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1.
Anticancer Res ; 41(4): 2101-2110, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33813420

RESUMEN

BACKGROUND/AIM: To evaluate if topical support therapy during static-intensity modulated radiotherapy (sIMRT) course is able to equal the characteristic minimum risk for radiation proctitis of Image-guided volumetric modulated arc therapy (IG-VMAT) treatment among localized prostate cancer patients. PATIENTS AND METHODS: Rectal toxicity data of the above patients were retrospectively collected throughout three different clinical periods at our Radiotherapy Deparment: from October 2011 to December 2012, prostate cancer patients were treated with sIMRT and in advance supported by means of daily topical corticosteroids; from January 2013 to November 2016, topical corticosteroids were replaced by daily hyaluronic acid enemas; from December 2016 to May 2018 eligible patients were treated with newly introduced IG-VMAT supported by only on-demand topical corticosteroids. RESULTS: Among 359 eligible patients, IG-VMAT was proven generally more effective than sIMRT supported by topical medications in terms of proctitis reduction, although without clinical and practical relevance. CONCLUSION: Topical medications might have a role in radiation proctitis prevention.


Asunto(s)
Antiinflamatorios/administración & dosificación , Proctitis/prevención & control , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/radioterapia , Radioterapia de Intensidad Modulada , Administración Tópica , Anciano , Anciano de 80 o más Años , Beclometasona/administración & dosificación , Enema/métodos , Humanos , Ácido Hialurónico/administración & dosificación , Italia , Masculino , Persona de Mediana Edad , Tratamientos Conservadores del Órgano/métodos , Proctitis/etiología , Neoplasias de la Próstata/patología , Hipofraccionamiento de la Dosis de Radiación , Traumatismos por Radiación/prevención & control , Planificación de la Radioterapia Asistida por Computador/métodos , Radioterapia Guiada por Imagen/efectos adversos , Radioterapia Guiada por Imagen/métodos , Radioterapia de Intensidad Modulada/efectos adversos , Radioterapia de Intensidad Modulada/métodos , Estudios Retrospectivos
2.
Anticancer Res ; 41(4): 2183-2186, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33813431

RESUMEN

BACKGROUND/AIM: The aim of this study was to identify simple and reliable factors to detect clinically insignificant prostate cancer (PC) for avoiding immediate prostate biopsies using biparametric magnetic resonance imaging (MRI), which consists of T2-weighted and diffusion-weighted imaging. PATIENTS AND METHODS: We retrospectively evaluated 427 men with suspected PC, who underwent biparametric MRI and standard 12-core transrectal prostate biopsy. MRI and prostate specific antigen density (PSAD) were analysed. To evaluate the combination of the two parameters, patients were divided into three groups (Group A: MRI negative and PSAD <0.23, Group B: MRI positive or PSAD ≥0.23, Group C: MRI positive and PSAD ≥0.23). A grade of ≥2 was defined as clinically significant PC. RESULTS: Clinically significant PC was detected in 46.5% of men with positive MRI findings, and 60.0% of men with PSAD ≥0.23. When combining MRI and PSAD, detection rates of clinically significant PC were 10.0%, 28.4% and 65.3% in group A, B and, C, respectively. CONCLUSION: Negative biparametric MRI findings with PSAD <0.23 might be a reliable evidence for avoiding immediate prostate biopsies.


Asunto(s)
Imagen por Resonancia Magnética/métodos , Antígeno Prostático Específico/análisis , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/patología , Adulto , Anciano , Anciano de 80 o más Años , Biopsia con Aguja Gruesa/métodos , Imagen de Difusión por Resonancia Magnética , Humanos , Biopsia Guiada por Imagen , Pruebas Inmunológicas , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Cuidados Preoperatorios , Próstata/patología , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/metabolismo , Estudios Retrospectivos , Carga Tumoral , Ultrasonografía Intervencional
3.
Nat Commun ; 12(1): 1426, 2021 03 03.
Artículo en Inglés | MEDLINE | ID: mdl-33658518

RESUMEN

Metastatic prostate cancer (mPC) comprises a spectrum of diverse phenotypes. However, the extent of inter- and intra-tumor heterogeneity is not established. Here we use digital spatial profiling (DSP) technology to quantitate transcript and protein abundance in spatially-distinct regions of mPCs. By assessing multiple discrete areas across multiple metastases, we find a high level of intra-patient homogeneity with respect to tumor phenotype. However, there are notable exceptions including tumors comprised of regions with high and low androgen receptor (AR) and neuroendocrine activity. While the vast majority of metastases examined are devoid of significant inflammatory infiltrates and lack PD1, PD-L1 and CTLA4, the B7-H3/CD276 immune checkpoint protein is highly expressed, particularly in mPCs with high AR activity. Our results demonstrate the utility of DSP for accurately classifying tumor phenotype, assessing tumor heterogeneity, and identifying aspects of tumor biology involving the immunological composition of metastases.


Asunto(s)
Perfilación de la Expresión Génica/métodos , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Antígenos B7/genética , Antígeno B7-H1/genética , Antígeno CTLA-4/genética , Regulación Neoplásica de la Expresión Génica , Receptor 2 Celular del Virus de la Hepatitis A/genética , Humanos , Masculino , Adhesión en Parafina , Fenotipo , Receptor de Muerte Celular Programada 1/genética , Neoplasias de la Próstata/metabolismo , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Análisis de Matrices Tisulares , Transcriptoma
4.
Lancet Oncol ; 22(3): 402-410, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33662287

RESUMEN

BACKGROUND: The international Intermediate Clinical Endpoints in Cancer of the Prostate working group has established metastasis-free survival as a surrogate for overall survival in localised prostate cancer based on the findings of 19 predominantly radiotherapy-based trials. We sought to comprehensively assess aggregate trial-level performance of commonly reported intermediate clinical endpoints across all randomised trials in localised prostate cancer. METHODS: For this meta-analysis, we searched PubMed for all trials in localised or biochemically recurrent prostate cancer published between Jan 1, 1970, and Jan 15, 2020. Eligible trials had to be randomised, therapeutic, reporting overall survival and at least one intermediate clinical endpoint, and with a sample size of at least 70 participants. Trials of metastatic disease were excluded. Intermediate clinical endpoints included biochemical failure, local failure, distant metastases, biochemical failure-free survival, progression-free survival, and metastasis-free survival. Candidacy for surrogacy was assessed using the second condition of the meta-analytical approach (ie, correlation of the treatment effect of the intermediate clinical endpoint and overall survival), using R2 weighted by the inverse variance of the log intermediate clinical endpoint hazard ratio. The intermediate clinical endpoint was deemed to be a surrogate for overall survival if R2 was 0·7 or greater. FINDINGS: 75 trials (53 631 patients) were included in our analysis. Median follow-up was 9·1 years (IQR 5·7-10·6). Biochemical failure (R2 0·38 [95% CI 0·11-0·64]), biochemical failure-free survival (R2 0·12 [0·0030-0·33]), biochemical failure and clinical failure (R2 0·28 [0·0045-0·65]), and local failure (R2 0·085 [0·00-0·37]) correlated poorly with overall survival. Progression-free survival (R2 0·46 [95% CI 0·22-0·67]) showed moderate correlation with overall survival, and metastasis-free survival (R2 0·78 [0·59-0·89]) correlated strongly. INTERPRETATION: Intermediate clinical endpoints based on biochemical and local failure did not meet the second condition of the meta-analytical approach and are not surrogate endpoints for overall survival in localised prostate cancer. Our findings validate metastasis-free survival as the only identified surrogate endpoint for overall survival to date. FUNDING: Prostate Cancer Foundation and National Institutes of Health.


Asunto(s)
Biomarcadores/análisis , Recurrencia Local de Neoplasia/mortalidad , Neoplasias de la Próstata/mortalidad , Anciano , Terapia Combinada , Estudios de Seguimiento , Humanos , Metástasis Linfática , Masculino , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/terapia , Pronóstico , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/terapia , Tasa de Supervivencia
5.
Nat Commun ; 12(1): 1946, 2021 03 29.
Artículo en Inglés | MEDLINE | ID: mdl-33782401

RESUMEN

Numerous substrates have been identified for Type I and II arginine methyltransferases (PRMTs). However, the full substrate spectrum of the only type III PRMT, PRMT7, and its connection to type I and II PRMT substrates remains unknown. Here, we use mass spectrometry to reveal features of PRMT7-regulated methylation. We find that PRMT7 predominantly methylates a glycine and arginine motif; multiple PRMT7-regulated arginine methylation sites are close to phosphorylations sites; methylation sites and proximal sequences are vulnerable to cancer mutations; and methylation is enriched in proteins associated with spliceosome and RNA-related pathways. We show that PRMT4/5/7-mediated arginine methylation regulates hnRNPA1 binding to RNA and several alternative splicing events. In breast, colorectal and prostate cancer cells, PRMT4/5/7 are upregulated and associated with high levels of hnRNPA1 arginine methylation and aberrant alternative splicing. Pharmacological inhibition of PRMT4/5/7 suppresses cancer cell growth and their co-inhibition shows synergistic effects, suggesting them as targets for cancer therapy.


Asunto(s)
Neoplasias de la Mama/genética , Neoplasias Colorrectales/genética , Ribonucleoproteína Nuclear Heterogénea A1/genética , Neoplasias de la Próstata/genética , Proteína-Arginina N-Metiltransferasas/genética , Empalme Alternativo , Secuencia de Aminoácidos , Arginina/metabolismo , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Ciclo Celular/efectos de los fármacos , Ciclo Celular/genética , Línea Celular Tumoral , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Inhibidores Enzimáticos/farmacología , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Células HEK293 , Ribonucleoproteína Nuclear Heterogénea A1/antagonistas & inhibidores , Ribonucleoproteína Nuclear Heterogénea A1/metabolismo , Humanos , Masculino , Metilación/efectos de los fármacos , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Unión Proteica , Procesamiento Proteico-Postraduccional , Proteína-Arginina N-Metiltransferasas/antagonistas & inhibidores , Proteína-Arginina N-Metiltransferasas/metabolismo , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Empalmosomas/efectos de los fármacos , Empalmosomas/genética , Empalmosomas/metabolismo , Especificidad por Sustrato
6.
Orv Hetil ; 162(13): 483-487, 2021 03 28.
Artículo en Húngaro | MEDLINE | ID: mdl-33774598

RESUMEN

Összefoglaló. Bevezetés: Az utóbbi években az oligometastaticus prosztatadaganatok kezelése során a szisztémás kezelés mellett egyre gyakrabban végzik a primer tumor lokális kezelését is. Célkituzés: A szerzok a tanulmányban a cytoreductiv radikális prostatectomia szerepét vizsgálták az oligometastaticus prosztatadaganatok kezelése során. Módszer: 2012. 01. 01. és 2019. 01. 01. között összesen hét betegben végeztek cytoreductiv radikális prostatectomiát oligometastaticus prosztatadaganat esetében. A betegek átlagos életkora 64 év, az átlagos PSA-koncentráció 43 ng/ml volt. Az áttétek száma minden beteg vonatkozásában maximum három volt, és valamennyi esetben csontáttét volt jelen. A betegek androgéndeprivatiós hormonkezelést kaptak, és közülük négy esetben már a mutét elott elkezdték a hormonterápiát. Négy betegnél a csontmetastasisok miatt az áttétek sugárkezelése is megtörtént. Eredmények: A cytoreductiv prostatectomia szövettana öt esetben igazolt lokálisan elorehaladott (pT3) daganatot, és két alkalommal marginpozitivitás volt jelen. Emiatt öt beteg kapott adjuváns lokális irradiációt a metastasisok besugárzásán kívül. A mutétet követoen biokémiai progresszió egy esetben jelentkezett. Ennek oka lokális recidíva volt, mely miatt a beteg 'salvage' irradiációt kapott. Az átlagosan 38 hónapos utánkövetés során új metastasist nem diagnosztizáltak, és tumor okozta halálozás nem fordult elo. Következtetés: A cytoreductiv prostatectomia oligometastaticus prosztatarákos betegek kezelésében - válogatott beteganyagon - megvalósítható lehetoség. Ugyanakkor a cytoreductiv prostatectomia elonyei a tumorprogresszió szempontjából még nem egyértelmuek, ennek eldöntéséhez további vizsgálatok szükségesek. Orv Hetil. 2021; 162(13): 483-487. INTRODUCTION: In recent years, in addition to systemic therapy, local treatment of primary tumor has become increasingly common in the treatment of oligometastatic prostate cancers. Objectve: The authors measured the role of cytoreductive radical prostatectomy in the treatment of oligometastatic prostate carcinoma. METHODS: From Janury 2012 to January 2019, they performed cytoreductive radical prostatectomy in seven patients with oligometastatic prostate cancer. The mean age of the patients was 64 years, and the mean PSA value was 43 ng/ml. The patients had maximum three distant metastases and all metastases were localized to the bones. The patients received androgene deprivation therapy and this treatment was started before the surgery in four cases. Irradiation of the bone metastasis was performed in four cases. RESULTS: The histology of the cytoreductive radical prostatectomy showed locally advanced tumor (pT3) in five patients and margin-positive status was present in two cases. Hence, adjuvant irradiation was administered locally in five patients in addition to the irradiation of bone metastases. Biochemical progression was detected in one patient during the follow-up period. It was caused by local recurrence of the tumor and the patient was treated with salvage irradiation. During the 38 months follow-up period neither new distant metastasis nor cancer-related mortality was detected. CONCLUSION: The cytoreductive radical prostatectomy is a feasible option in selected cases with oligometastatic prostate cancer. However, the benefits of cytoreductive radical prostatectomy regarding tumor progression are not clear yet and further studies are required. Orv Hetil. 2021; 162(13): 483-487.


Asunto(s)
Procedimientos Quirúrgicos de Citorreducción , Prostatectomía , Neoplasias de la Próstata , Estudios de Factibilidad , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Prostatectomía/métodos , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/cirugía , Resultado del Tratamiento
7.
Cancer Treat Rev ; 95: 102176, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33743409

RESUMEN

AIMS: The best therapeutic approach for local relapses of previously irradiated prostate cancer (PC) is still not defined. Re-irradiation (Re-I) could offer a chance of cure for highly selected patients, although high quality evidences are lacking. The aim of our study is to provide a literature review on efficacy and safety of Re-I. METHODS: Only studies where Re-I field overlaps with previous radiotherapy were considered. To determine 2 and 4 years overall mortality (OM), 2 and 4 years biochemical failure (BF) and pooled acute and late G ≥ 3 toxicities rate, a meta-analysis over single arm study was performed. RESULTS: Thirty-eight studies with 1194 patients were included. Median follow-up from Re-I was 30 months (10-94 months). Brachytherapy (BRT) was the most used Re-I technique (27 studies), followed by Stereotactic Body Radiotherapy (SBRT) (9) and External Beam Radiation Therapy (EBRT) (2). Re-I prescription doses ranged from 19 Gy in single HDR fraction to 145 Gy (interstitial BRT). The pooled 2 and 4 years OM rates were 2.1% (95%CI:1.1-3.7%, P < 0.001) and 12.5% (95%CI:8.1-19.5%; P < 0.001). The pooled 2 years BF rate was 24% (95% CI: 19.1-30.2%, P < 0.001). The pooled 4 years BF was 35.6% (95% CI: 28.7-44.3%, P < 0.001). The pooled result of G ≥ 3 acute toxicity was 1.4% (95%CI: 0.7-3%, P < 0.001). One hundred and three G ≥ 3 late adverse events were reported, with a pooled result of G ≥ 3 late toxicity of 8.7% (95%CI: 5.8-13%, P < 0.001). CONCLUSIONS: Re-I of local failures from PC showed promising OM and biochemical control rates with a safe toxicity profile.


Asunto(s)
Neoplasias de la Próstata/radioterapia , Traumatismos por Radiación/etiología , Traumatismos por Radiación/mortalidad , Reirradiación/efectos adversos , Reirradiación/mortalidad , Humanos , Masculino , Neoplasias de la Próstata/patología , Traumatismos por Radiación/patología , Dosificación Radioterapéutica
8.
Anticancer Res ; 41(3): 1197-1202, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33788710

RESUMEN

BACKGROUND/AIM: Previous studies have shown that the sandalwood oil constituent α-santalol inhibits growth of cultured human prostate cancer cells in vitro and PC-3 prostate cancer xenografts. Along with the studies from our laboratory, it is well established that α-santalol targets the phosphatidylinositol-4,5-bisphosphate 3-kinase-AKT serine/ threonine kinase 1 (AKT) pathway to induce apoptosis but its growth-suppressive effects have not been fully elucidated. The current study was undertaken to investigate the role of autophagy in α-santalol-induced prostate cancer cell death. MATERIALS AND METHODS: Cell lines LNCaP and PC-3 were maintained in an atmosphere of 95% air and 5% CO2 at 37°C. Trypan blue dye exclusion assay was employed to assess the effects of α-santalol with/without 3-methyl adenine on the cell viability of prostate cancer cells. Acidic vesicular organelles induced by α-santalol treatment were detected by staining with acridine orange. Immunofluorescence and immunoblotting were performed to analyze expression of proteins involved in the AKT-mammalian target of rapamycin (mTOR) pathway. RESULTS: LNCaP and PC-3 cells upon treatment with α-santalol resulted in characteristic features analogous to autophagic response, including formation of acidic vesicular organelles, recruitment and cleavage of microtubule-associated protein 1 light chain 3 (LC3) to autophagosomes. Alpha-santalol treatment further suppressed phosphorylation of activated AKT and mTOR, which are critical regulators of autophagic response. In addition, pre-treatment of PC-3 cells with specific inhibitor of autophagy (3-methyladenine) and co-treatment with α-santalol attenuated the expression of LC3-II and phospho-AKT, and significantly reduced the cell viability. CONCLUSION: The present study indicates that α-santalol induces autophagy by targeting the AKT-mTOR pathway in prostate cancer cells, which may serve as a protective mechanism.


Asunto(s)
Autofagia/efectos de los fármacos , Sesquiterpenos Policíclicos/farmacología , Neoplasias de la Próstata/tratamiento farmacológico , Adenina/análogos & derivados , Adenina/farmacología , Apoptosis/efectos de los fármacos , Autofagia/fisiología , Línea Celular Tumoral , Humanos , Masculino , Proteínas Asociadas a Microtúbulos/metabolismo , Fosforilación , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/fisiología , Serina-Treonina Quinasas TOR/metabolismo
9.
Anticancer Res ; 41(3): 1471-1474, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33788739

RESUMEN

BACKGROUND/AIM: The aim of this study was to analyze the survival predictions obtained from a web platform allowing for computation of the so-called Bone Metastases Ensemble Trees for Survival (BMETS). This prediction model is based on a machine learning approach and considers 27 prognostic covariates. PATIENTS AND METHODS: This was a retrospective single-institution analysis of 326 patients, managed with palliative radiotherapy for bone metastases. Deviations between model-predicted survival and observed survival were assessed. RESULTS: The median actuarial survival was 7.5 months. In total, 59% of patients survived for a period shorter than predicted. Twenty percent of the predictions of the median survival deviated from the observed survival by at least 6 months. Regarding actual survival <3 months (99 of 326 patients), the BMETS-predicted median survival was <3 months, i.e. correct in 67 of 99 cases (68%), whereas the model predicted a median of 4-6 months in 16 (16%) and of >6 months in another 16 cases. CONCLUSION: The model predicted survival with high accuracy in a large number of patients. Nevertheless, if the model predicts a low likelihood of 3-month survival, actual survival may be very poor (often 1 month or less). Also, in patients who died within 3 months from the start of radiotherapy, the model often predicted longer survival (16% had >6 months predicted median survival). It would, therefore, be interesting to feed the U.S. database utilized to develop the BMETS with additional poor-prognosis patients to optimize the predictions.


Asunto(s)
Neoplasias Óseas/radioterapia , Aprendizaje Automático , Cuidados Paliativos/métodos , Oncología por Radiación/métodos , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Óseas/diagnóstico , Neoplasias Óseas/secundario , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Humanos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/terapia , Masculino , Persona de Mediana Edad , Pronóstico , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/terapia , Estudios Retrospectivos
10.
Methods Mol Biol ; 2292: 115-120, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33651356

RESUMEN

The analysis of liquid biopsy as a source of diagnostic, prognostic, and predictive biomarkers is still object of the main research in the prostate cancer field. Many advantages, such as less invasiveness compared to plasma or serum analysis and the rich content, confer to urine a role as an interesting fluid to be analysed especially in urological diseases. Here we report a workflow focused on profile, concentration, and protein surface characterization of EVs from urinary supernatant.


Asunto(s)
Exosomas/patología , Neoplasias de la Próstata/diagnóstico , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/orina , Humanos , Biopsia Líquida/métodos , Masculino , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/orina , Proteínas/análisis , Proteinuria/diagnóstico , Proteinuria/patología , Proteinuria/orina , Toma de Muestras de Orina/métodos , Flujo de Trabajo
11.
Nat Commun ; 12(1): 1521, 2021 03 09.
Artículo en Inglés | MEDLINE | ID: mdl-33750801

RESUMEN

Resistance to next-generation anti-androgen enzalutamide (ENZ) constitutes a major challenge for the treatment of castration-resistant prostate cancer (CRPC). By performing genome-wide ChIP-seq profiling in ENZ-resistant CRPC cells we identify a set of androgen receptor (AR) binding sites with increased AR binding intensity (ARBS-gained). While ARBS-gained loci lack the canonical androgen response elements (ARE) and pioneer factor FOXA1 binding motifs, they are highly enriched with CpG islands and the binding sites of unmethylated CpG dinucleotide-binding protein CXXC5 and the partner TET2. RNA-seq analysis reveals that both CXXC5 and its regulated genes including ID1 are upregulated in ENZ-resistant cell lines and these results are further confirmed in patient-derived xenografts (PDXs) and patient specimens. Consistent with the finding that ARBS-gained loci are highly enriched with H3K27ac modification, ENZ-resistant PCa cells, organoids, xenografts and PDXs are hyper-sensitive to NEO2734, a dual inhibitor of BET and CBP/p300 proteins. These results not only reveal a noncanonical AR function in acquisition of ENZ resistance, but also posit a treatment strategy to target this vulnerability in ENZ-resistant CRPC.


Asunto(s)
Feniltiohidantoína/análogos & derivados , Feniltiohidantoína/farmacología , Neoplasias de la Próstata/metabolismo , Receptores Androgénicos/metabolismo , Antagonistas de Andrógenos/farmacología , Antagonistas de Receptores de Angiotensina , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Animales , Sitios de Unión , Proliferación Celular/efectos de los fármacos , Proteínas de Unión al ADN/metabolismo , Factor Nuclear 3-alfa del Hepatocito/metabolismo , Humanos , Masculino , Ratones , Ratones SCID , Organoides , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Transducción de Señal/efectos de los fármacos , Factores de Transcripción/metabolismo , Regulación hacia Arriba , Ensayos Antitumor por Modelo de Xenoinjerto
13.
Nat Commun ; 12(1): 935, 2021 02 10.
Artículo en Inglés | MEDLINE | ID: mdl-33568675

RESUMEN

Black men die more often of prostate cancer yet, interestingly, may derive greater survival benefits from immune-based treatment with sipuleucel-T. Since no signatures of immune-responsiveness exist for prostate cancer, we explored race-based immune-profiles to identify vulnerabilities. Here we show in multiple independent cohorts comprised of over 1,300 patient samples annotated with either self-identified race or genetic ancestry, prostate tumors from Black men or men of African ancestry have increases in plasma cell infiltrate and augmented markers of NK cell activity and IgG expression. These findings are associated with improved recurrence-free survival following surgery and nominate plasma cells as drivers of prostate cancer immune-responsiveness.


Asunto(s)
Células Plasmáticas/inmunología , Neoplasias de la Próstata/inmunología , Afroamericanos/genética , Anciano , Movimiento Celular , Estudios de Cohortes , Humanos , Inmunoglobulina G/genética , Inmunoglobulina G/inmunología , Células Asesinas Naturales/inmunología , Masculino , Persona de Mediana Edad , Próstata/inmunología , Próstata/patología , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/fisiopatología
14.
Lancet Digit Health ; 3(3): e158-e165, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33549512

RESUMEN

BACKGROUND: Accurate prognostication is crucial in treatment decisions made for men diagnosed with non-metastatic prostate cancer. Current models rely on prespecified variables, which limits their performance. We aimed to investigate a novel machine learning approach to develop an improved prognostic model for predicting 10-year prostate cancer-specific mortality and compare its performance with existing validated models. METHODS: We derived and tested a machine learning-based model using Survival Quilts, an algorithm that automatically selects and tunes ensembles of survival models using clinicopathological variables. Our study involved a US population-based cohort of 171 942 men diagnosed with non-metastatic prostate cancer between Jan 1, 2000, and Dec 31, 2016, from the prospectively maintained Surveillance, Epidemiology, and End Results (SEER) Program. The primary outcome was prediction of 10-year prostate cancer-specific mortality. Model discrimination was assessed using the concordance index (c-index), and calibration was assessed using Brier scores. The Survival Quilts model was compared with nine other prognostic models in clinical use, and decision curve analysis was done. FINDINGS: 647 151 men with prostate cancer were enrolled into the SEER database, of whom 171 942 were included in this study. Discrimination improved with greater granularity, and multivariable models outperformed tier-based models. The Survival Quilts model showed good discrimination (c-index 0·829, 95% CI 0·820-0·838) for 10-year prostate cancer-specific mortality, which was similar to the top-ranked multivariable models: PREDICT Prostate (0·820, 0·811-0·829) and Memorial Sloan Kettering Cancer Center (MSKCC) nomogram (0·787, 0·776-0·798). All three multivariable models showed good calibration with low Brier scores (Survival Quilts 0·036, 95% CI 0·035-0·037; PREDICT Prostate 0·036, 0·035-0·037; MSKCC 0·037, 0·035-0·039). Of the tier-based systems, the Cancer of the Prostate Risk Assessment model (c-index 0·782, 95% CI 0·771-0·793) and Cambridge Prognostic Groups model (0·779, 0·767-0·791) showed higher discrimination for predicting 10-year prostate cancer-specific mortality. c-indices for models from the National Comprehensive Cancer Care Network, Genitourinary Radiation Oncologists of Canada, American Urological Association, European Association of Urology, and National Institute for Health and Care Excellence ranged from 0·711 (0·701-0·721) to 0·761 (0·750-0·772). Discrimination for the Survival Quilts model was maintained when stratified by age and ethnicity. Decision curve analysis showed an incremental net benefit from the Survival Quilts model compared with the MSKCC and PREDICT Prostate models currently used in practice. INTERPRETATION: A novel machine learning-based approach produced a prognostic model, Survival Quilts, with discrimination for 10-year prostate cancer-specific mortality similar to the top-ranked prognostic models, using only standard clinicopathological variables. Future integration of additional data will likely improve model performance and accuracy for personalised prognostics. FUNDING: None.


Asunto(s)
Algoritmos , Aprendizaje Automático , Próstata/patología , Neoplasias de la Próstata/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Bases de Datos Factuales , Humanos , Masculino , Persona de Mediana Edad , Nomogramas , Pronóstico , Neoplasias de la Próstata/mortalidad , Neoplasias de la Próstata/patología , Estudios Retrospectivos , Medición de Riesgo , Análisis de Supervivencia , Estados Unidos/epidemiología
15.
Life Sci ; 271: 119180, 2021 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-33571513

RESUMEN

AIMS: N6-Methyladenosine (m6A) is the most frequent posttranscriptional modification and plays important roles in tumorigenesis and metastasis. The roles of fat mass and obesity-associated (FTO) in metabolic diseases have been widely explored. However, the molecular mechanisms and physiological functions of FTO in prostate cancer remain largely unknown. This study aimed to explore the exact functions of FTO in the progression of prostate cancer metastasis. MAIN METHODS: Dot blot and m6A RNA methylation quantification assays were performed to determine m6A levels. The protein and mRNA expression levels were detected using immunoblot (IB) and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analyses. Cell invasion and migration abilities were measured using transwell and wound healing assays. Bioinformatics was used to measure the expression level of FTO and possible correlation between FTO levels and advanced tumor stage. Immunofluorescence (IF) was performed to measure the cellular localization of FTO. KEY FINDINGS: FTO was downregulated in prostate cancer tissues and cell lines, and the m6A content was increased. Importantly, patients with lower FTO expression had advanced tumor stage and higher Gleason scores. Gain- and loss-of-function assays revealed that FTO inhibits prostate cancer cell invasion and migration in vitro. Moreover, we confirmed that FTO can decrease the total m6A level. SIGNIFICANCE: The present study revealed that the FTO m6A demethylase inhibits prostate cancer cell invasion and migration by regulating total m6A levels.


Asunto(s)
Adenosina/análogos & derivados , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/biosíntesis , Biomarcadores de Tumor/biosíntesis , Movimiento Celular/fisiología , Neoplasias de la Próstata/metabolismo , Adenosina/antagonistas & inhibidores , Adenosina/biosíntesis , Anciano , Carcinogénesis/metabolismo , Carcinogénesis/patología , Línea Celular Tumoral , Humanos , Masculino , Persona de Mediana Edad , Invasividad Neoplásica/patología , Próstata/metabolismo , Próstata/patología , Neoplasias de la Próstata/patología
16.
Nat Commun ; 12(1): 866, 2021 02 08.
Artículo en Inglés | MEDLINE | ID: mdl-33558541

RESUMEN

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly become a global public health threat. The efficacy of several repurposed drugs has been evaluated in clinical trials. Among these drugs, a second-generation antiandrogen agent, enzalutamide, was proposed because it reduces the expression of transmembrane serine protease 2 (TMPRSS2), a key component mediating SARS-CoV-2-driven entry, in prostate cancer cells. However, definitive evidence for the therapeutic efficacy of enzalutamide in COVID-19 is lacking. Here, we evaluated the antiviral efficacy of enzalutamide in prostate cancer cells, lung cancer cells, human lung organoids and Ad-ACE2-transduced mice. Tmprss2 knockout significantly inhibited SARS-CoV-2 infection in vivo. Enzalutamide effectively inhibited SARS-CoV-2 infection in human prostate cells, however, such antiviral efficacy was lacking in human lung cells and organoids. Accordingly, enzalutamide showed no antiviral activity due to the AR-independent TMPRSS2 expression in mouse and human lung epithelial cells. Moreover, we observed distinct AR binding patterns between prostate cells and lung cells and a lack of direct binding of AR to TMPRSS2 regulatory locus in human lung cells. Thus, our findings do not support the postulated protective role of enzalutamide in treating COVID-19 through reducing TMPRSS2 expression in lung cells.


Asunto(s)
/prevención & control , Especificidad de Órganos/genética , Feniltiohidantoína/análogos & derivados , Serina Endopeptidasas/genética , /genética , Animales , /virología , Línea Celular Tumoral , Células Cultivadas , Expresión Génica/efectos de los fármacos , Interacciones Huésped-Patógeno/efectos de los fármacos , Humanos , Masculino , Ratones Noqueados , Pandemias , Feniltiohidantoína/farmacología , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/virología , Unión Proteica/efectos de los fármacos , Serina Endopeptidasas/metabolismo
17.
Isr Med Assoc J ; 23(2): 111-115, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33595217

RESUMEN

BACKGROUND: Little is known about oncologic outcomes following robot-assisted-radical-prostatectomy (RALP) for clinical T3 (cT3) prostate cancer. OBJECTIVES: To investigate oncologic outcomes of patients with cT3 prostate cancer treated by RALP. METHODS: Medical records of patients who underwent RALP from 2010 to 2018 were retrieved. cT3 cases were reviewed. Demographic and pre/postoperative pathology data were analyzed. Patients were followed in 3-6 month intervals with repeat PSA analyses. Adjuvant/salvage treatments were monitored. Biochemical recurrence (BCR) meant PSA levels of ≥ 0.2 ng/ml. RESULTS: Seventy-nine patients met inclusion criteria. Median age at surgery was 64 years. Preoperative PSA level was 7.14 ng/dl, median prostate weight was 54 grams, and 23 cases (29.1%) were down-staged to pathological stage T2. Positive surgical margin rate was 42%. Five patients were lost to follow-up. Median follow-up time for the remaining 74 patients was 24 months. Postoperative relapse in PSA levels occurred in 31 patients (42%), and BCR in 28 (38%). Median time to BCR was 9 months. The overall 5-year BCR-free survival rate was 61%. Predicting factors for BCR were age (hazard-ratio [HR] 0.85, 95% confidence interval [95%CI] 0.74-0.97, P = 0.017) and prostate weight (HR 1.04, 95%CI 1.01-1.08, P = 0.021). Twenty-six patients (35%) received adjuvant/salvage treatments. Three patients died from metastatic prostate cancer 31, 52, and 78 months post-surgery. Another patient died 6 months post-surgery of unknown reasons. The 5-year cancer-specific survival rate was 92. CONCLUSIONS: RALP is an oncologic effective procedure for cT3 prostate cancer. Adjuvant/salvage treatment is needed to achieve optimal disease-control.


Asunto(s)
Antígeno Prostático Específico/análisis , Prostatectomía/métodos , Neoplasias de la Próstata/cirugía , Procedimientos Quirúrgicos Robotizados/métodos , Anciano , Supervivencia sin Enfermedad , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Neoplasias de la Próstata/patología , Estudios Retrospectivos , Terapia Recuperativa , Tasa de Supervivencia , Resultado del Tratamiento
18.
Mutat Res ; 861-862: 503306, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33551100

RESUMEN

Inhibiting inflammatory processes or eliminating inflammation represents a logical role in the suppression and treatment strategy of cancer. Several studies have shown that anti-inflammatory drugs (NSAIDs) act as anticancer agents while reducing metastases and mortality rate. NSAIDs are seriously limited by their side effects and toxicity, which can become cumulative with their long-term administration for chemoprevention. In the current ex vivo / in vitro study, the genotoxicity mechanisms of NSAIDS in bulk and nanoparticle forms allowed a strategy to prevent and minimise the damage in human lymphocytes. When compared to their bulk forms, acetylsalicylic acid (Aspirin) nano and ibuprofen nano (IBU N), both NSAIDs in 500 µg/mL concentration significantly decreased DNA damage measured by alkaline comet assay. Micronuclei (MNi) frequency also decreased after ASP N (500 µg/mL), ASP B (500 µg/mL) and IBU N (200 µg/mL) in prostate cancer patients and healthy individuals, however, the ibuprofen bulk (200 µg/mL) showed a significant increase in MNi formation in lymphocytes from healthy and prostate cancer patients when compared to the respective untreated lymphocytes. These findings suggest that a reduction in particle size had an impact on the reactivity of the drug, further emphasising the potential of nanoparticles to improve the current treatment options.


Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Aspirina/farmacología , Aberraciones Cromosómicas/efectos de los fármacos , Daño del ADN , Ibuprofeno/farmacología , Linfocitos/patología , Neoplasias de la Próstata/patología , Anciano , Estudios de Casos y Controles , Humanos , Técnicas In Vitro , Linfocitos/efectos de los fármacos , Masculino , Persona de Mediana Edad , Nanopartículas , Neoplasias de la Próstata/tratamiento farmacológico
19.
Med Sci Monit ; 27: e929913, 2021 Feb 08.
Artículo en Inglés | MEDLINE | ID: mdl-33556045

RESUMEN

BACKGROUND Two diagnostic models of prostate cancer (PCa) and clinically significant prostate cancer (CS-PCa) were established using clinical data of among patients whose prostate-specific antigen (PSA) levels are in the gray area (4.0-10.0 ng/ml). MATERIAL AND METHODS Data from 181 patients whose PSA levels were in the gray area were retrospectively analyzed, and the following data were collected: age, digital rectal examination, total PSA, PSA density (PSAD), free/total PSA (f/t PSA), transrectal ultrasound, multiparametric magnetic resonance imaging (mpMRI), and pathological reports. Patients were diagnosed with benign prostatic hyperplasia (BPH) and PCa by pathology reports, and PCa patients were separated into non-clinically significant PCa (NCS-PCa) and CS-PCa by Gleason score. Afterward, predictor models constructed by above parameters were researched to diagnose PCa and CS-PCa, respectively. RESULTS According to the analysis of included clinical data, there were 109 patients with BPH, 44 patients with NCS-PCa, and 28 patients with CS-PCa. Regression analysis showed PCa was correlated with f/t PSA, PSAD, and mpMRI (P<0.01), and CS-PCa was correlated with PSAD and mpMRI (P<0.01). The area under the receiver operating characteristic curves of 2 models for PCa (sensitivity=73.64%, specificity=64.23%) and for CS-PCa (sensitivity=71.41%, specificity=81.82%) were 0.79 and 0.87, respectively. CONCLUSIONS The prediction models had satisfactory diagnostic value for PCa and CS-PCa among patients with PSA in the gray area, and use of these models may help reduce overdiagnosis.


Asunto(s)
Calicreínas/sangre , Modelos Estadísticos , Antígeno Prostático Específico/sangre , Hiperplasia Prostática/diagnóstico , Neoplasias de la Próstata/diagnóstico , Factores de Edad , Anciano , Biopsia/estadística & datos numéricos , Diagnóstico Diferencial , Tacto Rectal/estadística & datos numéricos , Humanos , Masculino , Uso Excesivo de los Servicios de Salud/prevención & control , Imágenes de Resonancia Magnética Multiparamétrica/estadística & datos numéricos , Clasificación del Tumor , Próstata/diagnóstico por imagen , Próstata/patología , Hiperplasia Prostática/sangre , Hiperplasia Prostática/patología , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/patología , Curva ROC , Valores de Referencia , Estudios Retrospectivos , Medición de Riesgo/métodos , Ultrasonografía/estadística & datos numéricos
20.
Nat Commun ; 12(1): 723, 2021 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-33526787

RESUMEN

Bone metastatic prostate cancer (PCa) promotes mesenchymal stem cell (MSC) recruitment and their differentiation into osteoblasts. However, the effects of bone-marrow derived MSCs on PCa cells are less explored. Here, we report MSC-derived interleukin-28 (IL-28) triggers prostate cancer cell apoptosis via IL-28 receptor alpha (IL-28Rα)-STAT1 signaling. However, chronic exposure to MSCs drives the selection of prostate cancer cells that are resistant to IL-28-induced apoptosis and therapeutics such as docetaxel. Further, MSC-selected/IL-28-resistant prostate cancer cells grow at accelerated rates in bone. Acquired resistance to apoptosis is PCa cell intrinsic, and is associated with a shift in IL-28Rα signaling via STAT1 to STAT3. Notably, STAT3 ablation or inhibition impairs MSC-selected prostate cancer cell growth and survival. Thus, bone marrow MSCs drive the emergence of therapy-resistant bone metastatic prostate cancer yet this can be disabled by targeting STAT3.


Asunto(s)
Adenocarcinoma/secundario , Neoplasias Óseas/secundario , Células Madre Mesenquimatosas/patología , Neoplasias de la Próstata/patología , Receptores de Interferón/metabolismo , Ácidos Aminosalicílicos/farmacología , Ácidos Aminosalicílicos/uso terapéutico , Animales , Apoptosis/efectos de los fármacos , Bencenosulfonatos/farmacología , Bencenosulfonatos/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular , Medios de Cultivo Condicionados/metabolismo , Modelos Animales de Enfermedad , Docetaxel/farmacología , Docetaxel/uso terapéutico , Humanos , Interferones/genética , Interferones/metabolismo , Masculino , Ratones Noqueados , Osteoblastos/patología , Cultivo Primario de Células , Neoplasias de la Próstata/tratamiento farmacológico , ARN Interferente Pequeño/metabolismo , Receptores de Interferón/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Factor de Transcripción STAT1/metabolismo , Factor de Transcripción STAT3/antagonistas & inhibidores , Factor de Transcripción STAT3/metabolismo , Tibia/patología
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