Michael Naslund

MicroRNA-1 is a candidate tumor suppressor and prognostic marker in human prostate cancer

We previously reported that miR-1 is among the most consistently down-regulated miRs in primary human prostate tumors. In this follow-up study, we further corroborated this finding in an independent data set and made the novel observation that miR-1 expression is further reduced in distant metastasis and is a candidate predictor of disease recurrence. Moreover, we performed in vitro experiments to explore the tumor suppressor function of miR-1. Cell-based assays showed that miR-1 is epigenetically silenced in human prostate cancer. Overexpression of miR-1 in these cells led to growth inhibition and down-regulation of genes in pathways regulating cell cycle progression, mitosis, DNA replication/repair and actin dynamics. This observation was further corroborated with protein expression analysis and 3′-UTR-based reporter assays, indicating that genes in these pathways are either direct or indirect targets of miR-1. A gene set enrichment analysis revealed that the miR-1-mediated tumor suppressor effects are globally similar to those of histone deacetylase inhibitors. Lastly, we obtained preliminary evidence that miR-1 alters the cellular organization of F-actin and inhibits tumor cell invasion and filipodia formation. In conclusion, our findings indicate that miR-1 acts as a tumor suppressor in prostate cancer by influencing multiple cancer-related processes and by inhibiting cell proliferation and motility.

Complications after radical retropubic prostatectomy in the medicare population

OBJECTIVES Radical prostatectomy is the standard of care for the treatment of clinically localized prostate cancer in the appropriate patient. However, the morbidity associated with this procedure remains controversial, since complications from centers of excellence are low but nationwide surveys have reported a much higher risk of complications. This study reports the complication rates after radical retropubic prostatectomy (RRP) for men in the Medicare population. METHODS All men in the Medicare population who underwent RRP in 1991 were identified. All inpatient, outpatient, and physician (Part B) Medicare claims for these men for 1991 to 1993 were then analyzed to determine outcomes. Procedures performed for complications resulting from RRP were recorded, as were the diagnosis codes that may have heralded a complication after RRP. RESULTS In 1991, 25,651 men in the Medicare population underwent RRP. The mean age of these men was 70.5 years. Procedures for the relief of bladder outlet obstruction or urethral strictures after RRP occurred in 19.5% of these men. A penile prosthesis was implanted in 718 men (2.8%) after prostatectomy, and 593 men (2.3%) had an artificial urinary sphincter placed after prostatectomy. A diagnosis of urinary incontinence was reported in 5573 men (21.7%) after radical prostatectomy, but only 2025 of these men (7.9%) continued to carry this diagnosis more than 1 year after prostatectomy. A diagnosis of erectile dysfunction was reported in 5510 men (21.5%) after radical prostatectomy, but only 3276 of these men (12.8%) continued to carry this diagnosis more than 1 year after surgery. CONCLUSIONS A review of a large, nationwide, heterogenous cohort of men revealed a morbidity rate that is slightly higher than that reported by major centers that perform large numbers of radical retropubic prostatectomies but is lower than complication rates obtained by patient surveys. The limitations of claim information in determining patient outcomes, however, must be considered when evaluating these data.

Complications after prostate brachytherapy in the Medicare population

OBJECTIVES Prostate brachytherapy is gaining in popularity among patients and physicians for the treatment of clinically localized prostate cancer. Although several major centers have published their results and morbidity data, nationwide data concerning complications have not been available. This study reports complications after prostate brachytherapy for men in the Medicare population. METHODS All men in the Medicare population who underwent prostate brachytherapy in 1991 were identified. All inpatient, outpatient, and physician (Part B) Medicare claims for these men from 1991 to 1993 were then analyzed to determine outcomes. RESULTS In 1991, 2124 men in the Medicare population underwent prostate brachytherapy. A total of 176 men (8.3%) underwent a surgical procedure for bladder outlet obstruction during the follow-up period, including transurethral resection of the prostate in 141 men. Seven men (0.3%) underwent a colostomy for complications secondary to radiation, and 4 men (0.2%) had an artificial urinary sphincter placed after prostate brachytherapy. Penile prostheses were placed in 14 men (0.6%) in the first 24 to 36 months after prostate brachytherapy. A diagnosis of urinary incontinence was carried by 140 men (6.6%) after the procedure; 179 men (8.4%) carried a diagnosis of erectile dysfunction after their procedure. A diagnosis consistent with rectal injury secondary to radiation appeared in 116 men (5.5%) after prostate brachytherapy. CONCLUSIONS Prostate brachytherapy is being promoted as an effective treatment option for clinically localized prostate cancer that offers a low risk of complications. The low rate of urinary incontinence, bladder outlet obstruction, and erectile dysfunction was confirmed by analyzing a nationwide cohort of men. Rectal complications were also consistent with those described in published studies. The limitations of claim information in determining patient outcomes, however, must be kept in mind when evaluating these data.

Late invasive recurrence despite long-term surveillance for superficial bladder cancer

Superficial transitional cell carcinoma of the bladder is associated with a 15 to 70% recurrence rate within 2 years. Most recurrences are superficial. A recurrence after 2 disease-free years is unusual. A review of the tumor registry revealed 124 patients followed for superficial disease at the Veterans Administration Center in Baltimore. Of the patients 20 were identified with either stage Ta (7) or stage T1 (13) papillary transitional cell carcinoma who had completed at least 5 years of surveillance without tumor recurrence. Invasive transitional cell carcinoma of the bladder requiring cystectomy developed in 7 of these 20 patients after remaining tumor-free for 5 years (stage Ta in 4 and stage T1 in 3). All 7 patients had organ-confined disease and were alive with no evidence of disease at 18 months to 5 years after cystectomy. These results demonstrate that superficial, low grade transitional cell carcinoma of the bladder can become muscle invasive despite careful surveillance and a long dormant period. In our series yearly cystoscopy and urine cytology identified tumor recurrence before metastases developed, suggesting that long-term surveillance is required in patients with superficial bladder cancer.

Hyperbaric oxygen treatment for experimental cyclophosphamide-induced hemorrhagic cystitis

Acrolein is a toxic metabolite of cyclophosphamide that causes hemorrhagic cystitis in 2 to 40% of treated patients. Hyperbaric oxygen (HBO) is used to treat poorly healing wounds in conditions such as Fourniers gangrene and radiation-induced cystitis. The present study was designed to evaluate the effects of HBO on acute acrolein-induced hemorrhagic cystitis in a rat model. Rats were divided into 4 groups. Group I served as a control and received only HBO prior to sacrifice. Group II received acrolein only, while groups III and IV received acrolein as well as HBO therapy. Hyperbaric oxygen (100% oxygen, 2.8 atmospheres, 90 minutes) was delivered twice a day for 4 days, with group III receiving a fifth HBO treatment just before acrolein and group IV receiving the fifth HBO treatment just after acrolein. After therapy, the amount of urothelial injury was determined morphometrically. Group II untreated rat bladders had only 33% of the urothelium intact after acrolein injury, whereas groups III and IV rat bladders had 93% (p < 0.01) and 55% (p < 0.01) intact urothelium, respectively, after treatment with HBO. The timing of the HBO treatment appeared to be a critical factor, with less injury occurring if the fifth HBO treatment immediately preceded acrolein. These results suggest that HBO may be useful as prophylaxis and treatment of cyclophosphamide-induced hemorrhagic cystitis.

Risk group stratification in patients undergoing permanent 125I prostate brachytherapy as monotherapy

PURPOSE Patients undergoing prostate brachytherapy (PB) as monotherapy are often selected on the basis of favorable pretreatment factors. However, intermediate and high-risk prostate cancer patients are commonly offered PB as monotherapy without the addition of external beam radiotherapy (EBRT) or hormonal therapy. This series reports the outcome of patients undergoing PB as monotherapy who were stratified into low, intermediate, and high-risk groups with extended follow-up. METHODS AND MATERIALS A total of 102 patients with clinically localized prostate cancer underwent PB alone as monotherapy. EBRT or hormonal therapy was not part of their initial treatment. Prostate-specific antigen (PSA) relapse-free survival (PRFS) was determined in accordance with the American Society for Therapeutic Radiology and Oncology consensus statement. Patients were stratified as at favorable risk (Stage T1-2a, pretreatment PSA < or =10.0 ng/mL, and Gleason score < or =6), intermediate risk (one prognostic indicator with a higher value), or unfavorable risk (> or =2 indicators with higher values). The median follow-up period for patients in this series was 7 years (range 2.1-9.7). The median age at treatment was 71 years (range 54-80), and the median prescribed dose of (125)I was 145 Gy. RESULTS Forty patients experienced a biochemical relapse at a median of 1.9 years (range 0.4-4.2). The 5-year actuarial PRFS rate for patients with favorable, intermediate, and unfavorable risk was 85%, 63%, and 24%, respectively (p <0.0001). All but 1 patient had the relapse within the first 5 years of treatment. When stratifying patients on the basis of their pretreatment PSA level, the 5-year PRFS rate for men with a PSA < or =10 ng/mL vs. >10 ng/mL was 78% vs. 35%, respectively (p = 0.0005). Furthermore, the 5-year PRFS rate for men with a Gleason score of < or =6 vs. > or =7 was 74% vs. 33%, respectively (p = 0.0001). No difference was found between Stage T1-T2a and Stage T2b or higher (64% vs. 54%, respectively; p = 0.353). CONCLUSION On the basis of risk stratification, PB as monotherapy produces comparable PRFS to EBRT and surgery at 7 years of follow-up. PB as monotherapy is particularly ineffective in patients with unfavorable risk factors, and additional therapy is warranted.

THE COST VALUE OF MEDICAL VERSUS SURGICAL HORMONAL THERAPY FOR METASTATIC PROSTATE CANCER

PURPOSE The cost of luteinizing hormone releasing hormone analogue and antiandrogen for prostate cancer is being scrutinized by the Health Care Finance Administration and other insurers. We compared the discounted present value cost of medical hormonal therapy to that of orchiectomy as well as the value created by these treatments from the insurer and patient perspectives. MATERIALS AND METHODS We performed a telephone survey of 42 patients receiving hormonal therapy to estimate the value created by medical versus surgical castration from the patient perspective. The cost of medical hormonal therapy was discounted back to the present value and compared with the cost of bilateral orchiectomy. RESULTS The total cost of bilateral orchiectomy was

Redesigning a large-scale clinical trial in response to negative external trial results: the CAMUS study of Phytotherapy for Benign Prostatic Hyperplasia

2,022, while the discounted present value cost using the average wholesale price for 30 months of medical hormonal therapy was

Associations Between Improvements in Lower Urinary Tract Symptoms and Sleep Disturbance Over Time in the CAMUS Trial

13,620. Therefore, medical hormonal therapy costs

Impact of delaying 5-alpha reductase inhibitor therapy in men on alpha-blocker therapy to treat BPH: assessment of acute urinary retention and prostate-related surgery

11,598 more than orchiectomy (