Michael J. Droller

Re: Insulin-Like Growth Factor-I (IGF-I) and IGF Binding Protein-3 as Predictors of Advanced-Stage Prostate Cancer

A recent study (1) suggested that elevated plasma levels of insulin-like growth factor-I (IGF-I) were a predictor of advanced-stage prostate cancer. We have studied IGF-I in prostate cancer and have found no relationship to disease stage. We studied IGF-I in a group of 126 men with prostate cancer and benign prostatic hypertrophy (BPH). Participants in our study were found through urology and radiation oncology clinics, and all eligible patients were asked to take part. All cancer patients had initially been diagnosed on the basis of levels of prostate-specific antigen (PSA) or abnormal physical examination. All men with BPH had had negative prostate biopsy examinations. Histologic confirmation of cancer diagnosis was also obtained for all subjects. All participants gave written informed consent. All staging of cancer cases was clinical, because almost all of the patients were to receive I seed implant therapy. Serum IGF-I was measured by use of the Nichols Advantage, an automated chemiluminescent immunoassay analyzer (Nichols Institute Diagnostics, San Juan Capistrano, CA). There was no statistically significant difference in the IGF-I levels in men with BPH compared with those in men with prostate cancer, nor was there statistically significant variation of IGF-I level among men with stages T1, T2, or T3 prostate cancer (P .323, one-way analysis of variance; Fig. 1). Multivariable linear regression revealed no statistically significant effect of PSA level, Gleason score, or T stage on IGF-I level (P .277) in men with prostate cancer. Shariat et al. (2) have shown that systemic levels of IGF-I are not associated with metastasis, established markers of biologically aggressive disease, or disease progression in patients with clinically localized prostate cancer. Our results agree with those of Shariat et al. and suggest that serum IGF-I levels are not related to advanced-stage prostate cancer.

A possible role of prostaglandins in the inhibition of natural and antibody-dependent cell-mediated cytotoxicity against tumor cells☆

Abstract We recently observed that certain tumor cell lines in tissue culture produced prostaglandins and that increased production occurred when the tumor cells were exposed to lymphocytes. The present experiments tested the effect of prostaglandins E 1 and E 2 on natural and antibody-dependent lymphocyte cytotoxicity against the same target cells in order to determine whether the production of prostaglandins by the tumor cells might influence the efficacy of the cellular immune response. Target cell lines T 24 and HCV 29 were labeled with 51 Chromium and incubated at 37 °C for various times with lymphocytes prepared from venous blood of normal donors. Antiserum to T 24 and varying concentrations of prostaglandin E 1 or E 2 were added to the samples prior to incubation. In some experiments, lymphocytes or labeled target cells were preincubated with prostaglandins and then washed prior to their addition to the assay tubes. Cytotoxicity was determined by measuring the release of 51 Chromium from the target cells after incubation. Both prostaglandins E 1 and E 2 inhibited natural and antibody-dependent lymphocyte cytotoxicity against the target cells. The effect appeared to represent a direct one on lymphocytes, and it was amplified by the presence of theophylline in the medium. Inhibition could be effected early on in lymphocyte/target cell interaction, and only a short exposure of lymphocytes to prostaglandins was required for the effect to be manifested. It thus appears that the production of prostaglandins by tumor cells may constitute a means by which the tumor cells subvert the effect of a cellular immune response that is directed against them.

Sensitivity and specificity of NMP-22, telomerase, and BTA in the detection of human bladder cancer☆

OBJECTIVES The recent introduction of novel molecular markers into clinical urology has created a need to evaluate the efficacy and utility of these potential markers. The ideal assay for bladder cancer should be noninvasive, sensitive, specific, and cost-effective. We compared the Matritech nuclear maxtrix protein (NMP)-22 assay, telomerase activity, and the Bard bladder tumor antigen (BTA) assay for the detection of human bladder cancer. METHODS A single voided urine sample was obtained from patients with hematuria without bladder cancer and from patients with known bladder cancer before any treatment. Approximately 50 to 100 mL of voided urine sample was collected and aliquotted for the various assays. The results were compared to single cytologic results and ultimately to pathologic findings. RESULTS In 47 patients with bladder cancer, the overall sensitivity was 81% for NMP-22, 80% for telomerase, 40% for BTA, and 40% for cytology. For Ta tumors (n = 31), sensitivity was 81% for NMP-22, 70% for telomerase, 32% for BTA, and 26% for cytology. For T1 or higher stage tumors (n = 13), sensitivity was 82% for NMP-22, 91% for telomerase, 64% for BTA, and 64% for cytology. The remaining 3 patients had carcinoma in situ (CIS). When tumors were stratified by tumor grade, grade I tumors (n = 16) were detected at 69% with NMP-22, 65% with telomerase, 13% with BTA, and 6% with cytology. Grade II tumors (n = 14) were detected at 86% with NMP-22, 72% with telomerase, 36% with BTA, and 36% with cytology. Grade III tumors (n = 14) were detected at 93% with NMP-22, 93% with telomerase, 79% with BTA, and 79% with cytology. Patients with CIS (n = 3) were detected at 67% with NMP-22, 100% with telomerase, 33% with BTA, and 67% with cytology. In 30 patients with hematuria but without bladder cancer, the overall specificity of the assays was 77% for NMP-22, 80% for telomerase, 73% for BTA, and 94% for cytology. CONCLUSIONS In the population tested, NMP-22 and the telomerase assays gave similar sensitivity and specificity for the detection of bladder cancer, and appear to offer a greater sensitivity than the BTA assay and/or conventional cytology.

Photodynamic Diagnosis of Non–muscle-invasive Bladder Cancer with Hexaminolevulinate Cystoscopy: A Meta-analysis of Detection and Recurrence Based on Raw Data

BACKGROUND Studies on hexaminolevulinate (HAL) cystoscopy report improved detection of bladder tumours. However, recent meta-analyses report conflicting effects on recurrence. OBJECTIVE To assess available clinical data for blue light (BL) HAL cystoscopy on the detection of Ta/T1 and carcinoma in situ (CIS) tumours, and on tumour recurrence. DESIGN, SETTING, AND PARTICIPANTS This meta-analysis reviewed raw data from prospective studies on 1345 patients with known or suspected non-muscle-invasive bladder cancer (NMIBC). INTERVENTION A single application of HAL cystoscopy was used as an adjunct to white light (WL) cystoscopy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS We studied the detection of NMIBC (intention to treat [ITT]: n=831; six studies) and recurrence (per protocol: n=634; three studies) up to 1 yr. DerSimonian and Lairds random-effects model was used to obtain pooled relative risks (RRs) and associated 95% confidence intervals (CIs) for outcomes for detection. RESULTS AND LIMITATIONS BL cystoscopy detected significantly more Ta tumours (14.7%; p<0.001; odds ratio [OR]: 4.898; 95% CI, 1.937-12.390) and CIS lesions (40.8%; p<0.001; OR: 12.372; 95% CI, 6.343-24.133) than WL. There were 24.9% patients with at least one additional Ta/T1 tumour seen with BL (p<0.001), significant also in patients with primary (20.7%; p<0.001) and recurrent cancer (27.7%; p<0.001), and in patients at high risk (27.0%; p<0.001) and intermediate risk (35.7%; p=0.004). In 26.7% of patients, CIS was detected only by BL (p<0.001) and was also significant in patients with primary (28.0%; p<0.001) and recurrent cancer (25.0%; p<0.001). Recurrence rates up to 12 mo were significantly lower overall with BL, 34.5% versus 45.4% (p=0.006; RR: 0.761 [0.627-0.924]), and lower in patients with T1 or CIS (p=0.052; RR: 0.696 [0.482-1.003]), Ta (p=0.040; RR: 0.804 [0.653-0.991]), and in high-risk (p=0.050) and low-risk (p=0.029) subgroups. Some subgroups had too few patients to allow statistically meaningful analysis. Heterogeneity was minimised by the statistical analysis method used. CONCLUSIONS This meta-analysis confirms that HAL BL cystoscopy significantly improves the detection of bladder tumours leading to a reduction of recurrence at 9-12 mo. The benefit is independent of the level of risk and is evident in patients with Ta, T1, CIS, primary, and recurrent cancer.

The effect of age and gender on bladder cancer: a critical review of the literature

While patient age and gender are important factors in the clinical decision‐making for treating urothelial carcinoma of the bladder (UCB), there are no evidence‐based recommendations to guide healthcare professionals. We review previous reports on the influence of age and gender on the incidence, biology, mortality and treatment of UCB. Using MEDLINE, we searched for previous reports published between January 1966 and July 2009. While men are three to four times more likely to develop UCB than women, women present with more advanced disease and have worse survival rates. The disparity among genders is proposed to be the result of a differential exposure to carcinogens (i.e. tobacco and chemicals) as well as reflecting genetic, anatomical, hormonal, societal and environmental factors. Inpatient length of stay, referral patterns for haematuria and surgical outcomes suggest that inferior quality of care for women might be an additional cause of gender inequalities. Age is the greatest single risk factor for developing UCB and dying from it once diagnosed. Elderly patients face both clinical and institutional barriers to appropriate treatment; they receive less aggressive treatment and sub‐therapeutic dosing. Much evidence suggests that chronological age alone is an inadequate indicator in determining the clinical and behavioural response of older patients to UCB and its treatment. Epidemiological and mechanistic molecular studies should be encouraged to design, analyse and report gender‐ and age‐specific associations. Improved bladder cancer awareness in the lay and medical communities, careful patient selection, treatment tailored to the needs and the physiological and physical reserve of the individual patient, and proactive postoperative care are particularly important. We must strive to develop transdisciplinary collaborative efforts to provide tailored gender‐ and age‐specific care for patients with UCB.

Prevention of cyclophosphamide-induced hemorrhagic cystitis☆

The occurrence of hemorrhagic cystitis with the use of high-dose cyclophosphamide is thought to be a toxic effect of cyclophosphamide metabolites directly on the bladder mucosa. To decrease both the concentration of metabolites in contact with the bladder mucosa and the time of such contact, a regimen of diuresis and frequent voiding or catheter drainage was instituted in patients at risk for the development of hemorrhage. Prior to institution of this regimen, 8 of 97 patients experienced massive clot-producing hemorrhage, three-quarters of whom died as a direct result of such hemorrhage. Subsequent to use of this regimen, only 1 of 198 patients experienced this degree of hemorrhage. Although this is only a phase II study, the dramatic decrease in the incidence of hemorrhage strongly suggests the efficacy of this regimen in decreasing the potential morbidity associated with cyclophosphamide-induced hemorrhagic cystitis.

ICUD-EAU international consultation on bladder cancer 2012: Screening, diagnosis, and molecular markers

CONTEXT AND OBJECTIVE To present a summary of the 2nd International Consultation on Bladder Cancer recommendations on the screening, diagnosis, and markers of bladder cancer using an evidence-based strategy. EVIDENCE ACQUISITION A detailed Medline analysis was performed for original articles addressing bladder cancer with regard to screening, diagnosis, markers, and pathology. Proceedings from the last 5 yr of major conferences were also searched. EVIDENCE SYNTHESIS The major findings are presented in an evidence-based fashion. Large retrospective and prospective data were analyzed. CONCLUSIONS Cystoscopy alone is the most cost-effective method to detect recurrence of bladder cancer. White-light cystoscopy is the gold standard for evaluation of the lower urinary tract; however, technology like fluorescence-aided cystoscopy and narrow-band imaging can aid in improving evaluations. Urine cytology is useful for the diagnosis of high-grade tumor recurrence. Molecular medicine holds the promise that clinical outcomes will be improved by directing therapy toward the mechanisms and targets associated with the growth of an individual patients tumor. The challenge remains to optimize measurement of these targets, evaluate the impact of such targets for therapeutic drug development, and translate molecular markers into the improved clinical management of bladder cancer patients. Physicians and researchers eventually will have a robust set of molecular markers to guide prevention, diagnosis, and treatment decisions for bladder cancer.

Bladder cancer: State-of-the-art care†

The challenge in bladder cancer is to control superficial disease and prevent its recurrence or progression. Patients with invasive disease need to be identified earlier, when disease may be less advanced and more amenable to cure. An important area for further investigation is the biology of the various forms of bladder cancer and the various pathways of development they may follow.

Enhancement of natural and antibody-dependent lymphocyte cytotoxicity by drugs which inhibit prostaglandin production by tumor target cells.

Abstract Our previous observations suggested that the production of prostaglandins by tumor cells exposed to lymphocytes might constitute a mechanism by which the tumor cells Could subvert the effects of a cellular immune response directed against them. The present experiments tested this hypothesis by determining whether inhibition of prostaglandin production permitted enhanced expression of natural and antibody-dependent lymphocyte cytotoxicity against the target cells. Cell lines T 24 and HCV 29 were labelled with 51 Chromium and incubated with purified lymphocytes obtained from venous blood of normal donors. Antiserum to T 24 and varying concentrations of inhibitors of prostaglandin synthetase (indomethacin, fenclozic acid, acetylsalicylic acid, and 2,6-xylenol) were added at the onset of incubation and assay tubes were incubated for varying times at 37 °C. In some experiments, lymphocytes or labeled target cells were preincubated with inhibitors and then washed prior to their addition to the assay tubes. Cytotoxicity was determined by measuring 51 Chromium release and assessing any differences that might reflect the presence of the various drugs. Each prostaglandin synthetase inhibitor significantly enhanced both natural and antibody-dependent lymphocyte cytotoxicity. Enhancement appeared to reflect an effect on the target cells, presumeably by an inhibition of prostaglandin production. No increase in spontaneous 51 Chromium release was apparent. The inhibitors did not appear to activate lymphocytes. This evidence supports the suggestion of a mechanism in which tumor cells may prevent the effect of a cellular immune response by producing inhibitory levels of prostaglandins. These results also suggest that manipulation of this mechanism can enhance the effectiveness of the lymphocyte response and may be a consideration in assessing lymphocyte/tumor cell interaction in vitro and in vivo .

Putative protein markers in the sera of men with prostatic neoplasms

To describe the preliminary identification of serum proteins that may be diagnostic markers in prostate cancer.