Recent Insights on Genetic Testing in Primary Prostate Cancer.
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ABSTRACT:
SUBMITTER: Kafka M
PROVIDER: S-EPMC8249272 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Prostate cancer (PCa) has a high propensity for metastasis to bone. Despite the availability of multiple treatment options for relief of PCa-induced bone pain (PCIBP), satisfactory relief of intractable pain in patients with advanced bony metastases is challenging for the clinicians because currently available analgesic drugs are often limited by poor efficacy and/or dose-limiting side effects. Rodent models developed in the past decade show that the pathobiology of PCIBP comprises elements of inflammatory, neuropathic and ischemic pain arising from ectopic sprouting and sensitization of sensory nerve fibres within PCa-invaded bones. In addition, at the cellular level, PCIBP is underpinned by dynamic cross talk between metastatic PCa cells, cellular components of the bone matrix, factors associated with the bone microenvironment as well as peripheral components of the somatosensory system. These insights are aligned with the clinical management of PCIBP involving use of a multimodal treatment approach comprising analgesic agents (opioids, NSAIDs), radiotherapy, radioisotopes, cancer chemotherapy agents and bisphosphonates. However, a major drawback of most rodent models of PCIBP is their short-term applicability due to ethical concerns. Thus, it has been difficult to gain insight into the mal(adaptive) neuroplastic changes occurring at multiple levels of the somatosensory system that likely contribute to intractable pain at the advanced stages of metastatic disease. Specifically, the functional responsiveness of noxious circuitry as well as the neurochemical signature of a broad array of pro-hyperalgesic mediators in the dorsal root ganglia and spinal cord of rodent models of PCIBP is relatively poorly characterized. Hence, recent work from our laboratory to develop a protocol for an optimized rat model of PCIBP will enable these knowledge gaps to be addressed as well as identification of novel targets for drug discovery programs aimed at producing new analgesics for the improved relief of intractable PCIBP.
| S-EPMC3779011 | biostudies-literature
Project description:BackgroundAs prostate cancer (PCa) screening decisions often occur in outpatient primary care, a brief tool to help the PCa screening conversation in busy clinic settings is needed.MethodsA previously created 9-item tool to aid PCa screening discussions was tested in five diverse primary care clinics. Fifteen providers were recruited to use the tool for 4?weeks, and the tool was revised based upon feedback. The providers then used the tool with a convenience sample of patients during routine clinic visits. Pre- and post-visit surveys were administered to assess patients' knowledge of the option to be screened for PCa and of specific factors to consider in the decision. McNemar's and Stuart-Maxwell tests were used to compare pre-and post-survey responses.Results14 of 15 providers completed feedback surveys and had positive responses to the tool. All 15 providers then tested the tool on 95 men aged 40-69 at the five clinics with 2-10 patients each. The proportion of patients who strongly agreed that they had the option to choose to screen for PCa increased from 57 to 72% (p?=?0.018) from the pre- to post-survey, that there are factors in the personal or family history that may affect PCa risk from 34 to 47% (p?=?0.012), and that their opinions about possible side effects of treatment for PCa should be considered in the decision from 47 to 61% (p?=?0.009).ConclusionA brief conversation tool for the PCa screening discussion was well received in busy primary-care settings and improved patients' knowledge about the screening decision.
| S-EPMC6031706 | biostudies-literature
Project description:Developmental and epileptic encephalopathies (DEEs) are a group of severe, early onset epilepsies characterized by refractory seizures, developmental delay or regression associated with ongoing epileptic activity, and generally poor prognosis. DEE is genetically and phenotypically heterogeneous, and there is a plethora of genetic testing options to investigate the rapidly growing list of epilepsy genes. However, more than 50% of patients with DEE remain without a genetic diagnosis despite state-of-the-art genetic testing. In this review, we discuss the major advances in epilepsy genomics that have surfaced in recent years. The goal of this review is to reach a larger audience and build a better understanding of pathogenesis and genetic testing options in DEE.
| S-EPMC7076331 | biostudies-literature
Project description:Screening elderly men for prostate cancer is not recommended because definitive treatments are unlikely to extend life expectancy.Describe clinical outcomes after a negative prostate biopsy in a population-based cohort of men ages 65 and older.Retrospective cohort study.9,410 Medicare-eligible men who underwent a prostate biopsy in Los Angeles or New Mexico in 1992.We used Medicare and SEER databases to identify a cohort with an initial negative biopsy (n = 7,119) and to ascertain survival, subsequent PSA testing, prostate biopsies, and prostate cancer detection and treatment through 1997.The overall 5-year survival was 79.4% (95% CI 78.4-80.3), but only 74.6% (72.4-76.7) for men ages 75-79 at the time of the initial negative biopsy and 55.0% (51.9-57.9) for men ages 80+. During a median 4.5 years follow-up, a cumulative 75.0% (73.9-76.1) of the cohort underwent PSA testing. Among men ages 75-79 and 80+, the cumulative proportions that underwent PSA testing were 75.4% (73.0-77.8) and 74.3% (71.1-77.5), respectively. Additionally, 29.1% (26.7-31.6) of men ages 75-79 and 20.1% (17.6-23.1) of men ages 80+ underwent repeat prostate biopsy, and 10.9% (9.4-12.7) and 8.3% (6.6-10.4), respectively, were diagnosed with cancer. Among men ages 75+ with localized cancers, approximately 34% received definitive treatment.High proportions of men ages 75+ underwent PSA testing and repeat prostate biopsies after an initial negative prostate biopsy. Given the known harms and uncertain benefits for finding and treating localized cancer in elderly men, most continued PSA testing after a negative biopsy is potentially inappropriate.
| S-EPMC2305754 | biostudies-other
Project description:BackgroundA family history of prostate cancer (PrCa) is a strong risk factor for the disease, indicating that inherited factors are important in this disease. We previously estimated that about 2% of PrCa cases diagnosed ≤ 55 years harbour a BRCA2 mutation and PrCa among BRCA2 carriers has been shown to be more aggressive, with poorer survival.MethodsTo further evaluate the role of BRCA2 in PrCa predisposition, we screened 1864 men with PrCa aged between 36 and 88 years. We analysed the BRCA2 gene using a novel high-throughput multiplex fluorescence heteroduplex detection system developed for the ABI3130xl genetic analyzer.ResultsWe identified 19 protein-truncating mutations, 3 in-frame deletions and 69 missense variants of uncertain significance (UV) in our sample set. All the carriers of truncating mutations developed PrCa at ≤ 65 years, with a prevalence of BRCA2 mutation of 1.20% for cases in this age group.ConclusionBased on the estimated frequency of BRCA2 mutations in the United Kingdom we estimate that germline mutations in the BRCA2 gene confer an ∼ 8.6-fold increased risk of PrCa by age 65, corresponding to an absolute risk of ∼ 15% by age 65. These results suggest that routine testing of early onset PrCa cases for germline BRCA2 mutations will further help to refine the prevalence and risk associated with BRCA2 mutations and may be useful for guiding management options.
| S-EPMC3208504 | biostudies-literature
Project description:INTRODUCTION:In 2014, the Canadian Task Force on Preventive Health Care (CTFPHC) recommended against routine prostate cancer screening with the prostate-specific antigen (PSA) blood test. We surveyed Canadian primary care physicians (PCPs) to understand their opinions and attitudes towards prostate cancer screening in 2016. METHODS:Twenty PCPs piloted the survey to assess its accessibility. We distributed a flyer to 19 633 PCPs as an insert in a large mailed package inviting them to attend a national meeting, and later promoted the survey at the meeting. Multinomial logistic regression models examined factors associated with agreement of key guideline statements and the overall benefit of PSA screening. RESULTS:A total of 1254 PCPs responded (rate of 6.4%); 54.7% of physicians aware of the CTFPHC recommendations report screening less often as a result. Overall, 55.6% of PCPs feel that the risks of PSA screening outweigh the benefits. On multivariable analysis, physicians who did not read the guidelines, did not have an academic appointment, or were in practice for over 20 years were significantly more likely to disagree with the statement that men 55-69 years old should not be screened for prostate cancer with PSA. CONCLUSIONS:Our national survey found that the prostate cancer screening practices of Canadian PCPs varies widely across physician demographic groups, with almost equal numbers for or against. This has significant ethical, medical, and legal implications. The poor response rate to highly incentivized survey request may suggest a reluctance or general apathy towards this subject because of the Task Force recommendations. Future efforts should provide physicians with objective guidance around PSA screening, incorporating input from all stakeholders, including PCPs, urologists, and patients.
| S-EPMC5962947 | biostudies-literature
Project description:Importance:Prostate cancer is the third leading cause of cancer-related death in men in the United States. Although serious, most of these diagnoses are not terminal. Inherited risk for prostate cancer is associated with aggressive disease and poorer outcomes, indicating a critical need for increased genetic screening to identify disease-causing variants that can pinpoint individuals at increased risk for metastatic castration-resistant prostate cancer. Objective:To identify positive (pathogenic, likely pathogenic, and increased risk) germline variants in a large prostate cancer cohort and to evaluate the usefulness of current practice guidelines in recognizing individuals at increased risk for prostate cancer who would benefit from diagnostic genetic testing. Design, Setting, and Participants:Cross-sectional study of data from 3607 men with a personal history of prostate cancer who underwent germline genetic testing between 2013 and 2018 and were unselected for family history, stage of disease, or age at diagnosis. Referral-based testing was performed at a Clinical Laboratory Improvement Amendments/College of American Pathologists-certified diagnostic laboratory. All analysis took place between February 2017 and August 2018. Main Outcomes and Measures:The frequency and distribution of positive germline variants, and the percentage of individuals with prostate cancer who met National Comprehensive Cancer Network (NCCN) guidelines for germline genetic testing. Results:Of 3607 men (mean [SD] age at testing, 67 [9.51] years; mean age at diagnosis, 60 [9.05] years) with a personal diagnosis of prostate cancer who were referred for genetic testing, 620 (17.2%) had positive germline variants, of which only 30.7% were variants in BRCA1/2. Positive variants in HOXB13, a gene associated only with prostate cancer risk, were identified in 30 patients (4.5%). DNA mismatch repair variants with substantial known therapeutic implications were detected in 1.74% of variants in the total population tested. Examination of self-reported family histories indicated that 229 individuals (37%) with positive variants in this cohort would not have been approved for genetic testing using the NCCN genetic/familial breast and ovarian guidelines for patients with prostate cancer. Conclusions and Relevance:Current NCCN guidelines and Gleason scores cannot reliably stratify patients with prostate cancer for the presence or absence of pathogenic germline variants. Most positive genetic test results identified in this study have important management implications for patients and their families, which underscores the need to revisit current guidelines.
| S-EPMC6459112 | biostudies-literature
Project description:Abstract Recent studies show decreasing prostate-specific antigen utilization and increasing incidence of metastatic prostate cancer in the United States after national recommendations against screening in 2012. Yet, whether the increasing incidence of metastatic prostate cancer is consistent in magnitude with the expected impact of decreased screening is unknown. We compared observed incidence of metastatic prostate cancer from the Surveillance, Epidemiology, and End Results program and published effects of continued historical screening and discontinued screening starting in 2013 projected by 2 models of disease natural history, screening, and diagnosis. The observed rate of new metastatic prostate cancer cases in 2017 was 44%-60% of the projected increase under discontinued screening relative to continued screening. Thus, the observed increase in incident metastatic prostate cancer is consistent with the expected impact of reduced screening. Although this comparison does not establish a causal relationship, it highlights the plausible role of decreased screening in the observed trend.
| S-EPMC7791607 | biostudies-literature
Project description:Genetic variation was first shown to be important in systemic lupus erythematosus (SLE or lupus) in the 1970s with associations in the human leukocyte antigen region. Almost four decades later, and with the help of increasingly powerful genetic approaches, more than 25 genes are now known to contribute to the mechanisms that predispose individuals to lupus. Over half of these loci have been discovered in the past 2 years, underscoring the extraordinary success of genome-wide association approaches in SLE. Well-established risk factors include alleles in the major histocompatibility complex region (multiple genes), IRF5, ITGAM, STAT4, BLK, BANK1, PDCD1, PTPN22, TNFSF4, TNFAIP3, SPP1, some of the Fcgamma receptors, and deficiencies in several complement components, including C1q, C4 and C2. As reviewed here, many susceptibility genes fall into key pathways that are consistent with previous studies implicating immune complexes, host immune signal transduction and interferon pathways in the pathogenesis of SLE. Other loci have no known function or apparent immunological role and have the potential to reveal novel disease mechanisms. Certainly, as our understanding of the genetic etiology of SLE continues to mature, important new opportunities will emerge for developing more effective diagnostic and clinical management tools for this complex autoimmune disease.
| S-EPMC3144759 | biostudies-literature
Project description:Many identified genetic risk factors for systemic lupus erythematosus (SLE) contribute to the function of the immune system, which has expanded our understanding of disease pathogenesis. We outline the genetic variants in recently identified SLE-associated loci, the immunological pathways affected by these gene products and the disease manifestations linked to these loci. Pathways potentially influenced by SLE risk variants include: apoptosis, DNA degradation and clearance of cellular debris; antigen presentation; type I interferon, Toll-like receptor and nuclear factor kappa ?B activation; defective clearance of immune complexes containing nuclear antigens; B and T-cell function and signalling; and monocyte and neutrophil function and signalling. These identified SLE susceptibility loci are predominantly common variants that have been confirmed among multiple ancestries, suggesting shared mechanisms in disease aetiology. Ongoing genetic studies continue the investigation of specific functional variants, and their potential consequences on immune dysregulation, enhancing our understanding of links between genotypes and specific disease manifestations. The next generation of sequencing explores the identification of causal rare variants that may contribute robust genetic effects to developing SLE. Novel insights coming from genetic studies of SLE provide the opportunity to elucidate pathogenic mechanisms as well as contribute to the development of innovative therapeutic targets for this complex disease.
| S-EPMC3780983 | biostudies-literature