Stratification of high-risk prostate cancer into prognostic categories: a European multi-institutional study.

BACKGROUND: High-risk prostate cancer (PCa) is an extremely heterogeneous disease. A clear definition of prognostic subgroups is mandatory. OBJECTIVE: To develop a pretreatment prognostic model for PCa-specific survival (PCSS) in high-risk PCa based on combinations of unfavorable risk factors. DESIGN, SETTING, AND PARTICIPANTS: We conducted a retrospective multicenter cohort study including 1360 consecutive patients with high-risk PCa treated at eight European high-volume centers. INTERVENTION: Retropubic radical prostatectomy with pelvic lymphadenectomy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Two Cox multivariable regression models were constructed to predict PCSS as a function of dichotomization of clinical stage (< cT3 vs cT3-4), Gleason score (GS) (2-7 vs 8-10), and prostate-specific antigen (PSA; ≤ 20 ng/ml vs > 20 ng/ml). The first "extended" model includes all seven possible combinations; the second "simplified" model includes three subgroups: a good prognosis subgroup (one single high-risk factor); an intermediate prognosis subgroup (PSA >20 ng/ml and stage cT3-4); and a poor prognosis subgroup (GS 8-10 in combination with at least one other high-risk factor). The predictive accuracy of the models was summarized and compared. Survival estimates and clinical and pathologic outcomes were compared between the three subgroups. RESULTS AND LIMITATIONS: The simplified model yielded an R(2) of 33% with a 5-yr area under the curve (AUC) of 0.70 with no significant loss of predictive accuracy compared with the extended model (R(2): 34%; AUC: 0.71). The 5- and 10-yr PCSS rates were 98.7% and 95.4%, 96.5% and 88.3%, 88.8% and 79.7%, for the good, intermediate, and poor prognosis subgroups, respectively (p = 0.0003). Overall survival, clinical progression-free survival, and histopathologic outcomes significantly worsened in a stepwise fashion from the good to the poor prognosis subgroups. Limitations of the study are the retrospective design and the long study period. CONCLUSIONS: This study presents an intuitive and easy-to-use stratification of high-risk PCa into three prognostic subgroups. The model is useful for counseling and decision making in the pretreatment setting.

Pretreatment tables predicting pathologic stage of locally advanced prostate cancer.

BACKGROUND: Pretreatment tables for the prediction of pathologic stage have been published and validated for localized prostate cancer (PCa). No such tables are available for locally advanced (cT3a) PCa. OBJECTIVE: To construct tables predicting pathologic outcome after radical prostatectomy (RP) for patients with cT3a PCa with the aim to help guide treatment decisions in clinical practice. DESIGN, SETTING, AND PARTICIPANTS: This was a multicenter retrospective cohort study including 759 consecutive patients with cT3a PCa treated with RP between 1987 and 2010. INTERVENTION: Retropubic RP and pelvic lymphadenectomy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Patients were divided into pretreatment prostate-specific antigen (PSA) and biopsy Gleason score (GS) subgroups. These parameters were used to construct tables predicting pathologic outcome and the presence of positive lymph nodes (LNs) after RP for cT3a PCa using ordinal logistic regression. RESULTS AND LIMITATIONS: In the model predicting pathologic outcome, the main effects of biopsy GS and pretreatment PSA were significant. A higher GS and/or higher PSA level was associated with a more unfavorable pathologic outcome. The validation procedure, using a repeated split-sample method, showed good predictive ability. Regression analysis also showed an increasing probability of positive LNs with increasing PSA levels and/or higher GS. Limitations of the study are the retrospective design and the long study period. CONCLUSIONS: These novel tables predict pathologic stage after RP for patients with cT3a PCa based on pretreatment PSA level and biopsy GS. They can be used to guide decision making in men with locally advanced PCa. PATIENT SUMMARY: Our study might provide physicians with a useful tool to predict pathologic stage in locally advanced prostate cancer that might help select patients who may need multimodal treatment.

Prognostic factors of 'high-grade' Ta bladder cancers according to the WHO 2004 classification: are these equivalent to 'high-risk' non-muscle-invasive bladder cancer?

OBJECTIVE: To determine the impact of prognostic factors of a series of high-grade Ta non-muscle-invasive bladder cancers (NMIBCs) according to the new International Society of Urological Pathology (ISUP) 1998/WHO 2004 grading system (previously classified as either TaG2 or TaG3). METHODS: One hundred and thirty-one high-grade Ta (105 G2 and 26 G3) cases were identified after independent review by two pathologists. Univariable and multivariable Cox regression models addressed recurrence and progression-free survival. Progression was defined as appearance of any T ≥1 recurrence after complete TUR (type 1) or occurrence of T ≥2 (type 2). RESULTS: Ten-year recurrence, type-1 and type-2 progression-free survival were 60, 75 and 95%, respectively. The previous grading system (G3 vs. G2) significantly predicted type 1 progression in the univariate model only. In the multivariate model, Ki67 was the only independent predictor of progression according to both definitions (HR = 5.25, p = 0.002 and HR = 6.16, p = 0.03, respectively). CONCLUSIONS: High-grade Ta NMIBC as defined by the WHO 2004 grading system cannot be equated with high-risk NMIBC. The risk of progression to muscle-invasive disease (type 2) is low, more in keeping with an intermediate-risk category of NMIBC. The previous WHO 1973 subcategorization into G2 and G3 is of little help in the prediction of outcome. Ki67 is a strong independent predictor of progression worthy of consideration for a clinical setting.

125I brachytherapy for localized prostate cancer: a single institution experience.

AIMS AND BACKGROUND: To evaluate the clinical outcome of a cohort of localized prostate cancer patients treated with 125I permanent brachytherapy at the University of Turin. METHODS AND STUDY DESIGN: A retrospective analysis was carried out on 167 consecutive patients with early stage prostate adenocarcinoma who underwent 125I brachytherapy between January 2003 and December 2010. A minimum follow-up of ≥ 12 months was mandatory for inclusion. Biochemical disease-free survival (defined on the basis of the ASTRO definition and the ASTRO-Phoenix definition) was chosen as the primary end point. Secondary end points were gastrointestinal and genitourinary toxicity (acute and late, defined according to the RTOG scale). RESULTS: With a median follow-up of 42 months (range, 13.5-90.7), biochemical disease-free survival at 3 and 5 years was respectively 91.1% and 85.7%, according to the ASTRO definition and 94.5% and 85.1% according to ASTRO-Phoenix definition (for statistical purposes, only the ASTRO definition was used). Hormone treatment and nadir PSA (cutoff of 0.35 ng/ml) were the only factors affecting biochemical disease-free survival both on univariate (P = 0.02 and P = 0.001, respectively) and multivariate analysis (HR 0.024; P = 0.021 and HR 21.6; P = 0.006, respectively). Only 3.6% of patients experienced ≥ grade 3 acute urinary toxicity and 5% ≥ grade 3 late urinary toxicity. Prior transurethral prostate resection was the only independent predictor of grade 3 late urinary toxicity on multivariate analysis (HR 0.13; P = 0.009). CONCLUSIONS: This mono-institutional series confirmed that brachytherapy is an effective and safe treatment modality for localized prostate cancer, with acceptable short- and long-term morbidity rates.

Circulating immunosuppressive cells of prostate cancer patients before and after radical prostatectomy: profile comparison.

OBJECTIVES: A dendritic cell-based cancer vaccine has recently received Food and Drug Administration approval in the USA based on its ability to prolong the survival of prostate cancer patients with advanced disease. However, tumor-mediated immunosuppressive mechanisms might represent an obstacle to optimal performance of this therapy. We have recently shown that monocytes from the blood of prostate cancer patients can fully mature to dendritic cells only after the tumor is removed. Here, we have tested the hypothesis that these tumor-driven monocytes correspond to the recently described subset of CD14(+) HLA-DR(low) immunosuppressor cells. METHODS: Prostate cancer patients were studied before and 1 month after prostatectomy. Pre- and postsurgical patients with colorectal cancer were also included for comparison. Flow cytometric analysis was applied to define CD14(-) HLA-DR(low) CD33(+) CD11b(+) (myeloid) and CD14(+) HLA-DR(low) (monocytic) suppressor cells. Interferon-γ release was used to assess the immunocompetence of lymphocytes. RESULTS: In both prostate cancer and colorectal cancer patients, the percentage of CD14(+) HLA-DR(low) cells was several-fold higher compared with normal subjects. This was not the case for CD14(-) HLA-DR(low) CD33(+) CD11b(+) cells. Furthermore, postsurgical normalization of CD14(+) HLA-DR(low) cells only occurred in prostate cancer patients. In all patients, the interferon-γ response of T lymphocytes to phorbolmyristate acetate-ionomycin was higher compared with normal donors, but it was further increased after tumor ablation only in prostate cancer patients. CONCLUSIONS: The direct link between CD14(+) HLA-DR(low) increase and presence of primary tumor suggests a distinguishing immunosuppressive profile of prostate cancer. This observation supports the principle that the appropriate setting for prostate cancer vaccine therapy is a minimal disease status.

External validation of the preoperative Karakiewicz nomogram in a large multicentre series of patients with renal cell carcinoma.

PURPOSE: To perform a formal external validation of the preoperative Karakiewicz nomogram (KN) for the prediction of cancer-specific survival (CSS) using a large series of surgically treated patients diagnosed with organ-confined or metastatic renal cell carcinoma (RCC). METHODS: Patient population originated from a series of retrospectively gathered cases that underwent radical or partial nephrectomy between years 1995 and 2007 for suspicion of kidney cancer. The original Cox coefficients were used to generate the predicted risk of CSS at 1, 2, 5, and 10 years following surgery and compared to the observed risk of CSS in the current population. External validation was quantified using measures of predictive accuracy, defined as model discrimination and calibration. RESULTS: A total of 3,374 patients were identified. Relative to the original development cohort, the current sample population had a larger proportion of patients with localized (40.0 vs. 26.3 %, P < 0.001) and non-metastatic (92.2 vs. 88.1 %, P = 0.03) disease at presentation. Model discrimination for the prediction of CSS was 87.8 % (95 % CI, 84.4-91.4) at 1 year, 87.0 % (95 % CI, 84.4-89.5) at 2 years, 84.7 % (95 % CI, 82.3-87.1) at 5 years, and 85.9 % (95 % CI, 83.2-88.6) at 10 years. The relationship between predicted and observed CSS risk was adequate in the calibration plot. CONCLUSION: The use of the KN for the prediction of CSS in patients diagnosed with renal cell carcinoma was validated in the current study. In consequence, this tool may be recommended for routine clinical counseling in patients with various stages of RCC in the preoperative setting.

Prostate-specific antigen kinetics after I125-brachytherapy for prostate adenocarcinoma.

PURPOSE: To investigate a potential correlation between the achievement of a cut-off of nadir PSA (nPSA) after brachytherapy (BRT) with biochemical Disease-Free Survival (bDFS) and to define the rate of post-BRT PSA bounces. METHODS: Retrospective analysis was carried out in 105 consecutive patients affected with early-stage prostate adenocarcinoma who underwent (125)I BRT. Only patients with a minimum follow-up ≥24 months were included. Biochemical DFS was chosen as primary endpoint. RESULTS: At a median follow-up of 51.2 months, 3- and 5-year bDFS were 96.8 and 91.2%, respectively. Median time to biochemical failure (BF) was 54 months. By Kaplan-Meier analysis, patients achieving nPSA ≤ 0.35 ng/mL had significantly higher bDFS (3- and 5-year bDFS: 100 and 98.5 % vs. 83.3 and 66.7 %, respectively; p = 0.001). Bounce PSA occurred in 28.6% of patients, at a median time of 21.5 months. No BFs were observed in the bounce group. Achieving a nPSA ≤ 0.35 ng/mL was the only factor independently associated with long-term bDFS on both univariate (p = 0.000) and multivariate analysis (HR 3.82; p = 0.003). CONCLUSIONS: Patients attaining a nPSA ≤ 0.35 ng/mL are significantly more likely to experience long-term freedom-from-biochemical failure. Bounce PSA occurs in approximately 30% of patients. Time to onset of PSA increase seems the most reliable feature to distinguish bounce from failure. Tailored follow-up strategies are needed for patients at higher risk of recurrence, and caution is advised in interpreting an early increase in PSA levels in the first 24-30 months after BRT.

Identifying the best candidate for radical prostatectomy among patients with high-risk prostate cancer.

BACKGROUND: The current role of radical prostatectomy (RP) in patients with high-risk disease remains controversial. OBJECTIVE: To identify which high-risk prostate cancer (PCa) patients might have favorable pathologic outcomes when surgically treated. DESIGN, SETTING, AND PARTICIPANTS: We evaluated 1366 patients with high-risk PCa (ie, at least one of the following risk factors: prostate-specific antigen [PSA]>20 ng/ml, cT3, biopsy Gleason 8-10) treated with RP and pelvic lymph node dissection (PLND) at eight European centers between 1987 and 2009. A favorable pathologic outcome was defined as specimen-confined (SC) disease-namely, pT2-pT3a, node negative PCa with negative surgical margins. INTERVENTION: All patients underwent radical retropubic prostatectomy and PLND. MEASUREMENTS: Univariable and multivariable logistic regression models tested the association between predictors and SC disease. A logistic regression coefficient-based nomogram was developed and internally validated using 200 bootstrap resamples. The Kaplan-Meier method was used to depict biochemical recurrence (BCR) and cancer-specific survival (CSS) rates. RESULTS AND LIMITATIONS: Overall, 505 of 1366 patients (37%) had SC disease at RP. All preoperative variables (ie, age and PSA at surgery, clinical stage, and biopsy Gleason sum) were independent predictors of SC PCa at RP (all p≤0.04). Patients with SC disease had significantly higher 10-yr BCR-free survival and CSS rates than patients without SC disease at RP (66% vs 47% and 98 vs 88%, respectively; all p<0.001). A nomogram including PSA, age, clinical stage, and biopsy Gleason sum demonstrated 72% accuracy in predicting SC PCa. This study is limited by its retrospective design and by the lack of an external validation of the nomogram. CONCLUSIONS: Roughly 40% of patients with high-risk PCa have SC disease at final pathology. These patients showed excellent long-term outcomes when surgically treated, thus representing the ideal candidates for RP as the primary treatment for PCa. Prediction of such patients is possible using a nomogram based on routinely available clinical parameters.

Does kidney transplantation onto the external iliac artery affect the haemodynamic parameters of the cavernosal arteries?

Reduced cavernosal arterial inflow has been hypothesized to be the likely cause of erectile dysfunction after kidney transplants in recipients revascularized through end-to-end anastomosis to the internal iliac artery, suggesting that end-to-side anastomosis at the external iliac artery is preferable. The aim of this study was to prospectively evaluate the effect of the use of the external iliac artery on erectile function, hormone profiles and penile blood flow by evaluating changes in penile colour Doppler ultrasound parameters in a consecutive series of 22 recipients before and after end-to-side external iliac artery transplantation. The mean International Index of Erectile Function-Erectile Function (IIEF-EF) domain score decreased significantly 3 months after transplant (18.09±6.33 vs. 22.50±7.09, P=0.01). The reduction in peak systolic velocity (PSV) was significant for the cavernous artery homolateral to the side of transplant (42.60±18.77 vs. 52.01±19.91, P=0.01). The mean postoperative end diastolic velocity (EDV) did not differ significantly from the preoperative value (P=0.74). No statistical differences were found in the serum levels of testosterone or prolactin. Kidney grafts anastomosed at the external iliac artery produced significant (P=0.01) reductions in arterial inflow at the homolateral cavernosal artery that remained above the normal threshold. Whether these haemodynamic changes can explain the worsening of postoperative erectile function remains to be proven.

Retroperitoneal laparoscopic kidney biopsy: technical tips for a minimally invasive approach.

OBJECTIVES: Nowadays, ultrasound-guided percutaneous kidney biopsy (PKB) is the gold standard for renal biopsies. Nevertheless, PKB is still contraindicated by conditions such as bleeding diatheses, severe obesity, solitary kidney, uncontrolled hypertension, and previous failed attempts at PKB. In these cases, the laparoscopic approach may offer a valid and mini-invasive alternative to open biopsy. We describe our technique and report indications and outcomes of a consecutive series of retroperitoneal laparoscopic kidney biopsies (LKB). MATERIALS AND METHODS: In a retrospective review of patients who underwent LKB, we examined indications, outcomes, and complications, stratified according to the Clavien classification. RESULTS: In all, 40 patients underwent LKB between 2001 and 2010 (mean age 58.85 years, SD 10.87). Mean serum creatinine at surgery was 3.02 mg/dL. Indications for LKB included coagulopathy (30%), polycystic kidney or multiple renal cysts (30%), solitary kidney (12.5%), and morbid obesity (10%). All the biopsies were performed with a Trucut needle. All the procedures were successful and led to pathological diagnosis. The most common pathological findings were glomerulonephritis (47.5%) and glomerulosclerosis (27.5%). All biopsies were performed in less than 1 hour. Only three complications (7.5%) were reported: two grade I and one grade IIIa according to Clavien classification. In three selected cases, we used a particular "ready-to-laparo" open surgical technique, which allowed to view a part of kidney parenchima through the 10-mm incision made for the Hasson trocar sufficient for Trucut biopsies and hemostasis under direct vision. CONCLUSIONS: This study shows that LKB is a safe, effective, and minimally invasive procedure that allows direct control of hemostasis and lower risks of postoperative morbidity compared with open biopsy. When PKB is contraindicated, LKB should be the first-choice alternative.

[Alternative tests to PSA for prostate cancer diagnosis]. / Nuovi test in competizione con il PSA per la diagnosidel carcinoma prostatico.

Prostate specific antigen (PSA) is still the most useful tool to select the population requiring prostatebiopsy. The main downsides of PSA are an inadequate sensitivity to be used in screening and a low specificity for cancer detection. So far, a limited value for PSA derivates (velocity, density, free, proisoforms and doubling time) has been recognised. We present a short review of the literature describing a selection of the most promising alternatives to PSA being studied currently: PCA3, serum kallikreins, serum detectable prostate specific membrane antigen, the nuclear matrix protein EPCA, EPCA-2, prostatic acid phosphatase, urine detectable GSTP1, anti-AMACR antibodies, sarcosine, plasminogen activating urokinase, IGFBP, TGF beta 1,PSP94, IL6, plasmatic DNA, serum autoantibodies, neuroendocrine markers, proteomic analysis.

Is there a prostate-specific antigen upper limit for radical prostatectomy?

OBJECTIVE: • To assess the feasibility of radical prostatectomy (RP) in a series of patients with prostate cancer with very high prostate-specific antigen (PSA) levels by comparing the clinical outcomes of different PSA thresholds (20.1-50 ng/mL, 50.1-100 ng/mL and >100 ng/mL, respectively). PATIENTS AND METHODS: • Within a multicentre European retrospective database of 712 RP in patients with a baseline PSA level >20 ng/mL, we identified 48 patients with prostate cancer with a preoperative PSA level >100 ng/mL, 137 with a PSA level between 50.1 and 100 ng/mL and 527 with PSA values between 20.1 and 50 ng/mL. • Comparisons between groups were performed using chi-square test, analysis of variance and Kaplan-Meier analysis with log-rank test. RESULTS: • Ten-year projected cancer-specific survival (79.8% in the PSA >100 ng/mL group vs 85.4% in the PSA 50.1-99 ng/mL group vs 90.9% in the PSA 20.1-50 ng/mL interval; P = 0.037) but not overall survival (59.6% in the PSA >100 ng/mL group vs 71.8% in the PSA 50.1-99 ng/mL group vs 75.3% in the PSA 20.1-50 ng/mL interval; P = 0.087) appeared significantly affected by the different PSA thresholds. • At a median follow-up of 78.7 months, 25.8%, 6.6% and 8.3% of patients in the PSA level groups for 20.1-50 ng/mL, 50.1-100 ng/mL and >100 ng/mL respectively, were cured by surgery alone. CONCLUSIONS: • Ten-year cancer-specific survival, while showing significant reduction with increasing PSA values intervals, remain relatively high even for PSA levels >100 ng/mL. • As part of a multimodal treatment strategy, RP may therefore be an option, even in selected patients with prostate cancer whose PSA level is >100 ng/mL.

Pathological features and adverse prognosis of a contemporary series of neuroendocrine bladder tumours.

OBJECTIVE: Neuroendocrine bladder tumours are rare entities known for their aggressive behaviour. The aim of this study was to retrospectively evaluate the outcome of a contemporary series of 14 consecutive bladder neuroendocrine neoplasms observed at 2 institutional hospitals. MATERIALS AND METHODS: The charts of patients with a pathological diagnosis of neuroendocrine bladder tumours observed at 2 institutions in the last 5 years were reviewed. Fourteen cases were retrieved. The main endpoint was to evaluate the pathological features and the cancer-specific survival (CSS) of the cohort. Subanalysis of survival based on the type of treatment received was attempted. RESULTS: Mean age was 70.2 years. The rate of metastatic disease at diagnosis was 57.1%. Mean follow-up was 13.7 months (95% CI 5.1-22.3). The 6-month CSS rate was 57.1%, while the 2-year CSS rate was 21.4%. CSS and overall survival rates overlapped. The median survival for the cohort was 7 months. There was no statistically significant difference in survival between patients who underwent surgery and those who did not. CONCLUSION: Neuroendocrine bladder tumours remain a disease with an extremely unfavourable prognosis. The impact of radical surgery on survival remains questionable. Patients harbouring this rare bladder cancer should be referred for trials assessing neoadjuvant and adjuvant systemic treatment strategies.

Are referral centers for non-muscle-invasive bladder cancer compliant to EAU guidelines? A report from the vesical antiblastic therapy Italian study.

INTRODUCTION: Adherence to international guidelines is viewed as a prerequisite for optimal medical care delivery. Previously reported surveys for non-muscle-invasive bladder cancer (NMIBC) employed mailed questionnaires to urologists or patients resulting in conflicting degrees of agreement with existing guidelines. In the current study, contemporary information on the management of NMIBC was generated from a sample of italian centers. PATIENTS AND METHODS: Eight Italian referral centers for the treatment of NMIBC were asked to collect information relative to all consecutive patients with a histology-proven NMIBC undergoing a transurethral resection from January 1 to March 31, 2009. The primary study objective was to verify the level of adherence of disease management with European guidelines. RESULTS: 344 patients resulted in being evaluable. 49.2% of high-risk patients underwent a repeat transurethral resection. Bacillus Calmette-Guérin was employed in 35% of cases, while chemotherapy was in 22%. An early single regimen was adopted in 136 patients and only in 1 out of 3 low-risk patients. High-risk NMIBC received bacillus Calmette-Guérin and chemotherapy as first-line therapy in 66 and 12.5% respectively. After 3 months, cystoscopy had been reported for 82.5% of patients with a recurrence rate of 13%. CONCLUSION: Adherence of Italian Institutions to EAU guidelines was optimal when reporting baseline variables. Significant degrees of discrepancy emerged in treatment choices.

Prostatectomy restores the maturation competence of blood dendritic cell precursors and reverses the abnormal expansion of regulatory T lymphocytes.

OBJECTIVE: To verify the presence of deviated dendritic cell (DC) precursors and of suppressor lymphocytes (Treg) in tumor bearing prostate cancer (PCa) patients and to monitor the corrective effect of tumor ablation. METHODS: Monocytes isolated from the blood of patients before and 1 month after prostatectomy were allowed to reach complete maturation (mDC) ex vivo in a clinical grade two-step process. T-regulatory cells were identified in the lymphocyte cell fraction by the CD4(+)CD25(high)FoxP3(+)/CD4(+)CD25(high)CD127(low/-) phenotype. RESULTS: Despite loss of the monocytes marker CD14, cytokine-matured DCs of tumor bearing patients expressed lower levels of the costimulatory molecule CD80 and of the maturation markers CD83 and CCR7 compared to mDC of normal subjects (NS, P = 0.001, 0.001, and 0.008, respectively). Prostatectomy restored CD80, CD83, and CCR7 expression to values not different from those of NS (P = 0.15, 0.60, and 0.71) and significantly higher than those of the pre-surgery state (CD83, P = 0.0003 and CCR7, P = 0.002). The frequency of Tregs, identified as either CD4 + CD25(high)FoxP3(+) or CD4(+)CD25(high)CD127(low/-), was significantly higher in pre-surgery patients than in NS (P = 0.0001 and 0.0003) and significant recovery of the CD4(+)CD25(high)CD127(low/-) (P = 0.0005) was observed after surgery. CONCLUSIONS: The presence of defective DC precursors and suppressor lymphocytes in the tumor-bearing, but not tumor-free stage, positions the latter as the ideal setting for clinical success of PCa vaccine therapy.

Pharmacokinetic study to optimize the intravesical administration of gemcitabine.

OBJECTIVES: To assess in a phase II pharmacokinetic study whether different pH levels, dilution volumes and exposure times affect intracellular bioavailability and systemic absorption of gemcitabine. SUBJECTS AND METHODS: Six arms of three patients each with a non-muscle-invasive bladder cancer (NMIBC) were planned to receive six combinations of two different dilution volumes (50 mL vs 100 mL), two pH levels (2.5-3.5 vs 5.5) and two exposure times (1 h vs 2 h) of the study drug. Blood samples were taken before, during and 1 h after drug instillation. Cold biopsy specimens from the exophytic tumor, its base of implant and a macroscopically healthy mucosa were taken during transurethral resection. High-pressure liquid chromatography/high-resolution mass spectrometry (HPLC/HRMSn) analysis of plasma and tissue samples was used to determine concentrations of gemcitabine (dFdC) and its inactive metabolite (dFdU). RESULTS: The arm at pH 5.5 in 50 mL was withdrawn as 2000 mg dFdC are insoluble in these conditions. The different instillation conditions resulted in negligible plasma dFdC concentrations but significant differences in intracellular content and metabolism of dFdC. The lowest intratissue concentration of dFdC was detected in a 50 mL solution at a pH of 2.5-3.5 kept in the bladder for 1 h (standard arm). A pH 5.5 solution in 100 mL with a 2-h exposure favored the maximal intratumoral dFdC absorption which was 90 times higher than that recorded in the standard arm. CONCLUSIONS: The most commonly reported administration scheme of gemcitabine produced the lowest tissue bioavailability of dFdC. Other combinations of pH, dilution volume and duration of instillation proved more advantageous and merit testing in clinical trials.

The hidden life of NAD+-consuming ectoenzymes in the endocrine system.

Ectoenzymes are a family of cell surface molecules whose catalytic domain lies in the extracellular region. A subset of this family, nucleotide-metabolizing ectoenzymes, are key components in the regulation of the extracellular balance between nucleotides (e.g. NAD(+) or ATP) and nucleosides (e.g. adenosine). Their substrates and products are signalling molecules that act by binding to specific receptors, triggering signals that regulate a variety of functions, ranging from the migration of immune cells, to synaptic transmission in the brain, to hormone/receptor interactions in the glands. Almost two decades of accumulated data indicate that these regulatory processes significantly affect the endocrine system, a tightly controlled information signal complex with clear evidence of fine regulation. Functional models discussed in this review include insulin secretion, bone modelling and the association between hormones and behaviour. The emerging pattern is one of a system operating as a scale-free network that hinges around hubs of key molecules, such as NAD(+) or ATP. The underlying natural link between nucleotides, ectoenzymes and the endocrine system is far from being clearly demonstrated. However, the body of evidence supporting the existence of such connection is growing exponentially. This review will try to read the available evidence in a hypothesis-oriented perspective, starting from the description of NAD(+) and of ecto- and endoenzymes involved in its metabolism.

Outcome predictors of radical prostatectomy in patients with prostate-specific antigen greater than 20 ng/ml: a European multi-institutional study of 712 patients.

BACKGROUND: Prostate cancer (PCa) patients with pretreatment prostate-specific antigen (PSA) >20 ng/ml have a high risk of biochemical and clinical failure and even cancer-related death after local therapy. Pretreatment predictors of outcome after radical prostatectomy (RP) in this patient group are necessary. OBJECTIVE: Our aim was to assess how the use of additional high-risk factors (biopsy Gleason score [bGS] > or = 8 or clinical stage 3-4) can improve prediction of treatment failure and cancer-related death after RP in patients with PSA >20. DESIGN, SETTING, AND PARTICIPANTS: In a retrospective multicentre cohort study from six European centres between 1987 and 2005, 712 patients with PSA >20 ng/ml underwent RP and bilateral pelvic lymphadenectomy. MEASUREMENTS: Subgroups were analysed to determine the relationship between the number of high-risk factors and histopathology, biochemical progression-free survival, clinical evidence of progressive disease, prostate cancer-specific mortality (PCSM), and overall mortality. Kaplan-Meier analysis with log-rank test and Cox multivariable analysis were applied. RESULTS AND LIMITATIONS: Median follow-up was 77 mo. The number of high-risk factors was significantly associated with unfavourable histopathology. Among patients with only PSA >20 ng/ml, 33% had pT2 PCa, 57.9% had bGS <7, 54% had negative surgical margins, and 85% were lymph node negative (pN0), whereas among patients with all three high-risk factors, 4.5% had pT2 PCa, 2.3% had bGS <7, 20.5% had negative margins, and 49% were pN0 (p<0.001). The strongest predictor of progression and mortality was bGS. PSA >20 ng/ml associated with bGS < or =7 resulted in 10-yr PCSM of 5%; when associated with bGS > or =8, PCSM was 35%. The main limitations of the study were retrospective design and varying treatment modalities. CONCLUSIONS: PCa patients with PSA >20 ng/ml have varying risk levels of disease progression and PCSM. Considering additional risk factors further stratifies this group into four subgroups that can guide the clinician in preoperative patient counselling.

Primary bladder phaeochromocytoma diagnosed by a vet.

Bladder phaeochromocytomas are rare neuroendocrine neoplasms whose diagnosis can be missed in spite of their rather suggestive presentation. It is mandatory to collect a thorough medical history and to recognize their typical symptoms. This study reports the case of a woman, treated for hypertensive crisis, who was diagnosed with bladder phaeochromocytoma thanks to a vet noting her fainting after micturition.

ERCC1 haplotypes modify bladder cancer risk: a case-control study.

Bladder cancer risk is highly influenced by environmental and/or predisposing genetic factors. In the last decades growing evidence of the major role played by DNA repair systems in the developing of bladder cancer has been provided. To better investigate the involvement of DNA repair genes previously reported to be significantly associated with bladder cancer risk, we examined in a case-control study (456 cases and 376 hospital controls) 36 single nucleotide polymorphisms (SNPs) in 10 DNA repair genes, through a better gene coverage and a deep investigation of the haplotype role. A single SNP analysis showed a significantly increased risk given by XRCC1-rs915927 G allele (OR=1.55, CI 95% 1.02-2.37 for dominant model) and a protective effect of the rare alleles of 3 ERCC1 SNPs: rs967591 (OR=0.66, CI 95% 0.46-0.95), rs735482 (OR=0.62, CI 95% 0.42-0.90) and rs2336219 (OR=0.63, CI 95% 0.43-0.93). Haplotype analysis revealed that cases had a statistically significant excess of XRCC3-TAGT and ERCC1-GAT haplotypes, whereas ERCC1-AAC, MGMT-TA, XRCC1-TGCC and ERCC2-TGAA haplotypes were significantly underrepresented. Together with other published data on large case-control studies, our findings provide epidemiological evidence supporting a link between DNA repair gene variants and bladder cancer development, and suggest that the effects of high-order interactions should be taken into account as modulating factors affecting bladder cancer risk. A detailed characterization of DNA repair genetic variation is warranted and might ultimately help to identify multiple susceptibility variants that could be responsible for joint effects on the risk.