A meta-analysis of local anesthesia for transrectal ultrasound-guided biopsy of the prostate.

This meta-analysis evaluated the efficacy and safety of periprostatic nerve block (PPNB) and intrarectal local anesthestic (IRLA) gel in alleviating pain during prostate biopsy. Electronic databases MEDLINE, Cochrane Central Register of Controlled Trials and EMBASE were searched to identify all randomized controlled trials comparing PPNB with periprostatic placebo injection, no injection or with IRLA. Studies for inclusion were identified and extracted by two authors independently. The main outcome measure was patients' assessment of mean pain scores on a 10-point scale at the end of the biopsy procedure. Secondary outcomes were complications and adverse events. Continuous data from the trials were combined by calculating the weighted mean difference (WMD) with its 95% confidence interval. In total, 25 studies met the inclusion criteria. Twenty studies involving 1685 patients compared PPNB with either no anesthesia or with placebo injection controls, showing a significant reduction in pain score in the anesthetic group (WMD -2.09, 95% CI -2.44 to -1.75, P<0.00001). Five studies with 466 patients compared IRLA and control. Although IRLA was associated with pain reduction, the effect size was not statistically significant (WMD -0.22, 95% CI -0.56 to 0.12). Six studies with 872 patients compared PPNB with IRLA, showing a significant pain reduction in the former group (WMD -1.53, 95% CI -2.67 to -0.39, P=0.008). No trials reported an increase in complications in the treatment arms. In conclusion, the evidence from randomized controlled trials shows that local anesthetic given as a PPNB, but not as an intrarectal instillation, is effective and safe in alleviating pain from transrectal ultrasound biopsy of the prostate.

Uncommon benign intrascrotal tumours.

INTRODUCTION: Benign intrascrotal tumours are rare. CLINICAL PICTURE: Three patients with bilateral paratesticular leiomyomas, an adenomatoid tumour of the testis and a left paratesticular dermoid cyst coexisting with a synchronous left paratesticular epidermal cyst are presented. These tumours were discrete, hard and smooth lesions, in which the diagnosis of malignancy could not be safely excluded preoperatively even with ultrasonography. TREATMENT AND OUTCOME: The first patient had orchiectomy with contralateral testicular preserving surgery, the second patient underwent orchiectomy and the third had conservative testicular surgery. CONCLUSION: Awareness of these benign tumours may allow for testicular preservation.

Transfection of urothelial cells using methyl-beta-cyclodextrin solubilized cholesterol and Dotap.

the murine urothelial cell line, mb49 was transfected with the reporter gene pcmvlacz using a number of commercial transfection agents. the transfection efficiency of these agents, as determined by beta-galactosidase activity, is in the order of dotap>superfect>Fugene. The addition of methyl-beta-cyclodextrin solubilized cholesterol (MBC) to Dotap and Superfect further improved their transfection efficiency by 3.8-fold and 2.6-fold, respectively. beta-Galactosidase activity was detectable within 1 h of transfection and peaked at 48 h. Nuclear and cytoplasmic separation showed that with Dotap + methyl-beta-cyclodextrin solubilized cholesterol (DMBC), the DNA plasmid complex was found in both the nucleus and the cytoplasm. In vivo, murine bladders were transfected with an intravesical instillation of DMBC + DNA for 2 h. Two days later the bladder, lungs, liver, spleen and heart were assayed for the presence of the beta-galactosidase gene by staining and PCR. Expression of the gene was confined to the bladder. Both in vitro and in vivo expression was observed after as little as a 15 min exposure to DMBC:DNA. Expression of the marker gene was present up to 30 days after transfection in vivo. From our data it appears that DMBC is the best nonviral agent for the transfection of urothelial cells in vitro and in vivo.

Antitumour immunity of Bacillus Calmette-Guerin and interferon alpha in murine bladder cancer.

Intravesical Bacillus Calmette-Guerin (BCG) immunotherapy is currently the optimal choice for aggressive superficial bladder cancer, with a 70% response rate. This study investigated whether the antitumour response elicited by BCG could be improved by the addition of recombinant interferon alpha (IFN alpha) in the subcutaneous murine MB49 bladder tumour model. The combination of BCG and IFN alpha had superior and earlier antitumour activity than BCG alone for MB49 cells in culture. A total of 14/15 BCG plus interferon-treated mice and 8/16 BCG-treated mice became tumour free after treatment. BCG or the combination treatment significantly raised the T-helper 1 (Th1) cytokine IFN gamma levels compared with levels in all other groups. Whilst BCG therapy alone increased CD4+ and CD8+ populations in spleens, the combination of BCG and IFN alpha also increased alpha beta+ T cells significantly. Our results suggest that the combination of BCG and IFN alpha may represent a more efficacious therapeutic than BCG alone for superficial bladder cancer.

Evaluation of lymphocytic responses after treatment with Bacillus Calmette-Guerin and interferon-alpha 2b for superficial bladder cancer.

Bladder wash-derived lymphocytes from superficial bladder cancer patients involved in high dose BCG, low dose BCG, and low dose BCG with IFN-alpha treatments were examined. We found an increasing trend in the percentage of CD3 T cells with each weekly intravesical instillation and the proportion of CD3 T cells expressing the gammadelta T cell receptor was significantly higher in patients receiving standard dose BCG than those receiving low dose BCG or low dose BCG plus IFN-alpha. Most patients had a predominance of CD4 T cells, while some had more CD8 T cells. The CD4/CD8 ratio did not vary much during the instillations. Surprisingly, both patients and normal control individuals had high percentages of CD69- and CD45RO-positive lymphocytes in the bladder wash and this was not reflected in lymphocytes from peripheral blood collected in parallel. We found no differences in lymphocyte phenotypes, cytokine production, and clinical outcome in the patients from three arms. This may reflect that the qualitative and quantitative immune responses elicited from the three treatments are similar. However, the lymphokine-activated killing ability of peripheral blood lymphocytes against allogeneic cell-lines from the cancer patients was depressed compared to normal individuals and the cytotoxicity appeared to be enhanced after intravesical treatment.

Effects of bacillus Calmette-Guèrin and interferon alpha-2B on cytokine production in human bladder cancer cell lines.

PURPOSE: To determine the effects of live BCG, autoclaved BCG and interferon alpha-2b on cytokine production in human bladder cancer cell lines. MATERIALS AND METHODS: The release of nine cytokines from the human bladder cancer cell lines, RT4, RT112, SD, MGH and J82, was measured by ELISA assay. The mRNA level of IL-6 and GM-CSF was determined by RT-PCR. RESULTS: BCG and/or interferon alpha-2b differentially increased IL-1beta, IL-6, IL-8, GM-CSF and TNF-alpha production in the bladder cancer cells. High grade cell lines were more responsive to BCG whereas low grade lines were more sensitive to interferon alpha-2b. This correlated with cytotoxicity and growth inhibition induced by these agents. BCG could also induce low levels of IFN-alpha production in all the cell lines. Compared with live BCG, autoclaved BCG had no antiproliferative effect on MGH cells and was less effective in stimulating the production of IL-6, IL-8 and GM-CSF. However, autoclaved BCG was as effective as live BCG in inhibiting growth and stimulating IL-6 and TNF-alpha production of J82 cells. The combination of BCG and interferon alpha-2b also completely suppressed TGF-beta1 production in the MGH and RT112 cell lines. CONCLUSIONS: The combination of BCG and interferon alpha-2b has additive effects in cytokine production from bladder cancer cells. This correlates with cytotoxicity and growth inhibition induced by these agents.

Effects of bacillus Calmette-Guerin and interferon-alpha-2B on human bladder cancer in vitro.

The cytolytic and anti-proliferative effects of bacillus Calmette-Guerin (BCG) and/or interferon-alpha-2b (IFN-alpha-2b) on 5 human bladder carcinoma cell lines, RT4, RT112, MGH, SD and J82, were determined. The cell lines showed different sensitivities to BCG and IFN-alpha-2b. BCG had direct dose-dependent cytolytic and anti-proliferative effects on MGH, J82 and SD (grade 3 cell lines), whereas RT4 and RT112 (grades 1 and 2, respectively) were less sensitive. Surprisingly, higher concentrations of BCG enhanced cell growth of RT4. IFN-alpha-2b also had cytolytic and anti-proliferative effects on all 5 cell lines. Thus, the RT4 and RT112 cell lines that were not sensitive to BCG were highly sensitive to IFN-alpha-2b. A combination of BCG and IFN-alpha-2b had additive anti-proliferative effects on MGH, J82 and RT112. Interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) production by these 5 cell lines was measured after stimulation with BCG and/or IFN-alpha-2b, by ELISA immunoassays. Production of IL-6 and TNF-alpha was significantly increased in MGH and J82 cell lines by the combination of BCG and IFN alpha-2b. The enhanced cytolytic and anti-proliferative effects of the combination of BCG and IFN-alpha-2b may be related to the induction of cytokines.

A community based study of prostatic symptoms in Singapore.

PURPOSE: We describe the prevalence of prostatic symptoms, bother and related quality of life, as well as health seeking behavior in men 40 years old or older in Singapore. MATERIALS AND METHODS: A community based cross-sectional study was conducted in men 40 years old or older in Queenstown, Singapore. The International Prostate Symptom Score for benign prostatic hyperplasia was used to score symptom severity objectively. Results obtained were compared to those from United States, Scottish and Japanese populations. RESULTS: The prevalence of moderate to severe symptomatology was 10% after age adjustment to match the 1990 Singapore population. The most prevalent symptoms were frequency (22.5% of cases) and nocturia (21.5%) with consistently lower prevalence for bother (6.9% for frequency and nocturia). The prevalence of prostatic symptoms was approximately 3 or more times less than in the Scottish, United States and Japanese populations, while the prevalence of bother was approximately 10 times less. For symptomatic individuals there was poor correlation between symptom severity and bother scores. Bother scores correlated better with quality of life scores (r = 0.50) and were more closely associated with health seeking behavior (p = 0.03) than symptom severity scores (r = 0.39, p = 0.07). CONCLUSIONS: The prevalence of prostatic symptoms, severity and bothersomeness were all relatively low in Singapore. Bother was not analogous to symptom severity and should be considered independently in clinical decision making.

Interleukin-6 production by bladder tumors is upregulated by BCG immunotherapy.

PURPOSE: To determine whether BCG therapy could upregulate interleukin-6 (IL-6) production in human transitional cell carcinomas (TCC). MATERIALS AND METHODS: Immunohistochemistry of tumor biopsies and urinary cytospins and ELISA studies of urine from bladder cancer patients and TCC cell-line supernatants, before and after exposure to BCG, were performed. RESULTS: Constitutive staining for IL-6 was found in the majority of bladder tumors. Interleukin-6 was detected in the urine of all 13 patients with carcinoma in situ and increased 5-fold during BCG therapy. Levels were variable but were greater in nonresponders (p < 0.01). During therapy both detached bladder urothelial cells and polymorphonuclear leukocytes stained for IL-6. Production of IL-6 increased in only 3 cell lines after exposure to BCG, but all 7 cell lines showed increases after exposure to interferon-gamma (p = 0.015). Grade 3 cell lines showed much greater upregulation than grade 1 and 2 cell lines. CONCLUSIONS: The increase in IL-6 during BCG therapy may be caused by urothelial cells as well as leukocytes. The higher levels seen in nonresponders may be due to either higher grade or persisting tumor.

Changes in urinary cytokines and soluble intercellular adhesion molecule-1 (ICAM-1) in bladder cancer patients after bacillus Calmette-Guérin (BCG) immunotherapy.

Intravesical immunotherapy for carcinoma in situ of the bladder is arguably the most effective form of tumour immunotherapy described to date. Following repeated instillations of BCG organisms into the bladder, large quantities of cytokines are detected in patients' urine. This study concerns the production of IL-1 beta, IL-2, IL-4, IL-6, IL-8, IL-10, tumour necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) and soluble ICAM-1 (sICAM-1) throughout the six weekly instillations which comprise a therapeutic course. Sequential instillations of BCG induced secretion of IL-1 beta, IL-2, IL-6, IL-8, IL-10, TNF-alpha, IFN-gamma and sICAM-1 into urine. The responses were heterogeneous between patients and cytokines, but some general trends were evident. Although cytokine levels were initially low, their concentration increased with repeated instillation of BCG. Certain cytokines (e.g. IL-6, IL-8 and IL-10) could be detected after the first instillation, whilst others (e.g. IL-2 and IFN-gamma) were not detected until after the third or fourth instillation. Interestingly, IL-4 was not detected, perhaps suggesting a differential effect on Th2-like responses. Some patients produced particularly elevated or non-detectable levels of cytokines, and a positive correlation was found between the production of various cytokines. The production of a particular cytokine did not correspond with lack of production of another species. Whether monitoring the production of cytokines following therapy may be of prognostic value will be determined in a larger series of patients. However, as these potent immunomodulators are thought to be important for the 75% complete clinical response observed with BCG therapy, there remains the possibility that detection of the products of an activated immune system may correlate with eventual clinical outcome. This study is a necessary forerunner to full prognostic evaluation of such immunological data.

Autocrine regulation of ICAM-1 expression on bladder cancer cell lines: evidence for the role of IL-1 alpha.

We have studied the autocrine regulation of essential expression of the intercellular adhesion molecule-1 (ICAM-1) on 8 transitional cell carcinoma (TCC) cell lines (histopathological grades 1-3). The constitutive expression of ICAM-1 was regulated by soluble factors in an autocrine fashion. These factors were produced by all cell lines, with the exception of the MGH-U1 cell line. The effects observed could be largely attributed to IL-1 alpha. However, the residual ICAM-1 inducing activity (up to 30% of ICAM-1 induction) could not be associated with any known ICAM-1 inducers (IFN gamma, TNF alpha, TNF beta, IL-1 alpha, IL-1 beta, IL-4, retinoic acid, LPS). In contrast to recombinant derived cytokines, the IL-1 alpha present in tissue culture supernatant was only able to induce ICAM-1 on high-grade tumours and not low-grade cells. This discriminative effect is similar to that noted following in vitro culture of tumour cells with bacillus Calmette-Guerin organisms. Whether the production of soluble factors (e.g., IL-1 alpha) by TCC cell lines plays an essential autocrine role for bladder tumours and/or affects the interaction with cells of the immune system needs to be investigated further.

Induction of ICAM 1 expression on bladder tumours by BCG immunotherapy.

AIMS: To determine the expression of intercellular adhesion molecule 1 and 2 (ICAM 1 and 2) in transitional cell carcinoma cells before and after immunotherapy with Calmette-Guérin bacillus (BCG). METHODS: Frozen sections from 22 untreated bladder carcinomas were immunohistochemically examined with monoclonal antibodies to ICAM 1 and 2. Urinary cytospin slides were made for six patients for each of the six clinical instillations which constitute a therapeutic course. These slides were also stained for ICAM 1 and for leucocyte function associated antigen 1 (LFA 1). RESULTS: Bladder cancer cells did not essentially express either ICAM 1 or 2, but cells in the stromal areas surrounding tumour expressed both these antigens. After repeated instillations of BCG organisms ICAM 1 positive normal and neoplastic epithelial cells were observed in the urine. Cells obtained from the first three instillations expressed lower densities of ICAM 1 than those from the later instillations. Many neutrophils expressing LFA-1 and some lymphocytes were also noted in the cytospin slides and some of these were conjugated to tumour cells expressing ICAM 1. Six months after treatment a single maintenance dose of BCG induced ICAM 1 expression. CONCLUSION: Untreated superficial bladder carcinoma cells do not express ICAM 1 or 2, but these important immunological molecules were expressed in the stromal areas of tissue. Importantly, neoplastic cells in the urine expressed ICAM 1 after immunotherapy. This molecule can render bladder tumour cells vulnerable to non-antigen specific cytotoxicity mediated by activated lymphocytes.

Control of leucocyte function-associated antigen-1-dependent cellular conjugation by divalent cations.

The control of integrin activation is fundamental to an understanding of the integrin-dependent cellular adhesion thought to be important for a plethora of basic cellular functions. Using a cell-cell conjugation assay the role of divalent cations in leucocyte function-associated antigen-1 (LFA-1)-dependent cellular adhesion was further investigated. The conjugation of interleukin-2 (IL-2)-activated lymphocytes to tumour cells was found to be energy dependent and required the presence of various divalent cations, removal of which decreased the level of conjugation. Increased concentrations of calcium, magnesium and manganese ions resulted in a corresponding increase in levels of conjugation. This increase in conjugation was LFA-1 dependent. Interestingly, when calcium ions were first removed from LFA-1, treatment of lymphocytes with magnesium and manganese ions gave significantly higher levels of conjugation than in the presence of calcium. Using a simple displacement study, calcium ions were shown to displace magnesium ions resulting in decreased conjugation. However, calcium ions were unable to displace manganese ions for binding to LFA-1. That manganese was exerting its effect via an LFA-1-dependent mechanism was confirmed using monoclonal antibodies to CD11a which negated the increased conjugation frequency due to manganese.

Does transurethral laser ureterolithotripsy justify its cost?

A prospective consecutive series of 64 patients who underwent transurethral laser ureterolithotripsy using a 7.2F semirigid ureteroscope was compared to the immediately preceding consecutive series of 98 patients who had undergone ultrasound lithotripsy using rigid 9.5F or 12.5F ureteroscopes. The distribution of the calculi by size and composition in both series was similar. There was a higher proportion of upper ureteral calculi in the laser lithotripsy series. The success rate for a first attempt at laser lithotripsy was 92.2% versus 71.4% for the ultrasound series (p less than 0.01). When the stone could be reached ultrasound and laser lithotripsy had a fragmentation rate of 97%. The principal reason for the difference in results was the poorer ability to reach calculi when using the larger rigid ureteroscopes. One patient who had failed ultrasound lithotripsy was successfully treated with laser lithotripsy a year later. The overall morbidity was less for laser lithotripsy. The 3-year cost-benefit analysis revealed a smaller difference in cost than expected and the 5-year analysis was advantageous for laser lithotripsy because of its higher success rate. Savings were also realized in the laser series because of the higher proportion of subjects treated as outpatients, and a lower mean duration of hospitalization and time missed from work. For our center with an annual work load of approximately 100 cases laser lithotripsy achieved a superior cost-benefit ratio.

A study of 245 infected surgical wounds in Singapore.

The aims of the study were to correlate the laboratory detection rate of wound infections with the actual wound infection rate, and to analyse the bacteriology of these wounds to provide a rationale for antibiotic usage in prophylaxis and treatment of surgical wound infections. The wound infection rate in a general surgical unit was determined using the most comprehensive surveillance available to us and was correlated with the laboratory detection rate. A correlation coefficient of 0.8 was obtained, allowing a reasonable estimation of the actual wound infection rate from laboratory data. Review of the bacteriology of consecutive infected surgical wounds over a 4 year period in a university hospital, revealed that the commonest organisms cultured were Staphylococcus aureus, Escherichia coli, Klebsiella spp., Pseudomonas aeruginosa, enterococci and beta-haemolytic streptococci. Methicillin-resistant S. aureus (MRSA) caused 50% of all staphylococcal wound infections. All MRSA isolates were sensitive to fusidic acid and vancomycin. All the non-MRSA isolates of S. aureus were sensitive to cephalexin. Some 89% of E. coli were sensitive to gentamicin, with 93% and 100% sensitive to cefuroxime and ceftriaxone respectively. Klebsiella isolates have shown an increased resistance to aminoglycosides, with a new strain from one patient, isolated in 1990, resistant to penicillins, aminoglycosides and third generation cephalosporins. Pseudomonas spp., enterococci and beta-haemolytic streptococci did not show a change in resistance patterns over the same time period.

Stones in horseshoe kidneys: results of treatment by extracorporeal shock wave lithotripsy and endourology.

We report the results of 7 patients with calculi in a horseshoe kidney treated by extracorporeal shock wave lithotripsy (ESWL, 9 renal units) and percutaneous nephrolithotripsy (3 renal units) during a 3-year period. In the ESWL only group complete stone clearance was achieved in only 3 patients (50%) after an average of 3 sessions of therapy. On the other hand, complete stone clearance was achieved by percutaneous nephrolithotripsy with minimal complications. The poorer results with ESWL were due to difficulty in ultrasonographic localization of stones as well as poor drainage in these abnormal kidneys. Our experience with the Edap LT01 and the Sonolith 2000 lithotriptors suggests that while reasonable results are possible, treatment probably will require multiple sessions and the eventual outcome is less predictable than in normal kidneys. In contrast, the treatment of complicated stones in a horseshoe kidney presents no additional difficulty.