Metabolomic Profile in Patients with Malignant Disturbances of the Prostate: An Experimental Approach / Perfil metabolómico en pacientes con alteraciones malignas de la próstata: Un enfoque experimental

Purpose To identify metabolites in humans that can be associated with the presence of malignant disturbances of the prostate. Methods In the present study, we selected male patients aged between 46 and 82 years who were considered at risk of prostate cancer due to elevated levels of prostate-specific antigen (PSA) or abnormal results on the digital rectal examination. All selected patients came from two university hospitals (Hospital Universitario del Valle and Clínica Rafael Uribe Uribe) and were divided into 2 groups: cancer (12 patients) and non-cancer (20 patients). Cancer was confirmed by histology, and none of the patients underwent any previous treatment. Standard protocols were applied to all the collected blood samples. The resulting plasma samples were kept at -80°C, and a profile of each one was acquired by nuclear magnetic resonance (NMR) using established experiments. Multivariate analyses were applied to this dataset, first to establish the quality of the data and identify outliers, and then, to model the data. Results We included 12 patients with cancer and 20 without it. Two patients were excluded due to contamination with ethanol. The remaining ones were used to build an Orthogonal Projections to Latent Structures Discriminant Analysis (OPLS-DA) model (including 15 non-cancer and 10 cancer patients), with acceptable discrimination (Q2 = 0.33). This model highlighted the role of lactate and lipids, with a positive association of these two metabolites and prostate cancer. Conclusions The primary discriminative metabolites between patients with and without prostate cancer were lactate and lipids. These might be the most reliable biomarkers to trace the development of cancer in the prostate.

Objetivo Identificar metabolitos en humanos que pueden estar asociados con la presencia de alteraciones malignas de la próstata. Métodos Se incluyeron muestras de pacientes masculinos entre 46 y 82 años y que se consideraron en riesgo de cáncer de próstata debido a la elevación del antígeno prostático específico (PSA) o el examen rectal anormal. Todos los pacientes seleccionados procedían de dos hospitales universitarios (Hospital Universitario del Valle y Clínica Rafael Uribe Uribe) y se dividieron en dos grupos: Oncológicos (12) vs no oncológicos (20). El cáncer fue confirmado por histología, y ninguno de ellos recibió tratamiento previo. Se aplicaron protocolos estándar a todas las muestras de sangre recolectadas. Las muestras de plasma resultantes se mantuvieron a −80°C y se adquirió un perfil de cada muestra mediante RMN. Se aplicaron análisis multivariantes a este conjunto de datos, primero para establecer la calidad de los datos e identificar valores atípicos, y para modelar los datos. Resultados Se incluyeron 12 pacientes con cáncer y 20 pacientes sin cáncer. Dos pacientes fueron excluidos por contaminación con etanol. Los restantes se utilizaron para construir un modelo OPLS-DA (15 pacientes no oncológicos y diez oncológicos), con una discriminación aceptable (Q2 = 0,33). Este modelo destacó el papel del lactato y los lípidos, encontrando una asociación positiva entre estos dos metabolitos y el cáncer de próstata. Conclusiones Los principales metabolitos discriminativos entre pacientes con cáncer de próstata versus no cáncer fueron el lactato y los lípidos. Estos podrían ser los biomarcadores más confiables para rastrear el desarrollo del cáncer en la próstata.

Role of salvage lymph node dissection in patients previously treated for prostate cancer: systematic review

ABSTRACT Prostate cancer is the most common invasive cancer in men. Radical prostatectomy (RP) is a definitive treatment option, but biochemical recurrence can reach 40%. Salvage lymphadenectomy is a relatively recent approach to oligometasis and has been rapidly diffused primarily due to improvement in imaging diagnosis and results showing possibly promising therapy. A systematic literature review was performed in March 2020, according to the PRISMA statement. We excluded studies with patients with suspicion or confirmation of visceral and / or bone metastases. A total of 27 articles were included in the study. All studies evaluated were single arm, and there were no randomized studies in the literature. A total of 1,714 patients received salvage lymphadenectomy after previous treatment for localized prostate cancer. RP was the most used initial therapeutic approach, and relapses were based on PET / CT diagnosis, with Coline-11C being the most widely used radiopharmaceutical. Biochemical response rates ranged from 0% to 80%. The 5 years - Free Survival Biochemical recurrence was analyzed in 16 studies with rates of 0% up to 56.1%. The articles do not present high levels of evidence to draw strong conclusions. However, even if significant rates of biochemical recurrence are not evident in all studies, therapy directed to lymph node metastases may present good oncological results and postpone the onset of systemic therapy. The long-term impact in overall survival and quality of life, as well as the best strategies for case selection remains to be determined.

Prostate Cancer Screening in Brazil: a single center experience in the public health system

ABSTRACT Purpose: Incidence and mortality of prostate cancer (PCa) are still increasing in developing countries. Limited access to the health system or more aggressive disease are potential reasons for this. Ethnic and social differences in developed countries seem to make inappropriate to extrapolate data from other centers. We aim to report the epidemiological profile of a PSA-screened population from a cancer center in Brazil. Materials and Methods: We retrospectively selected 9.692 men enrolled in a PCa prevention program, comprising total PSA level and digital rectal examination at the first appointment, associated with complementary tests when necessary. Men aged over 40 years-old were included after shared decision-making process. Prostate biopsy (TRUS) was performed when clinically suspected for PCa. After the diagnosis, patients underwent appropriate treatment. Results: TRUS was performed in 5.5% of men and PCa incidence was 2.6%. Overall ratio between number of patients who needed to be screened in order to diagnose one cancer was 38.9 patients, with 2.1 biopsies performed to diagnose a cancer. Positive predictive value (PPV) of TRUS biopsy in this strategy was 47.2%, varying from 38.5% (<50 years-old) to 60% (>80 years-old). We evidenced 70 patients (27.9%) classified as low risk tumors, 74 (29.5%) as intermediate risk, and 107 (42.6%) as high-risk disease. Conclusions: PSA-screening remains controversial in literature. In front of a huge miscegenated people and considering the big proportion of high-risk PCa, even in young men diagnosed with the disease, it is imperative to inform patients and health providers about these data particularities in Brazil.

Investigação do tempo entre primeira consulta e diagnóstico e do tempo entre diagnóstico e início de tratamento e fatores associados em pacientes com câncer de pulmão, mama e próstata, atendidos em um hospital público de referência em Porto Alegre, de 2012-2016 / Investigation of the time between first consultation and diagnosis and of time between diagnosis and initiation of treatment and factors associated in patients with lung, breast and prostate, treated at a public referral hospital in Porto Alegre, from 2012-2016

Introdução: em 2018 o câncer causou 9 milhões de mortes, das quais 70% em países de baixa e média renda. As desigualdades sociais associadas ao câncer potencializam o atraso no acesso ao diagnóstico e início do tratamento e consequente aumento de letalidade. Objetivo: investigar o tempo entre a primeira consulta e o diagnóstico e o tempo entre o diagnóstico e o início do tratamento e possíveis fatores associados. Métodos: emprego de registros da base de dados hospitalar de um hospital de referência no Sul do Brasil, período 2012-2016. Os fatores associados incluíram variáveis sociodemográficas e clínicas. Os tempos investigados foram categorizados a partir de legislação específica. Comparações foram realizadas por meio do teste de homogeneidade de proporções baseado na estatística de qui- quadrado de Pearson. Os fatores associados aos tempos foram investigados por modelo de regressão de Poisson com variação robusta. Resultados: a amostra de casos estudados totaliza 2.606 pessoas, sendo 1.023 (39,3%) casos com câncer de mama, 983 (37,7%) câncer de pulmão e 600 (23%) câncer de próstata. Nos casos de câncer de pulmão há predomínio de pessoas com idade de 50 a 79 anos (86,8%), sexo masculino (57,6%), branca (88,9%), ensino fundamental completo (76,3%), estadiamento 4 (60,3%) e 45,1% evoluiu para o óbito. As pessoas com estadiamento 0 apresentaram o maior RR do tempo superior a 30 dias entre a primeira consulta e o diagnóstico (4,33 vezes maior do que para pacientes com estadiamento 4 - referência); o maior RR (1,76) do tempo superior a 60 dias entre o diagnóstico e o início do tratamento foi no grupo de estadiamento 2. Nos casos de câncer de mama há predomínio de pessoas com idade de 50 e 69 anos (50,8%), branca (92,8%), ensino fundamental completo (55,4%), estadiamento 2 (46,4%) e 6,6% evoluiu para o óbito. No desfecho tempo entre a primeira consulta e o diagnóstico acima de 30 dias os pacientes, quando comparados aos pacientes com estadiamento 4 (referência), o estadiamento 0 apresentou o maior RR ( 8,81); n o desfecho tempo entre o diagnóstico e o início de tratamento acima de 60 dias, pacientes com estadiamento 1 apresentaram o maior RR (2,46). Nos casos de câncer de próstata há predomínio de pessoas com idade de 60 a 69 anos (43,4%), branca (89,8%), ensino fundamental completo (76,5%), estadiamento classificação 2 (59,5%) e 5,8% evoluiu para o óbito. No desfecho de tempo entre a primeira consulta e o diagnóstico acima de 30 dias o estadiamento 1 apresentou o maior RR (1,50); no desfecho de tempo entre a primeira consulta e o diagnóstico acima de 60 dias, os pacientes com estadiamento 1 apresentaram o maior RR (2,45). Conclusão: o desfecho de tempo entre a primeira consulta e o diagnóstico acima de 30 dias, para os casos de câncer de pulmão, permaneceram no modelo como variáveis explicativas do desfecho a faixa etária (p = 0,05) e o estadiamento (p < 0,001); para o desfecho de tempo entre o diagnóstico e o início do tratamento acima de 60 dias, permaneceram variáveis explicativas do desfecho a faixa etária (p = 0,024) e o estadiamento (p = 0,03) e apresentaram-se com RR de proteção as faixas etárias de 20 a 49 anos (RR = 0,29, IC95% = 0,20 ­ 0,55) e 60 a 69 anos (RR = 0,53, IC95% = 0,31 ­ 0,90). Os respectivos riscos relativos brutos e ajustados para o desfecho tempo entre a primeira consulta e o diagnóstico acima de 30 dias, para os casos de câncer de mama ajustado por faixa etária, raça/cor e escolaridade, mostraram que o RR de estadiamento diminuiu a medida que a classificação aumentou; para o desfecho tempo entre o diagnóstico e o início de tratamento acima de 60 dias, permaneceram no modelo explicativo final as variáveis faixa etária (p = 0,003) e estadiamento (p = 0,003). O desfecho de tempo entre a primeira consulta e o diagnóstico acima de 30 dias, para os casos de câncer de próstata, o estadiamento ficou a variável explicativa do tempo entre a primeira consulta e o diagnóstico, com significância estatística para as classificações 1 e 2 quando comparadas à classificação 4; para o desfecho de tempo entre o diagnóstico e o início do tratamento acima de 60 dias, permaneceu no modelo explicativo somente a variável estadiamento.

Introdution: in 2018, cancer caused 9 million deaths, of which 70% in low- and middle-in- come countries. The social inequalities associated with cancer enhance the delay in access to diagnosis and initiation of treatment and the consequent increase in lethality. Objective: to investigate the time between the first consultation and diagnosis and the time between diagnosis and the start of treatment and possible associated factors. Methods: use of hos- pital database records from a reference hospital in southern Brazil, period 2012-2016. Asso- ciated factors included sociodemographic and clinical variables. The investigated times were categorized based on specific legislation. Comparisons were performed using the ho- mogeneity of proportions test based on Pearson's chi-square statistics. Factors associated with times were investigated using a Poisson regression model with robust variation. Re- sults: the sample of cases studied totals 2,606 people, with 1,023 (39.3%) cases with breast cancer, 983 (37.7%) lung cancer and 600 (23%) prostate cancer. In cases of lung cancer, there is a predominance of people aged 50 to 79 years (86.8%), male (57.6%), white (88.9%), complete elementary school (76.3%) , stage 4 (60.3%) and 45.1% progressed to death. People with stage 0 had the highest RR for the time greater than 30 days between the first consultation and diagnosis (4.33 times higher than for patients with stage 4 - reference); the highest RR (1.76) for the time greater than 60 days between diagnosis and the start of treatment was in the stage 2 group. In cases of breast cancer there is a predominance of people aged 50 and 69 years (50.8 %), white (92.8%), completed elementary school (55.4%), stage 2 (46.4%) and 6.6% progressed to death. In the outcome time between the first consultation and the diagnosis above 30 days, patients, when compared to patients with stage 4 (reference), stage 0 had the highest RR (8.81); in the outcome time between diagnosis and start of treatment above 60 days, patients with stage 1 had the highest RR (2.46). In cases of prostate cancer, there is a predominance of people aged 60 to 69 years (43.4%), white (89.8%), complete elementary education (76.5%), stage 2 classification (59.5%) and 5.8% progressed to death. In the outcome of time between the first consultation and diagnosis over 30 days, stage 1 had the highest RR (1.50); in the outcome of time between the first consultation and the diagnosis above 60 days, patients with stage 1 had the highest RR (2.45). Conclusion: The time outcome between the first consultation and the diagnosis above 30 days, for cases of lung cancer, remained in the model as explanatory variables of the outcome age (p = 0.05) and staging (p < 0.001); for the outcome of time between diagnosis and beginning of treatment above 60 days, the explanatory variables of the outcome were age (p = 0.024) and staging (p = 0.03) and presented with RR of protection as age groups from 20 to 49 years (RR = 0.29, 95%CI = 0.20 - 0.55) and 60 to 69 years (RR = 0.53, 95%CI = 0.31 - 0.90). The respective crude and adjusted relative risks for the outcome time between the first visit and the diagnosis above 30 days, for cases of breast cancer adjusted for age group, race/color and education, showed that the RR for staging decreased the measure. that the rating has increased; for the outcome time between diagnosis and start of treatment above 60 days, the variables age group (p = 0.003) and stage (p = 0.003) remained in the final explanatory model. The outcome of time between the first visit and diagnosis over 30 days, for cases of prostate cancer, staging was the explanatory variable of the time between the first visit and diagnosis, with statistical significance for classifications 1 and 2 when compared to classification 4; for the outcome of time between diagnosis and start of treatment above 60 days, only the staging variable remained in the explanatory model.

OTUB1 Promotes Progression and Proliferation of Prostate Cancer via Deubiquitinating and Stabling Cyclin E1.

Background: Prostate cancer (PCa) is currently the most common cancer among males worldwide. It has been reported that OTUB1 plays a critical role in a variety of tumors and is strongly related to tumor proliferation, migration, and clinical prognosis. The aim of this research is to investigate the regulatory effect of OTUB1 on PCa proliferation and the underlying mechanism. Methods: Using the TCGA database, we identified that OTUB1 was up-regulated in PCa, and observed severe functional changes in PC3 and C4-2 cells through overexpression or knock down OTUB1. Heterotopic tumors were implanted subcutaneously in nude mice and IHC staining was performed on tumor tissues. The relationship between OTUB1 and cyclin E1 was identified via Western blotting and immunoprecipitations assays. Results: We found that the expression of OTUB1 in PCa was significantly higher than that in Benign Prostatic Hyperplasia (BPH). Overexpression OTUB1 obviously promoted the proliferation and migration of PC3 and C4-2 cells via mediating the deubiquitinated Cyclin E1, while OTUB1 knockout has the opposite effect. The nude mice experiment further explained the above conclusions. We finally determined that OTUB1 promotes the proliferation and progression of PCa via deubiquitinating and stabling Cyclin E1. Conclusions: Our findings reveal the critical role of OTUB1 in PCa, and OTUB1 promotes the proliferation and progression of PCa via deubiquitinating and stabilizing Cyclin E1. Blocking OTUB1/Cyclin E1 axis or applying RO-3306 could significantly repress the occurrence and development of PCa. OTUB1/Cyclin E1 axis might provide a new and potential therapeutic target for PCa.

Comparison of PET/MRI with multiparametric MRI in diagnosis of primary prostate cancer: A meta-analysis.

OBJECTIVE: This meta-analysis aimed to compare the diagnostic performance of positron emission tomography (PET)/MRI using various radiotracers with multiparametric (mp) MRI for detection of primary prostate cancer (PCa). METHODS: A systematic literature search up to January 2019 was performed to identify studies that evaluated the diagnostic value of PET/MRI and mpMRI for detection of PCa in the same patient cohorts and had sufficient data to construct 2 × 2 contingency tables for true-positive (TP), false-positive (FP), false-negative (FN), and true-negative (TN) results. The quality of each study was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 tool, and pooled sensitivity (SEN) and specificity (SPE) were calculated. Summary receiver operating characteristic (ROC) curves and area under the curves (AUCs) were used to compare the performances of PET/MRI and mpMRI. RESULTS: We identified 9 eligible studies that included a total of 353 patients. PET/MRI had a SEN of 0.783 (95% CI, 0.758-0.807) and a SPE of 0.899 (95% CI, 0.879-0.917), and mpMRI had a SEN of 0.603 (95% CI, 0.574-0.631) and a SPE of 0.887 (95% CI, 0.866-0.906). PET/MRI had a higher AUC than mpMRI (0.9311, 95% CI, 0.8990-0.9632 vs. 0.8403, 95% CI, 0.7864-0.8942; P = 0.0036). There was no notable publication bias, but there was medium heterogeneity in outcomes. The meta-regression analysis showed the major potential cause of heterogeneity was the use of region-based rather than lesion-based analysis. CONCLUSION: PET/MRI has very good diagnostic performance and outperforms mpMRI for the diagnosis of primary PCa.

Combining the Prostate Cancer Risk Index (PRIX) with the Presence of Secondary Circulating Prostate Cells to Predict the Risk of Biochemical Failure after Radical Prostatectomy for Prostate Cancer

Introduction: The use of pre- and post-surgery variables has been used to create nomograms in order to identify patients at high risk of treatment failure. The PRIX nomogram is one such device; we compare the PRIX nomogram with the presence of secondary circulating prostate cells to predict those men who will undergo treatment failure. Methods and Patients: Men who underwent radical prostatectomy for prostate cancer entered the study. The PRIX score was calculated from the total serum PSA pre-surgery, the biopsy Gleason score and clinical stage. Circulating prostate cells were detected from venous blood one month after surgery, using differential gel centrifugation and standard immunocytochemistry with anti-PSA. A test was considered positive when 1 CPC/blood sample was detected. Patients were followed up for five years and biochemical failure was defined as a serum PSA >0.2ng/ml. Kaplan-Meier and Cox proportional models were used to calculate survival curves. Results: 321 men participated, of whom 131 (40.8%) underwent biochemical failure within 5 years. A higher PRIX score was associated with increased failure risk, as was the presence of CPCs. The predictive power of CPCs was significantly higher than the PRIX score. Combining the two methods, for equal PRIX scores, scores but CPC positive had a worse biochemical failure free survival than men with high PRIX scores but CPC negative. For men with PRIX scores of ≥4 the use of CPC detection did not aid in the clinical decision making process. For those with PRIX scores of 0 and 1, CPC detection identified men with a high risk of treatment failure. Conclusions: The combined PRIX/CPC score improved the predictive values of men at high risk of biochemical failure. Both are simple systems that could be incorporated in a general hospital. Further multicenter studies are warranted to confirm these results.

Efficient multicistronic co-expression of hNIS and hTPO in prostate cancer cells for nonthyroidal tumor radioiodine therapy.

Radioiodine therapy has proven to be a safe and effective approach in the treatment of differentiated thyroid cancer. Similar treatment strategies have been exploited in nonthyroidal malignancies by transfecting hNIS gene into tumor cells or xenografts. However, rapid radioiodine efflux is often observed after radioiodine uptake, limiting the overall antitumor effects. In this study, we aimed at constructing multicistronic co-expression of hNIS and hTPO genes in tumor cells to enhance the radioiodine uptake and prolong the radioiodine retention. Driven by the cytomegalovirus promoter, hNIS and hTPO were simultaneously inserted into the expression cassette of adenoviral vector. An Ad5 viral vector (Ad-CMV-hTPO-T2A-hNIS) was assembled as a gene therapy vehicle by Gateway technology and 2A method. The co-expression of hNIS and hTPO genes was confirmed by a double-label immunofluorescence assay. The radioiodine ((125)I) uptake and efflux effects induced by co-expression of hNIS and hTPO genes were determined in transfected and non-transfected PC-3 cells. Significantly higher uptake (6.58 ± 0.56 fold, at 1 h post-incubation) and prolonged retention (5.47 ± 0.36 fold, at 1 h of cell efflux) of radioiodine ((125)I) were observed in hNIS and hTPO co-expressed PC-3 cells as compared to non-transfected PC-3 cells. We concluded that the new virus vector displayed favorable radioiodine uptake and retention properties in hNIS-hTPO transfected PC-3 cells. Our study will provide valuable information on improving the efficacy of hNIS-hTPO co-mediated radioiodine gene therapy.

The value of screening tests for detection of prostate cancer in 1000 saudi men.

OBJECTIVES: Predicting the value of screening tests in the detection of prostate cancer in Saudi men. METHODS: The study was conducted in King Fahd Hospital of the University, Al-Khobar. Total, free and percent free serum prostate specific antigen (PSA) were measured in Saudi men above the age of 45 years. Transrectal ultrasonography (TRUS) and needle biopsy were performed on those with suspicious digital rectal examination (DRE) and or PSA >4ng/ml. A group of 849 Saudi men were with normal PSA levels and normal DRE were considered cancer free.. The remaining 151 patients with PSA >4ng/ml were suspicious for prostate cancer. Only 55 patients agreed to have TRUS and needle biopsy RESULTS: PSA testing and DRE had the highest positive predictive value but this value dropped when TRUS was added. CONCLUSION: PSA and DRE are the main tests for the detection of prostate cancer, while TRUS is valuable when sample are taken of a wide area of prostate tissue in men at high risk of cancer.