[Primary circulating prostate cells, age and prostatic volumen predict the presence of prostate cancer in men with indication of a second prostate biopsy.] / Las células prostáticas circulantes primarias, edad y volumen prostático predicen el cáncer prostático en sujetos con indicación de una segunda biopsia prostática. Primary circulating prostate cells, age and prostatic volumen predict the presence of prostate cancer in men with indication of a second prostate biopsy.

INTRODUCTION: The limitations of serumPSA as a screening test to detect prostate cancer remainproblematic, especially after an initial negative prostatebiopsy. Detection of primary circulating prostate cells(CPCs) has been reported to be useful in the detectionof prostate cancer in men with a serum PSA>4.0ng/ml.We present a prospective study comparing the detectionof CPCs, total PSA, percent free PSA, digital rectal examination(DRE) and prostate volumen (PV) to establisha predictive model for the detection of prostate cancerin men with an indication for a second prostate biopsy. OBJECTIVE: To establish a predictive model for the detectionof prostate cancer using the number of CPCs detectedper sample, DRE, age, total serum PSA, percentfree PSA and PV in men with an indication for a secondprostate biopsy. METHODS AND PATIENTS: A prospective, observationalstudy carried out in the Hospital de Carabineros deChile, between 2006 and 2014 including 199 menundergoing a second prostate biopsy. The variables,number of CPCs detected (nCPC), DRE, age, PSA, percentfree PSA and PV were registered for each patientand based on these findings and comparing them withthe results of the prostate biopsy a multivariate logistic regressionanalysis incorporating forward predictors. Themodel was evaluated for co-lineal tendency, reliabilityand error specificity, and analyzed using non-parametricreceiver operating characteristics and area under thecurve decision for the combined model and for eachvariable separately. RESULTS: The single variable nCPC had a superior predictivevalue with an area under the curve of 0.89 (95%CI 0.83-0.94). The final model incorporated nCPC (OR:2.03 95% CI 1.63-2.53) age (OR: 1.1 95% CI 1.04-1.17) and PV (OR: 0.96 95% CI 0.93-0.99) with anarea under the curve for the combined model of 0.92(95% CI 0.88-0.97). The combined model performedbetter than the variables used alone. CONCLUSIONS: The model incorporating nCPC, ageand PV had a greater diagnostic yield for the predictingprostate cancer at second biopsy.

INTRODUCCIÓN: Las limitaciones del antígeno prostático específico (PSA) total como examen de pesquisa de cáncer prostático sigue problemático, especialmente después de una biopsia prostática inicial negativa. El uso de la detección de células prostáticascirculantes primarias (CPCs) ha sido reportado de ser útil en la detección de cáncer prostático en hombres con un APE >4,0 ng/ml.OBJETIVO: Presentamos un estudio prospectivo utilizando la detección de CPCs, el PSA, el porcentaje libre del PSA, el tacto rectal (TR) y el volumen prostático (VP) para establecer un modelo predictivo para la detección de cáncer prostático en pacientes con indicación de una segunda biopsia prostática.MÉTODOS Y PACIENTES: En Hospital de Carabineros de Chile entre 2006 y 2014, se realiza un estudio observacional, consignando para 199 sujetos, en forma previa a segunda biopsia de próstata, lo siguiente: nCPC, TR, edad, PSA, porcentaje libre de PSA y VP. Apartir de estas variables y en relación a resultado de neoplasia en estudio histológico de próstata, se efectúa una regresión logística multivariante con incorporación "forward" de predictores. En el modelo seleccionado se efectúa una evaluación del ajuste, co-linealidad predictores y especificación del error. Además se realizaanálisis de "Receiver Operating Characteristic" (ROC) no paramétrico y análisis de curva de decisión (ACD) para el modelo obtenido y también para los predictores en forma separada.RESULTADOS: Como variable separado el nCPC tuvo un rendimiento superior con un área ROC de 0,89 (CI 95% 0,83 a 0,94). El modelo final incorpora nCPC (OR: 2,03; CI95%: 1,63 a 2,53), edad (OR: 1,1; CI95%: 1,04 a 1,17) y VP (OR: 0,96; CI95%: 0,93 a 0,99) con un rendimiento en área ROC (0,92; CI95%: 0,88 a 0,97) y ACD mayor al resto de las variables por separado.CONCLUSIÓN: El modelo que incorpora el NCPC, edad y VP, presenta un rendimiento mayor en la predicción de la presencia de malignidad, en sujetos que realizan una segunda biopsia prostática.

Las células prostáticas circulantes primarias, edad y volumen prostático predicen el cáncer prostático en sujetos con indicación de una segunda biopsia prostática / Primary circulating prostate cells, age and prostatic volumen predict the presence of prostate cancer in men with indication of a second prostate biopsy

Introducción: Las limitaciones del antígeno prostático específico (PSA) total como examen de pesquisa de cáncer prostático sigue problemático, especialmente después de una biopsia prostática inicial negativa. El uso de la detección de células prostáticas circulantes primarias (CPCs) ha sido reportado de ser útil en la detección de cáncer prostático en hombres con un APE >4,0 ng/ml. Objetivo: Presentamos un estudio prospectivo utilizando la detección de CPCs, el PSA, el porcentaje libre del PSA, el tacto rectal (TR) y el volumen prostático (VP) para establecer un modelo predictivo para la detección de cáncer prostático en pacientes con indicación de una segunda biopsia prostática. Métodos y pacientes: En Hospital de Carabineros de Chile entre 2006 y 2014, se realiza un estudio observacional, consignando para 199 sujetos, en forma previa a segunda biopsia de próstata, lo siguiente: nCPC, TR, edad, PSA, porcentaje libre de PSA y VP. A partir de estas variables y en relación a resultado de neoplasia en estudio histológico de próstata, se efectúa una regresión logística multivariante con incorporación "forward" de predictores. En el modelo seleccionado se efectúa una evaluación del ajuste, co-linealidad predictores y especificación del error. Además se realiza análisis de "Receiver Operating Characteristic" (ROC) no paramétrico y análisis de curva de decisión (ACD) para el modelo obtenido y también para los predictores en forma separada. Resultados: Como variable separado el nCPC tuvo un rendimiento superior con un área ROC de 0,89 (CI 95% 0,83 a 0,94). El modelo final incorpora nCPC (OR: 2,03; CI95%: 1,63 a 2,53), edad (OR: 1,1; CI95%: 1,04 a 1,17) y VP (OR: 0,96; CI95%: 0,93 a 0,99) con un rendimiento en área ROC (0,92; CI95%: 0,88 a 0,97) y ACD mayor al resto de las variables por separado. Conclusión: El modelo que incorpora el NCPC, edad y VP, presenta un rendimiento mayor en la predicción de la presencia de malignidad, en sujetos que realizan una segunda biopsia prostática

Introduction: The limitations of serum PSA as a screening test to detect prostate cancer remain problematic, especially after an initial negative prostate biopsy. Detection of primary circulating prostate cells (CPCs) has been reported to be useful in the detection of prostate cancer in men with a serum PSA>4.0ng/ml. We present a prospective study comparing the detection of CPCs, total PSA, percent free PSA, digital rectal examination (DRE) and prostate volumen (PV) to establish a predictive model for the detection of prostate cancer in men with an indication for a second prostate biopsy. Objective: To establish a predictive model for the detection of prostate cancer using the number of CPCs detected per sample, DRE, age, total serum PSA, percent free PSA and PV in men with an indication for a second prostate biopsy. Methods and patients: A prospective, observational study carried out in the Hospital de Carabineros de Chile, between 2006 and 2014 including 199 men undergoing a second prostate biopsy. The variables, number of CPCs detected (nCPC), DRE, age, PSA, percent free PSA and PV were registered for each patient and based on these findings and comparing them with the results of the prostate biopsy a multivariate logistic regression analysis incorporating forward predictors. The model was evaluated for co-lineal tendency, reliability and error specificity, and analyzed using non-parametric receiver operating characteristics and area under the curve decision for the combined model and for each variable separately. Results: The single variable nCPC had a superior predictive value with an area under the curve of 0.89 (95% CI 0.83-0.94). The final model incorporated nCPC (OR: 2.03 95% CI 1.63-2.53) age (OR: 1.1 95% CI 1.04-1.17) and PV (OR: 0.96 95% CI 0.93-0.99) with an area under the curve for the combined model of 0.92 (95% CI 0.88-0.97). The combined model performed better than the variables used alone. ConclusionS: The model incorporating nCPC, age and PV had a greater diagnostic yield for the predicting prostate cancer at second biopsy

Combining the Prostate Cancer Risk Index (PRIX) with the Presence of Secondary Circulating Prostate Cells to Predict the Risk of Biochemical Failure after Radical Prostatectomy for Prostate Cancer

Introduction: The use of pre- and post-surgery variables has been used to create nomograms in order to identify patients at high risk of treatment failure. The PRIX nomogram is one such device; we compare the PRIX nomogram with the presence of secondary circulating prostate cells to predict those men who will undergo treatment failure. Methods and Patients: Men who underwent radical prostatectomy for prostate cancer entered the study. The PRIX score was calculated from the total serum PSA pre-surgery, the biopsy Gleason score and clinical stage. Circulating prostate cells were detected from venous blood one month after surgery, using differential gel centrifugation and standard immunocytochemistry with anti-PSA. A test was considered positive when 1 CPC/blood sample was detected. Patients were followed up for five years and biochemical failure was defined as a serum PSA >0.2ng/ml. Kaplan-Meier and Cox proportional models were used to calculate survival curves. Results: 321 men participated, of whom 131 (40.8%) underwent biochemical failure within 5 years. A higher PRIX score was associated with increased failure risk, as was the presence of CPCs. The predictive power of CPCs was significantly higher than the PRIX score. Combining the two methods, for equal PRIX scores, scores but CPC positive had a worse biochemical failure free survival than men with high PRIX scores but CPC negative. For men with PRIX scores of ≥4 the use of CPC detection did not aid in the clinical decision making process. For those with PRIX scores of 0 and 1, CPC detection identified men with a high risk of treatment failure. Conclusions: The combined PRIX/CPC score improved the predictive values of men at high risk of biochemical failure. Both are simple systems that could be incorporated in a general hospital. Further multicenter studies are warranted to confirm these results.

How localized is pathologically localized prostate cancer? The use of secondary circulating prostate cells as a marker of minimal residual disease and their association with patient outcome.

OBJECTIVE: To determine the prognostic value of secondary circulating prostate cells (CPCs) in men with pT2 prostate cancer treated with radical prostatectomy. MATERIAL AND METHODS: Prospective observational study was performed in men with pathologically confined prostate cancer who had been treated with radical prostatectomy. CPCs were obtained by differential gel centrifugation from 8 mL venous blood and identified by standard immunocytochemistry using anti-Prostate Specific Antigen (PSA) monoclonal antibody. A positive test was defined as ≥1 PSA staining cell/blood sample. Biochemical failure was defined as a serum PSA >0.2 ng/mL. Age, PSA at diagnosis, pT2a versus pT2b/c, Gleason score and the presence/absence of CPCs were compared with patient outcomes using Kaplan-Meier curves and Cox's hazard model. RESULTS: Hundred and ninety-one men participated in the study, 107 (44.0%) had pT2b/c disease, 25 (13.1%) had a Gleason score ≥7, and 39 (20.4%) were positive for CPCs. Biochemical failure occurred in 39 (20.4%) patients which was associated with a Gleason score ≥ 7 and CPCs (+). Survival rates at 3, 5 and 10 years for men with CPC (-) and CPC (+) were 100%, 100% and 89.6%, and 74.4%, 64.1% and 18.5% respectively (HR: 18.70). The median time to failure was 5.1 years in CPC (+) men versus 8.1 years in CPC (-) patients. CONCLUSION: Secondary CPC is a marker for minimal residual disease and it is associated with a worse prognosis. The lead time to failure over serum PSA is approximately 5 years. However they do not define whether the failure is local or systemic.

[Comparison of two on-line risk calculators versus the detection of circulating prostate cells for the detection of high risk prostate cancer at first biopsy.] / Comparación entre dos calculadoras de riesgo en línea para la detección de cáncer de próstata versus el rendimiento de las células prostáticas circulantes en sangre para la detección de cáncer de próstata de alto riesgo en una biopsia inicial.

OBJECTIVE: The limitations of total serum PSA values remains problematic; nomograms may improve the prediction of a positive prostate biopsy (PB). We compare in a prospective study of Chilean men with suspicion of prostate cancer due to an elevated total serum PSA and/or abnormal digital rectal examination, the use of two on-line nomograms with the detection of primary malignant circulating prostate cells (CPCs) to predict a positive PB for high risk prostate cancer. METHODS: Consecutive men with suspicion of prostate cancer underwent 12 core TRUS prostate biopsy. Age, total serum PSA and percent free PSA, family history, ethnic origin and prostate ultrasound results were registered. Risk assessment was performed using the online nomograms. The European Randomized Study of Screening for Prostate Cancer derived Prostate Risk Indicator (SWOP-PRI) and the North American Prostate Cancer Prevention Trail derived Prostate Risk Indicator (PCPT-CRC) were used to calculate risk of prostate cancer. Immediately before PB an 8 ml blood sample was taken to detect CPCs. Mononuclear cells were obtained by differential gel centrifugation and identified using double immunomarcation with anti-PSA and anti- P504S. Biopsies were classified as cancer/no-cancer, CPC detection test as negative/positive and the total number of cells/8ml registered. Areas under the curve (AUC) for total serum PSA, free percent, PSA, SWOP-PRI, PCPT-CRC and CPCs were calculated and compared. Diagnostic yields were calculated, including the number of possible biopsies that could be avoided and the number of clinically significant cancers that would be missed. RESULTS: 1,223 men aged 〉 55 years were analyzed, 467 (38.2%) had a biopsy positive for cancer of which 114/467 (24.45) complied with the criteria for active observation; 177/467 (36.8%) were Gleason 7 or higher. Discriminative power of detecting prostate cancer, showed areas under the curve of total PSA 0.559, SWOP nomogram 0.687, PCPTRC nomogram 0.716, free percent PSA 0.765 and CPC detection 0.844. CPC detection was superior to the other models (p〈0.0001). Using the recommended cutoff values, free percent PSA avoided 81% of biopsies missing 58% of significant cancers; for the other models the values were SWOP 75% and 56%; PCPTRC 61% and 62%, CPC detection 57% and 4% respectively. CONCLUSIONS: CPC detection was superior to the other models in predicting the presence of clinically significant prostate cancer at initial biopsy; potentially reduces the number of unnecessary biopsy while missing few significant cancers. Being a positive/negative test it avoids defining a cutoff value which may differ between populations. Multicenter studies to validate this method are warrented.

The presence of primary circulating prostate cells is associated with upgrading and upstaging in patients eligible for active surveillance.

Active surveillance (AS) is a considered treatment option for men with low or very low-risk prostate cancer. However, on repeat biopsy some 25% were upgraded and recommended for active treatment. We compare the presence or absence of primary circulating prostate cells (CPCs) with the clinical pathological findings after radical prostatectomy in men fulfilling the criteria for active surveillance and the risk of reclassification for active observation (AO). METHODS AND PATIENTS: A single centre observational study was done involving 102 men who fulfilled the Epstein criteria for AS and underwent radical prostatectomy as mono-therapy for prostate cancer. The patients were classified according to the presence or absence of CPCs detected immediately before the prostate biopsy. Mononuclear cells were obtained by differential gel centrifugation of 8 mL of venous blood and CPCs identified using immunocytochemistry with anti-PSA and anti-P504S. A positive CPC test was defined as at least 1 PSA (+), P504S (+) cell detected/blood sample. The surgical specimen was analysed for Gleason score and pathological stage. RESULTS: A total of 25 out of 102 (24.5%) men were upgraded based on the pathological findings of the surgical specimen. Among which 45 (44%) men were positive for CPCs. They were younger, 63.9 versus 68.1 years (p = 0.0148), had a lower frequency of pT2 or lower disease (64.4% versus 91.2% p <0.001), higher median Gleason scores (6 versus 5 p < 0.001) in both the biopsy and surgical specimens, and a higher frequency of upgrading 44% versus 9% (p < 0.001). CONCLUSIONS: In men fulfilling the criteria for AS, the presence of primary CPCs suggests a high risk for disease upgrade and therefore these men may not be ideal for observational therapy. Further studies with a larger population are warranted.

Outcome of radical prostatectomy in primary circulating prostate cell negative prostate cancer.

INTRODUCTION: Around 90% of prostate cancers detected using the serum prostate specific antigen (PSA) as a screening test are considered to be localised. However, 20-30% of men treated by radical prostatectomy experience biochemical failure within two years of treatment. The presence of primary circulating prostate cells (CPCs) in the blood of these men implies a dissemination of the tumour and could indicate a greater risk of treatment failure. OBJECTIVE: To evaluate the use of the number of primary CPCs detected before surgery in the prediction of biochemical failure at ten years. HYPOTHESIS: The dissemination of cancer cells to distant sites will determine the patient's prognosis. The absence of primary CPCs in men undergoing radical prostatectomy for prostate cancer may imply a less aggressive disease and therefore could be utilised as a prognostic factor to predict biochemical failure after surgery. METHODS AND PATIENTS: A single-centre observational study of a cohort of 285 men who underwent radical prostatectomy as monotherapy for prostate cancer, in whom the number of CPCs prior to treatment was determined, and who were followed up for ten years to determine biochemical failure. A Cox proportional risks with polynomial fractions analysis was used to predict biochemical failure based on the number of primary CPCs detected. A decision curve analysis was performed for the model obtained. RESULTS: Kaplan-Meier curves for biochemical free survival at ten years was 47.34% (95% CI 38.71-55.48%). It is important to note that in CPC negative men, the ten years Kaplan-Meier biochemical-free survival was 90.35% (95% CI 75.0-96.27) whereas in men who were primary CPC positive, the biochemical free survival rate was 30.00% (95% CI 20.34-40.60%). The Coxs´model to predict biochemical failure using transformed data with a power of minus one for the number of primary CPCs detected, showed a Harrell´s C concordance index of 0.74 and a decision analysis curve showing a net benefit of CPC detection over other risk factors to predict biochemical failure. CONCLUSIONS: The number of primary CPCs detected before surgery permits a good prediction of subsequent biochemical failure in men undergoing radical prostatectomy as monotherapy for prostate cancer. Men negative for primary CPCs have a biochemical-free survival of over 90% at ten years and should be considered for curative surgery.

Does the Presence of Primary Circulating Prostate Cells Imply the Presence of Agressive Prostate Cancer with Early Biochemical Failure: a Comparison with the Walz Nomogram.

BACKGROUND: To determine the utility of primary circulating prostate cells (CPC) for predicting early biochemical failure after radical prostatectomy for prostate cancer and compare the results with the Walz nomogram. MATERIALS AND METHODS: A single centre prospective study of men with prostate cancer treated with radical prostatectomy was conducted between 2004 and 2014. Clinicalpathological details were registered, along with total serum PSA presurgery, Gleason score, extracapsular extension, positive surgical margins, infiltration of lymph nodes, seminal vesicles and pathological stage. Primary circulating prostate cells were obtained using differential gel centrifugation and detected using standard immunocytochemistry with antiPSA. Biochemical failure was defined as a PSA >0.2ng/ml, predictive values were calculated using the Walz nomagram and CPC detection. RESULTS: A total of 285 men participated, of whom 103/285 (36.1%) suffered biochemcial failure; 32/103 (31.1%) within two years of radical prostatectomy. Men with higher Gleason scores, higher pathological stage, infiltration of the surgical margin or prostate capsule and infiltration of seminal vesicles were more likely to undergo biochemical failure. There was a significant increase in the frequency of biochemical failure with increasing number of CPCs detected (p<0.0004 Chi squared for trend) and increasing percent prediction for the Walz nomogram (p<0.0001 Chi squared for trends). The positive predictive value of primary CPC detection, even using a cutoff point of ≥ 4 cells/sample was very low. CONCLUSIONS: The detection of primary CPCs in men as a prognostic factor pretreatment fails to identify those at high risk of biochemical failure within two years of curative therapy. This is in keeping with their biological significance, that the majority of them will be eliminated by the primary therapy and thus have no influence on the subsequent clinical history of the patient.

Efficacy of Using Sequential Primary Circulating Prostate Cell Detection for Initial Prostate Biopsy in Men Suspected of Prostate Cancer.

BACKGROUND: Sequential use of circulating prostate cell (CPC) detection has been reported to potentially decrease the number of unnecessary prostate biopsies in men suspected of prostate cancer. In order to determine the real world effectiveness of the test, we present a prospective study of men referred to two hospitals from primary care physicians, one using CPC detection to determine the necessity of prostate biopsy the other not doing so. MATERIALS AND METHODS: Men with a suspicion of prostate cancer because of elevated PSA >4.0ng/ml or abnormal DRE were referred to Hospitals A or B. In Hospital A all underwent 12 core TRUS biopsy, in Hospital B only men CPC (+), with mononuclear cells obtained by differential gel centrifugation identified using double immunomarking with antiPSA and antiP504S, were recommended to undergo TRUS biopsy. Biopsies were classifed as cancer or nocancer. Diagnostic yields were calculated, including the number of posible biopsies that could be avoided and the number of clinically significant cancers that would be missed. RESULTS: Totals of 649 men attended Hospital A, and 552 men attended Hospital B; there were no significant differences in age or serum PSA levels. In Hospital A, 228 (35.1%) men had prostate cancer detected, CPC detection had a sensitivity of 80.7%, a specificity of 88.6%, and a negative predictive value of 89.5%. Some 39/44 men CPC negative with a positive biopsy had low grade small volume tumors. In Hospital B, 316 (57.2%) underwent biopsy. There were no significant differences between populations in terms of CPC and biopsy results. The reduction in the number of biopsies was 40%. CONCLUSIONS: The use of sequential CPC testing in the real world gives a clear decision structure for patient management and can reduce the number of biopsies considerably.

Head to Head Comparison of the Chun Nomogram, Percentage Free PSA and Primary Circulating Prostate Cells to Predict the Presence of Prostate Cancer at Repeat Biopsy.

BACKGROUND: The limitations of total serum PSA values remain problematic, especially after an initial negative prostate biopsy. In this prospective study of Chilean men with a continued suspicion of prostate cancer due to a persistently elevated total serum PSA, abnormal digital rectal examination and initial negative prostate biopsy were compared with the use of the on-line Chun nomagram, detection of primary malignant circulating prostate cells (CPCs) and free percent PSA to predict a positive second prostate biopsy. We hypothesized that men negative for circulating prostate cells have a small risk of clinically significant prostate cancer and thus may be conservatively observed. Men positive for circulating prostate cells should undergo biopsy to confirm prostate cancer. MATERIALS AND METHODS: Consecutive men with a continued suspicion of prostate cancer underwent 12 core TRUS prostate biopsy; age, total serum PSA and percentage free PSA and Chun nomagram scores were registered. Immediately before biopsy an 8ml blood simple was taken to detect primary mCPCs. Mononuclear cells were obtained by differential gel centrifugation and identified using double immunostaining with anti-PSA and anti-P504S. Biopsies were classifed as cancer/no-cancer, mCPC detecton test as negative/positive and the total number of cells/8ml registered. Areas under the curve (AUC) for percentage free PSA, Chun score and CPCs were calculated and compared. Diagnostic yields were calculated with reference to the number of possible biopsies that could be avoided and the number of clinically significant cancers that would be missed. RESULTS: A total of 164 men underwent a second biopsy; 41 (25%) had cancer; the AUCs were 0.65 for free PSA, 0.76 for the Chun score and 0.87 for CPC detection, the last having a significantly superior prediction value (p=0.01). Using cut off values of free PSA <10%, Chun score >50% and ≥1 CPC detected, CPC detection had a higher diagnostic yield. Some 4/41 cancers complied with the criteria for active surveillance, free PSA and the Chun score missed a higher number of significant cancers when compared with CPC detection. CONCLUSIONS: Primary CPC detection outperformed the use of free PSA and the Chun nomagram in predicting clinically significant prostate cancer at repeat prostate biopsy.

Limited improvement of incorporating primary circulating prostate cells with the CAPRA score to predict biochemical failure-free outcome of radical prostatectomy for prostate cancer.

OBJECTIVE: To establish a prediction model for early biochemical failure based on the Cancer of the Prostate Risk Assessment (CAPRA) score, the presence or absence of primary circulating prostate cells (CPC) and the number of primary CPC (nCPC)/8ml blood sample is detected before surgery. PATIENTS AND METHODS: A prospective single-center study of men who underwent radical prostatectomy as monotherapy for prostate cancer. Clinical-pathological findings were used to calculate the CAPRA score. Before surgery blood was taken for CPC detection, mononuclear cells were obtained using differential gel centrifugation, and CPCs identified using immunocytochemistry. A CPC was defined as a cell expressing prostate-specific antigen and P504S, and the presence or absence of CPCs and the number of cells detected/8ml blood sample was registered. Patients were followed up for up to 5 years; biochemical failure was defined as a prostate-specific antigen>0.2ng/ml. The validity of the CAPRA score was calibrated using partial validation, and the fractional polynomial Cox proportional hazard regression was used to build 3 models, which underwent a decision analysis curve to determine the predictive value of the 3 models with respect to biochemical failure. RESULTS: A total of 267 men participated, mean age 65.80 years, and after 5 years of follow-up the biochemical-free survival was 67.42%. The model using CAPRA score showed a hazards ratio (HR) of 5.76 between low and high-risk groups, that of CPC with a HR of 26.84 between positive and negative groups, and the combined model showed a HR of 4.16 for CAPRA score and 19.93 for CPC. Using the continuous variable nCPC, there was no improvement in the predictive value of the model compared with the model using a positive-negative result of CPC detection. The combined CAPRA-nCPC model showed an improvement of the predictive performance for biochemical failure using the Harrell׳s C concordance test and a net benefit on DCA in comparison with either model used separately. The use of primary CPC as a predictive factor based on their presence or absence did not predict aggressive disease or biochemical failure. CONCLUSION: Although the use of a combined CAPRA-nCPC model improves the prediction of biochemical failure in patients undergoing radical prostatectomy for prostate cancer, this is minimal. The use of the presence or absence of primary CPCs alone did not predict aggressive disease or biochemical failure.

Prediction model for early biochemical recurrence after radical prostatectomy based on the Cancer of the Prostate Risk Assessment score and the presence of secondary circulating prostate cells.

OBJECTIVE: To establish a prediction model for early biochemical recurrence based on the Cancer of the Prostate Risk Assessment (CAPRA) score and the presence of secondary circulating prostate cells (CPCs). PATIENTS AND METHODS: We conducted a prospective single-centre study of men who underwent radical prostatectomy as monotherapy for prostate cancer. Clinicopathological findings were used to calculate the CAPRA score. At 90 days after surgery, blood was taken for CPC detection, mononuclear cells were obtained using differential gel centrifugation, and CPCs were identified using immunocytochemistry. A CPC was defined as a cell expressing prostate-specific antigen (PSA) but not CD45. The CPC test results were defined as positive or negative. Patients were followed up for up to 5 years and biochemical recurrence was defined as a PSA level >0.2 ng/mL. The validity of the CAPRA score was calibrated using partial validation, and Cox proportional hazard regression to build three models: a CAPRA score model, a CPC model and a CAPRA/CPC combined model. RESULTS: A total of 321 men, with a mean age of 65.5 years, participated in the study. After 5 years of follow-up the biochemical recurrence-free survival rate was 98.55%. For the model that included CAPRA score there was a hazard ratio (HR) of 7.66, for the CPC model there was an HR of 34.52 and for the combined model there were HRs of 2.60 for CAPRA score and 22.5 for CPC. Using the combined model, 23% of men changed from the low-risk to the high-risk category, or vice versa. CONCLUSION: The incorporation of CPC detection significantly improved the model's discriminative ability in establishing the probability of biochemical recurrence; patients in the high-risk group according to CAPRA score who are negative for CPCs have a much better prognosis. The addition of CPC detection gives clinically significant information to aid the decision on who may be eligible for adjuvant therapy.

Comparison of the Walz Nomogram and Presence of Secondary Circulating Prostate Cells for Predicting Early Biochemical Failure after Radical Prostatectomy for Prostate Cancer in Chilean Men.

PURPOSE: To determine the utility of secondary circulating prostate cells for predicting early biochemical failure after radical prostatectomy for prostate cancer and compare the results with the Walz nomagram. MATERIALS AND METHODS: A single centre, prospective study of men with prostate cancer treated with radical prostatectomy between 2004 and 2014 was conducted, with registration of clinical-pathological details, total serum PSA pre-surgery, Gleason score, extracapsular extension, positive surgical margins, infiltration of lymph nodes, seminal vesicles and pathological stage. Secondary circulating prostate cells were obtained using differential gel centrifugation and assessed using standard immunocytochemistry with anti-PSA. Biochemical failure was defined as a PSA >0.2ng/ml, predictive values werecalculated using the Walz nomagram and CPC detection. RESULTS: A total of 326 men participated, with a median follow up of 5 years; 64 had biochemical failure within two years. Extracapsular extension, positive surgical margins, pathological stage, Gleason score ≥ 8, infiltration of seminal vesicles and lymph nodes were all associated with higher risk of biochemical failure. The discriminative value for the nomogram and circulating prostate cells was high (AUC >0.80), predictive values were higher for circulating prostate cell detection, with a negative predictive value of 99%, sensitivity of 96% and specificity of 75%. CONCLUSIONS: The nomagram had good predictive power to identify men with a high risk of biochemical failure within two years. The presence of circulating prostate cells had the same predictive power, with a higher sensitivity and negative predictive value. The presence of secondary circulating prostate cells identifies a group of men with a high risk of early biochemical failure. Those negative for secondary CPCs have a very low risk of early biochemical failure.

Possible Role of HER-2 in the Progression of Prostate Cancer from Primary Tumor to Androgen Independence.

BACKGROUND: The expression of HER-2 in prostate cancer has been linked to disease progression. We analysed the presence of HER-2 expression in primary tumors in men undergoing radical prostatectomy, its association with clinical and pathological findings, and its expression in secondary circulating prostate cells (CPCs) during follow up, as well as links with biochemical failure and the effects of androgen blockade. MATERIALS AND METHODS: Consecutive men undergoing radical prostatectomy for histologically confirmed prostate cancer were analyzed. HER-2 expression in the primary tumor was assessed using the HercepTest®, CPCs were identified from blood samples using standard immunocytochemistry with anti-PSA and positive samples with the HercepTest® to determine HER-2 expression. The influence of HER-2 expression on the frequency of biochemical failure and effects of androgen blockade was determined. RESULTS: 144 men with a mean age of 64.8±10.3 years participated, with a median follow up of 8.2 years. HER-2 was expressed in 20.8% of primary tumors; it was associated with vascular infiltration and older age, but not with other clinical pathological findings. Some 40.3% of men had secondary CPCs detected, of which 38% expressed HER-2. Men CPC (+) had a higher frequency of biochemical failure, but there was no difference in HER-2 expression of CPCs with the frequency of biochemical failure. After androgen blockade, men with HER-2 (+) positive secondary CPCs had a higher frequency of disease progression to castrate resistant disease. CONCLUSIONS: HER-2 plays a dual role in the progression of prostate cancer; firstly it may increase the potential of tumor cells to disseminate from the primary tumor via the blood by increasing vascular infiltration. In the presence of androgens, there is no survival advantage of expressing HER-2, but once biochemical failure has occurred and androgen blockade started, HER-2 positive cells are resistant to treatment, survive and grow leading to castration resistant disease.

Comparison of the Formula of PSA, Age, Prostate Volume and Race Versus PSA Density and the Detection of Primary Malignant Circulating Prostate Cells in Predicting a Positive Initial Prostate Biopsy in Chilean Men with Suspicion of Prostate Cancer.

BACKGROUND: Combining risk factors for prostate cancer into a predictive tool may improve the detection of prostate cancer while decreasing the number of benign biopsies. We compare one such tool, age multiplied by prostate volume divided by total serum PSA (PSA-AV) with PSA density and detection of primary malignant circulating prostate cells (CPCs) in a Chilean prostate cancer screening program. The objectives were not only to determine the predictive values of each, but to determine the number of clinically significant cancers that would have been detected or missed. MATERIALS AND METHODS: A prospective study was conducted of all men undergoing 12 core ultrasound guided prostate biopsy for suspicion of cancer attending the Hospital DIPRECA and Hospital de Carabineros de Chile. Total serum PSA was registered, prostate volumecalculated at the moment of biopsy, and an 8 ml blood simple taken immediately before the biopsy procedure. Mononuclear cells were obtained from the blood simple using differential gel centrifugation and CPCs identified using immunocytchemistry with anti- PSA and anti-P504S. Biopsy results were classed as positive or negative for cancer and if positive the Gleason score, number of positive cores and percent infiltration recorded. RESULTS: A total of 664 men participated, of whom 234 (35.2%) had cancer detected. They were older, had higher mean PSA, PSA density and lower PSA-AV. Detection of CPCs had high predictive score, sensitivity, sensibility and positive and negative predictive values, PSA-AV was not significantly different from PSA density in this population. The use of CPC detection avoided more biopsies and missed fewer significant cancers. CONCLUSIONS: In this screening population the use of CPC detection predicted the presence of clinically significant prostate cancer better than the other parameters. The high negative predictive value would allow men CPC negative to avoid biopsy but remain in follow up. The formula PSA-AV did not add to the predictive performance using PSA density.

[Expression of P504S and matrix metalloproteinase-2 in circulating prostate cells disseminated as a result of transrectal ultrasound guided biopsy as determined by immunocytochemistry: Clinical implications]. / Condideraciones clínicas de la expressión de P504S y metaloproteinasa de matriz 2 en células prostáticas circulantes en sangre diseminadas como resultado de una biopsia prostática trans-rectal guiada por ecografía.

OBJECTIVES: Surgical manipulation of cancer has been shown to increase blood borne cancer cell dissemination and increase the risk of metastasis. We present the effect of prostate biopsy on prostate cell dissemination and the phenotypic characteristics of these cells. METHODS: 50 men undergoing initial prostate biopsy for suspicion of prostate cancer were studied. Blood samples were taken immediately before, and 1 and 24 hours after biopsy for circulating prostate cells (CPC) determination and phenotypic characterization. CPCs were detected and counted using standard immunocytochemistry using anti-PSA and then characterized using anti-P504S and anti-matrix metalloproteinase-2 (MMP-2). RESULTS: 14 (28%) men had cancer detected on biopsy. 13/14 had P504S (+) and MMP-2 (+) cells detected prior to biopsy. One hour after biopsy there was a mixture of P504S (+) and P504S (-) cells detected, as well as MMP-2 (+) and MMP-2 (-) cells detected. 24 hours after biopsy the same 13/14 men remained positive, although the number of CPCs increased 1 hour after biopsy and then the numbers decreased to pre-biopsy levels after 24 hours. In cancer negative men, P504S (-) and MMP-2 (-) cells were detected, some of these cells persisted 24 hours after biopsy. CONCLUSIONS: Prostate biopsy causes dissemination of prostate cells into the circulation, both malignant and benign; the majority of them are cleared within 24 hours. There was no conversion of negative to positive result in men with cancer, this suggests that the inherent capacity of malignant CPCs to disseminate is more important than the effect of dissemination caused by prostate biopsy.

Head-to-head comparison of the Montreal nomogram with the detection of primary malignant circulating prostate cells to predict prostate cancer at initial biopsy in Chilean men with suspicion of prostate cancer.

INTRODUCTION: The limitations of total serum prostate-specific antigen (PSA) level values remain problematic. Nomograms may improve the predictive value of a positive prostate biopsy (PB) finding. We compare in a prospective study of Chilean men suspicious of having prostate cancer (PC), owing to an elevated total serum PSA or abnormal digital rectal examination finding or both, the use of the online Montreal nomogram for the detection of primary malignant circulating prostate cells (mCPCs) to predict a positive PB finding. METHODS AND PATIENTS: Consecutive men suspicious of PC underwent 12-core transrectal ultrasound PB; their age, total serum PSA levels and percent free PSA values, and Montreal nomogram scores were registered. Immediately before the PB, an 8-ml blood sample was taken to detect primary mCPCs. Mononuclear cells were obtained by differential gel centrifugation and identified using double immunomarcations with anti-PSA and anti-P504S. Biopsies were classified according to presence of cancer/no cancer. The test results for the detection of mCPC were stated as negative/positive, and the total number of cells/8 ml of blood was registered. Areas under the curve for total serum PSA level, percent free PSA value, Montreal score, and detection of mCPCs were calculated and compared. Diagnostic yields, the number of possible biopsies that could be avoided, and the number of clinically significant cancers that would be missed were calculated. RESULTS: Overall, 607 men underwent biopsy, where 197 (32.5%) had cancer. These men were significantly older, had higher total serum PSA level and Montreal score, and lower percent free PSA value. The values for area under the curve were 0.56 for total PSA level, 0.78 for percent free PSA, 0.78 for Montreal score, and 0.84 for mCPC detection; mCPC detection had a significantly superior prediction value (P = 0.018). Using cutoff values of percent free PSA < 10%, Montreal score > 50%, and ≥ 1 mCPC detected, mCPC detection had a higher diagnostic yield. Of the 197 cancers, 41 complied with the criteria for active surveillance; percent free PSA and the Montreal score missed a higher number of significant cancers when compared with mCPC detection. CONCLUSIONS: Primary mCPC detection outperformed the use of percent free PSA and the Montreal nomogram in predicting clinically significant PC at initial PB.

Prostate cancer screening in the fit Chilean elderly: a head to head comparison of total serum PSA versus age adjusted PSA versus primary circulating prostate cells to detect prostate cancer at initial biopsy.

BACKGROUND: Prostate cancer is predominately a disease of older men, with a median age of diagnosis of 68 years and 71% of cancer deaths occurring in those over 75 years of age. While prostate cancer screening is not recommended for men>70 years, fit elderly men with controlled comorbidities may have a relatively long life expectancy. We compare the use of age related PSA with the detection of primary malignant circulating prostate cells mCPCs to detect clinically significant PC in this population. MATERIALS AND METHODS: All men undergoing PC screening with a PSA>4.0 ng/ml underwent TRUS 12 core prostate biopsy (PB). Age, PSA, PB results defined as cancer/no-cancer, Gleason, number of positive cores and percentage infiltration were registered. Men had an 8 ml blood sample taken for mCPC detection; mononuclear cells were obtained using differential gel centrifugation and mCPCs were identified using immunocytochemistry with anti-PSA and anti-P504S. A mCPC was defined as a cell expressing PSA and P504S; a positive test as at least one mCPC detected/sample. Diagnostic yields for subgroups were calculated and the number of avoided PBs registered. Esptein criteria were used to define small grade tumours. RESULTS: A total of 610 men underwent PB, 398 of whom were aged <70 yrs. Men over 70 yrs had: a higher median PSA, 6.24 ng/ml versus 5.59 ng/ml (p=0.04); and a higher frequency of cancer detected 90/212 (43%) versus 134/398 (34%) (p=0.032). Some 34/134 cancers in men<70 yrs versus 22/90 (24%) of men>70 yrs complied with criteria for active surveillance. CPC detection: 154/398 (39%) men<70 yrs were CPC (+), specificity for cancer 86%, sensitivity 88%, 14/16 with a false (-) result had a small low grade PC. In men>70 years, 88/212 (42%) were CPC (+); specificity 92%, sensitivity 87%, 10/12 with a false (-) had small low grade tumours. False (+) results were more common in younger men 36/154 versus 10/88 (p<0.02). With a PSA cutoff of 6.5 ng/ml, in men<70 yrs, 108 PB would be avoided, missing 56 cancers of which 48 were clinically significant. Using CPC detection, 124 biopsies would be avoided, missing only 2 clinically significant cancers. In men>70 yrs using a PSA>6.5 ng/ml would have resulted in 108 PB with 34 PC detected, of which 14(41%) were small low grade tumours. CONCLUSIONS: The use of CPC detection in the fit elderly significantly decreases the number of PBs without missing clinically significant cancers, indicating superiority to the use of age-related PSA.

Comparison between Use of PSA Kinetics and Bone Marrow Micrometastasis to Define Local or Systemic Relapse in Men with Biochemical Failure after Radical Prostatectomy for Prostate Cancer.

BACKGROUND: Treatment of biochemical failure after radical prostatectomy for prostate cancer is largely empirically based. The use of PSA kinetics has been used as a guide to determine local or systemic treatment of biochemical failure. We here compared PSA kinetics with detection of bone marrow micrometastasis as methods to determine local or systemic relapse. MATERIALS AND METHODS: A transversal study was conducted of men with biochemical failure, defined as a serum PSA >0.2ng/ml after radical prostatectomy. Consecutive patients having undergone radical prostatectomy and with biochemical failure were enrolled and clinical and pathological details were recorded. Bone marrow biopsies were obtained from the iliac crest and touch prints made, micrometastasis (mM) being detected using anti-PSA. The clinical parameters of total serum PSA, PSA velocity, PSA doubling time and time to biochemical failure, age, Gleason score and pathological stage were registered. RESULTS: A total of 147 men, mean age 71.6 ± 8.2 years, with a median time to biochemical failure of 5.5 years (IQR 1.0-6.3 years) participated in the study. Bone marrow samples were positive for micrometastasis in 98/147 (67%) of patients at the time of biochemical failure. The results of bone marrow micrometastasis detected by immunocytochemistry were not concordant with local relapse as defined by PSA velocity, time to biochemical failure or Gleason score. In men with a PSA doubling time of < six months or a total serum PSA of >2,5ng/ml at the time of biochemical failure the detection of bone marrow micrometastasis was significantly higher. CONCLUSIONS: The detection of bone marrow micrometastasis could be useful in defining systemic relapse, this minimally invasive procedure warranting further studies with a larger group of patients.

Extended use of P504S positive primary circulating prostate cell detection to determine the need for initial prostate biopsy in a prostate cancer screening program in Chile.

BACKGROUND: To determine the frequency of primary circulating prostate cells (CPC) detection according to age and serum PSA levels in a cohort of men undergoing screening for prostate cancer and to determine the diagnostic yield in those men complying with the criteria for prostate biopsy. MATERIALS AND METHODS: A prospective study was carried out to analyze all men evaluated in a hospital prostate cancer screening program. Primary CPCs were obtained by differential gel centrifugation and detected using standard immunocytochemistry using anti-PSA, positive samples undergoing a second process with anti-P504S. A malignant primary CPC was defined as PSA+ P504S+, and a test positive if 1 cell/4ml was detected. The frequency of primary CPC detection was compared with age and serum PSA levels. Men with a PSA >4.0ng/ml and/or abnormal rectal examination underwent 12 core prostate biopsy, and the results were registered as cancer/no-cancer and compared with the presence/absence of primary CPCs to calculate the diagnostic yield. RESULTS: A total of 1,117 men participated; there was an association of primary CPC detection with increasing age and increasing serum PSA. Some 559 men underwent initial prostate biopsy of whom 207/559 (37.0%) were positive for primary CPCs and 183/559 (32.0%) had prostate cancer detected. The diagnostic yield of primary CPCs had a sensitivity of 88.5%, a specificity of 88.0%, and positive and negative predictive values of 78.3% and 94.9%, respectively. CONCLUSIONS: The use of primary CPCs for testing is recommended, since its high negative predictive value could be used to avoid prostate biopsy in men with an elevated PSA and/or abnormal DRE. Men positive for primary CPCs should undergo prostate biopsy. It is a test that could be implemented in the routine immunocytochemical laboratory.