Functional Outcome and Complications following Ileal Neobladder Reconstruction in Male Patients without Tumor Recurrence. More than 35 Years of Experience from a Single Center.

PURPOSE: There is a lack of data on true long-term functional outcome of orthotopic bladder substitution. The primary study objective was to report our 35-year clinical experience. MATERIALS AND METHODS: Since October 1985, 259 male patients from a large single center radical cystectomy series with complete followup of more than 60 months (median 121, range 60-267) without recurrence, irradiation or undiversion that might have affected the functional outcome, were included. RESULTS: Median age at radical cystectomy and at survey was 63 (range 23-81) and 75 (range 43-92) years, respectively. Overall 87% of patients voided spontaneously and residual-free. This rate decreased with increasing age at the time of surgery (less than 50 years old 94%, 70 years old or older 82%). Overall day/nighttime continence rates were 90%/82%. These rates decreased with increasing age at the time of surgery from 100%/88% to 87%/80%. The overall pad-free rate was 71%/47%. Bicarbonate use decreased from 51% (5 years) to 19% (25 years). Patients with a followup of more than 20 years had the lowest rate of residual urine and clean intermittent catheterization (0.0%) as well as use of more than 1 pad at daytime/nighttime (6.3%/12.5%) and mucus obstruction (0.0%). Serum creatinine showed only the age related increase. The surgical complication rate was 27% and correlated inversely with functional results (chi-squared 11.227, p <0.005), even when the younger age at the time of surgery (younger than 60 years) was related to higher rates of surgical complications (chi-squared 6.80, p <0.05). CONCLUSIONS: The ileal neobladder represents an excellent long-term option for urinary diversion with an acceptable complication rate.

Genetic Variants of DICE1/INTS6 in German Prostate Cancer Families with Linkage to 13q14.

INTRODUCTION: Prostate cancer is the most frequent malignancy found to occur in Caucasian men, but its genetic basis remains elusive. A prostate cancer-susceptibility locus has been identified on chromosome 13q14. The tumour suppressor gene deleted in cancer cells 1 (DICE1/INTS6) is located within this interval on 13q14.3. MATERIALS AND METHODS: We performed mutation analysis of the DICE1/INTS6 gene in thirteen German prostate cancer families. RESULTS AND CONCLUSION: None of the patients harboured DICE1 mutations, and similar frequencies of the previously identified 13 bp deletion polymorphism in the DICE1 promoter were observed in the familial prostate cancer patients as compared with sporadic prostate cancer patients and controls. However, in one family with three affected brothers, the variations c.1215A>C (p.T405T) in exon 10 and c.2568A>G (p.S856S) in exon 17 were detected in a heterozygous pattern. In sporadic prostate cancer patients, variant c.2568A>G (p.S856S) was detected in 10/325 (3.08%) compared with 5/207 (2.42%) control samples (p > 0.05). We conclude that DICE1 appears to be involved in prostate cancer progression rather than in the initiation of prostate cancer.

Association of oncofetal protein expression with clinical outcomes in patients with urothelial carcinoma of the bladder.

PURPOSE: Oncofetal proteins are expressed in the developing embryo. Oncofetal protein expression correlates with the clinical outcome of nonmuscle invasive bladder urothelial carcinoma. IMP3, MAGE-A, glypican-3 and TPBG are oncofetal proteins that have not been well characterized in urothelial carcinoma of the bladder. MATERIALS AND METHODS: We investigated the expression of these 4 proteins and their association with clinical outcomes using tissue microarrays from 384 consecutive patients treated with radical cystectomy between 1988 and 2003 at 1 academic center. We stained for IMP3, MAGE-A, glypican-3 and TPBG. Univariable and multivariable Cox regression analyses were done to evaluate the association of oncofetal protein expression with disease recurrence and cancer specific mortality. RESULTS: IMP3, MAGE-A, glypican-3 and TPBG were expressed in 39.5%, 45%, 6% and 85% of urothelial bladder carcinomas, respectively. Expression was tumor specific and did not correlate with pathological features except for TPBG. At a median followup of 128 months 176 patients (46%) experienced disease recurrence, 175 (45.5%) had died of the disease and 96 (27.5%) had died of another cause. On univariable analysis IMP3 and MAGE-A expression was associated with an increased risk of disease recurrence (p <0.001 and 0.03) and cancer specific mortality (p = 0.004 and 0.03, respectively). On multivariable Cox regression analysis adjusted for the effects of standard clinicopathological features IMP3 and MAGE-A expression was independently associated with disease recurrence (p = 0.004, HR 1.55, 95% CI 1.15-2.11 and p = 0.02, HR 1.44, 95% CI 1.05-1.99, respectively) but not with cancer specific mortality. CONCLUSIONS: Oncofetal proteins are commonly and differentially expressed in urothelial carcinoma of the bladder compared to normal urothelium. IMP3 and MAGE-A expression was associated with disease recurrence and cancer specific mortality but glypican-3 and TPBG expression was not.

Protein kinase D2 is a crucial regulator of tumour cell-endothelial cell communication in gastrointestinal tumours.

BACKGROUND: Tumour angiogenesis is crucially dependent on the communication between the tumour and the associated endothelium. Protein kinase D (PKD) isoenzymes mediate vascular endothelial growth factor-A (VEGF-A) induced endothelial cell proliferation and migration and are also highly expressed in various tumours. AIM: To examine the role of PKDs for tumour proliferation and angiogenesis selectively in pancreatic and gastric tumours and in tumour-associated endothelium in vitro and in vivo. METHODS: PKD2 expression in human tumours was determined by immunohistochemistry. The effect of PKD2 depletion in endothelial cells by siRNAs was examined in sprouting assays, the chorioallantois model (CAM) and tumour xenografts. In murine endothelium in vivo PKD2 was knocked-down by splice switching oligonucleotides. Human PKD2 was depleted in xenografts by siRNAs and PKD2-miRs. PKD2 activation by hypoxia and its role for hypoxia-induced NR4/TR3- and VEGF-A promoter activity, expression and secretion was investigated in cell lines. RESULTS: PKD2 is expressed in gastrointestinal tumours and in the tumour-associated endothelium. Tumour growth and angiogenesis in the CAM and in tumour xenografts require PKD expression in endothelial cells. Conversely, hypoxia activates PKD2 in pancreatic cancer cells and PKD2 was identified as the major mediator of hypoxia-stimulated VEGF-A promoter activity, expression and secretion in tumour cells. PKD2 depletion in pancreatic tumours inhibited tumour-driven blood vessel formation and tumour growth in the CAM and in orthotopic pancreatic cancer xenografts. CONCLUSION: PKD2 regulates hypoxia-induced VEGF-A expression/secretion by tumour cells and VEGF-A stimulated blood vessel formation. PKD2 is a novel, essential mediator of tumour cell-endothelial cell communication and a promising therapeutic target to inhibit angiogenesis in gastrointestinal cancers.

Prostate carcinoma: diffusion-weighted imaging as potential alternative to conventional MR and 11C-choline PET/CT for detection of bone metastases.

In a technical development study approved by the institutional ethics committee, the feasibility of fast diffusion-weighted imaging as a replacement for conventional magnetic resonance (MR) imaging sequences (short inversion time inversion recovery [STIR] and T1-weighted spin echo [SE]) and positron emission tomography (PET)/computed tomography (CT) in the detection of skeletal metastases from prostate cancer was evaluated. MR imaging and carbon 11 ((11)C) choline PET/CT data from 11 consecutive prostate cancer patients with bone metastases were analyzed. Diffusion-weighted imaging appears to be equal, if not superior, to STIR and T1-weighted SE sequences and equally as effective as (11)C-choline PET/CT in detection of bone metastases in these patients. Diffusion-weighted imaging should be considered for further evaluation and comparisons with PET/CT for comprehensive whole-body staging and restaging in prostate and other cancers.

Membranous expression and prognostic implications of epidermal growth factor receptor protein in human renal cell cancer.

BACKGROUND: It has been indicated that altered expression of the epidermal growth factor receptor (EGFR) promotes the invasive and metastatic potential of a variety of human malignancies. Therefore, the aim of the present study was to determine EGFR expression in clear cell renal cell carcinomas (RCC) to evaluate its prognostic relevance for the clinical course of the disease. MATERIALS AND METHODS: EGFR protein expression, detected by immunohistochemistry and tissue microarray analysis (TMA), was investigated in a cohort of 149 randomly selected patients subjected to tumor nephrectomy for RCC. RESULTS: The tumor cells preferably exhibited a homogeneous membrane-bound reactivity for EGFR; EGFR overexpression was detected in 70 (47%) of the primary tumor specimens, but in only 12 (9%) of the benign tissue samples (p<0.0001; Fisher's t-test). Tumor-associated EGFR staining was stratified into three groups: I: low staining score (n=75, 50%); II: intense expression (n=56, 38%); and III: strong overexpression (n = 18, 12%). Strong reactivity for EGFR was identified as predicting the patients' survival both during uni- and multivariate analysis (p=0.03). Interestingly, the overall survival of the intense expression group surpassed even the low expression group (p=0.023). CONCLUSION: The observation that primary RCC specimens exhibit EGFR at higher levels when compared with benign renal parenchyma indicates its role in tumor development and progression. The availability of more refined prognostic factors would assist decision making in terms of the value of more aggressive treatment options for prognostically defined subgroups of patients. Additionally, if overexpression of EGFR identifies RCC with a more aggressive biological behavior, the latter receptor might serve as a novel target for a more effective therapeutical approach to RCC.

Loss of SPINK1 expression is associated with unfavorable outcomes in urothelial carcinoma of the bladder after radical cystectomy.

BACKGROUND: We assessed the association of serine protease inhibitor Kazal type I (SPINK1) expression with clinicopathologic outcomes in urothelial carcinoma of the bladder (UCB) patients treated with radical cystectomy (RC). MATERIALS AND METHODS: Tissue microarrays comprising 438 consecutive UCB patients treated with RC between 1988 and 2003 and 62 cases of normal urothelium controls were evaluated for SPINK1 protein expression by immunohistochemistry (IHC). Semiquantitative evaluation was performed by 2 pathologists blinded to clinical outcomes (loss of expression: <50% cells or intensity 0-2). RESULTS: In normal urothelium, SPINK1 expression was noted in umbrella cells of 32 of 62 controls (52%); 254 RC patients (57.9%) exhibited loss of SPINK1 expression. Loss of SPINK1 expression was significantly associated with higher pathologic stages (P = 0.002) and presence of lymph node metastasis (P = 0.04). At a median follow-up of 130 months (IQR: 98.4), loss of SPINK1 expression was associated with an increased risk of disease recurrence (P = 0.02) and cancer-specific mortality (P = 0.03). On multivariable analysis that adjusted for the effects of standard clinicopathologic parameters, SPINK1 was not an independent predictor of disease recurrence (P = 0.09) or cancer-specific mortality (P = 0.12). CONCLUSIONS: Over half of UCB patients treated with RC exhibit loss of SPINK1 expression. Loss of SPINK1 correlates with features of biologically aggressive UCB. Although SPINK1 expression did not have independent prognostic value in RC patients, it may serve as a biomarker for tumor staging and may be useful as an adjunct in clinical decision-making.

Frequent truncating mutations of STAG2 in bladder cancer.

Here we report the discovery of truncating mutations of the gene encoding the cohesin subunit STAG2, which regulates sister chromatid cohesion and segregation, in 36% of papillary non-invasive urothelial carcinomas and 16% of invasive urothelial carcinomas of the bladder. Our studies suggest that STAG2 has a role in controlling chromosome number but not the proliferation of bladder cancer cells. These findings identify STAG2 as one of the most commonly mutated genes in bladder cancer.

Metronomic treatment with low-dose trofosfamide leads to a long-term remission in a patient with docetaxel-refractory advanced metastatic prostate cancer.

The treatment of metastatic prostate cancer patients refractory to androgen withdrawal and docetaxel therapy is currently discouraging and new therapeutic approaches are vastly needed. Here, we report a long-term remission over one year in a 68-year-old patient with metastatic docetaxel-refractory prostate cancer employing low-dose trofosfamide. The patient suffered from distant failure with several bone lesions and lymph node metastases depicted by a (11) C-Choline positron emission tomography/computerized tomography (PET/CT). After initiation of trofosfamide 100 mg taken orally once a day we observed a steadily decreasing PSA value from initial 46.6 down to 2.1 mug/L. The Choline-PET/CT was repeated after 10 months of continuous therapy and demonstrated a partial remission of the bone lesions and a regression of all involved lymph nodes but one. Taken together we found an astonishing and durable activity of the alkylating agent trofosfamide given in a metronomic fashion. We rate the side effects as low and state an excellent therapeutic ratio of this drug in our patient.

Inhibition of glycogen synthase kinase-3 in androgen-responsive prostate cancer cell lines: are GSK inhibitors therapeutically useful?

The glycogen synthase kinase 3 (GSK-3) is a serine/threonine kinase widely expressed in mammalian tissues. Initially identified by its ability to modulate glycogen synthesis, GSK-3 turned out to be a multifunctional enzyme, able to phosphorylate many proteins, including members of the steroid receptor superfamily. Although GSK-3 was shown to phosphorylate the androgen receptor (AR), its effects on AR transcriptional activity remain controversial. Analysis of short hairpin RNA (shRNA)-mediated downmodulation of GSK-3 proteins in prostate cancer cells showed a reduction in AR transcriptional activity and AR protein levels. Pharmacological GSK-3 inhibitors such as the maleimide SB216763 or the aminopyrazole GSK inhibitor XIII inhibited AR-dependent reporter gene activity and AR expression in vitro. Analysis of androgen-induced nuclear translocation of the AR was performed in PC3 cells transfected with pAR-t1EosFP coding for EosAR, a green fluorescent AR fusion protein. When grown in presence of androgens, EosAR was predominantly nuclear. Incubation with SB216763 before and after androgen treatment almost completely reduced nuclear EosAR. In contrast, the thiazole-containing urea compound AR-A014418 increased rather than decreased AR-expression/function. Although not all GSK inhibitors affected AR-stability/function, our observations suggest a potential new therapeutic application for some of these compounds in prostate cancer.