The CAPRA-S Score and Immune Dysfunction as a Guide to Outcome in Men Treated with Prostatectomy Radical as Mono-Therapy for Prostate Cancer.

OBJECTIVE: Incorporate the immune function as determined by the absolute lymphocyte count (ALC) into the CAPRA-S risk stratification score to determine if predictive values could be improved. MATERIALS AND METHODS: The clinical pathological findings in the surgical specimen and total PSA were used to define the three CAPRA-S risk groups. One month after surgery and at each follow up total PSA and the ALC were determined, until biochemical failure (BF) or the end of the study period. A cut off value of <1,000 lymphocytes/mm3 was used to define lymphocytopenia (LCP). Each CAPRA-S group was sub-divided based on the presence or absence of LCP. Kaplan-Meier biochemical failure free survival (BFFS) curves and restricted mean biochemical failure free survival times were calculated for each group. RESULTS: 404 patients participated of whom 103 (25.5%) underwent BF. 270 men were CAPRA-S low risk (LR), 89 intermediate risk (IR) and 45 high risk (HR), of whom LCP was found in 22 (8%) of low risk, 24 (27%) of intermediate risk and 17 (38%) of high risk men. LCP was significantly associated with a higher PSA, higher Gleason and CAPRA-S scores and BF. HRs were 1.76 for IR, 2.49 for HR and 1.29 for LCP. Five-year BFFS for men without LCP, LR 93.5%, IR 61% and HR 36%, for those with LCP, LR 55%, IR 25% and HR 6%. All patients with LCP and IR or HR scores relapsed within 6 years. 10 year BFFS for men without LCP were 71% LR, 43% IR and 23% HR, LR with LCP 16%. Men with BF had increasing LCP approximately 18 months before BF. CONCLUSIONS: The incorporation of the ALC taken one month after surgery with the CAPRA-S improves risk stratification; decreases in the ALC suggest that BF is occuring. These results need to be confirmed with larger studies.

Increasing Immune Dysfunction is Associated with Increasing Matrix-Metalloproteinase-2 Expression and Predicts Biochemical Failure in Men with Bone Marrow Micro-Metastasis Positive Localized Prostate Cancer.

INTRODUCTION: To determine if there was an association of the ALC (absolute lymphocyte count) and LCP (lymphocytopenia) with the expression of MMP-2 in bone marrow micro-metastasis, the changes occurring during follow-up and association with biochemical failure. METHODS AND PATIENTS: One month after surgery blood and bone marrow samples were taken to determine the presence of micro-metastasis, the presence of circulating prostate cells (CPCs) and ALC. CPCs and micro-metastasis were detected using immunocytochemistry and MMP-2 expression determined in micro-metastasis. Only men positive for micro-metastasis participated in the study. At end follow blood was taken for serum PSA, ALC and CPCs, if the ALC decreased by more than 10% bone marrow sampling was repeated and MMP-2 expression determined, similarly for men with BF. Men who had stable ALCs had an end of study evaluation of the bone marrow. RESULTS: 402 men underwent radical prostatectomy, one month post surgery 79 men were positive for only bone marrow micro-metastasis and formed the study group; of whom 36/79 (45%) underwent BF. Clinical pathological findings were not significantly different between men with or without BF. In men with BF the ALC was significantly lower one-month post surgery. The 5 and 10 year Kaplan-Meier survival was 100% at 5-years and 65% at 10-years for the whole cohort. Men without BF had stable ALCs. A decrease of >10% in the ALC was associated with increasing MMP-2 expression in the micro-metastasis and surrounding stromal tissue, the appearance of CPCs 6-12 months later and BF. CONCLUSIONS: the immune host-tumour cell interaction in the microenvironment is dynamic and changes with time. A decreasing ALC may be a valuable marker in identifying men with high risk of BF and changes in immune mediated dormancy before the PSA rises.

The CAPRA-S score versus subtypes of minimal residual disease to predict biochemical failure after radical prostatectomy.

OBJECTIVE: The objective of this study was to compare the CAPRA-S score (based on clinicopathological findings) and the subtypes of minimal residual disease (MRD) (based on the biological properties of cancer cells) to predict biochemical failure (BF) after prostatectomy radical. PATIENTS AND METHODS: This was a prospective single-centre study of men who underwent radical prostatectomy. One month after surgery, the blood and bone marrow were taken for circulating prostate cell (CPC) and micrometastasis detection, identified using anti-PSA immunocytochemistry and defined as positive or negative. Patients were classified as Group A: CPC and micrometastasis negative, Group B: micrometastasis positive and CPC negative and Group C: CPC positive. CAPRA-S scores were classified as low, intermediate and high risk. Kaplan-Meier curves for biochemical failure-free survival (BFFS) and restricted mean survival time (RMST) to biochemical failure were determined and compared for up to 10 years. RESULTS: 347 men participated with a median follow-up of 7 years, BFFS decreased proportionally with increasing CAPRA-S score and HR 1.13 and 1.65 for intermediate and high risk, respectively. After 10 years, the BFFS and RMST were 68%, 47% and 16% and 9, 7 and 6 years, respectively. The BFFS curves for MRD were not proportional; Group A and B BFFSs were similar up to 5 years, and then, there was an increasing failure in Group B patients After 10 years, the BFFS and RMST were 95%, 57% and 27% and 10, 9 and 6 years respectively. The CAPRA-S score failed to distinguish between Groups A and B, and one-third of high-risk Group C had low-risk CAPRA-S scores. MRD hazard ratios were Group B 1.76 and Group C 4.03. CONCLUSIONS: The MRD prognostic classification was superior to the CAPRA-S score in predicting BFFS and differentiated between early and late BF. The results need to be confirmed in larger studies.

The Epstein criteria predict for organ-confined prostate cancer but not for minimal residual disease and outcome after radical prostatectomy.

OBJECTIVE: The Epstein criteria (EC) used to select men for active surveillance do not predict biologically insignificant diseases. Minimal residual disease (MRD) is an undetected microscopic disease that remains after radical prostectomy (RP) and is a biological classification associated with the risk of treatment failure. Subtypes of MRD, the 10-year biochemical failure free survival (BFFS), and restricted mean biochemical failure free survival time (RMST) were determined and compared in EC patients treated with RP. MATERIAL AND METHODS: Consecutive patients with a Gleason 6 biopsy treated at a single institution were divided into those who did or did not fulfill the EC and underwent RP. One month after surgery, samples were taken for the detection of circulating prostate cells (CPCs) and bone marrow micrometastasis. MRD was defined as negative for both CPCs and micrometastasis; patients were positive for micrometastasis and CPCs separately. BFFS for up to 10 years and RMST were determined for each MRD subgroup for EC positive and negative patients. RESULTS: EC positive men (137/426) were significantly older (p<0.05) and had negative MRD, pT2 (pathologically organ confined) disease (<0.02), and lower frequency of upgrading (p<0.02). Of the EC positive men, 71% were MRD negative, 13% were positive for micrometastasis, and 16% were positive for CPCs with respective 10-year BFFS of 99%, 89%, and 21% (<0.001) (hazard ratio: 1.00, 1.76, 4.03, respectively) with no signficant differences between the 10-year BFFS or RMST for MRD subgroups for EC positive and negative patients. CONCLUSIONS: EC predict pT2, MRD negative disease; however, 29% are MRD positive with a high risk of treatment failure.

The CAPRA score versus sub-types of minimal residual disease to predict biochemical failure after external beam radiotherapy.

INTRODUCTION: External beam radiotherapy is a treatment option for clinically localised prostate cancer; however, some 15% of patients will undergo treatment failure within 5 years. The objective was to compare the Cancer of the Prostate Risk Assessment (CAPRA) score (based on the clinical-pathological findings) and the sub-types of minimal residual disease (MRD) (based on the biological properties of the cancer cells) risk classifications to predict biochemical failure (BF) after external beam radiotherapy. METHODS AND PATIENTS: Clinical-pathological findings were obtained from the prostate biopsy to determine the CAPRA score and used to define low-, intermediate- and high-risk patients. Blood and bone marrow were obtained 3 months after radiotherapy; circulating prostate cells (CPCs) and micro-metastasis were detected using immunocytochemistry with anti-prostate specific antigen. CPCs and micro-metastasis were classified as positive if at least one cell was detected in the sample. Three subgroups were formed Group A (MRD negative), Group B (micro-metastasis positive, CPC negative) and Group C (CPC positive)Patients were followed up for 10 years or until biochemical failure. Biochemical failure free survival (BFFS) curves were constructed using Kaplan-Meier (observed), a flexible parameter model (predicted survival) and the restricted mean survival time (RMST) was calculated for each sub-group. RESULTS: 309 men participated with a median follow-up of 8 years. The risk of biochemical failure increased proportionally with increasing CAPRA score, hazard ratio 1.18 for intermediate and 1.69 for high risk patients. After 10 years, the percentage BFFS and RMST to failure were 74%, 49%, 16% and 9, 7 and 6 years, respectively. The agreement between observed and predicted BFFS was acceptable (Harrell´s C 0.62). The BFFS curves for MRD were different and not proportional, survival curves for men MRD negative and only micro-metastasis were similar up to 5 years, and then there was increasing failure in the micro-metastasis only group. After 10 years, the percentage BFFS and RMST to failure were 95%, 59%, 28% and 10, 9 and 6 years, respectively. The CAPRA score failed to distinguish between Groups A and B, one third of high risk Group C had low risk CAPRA scores. The agreement between observed and predicted BFFS was very good (Harrell´s C 0.92). Minimal residual disease hazard ratios were Group B 1.84 and Group C 4.51. CONCLUSIONS: The MRD prognostic classification is based on the biological characteristics of the tumour cell-microenvironment interaction, to give three groups, MRD negative, only bone marrow micro-metastasis and CPC positive prostate cancer. Differing from the CAPRA score classification the risk of treatment failure changes with time, differentiating between early and late treatment failures and incorporates the concept of dormancy. It proved to be superior to the CAPRA score in predicting biochemical failure and the results need to be confirmed in larger studies.

Platelet-to-lymphocyte ratio and systemic immune-inflammation index versus circulating prostate cells to predict significant prostate cancer at first biopsy.

OBJECTIVE: It has been reported that the systemic immune-inflammation index (SII) and platelet-to-lymphocyte ratio (PLR) are higher in men with prostate cancer. We compare their use with the percentage of free prostate-specific antigen (PSA), PSA density, and primary circulating prostate cells (CPCs) to predict clinically significant prostate cancer at first biopsy in men with a PSA of 4-10 ng/mL. MATERIAL AND METHODS: Consecutive men with suspicion of prostate cancer underwent a 12-core transrectal ultrasound-guided prostate biopsy; total serum PSA, the percentage of free PSA, prostate ultrasound to calculate PSA density, and absolute neutrophil, lymphocyte, and platelet counts were used for risk assessment. CPCs were detected using differential gel centrifugation and immunocytochemistry with anti-PSA and anti-P504S. A malignant CPC was defined as a cell-expressing PSA and P504S and defined as positive or negative. Biopsies were classified as indicating cancer or no cancer. Areas under the curve for each parameter were calculated and compared, and diagnostic yields were calculated. RESULTS: A total of 1223 men participated, and 467 (38%) had a biopsy positive for cancer, whereas 353/467 (76%) had clinically significant prostate cancer. The PLR was significantly higher in men with prostate cancer; there was no significant difference for the SII. The areas under the curves were CPC 0.84, the percentage of free PSA was 0.79, PLR 0.65, PSA density 0.62, and SII 0.46. Neither the PLR nor the SII discriminated between patients with clinically significant prostate cancer, indolent cancer, and benign prostatic disease. CONCLUSION: Based on the results of this study, neither the SII nor PLR could differentiate between clinically significant prostate cancer and indolent cancer/benign disease at initial biopsy.

Minimal Residual Disease Defines the Risk and Time to Biochemical Failure in Patients with Pt2 and Pt3a Prostate Cancer Treated With Radical Prostatectomy: An Observational Prospective Study.

PURPOSE: To compare Gleason score (GS), pathological stage, minimal residual disease (MRD) and outcome after prostatectomy radical for prostate cancer. PATIENTS AND METHODS: 290/357 men with GS 6 or 7 and pT2 or pT3a disease treated with radical prostatectomy participated. Blood and bone marrow were obtained one month after surgery. Circulating prostate cells (CPCs) were detected using differential gel centrifugation and immunocytochemistry with anti PSA, micro-metastasis weas detected using immunocytochemistry with anti-PSA. Biochemical failure free survival (BFFS) and restricted mean survival times (RMST) were calculated according to GS and stage. MRD was classified as negative, patients only positive for micro-metastasis and patients positive for CPCs; BFFS and RMST were calculated according to MRD sub-type. RESULTS: GS7 (HR 3.03) and pT3a (HR 3.68) cancers were associated with a higher failure rate, shorter time to failure and associated with CPC positive MRD (p < 0.001), while G6 and pT2 with MRD negative disease (p<0.001). Men with CPC (+) MRD were at high risk of early treatment failure; 15% BFFS at 10 years, RMST 3.0 years. Men positive for only micro-metastasis were at risk of late failure, 50% BFFS at 10 years, RMST 8.0 years compared with MRD negative patients; 80% BFFS at 10 years, RMST 9.0 years. CONCLUSION: The sub-type of MRD identifies Gleason 6 pT2 patients with a poor prognosis and Gleason 7 pT3a patients with a good prognosis and could be used to classify men according to personal risk characteristics for the use of adjuvant treatment.

[Circulating prostate cells and bone marrow micro-metastasis and not treatment modality determine the risk and time to biochemical failure in low risk prostate cancer.] / La enfermedad mínima residual y no el tratamiento predice la recidiva bioquímica en sujetos con cáncer prostático de bajo riesgo.

INTRODUCTION: Minimal residual disease (MRD) is that which persists after curative treatment for prostate cancer. It has the potential to grow and cause metastasis. The detection of circulating prostate cells (CPCs) and bone marrow micro-metastasis could represent different sub-types of MRD. OBJECTIVE: To determine biochemical failure free survival and time to failure, the presence of circulating prostate cells and bone marrow micro-metastasis in men treated for low risk prostate cancer. HYPOTHESIS: The presence of MRD and not the treatment modality determines the results of therapy. METHODS: Blood and bone marrow samples were taken one month after completing treatment to detect CPCs and micro-metastasis. Patients were classified into three groups; A: CPC negative, micro-metastasis negative, B: CPC negative, micro-metastasis positive and C: CPC positive. Biochemical failure was defined as a PSA >0.2ng/ml after radical prostatectomy and >2.0ng/ml post nadir after radiotherapy. After 10 years of follow up the Kaplan-Meier survival curve was determined and using a flexible adjusted parametric model the mean restricted survival time (MRST) was calculated for all groups. RESULTS: 343 men participated, 183 post surgery and 160 post radiotherapy, 181 (53%) had clinical stage T1 and 162 (47%) clinical stage T2a. There were no differences in treatment results between prostatectomy and radiotherapy. T1 patients had a significantly lower frequency of MRD than T2 patients (20% versus 67% p<0.001). Patients negative for MRD (Group A) had a 97% 10-year survival rate and a MRST to failure of 9.9 years. Men with only micro-metastasis (Group B) had a survival rate similar to Group A during the first five years, afterwards there was increasing treatment failure (late failure). Men positive for CPCs had a high risk of early failure. CONCLUSIONS: The treatment results of surgery and radiotherapy are similar and depend on the sub-type of MRD. Men negative for MRD could be considered cured with a biochemical failure free survival of >95% at 10 years. The sub-type of MRD determines early or late failure and could be useful in the risk classification of patients after curative treatment.

INTRODUCCIÓN: En cáncer de próstata de bajo riesgo (CPBR) tratado localmente, la recidiva bioquímica (RB) muestra frecuencias de 9 a 20% considerando su explicación la presencia de enfermedad mínima residual (EMR).OBJETIVO: Establecer pronóstico de supervivencia para RB de formas de EMR detectadas al mes de tratamiento por CPBR.MATERIAL Y MÉTODO: Se invita a participar a hombres con CPBR con indicación de prostatectomía radical o radioterapia, realizando al mes de efectuado el tratamiento la determinación sanguínea de células prostáticas circulantes secundarias (CPCs) y presencia de micrometastasis ósea en biopsia de cadera; así los sujetos fueron clasificados en tres formas de EMR cuales son: 1.-ausencia EMR (CPCs negativo y mM negativo); 2.-micrometástasis ósea presente (incluye CPCs negativo) y 3.-CPCs positivo. Se realiza una vigilancia periódica con antígeno prostático específico consignado los tiempos para RB. Se realiza un análisis de supervivencia de Kaplan-Meier; así como también una regresión flexible paramétrica (FP) valorando predictores tales como edad, tratamiento, etapa T y forma EMR. En ambos análisis de sobrevida para la RB se determina la proporción de supervivencia (PS) así como el tiempo medio de ocurrencia o media restringida (MR).RESULTADOS: Un total de 343 sujetos participaron en estudio con un tiempo máximo de seguimiento de 10 años, 183 post prostatectomia y 160 post-readioterapia. El modelo FP seleccionado con adecuado ajuste, calibración y discriminación; considera sólo como predictores de RB la etapa T y las formas EMR; siendo sus resultados concordantes con análisis de Kaplan-Meier. De este modo la PS para grupo sin EMR es de 96,40 a 93,61% con MR de 9,94 a 9,88 años; grupo micrometástasis ósea presente PS es de 69,60 a 52,07% con MR de 8,42 a 9,02 años; grupo CPCs positivo: PS es de 21,05 a 6,05% y MR de 5,71 a 4,28 años.CONCLUSIÓN: La EMR predice la RB en sujetos con CP de bajo riesgo, no hubo diferencias entre los grupos tratandos con cirugía o radioterapia.

La enfermedad mínima residual y no el tratamiento predice la recidiva bioquímica en sujetos con cáncer prostático de bajo riesgo / Circulating prostate cells and bone marrow micro-metastasis and not treatment modality determine the risk and time to biochemical failure in low risk prostate cancer

INTRODUCCIÓN: En cáncer de próstata de bajo riesgo (CPBR) tratado localmente, la recidiva bioquímica (RB) muestra frecuencias de 9 a 20% considerando su explicación la presencia de enfermedad mínima residual (EMR). Objetivo: Establecer pronóstico de supervivencia para RB de formas de EMR detectadas al mes de tratamiento por CPBR. MATERIAL Y MÉTODO: Se invita a participar a hombres con CPBR con indicación de prostatectomía radical o radioterapia, realizando al mes de efectuado el tratamiento la determinación sanguínea de células prostáticas circulantes secundarias (CPCs) y presencia de micrometastasis ósea en biopsia de cadera; así los sujetos fueron clasificados en tres formas de EMR cuales son: 1.-ausencia EMR (CPCs negativo y mM negativo); 2.-micrometástasis ósea presente (incluye CPCs negativo) y 3.-CPCs positivo. Se realiza una vigilancia periódica con antígeno prostático específico consignado los tiempos para RB. Se realiza un análisis de supervivencia de Kaplan-Meier; así como también una regresión flexible paramétrica (FP) valorando predictores tales como edad, tratamiento, etapa T y forma EMR. En ambos análisis de sobrevida para la RB se determina la proporción de supervivencia (PS) así como el tiempo medio de ocurrencia o media restringida (MR). RESULTADOS: Un total de 343 sujetos participaron en estudio con un tiempo máximo de seguimiento de 10 años, 183 post prostatectomia y 160 post-readioterapia. El modelo FP seleccionado con adecuado ajuste, calibración y discriminación; considera sólo como predictores de RB la etapa T y las formas EMR; siendo sus resultados concordantes con análisis de Kaplan-Meier. De este modo la PS para grupo sin EMR es de 96,40 a 93,61% con MR de 9,94 a 9,88 años; grupo micrometástasis ósea presente PS es de 69,60 a 52,07% con MR de 8,42 a 9,02 años; grupo CPCs positivo: PS es de 21,05 a 6,05% y MR de 5,71 a 4,28 años. CONCLUSIÓN: La EMR predice la RB en sujetos con CP de bajo riesgo, no hubo diferencias entre los grupos tratandos con cirugía o radioterapia

INTRODUCTION: Minimal residual disease (MRD) is that which persists after curative treatment for prostate cancer. It has the potential to grow and cause metastasis. The detection of circulating prostate cells (CPCs) and bone marrow micro-metastasis could represent different sub-types of MRD. OBJECTIVE: To determine biochemical failure free survival and time to failure, the presence of circulating prostate cells and bone marrow micro-metastasis in men treated for low risk prostate cancer. HYPOTHESIS: The presence of MRD and not the treatment modality determines the results of therapy. METHODS: Blood and bone marrow samples were taken one month after completing treatment to detect CPCs and micro-metastasis. Patients were classified into three groups; A: CPC negative, micro-metastasis negative, B: CPC negative, micro-metastasis positive and C: CPC positive. Biochemical failure was defined as a PSA > 0.2 ng/ml after radical prostatectomy and > 2.0 ng/ml post nadir after radiotherapy. After 10 years of follow up the Kaplan-Meier survival curve was determined and using a flexible adjusted parametric model the mean restricted survival time (MRST) was calculated for all groups. RESULTS: 343 men participated, 183 post surgery and 160 post radiotherapy, 181 (53%) had clinical stage T1 and 162 (47%) clinical stage T2a. There were no differences in treatment results between prostatectomy and radiotherapy. T1 patients had a significantly lower frequency of MRD than T2 patients (20% versus 67% p < 0.001). Patients negative for MRD (Group A) had a 97% 10-year survival rate and a MRST to failure of 9.9 years. Men with only micro-metastasis (Group B) had a survival rate s imilar to Group A during the first five years,afterwards there was increasing treatment failure (late failure). Men positive for CPCs had a high risk of early failure. CONCLUSIONS. The treatment results of surgery and radiotherapy are similar and depend on the sub-type of MRD. Men negative for MRD could be considered cured with a biochemical failure free survival of > 95% at 10 years. The sub-type of MRD determines early or late failure and could be useful in the risk classification of patients after curative treatment

Predictive Value of Neutrophil to Lymphocyte Ratio in the Diagnosis of Significant Prostate Cancer at Initial Biopsy: A Comparison with Free Percent Prostate Specific Antigen, Prostate Specific Antigen Density and Primary Circulating Prostate Cells.

INTRODUCTION: An elevated serum PSA is the only biomarker routinely used in screening for prostate cancer to indicate a prostate biopsy. However, it is not specific for prostate cancer and the neutrophil/lymphocyte ratio has been suggested as an alternative. We present a prospective study of men with an elevated PSA and compare the neutrophil/lymphocyte ratio, free percent PSA, PSA density and the presence of circulating prostate cells to detect clinically significant prostate cancer at first biopsy. PATIENTS AND METHODS: Prospective study of consecutive men with a PSA 4-10 ng/ml referred for initial prostate biopsy, the results were compared with the neutrophil/lymphocyte ratio, free percent PSA and PSA density. Circulating prostate cells (CPCs) were detected using immunocytochemistry. The blood sample was taken immediately before the prostate biopsy. RESULTS: 1,223 men participated, 38% (467) of whom had prostate cancer detected, of these 322 were clinically significant. The area under the curves were for neutrophil/lymphocyte ratio, free percent PSA, PSA density and CPC detection were 0.570, 0.785, 0,620 and 0.844 respectively. Sensitivity/specificity were 0.388/0.685, 0.419/0.897, 0.598/0.624 and 0.966/0.786 respectively. The neutrophil/lymphocyte ratio did not differentiate between benign and malignant disease. CONCLUSIONS: The neutrophil/lymphocyte ratio did not discriminate between benign and malignant prostatic disease in patients with a PSA between 4-10ng/ml.

Subtypes of minimal residual disease, association with Gleason score, risk and time to biochemical failure in pT2 prostate cancer treated with radical prostatectomy.

INTRODUCTION: The Gleason score is a strong prognostic factor for treatment failure in pathologically organ-confined prostate cancer (pT2) treated by radical prostatectomy (RP). However, within each Gleason score, there is clinical heterogeneity with respect to treatment outcome, even in patients with the same pathological stage and prostate-specific antigen (PSA) at diagnosis. This may be due to minimal residual disease (MRD) remaining after surgery. We hypothesise that the sub-type of MRD determines the risk of and timing of treatment failure, is a biological classification, and may explain in part clinical heterogeneity. We present a study of pT2 patients treated with RP, the subtypes of MRD for each Gleason score and clinical outcomes. PATIENTS AND METHODS: Patients with Gleason ≤6 (G6) or Gleason 7 (G7) pT2 cancer participated in the study. One month after surgery, blood was taken for circulating prostate cell (CPCs); mononuclear cells were obtained by differential gel centrifugation and identified using immunocytochemistry with anti-PSA. The detection of one CPC/sample was defined as a positive test. Touch-preparations from bone-marrow biopsies were used to detect micro-metastasis using immunocytochemistry with anti-PSA. Biochemical failure was defined as a PSA >0.2 ng/mL. Patients were classified as: Group A MRD negative (CPC and micro-metastasis negative), Group B (only micro-metastasis positive) and Group C (CPC positive). Biochemical failure-free survival (BFFS) using Kaplan-Meier and time to failure using Restricted Mean Survival Time (RMST) after 10 years of follow-up were calculated for each group based on the Gleason score. RESULTS: Of a cohort of 253 men, four were excluded for having Gleason 8 or 9 prostate cancer, leaving a study group of 249 men of whom 52 had G7 prostate cancer. G7 patients had a higher frequency of MRD (69% versus 36%) and worse prognosis. G6 and G7 patients negative for MRD had similar BBFS rates, 98% at 10 years, time to failure 9.9 years. Group C, G6 patients had a higher BFFS and longer time to failure compared to G7 patients (19% versus 5% and 7 versus 3 years). Group B showed similar results up to 5 years, thereafter G6 had a lower BFFS 63% versus 90%. CONCLUSIONS: G7 and G6 pT2 patients have different patterns of MRD and relapse. Risk stratification using MRD sub-types may help to define the need for adjuvant therapy. This needs confirmation with large randomised long-term trials.

[Circulating prostate cells and bone marrow micrometastasis are determinant in risk and time to biochemical progression in localized prostate cancer.] / Células prostáticas circulantes y micro-metástasis en médula ósea determinantes en el riesgo y en el tiempo de progresión bioquímica en cáncer prostático localizado.

INTRODUCTION: Minimal residual disease (MRD) is that which remains after curative therapy for prostate cancer. It has the potential for growth and later cause metastasis. After radical prostatectomy, the detection of circulating prostate cells (CPCs) and bone marrow micro-metastasis could represent different types of MRD. We proposed to determine the biochemical failure free survival rates, the time to biochemical failure after 10 years of follow-up and the presence of CPCs and micro-metastasis in patients treated with RP for pathologically organ confined prostate cancer. METHODS AND PATIENTS: One month after RP monotherapy for prostate cancer, blood and bone marrow samples were taken to detect CPCs and micro-metastasis. Men were classified as: group A (CPC negative and micro-metastasis negative), group B (CPC negative and micro-metastasis positive), group C (CPC positive and micro-metastasis negative), and group D (CPC positive and micro-metastasis positive). All subjects were followed with serial total PSA levels, recording the time at which failure occurred defined as a serum PSA > 0.2ng/ ml on two separate occasions. After ten years of follow- up for each group Kaplan-Meier survival curves were determined and using an adjusted flexible parametric model (FP), the Restricted Mean Survival Times for groups A, B, C and D were calculated. RESULTS: 191 men participated, 10-year biochemical failure survival rates were; group A (N=114) with a Kaplan-Meier of 98.7%; group B (N=39) 65.1%; group C (N=12) 10.4% and in group D (N=28) 12.8%. The Restricted Mean Survival Times (years) were group A: 9.95; group B: 9.45, group C: 5.11 and group D: 6.18 (p-value <0.001 between groups: A versus C, Aversus D, B versus C and B versus D). Frequency and time to failure was dependent on the type of MRD, those men CPC positive had a significantly higher failure rate and early failure. Those men only micro-metastasis positive had lower failure rate and late failure when compared with men negative for MRD. CONCLUSIONS: CPC positive men have a more aggressive disease with increased early failure; those men who are only positive for micro-metastasis are at risk for late or delayed failure. These two forms of measuring MRD represent different stages in the disease progression and may be used to guide clinical treatment decisions before increases in PSA levels.

INTRODUCCIÓN: La enfermedad mínima residual es aquella que persiste tras un tratamiento curativo. Tiene el potencial para crecer y causar metástasis. Tras una prostatectomía radical, la detección de células prostáticas circulantes (CPCs) y micrometástasis en médula ósea pueden representar diferentes tipos de la enfermedad mínima residual. Proponemos determinar la tasa de supervivencia libre de recidiva bioquímica, el tiempo hasta la recidiva bioquímica y la presencia de CPCs y micrometástasis en pacientes sometidos a prostatectomia por cáncer prostático localizado.MÉTODOS Y PACIENTES: Se tomaron muestras de sangre y médula ósea un mes después de la cirugía, para detectar CPCs y micro-metástasis. Los sujetos fueron clasificados en 4 grupos: Grupo A (CPCs negativo, micro-metástasis negativo), Grupo B (CPCs negativo, micro-metástasis positivo), Grupo C (CPCs positivo, micro-metástasis negativo), Grupo D (CPCs positivo, micro-metástasis positivo). Los sujetos se siguieron con PSA sérico; la recidiva bioquímica se definió como un PSA > 0,2ng/ml. Tras 10 años de seguimiento se determinó la curva se sobrevida de Kaplan-Meier y mediante un modelo paramétrico flexible ajustado, se calculó el tiempo de supervivencia medio restringido para todos los grupos.RESULTADOS: Participaron 191 hombres. La tasa de supervivencia a 10 años (KaplanMeier) en Grupo A (N=114) fue 98,7%, Grupo B (N=39) 65,1%, Grupo C (N=12) 10,4% y Grupo D (N=28) 12,8%. El tiempo de supervivencia medio restringido (años) fue; GrupoA 9,95, Grupo B 9,45, Grupo C 5,11 y Grupo D fue 6,18 (valor p<0,001 entre A versus C, A versus D,  B versus C y B versus D). La frecuencia y el tiempo hasta la recidiva fue dependiente del tipo de enfermedad mínima residual, sujetos CPC positivos tuvieron una tasa de recidiva significativamente mayor y más temprana. Sujetos que solo presentaron micro-metástasis tuvieron menor tasa de recidiva y más tardía que aquellos sin enfermedad mínima residual.CONCLUSIONES: Hombres CPC positivas presentaron una enfermedad más agresiva con recidiva temprana. Hombres con solo micro-metástasis tienen riesgo de recidiva tardía. Estas dos formas de medir la enfermedad mínima residual representan diferentes entidades clínicas y podría ser utilizada como una guía para la toma de decisiones clínicas previo al aumento del PSA sérico.

Células prostáticas circulantes y micro-metástasis en médula ósea determinantes en el riesgo y en el tiempo de progresión bioquímica en cáncer prostático localizado / Circulating prostate cells and bone marrow micrometastasis are determinant in risk and time to biochemical progression in localized prostate cancer

Introducción: La enfermedad mínima residual es aquella que persiste tras un tratamiento curativo. Tiene el potencial para crecer y causar metástasis. Tras una prostatectomía radical, la detección de células prostáticas circulantes (CPCs) y micrometástasis en médula ósea pueden representar diferentes tipos de la enfermedad mínima residual. Proponemos determinar la tasa de supervivencia libre de recidiva bioquímica, el tiempo hasta la recidiva bioquímica y la presencia de CPCs y micrometástasis en pacientes sometidos a prostatectomia por cáncer prostático localizado. Métodos y pacientes: Se tomaron muestras de sangre y médula ósea un mes después de la cirugía, para detectar CPCs y micro-metástasis. Los sujetos fueron clasificados en 4 grupos: Grupo A (CPCs negativo, micro-metástasis negativo), Grupo B (CPCs negativo, micro-metástasis positivo), Grupo C (CPCs positivo, micro-metástasis negativo), Grupo D (CPCs positivo, micro-metástasis positivo). Los sujetos se siguieron con PSA sérico; la recidiva bioquímica se definió como un PSA > 0,2ng/ml. Tras 10 años de seguimiento se determinó la curva se sobrevida de Kaplan-Meier y mediante un modelo paramétrico flexible ajustado, se calculó el tiempo de supervivencia medio restringido para todos los grupos. Resultados: Participaron 191 hombres. La tasa de supervivencia a 10 años (KaplanMeier) en Grupo A (N=114) fue 98,7%, Grupo B (N=39) 65,1%, Grupo C (N=12) 10,4% y Grupo D (N=28) 12,8%. El tiempo de supervivencia medio restringido (años) fue; Grupo A 9,95, Grupo B 9,45, Grupo C 5,11 y Grupo D fue 6,18 (valor p<0,001 entre A versus C, A versus D, B versus C y B versus D). La frecuencia y el tiempo hasta la recidiva fue dependiente del tipo de enfermedad mínima residual, sujetos CPC positivos tuvieron una tasa de recidiva significativamente mayor y más temprana. Sujetos que solo presentaron micro-metástasis tuvieron menor tasa de recidiva y más tardía que aquellos sin enfermedad mínima residual. Conclusiones: Hombres CPC positivas presentaron una enfermedad más agresiva con recidiva temprana. Hombres con solo micro-metástasis tienen riesgo de recidiva tardía. Estas dos formas de medir la enfermedad mínima residual representan diferentes entidades clínicas y podría ser utilizada como una guía para la toma de decisiones clínicas previo al aumento del PSA sérico

Introduction: Minimal residual disease (MRD) is that which persists after curative treatment for prostate cancer. It has the potential to grow and cause metastasis. The detection of circulating prostate cells (CPCs) and bone marrow micro-metastasis could represent different sub-types of MRD. Objective: To determine biochemical failure free survival and time to failure, the presence of circulating prostate cells and bone marrow micro-metastasis in men treated for low risk prostate cancer. Hypothesis: The presence of MRD and not the treatment modality determines the results of therapy. Methods: Blood and bone marrow samples were taken one month after completing treatment to detect CPCs and micro-metastasis. Patients were classified into three groups; A: CPC negative, micro-metastasis negative, B: CPC negative, micro-metastasis positive and C: CPC positive. Biochemical failure was defined as a PSA > 0.2 ng/ml after radical prostatectomy and > 2.0 ng/ml post nadir after radiotherapy. After 10 years of follow up the Kaplan-Meier survival curve was determined and using a flexible adjusted parametric model the mean restricted survival time (MRST) was calculated for all groups. Results: 343 men participated, 183 post surgery and 160 post radiotherapy, 181 (53%) had clinical stage T1 and 162 (47%) clinical stage T2a. There were no differences in treatment results between prostatectomy and radiotherapy. T1 patients had a significantly lower frequency of MRD than T2 patients (20% versus 67% p < 0.001). Patients negative for MRD (Group A) had a 97% 10-year survival rate and a MRST to failure of 9.9 years. Men with only micro-metastasis (Group B) had a survival rate similar to Group A during the first five years, afterwards there was increasing treatment failure (late failure). Men positive for CPCs had a high risk of early failure. Conclusions: The treatment results of surgery and radiotherapy are similar and depend on the sub-type of MRD. Men negative for MRD could be considered cured with a biochemical failure free survival of > 95% at 10 years. The sub-type of MRD determines early or late failure and could be useful in the risk classification of patients after curative treatment

[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.

Transitory Spontaneous Remission of Myelodysplasia in an Elderly Man while Receiving Intravesical Bacillus Calmette-Guérin for Bladder Cancer: A Case Report and Review of the Literature.

Myelodysplasia is a clonal disorder characterized by progressive cytopenias. Intravescial BCG is standard immunotherapy for superficial bladder cancer. We present a patient with transfusion-dependent myelodysplasia whose blood counts normalized during treatment with intravesical BCG for bladder cancer. After finishing treatment, the patient became transfusion dependent once more. We discuss possible mechanisms to explain this case report.

The presence of secondary circulating prostate tumour cells determines the risk of biochemical relapse for patients with low- and intermediate-risk prostate cancer who are treated only with external radiotherapy.

INTRODUCTION: The classification of patients with prostate cancer is used to determine treatments based on risk factors. The presence of secondary circulating prostate tumour cells (CPCs) detected in peripheral blood after a curative treatment has been associated with a worse prognosis. We present a prospective study of CPC detection post radiotherapy and the oncological results. PATIENTS AND METHODS: All of the patients classified as low and intermediate risk that were treated with radiotherapy were included. Three months after finishing treatment, an 8-ml blood sample was taken to detect CPCs. Mononuclear cells were obtained using gel centrifugation, and CPCs were identified using immunocytochemistry with anti-prostate-specific antigen. Patients were classified as low-risk CPC positive or negative and intermediate-risk CPC positive or negative. The biochemical relapse-free survival analysis was determined based on a follow-up of up to 15 years using the Kaplan-Meier and Cox regression models. Biochemical failure was defined according to the Pheonix II criteria. RESULTS: Of 241 patients, 181 (75.1%) were classified as low risk and 60 (24.9%) as intermediate risk. Biochemical failure was observed in 27.1% (49/181) of the low-risk prostate cancer participants and in 53.3% (32/60) of intermediate-risk participants after 15 years of follow-up. 20.4% (37/181) of the low-risk cancer participants had detectable CPCs in comparison with 43.3% (26/60) of the intermediate-risk cancer participants (p < 0.001 overall risk 2.98, confidence interval (CI) 95% 1.59-5.56; relative risk 2.12, CI 95% 1.41-3.19). Positive CPC patients had a worse prognosis, and a shorter time period until biochemical relapse, regardless of risk group. The biochemical relapse-free survival curves show that intermediate-risk participants who were CPC negative had a higher survival rate and slower disease progression than those participants who were low risk but CPC positive. CONCLUSIONS: CPC detection is a risk factor for biochemical relapse and could be useful in identifying patients that will need additional treatment.