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PubMed2026

Systematic characterization of neurotransmitter receptor dysregulation identifies a neural-related prognostic signature associated with biochemical recurrence in prostate cancer.

BACKGROUND: The nervous system is increasingly recognized to play a critical role in tumor initiation and progression. Central to this complex relationship are the interactions between neurotransmitters secreted by neurons and their receptors (neurotransmitter receptors, NTRs) expressed on cancer cells, which activate multiple intracellular signaling pathways. However, the spectrum of NTR dysregulation and its association with biochemical recurrence (BCR) in prostate cancer (PCa) has not been explored. Therefore, the aim of this study was to fill this gap. METHODS: We systematically characterized the expression profiles of 130 NTR genes by integrating bulk and single-cell transcriptomic data. Consistently dysregulated NTR (cdNTR) genes were identified and used to construct a PCa signature (PCaSig) using elastic-net regression. The robustness of PCaSig was evaluated across three independent cohorts. In addition, the associations of PCaSig with clinicopathological characteristics, genomic alterations, tumor immune-related characteristics, and biological pathways were comprehensively investigated. RESULTS: Thirteen cdNTR genes with strong cell-type specificity, particularly in luminal epithelial cells, were identified. PCaSig robustly stratified patients into distinct BCR risk groups across multiple independent cohorts and remained an independent predictor after adjustment for clinicopathological factors. High PCaSig scores were associated with aggressive clinicopathological features, elevated tumor mutation burden (TMB), suppression of neurotransmitter-related signaling, and activation of cell-cycle and immune-related pathways. Notably, PCaSig refined prognostic stratification regardless of TMB status and was associated with distinct immune-related characteristics, including immune checkpoint expression and immune cell infiltration. Incorporation of PCaSig into a clinical nomogram significantly improved prognostic accuracy and clinical net benefit. CONCLUSIONS: These findings establish NTR dysregulation as a previously underappreciated dimension of PCa and support PCaSig as a clinically relevant tool for personalized management.

Neurotransmitter receptor (NTR)↗
PubMed2006

Anatomic radical retropubic prostatectomy-long-term recurrence-free survival rates for localized prostate cancer.

Radical prostatectomy remains the mainstay for the treatment of localized prostate cancer. Long-term follow-up data showed excellent cancer control rates in several prostatectomy series. We report biochemical recurrence (BCR) outcomes after radical retropubic prostatectomy (RRP) in a European single center series of patients treated over a 13-year period. Between 1992 and 06/2005, 4,277 consecutive men underwent a RRP at the University Hospital Hamburg Eppendorf, Germany. Kaplan-Meier probabilities of BCR-free survival were determined for those patients with complete preoperative data, postoperative data, and follow-up information. Uni-and multivariate Cox regression models addressed PSA recurrence, defined as a PSA level > or = 0.1 ng/ml. Overall, BCR-free survival ranged between 84, 70 and 61% for 2, 5, and 8 years, respectively. In univariate and multivariate analyses, except for age and type of nerve-sparing technique, all traditional clinical and pathological variables represented statistically independent predictors of PSA recurrence-free survival (all P < or = 0.001). In organ-confined disease, the 10-year recurrence free survival rate was 80 and 30% in non-organ-confined cancers. Our findings confirm excellent long-term biochemical cancer-control outcomes after RRP. High grade prostate cancer at final pathology and seminal vesicle invasion proved to be the strongest risk factors of BCR after surgery.

Adult↗
PubMed2006

Molecular load of pathologically occult metastases in pelvic lymph nodes is an independent prognostic marker of biochemical failure after localized prostate cancer treatment.

PURPOSE: Thirty percent of patients treated with curative intent for localized prostate cancer (PC) experience biochemical recurrence (BCR) with rising serum prostate-specific antigen (sPSA), and of these, approximately 50% succumb to progressive disease. More discriminatory staging procedures are needed to identify occult micrometastases that spawn BCR. PATIENTS AND METHODS: PSA mRNA copies in pathologically normal pelvic lymph nodes (N0-PLN) from 341 localized PC patients were quantified by real-time reverse-transcriptase polymerase chain reaction. Based on comparisons with normal lymph nodes and PLN with metastases and on normalization to 5 x 10(6) glyceraldehyde-3'-phosphate dehydrogenase mRNA copies, normalized PSA copies (PSA-N) and a threshold of PSA-N 100 or more were selected for continuous and categorical multivariate analyses of biochemical failure-free survival (BFFS) compared with established risk factors. RESULTS: At median follow-up of 4 years, the BFFS of patients with PSA-N 100 or more versus PSA-N less than 100 was 55% and 77% (P = .0002), respectively. The effect was greatest for sPSA greater than 20 ng/mL, 25% versus 60% (P = .014), Gleason score 8 or higher, 21% versus 66% (P = .0002), stage T3c, 18% versus 64% (P = .001), and high-risk group (50% v 72%; P = .05). By continuous analysis PSA-N was an independent prognostic marker for BCR (P = .049) with a hazard ratio of 1.25 (95% CI, 1.001 to 1.57). By categorical analysis, PSA-N 100 or more was an independent variable (P = .021) with a relative risk of 1.98 (95% CI, 1.11 to 3.55) for BCR compared with PSA-N less than 100. CONCLUSION: PSA-N 100 or more is a new, independent molecular staging criterion for localized PC that identifies high-risk group patients with clinically relevant occult micrometastases in N0-PLN, who may benefit from additional therapy to prevent BCR.

Aged↗
PubMed2006

Comparative assessment of the 1992 and 2002 pathologic T3 substages for the prediction of biochemical recurrence after radical prostatectomy.

BACKGROUND: The objective of this study was to compare the ability of the 1992 American Joint Committee on Cancer (AJCC) TNM staging system for nonorgan-confined prostate carcinoma (PCa) (pathologic T3 [pT3a], pT3b,and pT3c) to predict biochemical recurrence (BCR) after radical prostatectomy with its revision from 1997/2002 (pT3a and pT3b). METHODS: The authors analyzed prospectively collected data from 971 consecutive patients with pT3 tumors who underwent radical prostatectomy alone at a single institution. According to the 1992 AJCC substages, 494 patients had pT3a PCa (51%), 85 patients had pT3b PCa (9%), 302 patients had pT3c PCa (31%) and 91 patients had pT3 PCa (9%) with metastatic lymph node invasion (LNI). Kaplan-Meier and Cox proportional hazards regression analyses were employed to assess the BCR rate using the preoperative prostate-specific antigen (PSA) level, surgical margin (SM) status, pathologic Gleason score, and LNI. The predictive accuracy of this "base" model was compared with models that added either the AJCC 1992 or the AJCC 1997/2002 staging definitions. RESULTS: BCR was observed in 345 patients (36%). The actuarial 5-year recurrence-free probability for patients with AJCC 1992 pT3a, pT3b, and pT3c PCa was 69%, 42%, and 33%, respectively, and differed significantly between men with pT3a tumors and men with pT3b tumors (log-rank test; P < 0.0005). In Cox regression analyses, the 1992 substages were associated significantly with BCR after controlling for PSA, SM status, Gleason grade, and LNI (P < 0.0005). The predictive accuracy of the base model (bootstrap-corrected concordance index, 0.739) was improved after addition of the 1992 TNM staging criteria (concordance index, 0.747). However, predictive accuracy was similar for the model that included the 1997/2002 substages (concordance index, 0.746). CONCLUSIONS: Substaging of pT3 tumors according to the less complex 1997/2002 pT3 classification improved the predictive accuracy of the BCR rate virtually to the same extent as the more detailed 1992 classification. Therefore, the current data favor the use of the 1997/2002 pT3 substaging system.

Biomarkers, Tumor↗
PubMed2006

Lymphovascular invasion in prostate cancer: prognostic significance in patients treated with radiotherapy after radical prostatectomy.

BACKGROUND: Lymphovascular invasion (LVI) is found in approximately 5% to 53% of specimens after radical prostatectomy (RP). Although LVI is associated with higher rates of recurrence after RP, its prognostic significance after postprostatectomy radiotherapy (P-XRT) is unclear. METHODS: The medical records of men who received P-XRT from 1991 to 2001 at 2 institutions were reviewed for the presence of LVI in RP specimens. Multiple patient variables were evaluated for their association with LVI using Fisher exact tests and Wilcoxon rank-sum tests. The time to biochemical recurrence (BCR) and the time to distant metastases (DM) after RP were analyzed using Kaplan-Meier estimations, log-rank tests, and Cox regression analyses. RESULTS: Eighteen of 160 patients (11%) who received P-XRT had LVI in their RP specimen. High Gleason score and seminal vesicle invasion were associated significantly with LVI. After a median follow-up of 8.3 years after RP, 16 patients with LVI had BCR after P-XRT, 9 of whom developed DM. The median time to BCR in patients with LVI was 2.6 years (95% confidence interval [95% CI], 1.8-5.4) compared with 7.8 years (95% CI, 6.8-10.3) in patients without LVI (P < .001). Multivariate analysis revealed an adjusted relative risk for LVI of 5.5 (P < .001). Other significant factors were Gleason score, undetectable post-RP serum prostate-specific antigen (PSA) levels, preradiotherapy serum PSA levels, and the interval from RP to P-XRT. LVI was the only significant factor associated with an increased risk of DM in univariate analysis (hazard ratio, 7.4; P < .001). CONCLUSIONS: LVI was useful as a pathologic marker for reduced efficacy of P-XRT after RP in terms of increased risk of BCR and DM. Future studies will be needed to validate these findings.

Aged↗
PubMed2006

Cancer-specific survival and predictors of prostate-specific antigen recurrence and survival in patients with seminal vesicle invasion after radical prostatectomy.

BACKGROUND: The objectives of the current study were to determine the long-term biochemical recurrence (BCR) and cancer-specific survival (CSS) rates for men with seminal vesicle invasion (SVI) and to identify risk factors for freedom from BCR and CSS in patients who received treatment in the prostate-specific antigen era and who had SVI identified at the time of radical prostatectomy (RP). METHODS: Prospective clinical, pathologic, and outcome data were collected for 5377 men who underwent RP between June 1983 and August 2004. There were 936 patients who were excluded because they received treatment before RP. Multivariable analysis was used to identify the factors that predicted BCR and CSS. RESULTS: Among 4441 eligible patients, 387 patients (8.7%) had SVI, and 91 of those 387 patients (24%) had lymph node involvement (LNI). In total, 210 patients experienced BCR. For patients without LNI, the 10-year and 15-year freedom from BCR rates were 36% and 32%, respectively, and the corresponding CSS rates were 89% and 81%, respectively. For the 91 men who had SVI and LNI, the 10-year BCR-free probability was 10%, but the 10-year CSS probability was 74%. By 10 years, patients with LNI were 3 times more likely to die from cancer than from other causes; nonetheless, 66% of patients were alive despite their advanced stage. The preoperative prostate-specific antigen level, extracapsular extension, LNI, and Gleason grade were associated independently with BCR. Gleason scores of 8 to 10 and LNI were significant predictors of CSS. CONCLUSIONS: SVI does not invariably signal BCR or death from cancer in patients who undergo RP and pelvic lymph node dissection. Fifteen years later, approximately 33% of men with SVI and negative lymph nodes are expected remain free of BCR, and CSS was surprisingly good.

Aged↗
PubMed2006

Risk assessment for biochemical recurrence prior to radical prostatectomy: significant enhancement contributed by human glandular kallikrein 2 (hK2) and free prostate specific antigen (PSA) in men with moderate PSA-elevation in serum.

Most models to predict biochemical recurrence (BCR) of prostate cancer use pretreatment serum prostate-specific antigen (PSA), clinical stage and prostate biopsy Gleason grade. We investigated whether human glandular kallikrein 2 (hK2) and free prostate-specific antigen (fPSA) measured in pretreatment serum enhance prediction. We retrospectively measured total PSA (tPSA), fPSA and hK2 in preoperative serum samples from 461 men with localized prostate cancer treated with radical prostatectomy between 1999 and 2001. We developed a regression model to predict BCR using preoperative tPSA, clinical stage and biopsy Gleason grade. We then compared the predictive accuracy of this "base" model with a model with fPSA and hK2 as additional predictors. BCR was observed in 90 patients (20%), including 48 patients with a pretreatment tPSA < or = 14 ng/ml (13%), and 28 patients (10%) with a pretreatment tPSA < or = 10 ng/ml. Overall, the predictive accuracy of the base model (bootstrap-corrected concordance index of 0.813) was not improved after the addition of fPSA or hK2 (0.818). However, for men with moderate tPSA-elevation (tPSA < or = 10 ng/ml), addition of fPSA and hK2 data increased predictive accuracy (from a base model concordance index of 0.756-0.815, p = 0.005). The improvement in accuracy was not sensitive to the threshold for "moderately elevated" PSA. For patients with a moderate tPSA-elevation (tPSA < or = 10 ng/ml), which closely corresponds to concurrent disease demographics, BCR-prediction was enhanced when fPSA and hK2 were added to the conventional model. Measurements of fPSA and hK2 improve on our ability to counsel patients prior to treatment as to their risk of BCR.

Aged↗
PubMed2006

Body mass index does not improve the ability to predict biochemical recurrence after radical prostatectomy.

PURPOSE: To test whether body mass index (BMI) improves pre- or post-operative biochemical recurrence (BCR) predictions after radical prostatectomy. MATERIALS AND METHODS: Pre- and post-operative data were available in 2416 and 2499 men, respectively. Cox regression models addressed the association between BMI and the rate of BCR after adjusting for pre- and post-operative predictors. Predictive accuracy was quantified using Harrell's concordance index, with and without BMI and subjected to 200 bootstraps to reduce overfit bias. Differences in predictive accuracy were compared using the Mantel-Haenszel test. RESULTS: After adjusting for either pre- or post-operative variables, increasing BMI was a statistically independent risk factor of BCR in both models (both p0.003). Its addition to pre- and post-operative variables respectively increased predictive accuracy measures from 69.6 to 70.2% (+0.6%, p=0.7) and from 78.1 to 78.4% (+0.3%, p=0.8). CONCLUSION: Our data emphasise that despite its significance, inclusion of BMI into models, to predict BCR, does not improve their accuracy.

Body Mass Index↗
PubMed2006

The 2002 AJCC pT2 substages confer no prognostic information on the rate of biochemical recurrence after radical prostatectomy.

INTRODUCTION: We examined the prognostic value of AJCC pT2 substages in prediction of biochemical recurrence (BCR) after radical prostatectomy (RP), in European patients. METHODS: A cohort of 1726 RP patients with pT2N0 prostate cancer (PCa) was studied. Multivariate Cox regression models addressed the association between either the 1997 or 1992/2002 pT2 substages after controlling for total PSA, primary and secondary pathologic Gleason scores and surgical margin status and time to PSA recurrence (PSA >0.1 and rising) after RP. Regression coefficients were then used to test the predictive accuracy of multivariate models in a nomogram setting. RESULTS: PSA recurrence occurred in 80 (4.6%) patients. Mean and median times to recurrence were respectively 28.9 and 24.4 months. In univariate analyses, neither the 1997 (p = 0.48) nor the 1992/2002 pT2 substages (p = 0.054) were predictive of recurrence. In multivariate analyses the lack of significance persisted (1997 p = 0.709; 1992/2002 p = 0.124). When either the 1997 or 1992/2002 pT2 substages were added to a multivariate nomogram without pT2 substage information, its accuracy respectively decreased by 0.8% and 1.1%. CONCLUSION: Our data indicate that pT2 substages offer no incremental value relative to pre-treatment total PSA, surgical margin status and pathologic Gleason scores. Therefore, it might be postulated that it is sufficient to confirm organ confinement according to Partin's pathologic staging.

Analysis of Variance↗
PubMed2006

Biochemical recurrence after localized treatment.

The quoted incidence of biochemical recurrence (BCR) after localized treatment varies significantly and depends on numerous well-known prognostic factors; however, it likely occurs in at least 30%-40% of patients who receive localized treatment. Because the clinical significance of BCR is often unclear, and depends in many cases on unknown factors, it is difficult to select the best treatment and determine when best to institute that therapy. This review examines some of the issues associated with BCR and attempts to shed some light on this common but controversial clinical scenario. Some treatment strategies discussed in this article include salvage radiotherapy after radical prostatectomy, salvage therapy after radiotherapy, and hormonal therapy.

Humans↗
PubMed2005

Does the time from biopsy to surgery affect biochemical recurrence after radical prostatectomy?

OBJECTIVE: To evaluate whether the time from biopsy to radical prostatectomy (RP) predicts the biochemical recurrence (BCR) after RP, as men diagnosed with clinically localized prostate cancer have several available treatment options and investigating these alternatives may delay the initiation of definitive therapy. PATIENTS AND METHODS: We identified 3969 consecutive patients who had RP for clinically localized prostate cancer from 1987 to 2002; those eligible for the study had RP within a year of diagnosis. The interval between biopsy and RP was analysed both as a continuous and as a dichotomous variable (divided at 3 months). Multivariate analysis was used to evaluate the impact of time to RP on BCR. Subsets were also analysed for the effect of time to RP in patients considered to be at high risk of recurrence, with group 1 having a prostate specific antigen (PSA) level of > or = 20 ng/mL, a biopsy Gleason score of > or = 8, or clinical stage > or = T2c; and group 2 assessed as having a >40% probability of BCR using a preoperative nomogram. RESULTS: In all, 3149 patients met the inclusion criteria and had a mean (interquartile range) follow-up after RP of 5.4 (2.2-7.9) years. Multivariate analysis showed that the year of biopsy, PSA level before biopsy, clinical stage and biopsy Gleason score (all P < 0.001) were significantly associated with BCR after RP. The time to RP, treated either as a continuous variable (P = 0.252) or when categorized at 3 months (P = 0.939), failed to predict BCR. Further, the time to RP was not an independent predictor of BCR for patients at high risk of recurrence in group 1 (P = 0.147) or group 2 (P = 0.548). CONCLUSIONS: The time from biopsy to RP did not influence the probability of BCR for men who had RP within a year of diagnosis, even for those considered to be at high risk of BCR. Instead, the clinical and pathological features of the cancer provided the best estimate of the risk of BCR.

Aged↗
PubMed2006

Defining biochemical recurrence of prostate cancer after radical prostatectomy: a proposal for a standardized definition.

PURPOSE: Prostate-specific antigen (PSA) defined biochemical recurrence (BCR) of prostate cancer is widely used for reporting the outcome of radical prostatectomy (RP). A standardized BCR definition is lacking, and overall progression-free probability and risk of subsequent metastatic disease progression may vary greatly depending on the PSA criterion used. Ten definitions of BCR were evaluated to identify the one that best explains metastatic progression. METHODS: Of 3,125 patients who underwent RP at our institution since 1985, 75 developed distant metastasis during a median follow-up of 49 months. To predict metastasis progression, we modeled the clinical information using multivariable Cox regression analysis. BCR was included in the model as a time-dependent covariate, and separate models were developed for each definition. A goodness-of-fit (R2) statistic was used to determine the Cox model (and thereby the BCR definition) that best explained metastatic progression. RESULTS: The 10-year progression-free probability ranged from 63% to 79%, depending on the BCR definition. The model containing BCR defined as a PSA of at least 0.4 ng/mL followed by another increase best explained metastatic progression (R2 = 0.21). This definition was also associated with a high probability of subsequent secondary therapy, continued PSA progression, and rapid PSA doubling time. CONCLUSION: BCR defined as a PSA value of at least 0.4 ng/mL followed by another increase best explains the development of distant metastasis among 10 candidate definitions, after controlling for clinical variables and the use of secondary therapy. On the basis of this evidence, we propose that this definition be adopted as the standard for reporting the outcome of RP.

Aged↗
PubMed2005

Pattern of prostate-specific antigen (PSA) failure dictates the probability of a positive bone scan in patients with an increasing PSA after radical prostatectomy.

PURPOSE: Physicians often order periodic bone scans (BS) to check for metastases in patients with an increasing prostate-specific antigen (PSA; biochemical recurrence [BCR]) after radical prostatectomy (RP), but most scans are negative. We studied patient characteristics to build a predictive model for a positive scan. PATIENTS AND METHODS: From our prostate cancer database we identified all patients with detectable PSA after RP. We analyzed the following features at the time of each bone scan for association with a positive BS: preoperative PSA, time to BCR, pathologic findings of the RP, PSA before the BS (trigger PSA), PSA kinetics (PSA doubling time, PSA slope, and PSA velocity), and time from BCR to BS. The results were incorporated into a predictive model. RESULTS: There were 414 BS performed in 239 patients with BCR and no history of androgen deprivation therapy. Only 60 (14.5%) were positive for metastases. In univariate analysis, preoperative PSA (P = .04), seminal vesicle invasion (P = .02), PSA velocity (P < .001), and trigger PSA (P < .001) predicted a positive BS. In multivariate analysis, only PSA slope (odds ratio [OR], 2.71; P = .03), PSA velocity (OR, 0.93; P = .003), and trigger PSA (OR, 1.022; P < .001) predicted a positive BS. A nomogram for predicting the bone scan result was constructed with an overfit-corrected concordance index of 0.93. CONCLUSION: Trigger PSA, PSA velocity, and slope were associated with a positive BS. A highly discriminating nomogram can be used to select patients according to their risk for a positive scan. Omitting scans in low-risk patients could reduce substantially the number of scans ordered.

Bone and Bones↗
PubMed2006

Comparison of free and total forms of serum human kallikrein 2 and prostate-specific antigen for prediction of locally advanced and recurrent prostate cancer.

BACKGROUND: We evaluated the association of total and free forms of serum human kallikrein 2 (hK2) and prostate-specific antigen (PSA) with prostate cancers of unfavorable prognosis. METHODS: We retrospectively measured total PSA (tPSA), free PSA (fPSA), and total hK2 (thK2) in preoperative serum samples from 867 men [and assessed free hK2 (fhK2) measured in 577 of these men] treated with radical prostatectomy for clinically localized prostate cancer. Associations between biomarker concentrations and extracapsular extension, seminal vesicle invasion, and biochemical recurrence (BCR) were evaluated. A subset of patients with PSA < or =10 microg/L, the group most commonly seen in clinical practice in the US, was analyzed. RESULTS: thK2 was the strongest predictor of extracapsular extension and seminal vesicle invasion (areas under the ROC curve [AUC], 0.662 and 0.719, respectively), followed by tPSA (AUC, 0.654 and 0.663). All biomarkers were significant predictors of BCR. hK2 forms, but not PSA forms, remained highly significant for predicting BCR in the low-PSA group. Combining tPSA, fPSA, and thK2 in a multivariable model improved prediction compared with any biomarker used individually (AUC, 0.711, 0.755, and 0.752 for this combination predicting extracapsular extension, seminal vesicle invasion, and BCR, respectively; P <0.001 for all). CONCLUSIONS: Increased concentrations of hK2 in the blood are significantly associated with unfavorable features of prostate cancer, and thK2 is predictive of locally advanced and recurrent cancer in patients with PSA < or =10 microg/L. Independent of tPSA and fPSA, hK2 predicts unfavorable prognosis.

Aged↗
PubMed2025

A Prospective Validation of the Decipher Genomic Classifier in Men With Early Localized Prostate Cancer: The VANDAAM Study.

BACKGROUND: The emergence of genomic precision oncology has advanced personalized care for some patients with prostate cancer (PCa), while threatening to widen existing disparities due to the historically low recruitment of African American men (AAM), who have the highest disease burden. Here, we report the first prospective validation of a genomic classifier (GC) to predict rapid-onset biochemical recurrence (BCR) in AAM. METHODS: Between 2016 and 2021, this multicenter prospective validation study recruited 243 patients with low- or intermediate-risk PCa who received treatment for their disease. Patients were recruited on a 1:1 basis (AAM:White) and matched by CAPRA score. Patients who elected active surveillance were ineligible for participation. Decipher GC testing was ordered for all patients using their biopsy and/or radical prostatectomy (RP) tumor tissue. The primary outcome was to determine whether the GC could predict 2-year BCR rates-used as a surrogate for disease aggressiveness-following standard treatment. The secondary outcome evaluated the concordance between biopsy- and RP-derived GC risk scores for treatment recommendations. RESULTS: The final analytical cohort included 226 matched patients with genomic information, and 207 evaluable cases (104 AAM, 103 White) with both genomic and complete clinical outcome data. Overall, a high genomic-risk GC score was associated with a 5.25-fold increase in the odds of rapid-onset 2-year BCR compared with the low-risk group (odds ratio, 5.25 [95% CI, 1.27-21.66]; P=.021). In a subset of the surgical cohort (n=74), biopsy- and RP-derived GC scores exhibited a 77% concordance rate, defined as no reclassification in GC risk-based categories. CONCLUSIONS: This study represents the first prospective validation of GC performance in predicting early 2-year BCR in both AAM and White men. The findings provide strong evidence supporting the integration of the GC into clinical practice guidelines to improve risk stratification and management of AAM with early-stage PCa. CLINICALTRIALS: gov identifier: NCT02723734.

Aged↗
PubMed2006

Does a delay between diagnosis and radical prostatectomy increase the risk of disease recurrence?

BACKGROUND: Men diagnosed with clinically localized prostate carcinoma have several treatment options. The investigation of these options may delay the initiation of definitive therapy. In the current study, the authors evaluated whether time from biopsy to radical prostatectomy (RP) was predictive of postoperative biochemical disease recurrence (BCR). METHODS: A total of 3149 consecutive patients who underwent RP as their initial treatment for prostate carcinoma within a year of diagnosis were identified. The time between diagnosis and RP was entered as a predictor in a multivariate logistic regression model predicting BCR at 3 years, 5 years, 8 years, and 10 years. The year surgery was performed and the nomogram-predicted probability of recurrence, which incorporates stage of disease, Gleason grade, and prostate-specific antigen (PSA) level, were used as covariates. RESULTS: The authors found no clear evidence of a significant effect of delay to diagnosis on BCR. For those patients treated within 6 months (96% of the total sample) the odds ratio for each additional month of delay was 1.04, 1.07, 1.08, and 1.02, respectively, for 3-year, 5-year, 8-year, and 10-year BCR-free survival (P>0.2 for all analyses). However, the 95% confidence intervals were wide and included the possibility that even a minor delay in surgery might have a large impact on the probability of BCR. CONCLUSIONS: The time between biopsy and surgery does not appear to have a large effect on the risk of disease recurrence. Counseling patients on the importance of avoiding undue delay to surgery must be based on clinical judgment, particularly with respect to modifying advice based on the patient's risk.

Aged↗
PubMed2003

Markers and meaning of primary treatment failure.

BCR is the most clinically used endpoint for identification of treatment failure. Approximately 15% to 53% of patients undergoing primary curative therapy will develop BCR. BCR often precedes clinically detectable recurrence by years. It does not necessarily translate directly into PCa morbidity and mortality, nor does it always reflect the desired endpoint. Furthermore, it has not been validated as a surrogate endpoint, in that interventions that have been shown to alter the PSA level have not been shown to also alter survival. The utility of PSA level as a surrogate endpoint is brought into question by the knowledge that the overall survival rate of patients at 10 years is similar in patients with and without BCR, and that in a significant proportion of men, the only evidence of disease during their lifetime will be a detectable PSA level. The likelihood of developing BCR post-therapy can be predicted by using multiple clinical and pathologic variables. With the development of nomograms that incorporate several markers, the accuracy of prediction has improved. Until recently, the natural history of BCR post-RRP has not been well understood. Pound et al showed the heterogenous and prolonged natural history of BCR. In this large series of men with BCR following RRP, only 34% of men developed metastatic disease. The median time from development of BCR to identification of metastases was 8 years, and the median time from the development of metastatic disease to death was just under 5 years. These data highlight the extremely variable and potentially indolent nature of BCR. The risk of metastatic disease following BCR has been relatively well defined and relates to PSADT and time to PSA recurrence. It generally is accepted that a PSADT of less than 6 to 10 months and a time to PSA recurrence of less than 1 to 2 years relates to a higher risk of developing metastatic disease. Local recurrence, however, remains poorly understood with respect to its true incidence, clinical significance, and natural history. The significance of BCR post-RT remains unclear due to the lack of data on its natural history. Attempts have been made to identify patients at high risk for metastatic progression by looking at time to PSA recurrence and PSADT. A PSADT of less than 6 to 12 months and a time to PSA recurrence of less than 12 months reflects a higher risk of developing metastatic disease. Accurate risk stratification by means of an algorithm similar to that produced by Pound et al has not been performed on a large cohort, thus making risk assessment for an individual patient difficult. The major dilemma for clinicians in the management of BCR is the identification of the site of disease recurrence, which ultimately guides therapy decisions. Clinicopathologic features allow for risk stratification for recurrence, and multiple investigations have attempted to localize the site of recurrence. Time to biochemical progression, Gleason score, and PSADT are predictive of the probability and time to development of metastatic disease, and allow for stratification of patients into different risk groups (see Table 2). TRUS, CT, PET, and DRE all have limited utility in the identification of local recurrence. ProstaScint and MRI have demonstrated encouraging initial results: however, they require further investigation. Bone scintigraphy is of little value for the initial investigation of BCR. In patients with a PSA level of less than 10 ng/mL, the risk of having a positive bone scan is less than 1% and, until the PSA level rises above 40 ng/mL, the risk of having a positive bone scan is less than 5%. Therefore, bone scintigraphy should be reserved for patients with a PSA level greater than 10 to 20 ng/mL or patients with a rapidly rising PSA level. Using new MRI sequences, there is some evidence that MRI is better for the detection of bony metastatic disease; however, this technique requires further investigation. BCR causes anxiety for the patient and the treating doctor, because the best way to manage patients with PSA-only progression is unknown. Currently, there are no validated treatment recommendations for the management of BCR. The information in this review provides the framework for assignment of patients into clinical trials based on different risk categories. Patients at high risk for metastatic progression could be identified early and thus entered into appropriate clinical trials for systemic therapies. Similarly, patients with a low risk of progression could be placed into observation protocols, potentially sparing them from exhaustive and inappropriate investigations.

Biomarkers↗
PubMed2001

Chronic myeloid leukemia presenting as gout.

A 53-year-old man presented with gouty arthritis. A physical examination and haematological and biochemical tests showed that he had chronic myeloid leukemia. He was treated with allopurinol, hydroxyurea and analgesics. The arthritis subsided completely within 2 weeks. He continues in haematologic remission (on interferon) with no further recurrence of the gout.

Arthritis, Gouty↗