Gleason grading after neoadjuvant hormonal therapy retains prognostic value for systemic progression following radical prostatectomy.

BACKGROUND: The Gleason grading system in prostatectomy specimens following receipt of neoadjuvant therapy has been considered inaccurate. However, with continuing expansion of novel therapeutics, it is important to understand whether the Gleason system can be effectively utilized in this setting. The aim of this study was to assess the ability of the Gleason grading system to predict systemic progression among prostatectomy specimens treated with neoadjuvant hormone therapy (NHT). METHODS: This was a single-institution retrospective analysis from 1987 to 2009 of 13,427 patients who underwent radical prostatectomy (RP) without NHT and 1148 patients with NHT. NHT consisted of leuprolide alone (n = 415), antiandrogen therapy alone (n = 400) and combined treatment (n = 333). Kaplan-Meier analysis estimated 15-year systemic progression-free survival among NHT and non-NHT patients. Cox proportional hazard regression models estimated risk of systemic progression following RP according to NHT use and nonuse. RESULTS: Median duration of NHT was 3 months (interquartile range (IQR) 2-4) whereas median follow-up after RP was 8.3 years (IQR 5-10.8). NHT patients were more likely to be D'Amico high risk, have locally advanced pathologic T stage (≥ pT3), pathologic Gleason scores (GS) of 8-10 and lymph node involvement (P<0.0001 for all). NHT use was associated with lower rates of positive surgical margins, more downgrading to pT0 and less GS upgrading from biopsy (P ≤ 0.001 for all). GS could not be assigned to only 3% of NHT patients. On multivariate analysis, pathologic GS remained a predictor of systemic progression (SP) following NHT (hazard ratio (HR) 1.6, P = 0.005), but the association was less strong compared with non-NHT patients (HR 2.9, P < 0.0001). CONCLUSIONS: Utilization of the Gleason system appears feasible among hormonally pretreated prostatectomy specimens and shows continued prognostication for systemic progression. Confirmatory investigations are needed before the Gleason system can be reliably applied in the setting of neoadjuvant therapy.

Sustained pyridoxine response in primary hyperoxaluria type 1 recipients of kidney alone transplant.

Combined liver kidney transplant is the preferred transplant option for most patients with primary hyperoxaluria type 1 (PH1) given that it removes the hepatic source of oxalate production and improves renal allograft survival. However, PH1 patients homozygous for the G170R mutation can develop normal urine oxalate levels with pyridoxine therapy and may be candidates for kidney alone transplant (KTx). We examined the efficacy of pyridoxine therapy following KTx in five patients homozygous for G170R transplanted between September 1999 and July 2013. All patients were maintained on pyridoxine posttransplant. Median age at transplant was 39 years (range 33-67 years). Median follow-up posttransplant was 8.5 years (range 0.2-13.9 years). At the end of follow-up, four grafts were functioning. One graft failed 13.9 years posttransplant due to recurrent oxalate nephropathy following an acute medical illness. After tissue oxalate stores had cleared, posttransplant urine oxalate levels were <0.5 mmol/24 h the majority of times checked. Calcium oxalate crystals were noted in only 3/13 allograft biopsies. This series suggests that a subgroup of PH1 patients demonstrate sustained response to pyridoxine therapy following KTx. Therefore, pyridoxine combined with KTx should be considered for PH1 patients with a homozygous G170R mutation.

The association of tumor volume with mortality following radical prostatectomy.

BACKGROUND: Data regarding the prognostic significance of tumor volume (TV) in prostate cancer are conflicting. Herein, we evaluated the association of TV with prostate cancer mortality following radical prostatectomy (RP), and assessed the additive prognostic value of TV to an established predictive model. METHODS: We identified 13,687 patients who underwent RP without preoperative therapy between 1987 and 2009. TV was estimated using the prolate ellipsoid formula. Survival was estimated using the Kaplan-Meier method and compared with the log-rank test. Cox proportional hazard regression models were used to evaluate the association of TV with mortality. The ability of TV to enhance the performance of an established prognostic model (Mayo Clinic GPSM (Gleason, PSA, seminal vesicle and margin status) score) was assessed using the c-index. RESULTS: Median TV was 1.57 cm(3) (interquartile range (IQR) 0.48-4.19). Increasing TV was associated with significantly higher risks of seminal vesicle invasion (hazard ratio (HR) 1.58; P<0.0001), positive surgical margins (HR 1.28; P<0.0001) and lymph node involvement (HR 1.26; P<0.0001). Median postoperative follow-up was 9.4 years (IQR 5.0-14.5). Patient grouping into quartiles according to TV resulted in a significant stratification of outcome, as the 15-year cancer-specific survival by TV quartile was 99%, 98%, 95% and 88%, respectively (P<0.0001). Moreover, on multivariate analysis, greater TV remained associated with significantly increased risks of systemic progression (HR 1.27; P<0.0001), death from prostate cancer (HR 1.29; P<0.0001) and all-cause mortality (HR 1.05; P<0.0001). Meanwhile, addition of TV to the GPSM score increased the c-index for the model's prediction of prostate cancer mortality from 0.803 to 0.822. CONCLUSIONS: TV is associated with survival following RP, and enhances, although modestly, the performance of an established prediction model. As such, TV warrants continued assessment in risk stratification tools.

A genomic classifier predicting metastatic disease progression in men with biochemical recurrence after prostatectomy.

BACKGROUND: Due to their varied outcomes, men with biochemical recurrence (BCR) following radical prostatectomy (RP) present a management dilemma. Here, we evaluate Decipher, a genomic classifier (GC), for its ability to predict metastasis following BCR. METHODS: The study population included 85 clinically high-risk patients who developed BCR after RP. Time-dependent receiver operating characteristic (ROC) curves, weighted Cox proportional hazard models and decision curves were used to compare GC scores to Gleason score (GS), PSA doubling time (PSAdT), time to BCR (ttBCR), the Stephenson nomogram and CAPRA-S for predicting metastatic disease progression. All tests were two-sided with a type I error probability of 5%. RESULTS: GC scores stratified men with BCR into those who would or would not develop metastasis (8% of patients with low versus 40% with high scores developed metastasis, P<0.001). The area under the curve for predicting metastasis after BCR was 0.82 (95% CI, 0.76-0.86) for GC, compared to GS 0.64 (0.58-0.70), PSAdT 0.69 (0.61-0.77) and ttBCR 0.52 (0.46-0.59). Decision curve analysis showed that GC scores had a higher overall net benefit compared to models based solely on clinicopathologic features. In multivariable modeling with clinicopathologic variables, GC score was the only significant predictor of metastasis (P=0.003). CONCLUSIONS: When compared to clinicopathologic variables, GC better predicted metastatic progression among this cohort of men with BCR following RP. While confirmatory studies are needed, these results suggest that use of GC may allow for better selection of men requiring earlier initiation of treatment at the time of BCR.

Obese men have more advanced and more aggressive prostate cancer at time of surgery than non-obese men after adjusting for screening PSA level and age: results from two independent nested case-control studies.

BACKGROUND: It remains unclear whether the hemodilution effect of body mass index (BMI) on PSA levels translates to inappropriate prostate cancer (PCa) screening in obese men. To address this, we conducted two nested case-control studies within prospective cohorts of men undergoing radical prostatectomy for newly diagnosed PCa. METHODS: We identified 1817 men with BMI 30 kg m(-2) (cases) and 1244 men with BMI <25 kg m(-2) (controls) who underwent surgery to treat PCa at Mayo Clinic in Rochester between 2000 and 2009. Cases and controls were frequency matched on age and PSA level. In a similar manner, we identified 206 cases and 133 controls treated at Mayo Clinic in Florida between 2006 and 2011. We employed logistic regression models to evaluate the association of pathologic features of aggressiveness with obesity status. RESULTS: After adjusting for age and PSA level, we noted that obese men in the Rochester population are more likely to present with Gleason grade 8-10 tumors (OR= 1.50; 95% CI 1.14-1.96; P=0.003) and pT3, pT4, pTxN+ stage disease (OR=1.30; 95% CI 1.05-1.62). We noted a similar association seminal vesicle involvement (OR= 1.41; 95% CI 1.03-1.92; P=0.03). Results from the smaller Florida population supported these same associations but did not achieve conventional statistical significance. CONCLUSIONS: Obese men present with more aggressive PCa tumors compared with non-obese men of similar age and PSA screening values. If confirmed, this would support the need to explore PSA-based screening in obese men to possibly account for a hemodilution effect.

Clinicopathological predictors of systemic progression and prostate cancer mortality in patients with a positive surgical margin at radical prostatectomy.

BACKGROUND: Although a positive surgical margin (PSM) at radical prostatectomy (RRP) has been consistently linked to an increased risk of biochemical recurrence, the impact of margin status on patient survival continues to be debated. We evaluated long-term outcomes of patients with a PSM at RRP and determined predictors of systemic progression (SP) and mortality in these men. METHODS: We reviewed our institutional registry of 16,749 patients who underwent RRP between 1990 and 2008 to identify 2895 patients with a PSM. Median follow-up was 10.6 years. Postoperative survival was estimated using the Kaplan-Meier method. Cox proportional hazard regression models were used to analyze clinicopathological variables associated with SP and death from prostate cancer. RESULTS: A 15-year SP-free and cancer-specific survival was 90 and 93%, respectively. On multivariate analysis, higher tumor volume, increased pathological Gleason score and advanced pathological tumor stage were associated with significantly increased risks of SP and death from prostate cancer, whereas number and location of PSM did not predict mortality. CONCLUSIONS: The risks of SP and prostate cancer death in patients with a PSM remain low on long-term follow-up. Tumor variables are the primary determinants of cancer death. These results should be considered when evaluating patients with a PSM for adjuvant therapy.

Use of tumor dynamics to clarify the observed variability among biochemical recurrence nomograms for prostate cancer.

BACKGROUND: Nomograms for biochemical recurrence (BCR) of prostate cancer (PC) after radical prostatectomy can yield very different prognoses for individual patients. Since the nomograms are optimized on different cohorts, the variations may be due to differences in patient risk-factor distributions. In addition, the nomograms assign different relative scores to the same PC risk factors and rarely stratify for tumor growth rate. METHODS: We compared BCR-free probabilities from the GPSM model with a cell kinetics (CK) model that uses the individual's tumor state and growth rate. We first created a cohort of 143 patients that reproduced the GPSM patient distribution in Gleason score, Prostate specific antigen (PSA), Seminal vesicle involvement and Margin status since they form the GPSM score. We then performed 143 CK calculations to determine BCR-free probabilities for comparison with the GPSM results for all scores and with four other prominent nomograms for a high-risk patient. RESULTS: The BCR-free probabilities from the CK model agree within 10% with those from the GPSM study for all scores once the CK model parameters are stratified in terms of the GPSM risk factors and the PSA doubling time (PSADT). However, the probabilities from widely used nomograms vary significantly. CONCLUSIONS: The CK model reproduces the observed GPSM BCR-free probabilities with a broad stratification of model parameters for PC risk factors and can thus be used to describe PC progression for individual patients. The analysis suggests that nomograms should stratify for PSADT to be predictive.

Transplantation outcomes in primary hyperoxaluria.

Optimal transplantation strategies are uncertain in primary hyperoxaluria (PH) due to potential for recurrent oxalosis. Outcomes of different transplantation approaches were compared using life-table methods to determine kidney graft survival among 203 patients in the International Primary Hyperoxaluria Registry. From 1976-2009, 84 kidney alone (K) and combined kidney and liver (K + L) transplants were performed in 58 patients. Among 58 first kidney transplants (32 K, 26 K + L), 1-, 3- and 5-year kidney graft survival was 82%, 68% and 49%. Renal graft loss occurred in 26 first transplants due to oxalosis in ten, chronic allograft nephropathy in six, rejection in five and other causes in five. Delay in PH diagnosis until after transplant favored early graft loss (p = 0.07). K + L had better kidney graft outcomes than K with death-censored graft survival 95% versus 56% at 3 years (p = 0.011). Among 29 year 2000-09 first transplants (24 K + L), 84% were functioning at 3 years compared to 55% of earlier transplants (p = 0.05). At 6.8 years after transplantation, 46 of 58 patients are living (43 with functioning grafts). Outcomes of transplantation in PH have improved over time, with recent K + L transplantation highly successful. Recurrent oxalosis accounted for a minority of kidney graft losses.

Referral and ascertainment bias in patients with synchronous and metachronous endometrial malignancy.

The purpose of this study was to evaluate the frequency in patients with endometrial cancer of other malignancies and the influence of referral and ascertainment biases on these associations. Analysis of 1,028 local and referred patients who had a hysterectomy for endometrial cancer was based on residence at the time of diagnosis. Altogether, 208 patients had a history of another malignancy, most frequently breast, colon, and ovary. At the time of surgery for endometrial cancer, the prevalence of lymphoma and breast and ovarian cancers was greater than expected although the higher prevalence of lymphoma was limited to referred patients. During follow-up after hysterectomy, the incidence of lung cancer was lower than expected, whereas the incidence of lymphoma was higher. Breast, colorectal, and bladder cancers were more common than expected although this finding was limited to local patients. We concluded that results of epidemiologic studies from tertiary care centers may be misleading if they do not account for referral and ascertainment biases.

Rituximab treatment of idiopathic membranous nephropathy.

Idiopathic membranous nephropathy is a common cause of nephrotic syndrome whose pathogenesis may involve B-cell functions. Rituximab is a monoclonal antibody that binds to the CD20 antigen on B cells thereby deleting them. We conducted an open-label pilot trial of rituximab treatment in 15 severely nephrotic patients with proteinuria refractory to angiotensin-converting enzyme inhibition and/or receptor blockade but with adequately controlled blood pressure. Rituximab was given 2 weeks apart and, at 6 months, patients who remained proteinuric but had recovered B-cell counts were given a second course of treatment. Proteinuria was significantly decreased by about half at 12 months. Of the 14 patients who completed follow-up, full remission was achieved in two and partial remission in six patients based upon the degree of proteinuria. Side effects were minor; however, we found no relationship between the response and number of B cells in the blood, CD20 cells in the kidney biopsy, degree of tubulointerstitial fibrosis, starting proteinuria or creatinine values. Rituximab appears effective in reducing proteinuria in some patients with idiopathic membranous nephropathy but prospective identification of responsive patients was not possible.

Renal stone epidemiology in Rochester, Minnesota: an update.

Studies in Western countries have suggested an increasing incidence of nephrolithiasis (NL) in the latter part of the 20th century. Therefore, we updated NL epidemiology data for the Rochester population over the years 1970-2000. All Rochester residents with any diagnostic code that could be linked to NL in the years of 1970, 1980, 1990, and 2000 were identified, and the records reviewed to determine if they met the criteria for a symptomatic kidney stone as defined in a previous Rochester, MN study. Age-adjusted incidence (+/-s.e.) of new onset symptomatic stone disease for men was 155.1 (+/-28.5) and 105.0 (+/-16.8) per 100,000 per year in 1970 and 2000, respectively. For women, the corresponding rates were 43.2 (+/-14.0) and 68.4 (+/-12.3) per 100,000 per year, respectively. On average, rates for women increased by about 1.9% per year (P=0.064), whereas rates for men declined by 1.7% per year (P=0.019). The overall man to woman ratio decreased from 3.1 to 1.3 during the 30 years (P=0.006). Incident stone rates were highest for men aged 60-69 years, whereas for women, they plateaued after age 30. Therefore, since 1970 overall NL incidence rates in Rochester have remained relatively flat. However, NL rates for men have declined, whereas rates for women appear to be increasing. The reasons remain to be determined.

Glomerular filtration rate estimated by cystatin C among different clinical presentations.

Glomerular filtration rate (GFR) estimates from serum creatinine has not been generalizable across all populations. Cystatin C has been proposed as an alternative marker for estimating GFR. The objective of this study was to compare cystatin C with serum creatinine for estimating GFR among different clinical presentations. Cystatin C and serum creatinine levels were obtained from adult patients (n=460) during an evaluation that included a GFR measurement by iothalamate clearance. Medical records were abstracted for clinical presentation (healthy, native chronic kidney disease or transplant recipient) at the time of GFR measurement. GFR was modeled using the following variables: cystatin C (or serum creatinine), age, gender and clinical presentation. The relationship between cystatin C and GFR differed across clinical presentations. At the same cystatin C level, GFR was 19% higher in transplant recipients than in patients with native kidney disease (P<0.001). The association between cystatin C and GFR was stronger among native kidney disease patients than in healthy persons (P<0.001 for statistical interaction). Thus, a cystatin C equation was derived using only patients with native kidney disease (n=204). The correlation with GFR (r(2)=0.853) was slightly higher than a serum creatinine equation using the same sample (r(2)=0.827), the Modification of Diet in Renal Disease equation (r(2)=0.825) or the Cockcroft-Gault equation (r(2)=0.796). Averaged estimates between cystatin C and serum creatinine equations further improved correlation (r(2)=0.891). Cystatin C should not be interpreted as purely a marker of GFR. Other factors, possibly inflammation or immunosuppression therapy, affect cystatin C levels. While recognizing this limitation, cystatin C may improve GFR estimates in chronic kidney disease patients.

Incidence of physician-diagnosed interstitial cystitis in Olmsted County: a community-based study.

OBJECTIVE: To obtain community-based information about the incidence of interstitial cystitis, a chronic disabling condition of the bladder where knowledge is limited because there are no definitive diagnostic criteria. PATIENTS AND METHODS: All residents of Olmsted County, MN, USA who had received a physician-assigned diagnosis of interstitial cystitis between 1976 and 1996 were identified through the resources of the Rochester Epidemiology Project. The clinical findings at diagnosis and during the follow-up were ascertained from the community medical records for each study subject. RESULTS: In all, 16 women and four men received a diagnosis of interstitial cystitis during the study period. The overall age- and sex-adjusted (95% confidence interval) incidence rate was 1.1 (0.6-1.5) per 100 000 population. The age-adjusted incidence rates were 1.6 per 100 000 in women and 0.6 per 100 000 in men (P = 0.04). The median (range) age at initial diagnosis was 44.5 (27-76) years in women and 71.5 (23-79) years in men (P = 0.26). The median number of episodes of care-seeking for symptoms before the diagnosis was one for women and 4.5 for men (P = 0.03). The median duration from the onset of symptoms until the first diagnosis was 0.06 and 2.2 years in women and men, respectively (P = 0.2). CONCLUSIONS: These findings suggest that the incidence of interstitial cystitis in the community is extremely low. Although the gender difference may be real, the trend toward a later diagnosis in men than in women suggests a potential for missed diagnosis in men. This might explain some of the gender difference in the incidence of interstitial cystitis in men and women.

Long-term results of treatment for ureteroenteric strictures.

OBJECTIVES: To review the long-term outcome for ureteroenteric stricture treatment. METHODS: The ileal conduit diversions that formed ureteroenteric strictures from 1966 to 1999 were reviewed. The strictures were diagnosed radiographically, and malignancy was excluded. The treatment, location, length, diameter, and timing of stricture development after conduit creation was evaluated and compared regarding the time until stricture recurrence (failure). Success was defined as symptomatic improvement and radiologic evidence of patency. RESULTS: Forty patients, after exclusions, returned for ureteroenteric stricture repair, comprising 79 procedures (27 open repairs and 52 balloon dilations). The open repair had a success rate at 1, 2, and 3 years of 92%, 87%, and 76%, respectively. Seven of the open cases were preceded by failed dilations. Balloon dilation had a success rate at 1, 2, and 3 years of 15%, 15%, and 5%, respectively (P = 0.0001 versus open). Similar patency results for open versus balloon (P = 0.0001) were noted with analysis restricted to each patient's first stricture repair. Strictures greater than 1.0 cm were more likely to recur (P = 0.03). All strictures forming within 6 months of the conduit creation were treated with dilation and failed within 1 year. Of note, 11 of the 40 patients were found to have less than 25% renal function on the strictured side. CONCLUSIONS: Open repair for ureteroenteric strictures offers excellent long-term patency (76% at 3 years, P = 0.0001). On review, balloon dilation appeared to have less successful patency rates and was often followed by open repair after failure. Patients with a history of anastomotic strictures should be closely monitored to avoid renal damage and failure.

Role of early adjuvant hormonal therapy after radical prostatectomy for prostate cancer.

PURPOSE: Recent prospective randomized studies have shown that adjuvant hormonal therapy combined with local treatment can significantly improve overall survival in patients with locally advanced disease. This finding challenges the previous belief that adjuvant hormonal therapy may not be beneficial for minimal stages TxN + M0 or less prostate cancer, particularly when combined with local treatment. We reviewed the benefits of adjuvant hormonal therapy in patients at risk for disease progression, especially when administered after radical prostatectomy. MATERIALS AND METHODS: We retrospectively reviewed the current literature and evaluated clinical information on stage pT3b cancer from a large single institution prostate cancer database to determine the current role of adjuvant hormonal therapy after radical prostatectomy for prostate cancer. RESULTS: Retrospective experimental and clinical studies have proved the impact of adjuvant hormonal therapy for decreasing prostate specific antigen (PSA) and clinical disease progression in patients with regionally limited prostatic cancer. This finding applies to stage pT3b as well as to lymph node positive cancer. Our literature review and current data from the Mayo Clinic database show that adjuvant hormonal therapy after prostatectomy has a significant impact on prostate specific antigen (PSA) progression but it also decreases systemic progression and cause specific death in patients with stage pT3b and lymph node positive disease. After adjusting for preoperative PSA, margins, grade, ploidy and patient age the risk ratio for stage pT3b disease in 707 cases was 0.3 (95% confidence interval 0.2 to 0.7). A recent prospective randomized trial showed a significant decrease in cancer death in N+ cases when adjuvant hormonal therapy was administered after radical prostatectomy, supporting previous Mayo Clinic data on N+ disease that favors combination therapy. In the PSA era, that is 1987 and after, our database data on stage pTxN+ cancer indicates that radical prostatectomy and hormonal therapy for single node positive disease resulted in 94% 10-year cause specific survival, which was not significantly different from the rate in patients with N0 disease after adjusting for local stage, Gleason grade, margins, ploidy, PSA and adjuvant hormonal therapy. CONCLUSIONS: Our literature review, including prospective randomized studies, and more recent results in the PSA era from our database indicate that early adjuvant hormonal therapy has a significant impact on time to progression and cause specific survival in patients with seminal vesicle invasion and limited lymph node disease who undergo radical prostatectomy, although in a retrospective nonrandomized study. Future prospective studies with longer followup are needed to evaluate the potential benefit of adjuvant treatment in regard to survival for stages pT2 and pT3a disease with unfavorable pathological variables.

A prospective, randomized, double-blind, placebo-controlled study of orbital radiotherapy for Graves' ophthalmopathy.

CONTEXT: Although widely used for more than 85 years, the efficacy of radiotherapy for Graves' ophthalmopathy (GO) has not been established convincingly. OBJECTIVE: To evaluate the efficacy of radiotherapy for GO. DESIGN: Prospective, randomized, internally controlled, double-blind clinical trial in a tertiary care academic medical center. PARTICIPANTS: The patients were ethnically diverse males and females over age 30 seen in a referral practice. The patients had moderate, symptomatic Graves' ophthalmopathy (mean clinical activity score, 6.2) but no optic neuropathy, diabetes, recent steroid treatment, previous decompression, or muscle surgery. Forty-two of 53 consecutive patients were enrolled after giving informed consent and fulfilling study entry criteria. Eleven eligible patients declined to participate because of inconvenience, desire for alternative therapy, or concern about radiation. INTERVENTION: One randomly selected orbit was treated with 20 Gy of external beam therapy; sham therapy was given to the other side. Six months later, the therapies were reversed. MAIN OUTCOME MEASURES: Every 3 months for 1 year, we measured the volume of extraocular muscle and fat, proptosis, range of extraocular muscle motion, area of diplopia fields, and lid fissure width. Effective treatment for GO will modify one or more of these parameters. RESULTS: No clinically or statistically significant difference between the treated and untreated orbit was observed in any of the main outcome measures at 6 months. At 12 months, muscle volume and proptosis improved slightly more in the orbit that was treated first. CONCLUSIONS: In this group of patients, representative of those for whom radiotherapy is frequently recommended, we were unable to demonstrate any beneficial therapeutic effect. The slight improvement noted in both orbits at 12 months may be the result of natural remission or of radiotherapy, but the changes are of marginal clinical significance.

PSA doubling time as a predictor of clinical progression after biochemical failure following radical prostatectomy for prostate cancer.

OBJECTIVES: To characterize the clinical progression of disease in men who have undergone prostatectomy for clinically localized prostate cancer and have postoperative biochemical failure (elevated prostate-specific antigen [PSA] level) and to identify predictors of clinical disease progression, including the possible effect of PSA doubling time (PSADT). PATIENTS AND METHODS: Between 1987 and 1993, 2809 patients underwent radical retropubic prostatectomy for clinically localized (< or =T2) disease. In our database, all patients with postoperative biochemical failure (PSA level > or =0.4 ng/mL) were identified. The PSADT was estimated using log linear regression on all PSA values (excluding those values determined after administration of hormonal therapy) within 15 months after biochemical failure. All patients had regular PSA measurements from the time of surgery through the follow-up period. Systemic progression (SP) was defined as evidence of metastatic disease on a bone scan. Local recurrence (LR) was defined on the basis of digital rectal examination, transrectal ultrasonography, and biopsy. The SP-free survival and LR/SP-free survival (survival free of both LR and SP) after biochemical failure was estimated with use of the Kaplan-Meier method. Patients with prostate cancer treatment after biochemical failure had their follow-up censored from this study at the time of treatment. RESULTS: Postoperative biochemical failure occurred in 879 men (31%). The mean follow-up from time of biochemical failure was 4.7 years (range, 0.5-11 years). The mean time to biochemical failure was 2.9 years (median, 2.4 years). The overall mean SP-free survival from time of biochemical failure was 94% and 91% at 5 and 10 years, respectively. The mean LR/SP-free survival was 64% and 53% at 5 and 10 years, respectively. By using univariate analysis on the 587 patients with PSADT data, significant risk factors for SP were PSADT (P<.001) and pathologic Gleason score (P=.005); for LR/SP, significant risk factors included PSADT (P<.001) and pathologic Gleason score (P<.001). In multivariate Cox models analysis, only PSADT remained a significant risk factor for both SP and LR/SP (P<.001). Mean 5-year SP-free survival was 99%, 95%, 93%, and 64% for patients with PSADT of 10 years or longer, 1.0 to 9.9 years, 0.5 to 0.9 year, and less than 0.5 year, respectively; the respective mean LR/SP-free survivals were 87%, 62%, 46%, and 38%. The percentage of patients with PSADT of less than 0.5 year was considerably higher if the type of first clinical event was SP (48%) compared with LR (18%) (P<.001). CONCLUSIONS: For patients who have undergone radical prostatectomy, a rising PSA level suggests evidence of residual or recurrent prostate cancer. Many men remain free of clinical disease for an extended time after biochemical failure following radical prostatectomy for clinically localized prostate cancer. The PSADT appears to be an important predictor of SP and also of any clinical progression (local or systemic). These data may be useful when counseling men regarding the timing of adjuvant therapies.

Neuroendocrine cells in human prostate over-express the anti-apoptosis protein survivin.

BACKGROUND: Neuroendocrine (NE) differentiation may be related to the growth and progression of prostate cancer, especially androgen-insensitive tumors. Recently the over-expression of a new anti-apoptosis protein, survivin, has attracted attention for its potential implication in many human cancers. The fact that NE cells in prostate are bcl-2 negative prompted us to investigate if the prostatic NE cells over-express survivin. METHODS: Double immunohistochemical staining and immunofluorescence of chromogranin A (CgA) and survivin were performed in 57 patients with localized prostate cancer who underwent radical prostatectomy. The terminal deoxynucleotidyl transferase (TDT)-mediated dUTP-digoxigenin nick end-labeling (TUNEL) method was used for apoptosis detection in three prostate cancer specimens with NE differentiation. The relationship between NE differentiation and clinicopathological characteristics, disease progression as well as patient survival, were analyzed retrospectively. RESULTS: It was found that NE cells in both benign and malignant prostate tissues over-expressed the anti-apoptosis protein survivin. While apoptosis was detected in non-NE epithelial cells, all NE cells were negative for apoptosis detection. During the period of follow-up, 17 (63%) of 27 patients with NE differentiation had prostate cancer progression, while 12 (40%) of 30 patients without NE differentiation had systemic prostate cancer progression. 10 (37%) of 27 patients with NE differentiation died from prostate cancer during the period of follow up, while 6 (20%) of 30 patients without NE differentiation died from prostate cancer. However, none of these characteristics reached statistical significance, probably because of the small number of cases enrolled. CONCLUSIONS: This study discovers that all the prostatic NE cells express the new anti-apoptosis protein survivin. This provides a strong molecular basis for the hypothesis that NE cells may endure stressful conditions and escape from apoptosis. While our results suggest a trend of NE differentiation with poorer prognosis, the prognosis implication cannot be concluded due to our small sample size.

Outcomes for men with clinically nonmetastatic prostate carcinoma managed with radical prostactectomy, external beam radiotherapy, or expectant management: a retrospective analysis.

BACKGROUND: With a lack of data from randomized trials, the optimal management of men with nonmetastatic prostate carcinoma is controversial. The authors sought to define the outcomes of three common strategies for managing patients with nonmetastatic prostate carcinoma: expectant management, radiotherapy, and radical prostatectomy. METHODS: The authors conducted a retrospective cohort study with standardized collection of key prognostic data, including centralized assignment of Gleason grades from original biopsy specimens. Participants included all Connecticut hospitals (the expectant management cohort) and three academic medical centers in other states (the radiotherapy and surgery cohorts). Two thousand three hundred eleven consecutive men ages 55-74 years who were diagnosed during 1971-1984 with nonmetastatic prostate carcinoma and were treated at the participating sites were included. RESULTS: Kaplan-Meier estimates with 95% confidence intervals (95% CI) of overall survival at 10 years for each cohort were as follows: expectant management cohort, 42% of patients (95% CI, 38-46%); radiotherapy cohort, 52% of patients (95% CI, 46-58%); and radical prostatectomy cohort, 69% of patients (95% CI, 67-71%); for disease specific mortality, the estimates were as follows: expectant management cohort, 75% of patients (95% CI, 71-79%); radiotherapy cohort, 67% of patients (95% CI, 61-73%); and radical prostatectomy cohort, 86% of patients (95% CI, 84-88%). There were large differences in distributions of important prognostic factors among men in the different treatment groups. CONCLUSIONS: These data provide precise estimates of the outcomes of patients who have been treated with different modalities for nonmetastatic prostate carcinoma in the recent past. Direct comparisons of outcomes between treatment groups are inadvisable because of the different characteristics of patients who select these alternative management strategies.

Contemporary identification of patients at high risk of early prostate cancer recurrence after radical retropubic prostatectomy.

OBJECTIVES: To develop a model that will identify a contemporary cohort of patients at high risk of early prostate cancer recurrence (greater than 50% at 36 months) after radical retropubic prostatectomy for clinically localized disease. Data from this model will provide important information for patient selection and the design of prospective randomized trials of adjuvant therapies. METHODS: Proportional hazards regression analysis was applied to two patient cohorts to develop and cross-validate a multifactorial predictive model to identify men with the highest risk of early prostate cancer recurrence. The model and validation cohorts contained 904 and 901 men, respectively, who underwent radical retropubic prostatectomy at Johns Hopkins Hospital. This model was then externally validated using a cohort of patients from the Mayo Clinic. RESULTS: A model for weighted risk of recurrence was developed: R(W)'=lymph node involvement (0/1)x1.43+surgical margin status (0/1)x1.15+modified Gleason score (0 to 4)x0.71+seminal vesicle involvement (0/1)x0.51. Men with an R(W)' greater than 2.84 (9%) demonstrated a 50% biochemical recurrence rate (prostrate-specific antigen level greater than 0.2 ng/mL) at 3 years and thus were placed in the high-risk group. Kaplan-Meier analyses of biochemical recurrence-free survival demonstrated rapid deviation of the curves based on the R(W)'. This model was cross-validated in the second group of patients and performed with similar results. Furthermore, similar trends were apparent when the model was externally validated on patients treated at the Mayo Clinic. CONCLUSIONS: We have developed a multivariate Cox proportional hazards model that successfully stratifies patients on the basis of their risk of early prostate cancer recurrence.