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The discovery of drivers of cancer has traditionally focused on protein-coding genes1-4. Here we present analyses of driver point mutations and structural variants in non-coding regions across 2,658 genomes from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium5 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). For point mutations, we developed a statistically rigorous strategy for combining significance levels from multiple methods of driver discovery that overcomes the limitations of individual methods. For structural variants, we present two methods of driver discovery, and identify regions that are significantly affected by recurrent breakpoints and recurrent somatic juxtapositions. Our analyses confirm previously reported drivers6,7, raise doubts about others and identify novel candidates, including point mutations in the 5' region of TP53, in the 3' untranslated regions of NFKBIZ and TOB1, focal deletions in BRD4 and rearrangements in the loci of AKR1C genes. We show that although point mutations and structural variants that drive cancer are less frequent in non-coding genes and regulatory sequences than in protein-coding genes, additional examples of these drivers will be found as more cancer genomes become available.
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Genoma Humano/genética , Mutación/genética , Neoplasias/genética , Roturas del ADN , Bases de Datos Genéticas , Regulación Neoplásica de la Expresión Génica , Estudio de Asociación del Genoma Completo , Humanos , Mutación INDELRESUMEN
PURPOSE: The aim of this study was to develop a model to predict high-genomic-risk prostate cancer (PCa) according to Decipher score, a validated 22 gene prognostic panel. By doing so, one might select the individuals who are likely to benefit from genomic testing and improve pre-op counseling about the need for adjuvant treatments. METHODS: We retrospectively reviewed IRB-approved databases at two institutions. All patients had preoperative magnetic resonance imaging (MRI) and Decipher prostate radical prostatectomy (RP), a validated 22 gene prognostic panel. We used binary logistic regression to estimate high-risk Decipher (Decipher score > 0.60) probability on RP specimen. Area under the curve (AUC) and calibration were used to assess the accuracy of the model in the development and validation cohort. Decision curve analysis (DCA) was performed to assess the clinical benefit of the model. RESULTS: The development and validation cohort included 622 and 185 patients with 283 (35%) and 80 (43%) of those with high-risk Decipher. The multivariable model included PSA density, biopsy Gleason Grade Group, percentage of positive cores and MRI extracapsular extension. AUC was 0.73 after leave-one-out cross-validation. DCA showed a clinical benefit in a range of probabilities between 15 and 60%. In the external validation cohort, AUC was 0.70 and calibration showed that the model underestimates the actual probability of the outcome. CONCLUSIONS: The proposed model to predict high-risk Decipher score at RP is helpful to improve risk stratification of patients with PCa and to assess the need for additional testing and treatments.
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Neoplasias de la Próstata , Masculino , Humanos , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/cirugía , Estudios Retrospectivos , Antígeno Prostático Específico , Próstata/patología , Clasificación del Tumor , Prostatectomía/métodos , GenómicaRESUMEN
PURPOSE OF REVIEW: African-American men in the USA have a higher incidence of and mortality from prostate cancer (PCa), with a longstanding debate about the cause for these worse outcomes. This review examines differences in tumour biology and socioeconomics for African-American and Non-Hispanic White (NHW) men to answer the question 'why AA men face higher risks for lethal PCa' and draw a management consensus to redress the imbalance. RECENT FINDINGS: Recent evidence from over the past 2âyears suggests the reasons why African-American men face a higher risk of lethal PCa are multifactorial, with contributions from differences in tumour biology as well as socioeconomic and healthcare access factors. Regarding tumour biology, genomic and transcriptome profiling suggests African-American men have upregulated expression of genes related to inflammatory pathways with downregulation of DNA repair genes. In contrast, NHW men have higher DNA repair pathways and metabolic pathways involving glycolysis and cell cycle activity. In addition, epidemiological evidence suggests equal healthcare access ensures equal PCa specific outcomes, implying African-American men's disease is not inherently more lethal. However, differences in tumour biology remain, which may explain specific differences in PCa incidence and the clinical findings of African-American men's increased response to immunotherapy and radiotherapy in recent trials. SUMMARY: Regardless of racial differences in disease outcomes and the factors causing them, African-American and NHW men seem to have diseases unique to their ancestry. This supports the exploration of personalized PCa treatment approaches, leveraging translational basic science research to uncover these differences and devise specific individualized methods therapeutic regimes to address them.
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Negro o Afroamericano , Neoplasias de la Próstata , Negro o Afroamericano/genética , Accesibilidad a los Servicios de Salud , Humanos , Inmunoterapia , Masculino , Neoplasias de la Próstata/epidemiología , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/terapia , Población Blanca/genéticaRESUMEN
Patients with cancer carry somatic sequence variants in their tumour in addition to the germline variants in their inherited genome. Although variants in protein-coding regions have received the most attention, numerous studies have noted the importance of non-coding variants in cancer. Moreover, the overwhelming majority of variants, both somatic and germline, occur in non-coding portions of the genome. We review the current understanding of non-coding variants in cancer, including the great diversity of the mutation types--from single nucleotide variants to large genomic rearrangements--and the wide range of mechanisms by which they affect gene expression to promote tumorigenesis, such as disrupting transcription factor-binding sites or functions of non-coding RNAs. We highlight specific case studies of somatic and germline variants, and discuss how non-coding variants can be interpreted on a large-scale through computational and experimental methods.
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Variación Genética , Neoplasias/genética , ARN no Traducido , Regulación Neoplásica de la Expresión Génica , Estudio de Asociación del Genoma Completo , Inestabilidad Genómica , Mutación de Línea Germinal , HumanosRESUMEN
Copy number variants (CNVs) are a recently recognized class of human germ line polymorphisms and are associated with a variety of human diseases, including cancer. Because of the strong genetic influence on prostate cancer, we sought to identify functionally active CNVs associated with susceptibility of this cancer type. We queried low-frequency biallelic CNVs from 1,903 men of Caucasian origin enrolled in the Tyrol Prostate Specific Antigen Screening Cohort and discovered two CNVs strongly associated with prostate cancer risk. The first risk locus (P = 7.7 × 10(-4), odds ratio = 2.78) maps to 15q21.3 and overlaps a noncoding enhancer element that contains multiple activator protein 1 (AP-1) transcription factor binding sites. Chromosome conformation capture (Hi-C) data suggested direct cis-interactions with distant genes. The second risk locus (P = 2.6 × 10(-3), odds ratio = 4.8) maps to the α-1,3-mannosyl-glycoprotein 4-ß-N-acetylglucosaminyltransferase C (MGAT4C) gene on 12q21.31. In vitro cell-line assays found this gene to significantly modulate cell proliferation and migration in both benign and cancer prostate cells. Furthermore, MGAT4C was significantly overexpressed in metastatic versus localized prostate cancer. These two risk associations were replicated in an independent PSA-screened cohort of 800 men (15q21.3, combined P = 0.006; 12q21.31, combined P = 0.026). These findings establish noncoding and coding germ line CNVs as significant risk factors for prostate cancer susceptibility and implicate their role in disease development and progression.
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Cromosomas Humanos Par 12 , Cromosomas Humanos Par 15 , Dosificación de Gen , Predisposición Genética a la Enfermedad , Neoplasias de la Próstata/genética , Estudios de Casos y Controles , Línea Celular Tumoral , Proliferación Celular , Estudios de Cohortes , Humanos , Masculino , Reacción en Cadena de la Polimerasa , Polimorfismo de Nucleótido Simple , Neoplasias de la Próstata/patologíaRESUMEN
The nonpolymorphic major histocompatibility complex E (MHC-E) molecule is up-regulated on many cancer cells, thus contributing to immune evasion by engaging inhibitory NKG2A/CD94 receptors on NK cells and tumor-infiltrating T cells. To investigate whether MHC-E expression by cancer cells can be targeted for MHC-E-restricted T cell control, we immunized rhesus macaques (RM) with rhesus cytomegalovirus (RhCMV) vectors genetically programmed to elicit MHC-E-restricted CD8+ T cells and to express established tumor-associated antigens (TAAs) including prostatic acidic phosphatase (PAP), Wilms tumor-1 protein, or Mesothelin. T cell responses to all three tumor antigens were comparable to viral antigen-specific responses with respect to frequency, duration, phenotype, epitope density, and MHC restriction. Thus, CMV-vectored cancer vaccines can bypass central tolerance by eliciting T cells to noncanonical epitopes. We further demonstrate that PAP-specific, MHC-E-restricted CD8+ T cells from RhCMV/PAP-immunized RM respond to PAP-expressing HLA-E+ prostate cancer cells, suggesting that the HLA-E/NKG2A immune checkpoint can be exploited for CD8+ T cell-based immunotherapies.
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Antígenos de Neoplasias , Linfocitos T CD8-positivos , Antígenos HLA-E , Animales , Humanos , Masculino , Fosfatasa Ácida , Presentación de Antígeno/inmunología , Antígenos de Neoplasias/inmunología , Vacunas contra el Cáncer/inmunología , Linfocitos T CD8-positivos/inmunología , Línea Celular Tumoral , Citomegalovirus/inmunología , Antígenos de Histocompatibilidad Clase I/inmunología , Antígenos de Histocompatibilidad Clase I/metabolismo , Macaca mulatta , MesotelinaRESUMEN
Neoadjuvant therapies can improve tolerability, reduce tumor volume to facilitate surgery, and assess subsequent treatment response. Therefore, there is much enthusiasm for expanding the benefits of cancer therapies to the neoadjuvant setting to reduce recurrence and improve survival in patients with localized or locally advanced genitourinary (GU) cancer. This approach is clinically pertinent because these treatments are administered primarily to treatment-naive patients and can elicit the greatest drug response. In addition, the results are not impacted by other anticancer treatments. While neoadjuvant therapies have been the standard treatment for bladder cancer in the past, they are presently restricted to clinical trials for renal and prostate cancer (PCa); however, changes are imminent. Precision neoadjuvant therapies will be ushered in by biomarker-stratified neoadjuvant trials with appropriate survival endpoints and comprehensive correlative and imaging studies. This review discusses neoadjuvant studies in GU malignancies and how they inform future study design considerations.
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Terapia Neoadyuvante , Neoplasias de la Próstata , Masculino , Humanos , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Quimioterapia AdyuvanteRESUMEN
Histone methylation has a key role in oestrogen receptor (ERalpha)-mediated transactivation of genes. Proline glutamic acid and leucine-rich protein 1 (PELP1) is a new proto-oncogene that functions as an ERalpha co-regulator. In this study, we identified histone lysine demethylase, KDM1, as a new PELP1-interacting protein. These proteins, PELP1 and KDM1, were both recruited to ERalpha target genes, and PELP1 depletion affected the dimethyl histone modifications at ERalpha target genes. Dimethyl-modified histones H3K4 and H3K9 are recognized by PELP1, and PELP1 alters the substrate specificity of KDM1 from H3K4 to H3K9. Effective demethylation of dimethyl H3K9 by KDM1 requires a KDM1-ERalpha-PELP1 functional complex. These results suggest that PELP1 is a reader of H3 methylation marks and has a crucial role in modulating the histone code at the ERalpha target genes.
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Receptor alfa de Estrógeno/metabolismo , Histona Demetilasas/metabolismo , Histonas/metabolismo , Transactivadores/metabolismo , Activación Transcripcional , Línea Celular Tumoral , Proteínas Co-Represoras , Estradiol/farmacología , Humanos , Metilación/efectos de los fármacos , Regiones Promotoras Genéticas/genética , Unión Proteica/efectos de los fármacos , Proto-Oncogenes Mas , Especificidad por Sustrato/efectos de los fármacos , Factores de Transcripción , Activación Transcripcional/efectos de los fármacosRESUMEN
INTRODUCTION: Prostate cancer (PCa) is a heterogenous disease with multiple etiological factors playing a role in its development. Recently, chronic and systemic inflammatory conditions such as inflammatory bowel disease were identified as key risk factors influencing its development. The study aimed to evaluate the relationship between diverticular disease (DD) (local and acute inflammation) and PCa. METHODS: Hypertensive patients with DD and hypertensive controls were identified between 1995 and 2010 from the Statewide Planning and Research Cooperative System database. Cohorts were queried for PCa incidence through 2015. Univariable and multivariable logistic regression analyses were used for determining independent predictors of PCa diagnosis. RESULTS: A total of 51,353 patients with DD and 111,541 controls were identified. In all, 6.26% of DD developed PCa, and 3.71% of controls developed PCa (p < 0.01). DD was a significant risk factor for PCa (OR: 1.27 CI: 1.19-1.34, p < 0.01). On subgroup analysis, the patients diagnosed with DD <50 years old had an OR of 3.39 for PCa (CI: 2.52-4.56, p < 0.01), age 50-59 had an OR of 2.12 (CI: 1.86-2.15, p < 0.01), and age 60-69 had an OR of 1.20 (CI: 1.10-1.31, p < 0.01). Finally, age and race stratification showed that white patients <50 had an OR of 2.56 (CI: 1.75-3.76, p < 0.01), while black patients <50 had an OR of 3.98 (CI: 2.61-6.07, p < 0.01). The trend in differing odds between these populations was the same for age groups 50-59 and 60-69. CONCLUSION: Our analysis shows that DD is associated with diagnosis of PCa in hypertensive men. Importantly, the earlier the diagnosis of DD, the higher the odds for development of PCa, particularly in black men.
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Enfermedades Diverticulares , Neoplasias de la Próstata , Masculino , Humanos , Persona de Mediana Edad , Anciano , Neoplasias de la Próstata/epidemiología , Neoplasias de la Próstata/etiología , Factores de Riesgo , Incidencia , Enfermedad CrónicaRESUMEN
Most patients with estrogen receptor alpha-positive (ER+) breast cancers initially respond to treatment but eventually develop therapy resistance with disease progression. Overexpression of oncogenic ER coregulators, including proline, glutamic acid, and leucine-rich protein 1 (PELP1), are implicated in breast cancer progression. The lack of small molecules that inhibits PELP1 represents a major knowledge gap. Here, using a yeast-two-hybrid screen, we identified novel peptide inhibitors of PELP1 (PIP). Biochemical assays demonstrated that one of these peptides, PIP1, directly interacted with PELP1 to block PELP1 oncogenic functions. Computational modeling of PIP1 revealed key residues contributing to its activity and facilitated the development of a small-molecule inhibitor of PELP1, SMIP34, and further analyses confirmed that SMIP34 directly bound to PELP1. In breast cancer cells, SMIP34 reduced cell growth in a dose-dependent manner. SMIP34 inhibited proliferation of not only wild-type (WT) but also mutant (MT) ER+ and therapy-resistant breast cancer cells, in part by inducing PELP1 degradation via the proteasome pathway. RNA sequencing analyses showed that SMIP34 treatment altered the expression of genes associated with estrogen response, cell cycle, and apoptosis pathways. In cell line-derived and patient-derived xenografts of both WT and MT ER+ breast cancer models, SMIP34 reduced proliferation and significantly suppressed tumor progression. Collectively, these results demonstrate SMIP34 as a first-in-class inhibitor of oncogenic PELP1 signaling in advanced breast cancer. SIGNIFICANCE: Development of a novel inhibitor of oncogenic PELP1 provides potential therapeutic avenues for treating therapy-resistant, advanced ER+ breast cancer.
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Neoplasias de la Mama , Proteínas Co-Represoras , Factores de Transcripción , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Proteínas Co-Represoras/antagonistas & inhibidores , Proteínas Co-Represoras/metabolismo , Receptor alfa de Estrógeno/genética , Estrógenos , Femenino , Ácido Glutámico , Humanos , Leucina , Prolina , Complejo de la Endopetidasa Proteasomal , Receptores de Estrógenos/metabolismo , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/metabolismoRESUMEN
The impact of pelvic inflammation on prostate cancer (PCa) biology and aggressive phenotype has never been studied. Our study objective was to evaluate the role of pelvic inflammation on PCa aggressiveness and its association with clinical outcomes in patients following radical prostatectomy (RP). This study has been conducted on a retrospective single-institutional consecutive cohort of 2278 patients who underwent robot-assisted laparoscopic prostatectomy (RALP) between 01/2013 and 10/2019. Data from 2085 patients were analyzed to study the association between pelvic inflammation and adverse pathology (AP), defined as Gleason Grade Group (GGG) > 2 and ≥ pT3 stage, at resection. In a subset of 1997 patients, the association between pelvic inflammation and biochemical recurrence (BCR) was studied. Alteration in tumor transcriptome and inflammatory markers in patients with and without pelvic inflammation were studied using microarray analysis, immunohistochemistry, and culture supernatants derived from inflamed sites used in functional assays. Changes in blood inflammatory markers in the study cohort were analyzed by O-link. In univariate analyses, pelvic inflammation emerged as a significant predictor of AP. Multivariate cox proportional-hazards regression analyses showed that high pelvic inflammation with pT3 stage and positive surgical margins significantly affected the time to BCR (p ≤ 0.05). PCa patients with high inflammation had elevated levels of pro-inflammatory cytokines in their tissues and in blood. Genes involved in epithelial-to-mesenchymal transition (EMT) and DNA damage response were upregulated in patients with pelvic inflammation. Attenuation of STAT and IL-6 signaling decreased tumor driving properties of conditioned medium from inflamed sites. Pelvic inflammation exacerbates the progression of prostate cancer and drives an aggressive phenotype.
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The estrogen receptor (ER) is implicated in the progression of breast cancer. Despite positive effects of hormonal therapy, initial or acquired resistance to endocrine therapies frequently occurs. Recent studies suggested ERα-coregulator PELP1 and growth factor receptor ErbB2/HER2 play an essential role in hormonal therapy responsiveness. Src axis couples ERα with HER2 and PELP1, thus representing a new pathway for targeted therapy resistance. To establish the significance of ER-Src axis in PELP1 and HER2 mediated therapy resistance, we have generated model cells that stably express Src-shRNA under conditions of PELP1, HER2 deregulation. Depletion of Src using shRNA substantially reduced E2 mediated activation of Src and MAPK activation in resistant model cells. Pharmacological inhibition of Src using dasatinib, an orally available inhibitor substantially inhibited the growth of therapy resistant MCF7-PELP1, MCF7-HER2, and MCF7-Tam model cells in proliferation assays. In post-menopausal xenograft based studies, treatment with dasatinib significantly inhibited the growth of therapy resistant cells. IHC analysis revealed that the tumors were ERα positive, and dasatinib treated tumors exhibited alterations in Src and MAPK signaling pathways. Combinatorial therapy of tamoxifen with dasatinib showed better therapeutic effect compared to single agent therapy on the growth of therapy resistant PELP1 driven tumors. The results from our study showed that ER-Src axis play an important role in promoting hormonal resistance by proto-oncogenes such as HER2, PELP1, and blocking this axis prevents the development of hormonal independence in vivo. Since PELP1, HER2, and Src kinase are commonly deregulated in breast cancers, combination therapies using both endocrine agents and dasatinib may have better therapeutic effect by delaying the development of hormonal resistance.
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Antineoplásicos/farmacología , Resistencia a Antineoplásicos , Receptor alfa de Estrógeno/metabolismo , Pirimidinas/farmacología , Tiazoles/farmacología , Familia-src Quinasas/metabolismo , Animales , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proteínas Co-Represoras/genética , Proteínas Co-Represoras/metabolismo , Dasatinib , Sinergismo Farmacológico , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Letrozol , Ratones , Ratones Desnudos , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Nitrilos/farmacología , Nitrilos/uso terapéutico , Fosforilación , Pirimidinas/uso terapéutico , Interferencia de ARN , Receptor ErbB-2/metabolismo , Tamoxifeno/farmacología , Tamoxifeno/uso terapéutico , Tiazoles/uso terapéutico , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Triazoles/farmacología , Triazoles/uso terapéutico , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Familia-src Quinasas/genéticaRESUMEN
BACKGROUND: African Americans (AAs) in the United States are known to have a higher incidence and mortality for Prostate Cancer (PCa). The drivers of this epidemiological disparity are multifactorial, including socioeconomic factors leading to lifestyle and dietary issues, healthcare access problems, and potentially tumor biology. RECENT FINDINGS: Although recent evidence suggests once access is equal, AA men have equal outcomes to Caucasian American (CA) men, differences in PCa incidence remain, and there is much to do to reverse disparities in mortality across the USA. A deeper understanding of these issues, both at the clinical and molecular level, can facilitate improved outcomes in the AA population. This review first discusses PCa oncogenesis in the context of its diverse hallmarks before benchmarking key molecular and genomic differences for PCa in AA men that have emerged in the recent literature. Studies have emphasized the importance of tumor microenvironment that contributes to both the unequal cancer burden and differences in clinical outcome between the races. Management of comorbidities like obesity, hypertension, and diabetes will provide an essential means of reducing prostate cancer incidence in AA men. Although requiring further AA specific research, several new treatment strategies such as immune checkpoint inhibitors used in combination PARP inhibitors and other emerging vaccines, including Sipuleucel-T, have demonstrated some proven efficacy. CONCLUSION: Genomic profiling to integrate clinical and genomic data for diagnosis, prognosis, and treatment will allow physicians to plan a "Precision Medicine" approach to AA men. There is a pressing need for further research for risk stratification, which may allow early identification of AA men with higher risk disease based on their unique clinical, genomic, and immunological profiles, which can then be mapped to appropriate clinical trials. Treatment options are outlined, with a concise description of recent work in AA specific populations, detailing several targeted therapies, including immunotherapy. Also, a summary of current clinical trials involving AA men is presented, and it is important that policies are adopted to ensure that AA men are actively recruited. Although it is encouraging that many of these explore the lifestyle and educational initiatives and therapeutic interventions, there is much still work to be done to reduce incidence and mortality in AA men and equalize current racial disparities.
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Negro o Afroamericano/estadística & datos numéricos , Disparidades en el Estado de Salud , Disparidades en Atención de Salud , Inmunoterapia/métodos , Neoplasias de la Próstata/etnología , Población Blanca/estadística & datos numéricos , Accesibilidad a los Servicios de Salud , Humanos , Masculino , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/terapia , Factores SocioeconómicosRESUMEN
BACKGROUND: Cancer patients with COVID-19 have a poor disease course. Among tumor types, prostate cancer and COVID-19 share several risk factors, and the interaction of prostate cancer and COVID-19 is purported to have an adverse outcome. METHODS: This was a single-institution retrospective study on 286,609 patients who underwent the COVID-19 test at Mount Sinai Hospital system from March 2020 to December 2020. Chi-square/Fisher's exact tests were used to summarize baseline characteristics of categorical data, and Mann-Whitney U test was used for continuous variables. Univariable logistic regression analysis to compare the hospitalization and mortality rates and the strength of association was obtained by the odds ratio and confidence interval. RESULTS: This study aimed to compare hospitalization and mortality rates between men with COVID-19 and prostate cancer and those who were COVID-19-positive with non-prostate genitourinary malignancy or any solid cancer, and with breast cancer patients. We also compared our studies to others that reported the incidence and severity of COVID-19 in prostate cancer patients. Our studies highlight that patients with prostate cancer had higher susceptibility to COVID-19-related pathogenesis, resulting in higher mortality and hospitalization rates. Hospitalization and mortality rates were higher in prostate cancer patients with COVID-19 when compared with COVID-19 patients with non-prostate genitourinary (GU) malignancies.
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BACKGROUND: A common side effect following radical prostatectomy is urinary incontinence. Here, we describe a novel surgical technique to reduce postoperative urinary incontinence and facilitate early return of continence. OBJECTIVE: To describe the novel "hood technique" for robotic-assisted radical prostatectomy (RARP). DESIGN, SETTING, AND PARTICIPANTS: This is an institutional review board-approved prospective study of 300 patients (median age 64 yr) with localized prostate cancer treated with the RARP hood technique at a major urban hospital between April 2018 and March 2019. The exclusion criteria were as follows: patients with anterior tumor location based on biopsy or multiparametric magnetic resonance imaging. All but one patient participated in follow-up over 12 mo after the procedure. SURGICAL PROCEDURE: The RARP "hood technique" was performed to preserve the detrusor apron, puboprostatic ligament complex, arcus tendineus, endopelvic fascia, and pouch of Douglas. MEASUREMENTS: Clinical data collected included pre- and intraoperative variables, and postoperative functional and oncological outcomes and complications. Descriptive statistical analysis was performed. RESULTS AND LIMITATIONS: Continence rates at 1, 2, 4, 6 12, 24, and 48 wk after catheter removal were 21%, 36%, 83%, 88%, 91%, 94%, and 95%, respectively. Positive surgical margin rate was 6%. Thirty patients (9.7%) experienced complications after RARP: 17 (5.7%), 11 (3.6%), and one (0.4%) had Clavien-Dindo grade I, II, and III complications, respectively. This study was conducted within a single health system and may not be generalizable. The study lacked randomization and a comparative arm. CONCLUSIONS: Results indicate that the hood technique spares musculofascial structures anterior to the urethral sphincter complex with early return of continence after surgery, without compromising positive surgical margin rates. Exclusion of anterior tumor location contributed to a reduction in positive surgical margins. PATIENT SUMMARY: By better preservation of anatomical structures around the urethra, we were able to achieve early return of urinary continence without a negative impact on complications and cancer outcomes.
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Neoplasias de la Próstata , Procedimientos Quirúrgicos Robotizados , Incontinencia Urinaria , Humanos , Masculino , Márgenes de Escisión , Persona de Mediana Edad , Estudios Prospectivos , Prostatectomía/efectos adversos , Neoplasias de la Próstata/cirugía , Procedimientos Quirúrgicos Robotizados/efectos adversos , Resultado del Tratamiento , Incontinencia Urinaria/etiología , Incontinencia Urinaria/prevención & controlRESUMEN
Racial disparities in prostate cancer have not been well characterized on a genomic level. Here we show the results of a multi-institutional retrospective analysis of 1,152 patients (596 African-American men (AAM) and 556 European-American men (EAM)) who underwent radical prostatectomy. Comparative analyses between the race groups were conducted at the clinical, genomic, pathway, molecular subtype, and prognostic levels. The EAM group had increased ERG (P < 0.001) and ETS (P = 0.02) expression, decreased SPINK1 expression (P < 0.001), and basal-like (P < 0.001) molecular subtypes. After adjusting for confounders, the AAM group was associated with higher expression of CRYBB2, GSTM3, and inflammation genes (IL33, IFNG, CCL4, CD3, ICOSLG), and lower expression of mismatch repair genes (MSH2, MSH6) (p < 0.001 for all). At the pathway level, the AAM group had higher expression of genes sets related to the immune response, apoptosis, hypoxia, and reactive oxygen species. EAM group was associated with higher levels of fatty acid metabolism, DNA repair, and WNT/beta-catenin signaling. Based on cell lines data, AAM were predicted to have higher potential response to DNA damage. In conclusion, biological characteristics of prostate tumor were substantially different in AAM when compared to EAM.
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Negro o Afroamericano/genética , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica , Genómica/métodos , Neoplasias de la Próstata/genética , Población Blanca/genética , Negro o Afroamericano/estadística & datos numéricos , Anciano , Disparidades en el Estado de Salud , Humanos , Sistema Inmunológico/inmunología , Sistema Inmunológico/metabolismo , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Neoplasias de la Próstata/etnología , Neoplasias de la Próstata/inmunología , Estudios Retrospectivos , Estados Unidos , Población Blanca/estadística & datos numéricosRESUMEN
Recent studies implicate that the estrogen receptor (ER) coregulator proline-, glutamic acid-, and leucine-rich protein (PELP) 1 as playing critical roles in ER-genomic, ER-nongenomic, and ER-signaling cross talk with growth factor signaling pathways. PELP1 expression is deregulated in hormonal cancers and recent studies further elucidated the molecular mechanisms by which PELP1 regulates hormone therapy response. Although PELP1 is important for normal functions of the ER, the possibility to target ER-PELP1 axis appears to be an effective strategy for preventing hormonal carcinogenesis and therapy resistance. Thus, PELP1 may be useful as prognostic marker for hormonal cancers and PELP1 signaling may be useful to generate targeted therapeutics to overcome hormonal therapy resistance.
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Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias Hormono-Dependientes/tratamiento farmacológico , Receptores de Estrógenos/efectos de los fármacos , Transactivadores/fisiología , Proteínas Co-Represoras , Resistencia a Antineoplásicos/genética , Femenino , Humanos , Metástasis de la Neoplasia/fisiopatología , Receptores de Estrógenos/fisiología , Transducción de Señal/fisiología , Transactivadores/efectos de los fármacos , Factores de TranscripciónRESUMEN
The advent of immunotherapy has revolutionized cancer treatment. Prostate cancer has an immunosuppressive microenvironment and a low tumor mutation burden, resulting in low neoantigen expression. The consensus was that immunotherapy would be less effective in prostate cancer. However, recent studies have reported that prostate cancer does have a high number of DNA damage and repair gene defects. Immunotherapies that have been tested in prostate cancer so far have been mainly vaccines and checkpoint inhibitors. A combination of genomically targeted therapies, with approaches to alleviate immune response and thereby make the tumor microenvironment immunologically hot, is promising.
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Productos Biológicos/administración & dosificación , Vacunas contra el Cáncer/administración & dosificación , Inmunoterapia/métodos , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/terapia , Microambiente Tumoral/efectos de los fármacos , Anciano , Animales , Antígenos de Neoplasias/efectos de los fármacos , Antígenos de Neoplasias/inmunología , Predicción , Humanos , Masculino , Ratones , Persona de Mediana Edad , Terapia Molecular Dirigida/métodos , Invasividad Neoplásica/patología , Metástasis de la Neoplasia/genética , Metástasis de la Neoplasia/inmunología , Estadificación de Neoplasias , Neoplasias de la Próstata/genética , Resultado del Tratamiento , Microambiente Tumoral/genéticaRESUMEN
PT150 is a clinical-stage molecule, taken orally, with a strong safety profile having completed Phase 1 and Phase 2 clinical trials for its original use as an antidepressant. It has an active IND for COVID-19. Antiviral activities have been found for PT150 and other members of its class in a variety of virus families; thus, it was now tested against SARS-CoV-2 in human bronchial epithelial lining cells and showed effective 90% inhibitory antiviral concentration (EC90) of 5.55 µM. PT150 is a member of an extended platform of novel glucocorticoid receptor (GR) and androgen receptor (AR) modulating molecules. In vivo, their predominant net effect is one of systemic glucocorticoid antagonism, but they also show direct downregulation of AR and minor GR agonism at the cellular level. We hypothesize that anti-SARS-CoV-2 activity depends in part on this AR downregulation through diminished TMPRSS2 expression and modulation of ACE2 activity. Given that hypercortisolemia is now suggested to be a significant co-factor for COVID-19 progression, we also postulate an additive role for its potent immunomodulatory effects through systemic antagonism of cortisol.