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.

Application of next-generation imaging in biochemically recurrent prostate cancer.

BACKGROUND: Biochemical recurrence (BCR) following primary interventional treatment occurs in approximately one-third of patients with prostate cancer (PCa). Next-generation imaging (NGI) can identify local and metastatic recurrence with greater sensitivity than conventional imaging, potentially allowing for more effective interventions. This narrative review examines the current clinical evidence on the utility of NGI for patients with BCR. METHODS: A search of PubMed was conducted to identify relevant publications on NGI applied to BCR. Given other relevant recent reviews on the topic, this review focused on papers published between January 2018 to May 2023. RESULTS: NGI technologies, including positron emission tomography (PET) radiotracers and multiparametric magnetic resonance imaging, have demonstrated increased sensitivity and selectivity for diagnosing BCR at prostate-specific antigen (PSA) concentrations <2.0 ng/ml. Detection rates range between 46% and 50%, with decreasing PSA levels for choline (1-3 ng/ml), fluciclovine (0.5-1 ng/ml), and prostate-specific membrane antigen (0.2-0.49 ng/ml) PET radiotracers. Expert working groups and European and US medical societies recommend NGI for patients with BCR. CONCLUSIONS: Available data support the improved detection performance and selectivity of NGI modalities versus conventional imaging techniques; however, limited clinical evidence exists demonstrating the application of NGI to treatment decision-making and its impact on patient outcomes. The emergence of NGI and displacement of conventional imaging may require a reexamination of the current definitions of BCR, altering our understanding of early recurrence. Redefining the BCR disease state by formalizing the role of NGI in patient management decisions will facilitate greater alignment across research efforts and better reflect the published literature.

Biochemical recurrence in patients with prostate cancer after primary definitive therapy: treatment based on risk stratification.

BACKGROUND: Nearly one-third of patients with prostate cancer (PCa) experience biochemical recurrence (BCR) after primary definitive treatment. BCR increases the risk of distant metastasis and mortality in patients with prognostically unfavorable features. These patients are best managed with a tailored treatment strategy incorporating risk stratification using clinicopathological factors, next-generation imaging, and genomic testing. OBJECTIVE: This narrative review examines the utility of risk stratification for the management of patients with BCR in the context of clinical trial data, referencing the latest recommendations by European and US medical societies. METHODS: PubMed was searched for relevant studies published through May 21 2023 on treatment of patients with BCR after radical prostatectomy (RP) or external beam radiotherapy (EBRT). RESULTS: European and US guidelines support the risk-stratified management of BCR. Post-RP, salvage EBRT (with or without androgen deprivation therapy [ADT]) is an accepted treatment option for patients with BCR. Post-EBRT, local salvage therapies (RP, cryotherapy, high-intensity focused ultrasound, stereotactic body radiotherapy, and low-dose-rate and high-dose-rate brachytherapy) have demonstrated comparable relapse-free survival rates but differing adverse event profiles, short and long term. Local salvage therapies should be used for local-only relapses while ADT should be considered for regional or distant relapses. In practice, patients often receive ADT, with varying guidance for intermittent ADT vs. continuous ADT, due to consideration of quality-of-life effects. CONCLUSIONS: Despite a lack of consensus for BCR treatment among guideline associations and medical societies, risk stratification of patients is essential for personalized treatment approaches, as it allows for an informed selection of therapeutic strategies and estimation of adverse events. In lower-risk disease, observation is recommended while in higher-risk disease, after failed repeat local therapy, ADT and/or clinical trial enrollment may be appropriate. Results from ongoing clinical studies of patients with BCR should provide consensus for management.

A multidisciplinary opioid-reduction pathway for robotic prostatectomy: outcomes at year one.

BACKGROUND: Opioid use has come under increasing scrutiny, driven in part by the opioid crisis and growing concerns that up to 6% of opioid-naïve patients may become chronic opioid users. This has resulted in a revaluation of perioperative practice. For this reason, we implemented a multidisciplinary pathway to reduce perioperative opioid usage through education and standardization of practice. METHODS: A single-centre retrospective evaluation was performed after 1 year, comparing the outcomes to those of the 2 years prior to pathway implementation. Comparisons were made between pre- vs. post pathway change by 2:1 propensity matching between cohorts. Univariate linear regression models were created using demographic variables with those that were p < 0.15 included in the final model and using post-operative opioid use (in oral morphine equivalents, OME) as the primary outcome. RESULTS: We found that intraoperative opioid use was significantly decreased 38.2 mg (28.3) vs. 18.0 mg (40.4) oral morphine equivalents (OME), p < .001, as was post-operative opioid use for the duration of the hospitalization, 46.3 mg (49.5) vs. 35.49 mg (43.7) OME, p = 0.002. In subgroup analysis of those that received some intraoperative opioids (n = 152) and those that received no opioids (n = 34), we found that both groups required fewer opioids in the post-operative period 47.0 mg (47.7) vs. 32.4 mg (40.6) OME, p = 0.001, + intraoperative opioids, 62.4 mg (62.9) vs. 35.8 mg (27.7) OME, p = 0.13, - intraoperative opioids. Time to discharge from the PACU was reduced in both groups 215 min (199) vs. 167 min (122), p < 0.003, + intraoperative opioids and 253 min (270) vs. 167 min (105), p = 0.028, - intraoperative opioids. The duration of time until meeting discharge criteria from PACU was 221 min (205) vs. 170 min (120), p = 0.001. Hospital length of stay (LOS) was significantly reduced 1.4 days (1.3) vs. 1.2 days (0.8), p = 0.005. Both sub-groups demonstrated reduced hospital LOS 1.5 days (1.4) vs. 1.2 days (0.8), p = 0.0047, + intraoperative opioids and 1.7 days (1.6) vs. 1.3 days (0.9), p = 0.0583, - intraoperative opioids. Average pain scores during PACU admission and post-PACU until discharge were not statistically different between cohorts. CONCLUSIONS: These findings underscore the effectiveness of a multidisciplinary approach to reduce opioids. Furthermore, it demonstrates improved patient outcomes as measured by both shorter PACU and almost 50% reduction in perioperative opioid use whilst maintaining similar analgesia as indicated by patient-reported pain scores.

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.

Disparities in Prostate Cancer Screening for Transgender Women: An Analysis of the MarketScan Database.

OBJECTIVE: To describe the prevalence of PSA screening amongst transgender women. A transgender individual is someone whose gender identity differs from their birth sex or the societal norms of that assigned sex. There are no formal guidelines regarding PSA screening in transgender women, even though they retain prostatic tissue throughout the gender-affirming process, and there is a lack of existing data to adequately inform clinical practice. METHODS: We identified a cohort of transgender women in the IBM MarketScan dataset using ICD codes. The patient...s eligibility for inclusion was determined on an annual basis for the years 2013-2019. For each year, we required continuous enrollment, 3 months of post-transgender diagnosis follow-up, and aged 40-80 without a prior diagnosis of prostate malignancy. This cohort was compared to cisgender men with similar eligibility criteria. The proportions of individuals undergoing PSA screening were compared using log-binomial regression. RESULTS: A group of 2957 transgender women met the inclusion criteria. We saw significantly lower PSA screening rates among transgender individuals for ages 40-54 and 55-69, but higher rates within the age group 70-80 (P.ß<.ß.001 for all). CONCLUSION: This is the first study evaluating PSA screening rates for insured transgender women. While the rates for screening in transgender women over the age of 70 are higher, the overall rate of screening for all other age groups lags below the general population in this dataset. Further investigation is necessary to provide equitable care for the transgender community.

Re-thinking How We Use Prostate Health Index for African American Men.

OBJECTIVE: To assess how the validated Prostate Health Index (PHI) risk stratifications perform with African American (AA) men and establish a threshold PHI value to potentially rule out the need for prostate biopsy. MATERIALS AND METHODS: AA men meeting FDA-specified indications for PHI testing (>50 years old, PSA 4-10 and negative DRE) who underwent subsequent biopsy were included. Rates of clinically significant prostate cancer (csPCa, as defined by Gleason score ≥7) across accepted PHI stratifications were recorded. Receiver operator curve (ROC) analysis was undertaken to assess PHI performance to predict csPCa. A phi cutoff providing 90% sensitivity was identified. Among AA men with PSA 4-10 ng/mL, the proportion of men who proceeded to biopsy upon physician recommendation was determined. RESULTS: Two hundred nine patients met primary criteria; 91 (43.5%) of which had csPCA. The area under the curve for PHI predicting csPCa was 0.68 (95% CI: 0.61-0.75). Using a phi threshold of <23.0 to avoid biopsy provided 98.9% sensitivity, 9.3% specificity, and would have avoided 4.7% of biopsies. The proportion of those who proceeded to biopsy upon physician recommendation was 81.8%. CONCLUSIONS: PHI demonstrated limited performance in our cohort, with current stratifications featuring misleadingly low cancer detection rates for these men. Furthermore, PHI had limited use to avoid prostate biopsy, as the proposed threshold of 23.0 only allowed 4.7% of men to avoid biopsy. Further work is needed to assess and optimize PHI usage in AA men; nonetheless, it may still have use in increasing compliance with biopsy recommendation.

Initial Longitudinal Outcomes of Risk-Stratified Men in Their Forties Screened for Prostate Cancer Following Implementation of a Baseline Prostate-Specific Antigen.

PURPOSE: Prostate cancer (PCa) screening can lead to potential over-diagnosis/over-treatment of indolent cancers. There is a need to optimize practices to better risk-stratify patients. We examined initial longitudinal outcomes of mid-life men with an elevated baseline prostate-specific antigen (PSA) following initiation of a novel screening program within a system-wide network. MATERIALS AND METHODS: We assessed our primary care network patients ages 40 to 49 years with a PSA measured following implementation of an electronic health record screening algorithm from 2/2/2017-2/21/2018. The multidisciplinary algorithm was developed taking factors including age, race, family history, and PSA into consideration to provide a personalized approach to urology referral to be used with shared decision-making. Outcomes of men with PSA ≥1.5 ng/mL were evaluated through 7/2021. Statistical analyses identified factors associated with PCa detection. Clinically significant PCa (csPCa) was defined as Gleason Grade Group (GGG) ≥2 or GGG1 with PSA ≥10 ng/mL. RESULTS: The study cohort contained 564 patients, with 330 (58.5%) referred to urology for elevated PSA. Forty-nine (8.7%) underwent biopsy; of these, 20 (40.8%) returned with PCa. Eleven (2.0% of total cohort and 55% of PCa diagnoses) had csPCa. Early referral timing (odds ratio [OR], 4.58) and higher PSA (OR, 1.07) were significantly associated with PCa at biopsy on multivariable analysis (both p<0.05), while other risk factors were not. Referred patients had higher mean PSAs (2.97 vs. 1.98, p=0.001). CONCLUSIONS: Preliminary outcomes following implementation of a multidisciplinary screening algorithm identified PCa in a small, important percentage of men in their forties. These results provide insight into baseline PSA measurement to provide early risk stratification and detection of csPCa in patients with otherwise extended life expectancy. Further follow-up is needed to possibly determine the prognostic significance of such mid-life screening and optimize primary care physician-urologist coordination.

Urinary microbiota and prostatic diseases: the key for the lock? A systematic review.

BACKGROUND: Urinary microbiota is implicated in many diseases of the urinary tract. The aim of this study was to perform a systematic review of the role of urinary microbiota in prostatic diseases. METHODS: A PubMed/Medline search was undergone from inception through June 2022 for studies investigating urinary microbiota alterations in prostatic diseases, subdivided into benign prostatic hyperplasia (BPH), prostate cancer (PCa), and chronic prostatitis (CP). Study selection followed the PRISMA statement. Phylum, family, genus and species of each bacterium in cancer patients and controls were recorded. Quality of included studies was evaluated using the Critical Appraisal Skills Program (CASP) checklist for non-randomized studies. RESULTS: A total of 16 studies (4 studies on BPH, 9 studies on PCa and 3 studies on CP) comprising 1486 patients were included in our final analysis. Patients with BPH had a different urinary microbial composition, with a certain pattern proven to be associated with a higher lower urinary tract symptoms severity. Regarding PCa, some bacterial phyla/genera/classes/species were more abundant in PCa and others predicted a higher grade disease. In patients with CP, a different microbiota composition and a higher diversity were found, with the symptom severity being influenced mainly by microbiota composition, favoring aerobic microorganisms. CONCLUSION: Urinary microbiota is implicated in prostatic diseases, especially in BPH, PCa and CP. However, given the relative heterogeneity among published studies, this implication suggests better delineation is needed. Further studies are needed to confirm these findings.

Molecular Mechanisms of Castrate-Resistant Prostate Cancer.

Despite newer therapies for castrate-resistant prostate cancer (CRPC), many patients do not experience a treatment response, and most eventually experience secondary resistance. Various androgen-receptor-related and alternative mechanisms of resistance in CRPC have been identified. This focus on understanding the molecular basis of therapeutic resistance, including lineage plasticity, neuroendocrine transformation, and a range of other implicated genomic alterations will hopefully inform decision-making in the care of this lethal cancer.

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.

Biomarkers Accurately Inform Treatment Decisions in Localized Prostate Cancer.

Biomarkers are now ubiquitous in prostate cancer care. In addition to longstanding use of prostate-specific antigen, we now have secondary serum-, urine-, and tissue-based markers that help in optimizing patient care and patient compliance with therapeutic recommendations. The ship has sailed: these markers are useful and are here to stay.

Focal p53 protein expression and lymphovascular invasion in primary prostate tumors predict metastatic progression.

TP53 is one of the most frequently altered genes in prostate cancer. The precise assessment of its focal alterations in primary tumors by immunohistochemistry (IHC) has significantly enhanced its prognosis. p53 protein expression and lymphovascular invasion (LVI) were evaluated for predicting metastatic progression by IHC staining of representative whole-mounted prostate sections from a cohort of 189 radical prostatectomy patients with up to 20 years of clinical follow-up. Kaplan-Meier survival curves were used to examine time to distant metastasis (DM) as a function of p53 expression and LVI status. TP53 targeted sequencing was performed in ten tumors with the highest expression of p53 staining. Nearly half (49.8%) of prostate tumors examined showed focal p53 expression while 26.6% showed evidence of LVI. p53(+) tumors had higher pathologic T stage, Grade Group, Nuclear Grade, and more frequent LVI. p53 expression of > 5% and LVI, individually and jointly, are associated with poorer DM-free survival. TP53 mutations were detected in seven of ten tumors sequenced. Four tumors with the highest p53 expression harbored likely pathogenic or pathogenic mutations. High levels of p53 expression suggest the likelihood of pathogenic TP53 alterations and, together with LVI status, could enhance early prognostication of prostate cancer progression.

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.

Postoperative changes in cognition and cerebrospinal fluid neurodegenerative disease biomarkers.

OBJECTIVE: Numerous investigators have theorized that postoperative changes in Alzheimer's disease neuropathology may underlie postoperative neurocognitive disorders. Thus, we determined the relationship between postoperative changes in cognition and cerebrospinal (CSF) tau, p-tau-181p, or Aß levels after non-cardiac, non-neurologic surgery in older adults. METHODS: Participants underwent cognitive testing before and 6 weeks after surgery, and lumbar punctures before, 24 h after, and 6 weeks after surgery. Cognitive scores were combined via factor analysis into an overall cognitive index. In total, 110 patients returned for 6-week postoperative testing and were included in the analysis. RESULTS: There was no significant change from before to 24 h or 6 weeks following surgery in CSF tau (median [median absolute deviation] change before to 24 h: 0.00 [4.36] pg/mL, p = 0.853; change before to 6 weeks: -1.21 [3.98] pg/mL, p = 0.827). There were also no significant changes in CSF p-tau-181p or Aß over this period. There was no change in cognitive index (mean [95% CI] 0.040 [-0.018, 0.098], p = 0.175) from before to 6 weeks after surgery, although there were postoperative declines in verbal memory (-0.346 [-0.523, -0.170], p = 0.003) and improvements in executive function (0.394, [0.310, 0.479], p < 0.001). There were no significant correlations between preoperative to 6-week postoperative changes in cognition and CSF tau, p-tau-181p, or Aß42 changes over this interval (p > 0.05 for each). INTERPRETATION: Neurocognitive changes after non-cardiac, non-neurologic surgery in the majority of cognitively healthy, community-dwelling older adults are unlikely to be related to postoperative changes in AD neuropathology (as assessed by CSF Aß, tau or p-tau-181p levels or the p-tau-181p/Aß or tau/Aß ratios). TRIAL REGISTRATION: clinicaltrials.gov (NCT01993836).

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.