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OBJECTIVE: To evaluate rebiopsy rates and clinicopathologic outcomes in patients after a negative MRI-guided biopsy to better inform the management of these patients. METHODS: Patients were included with a clinical suspicion of prostate cancer (PCa) referred for fusion biopsy for a PI-RADS v2.1 lesion ≥ 3 on multiparametric MRI and a negative MRI fusion biopsy. Biopsies included targeted and systematic cores. Patients with a prior cancer diagnosis were excluded. Both baseline and follow-up clinicopathological data, and long-term PSA values were examined in these patients. Statistical analyses included Wilcoxon rank-sum test and one-way tests. RESULTS: Of 685 total patients, 188 (27%) had a negative fusion biopsy. Of these 88 (47%), 74 (39%), and 26 (14%) had PI-RADS 3, 4, 5 lesions, respectively. Complete follow-up was available for 182/188 patients (97%), with a median of 24 months (interquartile range: 12-38). Post-biopsy PSA levels decreased the first and the second year (-0.24; and -0.84 ng/ml/yrs respectively). In follow-up, 44 patients had an MRI (24%) and 20 had a biopsy (10%). A positive PSA velocity was the only predictive variable for repeat MRI in univariate analysis. On repeat MRI, 9 (27%) patients had disappearance of the initial lesion, 21 (48%) had a lower PIRADS score and 14 (32%) higher. Only 12/182 (6.6%) were found to have PCa during follow-up, of those 7 (3.8%) were clinically significant. CONCLUSION: For patients with nonmalignant biopsy findings after an initial mpMRI showing a suspicious PI-RADS lesion, the majority of patients will have their PSAs return to baseline over time. To support this, repeat MRI frequently demonstrated a disappearance or downgrading of PIRADS lesions. These data support monitoring patients with this clinical scenario.
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Reduced SIRT2 deacetylation and increased p300 acetylation activity leads to a concerted mechanism of hyperacetylation at specific histone lysine sites (H3K9, H3K14, and H3K18) in castration-resistant prostate cancer (CRPC). We examined whether circulating tumor cells (CTCs) identify patients with altered p300/CBP acetylation. CTCs were isolated from 13 advanced PC patients using Exclusion-based Sample Preparation (ESP) technology. Bound cells underwent immunofluorescent staining for histone modifying enzymes (HMEs) of interest and image capture with NIS-Elements software. Using the cBioPortal PCF/SU2C dataset, the response of CRPC to androgen receptor signaling inhibitors (ARSI) was analyzed in 50 subjects. Staining optimization and specificity revealed clear expression of acetyl-p300, acetyl-H3K18, and SIRT2 on CTCs (CK positive, CD45 negative cells). Exposure to A-485, a selective p300/CBP catalytic inhibitor, reduced p300 and H3K18 acetylation. In CRPC patients, a-p300 strongly correlated with its target acetylated H3k18 (Pearson's R = 0.61), and SIRT2 expression showed robust negative correlation with a-H3k18 (R = -0.60). A subgroup of CRPC patients (6/11; 55%) demonstrated consistent upregulation of acetylation based on these markers. To examine the clinical impact of upregulation of the CBP/p300 axis, CRPC patients with reduced deacetylase SIRT2 expression demonstrate shorter response times to ARSI therapy (5.9 vs. 12 mo; p = 0.03). A subset of CRPC patients demonstrate increased p300/CBP activity based on a novel CTC biomarker assay. With further development, this biomarker suite may be used to identify candidates for CBP/p300 acetylation inhibitors in clinical development.
Asunto(s)
Células Neoplásicas Circulantes , Neoplasias de la Próstata Resistentes a la Castración , Masculino , Humanos , Histonas/metabolismo , Sirtuina 2 , Factores de Transcripción p300-CBP/metabolismo , AcetilaciónRESUMEN
BACKGROUND: We report an exceedingly rare case of bilateral external iliac artery pseudoaneurysms causing urinary obstruction and acute renal failure. CASE PRESENTATION: A young man presented with acute severe bilateral testicular pain radiating to the back. Clinical and radiological workup showed bilateral external iliac artery pseudoaneurysms, which caused bilateral ureterohydronephrosis due to urinary obstruction with subsequent renal failure. Management included immediate bilateral external iliac artery endovascular repair and bilateral ureterolysis using a retroperitoneal approach, with resolution of the obstruction and successful endovascular treatment of both pseudoaneurysms. The only identifiable risk factor for cardiovascular disease was cocaine addiction. CONCLUSIONS: This case highlights an unusual and severe clinical presentation of bilateral EIA pseudoaneurysms causing bilateral ureterohydronephrosis and subsequent renal failure. Awareness of this condition may help avoid misdiagnosis and delayed management, which is of utmost importance for a favorable outcome.
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OBJECTIVE: We conducted a systematic review of the literature aiming to identify original studies that have evaluated the effect of genes on the response to medications used to treat psychiatric disorders in children and adolescents. RESULTS: We included 35 original studies on the pharmacogenetics of childhood psychiatric disorders. Thirty-three studies addressed the association between genes particularly dopamine transporter gene (DAT1) and dopamine D4 receptor gene (DRD4) and response to medication for the treatment of attention-deficit/hyperactivity disorder (ADHD). Only two studies investigated atomoxetine as the pharmacological intervention, and the other 31 studies investigated methylphenidate (MPH). One study assessed children with depression and anxiety disorders and another assessed children with autism; in both of them selective serotonin reuptake inhibitors (SSRIs) were the pharmacological intervention. CONCLUSION: The existing literature on the pharmacogenetics of ADHD suggests that response to MPH is influenced by several different polymorphisms, each one exerting a small effect. Genome-wide association studies and multi-center collaborative projects are likely to overcome the barriers for the development of the field, mainly if a priori conceptual hypothesis and rigorous methodological strategies are followed. Future investigations should evaluate, besides improvement of symptoms, emergence of clinically relevant side effects. The lessons we have learned from the progress of the pharmacogenetics of ADHD can be relevant for developing pharmacogenetic studies in other child and adolescent psychiatric disorders.