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Background: Intravesical bacillus Calmette-Guérin (BCG) immunotherapy is effective in preventing recurrence and progression in nonmuscle-invasive bladder cancer but the dosing schedule and duration of treatment remain empirical. The outcome of BCG therapy was prospectively evaluated on patients according to the number of maintenance cycles received., Methods: Between 1997 and 2002, 111 patients with nonmuscle-invasive bladder cancer at high risk of recurrence and progression underwent transurethral resection followed by intravesical instillations of BCG. After an induction treatment of 6 weekly instillations, patients were scheduled to receive a 3-weekly maintenance treatment at the 3rd, 6th, 12th, 18th, 24th, 30th, and 36th month. At each visit a clinical assessment was obtained., Results: Over a median clinical follow-up of 31 months, 43% of patients experienced recurrence and 8.1% progressed to muscle-invasive disease or metastasis. Only 1 patient received all scheduled instillations. Patients who received at least 3 maintenance BCG cycles had a significantly reduced risk of recurrence (hazard ratio [HR] = 0.23, P = .0064, adjusted for gender, age, and stage) compared with patients receiving only induction BCG. Twelve months after the end of maintenance, the estimated Kaplan-Meier recurrence-free survival was 89% for patients who received at least 3 maintenance BCG cycles, 67% for those who received 2 maintenance BCG cycles, and 41% for those who received only the induction BCG or 1 maintenance cycle (P = .0003)., Conclusions: The results of this study suggest that a minimum of 3 cycles of maintenance BCG is required to significantly reduce the recurrence rate. It also suggests that more cycles may result in further improvements but the benefits may be outweighed by increasing side effects in some patients., (2008 American Cancer Society) more...

Background: Treatment of localised renal cell carcinoma consists of partial or radical nephrectomy. A substantial proportion of patients are at risk for recurrence because no effective adjuvant therapy exists. We investigated the use of an autologous, tumour-derived heat-shock protein (glycoprotein 96)-peptide complex (HSPPC-96; vitespen) as adjuvant treatment in patients at high risk of recurrence after resection of locally advanced renal cell carcinoma., Methods: In this open-label trial, patients were randomly assigned to receive either vitespen (n=409) or observation alone (n=409) after nephrectomy. Randomisation was done in a one to one ratio by a computer-generated pseudo-random number generator, with a block size of four, and was stratified by performance score, lymph node status, and nuclear grade. Vitespen was given intradermally once a week for 4 weeks, then every 2 weeks until vaccine depletion. The primary endpoint was recurrence-free survival. The final analysis of recurrence-free survival was planned to take place after 214 or more events of disease recurrence or deaths before recurrence had occurred. Analysis was by intention to treat (ITT). This study is registered with ClinicalTrials.gov, number NCT00033904., Findings: 48 patients in the vitespen group and 42 in the observation group were excluded from the ITT population because they did not meet post-surgery inclusion criteria; the ITT population thus consisted of 361 patients in the vitespen group and 367 in the observation group. Final analysis of recurrence-free survival was triggered in November, 2005. Re-review of all patients in the ITT population by the clinical events committee identified 149 actual recurrences (73 in the vitespen group and 76 in the observation group), nine deaths before recurrence (two in the vitespen group and seven in the observation group), and 124 patients with baseline metastatic or residual disease (61 in the vitespen group and 63 in the observation group). Thus, after a median follow-up of 1.9 years (IQR 0.9-2.5) in the ITT population, recurrence events were reported in 136 (37.7%) patients in the vitespen group and 146 (39.8%) in the observation group (hazard ratio 0.923, 95% CI 0.729-1.169; p=0.506). After continued follow-up until March, 2007, there had been 70 deaths in the vitespen group and 72 in the observation group (p=0.896); however, overall survival data were not mature, and patients continue to be followed up for survival. In predefined exploratory analyses by AJCC stage, recurrence events in patients with stage I or II disease were reported in 19 (15.2%) patients in the vitespen group and 31 (27.0%) in the observation group (hazard ratio 0.576, 95% CI 0.324-1.023; p=0.056). The most commonly reported adverse events in the vitespen group were injection-site erythema (n=158) and injection-site induration (n=153). One serious adverse event-autoimmune thyroiditis of grade 2 severity-was reported in the vitespen group; no treatment-related grade 3 or 4 adverse events were reported., Interpretation: No difference in recurrence-free survival was seen between patients given vitespen and those who received no treatment after nephrectomy for renal cell carcinoma. A possible improvement in recurrence-free survival in patients with early stage disease who received vitespen will require further validation. more...

Aim: To evaluate the clinical outcome of high-risk prostate cancer (PC) treated by radical prostatectomy (RP) according to risk factors., Methods: Patients with stage cT1-T3 PC were stratified in high and low/intermediate risk groups using D'Amico's criteria: PSA>or=20 ng/ml or Gleason score>or=8 or clinical stage>or=T2c. The Kaplan Meier and Log rank test were used to generate estimates of biochemical free-survival (BFS) and PC specific mortality (PCSM)., Results: We analysed 1,109 patients with a median age of 64.1 years, a mean PSA of 12.8 and a median follow-up of 8.18 years (max. 17.5 years). Overall PSA failures (PSAF) were observed in 23.4%, mortality by all causes in 11.4% and PCSM in 2.9%. The 10-year BFS of the 290 high-risk was 45 versus 75.5% for low/intermediate risk patients and the 10-year PCSM was 10.3 versus 1.4%, respectively. Of the 290 high-risk PC, 25% had organ-confined disease at surgery with 28% PSAF compared to 55% PSAF for non-organ-confined PC irrespective of nodal status. High-risk patients with 1 or>or=2 high risk criteria had 2.6 and 3.86 times increased risk of PSAF compared to low/intermediate risk. Ten-year PCSM for PC individual risk criteria was 4.5% for PSA>or=20, 9.2% for stage>or=T2c and 18.2% for Gleason>or=8., Conclusion: Patients with high-risk PC treated by RP by experienced surgeons can have a favourable long-term survival. Further substratification should take into account the variable prognostic implication of the different individual risk factors. more...

Tissue factor (TF), a transmembrane glycoprotein responsible for initiating the extrinsic pathway of blood coagulation plays a key role in cancer growth, metastasis and angiogenesis. Various studies have demonstrated the prognostic potential of TF expression in several cancers. However, its role in bladder cancer is unclear. This study evaluated the prognostic potential of TF expression in muscle-invasive bladder tumors from patients treated with radical cystectomies. Immunohistochemical staining using a monoclonal antibody (mAb) anti-TF was carried out on sections of tissue microarray blocks containing cores of muscle-invasive bladder tumors (4 cores/tumor) from 218 patients. The intensity of the staining was evaluated on a scale from 0 to 3 by two independent observers who were both unaware of the clinicopathological characteristics of the samples. TF was expressed in 77.6% of tumors, independently from baseline characteristics (age, gender, stage and grade) as assessed using the chi(2) and Student t tests. During follow-up (median: 2.6 years), 45.4% of the patients died from the progression of their cancer. Kaplan-Meier survival showed that among the 103 patients with node-negative (N0) transitional cell carcinoma (TCC), those with TF-positive tumors had shorter bladder cancer-specific survival (p = 0.0276). Moreover, multivariate Cox regression analysis showed they had a 3.15-fold greater risk of dying from bladder cancer (95% CI: 1.1-9.0; p = 0.032). In conclusion, TF expression was an independent predictor of disease-specific survival in N0 muscle-invasive TCCs treated by radical cystectomy and therefore, might help identify patients at higher risk of disease progression. These patients could potentially benefit from adjuvant chemotherapy., ((c) 2007 Wiley-Liss, Inc.) more...

Introduction: Our objective was to evaluate the usefulness of urinary prostate specific antigen (PSA) in the differential diagnosis of benign prostatic hyperplasia (BPH) and prostate cancer., Methods: We undertook a prospective study and obtained informed consent from 170 men. They provided blood samples to measure serum PSA and 50 mL of first-voided urine to measure urinary PSA. Seventy-seven men were diagnosed with BPH; 42 patients had newly diagnosed prostate cancer; and 51 were selected as age-matched control subjects. Data were analyzed using Wilcoxon signed rank tests, receiver operating characteristic (ROC) curves and logistic regression., Results: Prostate volume was 35 cm(3) and 45 cm(3) (p < 0.05), serum PSA was 9.7 ng/mL and 4.5 ng/mL (p < 0.001) and PSA density was 0.28 and 0.11 (p < 0.01) for prostate cancer and BPH patients, respectively. Overall, urinary PSA was not significantly different, but PSA ratio (urinary:serum) was significantly different at 6.7 and 30.6 (p < 0.001) for prostate cancer and BPH patients, respectively. A subgroup with serum PSA between 2.5 ng/mL and 10.0 ng/mL was selected and urinary PSA was significant: 52.6 ng/mL (n = 29) and 123.2 ng/mL (n = 35) (p < 0.05) for prostate cancer and BPH patients, respectively. PSA ratios were also significant (p = 0.007). ROC curves identified a cutoff for urinary PSA at > 150 ng/mL, with a sensitivity of 92.5%. When comparing prostate cancer patients with age-matched control subjects, serum PSA, urinary PSA and PSA ratio were different (p = 0.004)., Conclusion: Our study supports urinary PSA as a useful marker in the differential diagnosis of prostate cancer and BPH, especially when serum PSA is between 2.5 ng/mL and 10 ng/mL. Low urinary PSA and PSA ratios point toward prostate cancer. A urinary PSA threshold of > 150 ng/mL may be used to decrease the number of prostatic biopsies. more...

Background: PD-L1 (programmed death ligand 1, B7-H1) is a cell surface glycoprotein that can impair T-cell function. PD-L1 is aberrantly expressed by multiple human malignancies and has been shown to carry a highly unfavorable prognosis in patients with kidney cancer. The role of PD-L1 was evaluated as a mechanism for local stage progression in urothelial carcinoma (UC) of the bladder., Methods: Using immunohistochemistry, PD-L1 expression was evaluated in a cohort of 280 high-risk UCs of the bladder. PD-L1 was modeled as a predictor of bladder cancer stage using ordinal logistic regression. Other covariates evaluated as potential confounders included age, gender, tumor grade, and lymphocytic infiltration. Further, PD-L1 was evaluated as a potential mechanism of bacillus Calmette-Guerin (BCG) failure in the subset of high-risk nonmuscle-invasive tumors that received this treatment., Results: PD-L1 expression was observed in 7% of pTa, 16% of pT1, 23% of pT2, 30% of pT3/4, and 45% of carcinoma in situ (CIS) tumors. PD-L1 expression was associated with high-grade tumors (odds ratio [OR] = 2.4, P = .009) and tumor infiltration by mononuclear cells (OR = 5.5, P = .004). We observed that the key determinants of stage progression in this cohort were World Health Organization/International Society of Urologic Pathology (WHO/ISUP) high-grade tumor pathology (OR = 4.77, 95% confidence interval [CI]: 2.73-8.34; P < .001) and PD-L1 expression (OR = 2.20, P = .012). PD-L1 expression was found to be extremely abundant in the BCG-induced bladder granulomata in 11 of 12 patients failing BCG treatment., Conclusions: Collectively, these data indicate that tumor PD-L1 may facilitate localized stage-advancement of UC and attenuate responses to BCG immunotherapy by neutralizing T cells that normally guard against cancer invasion from the epithelium into the bladder musculature. more...

Purpose: Prostatic intraepithelial neoplasia (PIN) is considered as a precursor lesion for adenocarcinoma of the prostate. Most data supporting this relationship comes from the short-term follow-up of patients with repeated biopsies. We report a study in which patients were followed-up for 11 years to assess the relationships between the presence of high grade PIN, low grade PIN, and atypical adenomatous hyperplasia (AAH) and the subsequent occurrence of prostate cancer., Materials and Methods: For 601 men treated by TURP in 1990-1993, prostate specimens were reviewed to assess the presence of high grade PIN, low grade PIN, and AAH. Incidental carcinoma was observed in 67 men. Follow-up of the 534 men without incidental prostate cancer was conducted until December 2003 and 24 new prostate cancers were diagnosed. Multivariate regression models were used to assess the relationships between PIN and AAH and prostate cancer on both cross-sectional and prospective data., Results: High grade PIN (odds ratio (OR) = 6.16, 95% confidence interval (CI): 3.28-11.58), low grade PIN (OR = 3.06, 95% CI: 1.45-6.46), and AAH (OR = 2.06, 95% CI: 1.00-4.29) were significantly associated with incidental prostate cancer. In the prospective study, only high grade PIN was associated with a statistically significant increased risk of prostate cancer: hazard ratio = 3.12, 95% CI: 1.15-8.49., Conclusion: Although high grade PIN, low grade PIN, and AAH were all associated with incidental prostate cancer, the long-term prospective study showed that only high grade PIN was a significant determinant of the subsequent occurrence of prostate cancer. more...

Purpose: Superficial bladder tumors have a high recurrence rate and 10% to 20% of recurrences progress to invasive cancer. Recurrence and progression can best be prevented by nonspecific immunotherapy using intravesical BCG instillations. The NRAMP1 gene has been implicated in susceptibility to infectious and autoimmune diseases, and in response to BCG in murine models. We evaluated the association of 5 NRAMP1 gene polymorphisms with the risk of superficial bladder cancer recurrence and response to immunotherapy., Materials and Methods: The (GT)n, 274 C/T, 469 + 14 G/C, 1465-85 G/A and D534N polymorphisms were tested on peripheral blood DNA of individuals from three cohorts: 37 bladder tumor patients treated by transurethral resection and without recurrence after up to eight years, 67 patients at high risk of recurrence of their bladder tumors and treated with BCG and 109 controls, using restriction fragment length polymorphisms or microsatellite analysis following PCR amplification., Results: The D543N G:A genotype was found more frequently in patients at high risk of recurrence (8 of 67 or 12%) than in controls (2 of 109 or 2%) (p = 0.007). Patients with nonrecurrent tumors showed no difference with controls (1 of 37 or 3%) (p = 1.0). Moreover, in multivariate and survival analyses, both D543N and (GT)n polymorphisms showed association with recurrence-free survival in the cohort of patients at high risk of recurrence, following BCG treatment., Conclusions: These data suggest the implication of the NRAMP1 gene in bladder cancer recurrence and response to BCG immunotherapy. more...

This study compared the prevalence of psychological difficulties (i.e., anxiety and depression), psychophysiological problems (i.e., insomnia and fatigue), and sexual difficulties across three modalities of treatment for prostate cancer (radiotherapy, brachytherapy, and radical prostatectomy). A total of 861 men completed a battery of questionnaires assessing anxiety, depression, fatigue, insomnia, and quality of life. Patients who initially received radiotherapy had higher levels of depression, anxiety, and fatigue and a lower quality of life, and were more likely to report clinical levels of depression and fatigue. Patients who initially received surgery were more likely to report clinical levels of sexual difficulties but less likely to report clinical levels of depression and fatigue, while patients who received brachytherapy were less likely to report sexual difficulties. Although cross-sectional, these findings raise the possibility of a differential influence of treatments for prostate cancer on some aspects of psychological functioning. more...

Background: Evidence suggests that the insulin-like growth factor (IGF) family is important in prostate cancer. We evaluate the ability of IGF markers to predict biochemical recurrence-free survival (bRFS) following radical prostatectomy (RRP)., Methods: Preoperative sera from 141 patients undergoing RRP were analyzed for IGF-I, IGFBP-1, IGFBP-2 and IGFBP-3. A multivariate Cox model was created to assess the ability of these markers to predict bRFS. Preoperative covariables included: biopsy Gleason score, clinical TNM stage, serum PSA and neoadjuvant hormonotherapy. Kaplan-Meier curves were stratifying by IGF cutpoints (determined by ROC analysis) and hormonotherapy status., Results: Average follow-up was 6.92 years, median PSA was 6.9 ng/ml and 85.1% of patients had cT2NxM0 disease. 49 patients experienced a PSA failure. Average levels of IGF-I, IGFBP-1, IGFBP-2 and IGFBP-3 were 156.5 ng/ml, 48.1 ng/ml, 396.8 ng/ml and 3303.7 ng/ml, respectively. IGFBP-2 was an independent predictor of PSA failure. Patients treated with neoadjuvant ADT (n=71) and whom had high IGFBP-2 levels experienced a 5-year bRFS that was better than those with low IGFBP-2 levels (77.7% vs. 53.3%). Patients without neoadjuvant ADT whom had high IGFBP-2 levels had a 5-year bRFS that was worse than those with low IGFBP-2 levels (64.5% vs. 82.7%)., Conclusions: Preoperative IGFBP-2 predicts post-radical prostatectomy bRFS and is independent of stage, Gleason score and PSA. Increased IGFBP-2 is associated with better survival in patients with neoadjuvant hormonotherapy but worse survival in those without, suggesting a dramatic switch in function of this protein dependent on the presence or absence of androgens. more...

This study assessed the prevalence, clinical characteristics and risk factors for insomnia in patients treated with radical prostatectomy for prostate cancer. A total of 327 patients completed a battery of questionnaires assessing sleep and related issues (i.e. anxiety, depression, fatigue, quality of life). Results indicated that 31.5% of the patients currently reported non-specific sleep difficulties, while 18% met specific criteria for an insomnia syndrome. In most of these latter cases (95%), the insomnia was chronic (duration of 6 months or more). Nearly half of patients with an insomnia syndrome reported that the onset of their sleep difficulties followed the cancer diagnosis. A similar proportion had no comorbid clinical levels of anxiety or depression. Risk factors for the presence of an insomnia syndrome included a younger age, a worse prognosis, and the presence of intestinal, pain, depressive, and androgen blockade-related symptoms. Thus, insomnia is a frequent problem associated with prostate cancer, that often occurs independently of anxiety and depression, but seems to be influenced by the presence of physical and psychological symptoms associated with prostate cancer and its treatment., (Copyright (c) 2004 John Wiley & Sons, Ltd.) more...

In a placebo-controlled randomized clinical trial, zoledronic acid (4 mg via a 15-minute infusion every 3 weeks for 15 months) reduced the incidence of skeletal-related events (SREs) in men with hormone-refractory metastatic prostate cancer. Among 122 patients who completed a total of 24 months on study, fewer patients in the 4-mg zoledronic acid group than in the placebo group had at least one SRE (38% versus 49%, difference = -11.0%, 95% confidence interval [CI] = -20.2% to -1.3%; P =.028), and the annual incidence of SREs was 0.77 for the 4-mg zoledronic acid group versus 1.47 for the placebo group (P=.005). The median time to the first SRE was 488 days for the 4-mg zoledronic acid group versus 321 days for the placebo group (P =.009). Compared with placebo, 4 mg of zoledronic acid reduced the ongoing risk of SREs by 36% (risk ratio = 0.64, 95% CI = 0.485 to 0.845; P =.002). Patients in the 4-mg zoledronic acid group had a lower incidence of SREs than did patients in the placebo group, regardless of whether they had an SRE prior to entry in the study. Long-term treatment with 4 mg of zoledronic acid is safe and provides sustained clinical benefits for men with metastatic hormone-refractory prostate cancer. more...

Background: To assess whether the expression of p21, p27, and p53 could predict biochemical failure in prostate cancer patients treated with neoadjuvant androgen deprivation prior to salvage radiotherapy for a rising post-radical prostatectomy (RP) prostate-specific antigen (PSA)., Methods: The expression of p21, p27, and p53 was determined by immunohistochemistry in a cohort of 74 formalin-fixed paraffin-embedded prostate cancer samples obtained from RP. Expression of these markers was then correlated with clinicopathological parameters and biochemical failure-free survival after salvage radiotherapy., Results: Expression of p21, p27, and p53 was observed in 20%, 69%, and 74% of prostate cancer specimens, respectively. Overexpression of p21 correlated with a higher Gleason score (>7) (P = 0.024). Of the three markers, only p21 expression was correlated with PSA failure after radiotherapy (P = 0.034). In multivariate analysis, both positive p21 (P = 0.004) and pre-radiation serum PSA > 1 ng/ml (P < 0.0001) were independent predictors of biochemical failure after salvage radiotherapy. Patients with p21- tumors and a serum PSA level < or = 1 ng/ml before salvage radiotherapy had a biochemical failure-free survival at 5 years of 83%, compared to 16% at 5 years for those patients with either p21+ tumor or a PSA > 1 ng/ml. Patients with both p21+ and a PSA level > 1 ng/ml had a much lower biochemical failure-free survival rate of 25% at only 18 months (P < 0.0001)., Conclusions: The expression of p21 in prostatectomy specimens could help predict the likelihood of response to salvage radiotherapy, particularly in patients treated before PSA reaches 1 ng/ml., (Copyright 2003 Wiley-Liss, Inc.) more...

Purpose: Postoperative nasogastric tube (NGT) use has been shown to increase postoperative morbidity in patients undergoing nonurological abdominal surgery. We examine the omission of NGTs as a method of decreasing postoperative gastrointestinal complications and hospital stay in patients undergoing cystectomy with urinary diversion., Materials and Methods: Between January 1983 and December 2001, 430 patients underwent cystectomy with urinary diversion at our institution. We retrospectively compared patients who received postoperative NGTs with those who did not with regard to gastrointestinal recovery time, gastrointestinal complications and hospital stay., Results: After correcting for confounding factors using ANCOVA the time to first bowel sounds, time to first flatus and the duration of hospitalization were shorter in patients not receiving NGTs (p = 0.006, 0.001 and 0.032, respectively). Omitting NGTs did not increase the risk of ileus, bowel obstruction, wound dehiscence, anastomotic leakage or aspiration pneumonia and it did not result in more frequent postoperative NGT placement., Conclusions: The results of the current study suggest that gastric decompression with NGTs following cystectomy with urinary diversion may prolong gastrointestinal recovery, which may be a factor leading to increased duration of hospitalization. We propose that postoperative NGTs should not be used routinely in the management of cystectomy cases. more...

Purpose: We retrospectively evaluated the benefit of neoadjuvant androgen deprivation therapy administered before salvage external beam radiation treatment in patients with biochemical failure following retropubic radical prostatectomy (RRP)., Materials and Methods: A total of 81 patients were treated with neoadjuvant androgen deprivation therapy before salvage external beam radiation treatment because of an increased prostate specific antigen (PSA) level following RRP. Preoperative, pathological, postoperative, and pre-salvage treatment parameters and radiation therapy dosage were examined for influence on outcome. Biochemical failures after RRP or salvage external beam radiation treatment were defined as a PSA greater than 0.3 ng/ml on 2 consecutive measurements. Median radiation dose delivered was 60 Gy. Neoadjuvant androgen deprivation therapy consisted of a 3 month injection of a luteinizing hormone releasing hormone analogue. Median followup was 38 months (range 12 to 102) after completion of external beam radiation treatment and 91 months (range 20 to 163) after radical prostatectomy., Results: The actuarial free biochemical failure rates at 3 and 5 years were 75% and 50%, respectively. Two patients (2%) died of prostate cancer. Significant predictors of response to salvage external beam radiation treatment on a univariate analysis were a pre-radiation serum PSA less than 1 ng/ml and a pathological Gleason score less than 7. However, only pre-radiation PSA remained statistically significant on a multivariable analysis., Conclusions: External beam radiation with neoadjuvant androgen deprivation therapy is a viable option for patients with an increasing post-prostatectomy serum PSA. The most powerful predictor of biochemical failure was pre-radiation serum PSA. more...

Background: Bone metastases are a common cause of morbidity in patients with prostate carcinoma. We studied the effect of a new bisphosphonate, zoledronic acid, which blocks bone destruction, on skeletal complications in prostate cancer patients with bone metastases., Methods: Patients with hormone-refractory prostate cancer and a history of bone metastases were randomly assigned to a double-blind treatment regimen of intravenous zoledronic acid at 4 mg (N = 214), zoledronic acid at 8 mg (subsequently reduced to 4 mg; 8/4) (N = 221), or placebo (N = 208) every 3 weeks for 15 months. Proportions of patients with skeletal-related events, time to the first skeletal-related event, skeletal morbidity rate, pain and analgesic scores, disease progression, and safety were assessed. All statistical tests were two-sided., Results: Approximately 38% of patients who received zoledronic acid at 4 mg, 28% who received zoledronic acid at 8/4 mg, and 31% who received placebo completed the study. A greater proportion of patients who received placebo had skeletal-related events than those who received zoledronic acid at 4 mg (44.2% versus 33.2%; difference = -11.0%, 95% confidence interval [CI] = -20.3% to -1.8%; P =.021) or those who received zoledronic acid at 8/4 mg (38.5%; difference versus placebo = -5.8%, 95% CI = -15.1% to 3.6%; P =.222). Median time to first skeletal-related event was 321 days for patients who received placebo, was not reached for patients who received zoledronic acid at 4 mg (P =.011 versus placebo), and was 363 days for those who received zoledronic acid at 8/4 mg (P =.491 versus placebo). Compared with urinary markers in patients who received placebo, urinary markers of bone resorption were statistically significantly decreased in patients who received zoledronic acid at either dose (P =.001). Pain and analgesic scores increased more in patients who received placebo than in patients who received zoledronic acid, but there were no differences in disease progression, performance status, or quality-of-life scores among the groups. Zoledronic acid at 4 mg given as a 15-minute infusion was well tolerated, but the 8-mg dose was associated with renal function deterioration., Conclusion: Zoledronic acid at 4 mg reduced skeletal-related events in prostate cancer patients with bone metastases. more...

Purpose: We establish the relationship among symptom duration, cystometric and cystoscopic findings and potassium stimulation test in patients with interstitial cystitis., Materials and Methods: A retrospective chart review was performed of 189 patients treated at an ambulatory clinic between 1992 and 1998. Urodynamic parameters, potassium stimulation test results and subjective response to treatment were evaluated. Fisher's exact test was used for statistical analysis., Results: Of the 189 patients diagnosed with interstitial cystitis 173 (92%) were female and 16 (8%) were male. The potassium stimulation test was positive in 105 (83%) patients, negative in 16 (13%) and equivocal in 6 (4%). A cystometrogram and potassium stimulation test were done in 118 patients. Bladder capacity averaged 259 ml. in patients with tests potassium positive and negative, while average bladder volume at first sensation to void was 85 ml. and 148 ml. in those with negative and positive tests, respectively. Among the 102 patients with a positive potassium stimulation test 52 had normal cystoscopic findings., Conclusions: The potassium stimulation test is not correlated with either bladder capacity or cystoscopic findings. more...

There is little evidence that neoadjuvant androgen deprivation therapy (ADT) of 3 months' duration before radical prostatectomy (RP) favorably influences disease-free survival. However, recent data suggest that prolonged treatment may improve outcome. We conducted a prospective cohort study to determine whether ADT of either standard or prolonged duration before RP influences the risk of prostate-specific antigen (PSA) failure. We followed 756 men treated for prostate cancer by RP between 1991 and 1998 in Quebec City. Of these, 240 received combined neoadjuvant ADT for either /=93 days (111 men), and 516 were treated by RP alone. Multivariate Cox regression was used to estimate the hazard ratios (HR) of PSA failure (>0.3 ng/mL) associated with treatment regimen controlling for age, clinical stage, grade, and initial PSA level. The median duration of follow-up was 4 years. Compared with men treated by RP alone, those who received neoadjuvant ADT for >/=93 days had an HR of PSA failure of 0.60. The inverse association with the risk of PSA failure became statistically significant from the third year on, reached its greatest magnitude after 4 years, and was still present 8 years after RP. No association was observed for ADT of more...

The management of prostate cancer is based on several clinicopathological criteria. The ability to determine the tumor's biological potential is one goal of tumor markers in order to identify patients who may require more intensive treatment strategies. The purpose of our study was to determine if p21/(WAF1/CIP1) expression can predict biochemical failure in patients with locally advanced prostate cancer treated by radical retropubic prostatectomy (RRP). We used immunohistochemistry to analyze patterns of p21 expression in a population of 296 patients with locally advanced (pT3) prostate cancer treated by RRP. Results were correlated with clinicopathological parameters and time to PSA failure. For the entire cohort of 296 patients, after adjustment for prognostic factors, p21 expression was associated with an increased risk of PSA failure (relative risk [RR] = 1.48) of statistical significance at a median follow-up of 54.5 months. Other parameters that independently predicted the risk of PSA failure included lymph node metastasis and seminal vesicle involvement. Because neoadjuvant hormonal therapy (NHT) is known to lead to involutional changes in prostatic carcinoma, we performed multivariate analyses after stratifying for NHT prior to surgery. Among the 172 patients treated by RRP alone, p21 expression was an independent predictor of PSA failure (RR = 2.30), as were lymph node metastases (RR = 3.19) and pathological grade 5-7 and 8-10 (RR = 2.87 and 3.50, respectively). p21 over-expression is an independent predictor of PSA failure in pT3 patients treated by radical prostatectomy, especially if they did not receive NHT. This tumor marker may help clinicians identify patients who may require adjuvant treatment strategies following radical prostatectomy., (Copyright 2001 Wiley-Liss, Inc.) more...

Biological markers that are predictive of recurrence and progression of superficial bladder tumors must provide additional information to that provided by multiplicity, size and grade. Field anomalies in normal appearing urothelium of patients with papillary superficial transitional cell carcinoma have been associated with tumor antigens and chromosome 9 deletions. Also, primary tumors with chromosome 9 deletions are associated with a higher risk of recurrence. Abnormal expression of p53, p21 and Ki-67 cell cycle markers have little predictive value for recurrence. However, p53 overexpression or mutation and decreased expression of p27 are associated with cancer progression and survival. New markers, such as mutations in the fibroblast growth factor receptor 3 gene (found in 30% of tumors), anomalies of the PTEN gene and vascular endothelial growth factor expression, may have potential and require further evaluation. Molecular fingerprints of superficial tumors with distinct clinical behavior are being rapidly unravelled. Large-scale clinical studies are urgently needed to provide supportive evidence for their incorporation in clinical management. more...

Our aim was to determine whether the pattern of expression of the interrelated proteins p53, MDM2 and p21 could shed light on the etiopathogenic mechanisms of superficial bladder tumors. Protein expression was detected by immunohistochemistry (IHC) using monoclonal antibodies (MAbs) Pab 1801 for p53, IF2 for MDM2 and EA10 for p21 on 269 newly diagnosed bladder tumors (214 pTa and 55 pT1; 93 grade I, 145 grade 2 and 31 grade 3). While no p21 immunoreactivity was found in normal urothelium, 85% of tumors were strongly p21-positive. MDM2 was overexpressed in 44% of tumors, almost all being also positive for p21. p53 was overexpressed in 20% of cases: 66% of p53-positive tumors were also MDM2 positive, compared with only 38% of p53-negative tumors. p53 mutations were studied by direct DNA sequencing in a subset of 24 high-grade tumors. Both MDM2 and p21 were less frequently expressed in p53 mutated tumors compared with tumors with a wild-type gene. Distinct phenotypes were correlated with the frequency of poorly differentiated (grade 3) tumors. The most common phenotypes were p21+/MDM2-/p53- and p21+/MDM2+/p53- observed in 38% and 29% of tumors, respectively. Grade 3 tumors were found in 4% and 8% of these 2 groups, in contrast with 30% frequency in p21+/p53+ tumors (p = 0.002) regardless of their MDM2 phenotype. Four of the 5 (80%) tumors that were p53-positive but negative for p21 were grade 3. Our data suggest that several tumorigenic pathways for superficial bladder tumors can be reflected by the expression pattern of these 3 proteins. more...

Purpose: To date there is little information on the long-term effect of neoadjuvant hormonal therapy on prostate cancer progression. We performed a prospective study to determine whether patients with prostate cancer receiving neoadjuvant hormonal therapy before radical prostatectomy (hormonal therapy group) have a lower risk of prostate specific antigen (PSA) failure than those treated with radical prostatectomy alone (prostatectomy group). We also evaluated whether type of neoadjuvant hormonal therapy and duration were associated with the risk of PSA failure., Materials and Methods: We followed 680 men initially treated for prostate cancer with radical prostatectomy between January 1988 and December 1997 at our university hospital. Of the patients 292 received neoadjuvant hormonal therapy. Median followup was 38 months. Cox regression analysis was used to assess the association between neoadjuvant hormonal therapy and PSA failure (greater than 0.3 ng./ml.) controlling for age, clinical stage, grade, initial PSA and adjuvant therapies., Results: Surgical margins were positive less often in the hormonal therapy (25%) than the prostatectomy (47%) group (p = 0.0001). PSA failure was observed in 163 patients and the 5-year failure rate was 33%. No difference in risk of PSA failure was observed overall between the hormonal therapy and prostatectomy groups (hazards ratio 0.94, 95% confidence interval 0.68 to 1.30). Treatments with antiandrogen alone for any duration, and those combining antiandrogen and luteinizing hormone-releasing hormone analogue for 3 months or less were not associated with improved survival. However, patients receiving combined therapy for more than 3 months had a significantly lower risk of PSA failure than those treated with radical prostatectomy alone (hazards ratio 0.52, 95% confidence interval 0.29 to 0.93)., Conclusions: Prolonged neoadjuvant hormonal therapy combining antiandrogen and luteinizing hormone-releasing hormone analogue may improve disease-free survival after radical prostatectomy. more...

The aim of the study was to determine whether the expression of the cell cycle markers p53, MDM2, p21, and Ki-67 was predictive of superficial bladder cancer recurrence and to compare the relative predictive power for tumor recurrence of a cell cycle index based on the number of abnormally expressed cell cycle markers with a clinicopathological index based on primary clinical tumor characteristics. The expression of p53, MDM2, and p21 proteins and the value of the Ki-67 index were analyzed for 244 patients. One hundred ninety-four lesions were determined to be superficial papillary tumors (pTa), whereas 50 tumors invaded the lamina propria (pT1). Tumor grade was noted low (grade 1) in 83 cases and high (grades 2-3) in 161 cases. An avidin-biotin peroxidase method was performed using monoclonal antibodies against p53, MDM2, p21, and Ki-67 antigens after antigen retrieval treatment of formalin-fixed specimens. The cell cycle marker index was created using the number of abnormally expressed cell cycle markers according to the following cutoff points: p53 (>5%), MDM2 (>20%), p21 (<5%), and Ki-67 (>10%). The clinicopathological index was created using the following adverse tumor characteristics: grades G2-G3, stage pT1, multifocality, and diameter of tumors > 3 cm. Cox regression models were used to calculate the relative risks and their 95% confidence intervals associated with disease recurrence for the clinicopathological index and the cell cycle marker index. The chi2 test was performed to describe the correlation between the Ki-67 index and p53, MDM2, and p21 protein expression. Kaplan-Meier survival curves were generated to demonstrate the disease-free survival according to these two prognostic indexes. The clinicopathological index was a strong, independent predictor of disease recurrence where tumors with three or four adverse tumor characteristics at initial resection had over four times the risk of recurrence than tumors with no risk factors (P for trend = 0.0001). A strong correlation was observed between the Ki-67 index >10% and both MDM2 and p21 proteins. MDM2 was overexpressed in 106 tumors (43%), and p53 was overexpressed in 47 (19%); Ki-67 was >10% in 171 cases (70%). Thirty-nine tumors (16%) were p21 negative. The risk of recurrence increased slightly with the number of abnormally expressed cell cycle markers, but when the clinicopathological index was taken into account in multivariate analysis, the cell cycle marker index was not predictive of disease recurrence (P for trend = 0.72). The cell cycle markers studied provided no added prognostic information on disease recurrence after initial resection of papillary superficial tumors when the clinicopathological parameters were taken into account. more...

The biological behavior of urothelial carcinomas remains unpredictable. The objective of this study was to determine the prognostic value of Ki-67 index in superficial papillary bladder tumors and to correlate it with the S-phase fraction (SPF) measured by flow cytometry. Three hundred nineteen patients with newly diagnosed superficial (pTa, pT1) bladder tumors were included between September 1990 and April 1992. Patients with bladder carcinoma in situ alone were excluded. We observed 255 pTa tumors and 64 pT1 tumors, whereas 111 lesions were classified as grade G1 and 208 as grade G2-G3. Ki-67 immunostaining was performed on paraffin-embedded material using a 3-step immunoperoxidase procedure with the murine monoclonal antibody MiB1. The relation between Ki-67 expression and prognostic variables (stage, grade, tumor size, multifocality, age, and sex) was investigated by the chi-square test. Cox regression was used to describe the association between Ki-67 and tumor recurrence in 308 patients with follow-up while adjusting for potentially confounding prognostic variables. The frequency of high Ki-67 expression (> or =10%) increased with stage (P = .005) and grade (P = .001), but not with tumor size or multifocality. Two hundred one patients experienced tumor recurrence in a median follow-up of 68 months. Stage, grade, tumor size, and multifocality were all independent predictors of recurrence. Ki-67 index greater than 10% was found to be an independent predictor of tumor recurrence among patients with tumors larger than 3 cm in diameter (HR = 2.05, CI = 1.18-3.55), but not those with smaller size tumors. With regards to the DNA index, a significant but weak correlation was observed between Ki-67 expression and the SPF (Spearman's correlation coefficient = 0.23, P = .004). In addition, aneuploid tumors had significantly higher expression of Ki-67 (22.5%) than diploid tumors (10.1%) (P = .0006). Moreover, patients with DNA aneuploid bladder tumors were more likely to have more than 10% Ki-67-positive cells than those with diploid tumors. In patients with newly diagnosed pTa or pT1 bladder tumors, a Ki-67 index above 10% is an independent predictor of shorter time to recurrence only in those with tumors larger than 3 cm. more...

The INK4A and the INK4B genes map to chromosome 9p21, an area frequently deleted in bladder neoplasms. In addition to the p16 protein, the INK4A encodes for a second product, termed p19(ARF). We analyzed tissues from 121 patients with initial Ta and T1 tumors. Deletions of the INK4A gene were observed in 17 of 121 (14.1%) cases. Point mutations were identified in 2 of 64 (3.1%) tumors. The INK4A-exon 1beta and the INK4B gene were codeleted with INK4A in all of the homozygously deleted cases analyzed. The p16 promoter underwent de novo methylation in 7 of 47 (14.9%) evaluable cases. The p16-positive phenotype was observed in 18 of 56 (32%) evaluable cases. p16 negative phenotype correlated with deletion and methylation status. A statistically significant association between INK4A homozygous deletions and tumor size was observed (P = 0.003). Patients bearing tumors with INK4A homozygous deletions had a lower recurrence-free survival (P = 0.040) than those with wild type INK4A. In conclusion, deletions and methylation of the INK4A gene occur frequently in superficial bladder tumors. However, only those deletions that affect both the p16 and the p19(ARF), deregulating both the pRb and p53 pathways, correlated with clinicopathological parameters of worse prognosis. more...

Objectives: To evaluate our experience with primary carcinomas of the male urethra and to analyze the impact of tumor variables and treatment on overall, disease-specific, local recurrence-free, and metastasis-free survival., Methods: Between 1958 and 1996, we identified 46 men with primary carcinoma of the bulbar and anterior urethra. The median follow-up was 125 months (1 to 336). The patients were stratified by stage, nodal status, histologic type, treatment, type of surgery, site of disease, year at diagnosis, and smoking status., Results: The overall survival and disease-specific survival rates at 5 years were 42% and 50%, respectively. The recurrence-free survival and metastasis-free survival rates at 5 years were 51% and 56%, respectively. The overall survival rate was 83% for superficial disease versus 36% for invasive tumors. The overall survival rate was 26% for tumors of the bulbar urethra versus 69% for tumors of the anterior urethra., Conclusions: Current modalities of treatment are ineffective for local control and survival. New treatment strategies are needed for urethral cancer. more...

One of the concerns of patients undergoing radical retropubic prostatectomy (RRP) is the risk of intraoperative bleeding and the subsequent need of blood products. Patients can presently consider pre-operative autologuous blood donation (PAD) prior to elective urological oncology surgery to decrease the risk of allogenic transfusion. We reviewed the medical charts of 141 patients that had a RRP in the CHUQ-Pavillon Hôtel-Dieu de Québec in 1996 for prostate cancer. The average and median blood loss were respectively 804 cc and 650 cc, but more than 75% of patients lost less than 1,000 ml. Allogeneic transfusion was required in 11 (7.8%) patients. PAD was done in 45.4 %. The clinical characteristics of patients with PAD were similar to the patients who did not bank blood. The need for allogeneic transfusion was reduced to 3% (2/64) in the patients with PAD compared to 11.7% for the 77 patients without PAD. The average blood loss was higher in the 11 patients that received allogenic blood (1641 cc vs 734 cc, p < 0.01), but their average preoperative Hb was lower (127.9 vs 141.9, p < 0.01). These results suggest that there may be other effective methods in preventing the need for allogenic blood transfusion in RRP. more...

Objective: To evaluate our experience with primary carcinomas of the female urethra, by analysing the impact of tumour variables and treatment on overall, disease-specific, local recurrence- and metastasis-free survival., Patients and Methods: Between 1958 and 1994, 72 women (median age 60 years, mean 59, range 21-84) with primary urethral carcinoma were identified. They were followed for a median (range) of 85 (0-384) months. The patients were stratified by stage, nodal status, histology, treatment, type of surgery, site of disease, year of diagnosis and smoking habit., Results: In a univariate analysis, stage, nodal status, type of surgery and site of the disease were important factors for survival and recurrence. In a multivariate analysis, primary stage, nodal status and site of disease were independent predictors of survival., Conclusion: Current modalities of treatment are ineffective for local control and survival; new treatment strategies are needed for female urethral cancers. more...

The ABO(H) histoblood group genes have been mapped by linkage analysis to 9q34.1-34.2, an area of common deletions in bladder cancer. Lack of ABO(H) antigen expression in bladder tumors is a frequent and well-documented event. In bladder neoplasms the loss of A and B transferase activity is due to down-regulation of the ABO gene transcripts. Our study was undertaken in order to determine the presence of structural alterations of the ABO(H) gene-encoding locus in primary bladder tumors, to estimate the extent of allelic deletions and to characterize further the pattern of histoblood group antigen expression. Fifty-three primary bladder tumors were analyzed by immuno-histochemistry (IHC) using a panel of well-characterized antibodies and fresh frozen tissue sections. Normal and tumor DNA also were analyzed by PCR coupled with restriction enzyme analysis in order to establish the ABO genotype. Results obtained from these analyses were then compared to allelotyping data at the 9q34.1-4 region by Southern blotting. IHC data showed undetectable levels of antigen expression on neoplastic cells in 59% of informative cases. PCR-based genotypic results revealed allelic losses in 27% of heterozygous cases. Four of the 16 pheno- and/or genotypically altered cases (25%) presented loss of heterozygosity at D9S10 or D9S7 loci. Our data indicate that the lack of ABO antigen expression in certain bladder tumors is due to the allelic loss of the ABO glycosyltransferase-encoding genes and that in some of these tumors the loss involves the surrounding chromosomal region at 9q34.1-4. more...

Epidemiological studies suggest that bladder cancer may be caused by carcinogens in tobacco and certain occupational exposures. Molecular studies have shown that chromosome 9 alterations and TP53 mutations are the most frequent events in bladder cancer. To date, the relationships between epidemiological risk factors and genetic alterations have not been fully explored in bladder cancer. The purpose of this study was to explore the association between smoking and chromosome 9 aberrations in bladder cancer cases. Seventy-three patients with bladder cancer at Memorial Sloan-Kettering Cancer Center were evaluated for smoking history, occupational history, and chromosome 9 alterations. The epidemiological data were abstracted from medical charts. Patients' tumor tissues were analyzed using RFLP and microsatellite polymorphism assays for detection of chromosome 9 alterations. Elevated odds ratios (ORs) were found for chromosome 9 alterations in smokers compared to those in nonsmokers (OR = 4.2; 95% confidence interval, 1.02-17.0) after controlling for age, sex, race, occupational history, and stage of disease. The ORs were 3.6 for those smoking < or = 20 cigarettes per day and 5.8 for those smoking > 20 cigarettes per day. No association was found between occupational history and chromosome 9 alterations. This study supplies evidence suggestive of the link between smoking and chromosome 9 alterations in the etiology of bladder cancer and indicates that potential tumor suppressor genes on chromosome 9 may be involved in smoking-related bladder carcinogenesis. more...

The proliferative rate of tumor cells is frequently proportional to their degree of aggressiveness. The objective of the present study was to determine the correlation between the expression of three antigens associated with proliferation and the stage and ploidy of bladder cancers. The reactivity of antibodies against the nuclear antigen Ki-67 and membrane antigens T43 and the epidermal growth factor receptor (EGFR) was studied by flow cytometry on a series of 35 clinical samples of superficial and infiltrating bladder cancer and as well as on 5 specimens of normal urothelial cells. A preferential expression of the T43 antigen was observed on invasive cancer. EGFR was less frequently expressed; however, seven of the nine positive samples were from invasive cancers. Ki67 on the other hand did not show any selective expression according to tumor stage. When comparing Ki-67 and T43 expression on individual tumor samples, a negative correlation was found in that no tumor strongly expressed both markers simultaneously. These results suggest that markers of proliferation and activation do not all measure the same tumor parameters. Together, they may provide prognostic information that may be useful in the follow-up of patients with bladder cancer. more...

Purpose: We have previously demonstrated that p53 overexpression is predictive of disease progression and survival in Ta, Tis, and T1 tumors. Instillation of Bacillus Calmette-Guérin (BCG) is now accepted to be the most efficient adjuvant therapy for superficial bladder carcinoma. The aim of this study was to determine if p53 status, assessed before and after intravesical BCG therapy, can predict clinical outcome in a high-risk population of patients with superficial bladder carcinoma., Materials and Methods: We examined 196 tissue specimens from 98 patients, obtained immediately before and after intravesical BCG therapy. The pretherapy population was composed of 22 Ta, 57 Tis, and 19 T1 tumors. After BCG, 66 specimens were TO and 32 had residual tumors. Nuclear p53 overexpression was analyzed in relation to time to disease progression and disease-specific survival., Results: The median follow-up duration was 44 months. The detection of nuclear p53 overexpression before BCG therapy did not predict response to BCG therapy. Pre-BCG p53 protein overexpression, response to BCG therapy, and pre-BCG stage were all independent markers of disease progression. In patients with residual disease after BCG therapy (nonresponders), multivariate analysis confirmed that posttherapy p53 overexpression was the only independent marker of disease progression., Conclusion: In this high-risk population of patients with superficial bladder tumors, patients who have p53 nuclear overexpression in the tumor and stage T1 disease before BCG therapy are at high risk of disease progression. Furthermore, in the group of patients with residual disease after BCG therapy, p53 status is a better predictor of disease progression than post-BCG stage. more...

Despite the clinical relevance of prostate cancer, few aspects regarding the molecular alterations involved in the process of prostate carcinogenesis are clearly understood. Cytogenetic and molecular genetic studies have identified specific abnormalities in prostate tumors, mainly on chromosomes 8, 10 and 16. On the basis of these findings, we designed a study to further characterize the altered regions on chromosome 10, using 15 microsatellite markers on a population composed of 20 paired normal and primary non-metastatic prostatic-tumor samples. Overall, 65% (13/20) of the cases analyzed showed molecular alterations, mainly rearrangements and deletions. The locus presenting the highest rate of abnormalities was D1OS221, which maps to 10q23-q24. Another region with frequent alterations was 10q21, at the DIOS109 locus. There was no statistical association between microsatellite abnormalities and Gleason grade or tumor stage in the prostate cancer cases studied. These results suggest that microsatellite alterations on the long arm of chromosome 10 are non-random events occurring in prostate cancer and that they may play a role in the process of tumorigenesis in these neoplasms. more...

The p21WAF1/CIP1 gene is regulated by p53 and encodes a cyclin-dependent kinase (Cdk)-inhibitor involved in senescence and cell quiescence. The role of p21 as a negative regulator of cell proliferation suggests that it may function as a tumor suppressor gene. However, only a few mutations of the p21WAF1/CIP1 gene have been reported to date. In order to assess potential p21WAF1/CIP1 gene alterations in human bladder cancer, we have examined this gene and its encoded product in a well-characterized cohort of 27 primary bladder tumors. Mobility shifts by single-strand conformation polymorphism in the p21WAF1/CIP1 gene were identified in 2 cases. Sequencing analyses revealed that one of these cases had point mutations in the 3' untranslated region, while the other case had a frame shift mutation at positions 322 (C to A) and a deletion of 8 nucleotides (323-->331; CCG-->ACG, codon 81 Arg-->Thr) that produced a stop signal at codon 83 (Gly--Stop). This tumor had a p21-negative phenotype by immunohistochemistry, but did not lose any allele. We further characterized these cases by the study of TP53 mutations using single-strand conformation polymorphism (PCR-SSCP) and sequencing, as well as immunohistochemical assays. Seven mobility shifts were identified and seven cases showed p53 nuclear accumulation. The two cases displaying mutated p21WAF1/CIP1 had wild-type TP53. It is concluded that p21WAF1/CIP1 gene aberrations are infrequent in bladder carcinoma but may be occasionally identified in primary bladder tumors. more...

Background: Two genes, p16 (also known as CDKN2, INK4A, or MTS1) and p15 (also described as INK4B or MTS2), are found in tandem at chromosome 9p21. These genes are designated as candidate tumor suppressor genes because they encode proteins that function as negative cell cycle regulators. (The encoded polypeptides inactivate specific cyclin-protein kinase complexes that are required for progression through the cell cycle.) Molecular genetic studies have revealed that deletion of the p16 and p15 genes occurs frequently in cancer cell lines and in certain malignant neoplasms., Purpose: We evaluated the frequency of p16 and p15 gene alterations in a well-characterized cohort of human transitional cell bladder cancers, and we explored potential associations between alterations in these genes and tumor stage and/or grade., Methods: Tumor tissue and normal tissue from 110 patients with transitional cell carcinoma of the urinary bladder were examined. The status of the p16 and p15 genes in these tissues was determined by Southern blotting and hybridization with gene-specific probes, by coupled polymerase chain reaction and single-strand conformation polymorphism analysis (PCR-SSCP), and by sequencing DNA fragments produced during PCR. Associations between alterations in the genes and tumor stage and/or grade were evaluated using the two-tailed Fisher's exact test., Results: Homozygous deletion (both alleles lost) of the p16 and the p15 genes was observed in 11 and nine bladder tumors, respectively. Eight of the 11 tumors exhibiting complete loss of the p16 gene also displayed homozygous deletion of the p15 gene. Exclusive loss of either gene was detected in only three tumors. Hemizygous deletion (one allele lost, also referred to as loss of heterozygosity [LOH] of the p16 and/or p15 genes was observed in eight tumors. Rearrangement of the two genes was indicated in three additional tumors. No point mutations were identified in either gene. The overall frequency of alteration in this cohort of bladder tumors was approximately 18% for each gene (in 20 [18.3%, 95% confidence interval (CI) = 11.1%-25.6%] of 109 informative tumors for the p16 gene and in 18 [18%, 95% CI = 10.5%-25.5%] of 100 informative tumors for the p15 gene). A statistically significant association between p16 gene alteration and bladder tumors of low stage (P < .01) and grade (P < .01) was observed; a significant association between p15 gene alteration and tumors of low stage (P < .01) was also detected., Conclusions: Alteration of the p16 and p15 genes, especially coincident homozygous deletion, appears to be a common event in bladder cancer. more...

The 9p21 region of human chromosome 9 is a hot spot for chromosomal aberrations in both cultured cell lines and primary tumors. This region contains a gene, P16 (also called MTS1, CDKN2 and p16INK4), that encodes a presumptive negative cell cycle regulator called p16. P16 is deleted or mutated at high frequency in a variety of tumor cell lines including melanoma and bladder carcinoma lines. As such, it is likely to be a tumor suppressor gene. Here we show that P16 is mutated in primary bladder carcinomas (3 of 33) and melanomas (5 of 34). These findings support studies that show P16 mutations are not solely a product of growth in tissue culture but rather are involved in formation of tumors in viva. Some bladder primary tumors and some bladder and melanoma tumor cell lines contain mutations in both P16 and P53 at frequencies that suggest that p53 and p16 function in different pathways, each of which is important in suppressing malignant transformation. more...

The p27Kip1 gene codes for a cyclin-dependent kinase inhibitor implicated in G1 arrest by transforming growth factor beta, cell-cell contact, agents that elevate cyclic AMP, and the growth-inhibitory drug rapamycin. p27 binds to and inhibits complexes formed by cyclin E-cdk2, cyclin A-cdk2, and cyclin D-cdk4. The involvement of p27 in the negative regulation of cell proliferation suggests that it may also function as a tumor suppressor gene. Using a combination of somatic cell hybrid panels and fluorescence in situ hybridization p27Kip1 has been mapped to the short arm of chromosome 12 at the 12p12-12p13.1 boundary, reported to harbor deletions and rearrangements in leukemia and mesotheliomas. In order to assess potential p27Kip1 gene alterations, we have screened a total of 147 human primary solid tumors and found no detectable cancer-specific mutations. These results argue that the often observed loss of antimitogenic transforming growth factor beta responsiveness in human cancer cells is not due to structural defects in p27Kip1. more...

Chromosome 9 allelic losses have been reported as a frequent and early event occurring in bladder cancer. It has been postulated that a candidate tumor suppressor gene may reside on this chromosome, alterations of which may lead to the development of a subset of superficial bladder tumors. More recently, the involvement of two different regions harboring suppressor loci, one on each of both chromosome 9 arms, has been proposed. We undertook the present study with the objectives of better defining the deleted regions of chromosome 9 in bladder tumors, as well as evaluating the frequency of microsatellite alterations affecting certain loci on this chromosome in urothelial neoplasia. Seventy-three primary bladder tumors were analyzed using a set of highly polymorphic markers, and results were correlated with pathological parameters associated with poor clinical outcome. We observed that, overall, 77% of the tumors studied showed either loss of heterozygosity for one or more chromosome 9 markers and/or microsatellite abnormalities at chromosome 9 loci. Detailed analyses showed that two regions, one on 9p at the interferon cluster, and the other on 9q associated with the q34.1-2 bands, had the highest frequencies of allelic losses. Furthermore, Ta lesions appeared to present mainly with 9q abnormalities, while T1 tumors displayed a mixture of aberrant 9p and 9q genotypes. These observations indicate that loss of heterozygosity of 9p may be associated with the development of superficial tumors with a more aggressive biological behavior or, alternatively, they may be related to early disease progression. In addition, microsatellite alterations were documented in over 40% of amplified cases. Taken together, these data suggest that two different tumor suppressor gene loci on chromosome 9 are involved as tumorigenic events in bladder cancer and that chromosome 9 microsatellite alterations are frequent events occurring in urothelial neoplasia. more...

Various 2-alkyl-alpha-methyl- and 2-alkylindan-5-acetic acids have been prepared. The acids, which can exist in two diastereoisomeric forms that cannot be separated by crystallization or chromatography, can be analyzed in their mixture by NMR in the presence of Eu(dpm)3. It has been possible to reconstitute the two pure racemic 2-isopropyl-alpha-methylindan-5-acetic acids from their enantiomers obtained after resolution of the mixtures through salts with various active bases. The relative configuration of the two asymmetric centers of one of the diastereoisomers salts with various active bases. The relative configuration of the two asymmetric centers of one of the diastereoisomers has been determined by X-ray crystallography. The absolute configurations of the resolved acids have been established by a comparative study of their CD curves. The antiinflammatory and analgesic properties of these compounds as functions of their structure and stereochemistry are discussed. more...