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Objective: A subset of patients are diagnosed with lethal prostate cancer (CaP) early in life before prostate-specific antigen (PSA) screening is typically initiated. To identify opportunities for improved detection, we evaluated patient sociodemographic factors associated with advanced vs. localized (CaP) diagnosis across the age spectrum., Methods: We conducted a retrospective cohort study using the National Cancer Database, identifying patients diagnosed with CaP from 2004 to 2020. We compared characteristics of patients diagnosed at the advanced (cN1 or M1) versus localized (cT1-4N0M0) stage. Using multivariable logistic regression, we evaluated the associations among patient clinical and sociodemographic factors and advanced diagnosis, stratifying patients by age as ≤55 (before screening is recommended for most patients), 56 to 65, 66 to 75, and ≥76 years., Results: We identified 977,722 patients who met the inclusion criteria. The mean age at diagnosis was 65.3 years and 50,663 (5.1%) had advanced disease. Overall, uninsured (OR = 3.20, 95% CI 3.03-3.78) and Medicaid-insured (OR 2.58, 95% CI 2.48-2.69) vs. privately insured status was associated with higher odds of diagnosis with advanced disease and this effect was more pronounced for younger patients. Among patients ≤55 years, uninsured (OR 4.14, 95% CI 3.69-4.65) and Medicaid-insured (OR 3.39, 95% CI 3.10-3.72) vs. privately insured patients were associated with higher odds of advanced cancer at diagnosis. Similarly, residence in the lowest vs. highest income quartile was associated with increased odds of advanced CaP in patients ≤55 years (OR 1.15, 95% CI 1.02-1.30). Black vs. White race was associated with increased odds of advanced CaP at diagnosis later in life (OR 1.17, 95% CI 1.09-1.25); however, race was not significantly associated with advanced stage CaP in those ≤55 years (P = 0.635)., Conclusions: Sociodemographic disparities in diagnosis at advanced stages of CaP were more pronounced in younger patients, particularly with respect to insurance status. These findings may support greater attention to differential use of early CaP screening based on patient health insurance., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Accurate identification of prostate cancer Gleason grade group remains an important component of the initial management of clinically localized disease. However, Gleason score upgrading (GSU) from biopsy to radical prostatectomy can occur in up to a third of patients treated with surgery. Concern for disease undergrading remains a source of diagnostic uncertainty, contributing to both over-treatment of low-risk disease as well as under-treatment of higher-risk prostate cancer. This review examines the published literature concerning risk factors for GSU from time of biopsy to prostatectomy final pathology. Risk factors identified for Gleason upgrading include patient demographic and clinical factors including age, body mass index, race, prostate volume, and biomarker based assays, including prostate-specific antigen (PSA) density, and testosterone values. In addition, prostate magnetic resonance imaging (MRI) findings have also been associated with GSU. Biopsy-specific characteristics associated with GSU include lower number of biopsy cores and lack of targeted methodology, and possibly increasing percent biopsy core positivity. Recognition of risk factors for disease undergrading may prompt confirmatory testing including repeat sampling or imaging. Continued refinements in imaging guided biopsy techniques may also reduce sampling error contributing to undergrading., Competing Interests: The authors declare that they have no conflicts of interest., (© The Author(s) 2024.)

Prostate cancer (PCa) is the second most common cause of cancer death in males. Targeting MRI-visible lesions has led to an overall increase in the detection of clinically significant PCa compared to the prior practice of random ultrasound-guided biopsy of the prostate. Additionally, advances in MRI-guided minimally invasive focal treatments are providing new options for patients with PCa. This review summarizes the currently utilized real-time MRI-guided interventions for PCa diagnosis and treatment.

Background: While multiparametric MRI (mpMRI) has high sensitivity for detection of clinically significant prostate cancer (CSC), false positives and negatives remain common. Calculators that combine mpMRI with clinical variables can improve cancer risk assessment, while providing more accurate predictions for individual patients. We sought to create and externally validate nomograms incorporating Prostate Imaging Reporting and Data System (PIRADS) scores and clinical data to predict the presence of CSC in men of all biopsy backgrounds., Methods: Data from 2125 men undergoing mpMRI and MR fusion biopsy from 2014 to 2018 at Stanford, Yale, and UAB were prospectively collected. Clinical data included age, race, PSA, biopsy status, PIRADS scores, and prostate volume. A nomogram predicting detection of CSC on targeted or systematic biopsy was created., Results: Biopsy history, Prostate Specific Antigen (PSA) density, PIRADS score of 4 or 5, Caucasian race, and age were significant independent predictors. Our nomogram-the Stanford Prostate Cancer Calculator (SPCC)-combined these factors in a logistic regression to provide stronger predictive accuracy than PSA density or PIRADS alone. Validation of the SPCC using data from Yale and UAB yielded robust AUC values., Conclusions: The SPCC combines pre-biopsy mpMRI with clinical data to more accurately predict the probability of CSC in men of all biopsy backgrounds. The SPCC demonstrates strong external generalizability with successful validation in two separate institutions. The calculator is available as a free web-based tool that can direct real-time clinical decision-making., (Published by Elsevier Inc.)

Objective: The purpose of this study was to determine imaging and clinical features associated with Prostate Imaging Reporting and Data System (PI-RADS) category 5 lesions identified prospectively at multiparametric MRI (mpMRI) that were found benign at MRI-ultrasound fusion targeted biopsy., Materials and Methods: Between January 2015 and July 2016, 325 men underwent prostate mpMRI followed by MRI-ultrasound fusion targeted biopsy of 420 lesions prospectively identified and assessed with PI-RADS version 2. The frequency of clinically significant prostate cancer (defined as Gleason score ≥ 7) among PI-RADS 5 lesions was determined. Lesions with benign pathologic results were retrospectively reassessed by three abdominal radiologists and categorized as concordant or discordant between mpMRI and biopsy results. Multivariate logistic regression was used to identify factors associated with benign disease. Bonferroni correction was used., Results: Of the 98 PI-RADS 5 lesions identified in 89 patients, 18% (18/98) were benign, 10% (10/98) were Gleason 6 disease, and 71% (70/98) were clinically significant prostate cancer. Factors associated with benign disease at multivariate analysis were lower prostate-specific antigen density (odds ratio [OR], 0.88; p < 0.001) and apex (OR, 3.54; p = 0.001) or base (OR, 7.11; p = 0.012) location. On secondary review of the 18 lesions with benign pathologic results, 39% (7/18) were scored as benign prostatic hyperplasia nodules, 28% (5/18) as inflammatory changes, 5% (1/18) as normal anatomic structures, and 28% (5/18) as discordant with imaging findings., Conclusion: PI-RADS 5 lesions identified during routine clinical interpretation are associated with a high risk of clinically significant prostate cancer. A benign pathologic result was significantly correlated with lower prostate-specific antigen density and apex or base location and most commonly attributed to a benign prostatic hyperplasia nodule. Integration of these clinical features may improve the interpretation of high-risk lesions identified with mpMRI.

Purpose: Gleason 6 (3+3) is the most commonly diagnosed prostate cancer among men with prostate specific antigen screening, the most histologically well differentiated and is associated with the most favorable prognosis. Despite its prevalence, considerable debate exists regarding the genetic features, clinical significance, natural history, metastatic potential and optimal management., Materials and Methods: Members of the Young Urologic Oncologists in the Society of Urologic Oncology cooperated in a comprehensive search of the peer reviewed English medical literature on Gleason 6 prostate cancer, specifically focusing on the history of the Gleason scoring system, histological features, clinical characteristics, practice patterns and outcomes., Results: The Gleason scoring system was devised in the early 1960s, widely adopted by 1987 and revised in 2005 with a more restrictive definition of Gleason 6 disease. There is near consensus that Gleason 6 meets pathological definitions of cancer, but controversy about whether it meets commonly accepted molecular and genetic criteria of cancer. Multiple clinical series suggest that the metastatic potential of contemporary Gleason 6 disease is negligible but not zero. Population based studies in the U.S. suggest that more than 90% of men newly diagnosed with prostate cancer undergo treatment and are exposed to the risk of morbidity for a cancer unlikely to cause symptoms or decrease life expectancy. Efforts have been proposed to minimize the number of men diagnosed with or treated for Gleason 6 prostate cancer. These include modifications to prostate specific antigen based screening strategies such as targeting high risk populations, decreasing the frequency of screening, recommending screening cessation, incorporating remaining life expectancy estimates, using shared decision making and novel biomarkers, and eliminating prostate specific antigen screening entirely. Large nonrandomized and randomized studies have shown that active surveillance is an effective management strategy for men with Gleason 6 disease. Active surveillance dramatically reduces the number of men undergoing treatment without apparent compromise of cancer related outcomes., Conclusions: The definition and clinical relevance of Gleason 6 prostate cancer have changed substantially since its introduction nearly 50 years ago. A high proportion of screen detected cancers are Gleason 6 and the metastatic potential is negligible. Dramatically reducing the diagnosis and treatment of Gleason 6 disease is likely to have a favorable impact on the net benefit of prostate cancer screening., (Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Acute kidney injury (AKI) can occur spontaneously or iatrogenically, and rates of AKI continue to rise over the last two decades despite improvements in clinical care and development of preventive strategies. Serum creatinine (sCr) is the current gold standard for measuring changes in kidney function and identifying AKI. Detection of AKI by sCr, however, is delayed and small rises connote significantly increased morbidity and mortality. Diagnosis of AKI by sCr is therefore likely too late to prevent some of the early structural changes that characterize renal injury. Several urinary biomarkers including neutrophil gelatinase-associated lipocalin (NGAL), N-acetyl-β-D-glucosaminidase (NAG), Interleukin-18 (IL-18), kidney injury molecule-1 (KIM-1), liver fatty-acid-binding protein (L-FABP), and cystatin-C, have shown an ability to predict AKI days before an elevation in sCr, and a few even seem to predict AKI-related morbidity and mortality better than sCr alone. A review of the current literature regarding these biomarkers reveals that they individually have unique strengths and weaknesses that can provide different types of information about patients. Currently, NGAL is the urine biomarker with the most promise as an individual marker. However, combining multiple markers to form a 'biomarker panel' along with sCr is an improvement over current clinical risk prediction models alone, and may be able to provide more individualized detail about the type and location of renal injury.

Removal of toxic substances from the blood depends on patent connections between the kidney, ureters and bladder that are established when the ureter is transposed from its original insertion site in the male genital tract to the bladder. This transposition is thought to occur as the trigone forms from the common nephric duct and incorporates into the bladder. Here we re-examine this model in the context of normal and abnormal development. We show that the common nephric duct does not differentiate into the trigone but instead undergoes apoptosis, a crucial step for ureter transposition controlled by vitamin A-induced signals from the primitive bladder. Ureter abnormalities occur in 1-2% of the human population and can cause obstruction and end-stage renal disease. These studies provide an explanation for ureter defects underlying some forms of obstruction in humans and redefine the current model of ureter maturation.

The impact of low level lead exposure on human central nervous system function is a major public health concern. This study addresses the inhibition of the cation pump enzyme Na, K-ATPase by low level lead. Human brain tissue was obtained at autopsy and frozen until use. Brain homogenates were preincubated with PbCl2 for 20 min at 0 degrees C. Inhibition of K-paranitrophenylphosphatase (pNPPase), a measure of the dephosphorylation step of Na,K-ATPase, reached steady state within 10 min. K-pNPPase activity, expressed (mean +/- SEM) as a percentage of control (45.2 +/- 2.7 nmol/mg/min), fell to 96.3 +/- 0.9% at 0.25 uM [PbCl2] to 82.0 +/- 1.6% at 2.5 uM [PbCl2] in homogenates prepared from normal brain. Similar results were obtained with homogenates prepared from brains of patients with a history of alcohol abuse and of those with other miscellaneous conditions. Since the mean blood level of lead in the United States has ranged recently from 9.2 to 16.0 ug/dl (0.44 to 0.77 uM), these results indicate that current in vivo levels of lead exposure may impair important human brain function.

The effects of different light wavelengths at equal irradiance on testis weight, testis protein content, and testis K-paranitrophenylphosphatase (K-pNPPase) activity were studied in the Syrian hamster. One group (long photoperiod) was maintained on a light:dark cycle of 14:10, and another group (short photoperiod) on a cycle of 10:14. Five other groups were maintained on a cycle of 10:14 but with a one hour pulse of equally intense illumination in the middle of the dark period with UV, blue, green, yellow or red light. Animals exposed to a long photoperiod or UV, blue or green light pulses had significantly greater testis weights--up to eightfold greater than those in the yellow or red or short photoperiod groups. Organ protein content closely paralleled organ weight, but the protein/wet weight ratio was consistently higher in the large organ groups. K-pNPPase and Mg-pNPPase activities were significantly higher in the large organ groups, even when expressed per mg protein. Therefore, at a balanced irradiance of 0.2uW/cm2, light wavelength exerts a profound effect on testicular weight, protein content, and K-pNPPase and Mg-pNPPase activities. Testicular involution is a process that is selective with regard to protein biosynthesis.

Rat brain homogenates were preincubated with lead chloride for 20 min at 0 degrees C. Inhibition of K-pnitrophenylphosphatase (K-pNPPase), which measures the dephosphorylation step of Na,K-ATPase, reached steady state within 10 min and was readily reversible. The activity in brain, homogenates prepared from 60-day-old rats, expressed (mean +/- SE) as a percentage of control (100.0 +/- 0.48%), fell to 89.4 +/- 0.52% at 0.25 microM [Pb] to 64.2 +/- 1.65% at 5 microM [Pb]. However, between 5 and 25 microM [Pb] K-pNPPase activity significantly increased (to 85.4 +/- 3.14% at 25 microM) before it again fell above 30 microM. Similar results were obtained with brain homogenates prepared from 10-day-old rats. The multiphasic nature of this dose-response curve did not change with changes in buffer, substrate, anion, test tube order, or test tube composition (glass vs plastic), and appeared to be intrinsic to homogenate-Pb interactions. Microsomal preparations also exhibited multiphasicity, but with a shift in the inflection points. However, there was no multiphasicity with commercial hog brain Na,K-ATPase, suggesting an interaction between a component in the rat brain preparations and lead ion. Addition of boiled rat brain homogenate to commercial Na,K-ATPase resulted in partial protection from lead inhibition but did not produce multiphasicity over the ranges tested. Bovine serum albumin provided less protection. We conclude that there is a complex interaction among K-pNPPase activity, some factor in the rat brain homogenate, and low levels of lead ion.

This was a search for endogenous inhibitors of the cation pump enzyme in normal and ischemic gerbil brain. The first model of ischemia was bilateral common carotid clamping for 30 minutes followed by reperfusion periods of 0, 1, 2.5, and 4 hours. After bilateral clamping, K-paranitrophenylphosphatase (K-pNPPase) activity fell significantly after 0, 1, and 2.5 hours of reflow but only slightly by 4 hours. The second model was decapitation with timed delays of 0, 15, 60 and 240 minutes. There was no decline in K-pNPPase activity after total ischemia produced by decapitation. Thus, the model of partial ischemia was more deleterious to the cation pump enzyme than was the model of total ischemia. All brains contained endogenous K-pNPPase inhibitors. Boiled supernatant fractions inhibited K-pNPPase activity by about 50-60% while Amicon filtrates of brain homogenate inhibited about 12%. Factors in normal and ischemic brain may modify the activity of the cation pump enzyme, but no differences in inhibitory effects were found between normal and ischemic brain extracts.

Adult female Long-Evans rats were maintained on an automatically regulated artificial lighting schedule of light:dark (L:D) 14.5:9.5 for 12 wk. After sacrifice at 0630, 1130, 1600, 1800, 2000, 2200, 0230, or 0400, the pineals were removed, weighed, and assayed for N-acetyltransferase (NAT), melatonin, Mg++-paranitrophenylphosphatase (pNPPase), and K-pNPPase activity. The brains were quickly dissected into the following areas: cerebellum, superior colliculi, inferior colliculi, visual cortex, auditory cortex, sensorimotor cortex, and the hypothalamic area around the suprachiasmatic nucleus. These regions were weighed and 10% sucrose homogenates were prepared for determinations of protein, Mg++-pNPPase, and K+-pNPPase activity. Pineal melatonin rose over six-fold from 144 +/- 70 pg/gland at 1130 to 981 +/- 173 pg/gland at 0230. Similarly, pineal NAT activity rose over 11-fold, from 119 +/- 12 pmol/gland/h to 1315 +/- 232 pmol/gland/h at the same times. K+-pNPPase activity rose by about two-thirds, from 133 +/- 12.8 nmol/gland/h to 224 +/- 22.3 nmol/gland/h from 1600 to 0230. However, when expressed per mg protein, these differences in pNPPase activity were not significant. There were no significant daily rhythms discernible in any of the seven other brain regions across these times. We conclude that cation pump enzyme activity varies only slightly with time in the rat brain and pineal gland, in spite of definite daily rhythms of pineal melatonin and NAT activity.

The 2-deoxyglucose autoradiographic method was used to assess the effects of acute lead exposure on regional brain glucose metabolism in the rat. Eight male Long-Evans hooded rats weighing between 317 and 364 g were cannulated for access to the femoral artery and vein, then given an iv bolus of lead acetate (27 mg Pb/kg as 50 mg PbAc/kg) or saline and observed for the six hours prior to the start of the 2-deoxyglucose experiment. Under controlled conditions of light and sound, the rats were injected with 14C-2-deoxyglucose, then sacrificed after 45 min. The brains were frozen in isopentane cooled to -40 degrees C and 20 micron sections were made. Every third slice was dried on glass slides and apposed to Kodak SB5 X-ray film for five days. Local cerebral metabolic rates (1CMRglu) were measured by densitometry with a computerized image analyzer. Four other rats were similarly given lead (but not 2-deoxyglucose), and blood samples taken at -1, 15 30, 60, 120, and 360 min had corresponding lead levels of 1.8 +/- 1.4, 156 +/- 14.6, 182 +/- 20.4, 155 +/- 17.4, 134 +/- 12.5 and 36 +/- 2.3 ppm. Whole brain lead was 0.45 +/- 0.22 and 1.20 +/- 0.15 ppm in the control and lead-treated groups, respectively (p less than 0.025). Significant reductions in 1CMRglu occurred in the following structures: medial geniculate bodies (15.6 +/- 2.5%), inferior colliculus (13.8 +/- 4.6%), and sensory cortex (9.8 +/- 1.8%). Among those structures showing the greatest percent reductions were several auditory centers, including lateral lemniscus (13.0 +/- 4.6%), auditory cortex (10.4 +/- 4.1%), and superior olivary complex (8.0 +/- 7.0%).(ABSTRACT TRUNCATED AT 250 WORDS)