladder cancer. In addition, urine samples of 15 age-matched healthy individuals were also collected. The MMP 7 analyses were performed using electrical biochip technology and a standard ELISA technique in parallel. RESULTS Urinary MMP 7 concentrations measured by biochip technology were significantly higher in patients with metastatic bladder cancer compared to those with organ-confined cancer. The sensitivity for the detection of lymph node metastases was over 70 % using the biochip technology. CONCLUSIONS These results confirm MMP 7 as a promising metastasis marker in bladder cancer. The new electrical biochip technology provides a rapid and reliable quantitative method for measurement of protein markers in urine.

Von der Markerexpression zur individuellen Prognoseabschätzung urothelialer Neoplasien

Urothelial carcinoma of the bladder is a tumor entity with a heterogenous clinical course. At one end of the spectrum, patients are treated for low-grade carcinomas, which are likely to reccur but show low rates of tumor progression. At the other end, patients suffer from noninvasive or early invasive high-grade carcinomas. In these cases, risk-adapted treatment decisions are more complicated. The following article gives an overview of research activities on bladder cancer with the aim to individualize treatment of patients with bladder cancer.