Short-term cultured tumor fragments to study immunotherapy combinations based on CD137 (4-1BB) agonism.

Biomarkers for cancer immunotherapy are an unmet medical need. The group of Daniela Thommen at the NKI recently reported on novel methodologies based on short-term cultures of patient-derived tumor fragments whose cytokine concentrations in the supernatants and activation markers on infiltrating T cells were associated with clinical response to PD-1 blockade. We set up a similar culture technology with tumor-derived fragments using mouse tumors transplanted into syngeneic immunocompetent mice to test an agonist anti-CD137 mAb and its combinations with anti-PD-1 and/or anti-TGF-ß. Increases in IFNγ concentrations in the tissue culture supernatants were detected upon in-culture activation with the anti-CD137 and anti-PD-1 mAb combinations or concanavalin A as a positive control. No other cytokine from a wide array was informative of stimulation with these mAbs. Interestingly, increases in Ki67 and other activation markers were substantiated in lymphocytes from cell suspensions gathered at the end of 72 h cultures. In mice bearing bilateral tumors in which one was excised prior to in vivo anti-CD137 + anti-PD-1 treatment to perform the fragment culture evaluation, no association was found between IFNγ production from the fragments and the in vivo therapeutic outcome in the non-resected contralateral tumors. The experimental system permitted freezing and thawing of the fragments with similar functional outcomes. Using a series of patient-derived tumor fragments from excised solid malignancies, we showed IFNγ production in a fraction of the studied cases, that was conserved in frozen/thawed fragments. The small tumor fragment culture technique seems suitable to preclinically explore immunotherapy combinations.

Characterization of the perioperative changes of exosomal immune-related cytokines induced by prostatectomy in early-stage prostate cancer patients.

BACKGROUND: Myeloid-derived suppressor cells (MDSCs) are relevant in prostate cancer microenvironment collaborating in tumor development. The main tumor marker used in this disease, prostate-specific antigen (PSA), does not provide information related to this tumor microenvironment. Cancer cells secrete exosomes carrying bioactive molecules contributing to MDSCs recruitment and induction. The aim of this study was to characterize the perioperative changes of exosomal cytokines relevant in MDSCs recruitment induced by prostatectomy in prostate cancer patients. METHODS: Blood was drawn from 26 early-stage prostate cancer patients before and after radical prostatectomy and from 16 healthy volunteers. Serum exosomes were separated by precipitation. Cytokines related with MDSC cell recruitment and activation CCL2, CXCL2, CXCL5, CXCL8, CXCL12, MIF, S100A9 and TGF-ß were measured in serum and serum-derived exosomes using immunometric assays. RESULTS: All cytokines were detected both in serum and exosomes, except for CXCL12, which was detected only in serum. Exosomes were enriched specially in MIF, TGF-ß and CXCL2. Presurgical MIF levels in exosomes correlated negatively with serum PSA. Also, presurgical TGF-ß decreased both in serum and exosomes as Gleason score rises. Patients presurgical exosomes had increased CCL2, CXCL5 and TGF-ß levels than exosomes from healthy controls. These differences were not observed when cytokines were analyzed in serum, except for TGF-ß. Cytokine levels of CCL2, CXCL5 decreased in patients' postsurgical exosomes, while TGF-ß further increased. On the contrary, S100A9 levels were lower in patients presurgical exosomes but increased after radical prostatectomy. CONCLUSIONS: Blood exosomal content in cytokines constitute an attractive source to evaluate MDSCs immunomodulators providing additional information related to tumor microenvironment in prostate cancer.

Daily Pad Usage Versus the International Consultation on Incontinence Questionnaire Short Form for Continence Assessment Following Radical Prostatectomy.

PURPOSE: Continence assessment is an essential component of follow-up after radical prostatectomy (RP). Several methods exist to assess the severity of urinary incontinence (UI). Our study examined the relationship and degree of agreement between International Consultation on Incontinence Questionnaire Short Form (ICIQ-SF) scores and the number of pads used in a 24-hour period in the assessment of UI following RP. METHODS: Continence was prospectively assessed in 746 men from a Spanish urology clinic 12 months after RP using the ICIQ-SF and pad usage. The relationship between ICIQ-SF scores and pad usage was assessed using Spearman rank correlation coefficients. The Jonckheere-Terpstra trend test was used to determine whether the ICIQ-SF score and the component question scores increased with increasing pad usage. The Bonferroni-corrected pairwise Wilcoxon rank-sum test was used to determine which pairs of pad usage levels differed. The weighted kappa was used to evaluate the agreement between pad usage levels and ICIQ-SF questions. RESULTS: The continence rate was 82% using the "no pad usage" definition of continence versus 78% using the definition of an ICIQ-SF score of 0 (P<0.001). Strong positive correlations were observed between the number of pads and the ICIQ-SF total and component question scores (rs>0.85, P<0.001). The ICIQ-SF total and component question scores increased significantly with increasing pad usage (P<0.001). The ICIQ-SF scores (P<0.018) for all pairs of pad usage levels (0, 1, 2, or 3 or more) differed significantly. The agreement between the ICIQ-SF leakage amount question and pad usage was very good (rs=0.861, P<0.001). CONCLUSION: At 12 months post-RP, 24-hour pad usage was closely correlated with ICIQ-SF, although the continence rate differed depending on the definition used. Higher levels of pad usage were associated with higher questionnaire scores, more leakage, and poor quality of life (interference with everyday life).

[Design and validation of a satisfaction questionnaire in patients with urolithiasis treated by extracorporeal shock wave lithotripsy (ESWL).] / Diseño y validación de un cuestionario de salud en pacientes con urolitiasis tratados mediante litotricia extracorpórea por ondas de choque (LEOC).

OBJECTIVES: Studying the psychosocial sphere of patients who undergo any treatment allows to have more information about its repercussion and can help the choice of an appropriate and personalized treatment. Due to the absence of specific instruments at present, the objective is to design and validate a health questionnaire regarding the treatment received with ESWL. METHODS: It was carried out in 6 phases using a sampleof 50 patients treated with ESWL in 2015 in ourcenter, whom we interviewed by telephone. In phase1 the items were proposed based on bibliographic review,in phase 2 those that scored below 7 were eliminatedaccording to the evaluation from 0 to 10 on theitems made by specialists. In phase 3, values of 1 to 5were assigned to each item and those with correctedcorrelation more than 0.2 and not significant (p>0.05)discriminant power with U-Mann Whitney were eliminated.In phase 4 the reliability of the questionnaire waschecked with two indexes (Cronbach's alpha and twoGuttman's halves). In phase 5, the factor analysis withVarimax rotation was performed to calculate the constructvalidity and in stage 6, the scores were analyzedto establish reference values. RESULTS: 50 patients (32 men, 18 women). Medianage 59 years (27-79). In phase 1, 35 items were proposed,9 of which were eliminated in phase 2. The initialquestionnaire with 26 items was distributed, with 18being eliminated in phase 3. The final questionnaire wasformed with 8 items. In phase 4 the results of Cronbach'salpha and Guttman's two halves index were 0.44 and0.323 respectively. In phase 5 after factor analysis, wefound 4 factors with 2 items each (background, impactof the acute picture, post-treatment, quality of life) able toexplain 71.19% of the variance. The median scores ofthe scale, extreme values and quartiles studied in phase6 were respectively: P50: 17 (minimum-maximum 9-25),P25: 14 and P75: 20. CONCLUSIONS: The study carried out has provided anew instrument for assessing satisfaction after treatmentwith ESWL with adequate reliability and validity values.Future studies will be necessary to contrast its true clinicalusefulness.

OBJETIVO: Estudiar la esfera psicosocial de los pacientes que se someten a algún tratamiento permite tener más información sobre la repercusión del mismo y puede ayudar a la elección de un tratamiento adecuado y personalizado. Debido a la ausencia deinstrumentos específicos actualmente, el objetivo es diseñary validar un cuestionario de salud en pacientes tratados con LEOC.MATERIAL Y MÉTODOS: Se realizó en 6 fases utilizando una muestra de 50 pacientes tratados con LEOC en 2015 en nuestro centro, a los que entrevistamos por vía telefónica. En la fase 1 se propusieron ítems a partir de revisión bibliográfica. En la fase 2 se eliminaron losque puntuaban por debajo de 7 según la valoración de 0-10 sobre los ítems efectuada por especialistas en la materia. En la fase 3 se asignaron valores de 1 a 5 a cada ítem y se eliminaron aquellos cuya correlación corregida fuera mayor de 0,2 y cuya potencia discriminante con U-Mann Whitney no fuera significativa (p>0,05). En la fase 4 se comprobó la fiabilidad del cuestionario con dos índices (alfa de Cronbach y dos mitades de Guttman). En la fase 5 se realizó el análisis factorial con rotación Varimax para el cálculo de la validez de constructo. Finalmente, en la fase 6 se tipificaron de las puntuaciones para establecer valores de referencia. RESULTADOS: 50 pacientes (32 hombres, 18 mujeres). Mediana edad 59 años (27-79). Fase 1: 35 ítems propuestos. Fase 2: 9 ítems eliminados. Distribución de cuestionario con 26 ítems. Fase 3: 18 ítems eliminados.Cuestionario final constituido por 8 ítems. Fase 4: valores de fiabilidad del cuestionario (alfa de Cronbach 0,44 e índice por técnica de dos mitades de Guttman 0,323). Fase 5: análisis factorial hallando 4 factores con 2 ítems cada uno (antecedentes, repercusión delcuadro agudo, post-tratamiento, calidad de vida) capaces de explicar el 71,19% de la varianza. Fase 6: mediana puntuación  50:17(mínimo-máximo 9-25), P25:14 y P75:20. CONCLUSIONES: El trabajo realizado ha proporcionado un nuevo instrumento de evaluación de salud tras tratamiento con LEOC con valores de fiabilidad y validez adecuados. Serán necesarios futuros estudios para contrastar su verdadera utilidad clínica.

Diseño y validación de un cuestionario de salud en pacientes con urolitiasis tratados mediante litotricia extracorpórea por ondas de choque (LEOC) / No disponible

Objetivo: Estudiar la esfera psicosocial de los pacientes que se someten a algún tratamiento permite tener más información sobre la repercusión del mismo y puede ayudar a la elección de un tratamiento adecuado y personalizado. Debido a la ausencia de instrumentos específicos actualmente, el objetivo es diseñar y validar un cuestionario de salud en pacientes tratados con LEOC. Material y métodos: Se realizó en 6 fases utilizando una muestra de 50 pacientes tratados con LEOC en 2015 en nuestro centro, a los que entrevistamos por vía telefónica. En la fase 1 se propusieron ítems a partir de revisión bibliográfica. En la fase 2 se eliminaron los que puntuaban por debajo de 7 según la valoración de 0-10 sobre los ítems efectuada por especialistas en la materia. En la fase 3 se asignaron valores de 1 a 5 a cada ítem y se eliminaron aquellos cuya correlación corregida fuera mayor de 0,2 y cuya potencia discriminante con U-Mann Whitney no fuera significativa (p>0,05). En la fase 4 se comprobó la fiabilidad del cuestionario con dos índices (alfa de Cronbach y dos mitades de Guttman). En la fase 5 se realizó el análisis factorial con rotación Varimax para el cálculo de la validez de constructo. Finalmente, en la fase 6 se tipificaron de las puntuaciones para establecer valores de referencia. Resultados: 50 pacientes (32 hombres, 18 mujeres). Mediana edad 59 años (27-79). Fase 1: 35 ítems propuestos. Fase 2: 9 ítems eliminados. Distribución de cuestionario con 26 ítems. Fase 3: 18 ítems eliminados. Cuestionario final constituido por 8 ítems. Fase 4: valores de fiabilidad del cuestionario (alfa de Cronbach 0,44 e índice por técnica de dos mitades de Guttman 0,323). Fase 5: análisis factorial hallando 4 factores con 2 ítems cada uno (antecedentes, repercusión del cuadro agudo, post-tratamiento, calidad de vida) capaces de explicar el 71,19% de la varianza. Fase 6: mediana puntuación 50:17(mínimo-máximo 9-25), P25:14 y P75:20. Conclusiones: El trabajo realizado ha proporcionado un nuevo instrumento de evaluación de salud tras tratamiento con LEOC con valores de fiabilidad y validez adecuados. Serán necesarios futuros estudios para contrastar su verdadera utilidad clínica

Objectives: Studying the psychosocial sphere of patients who undergo any treatment allows to have more information about its repercussion and can help the choice of an appropriate and personalized treatment. Due to the absence of specific instruments at present, the objective is to design and validate a health questionnaire regarding the treatment received with ESWL. Methods: It was carried out in 6 phases using a sample of 50 patients treated with ESWL in 2015 in our center, whom we interviewed by telephone. In phase 1 the items were proposed based on bibliographic review, in phase 2 those that scored below 7 were eliminated according to the evaluation from 0 to 10 on the items made by specialists. In phase 3, values of 1 to 5 were assigned to each item and those with corrected correlation more than 0.2 and not significant (p>0.05) discriminant power with U-Mann Whitney were eliminated. In phase 4 the reliability of the questionnaire was checked with two indexes (Cronbach’s alpha and two Guttman's halves). In phase 5, the factor analysis with Varimax rotation was performed to calculate the construct validity and in stage 6, the scores were analyzed to establish reference values. Results: 50 patients (32 men, 18 women). Median age 59 years (27-79). In phase 1, 35 items were proposed, 9 of which were eliminated in phase 2. The initial questionnaire with 26 items was distributed, with 18 being eliminated in phase 3. The final questionnaire was formed with 8 items. In phase 4 the results of Cronbach’s alpha and Guttman’s two halves index were 0.44 and 0.323 respectively. In phase 5 after factor analysis, we found 4 factors with 2 items each (background, impact of the acute picture, post-treatment, quality of life) able to explain 71.19% of the variance. The median scores of the scale, extreme values and quartiles studied in phase 6 were respectively: P50: 17 (minimum-maximum 9-25), P25: 14 and P75: 20. Conclusions: The study carried out has provided a new instrument for assessing satisfaction after treatment with ESWL with adequate reliability and validity values. Future studies will be necessary to contrast its true clinical usefulness

[The role of chemotherapy in the treatment of hormone sensitive metastatic prostate cancer.] / Papel de la quimioterapia en el tratamiento del cáncer de próstata metastásico hormonosensible.

OBJECTIVE: Several studies have assessed the role of adding chemotherapy to hormonal treatment for metastatic hormone-sensitive prostate cancer (MHSPC). The objective of this manuscript is to review these studies and to provide recommendations for the management of these patients. METHODS: We identified published clinical trials comparing hormone blockade (HB) with HB plus docetaxel as first-line treatment of HSMPC and we analyzed their results in terms of efficacy and toxicity. RESULTS: Of the 3 trials published, two demonstrated increased overall survival by adding docetaxel to the first-line treatment of MHSPC (CHAARTED and Stampede-Docetaxel studies) and the third one did not show such an advantage (GETUG-AFU15). In the CHAARTED study, the survival advantage was limited to patients presenting high tumor volume. Toxicity was increased in patients who received docetaxel. CONCLUSIONS: The addition of docetaxel to treatment with HB should be considered in patients with MHSPC, especially in those with high tumor volume. However, the toxicity and recent results of trials performed with abiraterone in MHSPC should also be taken in consideration.

Papel de la quimioterapia en el tratamiento del cáncer de próstata metastásico hormonosensible / The role of chemotherapy in the treatment of hormone sensitive metastatic prostate cancer

OBJETIVO: Varios estudios han valorado el papel de añadir quimioterapia al tratamiento hormonal del cáncer de próstata metastásico hormonosensible (CPMHS). El objetivo de este trabajo es revisar estos estudios y dar recomendaciones sobre la actitud clínica ante dichos pacientes. Métodos Se identificaron los ensayos clínicos publicados que comparan bloqueo hormonal (BH) con BH más docetaxel como tratamiento de primera línea del CPMHS y se analizaron sus resultados de eficacia y toxicidad. RESULTADOS: De los 3 ensayos publicados, dos demostraron un aumento de la supervivencia global (SG) al añadir docetaxel al tratamiento de primera línea del CPMHS (estudios CHAARTED y Stampede) y el tercero no demostró diferencias (estudio GETUG-AFU15). En el estudio CHAARTED la ventaja en SG se limitó a los pacientes con alto volumen tumoral. La toxicidad fue mayor en los pacientes que recibieron docetaxel. CONCLUSIONES: La adición de docetaxel al tratamiento con BH debe contemplarse en los pacientes con CPMHS, especialmente en aquellos que presentan alto volumen tumoral. No obstante, también debe tenerse en cuenta la toxicidad y los recientes resultados de los ensayos realizados con abiraterona en CPMHS

OBJECTIVE: Several studies have assessed the role of adding chemotherapy to hormonal treatment for metastatic hormone-sensitive prostate cancer (MHSPC). The objective of this manuscript is to review these studies and to provide recommendations for the management of these patients. METHODS: We identified published clinical trials comparing hormone blockade (HB) with HB plus docetaxel as first-line treatment of HSMPC and we analyzed their results in terms of efficacy and toxicity. RESULTS: Of the 3 trials published, two demonstrated increased overall survival by adding docetaxel to the first-line treatment of MHSPC (CHAARTED and Stampede-Docetaxel studies) and the third one did not show such an advantage (GETUG-AFU15). In the CHAARTED study, the survival advantage was limited to patients presenting high tumor volume. Toxicity was increased in patients who received docetaxel. CONCLUSIONS: The addition of docetaxel to treatment with HB should be considered in patients with MHSPC, especially in those with high tumor volume. However, the toxicity and recent results of trials performed with abiraterone in MHSPC should also be taken in consideration

Prevalence analysis of urinary incontinence after radical prostatectomy and influential preoperative factors in a single institution.

AIMS: To assess prevalence of urinary incontinence (UI) after radical prostatectomy (RP) and to analyze which preoperative characteristics of the patients have influence on UI. METHODS: Between 2002 and 2012, 746 consecutive patients underwent RP for clinically localized prostate cancer. We defined UI according to International Continence Society (ICS) definition: "the complaint of any involuntary leakage of urine" after 12 months of recovery, international consultation on incontinence questionnaire (ICIQ-SF) and pads/day was collected too. Clinical features and magnetic resonance imaging measurements were assessed. A multivariable logistic regression model predicting incontinence were built-in after adjust by cofounding factors and bootstrapping. RESULTS: About 172 (23%) of the patients were classified as incontinent according to the ICS definition. The mean value of the ICIQ-SF was 10.87 (±4). 17.8% of patients use at least one pad/day, 11.9% use more than one pad/day. The preoperative factors independently influential in UI are: age [OR: 1.055; CI 95% (1.006-1.107), p = .028], urethral wall thickness [OR: 5.03; CI 95% (1.11-22.8), p = .036], history of transurethral resection of the prostate [OR: 6.13; CI 95% (1.86-20.18), p = .003] and membranous urethral length [OR: 0.173; CI 95% (0.046-0.64), p = .009]. The predictive accuracy of the model is 78.7% and the area under the curve (AUC) value 71.7%. CONCLUSIONS: Urinary incontinence after radical prostatectomy has different prevalence depending on the definition. Age, prior transurethral resection of the prostate (TURP), membranous urethral length (MUL) and urethral wall thickness (UWT) were risk factors.

Can low urinary tract symptoms influence postprostatectomy urinary incontinence?

BACKGROUND: The aim of this study was to analyze what kind of urinary symptoms patients have before receiving treatment by radical prostatectomy (RP), and to evaluate their influence on urinary incontinence (UI). METHODS: Between 2002 and 2012, 758 consecutive patients underwent RP for clinically localized prostate cancer (PCa). Surgery was carried out by open retropubic RP in 545 (73.1%) of patients and laparoscopic RP in 201 (27%) by 5 surgeons who were excluded from data collection and analysis. The following symptoms were collected from the last urological check-ups or pre-operative consultation and classified as: storage symptoms, voiding symptoms, post micturition symptoms, history of acute urinary retention, benign prostatic hyperplasia treatment, history of transurethral resection of the prostate (TURP). RESULTS: A total of 661 patients were included on analysis: 136 (20.6%) patients reported low urinary tract symptoms (LUTS), 162 (24.5%) were considered incontinent after RP, and 45 (33.1%) of them reported LUTS before surgery. Postprostatectomy urinary incontinence (PPUI) was significantly different in patients with LUTS (117 [22.3%] vs. 45 [33.1%], P=0.009). The presence of any LUTS influence significantly in the appearance of PPUI (OR=1.72 [95% CI: 1.14-2.6), P=0.01). TURP is independently influential in PPUI (OR=6.13 [95% CI: 1.86-20.18], P=0.003). A patient with LUTS before surgery has an increased risk of 70% or even 200% to suffer PPUI and a patient who received treatment by TURP is 6 times at higher risk of PPUI. CONCLUSIONS: In conclusion, patients with LUTS are likely to present PPUI. History of TURP is influential by itself over PPUI. A good preoperative consultation is important to assess continence status and to create realistic expectations to patients before RP.

Radical prostatectomy. Detailed surgical margins. Prognostic value of multifocal involvement in pT2 (+).

OBJECTIVES: We intend to analyze the prognostic value of positive surgical margins depending on their number and location in pT2 patients. METHODS: We analyze 448 (34.3%) patients with positive surgical margins from a series of 1,310 T1-T2 patients treated with radical prostatectomy between 1989-2012. Of them 164 are pT2 (+). 119 (72.6% ) have unifocal affectation (41 (34.5%) unifocal in right lobe; 35 (29.4%) unifocal in left lobe, 40 (33.6%) unifocal in apex, 3 (2.5% ) unifocal proximal) and 45 (27.4%) multifocal involvement. RESULTS: Unifocal and multifocal pT2(+)patients have not evidenced significant differences in any of the clinicopathologic variables compared. However the BPFS at 5 and 10 years is significantly worse in the multifocal group, (p<0.000) In the BPFS multivariate study of 164 pT2(+ )influential variables are: multifocal involvement (HR: 3.4; 95%IC 1.7-6.9 p<0.000) and PSA (HR: 1.03; 95%IC 1.02-1.05 p<0.000), being PSA >15 ng/ml )HR: 3.7; 95%IC 2.1-6.6 p<0.000 ( the best cut-off point. Risk groups: Using the independent influence variables, the best model (using Cox models ) includes two risk groups: Group 1 (0 variables): They are pT2(+) with unifocal affectation and PSA<15 ng/ml, (63%). Their BPFS are 81±4% and 77±4% (5 and 10 years). Grupo 2 (1-2 variables): They are pT2 (+) with multifocal involvement, PSA> 15 ng/ml or both of them, (37%). Their BPFS are 46±6% and 26±7% (5 and 10 years). The BPFS differs significantly between the two groups (p<0.000). The Group 1 BPFS is similar to the pT2 (-) patients, (p:0.242). The Group 2 BPFS is similar to the pT3(+) patients, (p:0.637). The model explained significantly better the BPFS than any of the individual variables analyzed. CONCLUSIONS: In pT2(+) patients the prognosis is significantly worse in multifocal involvement. In addition two groups of patients can be clearly distinguished from the BPFS point view according to their influential variables. The data suggest that since the prognostic point view the second group is understaged while the first is overstaged.

Prostatectomía radical. Margen quirúrgico pormenorizado. Valor pronóstico de la multifocalidad en pT2 con márgenes afectados / Radical prostatectomy. Detailed surgical margins. Prognostic value of multifocal involvement in pT2(+)

OBJETIVO: Pretendemos analizar en los pacientes pT2 con márgenes afectados el valor pronóstico real de los márgenes en función de su número y localización. MÉTODOS: Analizamos 448 (34,3%) pacientes con márgenes afectados de una serie de 1.310 pacientes T1-T2 tratados mediante prostatectomía radical entre 1.989-2.012. De ellos 164 son pT2(+), 119 (72,6%) tienen afectación unifocal 41 (34,5%) unifocal en lóbulo derecho; 35 (29,4%) unifocal en lóbulo izquierdo, 40 (33,6%) unifocal en ápex, 3 (2,5%) unifocal proximal) y 45 (27,4%) afectación multifocal. RESULTADOS: Los pT2(+) unifocales y multifocales no evidencian diferencias significativas en ninguna de las variables clínico-patológicas comparadas. Sin embargo la Supervivencia Libre de Progresión Bioquímica (SLPB) a 5 y 10 años es significativamente peor en el grupo multifocal, (p<0,000). En el estudio multivariado son influyentes en la SLPB de los 164 pT2(+): afectación multifocal (HR: 3,4; IC 95% 1,7-6,9 p<0,000) y PSA (HR: 1,03; IC 95% 1,02-1,05 p<0,000) siendo el mejor punto de corte, PSA >15 ng/ml (HR: 3,7; IC 95% 2,1-6,6 p<0,000). Grupos de Riesgo: Utilizando las variables de influencia independiente el mejor modelo utilizando los modelos de Cox incluye dos grupos de riesgo: Grupo 1 (0 variables presentes): Son pT2(+) con afectación unifocal y PSA<15 ng/ml, (63%). Su SLPB es 81±4% y 77±4% (5 y 10 años). Grupo 2 (1-2 variables presentes): Son pT2(+) con afectación multifocal, PSA>15 ng/ml o ambas, (37% restante). Su SLPB es 46±6% y 26±7% (5 y 10 años). La SLPB es significativamente diferente entre ambos grupos (p<0,000). La SLPB del Grupo 1 es similar a la de los pacientes pT2 márgenes (-), (p=0,242). La SLPB del Grupo 2 es similar a la de los pT3 márgenes (+), (p=0,637). El modelo explica significativamente mejor la SLPB que cualquiera de las variables analizadas individualmente (estudio multivariado, modelo de Cox). CONCLUSIONES: En los pT2(+) el pronóstico es significativamente peor cuando la afectación es multifocal. Además pueden diferenciarse claramente dos grupos de pacientes desde el punto de vista de la SLPB según sus variables influyentes. Los datos sugieren que desde el punto de vista del pronóstico el segundo grupo está infraestadiado mientras que el primero está sobreestadiado

OBJECTIVES: We intend to analyze the prognostic value of positive surgical margins depending on their number and location in pT2 patients. METHODS: We analyze 448 (34.3%) patients with positive surgical margins from a series of 1,310 T1-T2 patients treated with radical prostatectomy between 1989-2012. Of them 164 are pT2(+). 119 (72.6%) have unifocal affectation (41 (34.5%) unifocal in right lobe; 35 (29.4%) unifocal in left lobe, 40 (33.6%) unifocal in apex, 3 (2.5%) unifocal proximal) and 45 (27.4%) multifocal involvement. RESULTS: Unifocal and multifocal pT2(+) patients have not evidenced significant differences in any of the clinicopathologic variables compared. However the BPFS at 5 and 10 years is significantly worse in the multifocal group, (p<0.000). In the BPFS multivariate study of 164 pT2(+)influential variables are: multifocal involvement (HR: 3.4; 95%IC 1.7-6.9 p<0.000) and PSA (HR: 1.03; 95%IC 1.02-1.05 p<0.000), being PSA >15 ng/ml (HR: 3.7; 95%IC 2.1-6.6 p<0.000) the best cut-off point. Risk groups: Using the independent influence variables, the best model (using Cox models) includes two risk groups: Group 1 (0 variables): They are pT2(+) with unifocal affectation and PSA<15 ng/ml, (63%). Their BPFS are 81±4% and 77±4% (5 and 10 years). Grupo 2 (1-2 variables): They are pT2(+) with multifocal involvement, PSA>15 ng/ml or both of them, (37%). Their BPFS are 46±6% and 26±7% (5 and 10 years). The BPFS differs significantly between the two groups (p<0.000). The Group 1 BPFS is similar to the pT2(-) patients, (p:0.242). The Group 2 BPFS is similar to the pT3(+) patients, (p:0.637). The model explained significantly better the BPFS than any of the individual variables analyzed. CONCLUSIONS: In pT2(+) patients the prognosis is significantly worse in multifocal involvement. In addition two groups of patients can be clearly distinguished from the BPFS point view according to their influential variables. The data suggest that since the prognostic point view the second group is understaged while the first is overstaged

Little effects of insulin-like Growth Factor-I on testicular atrophy induced by hypoxia.

BACKGROUND: Insulin-like Growth Factor-I (IGF-I) supplementation restores testicular atrophy associated with advanced liver cirrhosis that is a condition of IGF-I deficiency. The aim of this work was to evaluate the effect of IGF-I in rats with ischemia-induced testicular atrophy (AT) without liver disease and consequently with normal serum level of IGF-I. METHODS: Testicular atrophy was induced by epinephrine (1, 2 mg/Kg intra-scrotal injection five times per week) during 11 weeks. Then, rats with testicular atrophy (AT) were divided into two groups (n = 10 each): untreated rats (AT) receiving saline sc, and AT+IGF, which were treated with IGF-I (2 microg.100 g b.w.(-1).day(-1), sc.) for 28 d. Healthy controls (CO, n = 10) were studied in parallel. Animals were sacrificed on day 29th. Hypophyso-gonadal axis, IGF-I and IGFBPs levels, testicular morphometry and histopathology, immuno-histochemical studies and antioxidant enzyme activity phospholipid hydroperoxide glutathione peroxidase (PHGPx) were assessed. RESULTS: Compared to controls, AT rats displayed a reduction in testicular size and weight, with histological testicular atrophy, decreased cellular proliferation and transferrin expression, and all of these alterations were slightly improved by IGF-I at low doses. IGF-I therapy increased significantly steroidogenesis and PHGPx activity (p < 0.05). Interestingly, plasma IGF-I did not augment in rats with testicular atrophy treated with IGF-I, while IGFBP3 levels, that reduces IGF-I availability, was increased in this group (p < 0.05). CONCLUSION: In testicular atrophy by hypoxia, condition without IGF-I deficiency, IGF-treatment induces only partial effects. These findings suggest that IGF-I therapy appears as an appropriate treatment in hypogonadism only when this is associated to conditions of IGF-I deficiency (such as Laron Syndrome or liver cirrhosis).

Hematotesticular barrier is altered from early stages of liver cirrhosis: effect of insulin-like growth factor 1.

AIM: The pathogenesis of hypogonadism in liver cirrhosis is not well understood. Previous results from our laboratory showed that IGF-1 deficiency might play a pathogenetic role in hypogonadism of cirrhosis. The administration of IGF-1 for a short period of time reverted the testicular atrophy associated with advanced experimental cirrhosis. The aim of this study was to establish the historical progression of the described alterations in the testes, explore testicular morphology, histopathology, cellular proliferation, integrity of testicular barrier and hypophyso-gonadal axis in rats with no ascitic cirrhosis. METHODS: Male Wistar rats with histologically-proven cirrhosis induced with carbon tetrachloride (CCl4) for 11 wk, were allocated into two groups (n = 12, each) to receive recombinant IGF-1 (2 microg/100 g.d, sc) for two weeks or vehicle. Healthy rats receiving vehicle were used as control group (n = 12). RESULTS: Compared to controls, rats with compensated cirrhosis showed a normal testicular size and weight and very few histopathological testicular abnormalities. However, these animals showed a significant diminution of cellular proliferation and a reduction of testicular transferrin expression. In addition, pituitary-gonadal axis was altered, with significant higher levels of FSH (P<0.001 vs controls) and increased levels of LH in untreated cirrhotic animals. Interestingly, IGF-1 treatment normalized testicular transferrin expression and cellular proliferation and reduced serum levels of LH (P = ns vs controls, and P<0.01 vs untreated cirrhotic group). CONCLUSION: The testicular barrier is altered from an early stage of cirrhosis, shown by a reduction of transferrin expression in Sertoli cells, a diminished cellular proliferation and an altered gonadal axis. The treatment with IGF-1 could be also useful in this initial stage of testicular disorder associated with compensated cirrhosis.