Evaluation of Matrix Metalloproteases by Artificial Intelligence Techniques in Negative Biopsies as New Diagnostic Strategy in Prostate Cancer.

Usually, after an abnormal level of serum prostate-specific antigen (PSA) or digital rectal exam, men undergo a prostate needle biopsy. However, the traditional sextant technique misses 15-46% of cancers. At present, there are problems regarding disease diagnosis/prognosis, especially in patients' classification, because the information to be handled is complex and challenging to process. Matrix metalloproteases (MMPs) have high expression by prostate cancer (PCa) compared with benign prostate tissues. To assess the possible contribution to the diagnosis of PCa, we evaluated the expression of several MMPs in prostate tissues before and after PCa diagnosis using machine learning, classifiers, and supervised algorithms. A retrospective study was conducted on 29 patients diagnosed with PCa with previous benign needle biopsies, 45 patients with benign prostatic hyperplasia (BHP), and 18 patients with high-grade prostatic intraepithelial neoplasia (HGPIN). An immunohistochemical study was performed on tissue samples from tumor and non-tumor areas using specific antibodies against MMP -2, 9, 11, and 13, and the tissue inhibitor of MMPs -3 (TIMP-3), and the protein expression by different cell types was analyzed to which several automatic learning techniques have been applied. Compared with BHP or HGPIN specimens, epithelial cells (ECs) and fibroblasts from benign prostate biopsies before the diagnosis of PCa showed a significantly higher expression of MMPs and TIMP-3. Machine learning techniques provide a differentiable classification between these patients, with greater than 95% accuracy, considering ECs, being slightly lower when considering fibroblasts. In addition, evolutionary changes were found in paired tissues from benign biopsy to prostatectomy specimens in the same patient. Thus, ECs from the tumor zone from prostatectomy showed higher expressions of MMPs and TIMP-3 compared to ECs of the corresponding zone from the benign biopsy. Similar differences were found for expressions of MMP-9 and TIMP-3, between fibroblasts from these zones. The classifiers have determined that patients with benign prostate biopsies before the diagnosis of PCa showed a high MMPs/TIMP-3 expression by ECs, so in the zone without future cancer development as in the zone with future tumor, compared with biopsy samples from patients with BPH or HGPIN. Expression of MMP -2, 9, 11, and 13, and TIMP-3 phenotypically define ECs associated with future tumor development. Also, the results suggest that MMPs/TIMPs expression in biopsy tissues may reflect evolutionary changes from prostate benign tissues to PCa. Thus, these findings in combination with other parameters might contribute to improving the suspicion of PCa diagnosis.

Prostate Cancer Tumor Stroma: Responsibility in Tumor Biology, Diagnosis and Treatment.

Prostate cancer (PCa) is a common cancer among males globally, and its occurrence is growing worldwide. Clinical decisions about the combination of therapies are becoming highly relevant. However, this is a heterogeneous disease, ranging widely in prognosis. Therefore, new approaches are needed based on tumor biology, from which further prognostic assessments can be established and complementary strategies can be identified. The knowledge of both the morphological structure and functional biology of the PCa stroma compartment can provide new diagnostic, prognostic or therapeutic possibilities. In the present review, we analyzed the aspects related to the tumor stromal component (both acellular and cellular) in PCa, their influence on tumor behavior and the therapeutic response and their consideration as a new therapeutic target.

Efficacy and Tolerability of 6-Month Treatment with Tamsulosin Plus the Hexanic Extract of Serenoa repens versus Tamsulosin Plus 5-Alpha-Reductase Inhibitors for Moderate-to-Severe LUTS-BPH Patients: Results of a Paired Matched Clinical Study.

The objective of this subset analysis was to evaluate and compare the efficacy and tolerability of two combination treatments for men with moderate-to-severe lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH). Data were from a real-world, open-label, prospective, and multicenter study performed in outpatient urology clinics. Men with moderate-to-severe LUTS/BPH received 6-month treatment with tamsulosin (TAM) in combination with either the hexanic extract of S. repens (HESr) or a 5-alpha-reductase inhibitor (5ARI). Changes in urinary symptoms and quality of life were measured using the IPSS and BII questionnaires, respectively. Treatment tolerability was assessed by recording adverse effects (AEs). Patients in the two study groups were matched using iterative and propensity score matching approaches. After iterative matching, data were available from 136 patients (n = 68 treated with TAM + 5ARI, n = 68 with TAM + HESr). After 6 months of treatment, mean (SD) IPSS total score improved by 7.7 (6.3) and 6.7 (5.0) points in the TAM + 5ARI and TAM + HESr groups, respectively (p = 0.272); mean BII total scores improved by 3.1 (2.9) and 2.9 (2.4) points (p = 0.751), respectively. AEs were reported by 26.5% and 10.3% of patients in the same groups, mostly affecting sexual function (p < 0.027). When used in a real-world setting to treat patients with moderate-severe LUTS/BPH, 6-month treatment with TAM + HESr was as effective as TAM + 5ARI, but with better tolerability.

Efficacy and Safety of the Hexanic Extract of Serenoa repens vs. Watchful Waiting in Men with Moderate to Severe LUTS-BPH: Results of a Paired Matched Clinical Study.

We investigated changes in symptoms and quality of life (QoL) in men with moderate-to-severe lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH) receiving the hexanic extract of Serenoa repens (HESr) and compared results with a matched group on watchful waiting (WW). Data was from a real-world, open-label, prospective, multicenter study. This sub-group analysis included patients with moderate-to-severe symptoms receiving either the HESr 320 mg/daily for six months (HESr) or who remained untreated for LUTS/BPH (WW). Changes in urinary symptoms and QoL were measured by IPSS and BII questionnaires. Two statistical approaches (iterative matching and propensity score pairing) were used to maximize between-group comparability at baseline. Tolerability was assessed in the HESr group. After iterative matching, data for analysis was available for 783 patients (102 WW, 681 HESr). IPSS scores improved by a mean (SD) of 3.8 (4.4) points in the HESr group and by 2.2 (4.5) points in the WW group (p = 0.002). Changes in BII score were 1.8 (2.4) points and 1.0 (2.2) points, respectively (p < 0.001). Three patients (0.9%) treated with the HESr reported mild adverse effects. Moderate-severe LUTS/BPH patients treated for six months with the HESr showed greater improvements in symptoms and QoL than matched patients on WW, with a very low rate of adverse effects.

Efficacy and tolerability of the hexanic extract of Serenoa repens compared to tamsulosin in moderate-severe LUTS-BPH patients.

In a subset analysis of data from a 6-month, multicenter, non-interventional study, we compared change in symptoms and quality of life (QoL), and treatment tolerability, in men with moderate to severe lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH) receiving tamsulosin (TAM, 0.4 mg/day) or the hexanic extract of Serenoa repens (HESr, 320 mg/day) as monotherapy. Symptoms and QoL were assessed using the IPSS and BII questionnaires, respectively. Patients in the treatment groups were matched using two statistical approaches (iterative and propensity score matching). Within the iterative matching approach, data was available from a total of 737 patients (353 TAM, 384 HESr). After 6 months, IPSS scores improved by a mean (SD) of 5.0 (4.3) points in the TAM group and 4.5 (4.7) points in the HESr group (p = 0.117, not significant). Improvements in QoL were equivalent in the two groups. TAM patients reported significantly more adverse effects than HESr patients (14.7% vs 2.1%; p < 0.001), particularly ejaculation dysfunction and orthostatic hypotension. These results show that HESr is a valid treatment option for men with moderate/severe LUTS/BPH; improvements in urinary symptoms and QoL were similar to those observed for tamsulosin, but with considerably fewer adverse effects.

Clinical Benefit of Tamsulosin and the Hexanic Extract of Serenoa Repens, in Combination or as Monotherapy, in Patients with Moderate/Severe LUTS-BPH: A Subset Analysis of the QUALIPROST Study.

To investigate whether tamsulosin (TAM) and the hexanic extract of Serenoa repens (HESr) are more effective in combination than as monotherapy in men with moderate-to-severe lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH). Subset analysis of data from a 6-month, multicenter observational study. Patients received either tamsulosin (0.4 mg/day) or HESr (320 mg/day) alone or in combination. Primary endpoints were change in symptoms and quality of life. Tolerability was also assessed. Seven hundred and nine patients were available for intention to treat (ITT) analysis, 263 treated with tamsulosin, 262 with HESr, and 184 with TAM + HESr. After 6 months, International Prostate Symptom Score (IPSS) scores improved by a mean (standard deviation) of 7.2 (5.0) points in the TAM + HESr group compared to 5.7 (4.3) points with TAM alone and 5.4 (4.6) points with HESr (p < 0.001). Quality of life showed greatest improvement with combination therapy (p < 0.02). Adverse effects were reported by 1.9% of patients receiving HESr, 13.3% receiving TAM, and 12.0% receiving TAM + HESr (p < 0.001). In men with moderate/severe LUTS/BPH, combination treatment with TAM + HESr produced more effective symptom relief and greater improvement in quality of life than with either treatment alone, with acceptable tolerability.

[Incidence of genitourinary pathology in the emergency department.] / Incidencia de la patología genitourinaria en urgencias.

OBJECTIVE: The increase of healthcare pressure in Emergency Departments compels us to have a better understanding of patients' characteristics and the pathology they consult for. This is the first study that estimates the waiting time in the emergency room and the factors that are independently related with hospital admission. METHODS: Descriptive and retrospective study of 2.741 patients who were admitted to the Emergency Department with genitourinary symptoms in 2011. Clinical and epidemiological features were reviewed. A multivariable study was performed to identify the factors related with the final resolution of patients, recurrence emergency attendance, and waiting time in the emergency room. RESULTS: Most of the patients were male (60.3%), being diagnosed with hematuria, acute urinary retention and genital pathology. Females complained more frequently for pyelonephritis, urinary tract infection and low-back pain. Male were hospitalized in greater proportion. Age, diagnosis of infection/sepsis or low-back pain, and yellow or orange MTS level were independent features for hospital admission. Also, in the univariate and multivariate study, age > 60 years (311 vs 220 min.), UTI/sepsis related diagnoses (300 vs 250 min.), and hospital admission as final resolution (440 vs 240 min.) had a significant influence in the waiting time in the Emergency Department. CONCLUSIONS: Age over 60 years, hospital admission as final resolution and infection/sepsis diagnosis were independent features for further waiting time in the Emergency Department. Persistent pain and symptoms of infection/sepsis behaved as independent features for hospital admission.

OBJETIVO: El aumento de la presión asistencial de los servicios de urgencias hospitalarios obliga a conocer las características de los pacientes y de los procesos por los que acuden. Este estudio es el primero que calcula tiempo de permanencia en urgencias y factores que se relacionan de manera independiente con ingreso hospitalario.MÉTODOS: Estudio descriptivo y retrospectivo de 2.741 pacientes que acudieron a Urgencias por sintomatología genitourinaria en el año 2011. Se examinaron rasgos clínicos y epidemiológicos. Se realizó un análisis multivariable para conocer los factores relacionados con la resolución final de los pacientes, recurrencia en la asistencia a urgencias y tiempo en urgencias. RESULTADOS: La mayoría de pacientes fueron varones (60,3%), con diagnósticos de hematuria, RAO y patología genital. Las mujeres, presentaron pielonefritis, ITU y dolor lumbar de manera más frecuente. Los varones ingresaron en mayor proporción. La edad, el diagnóstico de infección/sepsis o dolor lumbar y un nivel MTS amarillo o naranja, resultaron ser factores independientes de ingreso. Tanto en el estudio univariable como multivariable, la edad mayor de 60 años (311 vs 220 min), los diagnósticos relacionados con ITU y sepsis (300 vs 250 min) y el ingreso hospitalario como resolución final (440 vs 240 min) influyeron de forma significativa en el tiempo de estancia en Urgencias. CONCLUSIONES: La edad > 60 años, el resultado de ingreso y el diagnóstico de infección/sepsis fueron factores independientes de mayor tiempo en Urgencias. La presencia de dolor persistente y de infección/sepsis se comportaron como factores independientes de ingreso.

Incidencia de la patología genitourinaria en urgencias / Incidence of genitourinary pathology in the emergency department

Objetivo: El aumento de la presión asistencial de los servicios de urgencias hospitalarios obliga a conocer las características de los pacientes y de los procesos por los que acuden. Este estudio es el primero que calcula tiempo de permanencia en urgencias y factores que se relacionan de manera independiente con ingreso hospitalario. Métodos: Estudio descriptivo y retrospectivo de 2.741 pacientes que acudieron a Urgencias por sintomatología genitourinaria en el año 2011. Se examinaron rasgos clínicos y epidemiológicos. Se realizó un análisis multivariable para conocer los factores relacionados con la resolución final de los pacientes, recurrencia en la asistencia a urgencias y tiempo en urgencias. Resultados: La mayoría de pacientes fueron varones (60,3%), con diagnósticos de hematuria, RAO y patología genital. Las mujeres, presentaron pielonefritis, ITU y dolor lumbar de manera más frecuente. Los varones ingresaron en mayor proporción. La edad, el diagnóstico de infección/sepsis o dolor lumbar y un nivel MTS amarillo o naranja, resultaron ser factores independientes de ingreso. Tanto en el estudio univariable como multivariable, la edad mayor de 60 años (311 vs 220 min), los diagnósticos relacionados con ITU y sepsis (300 vs 250 min) y el ingreso hospitalario como resolución final (440 vs 240 min) influyeron de forma significativa en el tiempo de estancia en Urgencias. Conclusiones: La edad > 60 años, el resultado de ingreso y el diagnóstico de infección/sepsis fueron factores independientes de mayor tiempo en Urgencias. La presencia de dolor persistente y de infección/sepsis se comportaron como factores independientes de ingreso

Objective: The increase of healthcare pressure in Emergency Departments compels us to have a better understanding of patients' characteristics and the pathology they consult for. This is the first study that estimates the waiting time in the emergency room and the factors that are independently related with hospital admission. Methods: Descriptive and retrospective study of 2.741 patients who were admitted to the Emergency Department with genitourinary symptoms in 2011. Clinical and epidemiological features were reviewed. A multivariable study was performed to identify the factors related with the final resolution of patients, recurrence in emergency attendance, and waiting time in the emergency room. Results: Most of the patients were male (60.3%), being diagnosed with hematuria, acute urinary retention and genital pathology. Females complained more frequently for pyelonephritis, urinary tract infection and low-back pain. Male were hospitalized in greater proportion. Age, diagnosis of infection/sepsis or low-back pain, and yellow or orange MTS level were independent features for hospital admission. Also, in the univariate and multivariate study, age > 60 years (311 vs 220 min.), UTI/sepsis related diagnoses (300 vs 250 min.), and hospital admission as final resolution (440 vs 240 min.) had a significant influence in the waiting time in the Emergency Department. Conclusions: Age over 60 years, hospital admission as final resolution and infection/sepsis diagnosis were independent features for further waiting time in the Emergency Department. Persistent pain and symptoms of infection/sepsis behaved as independent features for hospital admission

Efficacy and safety of a hexanic extract of Serenoa repens (Permixon® ) for the treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH): systematic review and meta-analysis of randomised controlled trials and observational studies.

OBJECTIVES: To comprehensively evaluate the efficacy and safety of the hexanic extract of Serenoa repens (HESr, Permixon® ; Pierre Fabre Médicament, Castres, France), at a dose of 320 mg daily, as monotherapy for the treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH). MATERIALS AND METHODS: We conducted a systematic review and meta-analysis of randomised controlled trials (RCTs) and prospective observational studies in patients with LUTS/BPH identified through searches in Medline, Web of Knowledge (Institute for Scientific Information), Scopus, the Cochrane Library, and bibliographic references up to March 2017. Articles studying S. repens extracts other than Permixon were excluded. Data were collected on International Prostate Symptom Score (IPSS), maximum urinary flow rate (Qmax ), nocturia, quality of life, prostate volume, sexual function, and adverse drug reactions (ADRs). Data obtained from RCTs and observational studies were analysed jointly and separately using a random effects model. A sub-group analysis was performed of studies that included patients on longer-term treatment (≥1 year). RESULTS: Data from 27 studies (15 RCTs and 12 observational studies) were included for meta-analysis (total N = 5 800). Compared with placebo, the HESr was associated with 0.64 (95% confidence interval [CI] -0.98 to -0.31) fewer voids/night (P < 0.001) and an additional mean increase in Qmax of 2.75 mL/s (95% CI 0.57 to 4.93; P = 0.01). When compared with α-blockers, the HESr showed similar improvements on IPSS (weighted mean difference [WMD] 0.57, 95% CI -0.27 to 1.42; P = 0.18) and a comparable increase in Qmax to tamsulosin (WMD -0.02, 95% CI -0.71 to 0.66; P = 0.95). Efficacy assessed using the IPSS was similar after 6 months of treatment between the HESr and 5α-reductase inhibitors (5ARIs). Analysis of all available published data for the HESr showed a mean improvement in IPSS from baseline of -5.73 points (95% CI -6.91 to -4.54; P < 0.001). HESr did not negatively affect sexual function and no clinically relevant effect was observed on prostate-specific antigen. Prostate volume decreased slightly. Similar efficacy results were seen in patients treated for ≥1 year (n = 447). The HESr had a favourable safety profile, with gastrointestinal disorders being the most frequent ADR (mean incidence of 3.8%). CONCLUSION: The present meta-analysis, which includes all available RCTs and observational studies, shows that the HESr (Permixon) reduced nocturia and improved Qmax compared with placebo and had a similar efficacy to tamsulosin and short-term 5-ARI in relieving LUTS. HESr (Permixon) appears to be an efficacious and well-tolerated therapeutic option for the long-term medical treatment of LUTS/BPH.

Molecular classification of non-muscle-invasive bladder cancer (pTa low-grade, pT1 low-grade, and pT1 high-grade subgroups) using methylation of tumor-suppressor genes.

The role of epigenetics in distinguishing pathological and clinical subgroups in bladder cancer is not fully characterized. We evaluated whether methylation of tumor-suppressor genes (TSGs) would classify non-muscle-invasive (NMI) bladder cancer subgroups and predict outcome. A retrospective design included the following paraffin-embedded primary NMI tumor types (n = 251): pTa low grade (LG) (n = 79), pT1LG (n = 81), and pT1 high grade (HG) (n = 91). Methylation of 25 TSGs was measured using methylation-specific, multiplex, ligation-dependent probe amplification. The TSGs most frequently methylated in the overall series were STK11 (96.8%), MGMT2 (64.5%), RARB (63.0%), and GATA5 (63.0%). TSG methylation correlated to clinicopathological variables in each subgroup and in the overall NMI series. Methylation of RARB, CD44, PAX5A, GSTP1, IGSF4 (CADM1), PYCARD, CDH13, TP53, and GATA5 classified pTa versus pT1 tumors whereas RARB, CD44, GSTP1, IGSF4, CHFR, PYCARD, TP53, STK11, and GATA5 distinguished LG versus HG tumors. Multivariate analyses indicated that PAX5A, WT1, and BRCA1 methylation independently predicted recurrence in pTaLG, PAX6, ATM, CHFR, and RB1 in pT1LG disease; PYCARD, in pT1HG disease; and PAX5A and RB1, in the overall series. Methylation of TSGs provided a molecular classification of NMI disease according to clinicopathological factors. Furthermore, TSG methylation predicted recurrence in NMI subgroups.

Optimization of prostate biopsy in patients considered for active surveillance. The role of the confirmatory biopsy and transperineal techniques.

OBJECTIVES: To review the pathological criteria used to select patients for active surveillance, the optimization of biopsies and the role of confirmatory biopsy and of the transperineal approach. METHODS: A bibliographic revision of the last years about active surveillance in prostate cancer as well as prostate biopsy, optimal rebiopsy protocols and transperineal approach has been carried out. RESULTS: Misclassification of insignificant disease based on pathological criteria of the first standard biopsy range from 20% to 30% of men. It is likely that many patients who ultimately progress on active surveillance had at the time of diagnosis more advanced disease that was missed by transrectal ultrasound (TRUS) biopsy. This is the main cause of progression on initial follow-up biopsy within 1 year of starting active surveillance. Although the role of immediate prostate rebiopsy after the diagnosis of low-risk prostate cancer and has not been well described, repeat biopsy before the initiation of AS performed shortly after diagnosis (6 months) identifies most patients who harbor high grade or more extensive cancers that may not be appropriate for a surveillance strategy. CONCLUSIONS: PSA, PSAD, and number of cores at initial diagnosis are not helpful in predicting misclassification of AS eligibility. The role of MRI for AS remains unclear and the technique of MRI/US fusion biopsy still lacks consensus on a standardized procedure. Patients considering active surveillance should undergo immediate confirmatory biopsy within 6 months to decrease the risk of substantially underestimating cancer size and grade, even in patients with strict criteria in the initial biopsy and subsequently, to better assess the risk of progression. In this way, most protocols of AS recommend performing volume-based biopsies in the confirmatory procedure. Perhaps, an extensive transperineal template-guided mapping biopsy (TTMB) procedure could more accurately identify those men with occult significant disease. Due to confirmatory biopsy identifies a patient group that is unlikely to progress during the first 5 to 10 years of AS the need of intensive biopsy schedule during follow-up of patients undergoing active surveillance might be reduced.

Optimización de la biopsia prostatica en pacientes considerados para vigilancia activa. Papel de la biopsia confirmatoria y de la técnica transperineal / Optimization of prostate biopsy in patients considered for active surveillance. The role of confirmatory biopsy and transperineal techniques

OBJETIVO: Revisar los criterios patológicos utilizados para seleccionar a los pacientes para vigilancia activa en cáncer de próstata, la optimización de las biopsias y el papel de la biopsia confirmatoria y del abordaje transperineal. MÉTODOS: Se ha realizado una revisión bibliográfica de los últimos años sobre la vigilancia activa en cáncer de próstata, así como de la optimización de la biopsia próstata, los protocolos de rebiopsia y de la técnica transperineal en vigilancia activa. RESULTADOS: La clasificación inadecuada como tumor prostático insignificante basada en criterios patológicos de la biopsia inicial estándar se produce en el 20% al 30% de los hombres. Es probable que muchos pacientes en programas de vigilancia activa (VA) que progresan ya presentaban en el momento del diagnóstico una enfermedad más avanzada, no detectada por la biopsia transrectal (TRUS). Esta es la principal causa de progresión en las primeras biopsias de seguimiento en el primer año de un programa de vigilancia activa. Aunque el papel de rebiopsia de próstata inmediata tras el diagnóstico de cáncer de próstata de bajo riesgo no ha sido bien descrita, la repetición de la misma antes de la iniciación del programa de VA, realizada poco después de diagnóstico (6 meses), identifica la mayoría de los pacientes que albergan cánceres más extensos o de alto grado y que no resultan apropiados para una estrategia de vigilancia activa. CONCLUSIONES: La realización de un PSA, PSAD o el número de muestras en la biopsia inicial no son parámetros útiles en la predicción de un error en la clasificación patológica de un tumor como insignificante con vistas a la inclusión en un programa de VA. El papel de resonancia magnética (RM) permanece confuso y la técnica de la resonancia magnética / biopsia de fusión aún carece de consenso como un procedimiento estandarizado. Los pacientes en los que se considere la inclusión en VA deben someterse a una biopsia confirmatoria inmediata dentro de los 6 meses posteriores para disminuir el riesgo de subestimar el grado y tamaño del tumor, incluso en aquellos pacientes con criterios estrictos en la biopsia inicial, pudiendo además evaluar mejor el riesgo de progresión. La mayoría de los protocolos recomiendan tomar un número de cilindros basándose en el volumen prostático durante el procedimiento de confirmación. Tal vez un procedimiento de biopsia transperineal guiada mediante plantilla podría identificar con mayor precisión esos casos con enfermedad significativa oculta, sobre todo en la zona anterior de la glándula. Además dado que la biopsia confirmatoria identifica un grupo de pacientes en los que es poco probable la progresión durante los primeros 5 a 10 años, podría reducirse la necesidad de un protocolo intensivo de biopsias durante el seguimiento de pacientes sometidos a vigilancia activa

OBJECTIVES: To review the pathological criteria used to select patients for active surveillance, the optimization of biopsies and the role of confirmatory biopsy and of the transperineal approach. METHODS: A bibliographic revision of the last years about active surveillance in prostate cancer as well as prostate biopsy, optimal rebiopsy protocols and transperineal approach has been carried out. RESULTS: Misclassification of insignificant disease based on pathological criteria of the first standard biopsy range from 20% to 30% of men. It is likely that many patients who ultimately progress on active surveillance had at the time of diagnosis more advanced disease that was missed by transrectal ultrasound (TRUS) biopsy. This is the main cause of progression on initial follow-up biopsy within 1 year of starting active surveillance. Although the role of immediate prostate rebiopsy after the diagnosis of low-risk prostate cancer and has not been well described, repeat biopsy before the initiation of AS performed shortly after diagnosis (6 months) identifies most patients who harbor high grade or more extensive cancers that may not be appropriate for a surveillance strategy. CONCLUSIONS: PSA, PSAD, and number of cores at initial diagnosis are not helpful in predicting misclassification of AS eligibility. The role of MRI for AS remains unclear and the technique of MRI/US fusion biopsy still lacks consensus on a standardized procedure. Patients considering active surveillance should undergo immediate confirmatory biopsy within 6 months to decrease the risk of substantially underestimating cancer size and grade, even in patients with strict criteria in the initial biopsy and subsequently, to better assess the risk of progression. In this way, most protocols of AS recommend performing volume-based biopsies in the confirmatory procedure. Perhaps, an extensive transperineal template-guided mapping biopsy (TTMB) procedure could more accurately identify those men with occult significant disease. Due to confirmatory biopsy identifies a patient group that is unlikely to progress during the first 5 to 10 years of AS the need of intensive biopsy schedule during follow-up of patients undergoing active surveillance might be reduced

A quantitative proteomic analysis uncovers the relevance of CUL3 in bladder cancer aggressiveness.

To identify aggressiveness-associated molecular mechanisms and biomarker candidates in bladder cancer, we performed a SILAC (Stable Isotope Labelling by Amino acids in Cell culture) proteomic analysis comparing an invasive T24 and an aggressive metastatic derived T24T bladder cancer cell line. A total of 289 proteins were identified differentially expressed between these cells with high confidence. Complementary and validation analyses included comparison of protein SILAC data with mRNA expression ratios obtained from oligonucleotide microarrays, and immunoblotting. Cul3, an overexpressed protein in T24T, involved in the ubiquitination and subsequent proteasomal degradation of target proteins, was selected for further investigation. Functional analyses revealed that Cul3 silencing diminished proliferative, migration and invasive rates of T24T cells, and restored the expression of cytoskeleton proteins identified to be underexpressed in T24T cells by SILAC, such as ezrin, moesin, filamin or caveolin. Cul3 immunohistochemical protein patterns performed on bladder tumours spotted onto tissue microarrays (n = 284), were associated with tumor staging, lymph node metastasis and disease-specific survival. Thus, the SILAC approach identified that Cul3 modulated the aggressive phenotype of T24T cells by modifying the expression of cytoskeleton proteins involved in bladder cancer aggressiveness; and played a biomarker role for bladder cancer progression, nodal metastasis and clinical outcome assessment.

Polyamine-modulated factor-1 methylation predicts Bacillus Calmette-Guérin response in patients with high-grade non-muscle-invasive bladder carcinoma.

BACKGROUND: Bacillus Calmette-Guérin (BCG) is a standard treatment to reduce tumor recurrence and delay progression of high-risk non-muscle-invasive (NMI) bladder tumors. However, it is not clear yet which patients are more likely to respond to BCG. OBJECTIVE: The aim was to evaluate the role of polyamine-modulated factor-1 (PMF-1) methylation in predicting clinical outcome of T1 high-grade (T1HG) bladder tumors treated with BCG. DESIGN, SETTING, AND PARTICIPANTS: In a retrospective design, PMF-1 methylation was analyzed on tumor specimens belonging to 108 patients with T1HG NMI bladder cancer undergoing BCG treatment. Median follow-up was 77 mo (range: 5-235 mo). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: PMF-1 methylation was assessed by methylation-specific polymerase chain reactions. Recurrence, progression into muscle-invasive tumors, and disease-specific survival rates were analyzed using competing risks regression analysis. RESULTS AND LIMITATIONS: Among the 108 patients analyzed, 35 had recurring disease (32.4%), 21 progressed (19.4%), and 16 died of disease (14.8%); 71.3% of tumors had PMF-1 methylation. Univariate analyses using cumulative incidence curves revealed that an unmethylated PMF-1 was significantly associated with increased recurrence (p=0.026), progression (p=0.01), and shorter disease-specific survival (log-rank, p=0.03). Multivariate analyses indicated that among sex, age, focality, tumor size, and concomitant carcinoma in situ, only PMF-1 methylation provided significant hazard ratios (HRs) for recurrence of (HR: 2.032; p=0.042), and progression (HR: 2.910; p=0.020). Limitations of the study include its retrospective design, lymphovascular invasion status not available, short maintenance BCG, and that a second transurethral resection was not performed. CONCLUSIONS: Epigenetic analyses revealed that the methylation status of PMF-1 was associated with the clinical outcome of patients with T1HG tumors undergoing BCG treatment. An unmethylated PMF-1 correlated to recurrence and progression in T1HG disease using univariate and multivariate analyses. Thus, assessing the methylation status of PMF-1 may serve to distinguish patients responding to BCG from those who may require more aggressive therapeutic approaches.

Myopodin methylation is associated with clinical outcome in patients with T1G3 bladder cancer.

PURPOSE: Bacillus Calmette-Guerin is standard treatment to decrease tumor recurrence and delay progression of high risk, nonmuscle invasive bladder tumors. However, it is not yet clear which T1G3 cases are more prone to more aggressive clinical behavior or susceptible to respond to bacillus Calmette-Guerin. We evaluated the role of myopodin methylation as a clinical outcome prognosticator and predictive biomarker for the bacillus Calmette-Guerin response in patients with T1G3 bladder tumors. MATERIALS AND METHODS: We analyzed the methylation status of myopodin in tumor specimens from 170 patients with T1G3 bladder cancer, including a subset of 108 who underwent bacillus Calmette-Guerin treatment. Myopodin methylation was assessed by methylation specific polymerase chain reactions. Recurrence, progression to muscle invasive tumors and disease specific overall survival were analyzed using competing risks regression analysis. RESULTS: Of the 170 cases analyzed 72 recurred (42.4%) and 36 progressed (21.2%). A total of 24 patients (14.1%) died of the disease. Univariate and multivariate survival analysis revealed that myopodin methylation was significantly associated with an increased recurrence rate (p = 0.004), progression (p = 0.002) and shorter disease specific overall survival (p = 0.020). In a subset treated with bacillus Calmette-Guerin myopodin methylation was also related to an increased recurrence rate (p = 0.011), progression (p = 0.030) and shorter disease specific overall survival (p = 0.028). CONCLUSIONS: Epigenetic analysis revealed that myopodin methylation was associated with tumor aggressiveness and clinical outcome in patients with T1G3 disease. Myopodin methylation distinguished patients responding to bacillus Calmette-Guerin from those who may require a more aggressive therapeutic approach.

Anemia como factor pronóstico independiente en pacientes con carcinoma renal / Significance of anemia as an independent prognostic factor in patients with renal cell carcinoma

Fundamento y objetivo: Valorar el significado pronóstico de la anemia para el carcinoma de células renales (CCR), así como otros factores implicados en la supervivencia. Pacientes y método: Se realizó un análisis retrospectivo de los datos de 316 pacientes con carcinoma renal intervenidos entre los años 1970 y 2003. Se investigaron las principales características implicadas en el pronóstico de pacientes con CCR. Resultados: La mayoría de los tumores presentaron estadios bajos T1b-T2, con grados nucleares bajos (I–II) y un tumor único. En un 8,2% se encontró afectación ganglionar en el momento del diagnóstico y en casi un 9% existían metástasis a distancia. La clínica más frecuente al inicio fue hematuria o dolor, y la anemia (hemoglobina<10g/dl) estuvo presente en 69 casos Resultados: Con una mediana de seguimiento de 50 meses, recidivó un 24,1% de casos, de los que más del 50% ocurrió en el primer año tras la intervención. Los tumores avanzados (T3-4) tendieron a presentar un grado nuclear mayor (III–IV), más tamaño, necrosis, afectación vascular y ganglionar, asociándose más frecuentemente a metástasis a distancia. Los factores que influyeron de forma independiente en la mortalidad específica por cáncer fueron la presencia de adenopatías metastásicas, el tiempo libre de enfermedad en los casos con recidiva, así como el tratamiento de esa recidiva y la presencia de anemia. Conclusión: La existencia de anemia en pacientes intervenidos por carcinoma renal puede ser un marcador de recidiva y progresión de la enfermedad que implica, finalmente, un mayor riesgo de mortalidad por este tumor (AU)

Background and Objective: The aim of this study was to analyze the significance of anemia as well as other prognostic factors influencing survival in patients with renal cell carcinoma (RCC). Patients and methods: A retrospective review of data of 316 patients who underwent surgery between 1970 and 2003 was performed. Most important known prognostic factors of RCC were investigated. Results: Most of patients had T1b-T2, low nuclear grade and single tumours. In 8.2% and 9% of cases, lymph node and metastatic dissemination were detected at the time of diagnosis, respectively. At the beginning, most frequent symptoms were hematuria and pain, with anemia (Hb >10g/dl) in 69 patients. Results: After a median follow-up of 50 months, 24.1% of patients had a recurrence. From these, more than 50% developed recurrence within one year after nephrectomy. Advanced tumours (T3-4) consisted of high nuclear grade (III–IV) tumours, larger size tumours, with necrosis and vascular infiltration in surgical specimen, as well as lymph node and metastatic dissemination. In multivariate analysis, anemia, time to recurrence, type of treatment for recurrence as well as lymph node dissemination were independent factors of cancer specific survival. Conclusion: Anemia seems to be a marker of recurrence and progression in patients with renal cell carcinoma undergoing nephrectomy. From our point of view, anemia could be considered a significantly high mortality rate for renal cancer in these patients (AU)