Follow-up care over 12months of patients with prostate cancer in Spain. A multicenter prospective cohort study

This study was funded by an Instituto de Salud Carlos III (ISCIII) Grant PS09/01204 (Fondo de Investigación Sanitaria [FIS], Spain). Dr María José Martinez Zapata is funded by a Miguel Servet II research contract from the ISCIII (CP1120/00023). ISCIII had any role in the design or execution of the study; in the data collection, management, or interpretation; or in the writing, reviewing, or approval of the manuscript.Ailish Maher and Andrea Cervera Alepuz revised the English in a version of this manuscript. Maria José Martinez Zapata is funded by a Miguel Servet research contract (CPII20/00023). EMPARO Study Group: Coordinating investigator: Xavier Bonfill Cosp (Iberoamerican Cochrane Centre, Public Health and Clinical Epidemiology Service, Hospital de la Santa Creu i Sant Pau, IIB Sant Pau, Barcelona, Spain). Project manager: María José Martínez Zapata (Iberoamerican Cochrane Centre, IIBSant Pau, Barcelona, Spain). Clinical research assistants: Alborada Martínez (Universidad de Valencia); Enrique Morales Olivera (Escuela Andaluza de Salud Publica, Granada, Spain); Esther Canovas, Laura Muñoz, Gemma Mas, René Acosta, Ekaterina Popova (Iberoamerican Cochrane Centre, IIB Sant Pau, Barcelona, Spain); Irma Ospina (Hospital 12 de Octubre, Madrid, Spain); María José Velázquez (Hospital Donostia, Donostia, Spain); Tamara Ruiz Merlo (Hospital Ramón y Cajal, Madrid, Spain); Gael Combarros Herman, Judit Tirado Muñoz (IMIM-Hospital del Mar Medical Research Institute, Barcelona, Spain). Statistical analysis: Robin W.M. Vernooij (Iberoamerican Cochrane Centre, IIB Sant Pau, Barcelona, Spain); Javier Zamora and Claudia Coscia Requena (Hospital Ramón y Cajal, Madrid, Spain). Co-investigators: Barcelona, Spain Albert Frances (Hospital del Mar); Carola Orrego Villagran, Rosa Suñol (Instituto Universitario Avedis Donabedian); Dimelza Osorio, Gemma Sancho Pardo, Ignasi Bolívar, José Pablo Maroto, María Jesus Quintana, Cristina Martin (Hospital de la Santa Creu i Sant Pau); Ferran Algaba, Palou Redorta, Salvador Esquena (Fundació Puigvert); Jordi Bachs (Fundació Privada Hospital de la Santa Creu i Sant Pau); María José Martínez Zapata (Iberoamerican Cochrane Centre, IIB Sant Pau); Montserrat Ferrer Fores, Stefanie Schmidt, Olatz Garin, Virginia Becerra Bachito, Yolanda Pardo (IMIM-Hospital del Mar Medical Research Institute). Bilbao, Spain Amaia Martínez Galarza, José Ignacio Pijoán Zubizarreta (Hospital Universitario Cruces/BioCruces Health Research Institute). Granada, Spain Armando Suárez Pacheco, Cesar García López, José Manuel Cozar Olmo (Hospital Universitario Virgen de las Nieves); Carmen Martínez, Daysy Chang Chan, María José Sánchez Pérez (Escuela Andaluza de Salud Publica). Madrid, Spain Ana Isabel Díaz Moratinos, Angel Montero Luis, Asunción Hervás, Carmen Vallejo Ocaña, Costantino Varona, Javier Burgos, Javier Zamora, Jose Alfredo Polo Rubio, Luis López Fando Lavalle, Miguel Angel Jimenez Cidre, Muriel García, Alfonso, Nieves Plana Farras, Rosa Morera Lopez, Sonsoles Sancho Garcia, Victor Abraira, Victoria Gomez Dos Santos (Hospital Ramón y Cajal); Agustín Gómez de la Cámara, Javier de la Cruz, Juan Passas Martínez, Humberto García Muñoz, María Ángeles Cabeza Rodríguez (Hospital 12 de Octubre). San Sebastián, Spain Irune Ruiz Díaz, José Ignacio Emparanza, Juan Pablo Sanz Jaka (Hospital Universitario Donostia). Valencia, Spain Agustín Llopis González, María Morales (Universidad de Valencia); Carlos Camps, Cristina Caballero Díaz, Emilio Marqués Vidal, Francisco Sánchez Ballester, Joaquín Ulises Juan Escudero, Jorge Pastor Peidro, José López Torrecilla, María Macarena Ramos Campos, Miguel Martorell Cebollada (Consorcio Hospital General Universitario de Valencia).The therapeutic approach is crucial to prostate cancer prognosis. We describe treatments and outcomes for a Spanish cohort of patients with prostate cancer during the first 12 months after diagnosis and identify the factors that influenced the treatment they received. This multicenter prospective cohort study included patients with prostate cancer followed up for 12 months after diagnosis. Treatment was stratified by factors such as hospital, age group (<70 and ≥70 years), and D’Amico cancer risk classification. The outcomes were Eastern Cooperative Oncology Group (ECOG) performance status, adverse events (AEs), and mortality. The patient characteristics associated with the different treatment modalities were analyzed using multivariate logistic regression. We included 470 men from 7 Spanish tertiary hospitals (mean (standard deviation) age 67.8 (7.6) years), 373 (79.4%) of which received treatment (alone or in combination) as follows: surgery (n = 163; 34.7%); radiotherapy (RT) (n = 149; 31.7%); and hormone therapy (HT) (n = 142; 30.2%). The remaining patients (n = 97) were allocated to no treatment, that is, watchful waiting (14.0%) or active surveillance (5.7%). HT was the most frequently administered treatment during follow-up and RT plus HT was the most common therapeutic combination. Surgery was more frequent in patients aged <70, with lower histologic tumor grades, Gleason scores <7, and lower prostate-specific antigen levels; while RT was more frequent in patients aged ≥70 with histologic tumor grade 4, and higher ECOG scores. HT was more frequent in patients aged ≥70, with histologic tumor grades 3 to 4, Gleason score ≥8, ECOG ≥1, and higher prostate-specific antigen levels. The number of fully active patients (ECOG score 0) decreased significantly during follow-up, from 75.3% at diagnosis to 65.1% at 12 months (P < .001); 230 (48.9%) patients had at least 1 AE, and 12 (2.6%) patients died. Surgery or RT were the main curative options. A fifth of the patients received no treatment. Palliative HT was more frequently administered to older patients with higher tumor grades and higher Gleason scores. Close to half of the patients experienced an AE related to their treatment.Instituto de Salud Carlos III CP1120/00023, PS09/0120

Health‑related quality of life in patients newly diagnosed with prostate cancer: CAPLIFE study

Funding Funding for open access charge: Universidad de Granada / CBUA. This research was funded by Regional Ministry of Health and Families of Andalusia/Consejería de Salud y Familias de la Junta de Andalucía (PI-0514-2016).Purpose To analyse the Health-Related Quality of Life (HRQoL) at diagnosis of patients with prostate cancer (PCa) according to tumour extension and urinary symptomatology and to explore factors associated with HRQoL. Methods 408 Controls and 463 PCa cases were included. Eligibility criteria were a new diagnosis of PCa (cases), 40–80 years of age, and residence in the participating hospitals’ coverage area for ≥ 6 months before recruitment. HRQoL was evaluated using the 12-Item Short-Form Health Survey, Mental (MCS) and Physical Component Summaries (PCS), and urinary symptoms with the International Prostate Symptom Score. HRQoL scores for all PCa cases, according to tumour extension and urinary symptoms, were compared with controls. In addition, information about lifestyles and comorbidities was collected and its association with low HRQoL (lower scores) were explored using logistic regression models. Results Overall cases had similar PCS score, but lower MCS score than controls. The lowest standardised scores for both PCS and MCS were reached by cases with severe urinary symptoms and a metastatic tumour [mean (SD); PCS: 41.9 (11.5), MCS: 42.3 (10.3)]. Having “below” PCS and MCS scores was associated with the presence of three or more comorbidities in the cases [aOR = 2.86 (1.19–6.84) for PCS and aOR = 3.58 (1.37–9.31) for MCS] and with severe urinary symptomatology [aOR = 4.71 (1.84–12.08) for PCS and aOR = 7.63 (2.70–21.58) for MCS]. Conclusion The mental dimension of HRQoL at diagnosis of patients with PCa was lower than in controls, especially for cases with severe urinary symptoms and a metastatic tumour. Comorbidities and urinary symptoms were variables associated with the HRQoL of PCa cases.Funding for open access charge: Universidad de Granada/CBUARegional Ministry of Health and Families of Andalusia/Consejería de Salud y Familias de la Junta de Andalucía (PI-0514-2016

The influence of nutritional factors on prostate cancer incidence and aggressiveness

There is an increasing evidence for a link between nutrition, lifestyle and prostate cancer (PCa) development and/or progression of disease. The objective of this study was to examine the association between dietary factors and PCa incidence and aggressiveness in a case-control study. After the analysis of the anatomic pathology, subjects were classified in patients with PCa (n = 157) and controls (n = 158). Clinical data including Gleason score, PSA values and biopsy results, were compiled. Frequencies of food consumption and sociodemographic data were also obtained. The results showed that physical activity was significantly higher in control (p <.022). It was also found that some nutritional habits offer a protective effect among studied subjects, like high nuts (p =.041) and fish (p =.041) intakes. Moreover, there was a significant reduction in risk (p =.029) in cases with a higher fruits and vegetables intakes. A decreased risk of aggressive PCa was associated with fruits, vegetables, legumes and fish intakes. However, these relationships were not statistically significant when data were adjusted for covariates. In conclusion, this study found an inverse association between PCa risk and the intake of fruits and vegetables, fish and nuts. The results suggested that a diet with higher intakes of these foods as Mediterranean diet may lower the risk of PCa in the studied population. As dietary factors are modifiable, identifying food groups or dietary patterns that modulate the risk of PCa and its aggressiveness can offer effective and practical strategies for its primary prevention

Biofabrication of a Tubular Model of Human Urothelial Mucosa Using Human Wharton Jelly Mesenchymal Stromal Cells

Several models of bioartificial human urothelial mucosa (UM) have been described recently. In this study, we generated novel tubularized UM substitutes using alternative sources of cells. Nanostructured fibrin–agarose biomaterials containing fibroblasts isolated from the human ureter were used as stroma substitutes. Then, human Wharton jelly mesenchymal stromal cells (HWJSC) were used to generate an epithelial-like layer on top. Three differentiation media were used for 7 and 14 days. Results showed that the biofabrication methods used here succeeded in generating a tubular structure consisting of a stromal substitute with a stratified epithelial-like layer on top, especially using a medium containing epithelial growth and differentiation factors (EM), although differentiation was not complete. At the functional level, UM substitutes were able to synthesize collagen fibers, proteoglycans and glycosaminoglycans, although the levels of control UM were not reached ex vivo. Epithelial differentiation was partially achieved, especially with EM after 14 days of development, with expression of keratins 7, 8, and 13 and pancytokeratin, desmoplakin, tightjunction protein-1, and uroplakin 2, although at lower levels than controls. These results confirm the partial urothelial differentiative potential of HWJSC and suggest that the biofabrication methods explored here were able to generate a potential substitute of the human UM for future clinical use.CTS-115 Tissue Engineering Group and by the Spanish Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica, Ministry of Science and Innovation, Instituto de Salud Carlos III, grant FIS PI21/0981 (cofinanced by FEDER funds, European Union)

Type 2 Diabetes-Related Variants Influence the Risk of Developing Prostate Cancer: A Population-Based Case-Control Study and Meta-Analysis

This study was supported by grants from the FIBAO foundation (Granada, Spain) and from the Instituto de Salud Carlos III (PI12/02688, PI17/02256 and PI20/01845; Madrid, Spain).In this study, we have evaluated whether 57 genome-wide association studies (GWAS)-identified common variants for type 2 diabetes (T2D) influence the risk of developing prostate cancer (PCa) in a population of 304 Caucasian PCa patients and 686 controls. The association of selected single nucleotide polymorphisms (SNPs) with the risk of PCa was validated through meta-analysis of our data with those from the UKBiobank and FinnGen cohorts, but also previously published genetic studies. We also evaluated whether T2D SNPs associated with PCa risk could influence host immune responses by analysing their correlation with absolute numbers of 91 blood-derived cell populations and circulating levels of 103 immunological proteins and 7 steroid hormones. We also investigated the correlation of the most interesting SNPs with cytokine levels after in vitro stimulation of whole blood, peripheral mononuclear cells (PBMCs), and monocyte-derived macrophages with LPS, PHA, Pam3Cys, and Staphylococcus Aureus. The meta-analysis of our data with those from six large cohorts confirmed that each copy of the FTOrs9939609A, HNF1B(rs7501939T), HNF1B(rs75721T), HNF1B(rs4430796G), and JAZF1(rs10486567A) alleles significantly decreased risk of developing PCa (p = 3.70 x 10(-5), p = 9.39 x 10(-54), p = 5.04 x 10(-54), p = 1.19 x 10(-71), and p = 1.66 x 10(-18), respectively). Although it was not statistically significant after correction for multiple testing, we also found that the NOTCH2(rs10923931T) and RBMS1(rs7593730) SNPs associated with the risk of developing PCa (p = 8.49 x 10(-4) and 0.004). Interestingly, we found that the protective effect attributed to the HFN1B locus could be mediated by the SULT1A1 protein (p = 0.00030), an arylsulfotransferase that catalyzes the sulfate conjugation of many hormones, neurotransmitters, drugs, and xenobiotic compounds. In addition to these results, eQTL analysis revealed that the HNF1B(rs7501939), HNF1B(rs757210), HNF1B(rs4430796), NOTCH2(rs10923931), and RBMS1(rs7593730) SNPs influence the risk of PCa through the modulation of mRNA levels of their respective genes in whole blood and/or liver. These results confirm that functional TD2-related variants influence the risk of developing PCa, but also highlight the need of additional experiments to validate our functional results in a tumoral tissue context.FIBAO foundation (Granada, Spain)Instituto de Salud Carlos III PI12/02688 PI17/02256 PI20/0184

Follow-Up Biomarkers in the Evolution of Prostate Cancer, Levels of S100A4 as a Detector in Plasma

The management and screening of prostate cancer (PC) is still the main problem in clinical practice. In this study, we investigated the role of aggressiveness genetic markers for PC stratification. We analyzed 201 plasma samples from PC patients and controls by digital PCR. For selection and validation, 26 formalin-fixed paraffin-embedded tissues, 12 fresh tissues, and 24 plasma samples were characterized by RNA-Seq, immunochemistry, immunofluorescence, Western blot, and extracellular-vesicles analyses. We identified three novel non-invasive biomarkers; all with an increased expression pattern in patients (PCA3: p = 0.002, S100A4: p <= 0.0001 and MRC2: p = 0.005). S100A4 presents the most informative AUC (area under the curve) (0.735). Combination of S100A4, MRC2, and PCA3 increases the discriminatory power between patients and controls and between different more and less aggressive stages (AUC = 0.761, p <= 0.0001). However, although a sensitivity of 97.47% in PCA3 and a specificity of 90.32% in S100A4 was reached, the detection signal level could be variable in some analyses owing to tumor heterogeneity. This is the first time that the role of S100A4 and MRC2 has been described in PC aggressiveness. Moreover, the combination of S100A4, MRC2, and PCA3 has never been described as a non-invasive biomarker for PC screening and aggressiveness.Ministry of Health, Andalusia Government Leonardo de la Pena 2020 research grant - Urology Research Foundation (FIU) PI-0319-201

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

Type 2 Diabetes-Related Variants Influence the Risk of Developing Prostate Cancer:A Population-Based Case-Control Study and Meta-Analysis

In this study, we have evaluated whether 57 genome-wide association studies (GWAS)-identified common variants for type 2 diabetes (T2D) influence the risk of developing prostate cancer (PCa) in a population of 304 Caucasian PCa patients and 686 controls. The association of selected single nucleotide polymorphisms (SNPs) with the risk of PCa was validated through meta-analysis of our data with those from the UKBiobank and FinnGen cohorts, but also previously published genetic studies. We also evaluated whether T2D SNPs associated with PCa risk could influence host immune responses by analysing their correlation with absolute numbers of 91 blood-derived cell populations and circulating levels of 103 immunological proteins and 7 steroid hormones. We also investigated the correlation of the most interesting SNPs with cytokine levels after in vitro stimulation of whole blood, peripheral mononuclear cells (PBMCs), and monocyte-derived macrophages with LPS, PHA, Pam3Cys, and Staphylococcus Aureus. The meta-analysis of our data with those from six large cohorts confirmed that each copy of the FTOrs9939609A, HNF1Brs7501939T, HNF1Brs757210T, HNF1Brs4430796G, and JAZF1rs10486567A alleles significantly decreased risk of developing PCa (p = 3.70 × 10−5, p = 9.39 × 10−54, p = 5.04 × 10−54, p = 1.19 × 10−71, and p = 1.66 × 10−18, respectively). Although it was not statistically significant after correction for multiple testing, we also found that the NOTCH2rs10923931T and RBMS1rs7593730 SNPs associated with the risk of developing PCa (p = 8.49 × 10−4 and 0.004). Interestingly, we found that the protective effect attributed to the HFN1B locus could be mediated by the SULT1A1 protein (p = 0.00030), an arylsulfotransferase that catalyzes the sulfate conjugation of many hormones, neurotransmitters, drugs, and xenobiotic com-pounds. In addition to these results, eQTL analysis revealed that the HNF1Brs7501939, HNF1Brs757210, HNF1Brs4430796, NOTCH2rs10923931, and RBMS1rs7593730 SNPs influence the risk of PCa through the modulation of mRNA levels of their respective genes in whole blood and/or liver. These results confirm that functional TD2-related variants influence the risk of developing PCa, but also highlight the need of additional experiments to validate our functional results in a tumoral tissue context