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ABSTRACT: BACKGROUND: Significance of Urocortin (Ucn or UcnI), Ucn2, Ucn3 and their receptors, Corticotropin Releasing Factor Receptor 1 and 2 (CRFR1 and CRFR2), and the binding protein, Corticotropin-Releasing Hormone-Binding Protein (CRHBP) in oncology is growing rapidly. The objective of our study was to assess the expression of the CRHBP mRNA and protein in renal cancer. METHODS: Tumoral tissues of 78 patients with clear cell renal cell cancer and their corresponding normal tissues were analyzed using quantitative mRNA expression analysis for detection of mRNA expression level. Protein expression and tissue localization of CRHBP protein in renal specimens was evaluated using western blotting, immunohistochemistry and double immunofluorescence, respectively. RESULTS: We found an approx. 33 fold decrease of average CRHBP mRNA level in tumoral tissues compared to paired normal tissues (p<0.001). Diminished CRHBP mRNA expression was positively correlated with advanced, metastasized and higher stage of disease (p<0.001, p=0.026, p=0.028 respectively). CRHBP protein was detected in glomeruli and proximal tubules of normal kidney while none or weak immunopositivity was found in cc-RCC (p<0.001). CONCLUSIONS: The expression analysis of CRHBP shows that cc-RCC is characterized by a significant loss of CRHBP mRNA expression that furthermore is associated with a more aggressive state of tumors. Depletion of CRHBP proteins also indicate that the protein as part of the UCN system may be involved in renal carcinogenesis.
BMC Cancer 04/2013; 13(1):199. · 3.01 Impact Factor
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Tilman Todenhöfer, Jörg Hennenlotter,
Philipp Leidenberger,
Alexander Wald,
Andrea Hohneder,
Ursula Kühs,
Johannes Mischinger,
Stefan Aufderklamm,
Georgios Gakis,
Gunnar Blumenstock,
Arnulf Stenzl,
Christian Schwentner
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ABSTRACT: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: There is increasing evidence that the receptor activator of nuclear factor κB ligand (RANKL) pathway not only contributes to the development of bone metastases, but also influences tumour biology in earlier stages of cancer. The study shows that preoperative serum levels of RANKL and its inhibitor osteoprotegerin (OPG) have a prognostic impact in patients undergoing radical prostatectomy for clinically localized prostate cancer. Both high levels of RANKL and a higher RANKL/OPG ratio are independent predictors of early biochemical recurrence in these patients. OBJECTIVE: To assess the prognostic impact of proteins of the receptor activator of nuclear factor κB (RANKL) pathway in serum samples from patients undergoing radical prostatectomy. PATIENTS AND METHODS: We retrospectively determined soluble RANKL (sRANKL) and osteoprotegerin (OPG) by ELISA in serum samples of 178 patients undergoing radical prostatectomy between 2004 and 2006. Clinical and patient follow-up data were analysed using the Wilcoxon-Mann-Whitney test, the Kaplan-Maier method, and single variable or multifactorial Cox proportional hazards analysis. RESULTS: Higher serum sRANKL levels (P = 0.01), lower serum OPG levels (P = 0.01) and a higher sRANKL/OPG ratio (P = 0.004) were significant risk factors for biochemical recurrence (BCR). In multifactorial analysis, adjusted for the common risk factors for BCR, sRANKL and sRANKL/OPG ratio were confirmed as independent prognostic factors. Neither sRANKL nor OPG showed a clear association with histopathological factors such as pT stage, pN Gleason score or resection margin status, nor were they associated with prostate-specific antigen level. CONCLUSIONS: Greater activity of the RANKL pathway in the serum of patients with prostate cancer undergoing radical prostatectomy is a risk factor for BCR. The RANKL pathway seems to contribute to the biological behaviour of prostate cancer even at the organ-confined stage of the disease.
BJU International 01/2013; · 2.84 Impact Factor
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ABSTRACT: BACKGROUND: The sensitivity of cytology for the detection of urothelial carcinoma (UC) is limited. Newer methods such as fluorescence in situ hybridization (FISH), immunocytology (uCyt+), and protein markers have been developed to improve urine-based detection of UC. As only little is known regarding the combined application of these markers, we investigated whether combinations of 4 of the most broadly available tests (cytology, FISH, uCyt+, and nuclear matrix protein 22 [NMP22-ELISA]) may improve their diagnostic performance. METHODS: The study was comprised of 808 patients who were suspected of having UC. All patients underwent urethrocystoscopy and upper urinary tract imaging and, in the case of positive findings, transurethral resection/biopsy. FISH, uCyt+, cytology, and NMP22-ELISA were performed in all patients. RESULTS: UC was diagnosed in 115 patients (14.2%). Cytology and FISH were found to be the single tests with the best overall performance (area under the curve [AUC], 0.78/0.79). Combinations of 2, 3, and 4 markers were found to increase the AUC to various extents compared with the use of single markers. Combining cytology and FISH improved the sensitivity and performance (AUC, 0.83) compared with the single tests and identified 12 tumors that were not detected by cytology alone. The percentage of WHO grade 3/carcinoma in situ tumors not detected by cytology was reduced by 62.5% when FISH was performed in cytology-negative patients. The addition of uCyt+ as a third test further improved performance (AUC, 0.86), whereas the addition of NMP22-ELISA was not found to have any additional influence on the performance of the test combination. CONCLUSIONS: The results of the current study support the combined use of urine markers and may form the basis of further studies investigating whether risk stratification based on urine marker combinations may individualize diagnostic algorithms and the surveillance of patients suspected of having UC. Cancer (Cancer Cytopathol) 2012. © 2012 American Cancer Society.
Cancer Cytopathology 11/2012; · 3.33 Impact Factor
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ABSTRACT: BACKGROUND: Galactin-3 is a cell adhesion molecule involved in tumor progression. Our aim was to examine Gal-3 expression in tumor, benign tissue adjacent to the tumor (adjacent-benign) and benign prostate specimens and correlated it with biochemical recurrence. MATERIALS AND METHODS: Tissue microarrays were prepared from 83 tumor, 78 adjacent-benign and 75 benign tissues obtained from 83 patients undergoing prostatectomy for clinically localized prostate cancer. Tissues were stained using a Gal-3 antibody and immunohistochemistry. The staining was graded between 0 and 300 depending upon staining intensity and the area of staining. In 37 patients on whom there was follow-up (Mean: 57.8 months; Median: 68 months), staining intensity was correlated with biochemical recurrence. RESULTS: Gal-3 showed both nuclear and cytoplasmic localization in benign, adjacent-benign and tumor tissues. Median Gal-3 staining scores significantly decreased from benign (192.5) to adjacent-benign (148.8 p = 0.007) and to tumor (108.8; p < 0.0001) tissues. In univariate analysis, age (p = 0.028), Gleason sum (p = 0.007), T stage (p = 0.011), seminal vesicle invasion (p = 0.009), pre-operative prostate-specific antigen (p = 0.045) and Gal-3 staining in tumor tissues (0.018) significantly correlated with biochemical recurrence. In multivariate analysis, Gal-3 expression in tumor (p = 0.04), adjacent-benign (p = 0.037) and benign (p = 0.005) tissues significantly correlated with biochemical recurrence. Gal-3 staining in tumor tissues had 91.7 % sensitivity, 64 % specificity and 73 % accuracy in predicting biochemical recurrence. CONCLUSIONS: This is the first study that showed a decreasing gradient of Gal-3 expression in benign, adjacent-benign and tumor tissues. Gal-3 expression may be useful in predicting biochemical recurrence.
World Journal of Urology 08/2012; · 2.41 Impact Factor
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ABSTRACT: PURPOSE: To investigate whether a combined application of urine cytology (CYT) and molecular markers for bladder cancer (BC) can predict tumor aggressiveness. METHODS: The study comprised 2,113 patients who underwent urethrocystoscopy and transurethral resection of the bladder. CYT, fluorescence in situ hybridization (FISH), immunocytology (uCyt+) and nuclear matrix protein 22 test (NMP22-ELISA) were performed. Results of the individual tests and of a multi-marker panel were correlated with pT-stages and tumor grades. RESULTS: Five hundred and two of 2,113 (23.8 %) patients had BC. False-negative test rates of CYT (p < 0.001), FISH (p = 0.01) and NMP22-ELISA (p = 0.05) were lower in patients with muscle-invasive BC compared with patients with non-muscle-invasive BC. Furthermore, false-negative rates of CYT (p < 0.001), FISH (p = 0.0002) and NMP22-ELISA (p < 0.001) were lower in patients with G3/CIS compared with patients with G1-G2 BC. In patients with evidence of tumor in urethrocystoscopy, the presence of simultaneously positive CYT and NMP22 was associated with a 20-fold risk for G3/CIS (p < 0.0001). CONCLUSIONS: This is the first study investigating the combined use of four urine markers in addition to cystoscopy to predict tumor aggressiveness. Our results indicate that combined application of urine markers as an adjunct to cystoscopy may facilitate identification of patients harboring high-grade tumors.
Journal of Cancer Research and Clinical Oncology 08/2012; · 2.56 Impact Factor
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Tilman Todenhöfer, Jörg Hennenlotter,
Susan Feyerabend,
Stefan Aufderklamm,
Johannes Mischinger,
Ursula Kühs,
Valentina Gerber,
Jasmin Fetisch,
David Schilling,
Siegfried Hauch,
Arnulf Stenzl,
Christian Schwentner
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ABSTRACT: The Adnatest® system combines immunomagnetic enrichment of epithelial cells with polymerase chain reaction for prostate cancer (PC)-specific transcripts for the detection circulating tumor cells (CTCs). We evaluated the Adnatest® in patients with castration-resistant PC receiving docetaxel chemotherapy.
CTCs were assessed in 16 patients with castration-resistant PC before cycles one and three of chemotherapy. Furthermore, markers of stem cells and epithelial-mesenchymal transition were assessed. Treatment response was assessed by imaging and prostate-specific antigen measurements.
Before chemotherapy, 11 patients were Adnatest®-positive whereas five patients were Adnatest®-positive before cycle three. A positive Adnatest® correlated with radiological progression (p=0.02). Rates of disease progression in epidermal growth factor receptor (EGFR)-positive and -negative patients were 100% and 7.7% (p=0.03).
In this preliminary study, the Adnatest® detected CTCs in a considerable proportion of patients with castration-resistant PC. First data on certain markers (EGFR and aldehyd dehydrogenase 1) encourage future studies investigating transcripts predicting treatment response.
Anticancer research 08/2012; 32(8):3507-13. · 1.73 Impact Factor
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ABSTRACT: The loss of single cells from a tumour cell cluster marks an early event in the metastatic process of cancer progression. Although the metastatic cascade in prostate cancer is yet to be fully understood, monitoring circulating tumour cells (CTCs) and quantifying the load of tumour cell dissemination is currently being implemented into routine clinical practice for diagnosing minimal residual disease (MRD), estimating prognosis and monitoring treatment success. Current methods for enrichment of CTCs or disseminated tumour cells (DTCs) and detection of MRD rely on the expression of specific marker genes or proteins that might be altered during the process of tumour cell dissemination, therefore disrupting tumour cell detection. The tumour origin and malignant potential for metastasis of marker-positive cells is not yet clear. Some studies have demonstrated the potential of CTCs or DTCs as prognostic or predictive markers, leading to the increasing implementation of CTC measurement as an end point in clinical trials.
Nature Reviews Urology 07/2012; · 4.41 Impact Factor
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Tilman Todenhöfer, Jörg Hennenlotter,
Benjamin Joachim Schmiedel,
Andrea Hohneder,
Sabrina Grimm,
Ursula Kühs,
Helmut Rainer Salih,
Hans-Jörg Bühring,
Tanja Fehm,
Georgios Gakis,
Gunnar Blumenstock,
Stefan Aufderklamm,
David Schilling,
Arnulf Stenzl,
Christian Schwentner
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ABSTRACT: OBJECTIVES: The receptor activator of the NF-kB ligand (RANKL) pathway is a key mediator of prostate cancer (PC)-induced bone disease. However, little is known about this pathway in patients with non-metastatic PC. We aimed to investigate whether changes of RANKL, its inhibitor osteoprotegerin (OPG) and bone marrow-mesenchymal stromal cells (BM-MSCs) occur in PC patients without manifest bone metastases. PATIENTS AND METHODS: We determined OPG and soluble RANKL (sRANKL) in serum and corresponding bone marrow (BM) samples of 140 patients before radical prostatectomy by enzyme-linked immunosorbent assay (ELISA). As control serum samples of 50 patients with benign prostate hyperplasia were analyzed. BM mononuclear cells (BMNCs) of 16 PC patients were analyzed for expression of RANKL and CD271 (as marker for MSCs) by flow cytometry. RESULTS: PC patients had significantly lower serum levels of OPG compared to BPH patients (P = 0.007), whereas no differences were observed for serum sRANKL (P = 0.74). Both OPG and sRANKL concentrations of serum and corresponding BM samples correlated significantly (P < 0.0001 each). Interestingly, in PC patients, lower serum and BM OPG levels were associated with a higher proportion of BM-MSCs (P = 0.04 and 0.0016, respectively). No correlations were observed for sRANKL, OPG, BM-MSCs, and established risk parameters of PC. DISCUSSION: The results of the study indicate that localized PC is associated with early specific changes of the RANKL pathway in serum and bone marrow (BM). These changes might be part of the pre-metastatic niche of PC and implicate a potential benefit of RANKL inhibition in patients with localized PC. Prostate © 2012 Wiley Periodicals, Inc.
The Prostate 06/2012; · 3.48 Impact Factor
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Faranaz Atschekzei, Jörg Hennenlotter,
Stefanie Jänisch,
Annika Großhennig,
Wolfgang Tränkenschuh,
Sandra Waalkes,
Inga Peters,
Thilo Dörk,
Axel S Merseburger,
Arnulf Stenzl,
Markus A Kuczyk,
Jürgen Serth
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ABSTRACT: Loss of the secreted Fzd-related protein 1 (SFRP1) and concurrent alteration of the SFRP1/WNT pathway are frequently observed in human cancers such as in renal cell cancer (RCC). Whether methylation of a SFRP1 CpG island locus in normal human solid tissues is associated with increased tissue specific cancer risk has not been determined to date. Here we measure the cancer risk attributable to SFRP1 DNA methylation in renal tissue. Pyrosequencing of bisulfite treated DNA was used for a case-control study including 120 normal-appearing renal tissues of autopsy specimens and 72 normal-appearing tissues obtained from tumor adjacent areas, and a cross sectional study of 96 RCCs. Association of methylation with demographic risk factor age, clinicopathological parameters and course of patients was investigated. We show significant hypermethylation of a SFRP1 CpG island locus in normal-appearing renal tissues from RCC patients compared with normal-appearing autopsy kidney tissues. Inter quartile analysis revealed a 6-, 13- and 11-fold increased cancer risk for the second, third and fourth quartiles of methylation in the age matched subgroup of tissues (p = 0.001, p = 1.3E-6, p = 6.9E-6). Methylation in autopsy tissues increased with age and methylation in tumors was an independent predictor of recurrence free survival. SFRP1 DNA methylation, accumulates with age in normal-appearing kidney tissues and is associated with increased renal cancer risk, suggesting this CGI sub region as an epigenetic susceptibility locus for RCC. Our data underline the need to further analyze the tissue specific risks conferred by methylated loci for the development of human cancers.
Epigenetics: official journal of the DNA Methylation Society 05/2012; 7(5):447-57. · 4.58 Impact Factor
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Tilman Todenhöfer, Jörg Hennenlotter,
Ursula Kühs,
Valentina Gerber,
Georgios Gakis,
Ulrich Vogel,
Stefan Aufderklamm,
Axel Merseburger,
Judith Knapp,
Arnulf Stenzl,
Christian Schwentner
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ABSTRACT: BACKGROUND: Preclinical studies demonstrated effects of drugs inhibiting the mevalonate pathway including nitrogen-containing bisphosphonates (N-BPs) and statins on tumor growth and progression. The exact role of this pathway in prostate cancer (PC) has not been identified yet. Herein, we evaluate the expression of farnesyl pyrophosphate synthase (FPPS), the key enzyme of the mevalonate pathway, in PC. PATIENTS AND METHODS: Prostate cancer (PC) and benign prostate tissue of 114 men who underwent radical prostatectomy were constructed to a tissue microarray. Immunohistochemical staining of FPPS was quantified by the Remmele/Stegner immunoreactivity-score. Patients' clinical follow-up was assessed. IRS was correlated to pathological and clinical data. The impact of FPPS expression on clinical course was assessed univariate and multivariate. RESULTS: Mean IRS in PC and benign tissue was 5.7 (95% CI 5.0-6.5) and 2.6 (2.1-3.0, p < 0.0001). Mean IRS in PC tissue of patients with organ-confined and locally advanced disease (pT ≥ 3) was 5.09 (4.22-5.96) and 6.87 (5.57-8.17, p = 0.035). IRS of PC tissue significantly correlated with Gleason score (p = 0.03). Patients with PC tissue IRS >3 showed shorter recurrence-free survival compared to the remaining (p = 0.01). Increased FPPS expression is an independent risk factor for early biochemical recurrence (p = 0.032). CONCLUSIONS: This is the first study on FPPS in PC specimens. The association of FPPS with established histopathological risk parameters and biochemical recurrence implicates a contribution of the mevalonate pathway to PC progression. Further functional analysis is required to explore the role of this pathway in PC and to investigate whether FPPS expression affects the response of PC cells to N-BPs.
World Journal of Urology 03/2012; · 2.41 Impact Factor
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ABSTRACT: To evaluate the impact of inflammation and sampling on cytology, immunocytology, and fluorescence in situ hybridization (FISH) in comparison with NMP22 in hematuria patients. The specificity of urine markers for urothelial cancer is subject to exogenous factors. There is evidence that nuclear matrix protein 22 (NMP22) is influenced by urinary tract infection and instrumented urinary sampling (IUS).
Samples from 1386 patients with histologic work-up were included. Cytology, immunocytology, FISH, and NMP22-enzyme-linked immunosorbent assay were performed. The presence of inflammation was evaluated by microscopy. The method of urine sampling was recorded in all cases. Any type of urinary tract manipulation was considered as IUS. False-positive results were compared with regard to the presence or absence of inflammation and mechanical manipulation.
In all, 1050 (75.7%) patients had no evidence of urothelial cancer. NMP22 results were false positive in 74.3% and 38.4% of patients with and without IUS (P < .0001). False-positive test rates of cytology, immunocytology, and FISH were not increased after manipulation. Inflammation led to a rise in false-positive NMP22 test results (85.3% vs 61.4%, P < .0001). The presence of inflammation did not change the rate of false-positive cytology, immunocytology, and FISH results.
This is the first study to investigate the impact of inflammation and IUS on cell-based urine markers. In contrast to the protein test NMP22, these factors did not impair the performance of cell-based tests. Hence, patients with positive cytology, immunocytology, and FISH results should undergo diagnostic work-up, even in the case of concomitant inflammation or IUS.
Urology 03/2012; 79(3):620-4. · 2.43 Impact Factor
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ABSTRACT: What's known on the subject? and What does the study add? Metastatic spread to the regional lymph nodes (LNs) is the single worst predictor of survival in prostate cancer. Knowledge of the LN status is crucial, as the treatment strategy is substantially altered in non-organ-confined disease. Current routine pathological protocols for evaluation of LN resection specimens do not demand a minimum of cross-sections per LN to be examined. Depending on the LN size, usually one to two sections are examined. This might lead to underestimation of the true metastatic burden. The present study shows that additional examination of cross-sections in pelvic LNs and applying prostate cancer-specific cytokeratine immunostaining does not lead to significantly increased detection of prostate cancer metastases. However, the work-load and the expenses were significantly higher compared with routine evaluation.
To evaluate the diagnostic gain in the detection of lymph node (LN) metastases of prostate cancer and the additional expenses of histological step-section analysis, including immunohistochemistry compared with routine histopathological evaluation.
In a prospective study, 19 patients with prostate cancer at high risk of LN metastases (>cT2c and/or PSA level of >20 ng/mL and/or Gleason score >8) underwent sentinel-guided LN resection. All palpable LNs were submitted to step-section analysis in 200-µm sections and concomitant immunohistochemical staining for cytokeratine (AE1/AE3), in addition to routine histopathology of one or two haematoxylin and eosin-stained sections per LN. The number of positive LNs and LN-positive patients for each method was compared; additional expenses in labour time and material for the extended evaluation were estimated.
In all, 413 LNs were resected; 220 LNs were palpable and were included in the study. In seven of the 19 patients routine histopathological evaluation revealed LN metastases in 24 of 220 LNs (10.9%). Extended LN evaluation with step sectioning and cytokeratin immunohistochemistry did not reveal any additional patients with LN metastases. In one patient already diagnosed with LN metastases on routine histology, four additional LN metastases were detected upon extended LN evaluation. Three LNs of two patients, one of them pN0, contained disseminated tumour cells. Compared with conventional histological evaluation, serial-section analysis and immunohistochemistry increased expenses in materials and labour time 18.7-fold.
Serial-section analysis seems to have only a minimal diagnostic gain; however, valid conclusions cannot be drawn, as not all LNs were submitted to extended evaluation. Considering the additional expenses, extensive LN evaluation in prostate cancer cannot generally be recommended.
BJU International 02/2012; 110(6 Pt B):E166-71. · 2.84 Impact Factor
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Inga Peters,
Hendrik Eggers,
Faranaz Atschekzei, Jörg Hennenlotter,
Sandra Waalkes,
Wolfgang Tränkenschuh,
Anika Grosshennig,
Axel S Merseburger,
Arnulf Stenzl,
Markus A Kuczyk,
Jürgen Serth
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ABSTRACT: GATA5 CpG island (CGI) methylation and transcriptional inactivation is involved in colorectal and gastric cancer. Whether DNA methylation of GATA5 affects clinical pathology is still unclear. In the present study, we analysed, for the first time, CGI methylation in RCC and its association with clinicopathological parameters and progression-free survival of patients. We show for the first time GATA5 CGI hypermethylation in RCC. Moreover, we found out that increased methylation is statistically associated with status of metastasis, progressive disease and shortened progression-free survival. The present study underline the necessity for further functional investigations as well as prospective survival analyses to clarify whether GATA5 promoter methylation can provide independent information for future clinical management of patients with RCC.
To investigate whether GATA5 CpG island (CGI) methylation occurs in renal cell carcinoma (RCC) and is associated with clinical, histopathological characteristics or progression-free survival of patients.
Methylation was quantified in 117 RCC samples and 89 paired adjacent normal tissues using quantitative combined bisulphite restriction analysis (COBRA). COBRA was evaluated in advance by pyrosequencing analyses of control RCC cell lines (coefficient of correlation, R = 0.95). Statistical analyses were carried out using the paired t-test for matched tumour tissue (TU) and adjacent normal tissue (adN) samples, logistic regression for comparisons of independent sample groups and Cox regression for analysis of progression-free survival.
In the present study, we found a significant higher mean relative methylation in TU (20.4%) than in adN (7.9%, P < 0.001) in paired samples of all RCCs. Increased GATA5 methylation in tumours was associated with metastasis (P = 0.005) and decreased progression-free survival (P = 0.005, HR = 4.59) in the clear-cell RCC (ccRCC) group. CGI methylation in advanced ccRCCs (pT ≥3 and/or N1, M1 or G2-3/G3) exceeds those detected in localized tumours (pT ≤2, N0, M0, G1/G1-2) (27.8% vs 11.0%, P < 0.001).
The association of GATA5 hypermethylation with metastasis and progression-free survival of patients indicates that epigenetic alterations of GATA5 participate in renal cell carcinogenesis. Moreover, GATA5 CGI methylation could serve as a biomarker for tumour progression, although prospective and functional investigations are necessary to clarify whether independent information for future clinical management of patients with RCC can be obtained.
BJU International 01/2012; 110(2 Pt 2):E144-52. · 2.84 Impact Factor
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Martin Heni, Jörg Hennenlotter,
Marcus Scharpf,
Stefan Z Lutz,
Christian Schwentner,
Tilman Todenhöfer,
David Schilling,
Ursula Kühs,
Valentina Gerber,
Fausto Machicao,
Harald Staiger,
Hans-Ulrich Häring,
Arnulf Stenzl
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ABSTRACT: In different cancers types, insulin receptor isoform composition or insulin receptor substrate (IRS) isoforms are different to healthy tissue. This may be a molecular link to increased cancer risk in diabetes and obesity. Since this is yet unclear for prostate cancer, we investigated IR isoform composition and IRS balance in prostate cancer compared to benign and tumor adjacent benign prostate tissue and brought this into relation to cell proliferation.
We studied 23 benign prostate samples from radical cystectomy or benign prostatic hyperplasia surgery, 30 samples from benign tissue directly adjacent to prostate cancer foci and 35 cancer samples from different patients. RNA expression levels for insulin receptor isoforms A and B, IRS-1, IRS-2, and IGF-1 receptor were assessed by quantitative real-time RT-PCR. In addition, RNA- and protein expression of the cell cycle regulator p27(Kip1) was quantified by real-time RT-PCR and immunohistochemistry.
Insulin receptor isoform A to B ratio was significantly higher in cancer as well as in tumor adjacent benign prostate tissue compared to purely benign prostates (p<0.05). IRS-1 to IRS-2 ratios were lower in malignant than in benign prostatic tissue (p<0.05). These altered ratios both in cancer and adjacent tissue were significantly associated with reduced p27(Kip1) content (p<0.02). Interestingly, IGF-1 receptor levels were significantly lower in patients with type 2 diabetes (p = 0.0019).
We found significant differences in the insulin signaling cascade between benign prostate tissue and prostate cancer. Histological benign tissue adjacent to cancer showed expression patterns similar to the malignancies. Our findings suggest a role of the insulin signaling pathway in prostate cancer and surrounding tissue and can hence be relevant for both novel diagnostic and therapeutic approaches in this malignancy.
PLoS ONE 01/2012; 7(12):e50953. · 4.09 Impact Factor
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ABSTRACT: In hematuria cases urine based tests are used to detect bladder cancer, although the diagnostic yield remains insufficient due to influencing variables, including urinary tract infection. Many patients are elderly with renal insufficiency and have proteinuria as an additional influencing factor. To our knowledge no data are available on the accuracy of urine based bladder cancer tests in conjunction with renal function.
Urine samples of 449 patients with hematuria and histology were included in analysis. Cytology, fluorescence in situ hybridization, immunocytology and nuclear matrix protein 22 assay were done. Renal function was classified as normal, impaired or severely impaired based on serum creatinine, the glomerular filtration rate and proteinuria. False-positive rates were statistically compared in regard to renal function.
A total of 382 patients did not have bladder cancer. There was an increased false-positive rate for creatinine and the glomerular filtration rate. The nuclear matrix protein 22 test showed a 22.0% and 46.7% false-positive rate in the normal and limited function cohorts, respectively (p = 0.05). Similar trends were noted for proteinuria. Indeterminate significance was detected, separating those with severely impaired function for immunocytology and those in the normal group for fluorescence in situ hybridization (p = 0.08 and 0.06, respectively). Proteinuria was a significant factor for urine cytology with increased false-positive results in the absence of urinary tract infection (p = 0.0017 and 0.05, respectively).
To our knowledge this is the first study of renal function and the accuracy of urine based bladder cancer markers. Renal function influences the diagnostic yield. A decreased glomerular filtration rate was associated with increased false-positive nuclear matrix protein 22 results while proteinuria decreased urine cytology specificity. Renal function should be considered when urine based bladder cancer tests are interpreted.
The Journal of urology 11/2011; 187(1):68-73. · 4.02 Impact Factor
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Stefan Aufderklamm, Jörg Hennenlotter,
Tilman Todenhoefer,
Georgios Gakis,
David Schilling,
Ulrich Vogel,
Ursula Kuehs,
Johannes Dlugosch,
Judith Knapp,
Axel Merseburger,
Valentina Gerber,
Anna Ordelheide,
Joachim Hevler,
Arnulf Stenzl,
Christian Schwentner
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ABSTRACT: XPA-210 is a proliferation marker derived from Thymidine kinase-1. It is of clinical significance in kidney, breast, and bladder cancer. There are no data available for XPA-210 in prostate cancer (PC). Herein, we aim to determine the clinical usefulness of XPA-210 in PC.
In a retrospective study, cancer and benign tissue samples of 103 patients (median age 65 years, median PSA 9.04 ng/ml, median Gleason score 6) who underwent prostatectomy were constructed to a tissue micro array and stained for XPA-210. Semi-quantitative results were correlated with pathological and clinical data by Wilcoxon-Kruskall-Wallis and linear regression analysis. Expression levels in PC were correlated between the time of biochemical recurrence and the time to development of metastasis by the Kaplan-Meier method. Multivariate analysis was done to correlate those with the resection status.
Mean staining score was 0.51-0.14 for tumor and benign tissue (P < 0.0001). Tumor staining score was significantly associated with Gleason score <6/≥6 (P < 0.0001) and T2/T >2 (P = 0.0007). When dividing the tumor score by the mean value, higher expression of XPA-210 was associated with a shorter time to biochemical recurrence (P = 0.003) and time to development of metastasis (P = 0.0061). Tumor staining (P = 0.0371) was an independent prognostic factor for biochemical relapse regardless of resection status.
XPA-210 is a new tissue-based prognostic marker for prostate cancer histopathology. It reliably differentiates tumor and normal prostatic tissue predicting biochemical relapse and onset of metastatic disease. XPA-210 might be clinically useful for individual decision-making in PC-treatment.
World Journal of Urology 10/2011; 30(4):547-52. · 2.41 Impact Factor
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ABSTRACT: Virtual reality (VR) simulation has been known to shorten learning curves. The aim of this research was to determine whether VR transurethral bladder tumor resection (TURBT) with and without photodynamic diagnostic (PDD) can improve endourological skills in novice and trained endoscopists.
Residents without experience (n = 15) completed five 5-min white light VR-TURBT scenarios. The trained endoscopists (≥25 TURBTs; n = 15) performed five 5-min VR resections using white light and PDD cystoscopy. The VR-TURBT performance with the Uro-Trainer® (Karl Storz GmbH, Germany) was compared between the first and last 5 cases using computer-generated parameters [inspected area (%), resected tumor mass (%) and bleeding (ml)]. The trained endoscopists' parameters were compared with white light versus PDD-VR-TURBT.
Among novices, the inspected area increased from 36.8 (±12.9) to 54.3% (±7.3), p < 0.05. Significant improvements were noted for resection rates from 26.5 (±9.6) to 52.0% (±6.0), p < 0.05. Trained urologists showed superior inspection [52.2 (±3.4) vs. 62.7% (±4.3), p = 0.003] and resection rates [43.8 (±3.3) vs. 57.1% (±5.3), p = 0.002] with PDD.
The opportunity to evaluate objective patient-independent measurements establishes the Uro-Trainer as a beneficial tool in enhancing TURBT quality. Results demonstrated that novices improved their ability to perform complete resection, and the TURBT rates of trained urologists were superior in PDD compared with a white light setting.
Urologia Internationalis 08/2011; 87(2):138-42. · 0.99 Impact Factor
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Melanie Widenmeyer,
Heinrich Griesemann,
Stefan Stevanović,
Susan Feyerabend,
Reinhild Klein,
Sebastian Attig, Jörg Hennenlotter,
Dorothee Wernet,
Dmitri V Kuprash,
Alexei Y Sazykin,
Steve Pascolo,
Arnulf Stenzl,
Cécile Gouttefangeas,
Hans-Georg Rammensee
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ABSTRACT: CD4(+) T cells have been shown to be crucial for the induction and maintenance of cytotoxic T cell responses and to be also capable of mediating direct tumor rejection. Therefore, the anticancer therapeutic efficacy of peptide-based vaccines may be improved by addition of HLA class II epitopes to stimulate T helper cells. Survivin is an apoptosis inhibiting protein frequently overexpressed in tumors. Here we describe the first immunological evaluation of a survivin-derived CD4(+) T cell epitope in a multipeptide immunotherapy trial for prostate carcinoma patients. The survivin peptide is promiscuously presented by several human HLA-DRB1 molecules and, most importantly, is naturally processed by dendritic cells. In vaccinated patients, it was able to induce frequent, robust and multifunctional CD4(+) T cell responses, as monitored by IFN-γ ELISPOT and intracellular cytokine staining. Thus, this HLA-DR restricted epitope is broadly immunogenic and should be valuable for stimulating T helper cells in patients suffering from a wide range of tumors.
International Journal of Cancer 08/2011; 131(1):140-9. · 5.44 Impact Factor
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ABSTRACT: To investigate galectin-8 expression patterns in normal urothelium and bladder cancer specimens and to elucidate its prognostic value.
162 samples of non-muscle-invasive transitional cell carcinoma, 25 samples of muscle-invasive transitional cell carcinoma and 10 samples of normal urothelium were investigated by immunohistochemistry using tissue microarrays. Complete patient and tumor characteristics were compared with galectin-8 staining patterns. The likelihood of tumor recurrence and progression was analyzed based on a 3-year follow-up.
Loss of galectin-8 was associated with the likelihood of tumor recurrence in univariate (p < 0.05) and multivariate analyses (p < 0.01). No significance was observed for tumor progression. Patients whose specimens showed weak galectin-8 expression had a shorter recurrence-free interval (42 vs. 12 months; p < 0.01, log-rank test). All of the 10 normal urothelium samples showed high galectin-8 expression. Decreased staining was found to be associated with higher tumor stages and grades (p < 0.0001, one-way ANOVA). A significant difference was found comparing normal urothelium with any tumor stage (p < 0.01), pTa vs. pT1 tumors (p < 0.05) and non-muscle-invasive vs. muscle-invasive tumors (p < 0.0001).
Loss of galectin-8 might be an early step in the development of malignant lesions of the bladder and is a significant independent predictor of recurrence.
Urologia Internationalis 07/2011; 87(2):143-50. · 0.99 Impact Factor
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Sandra Waalkes,
Hendrik Eggers,
Hanna Blasig,
Faranaz Atschekzei,
Mario W Kramer, Jörg Hennenlotter,
Wolfgang Tränkenschuh,
Arnulf Stenzl,
Jürgen Serth,
Andres J Schrader,
Markus A Kuczyk,
Axel S Merseburger
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ABSTRACT: Caveolae play a significant role in disease phenotypes, such as cancer, diabetes, bladder dysfunction and muscular dystrophy. The aim of this study was to elucidate the expression of caveolin (CAV)1 in the development of renal cell cancer (RCC) and to determine a possible prognostic relevance for optimal clinical management.
109 RCC and 81 corresponding normal tissue specimens from the same kidney were collected from patients undergoing surgery for renal tumors and subjected to total RNA extraction. Quantification of CAV1 mRNA expression was performed using real-time reverse transcription PCR with three endogenous controls for renal proximal tubular epithelial cells and the ΔΔCt method for calculation of relative quantities. Expression levels were correlated to clinical variables.
Tissue-specific mean CAV1 expression was significantly increased in RCC compared with normal renal tissue (p = 0.0003; paired Wilcoxon rank sum test). CAV1 expression was increased 1.9-fold in clear cell RCC compared with papillary RCC (p = 1.48 × 10(-7); unpaired Wilcoxon rank sum test). Patients with advanced disease had higher CAV1 expression when compared with organ-confined disease (p = 0.019; unpaired Wilcoxon rank sum test). Moreover, mean tissue-specific CAV1 expression was increased in patients with distant metastasis at the time of diagnosis compared with patients without metastasis (p = 0.0058; unpaired Wilcoxon rank sum test).
To our knowledge, this is the first study to show that CAV1 mRNA expression, using quantitative real-time PCR, is significantly higher in RCC compared with normal renal tissue and increases with tumor stage. CAV1 mRNA expression might serve as a candidate biomarker for objective prognosis indicating RCC aggressiveness. Our data encourage further investigations to determine the role of CAV1 in RCC.
Biomarkers in Medicine 04/2011; 5(2):219-25. · 0.86 Impact Factor
