Psychometric validation of the Spanish version of the Expanded Prostate Cancer Index Composite-26.

PURPOSE: To assess the validity, reliability, and responsiveness of the Spanish version of the Expanded Prostate cancer Index Composite (EPIC) with 26 items. METHODS: Multicentric longitudinal study of patients diagnosed with localized or locally advanced prostate cancer (any T, any N, M0) treated with active surveillance, surgery, external radiotherapy, or brachytherapy. The EPIC-50 was administered initially to the cohort (n = 324 patients), until it was replaced in November 2019 by the EPIC-26 (n = 543), in both groups before treatment and 12 months after. We assessed confirmatory factor analysis (CFA), reliability with Cronbach's alpha coefficient, criterion validity with the intraclass correlation coefficient (ICC), and responsiveness by testing a priori hypotheses on deterioration effect size (ES). RESULTS: The CFA confirmed the five-domain structure of the EPIC-26 proposed by the original instrument (comparative fit index = 0.95). The agreement between EPIC-50 (gold standard) and EPIC-26 domains was excellent (ICC > 0.90). Cronbach's alpha was > 0.7 in almost all domains, and the floor effect was near zero, although ceiling effect was higher than 50% in urinary incontinence and bowel domains. Hypothesized changes between before and 12 months after treatment were confirmed: ES > 0.8 in both urinary incontinence and sexual domains among patients who underwent surgery; and ES ranging 0.44-0.48 for bowel and sexual domains in patients treated with external radiotherapy. CONCLUSION: The Spanish version of the EPIC-26 has demonstrated adequate metric properties, similar to those of the original version, with acceptable goodness-of-fit indices, good criterion validity, reliability, and responsiveness to detect changes after radical prostatectomy or external radiotherapy.

A Web-Based Self-assessment Model for Evaluating Multidisciplinary Cancer Teams in Spain: Development and Validation Pilot Study.

BACKGROUND: Tumor boards constitute the main consensus and clinical decision-making body of multidisciplinary teams (MDTs) in cancer care. With the increasing clinical complexity of treatment options (eg, targeted therapies, multimodal treatments) and the progressive incorporation of new areas of intervention (eg, survivorship care), tumor boards are now required to play a central role in all cancer processes. However, although frameworks are in place to evaluate MDT quality, only few web-based tools are available for this purpose; indeed, no web-based MDT evaluation tools have been developed for or adapted to the Spanish National Health System. OBJECTIVE: The first aim of this study was to develop a web-based self-assessment model (Autoevaluación de Equipos Multidisciplinares de Atención al Cáncer [AEMAC]) for evaluating multidisciplinary cancer teams in Spain and the second aim was to validate this tool by testing its metric properties, acceptability, and usability. METHODS: We designed and validated the AEMAC program in 3 stages. In the first stage (research), we reviewed the available scientific evidence and performed a qualitative case study of good practice in multidisciplinary care within the Spanish National Health System (n=4 centers and 28 health care professionals). The results were used to define the thematic areas and quality criteria for the self-evaluation model, which were then discussed and validated by a group of experts. The second stage (development) involved the technological development of a web app that would be accessible from any mobile device. In the third stage (piloting and validation), we conducted 4 pilot tests (n=15 tumor boards, 243 professionals) and used the results to analyze the acceptability and usefulness of the tool. RESULTS: We designed a self-assessment model based on 5 thematic areas encompassing a total of 25 quality components, which users rated on a 3-option development scale. The evaluation process, which was managed entirely from the web app, consisted of individual self-assessment, group prioritization, and creation of an improvement plan. Cronbach alpha (.86), McDonald's omega (0.88), and various fit indices (comparative fit index between 0.95 and 1 and goodness-of-fit index between 0.97 and 0.99 for all 5 aspects) confirmed internal consistency. The mean rating for overall satisfaction with the tool and for consistency between the content of the tool and the reality of tumor boards was 7.6 out of 10. CONCLUSIONS: The results obtained during the period of research and piloting of the AEMAC program showed that it has an appropriate structure and metric properties and could therefore be implemented in a real context and generalized to other hospitals. As a virtual tool, it helps to measure the key aspects of MDT quality, such as effectiveness of collaboration and communication, leadership, and the organizational environment.

SPOP and CHD1 alterations in prostate cancer: Relationship with PTEN loss, tumor grade, perineural infiltration, and PSA recurrence.

BACKGROUND: In the non-ETS fusion of prostate cancer (PCa) pathway, SPOP mutations emerge as a distinct oncogenic driver subclass. Both SPOP downregulation and mutation can lead to SPOP target stabilization promoting dysregulation of key regulatory pathways. CHD1 gene is commonly deleted in PCa. CHD1 loss significantly co-occurs with SPOP mutations, resulting in a PCa subclass with increased AR transcriptional activity and with a specific epigenetic pattern. METHODS: In this study, SPOP alterations at mutational and protein levels and CHD1 copy number alterations have been analyzed and correlated with ERG and PTEN protein expression and with the clinical pathological features of the patients. RESULTS: SPOP protein loss has been detected in 42.9% of the cases, and it has been strongly associated with PTEN protein loss (p < .001). CHD1 gene loss has been detected in 24.5% and SPOP mutations in 5.9% of the cases. Loss of CHD1 has been strongly associated with SPOP mutations (p = .003) and has shown a trend to be associated with ERG wt cancers (p = .08). The loss of SPOP protein (p = .01) and the combination of PTEN and SPOP protein loss (p = .002) were both statistically more common in grade group 5 cancers, with a prevalence of 60% and 37.5%, respectively. Furthermore, SPOP loss/PTEN loss and SPOP wt/PTEN loss phenotypes were strongly associated with extraprostatic perineural infiltration (p = .007). Strong CHD1 loss was associated with a shorter time to PSA recurrence in the univariate (p = .04), and showed a trend to be associated with the PSA recurrence risk in the multivariate analysis (p = .058). CONCLUSIONS: The results of the present study suggest that the loss of SPOP protein expression, either alone or in combination with loss of PTEN and, on the other hand, a marked loss of the CHD1 gene are very promising prognostic biomarkers in PCa.

SPOP and FOXA1 mutations are associated with PSA recurrence in ERG wt tumors, and SPOP downregulation with ERG-rearranged prostate cancer.

BACKGROUND: ERG fusion-related prostate cancer (PrCa) is the most prevalent oncogenic driver subclass. SPOP, FOXA1, and IDH1 mutations are other three main oncogenic driver subclasses in non-ETS-fusion PrCa. ERG protein levels seem to be increased in SPOP-mutated cases, and different studies reported that SPOP mutations and ERG fusions are mutually exclusive. The aim of this study has been to analyze the alterations in non-ETS-oncogenic drivers in PrCa. METHODS: SPOP, FOXA1, and IDH mutations were investigated by polymerase chain reaction (PCR) and Sanger direct sequencing. ERG, SPOP, and TMPRSS2-ERG messenger RNA expression was assessed by quantitative real-time PCR from complementary DNA, and the presence of the fusion was also analyzed by nonquantitative PCR. The clinical pathological features were retrieved from the charts of the 111 patients included in the study (MARBiobanc, Barcelona, Spain). RESULTS: Loss of SPOP expression (25.2%) was associated with ERG overexpression (P = 0.0036). SPOP mutations were found in 5.4% cases, all with wild-type (wt) ERG (P = 0.007). FOXA1 mutations were found in 8.2% cases, most of them ERG wt (P = 0.06). No IDH1 mutations were found. SPOP or FOXA1 mutations were found in 1.7% of ERG-rearranged, and 34.2% of non-ERG-rearranged cases (P < 0.0001). SPOP or FOXA1 alterations (mutations or expression loss) were significantly more common in GG5, while isolated ERG overexpression was more common in GG1 tumors (P = 0.042). SPOP-or FOXA1-mutated cases were associated with a shorter time to prostate-specific antigen (PSA) recurrence in the univariate (P = 0.0009), and with the PSA recurrence risk in the multivariate (P = 0.023) analysis. CONCLUSIONS: In conclusion, SPOP and FOXA1 mutations may have prognostic value in ERG wt tumors. Interestingly, in absence of SPOP mutations, downregulation of this gene is a feature of many ERG-rearranged prostate tumors.

Concurrent TMPRSS2-ERG and SLC45A3-ERG rearrangements plus PTEN loss are not found in low grade prostate cancer and define an aggressive tumor subset.

BACKGROUND: SLC45A3 is the second most common ERG partner in prostate cancer (PrCa). Coexisting TMPRSS2 and SLC45A3 rearrangements are found in a subset of cases, but the meaning is still unknown. METHODS: SLC45A3-ERG and TMPRSS2-ERG rearrangements and their association with ERG and PTEN expression and with clinical and pathological features have been analyzed in 80 PrCa (PSMAR-Biobank, Barcelona, Spain). ERG and PTEN mRNA were assessed by qRT-PCR; TMPRSS2-ERG and SLC45A3-ERG by RT-PCR, FISH, and direct sequencing; and ERG expression by IHC. The endpoints were Gleason score (GS), stage, and PSA progression-free survival. RESULTS: Single TMPRSS2-ERG was found in 51.6% GS ≤ 7 and 22.2% GS ≥ 8 tumors (P = 0.027). SLC45A3-ERG was found in 25 cases, 20 of them with concurrent TMPRSS2-ERG rearrangement: 11.5% GS = 6, 22.2% GS = 7, and 50% GS ≥ 8 tumors (P = 0.013). Double rearrangements were associated with higher levels of ERG mRNA (P = 0.04). Double rearrangement plus PTEN loss was detected in 0% GS = 6; 14.7% GS = 7, and 29.4% GS ≥ 8 tumors (P = 0.032). Furthermore, this triple change was present in 19.2% stage T3-4 but not in any of stage T2 tumors (P = 0.05). No relationship was found with PSA progression-free survival. CONCLUSIONS: Single TMPRSS2-ERG translocation is associated with low grade PrCa. Subsequent development of SLC45A3-ERG results in higher ERG expression. The combination of double rearrangement plus PTEN loss, according to our series, is never found in low grade, low stage tumors. These findings could be potentially useful in therapeutic decision making in PrCa. Tumors with combined TMPRSS2-ERG/SLC45A3-ERG fusions plus PTEN loss should be excluded from watchful waiting and are candidates for intensive therapy. Prostate 76:854-865, 2016. © 2016 Wiley Periodicals, Inc.

Association of ERG and TMPRSS2-ERG with grade, stage, and prognosis of prostate cancer is dependent on their expression levels.

BACKGROUND: There is controversy in the literature on the role of the fusion TMPRSS2-ERG in the pathogenesis and progression of prostate cancer. The quantitative differences in TMPRSS2-ERG fusion expression have received very limited attention in the literature. METHODS: We have quantitatively analyzed the mRNA levels of TMPRSS2-ERG, ERG, PTEN, and AR (n = 83), as well as ERG immunostaining (n = 78) in a series of prostate tumors. RESULTS: Among the TMPRSS2-ERG cases (n = 57), high fusion levels were associated with GS ≥8 (P = 0.025). ERG mRNA overexpression was associated with GS ≥8 (P = 0.047), and with stage T3-T4 tumors (P = 0.032). Among the ERG overexpressing cases (n = 54), higher expression levels were found in 92.3% of GS ≥8 tumors (P = 0.02). ERG immunostaining, regardless of staining intensity, was also associated with high stage (P = 0.05). There was a statistical association between ERG immunostaining and PSA progression-free survival (Log Rank test, P = 0.048). Decreased PTEN expression was associated with TMPRSS2-ERG (P = 0.01), ERG mRNA overexpression (P = 0.003) and ERG immunostaining (P = 0.007). Furthermore, decreased PTEN expression, alone (P = 0.041) and also combined with TMPRSS2-ERG (P = 0.04) or with ERG overexpression (P = 0.04) was associated with GS ≥7 tumors. CONCLUSIONS: Although more studies are needed to further clarify their role, our findings emphasize that the expression levels of the TMPRSS2-ERG fusion and ERG mRNA, rather than their mere presence, are related to a more aggressive phenotype, have an effect on prognosis and could be molecular markers of progression for prostate cancer. Furthermore, ERG immunohistochemistry could be also a potentially useful prognostic factor.

Twelve Core Template Prostate Biopsy is an Unreliable Tool to Select Patients Eligible for Focal Therapy.

INTRODUCTION: To determine whether unilateral prostate cancer diagnosed at 12-core prostate biopsy harbours relevant prostate cancer foci in contralateral lobe in cases eligible for hemiablative focal therapy. MATERIAL AND METHODS: We analysed 112 radical prostatectomies of unilateral Gleason 6/7 prostate cancer based on prostate biopsy information. The presence of significant prostate cancer foci and/or the index lesion in the contralateral lobe is described. A subanalysis is performed in cases of Gleason score 6 and in cases of very-low-risk prostate cancer. RESULTS: Contralateral prostate cancer was present in 69.6% of cases, fulfilling significant prostate cancer criteria in 33% and being the index lesion in 32%. No significant differences were found when analysing the Gleason 6 group (73% contralateral prostate cancer, 34% significant prostate cancer and 35% index lesion) or the very-low-risk prostate cancer group (80% contralateral prostate cancer, 29% significant prostate cancer and 45% index lesion). CONCLUSIONS: The assumption of unilateral prostate cancer based on 12-core template prostate biopsy information is unreliable. In about one third of the cases, there will be focus of significant prostate cancer or the index lesion in the contralateral lobe. This information should be taken into account when hemiablative focal therapies are considered.

A Multicentre Clinical Trial Evaluating a Drop-in Gamma Probe for Minimally Invasive Sentinel Lymph Node Dissection in Prostate Cancer.

BACKGROUND: This study evaluated the safety and performance of a drop-in gamma probe for prostate cancer (PCa) sentinel lymph node biopsy (SeLNB) in a prospective, open-label, multicentre, single-arm clinical trial. OBJECTIVE: The main objective was to determine the sentinel lymph node (SeLN) detection rate with the drop-in gamma probe system. The secondary objectives were overall performance and safety. DESIGN, SETTING, AND PARTICIPANTS: At three European centres, patients received an ultrasound-guided systemic and tumour-targeted injection of [99mTc]Tc-nanocolloid followed by planar lymphoscintigraphy and/or single-photon emission computerised tomography. The next day, manual laparoscopic or robot-assisted radical prostatectomy was performed, including SeLN dissection (SeLND) and extended pelvic lymph node dissection (ePLND). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: SeLNs were detected with the drop-in probe and a rigid laparoscopic gamma probe (RLGP). The primary endpoint of the study was the SeLND rate defined as the percentage of patients with at least one SeLN detected in vivo by the drop-in probe. The secondary endpoints included diagnostic performance, ease of SeLN detection, number of SeLNs detected, and safety. The first two patients at each site (six in total) were used for familiarisation. RESULTS AND LIMITATIONS: A total of 27 patients were included in the main analysis. SENSEI successfully detected at least one SeLN in all 27 patients, resulting in a detection rate of 100% (95% confidence interval 87.2-100%). The total number of SeLNs identified with SENSEI was 85 (median three SeLNs per patient, range 1-6); of these 85 SeLNs, 12 were located outside of the ePLND template. In the nine patients in whom the RLGP was used, SENSEI detected two SeLNs that could not be detected with the RLGP due to manoeuvrability restrictions. Ten of the 27 patients were pN1; four patients had a false-negative SeLNB. No adverse events or complications were related to the use of the drop-in probe. CONCLUSIONS: The study demonstrated that the drop-in gamma probe meets the performance and safety requirements for SeLNB in PCa. The device provided improved manoeuvrability and SeLN detection compared with the conventional RLGP. PATIENT SUMMARY: A novel device was tested for detecting sentinel lymph nodes during minimally invasive surgery for prostate cancer. In this first evaluation, the performance and safety of the device were evaluated positively.

A Drop-in Gamma Probe for Minimally Invasive Sentinel Lymph Node Dissection in Prostate Cancer: Preclinical Evaluation and Interim Results From a Multicenter Clinical Trial.

PURPOSE: This study evaluated the performance of a drop-in gamma probe for prostate cancer (PCa) sentinel lymph node dissection (SLND) in a pelvic phantom, porcine model, and in PCa patients as part of an ongoing prospective multicenter clinical trial. METHODS: Two design variants of the drop-in gamma probe (SENSEI; Lightpoint Medical Ltd) were assessed in the pelvic phantom, and the preferred design was evaluated in a porcine model with clinically representative volumes and 99mTc activities. In the clinical trial, radical prostatectomy, SLND, and extended pelvic lymph node dissection were performed the day after 99mTc-nanocolloid injection and imaging. Sentinel lymph nodes (SLNs) were detected with the drop-in probe and a rigid laparoscopic gamma probe (RLGP). An interim analysis was performed after 10 patients were recruited. RESULTS: The narrow field of view probe design outperformed the wide field of view design in the pelvic phantom (detection rate, 100% vs 50%). In the porcine model, all activity concentrations could be successfully detected. The drop-in gamma probe successfully detected SLNs in all 10 patients (detection rate, 100%). Two of the SLNs identified by the drop-in gamma probe could not be found with the RLGP. No false-negative cases and no adverse events related to the SLND procedure or the drop-in gamma probe occurred. CONCLUSION: The drop-in gamma probe meets the usability and performance requirements for SLND in PCa and provides performance advantages over the RLGP. The final clinical study results will confirm the performance of the technique across multiple sites.

Immunohistochemical markers as predictors of prognosis in multifocal prostate cancer.

The impact of tumor focality on prostate cancer (PCa) prognosis has been addressed in several studies with conflicting results. Tumor foci from multifocal (MF) PCa can show highly heterogeneous molecular features. Our aim was to analyze the protein expression of PTEN, SPOP, SLC45A3, ETV1, ERG and the "triple hit" (ERG overexpression, PTEN plus SLC45A3 loss) in unifocal (UF) and MF PCa, to evaluate their value as prognostic markers according to focality, and the role of tumor heterogeneity in MF disease. PTEN, SPOP, SLC45A3, ETV1 and ERG immunohistochemical expression was evaluated in 185 PCa from 9 TMAs, 51 UF and 134 MF. In a subset of 69 MF cases, the dominant and secondary foci (DF and SF) were compared. Heterogeneity was considered when both tumor foci presented different expression patterns. Relationship with clinicopathological features was also analyzed. MF PCa was diagnosed in significantly younger patients when compared to UF ones (p = 0.007). ETV1 overexpression was associated with UF disease (p = 0.028). A shorter time to PSA recurrence was related to SLC45A3 wt expression in UF PCa (p = 0.052), and to SPOP expression loss (p = 0.043) or "triple hit" phenotype in MF PCa (p = 0.041). In MF cases, PTEN loss, SLC45A3 loss and "triple hit" phenotype were associated with the DF and had significant heterogeneity. In conclusion, our results indicate that UF and MF PCa have relevant and consistent molecular differences. The analysis of an immunohistochemical panel, composed by PTEN, SPOP, SLC45A3, ETV1 and ERG, could be useful to predict outcome in MF cases.

Sentinel Lymph Node Biopsy in Prostate Cancer Using the SENSEI® Drop-In Gamma Probe.

ABSTRACT: Minimally invasive surgery in the form of laparoscopic and robot-assisted procedures has been widely adopted in the field of prostate cancer. When performing minimally invasive radioguided surgery, conventional rigid laparoscopic gamma probes have limited maneuverability and control due to their form factor, which may hinder detection of radiotracer-avid lesions in anatomically challenging areas. A drop-in gamma probe has been developed to address these limitations. Our group report on the first clinical use of this probe (SENSEI®) as part of an ongoing prospective, international, multicenter clinical trial in primary prostate cancer patients undergoing 99mTc-nanocolloid sentinel lymph node biopsy.

Sentinel Lymph Node Biopsy in Prostate Cancer Patients: Results From an Injection Technique Targeting the Index Lesion in the Prostate Gland.

Objectives: To determine the accuracy of nodal staging in patients with prostate cancer (PCa) when 99 m Tc-nanocolloid radiotracer is injected into an index lesion (IL). Methods: This prospective study was conducted at our institution between June 2016 and October 2020. It included 64 patients with localized PCa with at least a 5% possibility for lymph node involvement in the Memorial Sloan Kettering Cancer Center nomogram, suitable for surgical treatment. All patients underwent magnetic resonance imaging (MRI) with IL and were pathologically confirmed. The day before surgery, transrectal ultrasound-guided injection (TRUS) of 99 m Tc-nanocolloid into the IL was performed. Surgical procedures included radical prostatectomy (RP), sentinel lymph node biopsy (SLNB), and extended pelvic lymphadenectomy (ePLND). Analysis was performed, including histopathological findings of RP, ePLND, and SLNB. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), false negative (FN), false positive (FP), diagnostic yield, and non-diagnostic rate were calculated. Results: A total of 1,316 lymph nodes were excised, including 1,102 from the ePLND (83.7%) and 214 (16.3%) sentinel lymph nodes (SLN). 26 SLN were dissected outside the ePLND template. The final pathology demonstrated 46 (3.5%) lymph node metastasis, 31 (67.4%) in the SLNB and 15 (32.6%) in the non-SLN ePLND. At the patient level, 18 (28.1%) patients had pN1. With a mean follow-up of 33.1 months, 4/19 (21.1%) pN1 patients had undetectable PSA, and 3/19 (15.8%) had a PSA < 0.1 ng/mL. Lymph node dissection included 20.6 lymph nodes per patient (IQR 15-24.2), with 3.3 SLNB nodes per patient (IQR 2-4.2). PPV and NPV were 100 and 97.8%, respectively. Sensitivity and specificity were 94.4 and 100%, respectively. FN was 5.5% and FP was 4.3%. Diagnostic yields were 95.3% and the non-diagnostic rate was 4.7%. Conclusion: Radiotracer injection into the prostate IL offers promising results for staging purposes in cases in which ePLND is considered. Negative SLNB is a predictor of negative ePLND. Patients with a limited burden of nodal metastasis have a significant chance of remaining free of biochemical recurrence at mid-term follow-up.

Positive margins after nephron-sparing surgery for renal cell carcinoma: long-term follow-up of patients on active surveillance.

OBJECTIVE: To analyse our long-term oncological outcomes with active surveillance in patients with positive surgical margins (PSMs) after nephron-sparing surgery (NSS) for renal cell carcinoma (RCC), as this situation is a difficult therapeutic dilemma. PATIENTS AND METHODS: We performed open NSS for renal masses with frozen-section analysis of any suspicious zone of the surgical bed, followed by extensive argon-beam coagulation. In patients where the final histopathological examination of the renal mass revealed PSMs, follow-up consisted of computed tomography (CT) every 6 months in the first 2 years and then annually up to 5 years, and thereafter we alternated ultrasonography with CT. RESULTS: From 1995 to 2003 we had 11 cases of microscopic definitive PSMs after NSS for RCC. Two patients required nephrectomy (one for postoperative bleeding and another as an elective procedure), so nine were followed. These patients were either operated under elective (seven) or imperative (two) conditions. The histological subtype was clear cell carcinoma in three, papillary in two, chromophobe in two and hybrid oncocytic RCC in two, with a Furhman grade of 2 in six and 3 in three. The mean size was 31.4 mm, and the stage was pT1a in six, pT1b in one and pT3a in two. After a median follow-up of 80.5 months, there was no local recurrence or distant progression. CONCLUSIONS: In our experience, microscopic PSMs in NSS specimens can be managed conservatively with active surveillance, achieving excellent results and avoiding extensive reoperation without compromising long-term oncological outcomes.

Immunohistochemical expression of mismatch repair proteins (MSH2, MSH6, MLH1, and PMS2) in prostate cancer: correlation with grade groups (WHO 2016) and ERG and PTEN status.

The role of DNA MMR genes in prostate cancer (PrCa) is controversial, as genetic alterations leading to microsatellite instability are incompletely defined in these tumors. ERG rearrangements and PTEN loss are concomitant events in PrCa. The aim of this study has been to analyze the immunohistochemical (IHC) expression of MSH2, MSH6, MLH1, PMS2, ERG, and PTEN and their potential association with the grade group (GG) grading system (WHO 2016) and PSA recurrence in a series of 200 PrCa (PSMAR-Biobank, Barcelona, Spain). MSH2, MLH1, PMS2, and PTEN losses were documented in 8%, 5%, 2%, and 36.5%, respectively. ERG expression was found in 48%. MSH6 showed an increase of expression with respect to basal levels in 42.1% of the cases. A statistical association between MSH6 overexpression and GG5 was found (p = 0.0281). ERG-wild-type cases were associated with single MSH2 loss (p = 0.024), and MSH2 and/or MLH1 loss (p = 0.019). The percentage of cases with PTEN loss was 20.5% (8/39) in GG1, 37.6% (53/141) of clustered GG2 to 4, and 60% (12/20) of GG5 (chi-square test, p = 0.01). Thus, PTEN expression loss was statistically more frequent in the upper-grade tumors. PMS2 loss was an infrequent event, but it was statistically associated with shorter time to PSA recurrence (p = 0.011). These results suggest the existence of an alternative non-ERG pathway associated with MSH2 or MLH1 expression loss. MSH6 overexpression could be a marker of aggressiveness in PrCa. The IHC assessment of DNA MMR proteins, ERG and PTEN, could identify different altered PrCa pathways, which could aid patient stratification.

Strong cytoplasmic ETV1 expression has a negative impact on prostate cancer outcome.

Overexpression of ETS genes is involved in prostate cancer (PrCa), but there is little information on the non-ERG components of this family. We have investigated ETV1, ETV4, and ETV5 overexpression, with or without PTEN loss, and their association with grade group (GG), pathological stage, focality, and PSA recurrence in PrCa. ETS gene expression was analyzed by qPCR in 104 cases. ETV1 and PTEN immunohistochemistry was assessed in TMA sections from 194 additional cases (PSMAR-Biobank, Barcelona, Spain). ETS mRNA overexpression was found in 23.1%, being ETV1 the most frequently overexpressed (18.3%). ETV1 protein overexpression was detected in 30.4% cases (moderate in 19.6%, strong in 10.8%). PTEN protein expression loss was detected in 36.1% cases and was not associated with ETV1. Strong-moderate ETV1 protein overexpression reaches its highest values in GG3-4, whereas its negativity was significantly more common in GG1 tumors (p = 0.034). ETV1-overexpressing tumors were more often unifocal (p = 0.0007) and high stage (p = 0.032). PTEN loss was less common in GG1 (p = 0.012) and showed a trend to be less frequent in pT2 (p = 0.062) tumors. Strong ETV1 immunostaining (histoscore > 177) was associated with shorter time to PSA recurrence in the univariate (p = 0.002) and in the multivariate analysis (p = 0.018). Moreover, when strong ETV1 overexpression was not combined with PTEN loss, its association with PSA recurrence was even stronger (p = 0.0004). In conclusion, non-ERG ETS overexpression, particularly ETV1 overexpression, has a non-negligible role in PrCa. Strong ETV1 protein expression has a negative impact on prostate cancer outcome that seems to be independent of PTEN status.

Factors associated with renal function compensation after donor nephrectomy. / Factores asociados a la compensación de la función renal tras la nefrectomía para donación.

INTRODUCTION: Kidney transplant donors lose 50% of their renal mass after nephrectomy. The remaining kidney compensates for this loss and it is estimated that 70% of the baseline renal function prior to donation is recovered. Factors associated with post-donation renal compensation are not well understood. METHODS: Retrospective study of 66 consecutive kidney donors (mean age 48.8 years, 74.2% women). We analysed the potential factors associated with the compensatory mechanisms of the remaining kidney by comparing donors according to their renal compensation rate (RCR) (Group A, infra-compensation [<70%]; Group B, normal compensation [>70%]). RESULTS: We compared Group A (n=38) and group B (n=28). Predictors for RCR>70% were higher baseline creatinine (A vs B: 0.73±0.14 vs 0.82±0.11; P=.03) and a lower baseline glomerular filtration rate (GFR), estimated both by MDRD-4 (A vs B: 97.7±18.8 vs 78.6±9.6ml/min; P<.001) and CKD-EPI (A vs B: 101.7±15 vs. 88.3±11.7ml/min; P≤.001). Age, gender, smoking, hypertension and GFR measured by Tc-DTPA did not show any correlation with the RCR. The multivariate analysis confirmed baseline estimated glomerular filtration rate (eGFR) to be a predictor of compensation: the higher the baseline eGFR, the lower the likelihood of >70% compensation (MDRD-4, OR=0.94 [95% CI 0.8-0.9], P=.01). The compensation rate decreased by 0.4% (P<.001) and 0.3% (P=.006) for every ml/min increase in baseline eGFR estimated by MDRD-4 and CKD-EPI, respectively. CONCLUSIONS: One year after living donor nephrectomy, the remaining kidney partially compensates baseline renal function. In our experience, baseline eGFR is inversely proportional to the one-year renal compensation rate.

MDRD or CKD-EPI for glomerular filtration rate estimation in living kidney donors. / MDRD o CKD-EPI en la estimación del filtrado glomerular del donante renal vivo.

INTRODUCTION: The evaluation of the measured Glomerular Filtration Rate (mGFR) or estimated Glomerular Filtration Rate (eGFR) is key in the proper assessment of the renal function of potential kidney donors. We aim to study the correlation between glomerular filtration rate estimation equations and the measured methods for determining renal function. MATERIAL AND METHODS: We analysed the relationship between baseline GFR values measured by Tc-99m-DTPA (diethylene-triamine-pentaacetate) and those estimated by the four-variable Modification of Diet in Renal Disease (MDRD4) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations in a series of living donors at our institution. RESULTS: We included 64 donors (70.6% females; mean age 48.3±11 years). Baseline creatinine was 0.8±0.1 mg/dl and it was 1.1±0.2 mg/dl one year after donation. The equations underestimated GFR when measured by Tc99m-DTPA (MDRD4-9.4 ± 25ml/min, P<.05, and CKD-EPI-4.4 ± 21ml/min). The correlation between estimation equations and the measured method was superior for CKD-EPI (r=.41; P<.004) than for MDRD4 (r=.27; P<.05). eGFR decreased to 59.6±11 (MDRD4) and 66.2±14ml/min (CKD-EPI) one year after donation. This means a mean eGFR reduction of 28.2±16.7 ml/min (MDRD4) and 27.31±14.4 ml/min (CKD-EPI) at one year. CONCLUSIONS: In our experience, CKD-EPI is the equation that better correlates with mGFR-Tc99m-DTPA when assessing renal function for donor screening purposes.

ERG overexpression plus SLC45A3 (prostein) and PTEN expression loss: Strong association of the triple hit phenotype with an aggressive pathway of prostate cancer progression.

TMPRSS2 and SLC45A3 rearrangements may coexist in the same tumor. ERG rearrangements and PTEN loss are concomitant events in prostate cancer (PrCa), and can cooperate in progression. We have reported that mRNA expression of TMPRSS2-ERG and SLC45A3-ERG rearrangements plus PTEN loss define an aggressive tumor subset. The aim of this study has been to validate these results by immunohistochemistry in a large cohort of tumors. ERG, SLC45A3 and PTEN immunostaining and their association with pathological features and PSA progression-free survival were analyzed in 220 PrCa (PSMAR-Biobank, Barcelona, Spain). ERG protein expression was found in 46.8% and SLC45A3 and PTEN loss in 30% and 34% tumors, respectively. Single ERG positive immunostaining was associated with GS = 6 tumors (p = 0.016), double ERG+/PTEN loss with GS = 7 (p = 0.008) and Grade Group 2 (GG) or GG3 cases (p = 0.042), ERG+/SLC45A3 loss/PTEN loss ("triple hit") with GS ≥ 8 (p < 0.0001) and GG4 or GG5 tumors (p = 0.0003). None of GS = 6 nor = GG1 cases showed this combination. In the GS ≥ 8 group, ERG+ (p = 0.002), PTEN loss (p = 0.009) and "triple hit" (p = 0.003) were associated with Gleason pattern 3 component, and single SLC45A3 loss (p = 0.036) with GS ≥ 8 without pattern 3. The number of aberrant events and the triple hit were strongly associated with shorter PSA progression-free survival. In GS = 6 PrCa, single ERG+ was also associated with progression. ERG+ identifies a distinct pathway of PrCa. Additional assessment of PTEN and SLC45A3 adds relevant prognostic information. The triple hit phenotype (ERG+/SLC45A3 loss/PTEN loss) is associated with progression and could be used for patient stratification, treatment and follow-up.

The management of active surveillance in prostate cancer: validation of the Canary Prostate Active Surveillance Study risk calculator with the Spanish Urological Association Registry.

The follow up of patients on active surveillance requires to repeat prostate biopsies. Predictive models that identify patients at low risk of progression or reclassification are essential to reduce the number of unnecessary biopsies. The aim of this study is to validate the Prostate Active Surveillance Study risk calculator (PASS-RC) in the multicentric Spanish Urological Association Registry of patients on active surveillance (AS), from common clinical practice. RESULTS: We find significant differences in age, PSA and clinical stage between our validation cohort and the PASS-RC generation cohort (p < .0001), with a reclassification rate of 10-22% on the follow-up Bx, no cancer was found in 43% of the first follow-up Bx. The calibration curve shows underestimation of real appearance of reclassification. The AUC is 0.65 (C.I.95%: 0.60-0.71). PDF and CUC do not suggest a specific cut-off point of clinical use. METHODS: We select 498 patients on AS with a minimum of one follow-up biopsy (Bx) from the 1,024 males registered by 36 Spanish centers recruiting patients on the Spanish Urological Association Registry on AS. PASS-RC external validation is carried by means of calibration curve and area under de ROC-curve (AUC), identifying cut-offs of clinical utility by probability density functions (PDF) and clinical utility curves (CUC). CONCLUSIONS: In our first external validation of the PASS-RC we have obtained a moderate discrimination ability, although we cannot recommend cut-off points of clinical use. We suggest the exploration of new biomarkers and/or morpho-functional parameters from multiparametric magnetic resonance image, to improve those necessary tools on AS.