Effect of enzalutamide on health-related quality of life, pain, and skeletal-related events in asymptomatic and minimally symptomatic, chemotherapy-naive patients with metastatic castration-resistant prostate cancer (PREVAIL): results from a randomised, phase 3 trial.

BACKGROUND: Enzalutamide significantly increased overall survival and radiographic progression-free survival compared with placebo in the PREVAIL trial of asymptomatic and minimally symptomatic, chemotherapy-naive patients with metastatic castration-resistant prostate cancer. We report the effect of enzalutamide on health-related quality of life (HRQoL), pain, and skeletal-related events observed during this trial. METHODS: In this phase 3, double-blind trial, patients were randomly assigned (1:1) to receive enzalutamide 160 mg/day (n=872) or placebo (n=845) orally. HRQoL was assessed at baseline and during treatment using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) and EQ-5D questionnaires. Pain status was assessed at screening, baseline, week 13, and week 25 with the Brief Pain Inventory Short Form (BPI-SF). The primary analysis of HRQoL data used a mixed-effects model to test the difference between least square means change from baseline at week 61. We assessed change from baseline, percentage improvement, and time to deterioration in HRQoL and pain, the proportion of patients with a skeletal-related event, and time to first skeletal-related event. Analysis was done on the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01212991. FINDINGS: Median treatment duration was 16·6 months (IQR 10·1-21·1) in the enzalutamide group and 4·6 months (2·8-9·7) in the placebo group. The mixed-effects model analyses showed significant treatment differences in change from baseline to week 61 with enzalutamide compared with placebo for most FACT-P endpoints and EQ-5D visual analogue scale. Median time to deterioration in FACT-P total score was 11·3 months (95% CI 11·1-13·9) in the enzalutamide group and 5·6 months (5·5-5·6) in the placebo groups (hazard ratio [HR] 0·62 [95% CI 0·54-0·72]; p<0·0001). A significantly greater proportion of patients in the enzalutamide group than in the placebo group reported clinically meaningful improvements in FACT-P total score (327 [40%] of 826 vs 181 [23%] of 790), in EQ-5D utility index (224 [28%] of 812 vs 99 [16%] of 623), and visual analogue scale (218 [27%] of 803 vs 106 of [18%] 603; all p<0·0001). Median time to progression in BPI-SF pain at its worst was 5·7 months (95% CI 5·6-5·7) in the enzalutamide group and 5·6 months (5·4-5·6) in the placebo group (HR 0·62 [95% CI 0·53-0·74]; p<0·0001). Progression of pain at its worst was less common in the enzalutamide group than in the placebo group at week 13 (220 [29%] of 769 vs 257 [42%] of 610; p<0·0001), but not at week 25 (225 [32%] of 705 vs 135 [38%] of 360; p=0·068). 278 (32%) of 872 patients in the enzalutamide group and 309 (37%) of 845 patients in the placebo group had experienced a skeletal-related event by data cutoff. Median time to first skeletal-related events in the enzalutamide group was 31·1 months (95% CI 29·5-not reached) and 31·3 months (95% CI 23·9-not reached) in the placebo group (HR 0·72 [95% CI 0·61-0·84]; p<0·0001). INTERPRETATION: In addition to improving overall survival relative to placebo, enzalutamide significantly improves patient-related outcomes and delays occurrence of first skeletal-related event in chemotherapy-naive men with metastatic castration-resistant prostate cancer. FUNDING: Astellas Pharma and Medivation.

Cell-free circulating DNA: diagnostic value in patients with testicular germ cell cancer.

PURPOSE: Increased levels of cell-free circulating DNA have been described in various malignancies as a diagnostic and prognostic biomarker. We analyzed the significance of cell-free DNA in patients with testicular cancer. MATERIALS AND METHODS: Cell-free DNA was isolated from the serum of 74 patients with testicular cancer, including 39 with seminoma and 35 with nonseminoma, and 35 healthy individuals. Real-time polymerase chain reaction was used to quantify a 106, a 193 and a 384 actin-beta DNA fragment. DNA integrity is expressed as the ratio of large (193 or 384 bp) to short (106 bp) DNA fragments. RESULTS: Actin-beta-106/193/384 fragment levels were significantly increased in patients with cancer compared to those in healthy individuals (each p <0.001). DNA integrity was significantly decreased in patients with cancer (p <0.001). Cell-free DNA fragment levels were not different when comparing patients with nonseminoma and seminoma (p >0.24). ROC analysis demonstrated that cell-free DNA levels distinguished patients with cancer from healthy individuals with 87% sensitivity and 97% specificity. Even in 31 patients in whom the established serum tumor markers alpha-fetoprotein, human chorionic gonadotropin, placental alkaline phosphatase and lactate dehydrogenase were normal cell-free DNA levels allowed us to distinguish between patients with cancer and healthy individuals with 84% sensitivity and 97% specificity. Cell-free DNA levels were more frequently increased in patients with clinical stage 3 than in patients with stage 1 or 2 disease (p <0.046). CONCLUSIONS: Cell-free DNA levels are increased in patients with testicular cancer and they allow the accurate discrimination of healthy individuals. The high sensitivity of cell-free DNA could facilitate the management of testicular cancer, especially in patients with conventional tumor markers that are not increased.

CpG island hypermethylation of cell-free circulating serum DNA in patients with testicular cancer.

PURPOSE: DNA hypermethylation is a common cancer associated alteration. We analyzed methylation patterns of cell-free serum DNA in patients with testicular cancer. MATERIALS AND METHODS: Hypermethylation at APC, GSTP1, PTGS2, p14(ARF), p16(INK) and RASSF1A was analyzed using real-time polymerase chain reaction following methylation sensitive restriction endonuclease treatment in 73 patients with testicular cancer and 35 healthy individuals. RESULTS: Hypermethylation was more common in patients with testicular cancer than in healthy individuals, including APC 57% and 6%, p16(INK) 53% and 17%, p14(ARF) 53% and 0%, RASSF1A 47% and 0%, PTGS2 45% and 0%, and GSTP1 25% and 0%, respectively (each p <0.01). Methylation frequencies at the investigated gene sites were similar in nonseminoma and seminoma cases (p >0.05). Diagnostic information was increased when multiple gene sites were analyzed in combination (ROC AUC 0.834, 67% sensitivity and 97% specificity). Diagnostic information was superior to the analysis of AFP/HCG/PLAP/LDH (combined sensitivity 58% and AUC 0.791). The sensitivity of hypermethylation in patients with unsuspicious conventional tumor markers was 71% (AUC 0.871, 97% specificity). Hypermethylation at PTGS2 was more common in patients with pT1 stage tumors (p = 0.011). CONCLUSIONS: The detection of hypermethylated cell-free serum DNA has the potential of a useful additional diagnostic parameter in patients with testicular germ cell cancer. Furthermore, in cases without conventional tumor marker increases testing CpG island hypermethylation in cell-free circulation DNA may improve the ability to detect early and/or recurrent testicular cancer.

Hypermethylation of cell-free serum DNA indicates worse outcome in patients with bladder cancer.

PURPOSE: CpG island hypermethylation is a frequent event in bladder carcinogenesis and progression. We investigated the diagnostic and prognostic value of hypermethylation in cell-free serum DNA of patients with bladder cancer. MATERIALS AND METHODS: The study cohort consisted of 45 patients with bladder cancer undergoing cystectomy and 45 with histologically confirmed benign prostatic hyperplasia serving as controls. Hypermethylation at APC, DAPK, GSTP1, PTGS2, TIG1 and Reprimo was analyzed using real-time polymerase chain reaction following methylation sensitive restriction endonuclease treatment. RESULTS: Hypermethylation at the APC and GSTP1 promoter was detected in 59% of cases, whereas TIG1 (32%), PTGS2 (24%) and DAPK (2%) were less frequently hypermethylated. In the benign prostatic hyperplasia group 3 patients also harbored methylated GSTP1 DNA, whereas none of the other gene sites was methylated. Hypermethylation at APC, GSTP1 or TIG1 distinguished patients with bladder cancer and controls most accurately with 80% sensitivity and 93% specificity. Hypermethylation significantly correlated with prognostic unfavorable clinicopathological parameters, including APC with pT stage, GSTP1, or GSTP1 or TIG1 with multifocal bladder cancer and APC, or APC or TIG1 with surgical margin positivity. Bladder cancer specific mortality was significantly increased in patients with APC hypermethylation. CONCLUSIONS: The detection of hypermethylation in cell-free serum DNA provides valuable diagnostic and prognostic information that can still be improved by combining the results of 3 gene sites (APC, GSTP1 and TIG1). The presence of hypermethylated DNA in the serum of patients with bladder cancer is associated with a worse outcome. Our results suggest that measuring hypermethylation in the serum of patients with bladder cancer is a useful biomarker.

Apoptotic DNA fragments in serum of patients with muscle invasive bladder cancer: a prognostic entity.

Patients with malignancies often possess increased concentrations of cell-free serum DNA. In this study, we investigated serum DNA levels in each 45 patients with bladder cancer (BCA) undergoing radical cystectomy and with benign prostate hyperplasia. A quantitative real-time PCR was used to amplify a 124 bp (PTGS2; mostly apoptotic origin) and a 271 bp (Reprimo; mostly necrotic origin) DNA fragment. Changes in the origin of DNA fragments were specified as the Apoptosis Index (AI, ratio of 124 bp/271 bp fragments). Small and large fragments were increased (p<0.001 and p=0.041) in BCA patients. The AI increase suggests that DNA fragmentation was mostly (p<0.001) caused by apoptosis. High levels of small DNA fragments distinguished between BCA and BPH with high sensitivity (96%) and moderate specificity (62%). DNA levels and the AI were not correlated with clinicopathological parameters. However, an increased AI was correlated with BCA-specific mortality in a multivariate analysis (p=0.011) indicating that the AI is an independent prognostic factor. Thus, cell-free DNA seems to be a useful prognostic marker in patients with BCA.

Review. Facts and fiction of phytotherapy for prostate cancer: a critical assessment of preclinical and clinical data.

The objective of this work was to substantially review all preclinical and clinical data on phytochemicals, such as genistein, lycopene, curcumin, epigallocatechin-gallate, and resveratrol, in terms of their effects as a potential treatment of prostate cancer. It is known, that prostate cancer patients increasingly use complementary and alternative medicines in the hope of preventing or curing cancer. The preclinical data for the phytochemicals presented in this review show a remarkable efficacy against prostate cancer cells in vitro, with molecular targets ranging from cell cycle regulation to induction of apoptosis. In addition, well-conducted animal experiments support the belief that these substances might have a clinical activity on human cancer. However, it is impossible to make definite statements or conclusions on the clinical efficacy in cancer patients because of the great variability and differences of the study designs, small patient numbers, short treatment duration and lack of a standardised drug formulation. Although some results from these clinical studies seem encouraging, reliable or long-term data on tumor recurrence, disease progression and survival are unknown. At present, there is no convincing clinical proof or evidence that the cited phythochemicals might be used in an attempt to cure cancer of the prostate.

Indirubin-3'-monoxime, a CDK inhibitor induces growth inhibition and apoptosis-independent up-regulation of survivin in transitional cell cancer.

In traditional Chinese Medicine, the preparation Danggui Longhui Wan has been used for years in the treatment of chronic myelocytic leukemia. The compound indirubin has been shown to be the active constituent. A cell permeable derivative, indirubin-3'-monoxime, is a selective and potent inhibitor of cyclin-dependent kinases (cdk). The ability of indirubin-3'-monoxime to induce apoptosis and tumor cell death in transitional cell cancer cell lines was investigated here. The growth-inhibitory properties were evaluated by EZ4U, a cytotoxic assay; apoptosis induction was determined by immunoblotting of cleaved PARP and flow cytometry of Annexin-V/PI staining during treatment. To evaluate further the underlying molecular action of indirubin-3'-monoxime on the cell cycle, the levels of cdk-1 and survivin, a mitotic spindle checkpoint and apoptosis-regulating protein, respectively, were additionally determined by flow cytometry and immunoblotting. The results indicated that indirubin-3'-monoxime induced reversible growth arrest in all four cell lines and an increase of apoptosis in two of them. The treatment with indirubin-3'-monoxime increased the expression of survivin almost four times in the RT4 cells and more than doubled it in the RT112 and T24 cells. In the SUP cells, the expression of survivin increased more than seven-fold after 72-h incubation. No clear correlation between the low apoptosis induction rate and extent of survivin expression was found. Cdk expression was not significantly altered by indirubin-3'-monoxime. In summary, indirubin-3'-monoxime might be a promising candidate for targeted cancer therapy, however, its molecular action remains to be further evaluated.

Flavopiridol, an inhibitor of cyclin-dependent kinases, induces growth inhibition and apoptosis in bladder cancer cells in vitro and in vivo.

Flavopiridol is a semi-synthetic flavone analog of the alkaloid, rohitukine, a compound from an Indian tree, Dysoxylum binectariferum. It has been shown to inhibit cyclin-dependent kinases (CDKs), causing cell cycle arrest and growth inhibition. Flavopiridol is reported to have cytotoxic activity against a wide range of cancer cell lines and has demonstrated its efficacy in several clinical trials. Flavopiridol seems a well-suited potential new agent for the treatment of bladder cancer. We, therefore, evaluated whether flavopiridol inhibits growth and induces apoptosis in bladder cancer cells and additionally examined the toxicity and efficacy of this drug in vivo in a rat bladder cancer model. The in vitro experiments showed an IC20 of 50-100 nM in all cell lines tested. However, there was a difference in the response with regard to the grading of the tumor cells at higher doses. The IC50 was found to be 150-350 nM in the well-differentiated RT4 and RTI12 cell lines after treatment with flavopiridol, in comparison to a IC50 of 1000 nMfor the poorly-differentiated cell lines T24 and SUP. After exposure to flavopiridol, all tumor cell lines underwent significant apoptosis in comparison to untreated cells, beginning at a dose of 50 nM flavopiridol. At high concentrations (500 nM) of flavopiridol, 80-90% of all cells showed severe apoptotic alterations. The treatment of rat urinary bladder cancer with flavopiridol demonstrated the best efficacy with an intermittent treatment of 0.1 mg/kg, 3 times weekly over a total of 3 weeks, resulting in 7/12 animals tumor-free and a trend for the remaining tumors to have lower stage and grade. There seems to be a small advantage in intermittent versus daily application of flavopiridol. In summary, our results indicated that flavopiridol could be a useful therapeutic agent for bladder cancer, inhibiting tumor growth, malignant progression and inducing apoptosis.

Superantigen-activated mononuclear cells induce apoptosis in transitional cell carcinoma.

BACKGROUND: Superantigens are among the most potent T-cell mitogens known. Since T-cell activation and T-cell-derived cytokines play a role in the immune response associated with intravesical Bacillus Calmette-Guerin (BCG) application, this study was initiated to explore the fundamental aspects of a potential new immunomodulatory therapy for superficial bladder cancer. Since Superantigen-induced cytotoxicity is mediated by apoptosis, the effects of SEB (staphylococcal enterotoxin B)-Superantigen-activated PBMC (peripheral blood mononuclear cells) on bladder cancer cells were evaluated with regard to Fas/Fas-ligand-based interactions. MATERIALS AND METHODS: Whether SEB can induce Fas-ligand expression on PBMC and the extent of cytokine secretion were examined by flow cytometry and specific ELISA. In addition, whether the SEB-activated PBMC are able to induce apoptosis in transitional cell carcinoma cells (TCC) was evaluated in co-culture experiments. RESULTS: It was shown that SEB induced pronounced time- but not dose-dependent specific Fas-ligand expression on PBMC, lasting 1 h to 7 h after initiation of the experiment. Cleaved soluble Fas-ligand was detected in the culture supernatants 24 h after stimulation, but not earlier. Further, a strong time-dependent secretion of cytokines IL-2, IFN-gamma and TNF-alpha released from the SEB-stimulated PBMC was shown. In co-culture experiments, it was demonstrated that SEB-activated PBMC significantly induced apoptosis in TCC cells. The released cytokines from SEB-treated PBMC demonstrated only a minor, not significant, apoptotic response in TCC cells. CONCLUSION: This first evaluation of the possible mode of action of a Superantigen opens the door for extended studies of this interesting approach to the treatment of bladder cancer.

Carboxyamido-triazole (CAI) reverses the balance between proliferation and apoptosis in a rat bladder cancer model.

Carboxyamido-triazole (CAI) is an orally bioavailable calcium influx and signal transduction inhibitor that has been shown to be anti-invasive, anti-angiogenic and anti-metastatic in different human tumors including transitional cell carcinoma. This study was undertaken to further evaluate the activity of CAI in a rat bladder cancer model. A transitional cell carcinoma (TCC) was chemically induced by intravesical installation of methyl-nitrosurea (MNU) in the bladder of female Fischer 344 rats. First, a toxicity study was performed which revealed no side-effects of CAI in the animals up to a dose of 250 mg/kg CAI. For treatment, a dose of 100 mg/kg CAI dissolved in PEG-400 vehicle was chosen. Oral administration of CAI continuously daily for 4 weeks (group A), 3 days/week over 6 weeks (group B), or intravesically twice a week for 6 weeks (group C) caused a reduction of spontaneous development of TCC. Lower stage and grade of tumors were seen in all CAI-treated animals. Under CAI treatment, the apoptotic rate in tumors increased, whereas the proliferation rate decreased, as shown by TUNEL assay and KI-67-immunhistochemistry, respectively. The highest efficacy was seen in group B, with 5 out of 10 animals tumor-free. Intravesical application (group C) resulted in 3 out of 10 animals tumor-free. Normal urothelium was not affected by CAI. This animal model confirms the anti-tumor effect of CAI and shows induction of apoptosis and growth inhibition in bladder cancer by the drug.

Carboxyamido-triazole (CAI), a signal transduction inhibitor induces growth inhibition and apoptosis in bladder cancer cells by modulation of Bcl-2.

Pro- and anti-apoptotic factors and intracellular signaling pathways are targets for therapeutic development of anticancer agents. Carboxyamido-triazole (CAI) is an inhibitor of transmembrane calcium influx and intracellular calcium-requiring signal transduction pathways. The present study investigates the effects of CAI on human transitional cancer cell (TCC) viability and apoptosis, and evaluates whether apoptotic resistance may be overcome pharmacologically. Both well-differentiated (RT4, RT112/grade 1) and poorly-differentiated (T24/grade 3; SUP/grade 4) human TCC lines were shown to express Fas. Upon exposure to agonistic monoclonal Fas antibody, only well-differentiated TCC lines underwent apoptotic cell death. CAI exposure reduced cell viability and caused an at least additive anti-apoptotic effect in combination with the Fas antibody in the Fas-insensitive TCC lines. Under the same conditions under which CAI treatment augmented Fas-mediated apoptosis, it was shown to reduce intracellular bcl-2 quantity. This response to CAI indicates that apoptotic cell death is enhanced by the reduction of bcl-2 protein expression. We suggest that the antitumor effect of CAI is at least partially based on restoring a pathway of apoptosis. It may cause transformation of cell homeostasis that leads to the alteration of apoptotic mechanisms, thus allowing highly malignant tumor cells to re-enter the physiological course of cell elimination.

Preclinical evaluation of gemcitabine/paclitaxel-interactions in human bladder cancer lines.

BACKGROUND: Gemcitabine and paclitaxel are currently co-administered in clinical studies for bladder cancer as this drug combination may offer better tumor responses. However, the drugs may antagonize the cytotoxic capacity of each other due to cell cycle perturbations. In this study, we evaluated different application schedules to determine the efficacy of the combination and its potential interactions. MATERIALS AND METHODS: Bladder cancer cell lines were exposed to either gemcitabine or paclitaxel, in concentrations ranging from 1-1000 nM. The inhibition concentrations (IC) 20, 50 and 70 were assessed by MTT assay after 24, 48 and 72 hours. Then, the cytotoxic activity and apoptosis induction abilities of the combined agents using the IC20 concentration were analyzed by MTT and Annexin-V/PI staining, respectively. The effects on the cell cycle were assessed by flow cytometry of bromodeoxyuridine (BrdU) and propidium iodide (PI). RESULTS: Gemcitabine and paclitaxel dose-dependently inhibited cell proliferation. Simultaneous application of gemcitabine/paclitaxel yielded superior cytotoxicity rates after 48 and 72 hours. Sequential treatment of cells showed similar results when gemcitabine was given 24 hours before paclitaxel. However, when paclitaxel was given before gemcitabine, the cell kill was less. Gemcitabine as well as paclitaxel have potent apoptosis inducing abilities. Cell cycle evaluation demonstrated a shift towards the S-phase after gemcitabine and a progressive G2/M block after paclitaxel treatment. CONCLUSION: The combination of gemcitabine and paclitaxel in vitro yields superior cytotoxic efficacy, if given simultaneously or with gemcitabine first. While in vitro cell models may not necessarily predict clinical outcome, they do provide a basis for rational scheduling of drugs in clinical trials.

Antiproliferative and apoptosis inducing effects of indirubin-3'-monoxime in renal cell cancer cells.

OBJECTIVES: Indirubin-3'-monoxime, which is a selective and potent inhibitor of cyclin-dependent kinases (CDKs) has shown preclinical activity in several human cancer cells. This study investigated if indirubin-3'-monoxime can induce apoptosis and tumor cell death in 3 human (A498, CAKI-1, CAKI-2) and 1 murine renal cell cancer (RENCA) cell line. METHODS: The growth inhibitory and apoptosis induction properties were evaluated by EZ4U, a cytotoxic assay and by flow cytometry of annexin-V/PI staining during treatment with doses ranging from 5.0 to 15.0 µM indirubin-3'-monoxime over 72 hours. To further establish the underlying molecular targets of indirubin-3'-monoxime, survivin, a major anti-apoptotic protein was additionally determined by intracellular flow cytometry. RESULTS: Our results show that indirubin-3'-monoxime induces growth arrest and apoptosis in all renal cell cancer (RCC) cell lines. All RCC lines expressed survivin. However, a clear correlation between apoptosis induction and expression of survivin was not found. CONCLUSIONS: As treatment of metastatic renal cell cancer (mRCC) remains a challenge, and the need for continuing assessment of novel agents in the treatment of this disease is mandatory. Indirubin-3'-monoxime seems to be a candidate for further evaluation.

New agents in intravesical chemotherapy of superficial bladder cancer.

Although intravesical chemotherapy has been used in the management of superficial bladder cancer for some decades, until recently there has been little or no progress in the search for new agents. However, in the past few years there have been developments of investigational drugs that may play a future role in this indication. This review highlights the mode of action, indications, dose and administration, efficacy, safety and significance of new chemotherapeutic agents such as intravesical valrubicin, gemcitabine, suramin, gamma-linolenic acid, eflornithine (DFMO), tipifarnib (R115777), fenritinide and celecoxib. Although the initial results achieved with these agents in clinical development seem encouraging, long-term data on the prevention of recurrence, disease progression and survival have yet to be obtained.

Preclinical evaluation of superantigen (staphylococcal enterotoxin B) in the intravesical immunotherapy of superficial bladder cancer.

Superantigens are potent activators of T lymphocytes; therefore, their characteristics can be exploited in diseases where immunomodulation is known to be effective. In this study, we evaluated a new approach for the intravesical therapy of superficial bladder cancer. We investigated in coculture experiments if staphylococcal enterotoxin B (SEB)-activated PBMCs are able to induce apoptosis in human transitional cell carcinoma (TCC) cells. Additionally, we tested the toxicity and efficacy of SEB dissolved in NaCl 0.9% administered intravesically once weekly for 6 weeks in a rat bladder cancer model. To validate the coculture in vitro findings, we evaluated tumor stage, grade, apoptotic cells in the urothelium and stroma of the bladder and infiltration of the bladder wall by lymphocytes, macrophages and mononuclear cells. Coculture experiments revealed that SEB-activated PBMCs are able to kill TCC cells by inducing apoptosis. The intravesical toxicity study with a maximum dose of 100 microg/ml SEB demonstrated no side effects. In the intravesically SEB-treated animals (10 microg/ml), only 3 tumors remained vs. 15 persisting tumors in the control group. The remaining tumors of the therapy group showed a significant amount of apoptosis and granulocytes, mainly in the urothelium, whereas no relevant apoptosis or infiltration of the bladder with lymphocytes or macrophages was found in the control group. These preclinical findings suggest that SEB might be an interesting candidate for further clinical evaluation.

Treatment of penile strangulation caused by constricting devices.

Constricting devices placed on the penis present a challenge to urologists. Various nonmetallic and metallic objects are placed on the penis to increase sexual performance or because of autoerotic intentions. We describe five different cases of strangulating objects (wedding ring, metal plumbing cuff, bull ring, hammer- head, and plastic bottle neck) and demonstrate that each case needs individual handling in removing the object. The treatment of penile strangulation is decompression of the constricted penis to facilitate free blood flow and micturition. It requires no particular skill but does require resourcefulness to perform the removal simply and effectively, and with as little discomfort for the patient as possible.