Hossein Tezval

The involvement of altered corticotropin releasing factor receptor 2 expression in prostate cancer due to alteration of anti-angiogenic signaling pathways

Expression of urocortin (Ucn) in the human benign prostate and prostate cancer has been reported recently. Ucn binds and activates corticotropin releasing factor (CRF) receptor 1 (CRFR1) and 2 (CRFR2). Activation of CRFR2 has been shown to inhibit tumor growth by regulation of proliferation and apoptosis as well as suppression of vascularization. However, there is no report demonstrating expression profile of CRFR2 in normal prostate versus prostate cancer.

Neurofilament Heavy polypeptide CpG island methylation associates with prognosis of renal cell carcinoma and prediction of antivascular endothelial growth factor therapy response

Neurofilament Heavy polypeptid (NEFH) belongs to the group of type IV intermediate filament proteins. DNA methylation of the NEFH promoter and loss of expression have previously been shown to activate the AKT/β‐catenin pathway in tumor cells. When identifying hypermethylation of the NEFH CpG island (CGI) in renal cell cancer (RCC) we asked whether methylation could provide clinical or prognostic information for RCC and/or predict therapy response in patients with metastatic RCC (mRCC) undergoing antiangiogenic therapy. Relative methylation of the NEFH CGI was analyzed in 132 RCC samples and 83 paired normal tissues using quantitative methylation‐specific PCR. Results were statistically compared with tumor histology, clinicopathological parameters, progression‐free survival (PFS) as well as with overall survival (OS) in a subset of 18 mRCC patients following antiangiogenic therapy regimens. The NEFH CGI methylation demonstrated a tumor‐specific increase (P < 0.001), association with advanced disease (P < 0.001), and distant metastasis (P = 0.005). Higher relative methylation was also significantly associated with a poor PFS (HR = 8.6, P < 0.001) independent from the covariates age, gender, diameter of tumors, state of advanced disease, and local and distant metastasis. Median OS following targeted therapy was 29.8 months for patients with low methylation versus 9.8 months for the group with high methylation (P = 0.028). We identified NEFH methylation as a candidate epigenetic marker for prognosis of RCC patients as well as prediction of anti‐vascular endothelial growth factor‐based therapy response.

GATA5 CpG island hypermethylation is an independent predictor for poor clinical outcome in renal cell carcinoma

Transcriptional inactivation and CpG island (CGI) methylation of GATA transcription factor family members GATA3 and GATA5 have been reported for a few types of human cancer. Whether high-density CGI methylation of GATA3 or GATA5 is associated with the clinical course of patients with renal cell cancer (RCC) has not been clarified. Quantitative methylation-specific PCR assays were carried out to analyze 25 tumor cell lines including 6 RCC lines and 119 RCC and 87 adjacent normal tissues for the presence of densely methylated sequences. Methylation values were statistically compared with clinicopathological and recurrence-free survival (RFS) data for patients. Comparison of GATA3 and GATA5 methylation in different tumor cell lines revealed a marker-specific methylation characteristic with high and frequent signals for both methylation marks in RCC lines. GATA3 and GATA5 CGI relative methylation levels were found to be strongly associated with the state of metastasis (P=0.003 and P<0.001, respectively) and advanced disease (P=0.024 and P<0.001, respectively). Moreover, an independent decrease in RFS in Cox proportional hazard analysis was found for tumors exhibiting high GATA5 methylation (P<0.001, hazard ratio, 19.3; 95% confidence interval, 4.58–81.6). Epigenetic alterations in GATA family members may be associated with aggressive tumor phenotypes in RCC, and in the case of GATA5, may serve as a new independent molecular marker for aggressiveness and disease progression.

Reduced mrna expression level of corticotropin- releasing hormone-binding protein is associated with aggressive human kidney cancer

BackgroundSignificance 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.MethodsTumoral 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.ResultsWe 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).ConclusionsThe 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.

Role of free testosterone levels in patients with metastatic castration-resistant prostate cancer receiving second-line therapy

A range of new treatment options has recently become available for patients with advanced metastatic castration-resistant prostate cancer (mCRPC). Androgen deprivation therapy (ADT) with luteinizing hormone-releasing hormone is continued when performing chemotherapy or androgen deprivation with new second-generation therapeutic agents such as enzalutamide or abiraterone acetate. Despite the fact that free testosterone (FT) is the biologically active form, it is common practice that androgen suppression is monitored via total testosterone levels only. The aim of the present study was to evaluate the role of FT as a prognostic biomarker for cancer-specific survival (CSS) and its feasibility as an ADT monitoring biomarker in patients with mCRPC for the first time. The requirement for continued ADT in mCRPC patients is discussed within the basis of the current literature. A total of 34 patients with continuous measurements of FT levels and mCRPC status underwent therapy with docetaxel, abiraterone acetate, enzalutamide, cabozantinib, carboplatin or cabazitaxel. Data were obtained from the Departments of Urology and Urological Oncology, Hannover Medical School (Hannover, Germany) between March 2009 and April 2014. A cutoff point of 0.5 pg/ml was used to discriminate between patients according to FT levels. Statistical evaluation of CSS was performed by applying Kaplan Meier survival estimates, multivariate Cox regression analyses and log-rank tests. The median age of all 34 patients was 72 years (range, 51–86 years). The mean follow-up interval was 16.1 months (range, 0.7–55.6 months). Despite the fact that all patients were undergoing androgen deprivation, the mean serum FT levels for each patient varied; the mean FT concentration in the cohort was 0.328 pg/ml, ranging from 0.01–9.1 pg/ml. A notable difference with regard to CSS was observed for patients with regard to serum FT concentration; CSS was significantly longer for patients with a serum FT level below the cutoff level (43.6 vs. 17.3 months, respectively, P=0.0063). Upon multivariate Cox regression analysis, the mean FT concentration during treatment remained a significant prognostic factor for CSS (hazard ratio, 1.22; 95% confidence interval, 1.03–1.43; P=0.0182). In conclusion, in patients with mCRPC, the serum FT level is a strong predictor of CSS in patients under therapy with second-line anti-hormonal therapeutic medication and chemotherapy. It may be concluded that FT levels should be included into the routine control of androgen suppression while under treatment with ADT and second-generation hormonal therapy.

Decreased mRNA expression of GATA1 and GATA2 is associated with tumor aggressiveness and poor outcome in clear cell renal cell carcinoma

GATA-binding proteins 1 (GATA1) and 2 (GATA2) are zinc-finger transcription factors and belong to the GATA family proteins 1–6. GATA1 interacts with the TP53 tumor suppressor gene, and both GATAs have been shown to be involved in cell growth, apoptosis, and tumorigenesis of several solid tumors. GATA1 and GATA2 expression alterations are associated with poor survival and adverse clinicopathology in prostate and colorectal cancer, while the significance and prognostic value in clear cell renal cell carcinoma (ccRCC) has not been investigated as yet. We investigated relative messenger RNA (mRNA) expression levels of GATA1 and GATA2 in 77 ccRCC and 58 paired adjacent noncancerous renal tissues by quantitative real-time reverse-transcribed PCR. Relative mRNA expression levels were determined using the ΔΔCt method. GATA1 and GATA2 expression levels were significantly decreased in tumor tissues compared with normal tissues (p < 0.001, paired t test). In univariate logistic regression analysis, decreased GATA1 and GATA2 expression levels were associated with advanced tumor disease (p = 0.005 and 0.008), positive distant metastasis (p = 0.03 and 0.001), and lymph node metastasis status (p = 0.011 and 0.038). Reduced expression levels of GATA1 and GATA2 were associated with an increased risk of disease recurrence (p = 0.005 and 0.006; hazard ratio = 0.05 and 0.21). Pairwise bivariate analysis after adjusting for clinicopathological parameters revealed relative mRNA expression of GATA1, but not GATA2, as an independent candidate prognosticator for ccRCC. Our results support that GATA1 and GATA2 are involved in ccRCC tumor biology possibly affecting tumor development and aggressiveness.

The Influence of Skull Base Chordoma on Lower Urinary Tract Symptoms

OBJECTIVE To provide the first insights into the potential role of skull base chordoma, which causes brainstem compression in and around Barringtons nucleus and its effect on the micturition center. Chordoma is a rare malignant bone tumor that originates from the remnants of the embryonic notochord, which normally forms and dissolves during early fetal development. Although it is a slowly growing tumor, it displays local invasive growth. METHODS Urodynamic testing of 22 symptomatic patients was performed. All women and men with skull base chordoma treated in 2 hospitals in Germany between 1986 and 2007 were studied. Follow-up periods ranged from 6 months to 10 years. Lower urinary tract symptoms were documented in patients with acute brainstem compression because of local chordoma growth. RESULTS Of 74 patients treated, 22 (7 women, 15 men) with a median age of 37 years were evaluated with voiding diaries and computer urodynamic investigation. Urodynamic testing of 22 symptomatic patients revealed detrusor overactivity in 55%, low compliance bladder in 14%, detrusor-sphincter dyssynergia in 45%, and uninhibited sphincter relaxation in 27%. Despite the description of incomplete emptying and urgency, 4 patients had normal urodynamic findings (18%). Brain magnetic resonance images of the lesions of the symptomatic patients were obtained to determine the side of lesions. CONCLUSION The dorsolateral pons, including pontine reticular nucleus and the reticular formation and the locus coeruleus, seems to be mainly responsible for lower urinary tract symptoms in our patients with skull base chordoma and brainstem compression.

Pyelovenous backflow or veno-caliceal valve fistula?

A 70-year-old male with urinary bladder carcinoma was admitted for follow-up. Retrograde pyelography demonstrated transfer of contrast medium into the left renal vein in two independent sessions. The absence of hematuria and a negative CT scan ruled out a classical veno-caliceal fistula. The presence of a veno-caliceal valve fistula into the left renal vein was hypothesized.

Diarrhea and flatulence are major bowel disorders after radical cystectomy: Results from a cross-sectional study in bladder cancer patients

OBJECTIVES We had previously demonstrated changes in defecation after radical cystectomy (RC). Reports addressing long-term bowel disorders following RC are rare. This cross-sectional study evaluates long-term bowel issues in a large cohort. MATERIAL AND METHODS A questionnaire assessing changes in bowel function (diarrhea, constipation, urge to defecate, sensation of incomplete defecation, and flatulence) and its effect on quality of life was developed based on the gastrointestinal quality of life index and distributed in collaboration with the German bladder cancer support group. There were 431 evaluable questionnaires. For the analyses, we focused on patients that had the RC>1 year ago (n = 324). RESULTS Current bowel problems were reported by 42.6% of patients. The most frequent bowel problems were flatulence (48.8%), diarrhea (29.6%), and sensation of incomplete defecation (22.5%). In cases of bowel problems, 39.7% and 59.8% of the patients indicated life restriction and dissatisfaction, respectively. Prevalence of diarrhea and flatulence were significantly higher>12 (vs. ≤12) months following RC. Both symptoms significantly correlated with younger age at RC, life restriction, lower quality of life, lower health state, and lower energy level. Additionally, diarrhea significantly correlated with pouches as urinary diversion (vs. ileal conduit or ureterocutaneostomy) and higher dissatisfaction level. CONCLUSIONS To our knowledge this is the largest cohort evaluating long-term bowel symptoms after RC. Diarrhea is a prominent symptom after RC with a high impact on daily life that leads to dissatisfaction. A better understanding of long-term bowel symptoms could be translated into optimized surgical procedures, postoperative medication/nutrition, and patient education.

Massive Urogenitalblutung@@@Massive bleeding of the urogenital tract

Massive bleeding of the urogenital tract is, in the same way as acute bleeding from all other organs, a medical emergency and necessitates precise diagnostics and treatment. In this article the topic is addressed in four main categories: first the inflammatory causes are discussed, followed by surgical, traumatic and neoplastic causes of massive bleeding. Subsequently, the rare but clinically relevant causes of acute and massive bleeding are described.