Hypoxia Marker GLUT-1 (Glucose Transporter 1) is an Independent Prognostic Factor for Survival in Bladder Cancer Patients Treated with Radical Cystectomy.

BACKGROUND: Tumour hypoxia, which is frequent in many cancer types, is associated with treatment resistance and poor prognosis. The role of hypoxia in surgically treated bladder cancer (BC) is not well described. We studied the role of hypoxia in two independent series of urothelial bladder cancers treated with radical cystectomy. METHODS: 279 patients from the University Hospital Network (UHN), Toronto, Canada, and Turku University, Finland were studied. Hypoxia biomarkers (HIF1-α, CAIX, GLUT-1) and proliferation marker Ki-67 were analyzed with immunohistochemistry using defined tissue microarrays. Kaplan-Meier methods and Cox proportional hazards regression models were used to investigate prognostic role of the factors. RESULTS: In univariate analyses, strong GLUT-1 positivity and a high Ki-67 index were associated with poor survival. In multivariate model containing clinical prognostic variables, GLUT-1 was an independent prognostic factor associated with worse disease-specific survival (HR 2.9, 95% CI 0.7-12.6, Wald p = 0.15 in the Toronto cohort and HR 3.2, 95% CI 1.3-7.5, Wald p = 0.0085 in the Turku cohort). CONCLUSION: GLUT-1 is frequently upregulated and is an independent prognostic factor in surgically treated bladder cancer. Further studies are needed to evaluate the potential role of hypoxia-based and targeted therapies in hypoxic bladder tumours.

Tumor heterogeneity of fibroblast growth factor receptor 3 (FGFR3) mutations in invasive bladder cancer: implications for perioperative anti-FGFR3 treatment.

BACKGROUND: Fibroblast growth factor receptor 3 (FGFR3) is an actionable target in bladder cancer. Preclinical studies show that anti-FGFR3 treatment slows down tumor growth, suggesting that this tyrosine kinase receptor is a candidate for personalized bladder cancer treatment, particularly in patients with mutated FGFR3. We addressed tumor heterogeneity in a large multicenter, multi-laboratory study, as this may have significant impact on therapeutic response. PATIENTS AND METHODS: We evaluated possible FGFR3 heterogeneity by the PCR-SNaPshot method in the superficial and deep compartments of tumors obtained by transurethral resection (TUR, n = 61) and in radical cystectomy (RC, n = 614) specimens and corresponding cancer-positive lymph nodes (LN+, n = 201). RESULTS: We found FGFR3 mutations in 13/34 (38%) T1 and 8/27 (30%) ≥T2-TUR samples, with 100% concordance between superficial and deeper parts in T1-TUR samples. Of eight FGFR3 mutant ≥T2-TUR samples, only 4 (50%) displayed the mutation in the deeper part. We found 67/614 (11%) FGFR3 mutations in RC specimens. FGFR3 mutation was associated with pN0 (P < 0.001) at RC. In 10/201 (5%) LN+, an FGFR3 mutation was found, all concordant with the corresponding RC specimen. In the remaining 191 cases, RC and LN+ were both wild type. CONCLUSIONS: FGFR3 mutation status seems promising to guide decision-making on adjuvant anti-FGFR3 therapy as it appeared homogeneous in RC and LN+. Based on the results of TUR, the deep part of the tumor needs to be assessed if neoadjuvant anti-FGFR3 treatment is considered. We conclude that studies on the heterogeneity of actionable molecular targets should precede clinical trials with these drugs in the perioperative setting.

Pre-treatment neutrophil-to-lymphocyte ratio as predictor of adverse outcomes in patients undergoing radical cystectomy for urothelial carcinoma of the bladder.

BACKGROUND: An elevated neutrophil-to-lymphocyte ratio (NLR) is associated with poor outcome in various tumours. Its prognostic utility in patients with urothelial carcinoma of the bladder (UCB) undergoing radical cystectomy (RC) is yet to be fully elucidated. METHODS: A cohort of patients undergoing RC for UCB in a tertiary referral centre between 1992 and 2012 was analysed. Neutrophil-to-lymphocyte ratio was computed using complete blood counts performed pre-RC, or before neo-adjuvant chemotherapy where applicable. Time-dependent receiver operating characteristic curves were used to determine the optimal cutoff point for predicting recurrence-free survival (RFS), cancer-specific survival (CSS) and overall survival (OS). The predictive ability of NLR was assessed using Kaplan-Meier analyses and multivariable Cox proportional hazards models. The likelihood-ratio test was used to determine whether multivariable models were improved by including NLR. RESULTS: The cohort included 424 patients followed for a median of 58.4 months. An NLR of 3 was determined as the optimal cutoff value. Patients with an NLR⩾3.0 had significantly worse survival outcomes (5y-RFS: 53% vs 64%, log-rank P=0.013; 5y-CSS: 57% vs 75%, log-rank P<0.001; 5y-OS: 43% vs 64%, log-rank P<0.001). After adjusting for disease-specific predictors, an NLR ⩾3.0 was significantly associated with worse RFS (HR=1.49; 95% CI=1.12-2.0, P=0.007), CSS (HR=1.88; 95% CI=1.39-2.54, P<0.001) and OS (average HR=1.67; 95% CI=1.17-2.39, P=0.005). The likelihood-ratio test confirmed that prognostic models were improved by including NLR. CONCLUSIONS: Neutrophil-to-lymphocyte ratio is an inexpensive prognostic biomarker for patients undergoing RC for UCB. It offers pre-treatment prognostic value in addition to established prognosticators and may be helpful in guiding treatment decisions.

An evaluation of urinary microRNA reveals a high sensitivity for bladder cancer.

BACKGROUND: Urinary biomarkers are needed to improve the care and reduce the cost of managing bladder cancer. Current biomarkers struggle to identify both high and low-grade cancers due to differing molecular pathways. Changes in microRNA (miR) expression are seen in urothelial carcinogenesis in a phenotype-specific manner. We hypothesised that urinary miRs reflecting low- and high-grade pathways could detect bladder cancers and overcome differences in genetic events seen within the disease. METHODS: We investigated urinary samples (n=121) from patients with bladder cancer (n=68) and age-matched controls (n=53). Fifteen miRs were quantified using real-time PCR. RESULTS: We found that miR is stable within urinary cells despite adverse handling and detected differential expression of 10 miRs from patients with cancer and controls (miRs-15a/15b/24-1/27b/100/135b/203/212/328/1224, ANOVA P<0.05). Individually, miR-1224-3p had the best individual performance with specificity, positive and negative predictive values and concordance of 83%, 83%, 75% and 77%, respectively. The combination of miRs-135b/15b/1224-3p detected bladder cancer with a high sensitivity (94.1%), sufficient specificity (51%) and was correct in 86% of patients (concordance). CONCLUSION: The use of this panel in patients with haematuria would have found 94% of urothelial cell carcinoma, while reducing cystoscopy rates by 26%. However, two invasive cancers (3%) would have been missed.

Role of surgery in high-risk localized prostate cancer.

Men with high-risk localized prostate cancer (PCa) remain a challenge for clinicians. Until recently, surgery was not the preferred approach, in part because risk of subclinical metastatic disease, elevated rates of positive surgical margins, absence of randomized studies, and suboptimal cancer control did not justify the morbidity of surgery. No randomized data comparing surgery with radiation therapy are yet available. Data for and comparisons between treatment options should therefore be analyzed with extreme caution.When selecting the best treatment for patients with clinically localized high-risk PCa, considerations should include the life expectancy of the patient, the natural history of PCa, the curability of the disease, and the morbidity of treatment. High-grade PCa managed with noncurative intent greatly reduces life expectancy, but overall, it must also be remembered that radical prostatectomy (RP) and radiotherapy (RT) appear to have similar effects on quality of life. In this population, RP necessitates an extended pelvic lymph node dissection (PLND), but in selected cases, nerve-sparing is a therapeutic possibility and may offer a significant advantage over rt in terms of local control and-although absolutely not yet proved-maybe even in survival. One clear advantage is the ease of administering adjuvant or salvage external-beam rt (EBRT) after rp; conversely, salvage rp after failed EBRT is an exceedingly difficult surgery, with major complications. Surgery therefore has its place, but must be considered in the context of multimodality treatment and the risk of micrometastatic disease. Awaited trial results will help to further refine management in this group of patients.

[Laparoscopy in urology]. / La laparoscopie en urologie.

Since the past 10 years, results have established laparoscopy's efficacy. It is actually a consistent surgical option for a lot of indications met in urology. The rational behind performing laparoscopic procedures includes shorter hospital stays, less postoperative pain and a more rapid return to usual activity. Drawbacks of laparoscopy include significant learning curve, longer operative times and higher overall costs. One particular focus is the oncologic applications of laparoscopy for nephrectomy and specially for radical prostatectomy. Laparoscopy become nowadays an usual part of the armamenturium of urological teams.

Extraperitoneal laparoscopic radical prostatectomy. Results after 50 cases.

INTRODUCTION: After an initial experience using transperitoneal laparoscopic radical prostatectomy as described by Vallancien and Guillonneau, we developed a pure extraperitoneal approach. This approach seems more comparable to the open technique and avoid potential risks of specific complications due to the transperitoneal approach. We evaluated the perioperative parameters (blood loss, operating time, transfusion rate) and postoperative results (oncological results, continence and potency) after our first 50 cases. MATERIAL AND METHOD: Between September 1999 and September 2000, we performed 50 laparoscopic radical prostatectomy. On average, patients were 63.3 years old (range 47-71), had preoperative mean PSA values of 9.14 ng/ml (1.1-23). Median Gleason score was 6 (4-10) with 2.5 (1-6) positive biopsies for a mean prostate volume of 40 cm(3) (17.5-95.0). Clinical stage was T1, T2a, T2b and T3 in 46.3, 41.5, 9.8 and 2.4% of the cases, respectively. We used a pure extraperitoneal approach and we performed a descending technique starting with the dissection at the bladder neck. The seminal vesicles dissection is comparable to the open approach. RESULTS: 42 extraperitoneal and 8 transperitoneal procedures were performed (2 in the initial experience, 3 because of previous abdominal surgery and 3 because of incidental peritoneal opening). Mean operative time was 317 min, mean blood loss 680 cm(3), transfusion rate of 13%. 1 patient/50 was converted to an open procedure. Pathological stage was pT1a, pT2a, pT2b, pT2c, pT3a and pT3b in 2.2, 8.5, 42.5, 2.2, 34 and 10.6% of cases, respectively. Positive surgical margins were observed in 22% of cases. The potency rate after neurovascular bilateral bundle preservation was 43% at 3 months (n = 7) and 67% at 6 months and (n = 6) without any further treatment. The continence rate (no pad) was 39% at 3 months and 85% at 6 months. Detectable postoperative PSA at 3 month was observed in 2 patients only. Two major complications occurred: one acute transient renal failure one uretrorectal fistula at day 20. CONCLUSIONS: The extraperitoneal laparoscopic radical prostatectomy results seem comparable to transperitoneal laparoscopic radical prostatectomy or open surgery. This approach is reproducible and seems to avoid the potential risks of intraperitoneal injury. Long-term follow up and comparative series are however necessary to further evaluate these new techniques.

[Can we prevent prostatic cancer: role of nutrition?]. / Peut-on prevenir le cancer de la prostate: role de la nutrition?

The present paper gives a comprehensive overview of recent data, especially prospective randomized trials, which support an important role for nutrition in the development of prostate cancer. Prostate cancer seems to be an ideal candidate for chemoprevention, in order to interfere by modification of nutritional habits with its onset, its incidence and ultimately with its progression, especially in high risk groups.

4-Year follow-up results of a European prospective randomized study on neoadjuvant hormonal therapy prior to radical prostatectomy in T2-3N0M0 prostate cancer. European Study Group on Neoadjuvant Treatment of Prostate Cancer.

OBJECTIVES: To evaluate the long-term effects of 3-month neoadjuvant hormonal treatment in patients treated by radical prostatectomy for locally confined prostate cancer. METHODS: We report the results of 402 patients (220 with a clinical T2 tumor and 182 with a clinical T3 tumor) of whom 192 randomly received neoadjuvant total androgen deprivation using a LHRH analogue (goserelin) plus flutamide for a period of 3 months and 210 underwent radical prostatectomy only. RESULTS: 'Clinical downstaging' was seen in 30% of cases in the neoadjuvantly treated group (NEO). 'Pathological downstaging' occurred in 7 and 15% of cases in the direct radical prostatectomy (DP) group and the NEO group, respectively (p<0.01). In patients with clinical T2 as well as in patients with clinical T3 tumors, a significant difference in the number of positive margins was shown in favor of the NEO group (cT2, p<0.01; cT3, p = 0.01). This advantage, although there was a trend in favor of the NEO group, specifically in cT2 tumors, did not translate in a significantly better PSA progression rate (p = 0.18). However, when evaluating the local control rate in cT2 tumors, we observed local recurrence in 3 of 102 (3%) patients in the NEO group versus 12 of 114 (11%) patients in the DP group. The difference is statistically significant (p = 0.03). In the cT3 group, this difference was not statistically significant (NEO group: 15 of 87 (17%), and DP group: 21 of 95 (22%) patients; p = 0.41). CONCLUSIONS: In this study, the clinical revelance of pathological downstaging and the lower percentage of patients with positive margins in the neoadjuvantly treated group with a clinical T2 tumor is not confirmed by a lower PSA progression rate. However, this study indicates that there may be a trend that this advantage in favor of the NEO group directly translates into a better local control rate in clinical T2 tumors. Better local control in cT2 tumors is only going to be of relevance if subsequently you can show that there is a better survival for these patients. Unfortunately, this article reports a study which is not yet mature enough to show relevant information. Presently, neoadjuvant therapy should not be given outside clinical research settings.

What are the immunologically active components of bacille Calmette-Guérin in therapy of superficial bladder cancer?

The subcomponents of bacille Calmette-Guérin (BCG) involved in the mechanism of action of intravesical BCG immunotherapy used for prophylaxis of superficial bladder cancer recurrences have been poorly investigated. We purified various BCG subcomponents and analyzed in vitro their ability to enhance a Th1 polarized immune response as well as to increase lymphocyte-mediated cytotoxicity against bladder tumors. Human peripheral blood mononuclear cells (PBMCs) from healthy purified protein derivative-positive subjects were incubated for 7 days with whole BCG and various fractions (BCG cell wall, plasma membrane, cytosol, purified polysaccharides as glucan or arabinomannan, purified native proteins from BCG culture filtrate, recombinant 22 kDa protein, phosphate transporter PstS-2 and -3 proteins). IFN-gamma, IL-12, IL-2, and IL-6 production by stimulated PBMCs was compared to unstimulated controls and the phenotype of expanded cells analyzed by flow cytometry (FACS analysis). A (51)Cr-release assay monitored the cytotoxicity of amplified effector cells against T24 bladder tumor cells. Live BCG and most of its subcomponents (with the exception of cytosol, PstS-2 and -3) significantly enhanced IFN-gamma and IL-12 secretion, expanded CD3(-)CD56(+) cells and the non-MHC-restricted cytotoxicity against bladder tumor cells compared to unstimulated controls (all P < 0.001, t-test). IL-2 receptor blockage resulted in a clear reduction in the cytotoxic activity of stimulated PBMCs. Numerous BCG subcomponents thus provide positive stimuli for Th1 cell differentiation and enhance in vitro, non-MHC-restricted cytotoxicity against bladder tumor cells. Our findings provide the basis for the therapeutic use of several of these subfractions in experimental animal models bearing bladder tumors.

Is one set of sextant biopsies enough to rule out prostate Cancer? Influence of transition and total prostate volumes on prostate cancer yield.

PURPOSE: Although the sextant biopsy technique has been widely used, concern has arisen that this method may not include an adequate sampling of the prostate, especially for large prostate volumes. We conducted a multicenter study in patients with PSA levels <10 ng/ml to determine the influence of the total and transition zone (TZ) volumes of the prostate for predicting whether one single set of biopsies was sufficient to rule out prostate cancer (PCa). These parameters were evaluated in patients in whom PCa was found after one set of systematic sextant biopsies and those in whom PCa was found after a repeat biopsy. MATERIALS AND METHODS: A total of 1,018 patients were included in this study. All underwent transrectal ultrasound-guided needle sextant and two TZ biopsies of the prostate. Total and TZ volumes of the prostate were measured (prolate ellipsoid method). From this cohort, all patients in whom a benign disease was found after the first set of biopsies underwent a second similar set of biopsies within 6 weeks. Only patients with PCa were included in this study, whether diagnosed on first or repeat biopsy. Uni- and multivariate statistical analysis using the SAS system (Cary, N.C., USA) and ROC curves were used to compare patients in whom the diagnosis was performed after the first set of biopsies and those who required a second set. RESULTS: Of the 1,018 patients, 344 (33.8%) had PCa diagnosed, 285 (28%) after the first set of biopsies, and 59 (8.1%) on repeat biopsy. As compared to patients diagnosed with PCa after the first set of biopsies, patients diagnosed after the second set had larger total prostate and TZ volumes (43.1+/-13.0 vs. 32.5+/-10.6 cm(3), p<0.0001 and 20.5+/-8.3 vs. 12.8+/-6.0 cm(3), p<0.0001). ROC curves showed that total and TZ volumes of 45 and 22. 5 cm(3), respectively, provided the best combination of sensitivity and specificity for discriminating between patients diagnosed with PCa after the first from those diagnosed after a second set. CONCLUSION: In patients with total prostate volume >45 cm(3) and TZ >22.5 cm(3), a single set of sextant biopsies may not be sufficient to rule out PCa. In these patients, a repeat biopsy should be considered in case of a negative first biopsy.

Biological response modifiers for the treatment of superficial bladder tumors.

BACKGROUND: For more than 20 years, superficial bladder tumors have been demonstrated to be sensitive to several biological response modifiers and especially to immunomodulators. The best-known and studied immunomodulator is the bacillus Calmette-Guérin (BCG). However, despite its well-recognized efficacy, BCG is not a universal panacea and is associated with potentially significant side effects. METHODS: New perspectives in BCG therapy aiming to increase BCG efficacy or to decrease side effects include the use of genetically engineered BCG strains producing cytokines as well as the use of purified BCG subcomponents. Because a cascade of immunological reactions including the secretion of several cytokines has been demonstrated in the BCG mode of action, many other biological response modifiers and especially immunomodulators have been studied for superficial transitional cell carcinoma therapy. Some were investigated in human trials, others are still in laboratory studies; some are administered intravesically whereas others are given orally. Interferon-alpha (IFN-alpha) intravesical instillations have been evaluated in several controlled studies. RESULTS: Although toxicity of intravesical IFN is minimal, its optimal dose, schedule and efficacy remain to be defined. Recent prospective studies comparing IFN to BCG intravesical therapy have been somewhat disappointing although this cytokine may be effective in some patients with T(a)-T(1) disease who have failed BCG therapy. Other immunomodulators administered intravesically investigated in clinical studies include interleukin 2 (recently used in a clinical study with a marker tumor response), levamisole, Rubratin, a Nocardia rubra cell wall skeleton, and keyhole limpet hemocyanin. Several biological response modifiers administered orally such as vitamin A (and its derivatives), Lactobacillus casei or bropirimine have been tested in clinical trials as well. In contrast, Allium sativum (garlic) or OK-432 (a streptococcal preparation) or BCG subfractions have been tested in laboratory studies only. CONCLUSIONS: Published reports on several of these biological response modifiers suggest that these compounds may be an alternative in patients with superficial bladder cancer who have failed or have not tolerated BCG, but further evaluation to improve efficacy, durability and understand their mechanism of action is warranted.

What is the optimal regimen for BCG intravesical therapy? Are six weekly instillations necessary?

OBJECTIVE: For more than 20 years, BCG intravesical therapy schedule has included 6 weekly instillations. Very few studies have, however, analyzed the rationale of this regimen. We previously demonstrated that intravesical BCG induced an increased peripheral immune response against mycobacterial antigens as compared to pretreatment values. In the present work, we have studied the weekly evolution of this immune response induced by intravesical BCG instillations. MATERIALS AND METHODS: The evolution of the lymphoproliferative response of peripheral blood mononuclear cells against BCG culture filtrate (CF), tuberculin (PPD) and BCG extract (EXT) was tested before, every week during the BCG instillations and at 3 and 6 months follow-up in 9 patients with superficial bladder cancer treated with 6 weekly BCG instillations. Lymphoproliferation was measured by means of a tritiated thymidine incorporation test. RESULTS: A significant increase in the lymphoproliferative response against PPD, CF and EXT was observed in 9, 8 and 7 of the 9 patients, respectively, as compared to pre-BCG values. The maximal lymphoproliferation was achieved after 4 instillations in 4/5 patients initially reactive against mycobacterial antigens whereas 2 of 4 initially nonreactive patients required 6 instillations. At 6 months' follow-up, lymphoproliferation against BCG and the other mycobacterial antigens returned to pre-BCG values in all patients. In 3 patients who received additional instillations because of tumor recurrence within 1 year of follow-up, the maximum immune response was observed already after 2 instillations. CONCLUSION: In most patients, the maximal peripheral immune response is already observed after 4 weekly instillations. However, patients not previously immunized against mycobacterial antigens may require 6 weekly instillations to achieve a maximum stimulation level. Our data support the need to further evaluate the role of this status before starting BCG instillations. It could be of interest to study whether 6 BCG instillations are really necessary in patients previously immune against mycobacterial antigens.

Biological markers in superficial bladder tumors and their prognostic significance.

This article reviews the literature on some of the available biomarkers such as p53 and its down-stream effector p21 on superficial bladder tumor biology and their prognostic significance. The role of p53 tumor suppressor gene is controversial in superficial bladder cancer, possibly because analyzing one single effector of a pathway might hide the role of downstream effectors. The aggressiveness of this condition is related to proliferative activity as measured by Ki-67. Further studies are still necessary to draw definitive conclusions about the role of these different biological markers in superficial bladder cancer.

Current status of minimally invasive treatment options for localized prostate carcinoma.

INTRODUCTION: Prostate cancer is the leading malignancy in men today and an increase in detected localized prostate cancers is expected in the years to come. Even though radical prostatectomy is an effective treatment, it is associated with a considerable morbidity in some cases and efforts are made to provide minimally invasive alternative treatment options with equal efficacy but fewer side effects. METHODS: Cryosurgical ablation of the prostate (CSAP), brachytherapy, high-intensity focused ultrasound (HIFU) and radiofrequency interstitial tumor ablation (RITA) were evaluated after a literature review from a Medline Search (1966-1998). Furthermore, personal experience and latest data from the authors were taken into account. RESULTS: All alternative treatments nowadays make use of sophisticated technology, including the latest ultrasound devices for exact planning and monitoring of treatment, leading to increased safety compared to treatments in the 1960s and 1970s. Five-year results of CSAP show a PSA <1 ng/ml in 60% of cases whereas brachytherapy is able to achieve PSA <1 ng/ml in 80% of cases in a selected group. Recent outcome data come close to results of radical prostatectomy series. HIFU and RITA are promising new technologies that proved to be able to induce extensive necrosis, but the follow-up is too short to determine their definite places in the treatment of prostate cancer. CONCLUSION: Two alternative treatment options for localized prostate carcinoma, CSAP and brachytherapy, have been studied with a sufficient number of patients and an adequate follow-up. The overall results of brachytherapy are favorable when compared to CSAP and are in the same range as the outcome after radical prostatectomy. HIFU and RITA are relatively new techniques based on sophisticated technology that are very promising at present, but a longer follow-up is mandatory.

Prevention of prostate cancer.

Prostate cancer lends itself ideally to chemoprevention due to a number of specific features of the disease. These include a high prevalence, long latency time, hormone dependency, the availability of an ideal marker (prostate serum antigen) and, last but not least, the availability of a defined precursor lesion (prostatic intraepithelial neoplasia) among the pathways leading to clinical disease. The large variability in the incidence of the tumor in different geographical regions suggests the possibility of nutritional influences regarding the stimulation and/or inhibition of clinical cancer, as there is a similar prevalence worldwide of the precursor lesion. A great number of publications have dealt with a number of nutritional factors, including fat, phytoestrogens, vitamins (especially vitamin E) and minerals such as selenium and calcium. These are among the most reported substances with a possible influence on disease development; however, unfortunately there are no conclusive results or study outcomes at present which satisfy accepted standards of evidence. Ongoing studies on nutrition and prostate cancer may bring the required evidence to support what is still only an hypothesis at present.