Cognitive and Cerebrospinal Fluid Alzheimer's Disease-related Biomarker Trajectories in Older Surgical Patients and Matched Nonsurgical Controls.

BACKGROUND: Anesthesia and/or surgery accelerate Alzheimer's disease pathology and cause memory deficits in animal models, yet there is a lack of prospective data comparing cerebrospinal fluid (CSF) Alzheimer's disease-related biomarker and cognitive trajectories in older adults who underwent surgery versus those who have not. Thus, the objective here was to better understand whether anesthesia and/or surgery contribute to cognitive decline or an acceleration of Alzheimer's disease-related pathology in older adults. METHODS: The authors enrolled 140 patients 60 yr or older undergoing major nonneurologic surgery and 51 nonsurgical controls via strata-based matching on age, sex, and years of education. CSF amyloid ß (Aß) 42, tau, and p-tau-181p levels and cognitive function were measured before and after surgery, and at the same time intervals in controls. RESULTS: The groups were well matched on 25 of 31 baseline characteristics. There was no effect of group or interaction of group by time for baseline to 24-hr or 6-week postoperative changes in CSF Aß, tau, or p-tau levels, or tau/Aß or p-tau/Aß ratios (Bonferroni P > 0.05 for all) and no difference between groups in these CSF markers at 1 yr (P > 0.05 for all). Nonsurgical controls did not differ from surgical patients in baseline cognition (mean difference, 0.19 [95% CI, -0.06 to 0.43]; P = 0.132), yet had greater cognitive decline than the surgical patients 1 yr later (ß, -0.31 [95% CI, -0.45 to -0.17]; P < 0.001) even when controlling for baseline differences between groups. However, there was no difference between nonsurgical and surgical groups in 1-yr postoperative cognitive change in models that used imputation or inverse probability weighting for cognitive data to account for loss to follow up. CONCLUSIONS: During a 1-yr time period, as compared to matched nonsurgical controls, the study found no evidence that older patients who underwent anesthesia and noncardiac, nonneurologic surgery had accelerated CSF Alzheimer's disease-related biomarker (tau, p-tau, and Aß) changes or greater cognitive decline.

Clinical utility of multiple secondary combined tests in prostate cancer screening.

INTRODUCTION: The clinical utility of concurrent Prostate Health Index (PHI) and ExosomeDx Prostate Intelliscore (EPI) testing is unclear. We sought to examine the performance of combined PHI and EPI testing on men undergoing elevated PSA work up. MATERIALS AND METHODS: Patients who received both EPI and PHI testing were identified from an institutional database of men referred to urology for an elevated total PSA. Cut points of EPI > 15.6 and PHI ≥ 36 were used to denote a positive test. Patients were placed into one of four groups determined by combination of EPI and PHI results. Demographic variables and biopsy recommendations were compared between groups. The concordance of test positivity between EPI and PHI was compared by Cohen's kappa. Demographic variables and secondary testing results were compared between patients' compliant and non-compliant with prostate biopsy recommendation. Biopsy pathology was compared between groups. RESULTS: A total of 162 patients had both EPI and PHI testing. Median age was 65 years, with a median PSA of 6.64 ng/mL. Age (p = 0.001), PSA (< 0.001) and biopsy recommendation (< 0.001) differed between combined secondary screening test result groups. Seventy-five percent of patients with both a positive EPI and PHI were found to have prostate cancer, with 54.2% being ≥ Gleason 7. Cohen's kappa was 0.19, indicating poor concordance. The AUC of EPI and PHI for clinically significant cancer was 0.563 (95% CI: 0.4331-0.6923) and 0.685 (95% CI: 0.569-0.8) (p = 0.147). CONCLUSIONS: Concurrently positive EPI and PHI indicate increased prostate cancer risk, with combined usage potentially influencing biopsy recommendation and compliance.

Relationship Between Depression/Anxiety and Cognitive Function Before and 6 Weeks After Major Non-Cardiac Surgery in Older Adults.

OBJECTIVE: To determine the relationship between affective measures and cognition before and after non-cardiac surgery in older adults. METHODS: Observational prospective cohort study in 103 surgical patients age ≥ 60 years old. All participants underwent cognitive testing, Center for Epidemiologic Studies-Depression, and State Anxiety Inventory screening before and 6 weeks after surgery. Cognitive test scores were combined by factor analysis into 4 cognitive domains, whose mean was defined as the continuous cognitive index (CCI). Postoperative global cognitive change was defined by CCI change from before to after surgery, with negative CCI change indicating worsened postoperative global cognition and vice versa. RESULTS: Lower global cognition before surgery was associated with greater baseline depression severity (Spearman's r = -0.30, p = 0.002) and baseline anxiety severity (Spearman's r = -0.25, p = 0.010), and these associations were similar following surgery (r = -0.36, p < 0.001; r = -0.26, p = 0.008, respectively). Neither baseline depression or anxiety severity, nor postoperative changes in depression or anxiety severity, were associated with pre- to postoperative global cognitive change. CONCLUSIONS: Greater depression and anxiety severity were each associated with poorer cognitive performance both before and after surgery in older adults. Yet, neither baseline depression or anxiety symptoms, nor postoperative change in these symptoms, were associated with postoperative cognitive change.

Successful Diagnosis and Treatment of Occult Prostate Cancer Despite Multiple Negative Prostate Biopsies and Negative Prostate MRIs.

Prostate-specific antigen (PSA) values above 100 ng/mL often suggest metastatic prostate cancer. We present the case of a patient with a PSA of 110 ng/mL, 4 negative prostate biopsies, and 4 negative prostate MRIs. After his fifth MRI revealed a PI-RADS 5 lesion, he underwent his fifth transrectal biopsy; this revealed Gleason 3 + 4 = 7. He was found to have organ-confined pT2 disease on subsequent radical prostatectomy pathology. This case highlights that there may be no PSA for which one can assume metastatic disease with certainty. Depending on life expectancy, patients with extremely elevated PSA may still warrant a full staging workup.

How I Use It: The Exosome Diagnostics (EPI) prostate cancer biomarker utility in urology and primary care.

Prostate-specific antigen (PSA) screening remains the mainstay for early detection of prostate cancer. Although PSA is a nonspecific prostate cancer biomarker, its specificity for high grade prostate cancer can be enhanced by pre-biopsy liquid biomarkers including the Exosome Dx Prostate IntelliScore (EPI) test. EPI is a stand-alone urine genomic test that measures 3 exosome-derived gene expression signatures without the need for digital rectal examination (DRE) or inclusion of standard of care parameters in the test algorithm. EPI has broad clinical utility as a risk stratification tool for clinically significant high grade prostate cancer in men considering diagnostic prostate biopsy (MRI-targeted and systematic biopsy). During the COVID-19 pandemic, the EPI At-Home Collection Kit was introduced and quickly became an important component of tele-urology. The EPI test has emerged as a prioritization tool for primary care referral to urologists and for prostate biopsy scheduling. EPI provides an objective and actionable genomic risk assessment tool for high grade prostate cancer and is a critical part of the informed decision-making regarding biopsy (targeted, systematic or both) in both urology and primary care practices.

Impact of Late Dosing on Testosterone Suppression with 2 Different Leuprolide Acetate Formulations: In Situ Gel and Microsphere. An Analysis of United States Clinical Data.

PURPOSE: Nonadherence to dosing schedules for androgen deprivation therapy increases the risk of testosterone escape for patients with prostate cancer. Two approved formulations of leuprolide acetate, the most commonly prescribed androgen deprivation therapy in the United States, use different extended release delivery technologies: an in situ gel and microspheres. We evaluated the prevalence and impact of late dosing on testosterone suppression for gel and microsphere formulations of leuprolide acetate. MATERIALS AND METHODS: We retrospectively analyzed records of patients with prostate cancer treated with gel or microsphere delivery of leuprolide acetate. Analyses used 2 definitions of "month," "28-day" (late dosing after day 28, 84, 112 or 168) and "extended" (late dosing after day 32, 97, 128 and 194). Frequencies of late dosing and associated testosterone values were calculated. RESULTS: A total of 2,038 patients received gel and 8,360 received microsphere formulations of leuprolide acetate. More than 80% and 27% of injections were late for 28-day and extended month, respectively. For 28-day month late injections 10% (gel delivery) and 14% (microsphere delivery) of testosterone values were above 50 ng/dl, and 25% (gel) vs 33% (microsphere) were above 20 ng/dl. For extended month 18% (gel) vs 25% (microsphere) were above 50 ng/dl, and 34% (gel) vs 44% (microsphere) were above 20 ng/dl. Microsphere leuprolide acetate was 1.5 times more likely to have testosterone above 50/20 ng/dl vs gel. Least square mean testosterone was 34 ng/dl (gel) vs 46 ng/dl (microsphere) for 28-day month, and 48 ng/dl (gel) vs 76 ng/dl (microsphere) for extended month. CONCLUSIONS: Leuprolide acetate therapies were frequently administered late. Gel formulation demonstrated higher rates of testosterone 50 ng/dl or less and 20 ng/dl or less than microsphere formulation. Optimal testosterone suppression can impact prostate cancer progression and patient survival, and differences in extended release technology for androgen deprivation therapy appear relevant.

Aggressive prostate cancer masquerading as acute prostatitis.

Prostatitis is a common cause of prostate-specific antigen (PSA) elevation but can masquerade underlying prostate cancer. We present a case of a man with undiagnosed prostate cancer whose initial PSA elevation of > 999.0 ng/mL was initially ascribed entirely to prostatitis. In the setting of possible prostatitis clinicians should avoid the knee jerk reaction to blame the totality of PSA elevation on prostatitis. A greatly elevated PSA may be a sign of an underlying prostate cancer and should be explored in the proper clinical setting.

The Impact of Late Luteinizing Hormone-Releasing Hormone Agonist Dosing on Testosterone Suppression in Patients with Prostate Cancer: An Analysis of United States Clinical Data.

PURPOSE: We evaluated the timeliness of androgen deprivation therapy dosing, the impact of dosing nonadherence on testosterone, and the frequency of testosterone and prostate specific antigen testing in patients with prostate cancer. MATERIALS AND METHODS: We retrospectively analyzed the records of 22,860 patients with prostate cancer treated with luteinizing hormone-releasing hormone agonists. Analyses were done using 2 definitions of month, including a 28-day month (late dosing after day 28, 84, 112 or 168) and an extended month (late after day 32, 97, 128 or 194) for 1, 3, 4 and 6-month formulations, respectively. The prevalence of late dosing, associated testosterone values, and the frequency of testosterone and prostate specific antigen testing were assessed. Statistical significance was assessed with the unpaired t-test. RESULTS: Of the injections 84% and 27% were late for the 28-day and extended month analyses, respectively. For the 28-day month 60% and 29% of injections were late by more than 1 and more than 2 weeks, respectively. Of testosterone values 4% were greater than 50 ng/dl for early/on time injections using both definitions, and 15% and 27% were greater than 50 ng/dl when late, and for the 28-day month and the extended month, respectively. For early/on time vs late injections 22% vs 31% of testosterone values were greater than 20 ng/dl for the 28-day month and 21% vs 43% for the extended month. Mean testosterone was higher when late (49 ng/dl for 28-day month, 79 ng/dl for extended month) vs early/on time (both 21 ng/dl). Of the injections prostate specific antigen measurements were performed in 83% and testosterone assessment was done in only 13%. CONCLUSIONS: Luteinizing hormone-releasing hormone agonists were frequently (84%) administered later than the schedules used in pivotal trials. Nearly half of the late testosterone values for the extended month were greater than 20 ng/dl and mean testosterone was almost double the castration level. Elevated testosterone remained unidentified with infrequent testing.

Are COVID-19 Delays a Basis for Concern? Can We Use This for Future Good?

Judd W. Moul, MD, discusses the effects that COVID-19 may have on the outcomes for patients with cancer in the United States and throughout the world.

Managing Prostate Cancer Surgical Patients during the COVID-19 Pandemic: A Brief Report of the Duke Cancer Institute's Initial Experience.

The coronavirus disease 2019 pandemic has rapidly placed tremendous stress on health systems around the world. In response, multiple health systems have postponed elective surgeries in order to conserve hospital beds and personal protective equipment, minimize patient traffic, and prevent unnecessary utilization and exposure of healthcare workers. The American College of Surgeons released the following statement on March 13, 2020: "Each hospital, health system and surgeon should thoughtfully review all scheduled elective procedures with a plan to minimize, postpone, or cancel electively scheduled operations, endoscopes, or other invasive procedures until we have passed the predicted inflection point in the exposure graph and can be confident that our health care infrastructure can support a potentially rapid and overwhelming uptick in critical patient care needs." In our state, North Carolina, Governor Roy Cooper requested that all hospitals postpone elective and non-urgent procedures and surgeries effective March 23, 2020.

Evaluation and Active Treatment versus Active Surveillance of Localized Prostate Cancer in Renal Transplant Patients in the Era of Low and Very Low Risk Prostate Cancer.

PURPOSE: Current trends in renal transplantation, such as improved allograft/recipient survival and expanded organ transplantation eligibility criteria in older recipients, are concomitant with increasingly detected low risk prostate cancer in candidates for or recipients of renal transplantation. We reviewed the evidence regarding prostate cancer screening, diagnosis and management in renal transplant candidates and recipients. We focused on published reports of prostate cancer incidence and diagnosis in patients with end stage renal disease, pretransplant screening recommendations, and recommendations regarding waiting time between treatment and active wait listing after the prostate cancer diagnosis in renal transplant candidates. In addition, we examined the natural history of prostate cancer development after renal transplantation in the setting of standard immunosuppression. MATERIALS AND METHODS: We reviewed the English language literature using search terms including prostate cancer, end stage renal disease, renal transplantation, prostate cancer screening, prostate specific antigen, prostate cancer treatment and active surveillance in various combinations. RESULTS: Prostate cancer screening is still widely done in almost all patients with end stage renal disease before and after transplantation. Active treatment of any patients with prostate cancer and a 5-year waiting period before transplantation can negatively affect the collective pool of participants and the overall survival of patients on dialysis. Several groups have proposed a shorter waiting time to kidney transplantation in patients with low risk prostate cancer. CONCLUSIONS: There are no standardized guidelines for screening and management of prostate cancer before and after transplantation. In the era of low risk prostate cancer end stage renal disease is a significant competing mortality risk factor. The role of active surveillance in these complex cases has yet to be well investigated. Further studies and nomograms are urged to integrate risk stratified screening and treatment protocols before and after renal transplantation.

How I do it: Apalutamide use in non-metastatic castrate resistant prostate cancer.

Urologists have been using oral nonsteroidal antiandrogens (AA) for 30 years as a component of combined androgen blockade. In February 2018, a new third generation AA, apalutamide, became available for the first time for non-metastatic (M0) castrate resistant prostate cancer (CRPC). Apalutamide was found to delay the presence of metastases (metastases free survival-MFS) by approximately 2 years versus placebo in M0 CRPC. While overall survival benefit has yet to be established, the MFS benefit is clinically meaningful and urology practices should be equipped to manage patients using this new oral agent. Since the majority of patients remain under urologic care when this disease stage develops and because the drug is straightforward to administer, urology practices are ideal to identify and treat. The objective of this brief article is to discuss the typical patient profile for use of apalutamide and to review the pros and cons of use and common side effects and management.

Most Gleason 8 Biopsies are Downgraded at Prostatectomy-Does 4 + 4 = 7?

PURPOSE: Nonrepresentative biopsy sampling of prostate cancers with a biopsy Gleason score of 8 can adversely influence decisions regarding androgen deprivation in men receiving primary radiation therapy. The frequency of and factors associated with downgrading Gleason 8 biopsies at prostatectomy are not well known. MATERIALS AND METHODS: We used records from NCDB (National Cancer Database), a hospital based registry in the United States, of 72,556 men with prostate cancer diagnosed from 2010 to 2013, including 5,474 with Gleason 8 biopsies and no other high progression risk criteria according to NCCN (National Comprehensive Cancer Network®) Guidelines®. The prevalence of Gleason 8 downgrading was calculated. Generalized estimating equation multivariable regression models were used to estimate the prevalence ratios and 95% CIs of downgrading by demographic and clinical factors, and evaluate the association of Gleason 8 downgrading with cT (clinical T) to pathological T category up staging. RESULTS: Of 5,474 Gleason 8 biopsies in men lacking other high progression risk criteria 3,263 (60%) were downgraded, changing the progression risk category from high to intermediate. A higher prevalence of Gleason 8 downgrading was significantly and independently associated with decreasing age, African American race, lower cT category, lower prostate specific antigen quartile and certain combinations of primary and secondary Gleason grades (3 + 5 greater than 4 + 4 greater than 5 + 3). Gleason 8 downgrading in cases of cT less than 3 was independently and significantly associated with a lower prevalence of up staging (prevalence ratio = 0.65, 95% CI 0.61-0.69). CONCLUSIONS: Downgrading Gleason 8 biopsies is common. Patient evaluation based on Gleason 8 biopsies often results in overestimating progression risk and disease extent, which may lead to overtreatment.

Androgen Receptor Targeted Treatments of Prostate Cancer: 35 Years of Progress with Antiandrogens.

PURPOSE: Antiandrogens inhibit the androgen receptor and have an important role in the treatment of prostate cancer. This review provides a historical perspective on the development and clinical benefit of antiandrogens in the treatment of prostate cancer. MATERIALS AND METHODS: We searched PubMed® for clinical trials with the search terms antiandrogens and prostate cancer combined with drug names for antiandrogens. This article represents a collaboration of clinical investigators who have made critical scientific contributions leading to the approval of antiandrogens for treating patients with prostate cancer. RESULTS: Antiandrogens differ in chemical structure and exert varying efficacy and safety profiles. The unfavorable therapeutic index of steroidal antiandrogens led to replacement by safer nonsteroidal agents. Flutamide, nilutamide and bicalutamide, which were designed to target the androgen receptor, were developed primarily for use in combination with castration to provide combined androgen blockade. Modest clinical benefits were observed with the combination of first generation antiandrogens and castration vs castration alone. With increased knowledge of androgen receptor structure and its biological functions a new generation of antiandrogens without agonist activity was designed to provide more potent inhibition of the androgen receptor. Randomized clinical trials in patients with metastatic, castration resistant prostate cancer showed significant survival benefits, which led to the approval of enzalutamide in August 2012. Apalutamide was recently approved while darolutamide is not yet approved in the United States. These next generation antiandrogens are being actively tested in earlier disease states such as nonmetastatic prostate cancer. Evolving knowledge of resistance mechanisms to androgen receptor targeted treatments will stimulate research and drug discovery for additional compounds. Further testing in nonmetastatic castration resistant prostate cancer as well as castration sensitive disease states will hopefully augment our ability to treat a broader spectrum of patients with prostate cancer. CONCLUSIONS: Antiandrogens have already provided important benefits for prostate cancer treatment. Greater knowledge about the structural and functional biology of the androgen receptor in prostate cancer will facilitate further discovery and development of further improved antiandrogens with enhanced clinical activity in patients with advanced metastatic disease. Testing these new agents earlier in the course of prostate cancer may further improve the survival and quality of life of patients with current local and/or systemic treatment modalities.

How Can We Effectively Address the Medical and Psychological Concerns of Survivors of Pelvic Malignancies?

Sexual and urinary morbidities resulting from treatment of pelvic malignancies are common. These treatment sequelae are significantly bothersome to patients and challenging to address. Awareness of these complications is critical in order to properly counsel patients regarding potential side effects and to facilitate prompt diagnosis and management. Addressing these issues often necessitates a coordinated multidisciplinary approach; however, the effort required often translates into improvement in patient quality of life. Herein we review the sexual and urinary side effects that may arise during or after treatment of pelvic malignancies.

The Contemporary Role of Multiparametric Magnetic Resonance Imaging in Active Surveillance for Prostate Cancer.

PURPOSE OF REVIEW: Growing research supports the use of multiparametric magnetic resonance imaging (mpMRI) for the evaluation of localized prostate cancer (PCa). We highlight contemporary evidence supporting its use in active surveillance (AS). RECENT FINDINGS: The emerging approach to localized PCa favors risk-adapted screening, image-guided biopsies, and selective therapeutic interventions. mpMRI is increasingly critical to achieve each of these aims. Early evidence suggests a value of mpMRI before initial biopsy to guide fusion targeting and to rule out non-organ confined disease as well as in the initiation and serial monitoring of men on AS. There remain concerns regarding understaging cancer with mpMRI and the standardization of expertise beyond the most experienced centers. mpMRI is emerging as a critical decision point for staging localized PCa and guiding AS strategies. While there is increasing enthusiasm, the optimal clinical scenario and sequencing remains to be defined.

Over half of contemporary clinical Gleason 8 on prostate biopsy are downgraded at radical prostatectomy.

INTRODUCTION: Contemporary clinical guidelines utilize the highest Gleason sum (HGS) in any one core on prostate biopsy to determine prostate cancer treatment. Here, we present a large discrepancy between prostate cancer risk stratified as high risk on biopsy and their pathology after radical prostatectomy. MATERIALS AND METHODS: We retrospectively reviewed 1424 men who underwent either open or robotic-assisted prostatectomy between 2004 and 2015. We analyzed 148 men who were diagnosed with HGS 8 on prostate biopsy. Biopsy and prostatectomy pathology were compared in aggregate and over 1 year time intervals. Chi-squared test, Fisher's exact test, Student's t-test, and Wilcoxon Rank-Sum test were used for statistical analysis. RESULTS: A total of 61.5% (91/148) of clinical HGS 8 diagnoses were downgraded on prostatectomy, with 58.8% (87/148) downgraded to Gleason 7 (Gleason 4 + 3 n = 59; Gleason 3 + 4 n = 28). Factors associated with downgrading include lower prostate-specific antigen (PSA) at biopsy (median 6.8 ng/mL versus 9.1 ng/mL, p < 0.001), number of Gleason 8 biopsy cores (median 1 versus 2, p < 0.02), presence of Gleason pattern 3 on biopsy cores (67.9% versus 44.8%, p < 0.03), pT2 staging (72.4% versus 55.1%, p < 0.04), positive margins (53.9% versus 69.1%, p < 0.04), extracapsular extension (53.4% versus 74.1%, p < 0.02), and smaller percent tumor (median 10% versus 15%, p < 0.004). CONCLUSION: The large percentage of pathology downgrading of biopsy-diagnosed HGS 8 suggests suboptimal risk-stratification that may lead to suboptimal treatment strategies and much patient distress. Our study adds great urgency to the efforts refining prostate cancer clinical assessment.

Screening for familial and hereditary prostate cancer.

Prostate cancer (PC) has the highest degree of genetic transmission of any form of malignancy. In some families, the hereditary pattern is so strong as to mimic an autosomal dominance trait. We reviewed the known predisposing genetic markers to assess possible strategies for screening of families at risk. We carried out a systematic literature search using the Pubmed service of the National Center for Biotechnology Information (NCBI) and several gene libraries, including the NCBI SNP Library, the Online Mendelian Inheritance in Man® Catalog of Human Genes and Genetic Disorders (OMIM) and SNPedia to obtain known gene loci, SNPs and satellite markers associated with PC. We further cross referenced information on identified loci comparing data from different articles and gene reference sites. Whenever possible, we recorded the odds ratio (OR) for the allele associated with PC. In multiple different linkage studies, many independent PC associated loci have been identified on separate chromosomes. Genome-wide association studies have added many more markers to the set derived from linkage investigations. A subset of the alleles is associated with early onset and aggressive cancer. Due to the great heterogeneity, the OR for any one allele predicting future development of this malignancy is low. The strongest predictors are the BRCA2 mutations, and the highly penetrant G84E mutation in HOXB13. The presence of multiple risk alleles is more highly predictive than a single allele. Technical limitations on screening large panels of alleles are being overcome. It is appropriate to begin supplementing prostate specific antigen testing with alleles, such as BRCA2 and HOXB13, disclosed by targeted genomic analysis in families with an unfavorable family cancer history. Future population studies of PC should include genomic sequencing protocols, particularly in families with a history of PC and other malignancies.