Comparative Effectiveness of Partial Gland Cryoablation Versus Robotic Radical Prostatectomy for Cancer Control.

BACKGROUND AND OBJECTIVE: There is an absence of high-level evidence comparing oncologic endpoints for partial gland ablation, and most series use prostate-specific antigen (PSA) rather than biopsy endpoints. Our aim was to compare oncologic outcomes between partial gland cryoablation (PGC) and radical prostatectomy (RP) for prostate cancer. METHODS: This was a retrospective, single-center analysis of subjects treated with PGC (n = 98) or RP (n = 536) between January 2017 and December 2022 as primary treatment for intermediate-risk (Gleason grade group [GG] 2-3) prostate cancer. Oncologic endpoints included surveillance biopsies per protocol after PGC in comparison to serial PSA testing after RP. The primary outcome was treatment failure, defined as a need for any salvage treatment or development of metastatic disease. Treatment failure and survival analyses were conducted using Cox proportional-hazard regression and Kaplan Meier survival curves. KEY FINDINGS AND LIMITATIONS: After applying the inclusion/exclusion criteria, the PGC (n = 75) and RP (n = 298) groups were compared. PGC patients were significantly older (71 vs 64 yr; p < 0.001), but there were no differences in PSA, biopsy GG, or treatment year between the groups. The PGC group had higher rates of treatment failures at 24 mo (33% vs 11%; p < 0.001) and 48 mo (43% vs 14%; p < 0.001). One PGC patient (2.1%) and one RP patient (0.7%) developed metastases by 48-mo follow-up (p = 0.4). On adjusted analysis, PGC was associated with a higher risk of treatment failure (hazard ratio 4.6, 95% confidence interval 2.7-7.9; p < 0.001). Limitations include observational biases associated with the retrospective study design. CONCLUSIONS: This is the first comparative effectiveness study of cancer control outcomes for PGC versus RP. The results demonstrate an almost fivefold higher risk of treatment failure with PGC during short-term follow-up. PATIENT SUMMARY: We compared cancer control outcomes for patients with intermediate-risk prostate cancer treated with partial gland cryoablation versus radical prostatectomy. We found that partial gland cryoablation had an almost fivefold higher risk of treatment failure. Men with prostate cancer should be counseled regarding this difference in treatment failure.

Individual-level home values and cancer mortality in a statewide registry.

BACKGROUND: Prior work assessing disparities in cancer outcomes has relied on regional socioeconomic metrics. These metrics average data across many individuals, resulting in a loss of granularity and confounding with other regional factors. METHODS: Using patients' addresses at the time of diagnosis from the Ohio Cancer Incidence Surveillance System, we retrieved individual home price estimates from an online real estate marketplace. This individual-level estimate was compared with the Area Deprivation Index (ADI) at the census block group level. Multivariable Cox proportional hazards models were used to determine the relationship between home price estimates and all-cause and cancer-specific mortality. RESULTS: A total of 667 277 patients in Ohio Cancer Incidence Surveillance System were linked to individual home prices across 16 cancers. Increasing home prices, adjusted for age, stage at diagnosis, and ADI, were associated with a decrease in the hazard of all-cause and cancer-specific mortality (hazard ratio [HR] = 0.92, 95% confidence interval [CI] = 0.92 to 0.93, and HR = 0.95, 95% CI = 0.94 to 0.95, respectively). Following a cancer diagnosis, individuals with home prices 2 standard deviations above the mean had an estimated 10-year survival probability (7.8%, 95% CI = 7.2% to 8.3%) higher than those with home prices 2 standard deviations below the mean. The association between home price and mortality was substantially more prominent for patients living in less deprived census block groups (Pinteraction < .001) than for those living in more deprived census block groups. CONCLUSION: Higher individual home prices were associated with improved all-cause and cancer-specific mortality, even after accounting for regional measures of deprivation.

Same-Day Discharge vs Inpatient Robotic-Assisted Radical Prostatectomy: Complications, Time-Driven Activity-Based Costing, and Patient Satisfaction.

PURPOSE: Historically, robotic-assisted radical prostatectomy is accompanied by an inpatient hospital admission. The COVID-19 pandemic necessitated a transition to same-day discharge robotic-assisted radical prostatectomy in some centers to free up critically needed inpatient beds. This study aims to compare complications, total health care costs, and patient satisfaction for same-day discharge vs inpatient robotic-assisted radical prostatectomy. MATERIALS AND METHODS: We compared 392 consecutive robotic-assisted radical prostatectomies performed as same-day discharge (n = 206) vs inpatient (n = 186) from February 2020 to November 2022 at 2 academic medical centers. We utilized propensity score analysis to assess the impact of same-day discharge vs inpatient robotic-assisted radical prostatectomy on 30-day complications (primary outcome). Time-driven activity-based costing analysis was applied to compare total costs of robotic-assisted radical prostatectomy care, and we administered a validated Patient Satisfaction Outcome Questionnaire to compare satisfaction scores. RESULTS: Inpatient robotic-assisted radical prostatectomy patients were more likely to be older, self-reported Black race or Hispanic ethnicity, and have higher American Society of Anesthesiologists classification. Complication rates were nonsignificantly lower for same-day discharge vs inpatient robotic-assisted radical prostatectomy (OR 0.87, 95% CI 0.35 to 2.21; P = .8). Same-day discharge vs inpatient robotic-assisted radical prostatectomy demonstrated a $2106 (19%) overall cost reduction. Median satisfaction survey scores were similar, and a clinically significant difference can be excluded. CONCLUSIONS: Same-day discharge robotic-assisted radical prostatectomy is cost-effective and should be the preferred approach in appropriately selected patients.

Trends, Cost, and Predictors of Local Hemostatics Use in Major Urological Surgery.

INTRODUCTION: The national usage and cost trends associated with hemostatic agents in major urologic procedures remain unknown. This study aims to describe the trends, costs, and predictors of local hemostatic use in major urologic surgeries. METHODS: We utilized the Premier Healthcare Database to analyze 385,261 patient encounters between 2000 and 2020. Our primary objective was to describe the usage patterns of topical hemostatic agents in open and laparoscopic/robotic major urological surgeries. The data from the last 5 years (2015-2020) were used to characterize specific cost trends, and multivariable regression analysis was performed to identify predictors of hemostatic agent use in relation to surgical approach, patient, and hospital characteristics. RESULTS: By 2020, at least 1 topical hemostatic agent was used in 37.3% (95% CI: 35.5-39.1) of laparoscopic/robotic prostatectomies and 30.7% (95% CI: 24.2-37.1) of open prostatectomies; 60.8% (95% CI: 57.6-64.1) of laparoscopic/robotic partial nephrectomies and 55.9% (95% CI: 47.3-64.5) of open partial nephrectomies; 40.7% (95% CI: 36.9-44.3) of laparoscopic/robotic radical nephrectomies and 43.2% (95% CI: 38.8-47.6) of open radical nephrectomies; and 40.52% (95% CI: 35.02-46.02) of open radical cystectomies. For the 2015-2020 cohort, predictors for hemostatic agent use varied by surgery type and included gender, race, surgical approach, insurance coverage, geographical location, urbanicity, and attending volume. The cost of the hemostatic agent accounted for less than 1.6% of the total cost of hospitalization for each procedure. CONCLUSIONS: The use of hemostatic agents in major urologic surgeries has grown over the past 2 decades. For all procedures, the specific cost of using a hemostatic agent constitutes a small fraction of the total hospitalization cost and does not vary significantly between open and laparoscopic/robotic approaches. Some patient, surgeon, and hospital characteristics are highly correlated with their use.

Partial-gland Cryoablation Outcomes for Localized Prostate Cancer in Patients with Magnetic Resonance Imaging (MRI)-visible and MRI-invisible Lesions.

Background: Expert consensus recommends treatment of magnetic resonance imaging (MRI)-visible prostate cancer (PCa). Outcomes of partial-gland ablation (PGA) for MRI-invisible PCa remain unknown. Objective: To compare recurrence-free survival, adverse events, and health-related quality of life (HRQoL) outcomes following cryoablation of MRI-visible vs invisible PCa. Design setting and participants: We analyzed data for 75 men who underwent cryoablation therapy between January 2017 and January 2022. PCa identified on MRI-targeted and/or adjacent systematic biopsy cores was defined as MRI-visible, whereas PCa identified on systematic biopsy beyond the targeted zone was defined as MRI-invisible. Outcome measurements and statistical analysis: The primary outcome was recurrence at 12 mo after PGA, defined as the presence of clinically significant PCa (grade group [GG] ≥2) on surveillance biopsy. Adverse events were captured using the Clavien-Dindo classification and HRQoL was captured using the Expanded Prostate Cancer Index-Clinical Practice (EPIC-CP) tool. Results and limitations: Of the 58 men treated for MRI-visible and 17 treated for MRI-invisible lesions, 51 (88%) and 16 (94%), respectively, had at least one surveillance biopsy performed. There were no statistically significant differences in age, race, body mass index, biopsy GG, prostate-specific antigen, prostate volume, or treatment extent between the MRI-visible and MRI-invisible groups. Median follow-up was 44 mo (interquartile range 17-54) and did not significantly differ between the groups. The recurrence rate at 12 mo did not significantly differ between the groups (MRI-visible 39%, MRI-invisible 19%; p = 0.2), and log-rank survival analysis demonstrated no significant difference in recurrence-free survival (p = 0.15). Adverse event rates did not significantly differ (MRI-visible 29%, MRI-invisible 53%; p = 0.092); no man in the MRI-visible group had a Clavien-Dindo grade ≥III complication, while one subject in the MRI-invisible group had a Clavien-Dindo grade III complication. Median EPIC-CP urinary and sexual function scores were similar for the two groups at baseline and at 12 mo after PGA. Study limitations include the retrospective design and small sample size. Conclusions: We observed similar cancer control, adverse event, and HRQoL outcomes for MRI-visible versus MRI-invisible PCa in the first comparison of partial-gland cryoablation. Longer follow-up and external validation of our findings are needed to inform patient selection for PGA for MRI-invisible PCa. Patient summary: Patients with prostate cancer lesions that are not visible on magnetic resonance imaging (MRI) scans who undergo partial gland ablation may have similar treatment outcomes compared to patients with cancer lesions that are visible on MRI.

Adoption and Outcomes of Holmium Laser Enucleation of the Prostate in the United States.

OBJECTIVE: To investigate the utilization of holmium laser enucleation of the prostate (HoLEP) using a large real-world cohort. We compare the safety, readmission, and retreatment rates of HoLEP to other widely used endoscopic surgical interventions for benign prostatic hyperplasia (BPH) including transurethral resection of the prostate (TURP), photoselective vaporization of the prostate, and prostatic urethral lift. METHODS: Men who underwent endoscopic treatments for BPH from 2000 to 2019 were identified in the Premier Healthcare Database (n = 218,793). We compared the relative proportion of each procedure performed and annual physician volume data to identify trends in adoption and utilization. Readmission and retreatment rates were determined at both 30- and 90-days postoperation. Multivariable logistic regression was used to assess the association between procedure type and outcomes. RESULTS: HoLEP accounted for 3.2% (n = 6967) of all the BPH procedures performed between 2000 and 2019 and increased from 1.1% of the procedures in 2008 to 4% in 2019. Patients undergoing HoLEP had lower odds of 90-days readmission compared to TURP (Odds ratio (OR) 0.87, p = 0.025). HoLEP had similar odds of retreatment compared to TURP at both 1-year (OR 0.96, p = 0.7) and 2-years (OR 0.98, p = 0.9), while patients undergoing photoselective vaporization of the prostate and prostatic urethral lift were more likely to retreat within 2-years (OR 1.20, P < 0.001; OR 1.87, P < 0.001). CONCLUSION: HoLEP is a safe therapy for BPH with lower readmission and comparable retreatment rates to the gold standard TURP. Despite this, the utilization of HoLEP has lagged behind other endoscopic procedures and remains low.

Insurer coverage of prostate cancer biomarkers.

INTRODUCTION: Several recently-developed prostate cancer (CaP) biomarkers are recommended per national guidelines, yet feasibility of obtaining these tests is unknown. We used a national database to assess insurance coverage of CaP biomarkers. MATERIALS AND METHODS: Insurance policies regarding 4K Score, ExoDx, My Prostate Score, Prostate Cancer Antigen 3, Prostate Health Index, and SelectMDx as of January 1, 2022 were extracted from the policy reporter database. Coverage was defined as a biomarker being deemed medically necessary, conditionally covered, or covered with prior authorization. Overall rates of biomarker coverage were compared by insurance type and region using Chi-squared test. SelectMDx was not covered by any queried policies and was omitted from analysis. RESULTS: A total of 186 insurance plans were identified among 131 payers. Of the 186 plans, 109 (59%) covered at least one biomarker, with prior authorization required for 38 (35%) of these plans. Prostate Cancer Antigen 3 and 4K Score had higher rates of coverage compared to ExoDx, Prostate Health Index, and My Prostate Score (52% and 43% vs. 26%, 26%, and 5%, respectively, P < 0.01). Medicare plans had higher rates of coverage compared to non-Medicare plans (80% Medicare vs. 17% commercial, 15% federal employer, and 13% Medicaid, P < 0.01), and nationwide plans had higher coverage rates compared to regional plans (43% nationwide vs. 32% midwest, 27% northeast, 25% south, 24% west, P < 0.01). Covered biomarkers under Medicare plans were less likely to require prior authorization compared to those covered by non-Medicare plans (12% Medicare vs. 63% commercial, 100% federal employer, 70% Medicaid, P < 0.01). CONCLUSIONS: Coverage of novel CaP biomarkers are relatively robust for Medicare plans but sparse for non-Medicare plans, with the majority of non-Medicare plans requiring prior authorization. Non-Medicare eligible men may face significant barriers to obtaining these tests.

Protocol of a multicentre randomised controlled trial assessing transperineal prostate biopsy to reduce infectiouscomplications.

INTRODUCTION: Approximately one million prostate biopsies are performed annually in the USA, and most are performed using a transrectal approach under local anaesthesia. The risk of postbiopsy infection is increasing due to increasing antibiotic resistance of rectal flora. Single-centre studies suggest that a clean, percutaneous transperineal approach to prostate biopsy may have a lower risk of infection. To date, there is no high-level evidence comparing transperineal versus transrectal prostate biopsy. We hypothesise that transperineal versus transrectal prostate biopsy under local anaesthesia has a significantly lower risk of infection, similar pain/discomfort levels and comparable detection of non-low-grade prostate cancer. METHODS AND ANALYSIS: We will perform a multicentre, prospective randomised clinical trial to compare transperineal versus transrectal prostate biopsy for elevated prostate-specific antigen in the first biopsy, prior negative biopsy and active surveillance biopsy setting. Prostate MRI will be performed prior to biopsy, and targeted biopsy will be conducted for suspicious MRI lesions in addition to systematic biopsy (12 cores). Approximately 1700 men will be recruited and randomised in a 1:1 ratio to transperineal versus transrectal biopsy. A streamlined design to collect data and to determine trial eligibility along with the two-stage consent process will be used to facilitate subject recruitment and retention. The primary outcome is postbiopsy infection, and secondary outcomes include other adverse events (bleeding, urinary retention), pain/discomfort/anxiety and critically, detection of non-low-grade (grade group ≥2) prostate cancer. ETHICS AND DISSEMINATION: The Institutional Review Board of the Biomedical Research Alliance of New York approved the research protocol (protocol number #18-02-365, approved 20 April 2020). The results of the trial will be presented at scientific conferences and published in peer-reviewed medical journals. TRIAL REGISTRATION NUMBER: NCT04815876.

Immune Checkpoint Inhibitors and Long-term Survival of Patients With Metastatic Urothelial Cancer.

This cohort study uses published clinical trial data to assess long-term survival of patients with metastatic urothelial carcinoma who are treated with immune checkpoint inhibitors.

Use of Active Surveillance vs Definitive Treatment Among Men With Low- and Favorable Intermediate-Risk Prostate Cancer in the US Between 2010 and 2018.

This cross-sectional study of data from the Surveillance, Epidemiology and End Results database assesses temporal trends in the use of active surveillance and watchful waiting vs definitive treatment in men with low- and favorable intermediate­risk prostate cancer in the US between 2010 and 2018.

Price transparency of prostate cancer care in the United States: An analysis of pricing and disclosure following the centers for medicare and medicaid mandate.

BACKGROUND: Starting January 1, 2021, Centers for Medicare and Medicaid Services required United States hospitals to publicly disclose prices of their services provided. We analyzed publicly-disclosed prices of prostate cancer-related services. METHODS: All United States hospitals were queried for publicly-disclosed prices of total and free prostate-specific antigen, prostate magnetic resonance imaging, prostate biopsy, radical prostatectomy, and intensity-modulated radiation therapy as of May 2022. Prices were adjusted by regional price parity. Hospitals disclosing prices were compared with non-disclosing hospitals. RESULTS: Of 6013 hospitals, 3840 (64%) disclosed pricing for at least one prostate cancer-related service. Compared to non-disclosing hospitals, disclosing hospitals had higher median gross annual revenue ($318,502,426 vs. $62,930,436, p < 0.001) and were more likely to be non-profit (56% vs. 30%, p < 0.001), academic-affiliated (46% vs. 13%, p < 0.001), and in neighborhoods with low hospital density (68% vs 62%, p < 0.001). Self-pay prices were higher than insurance-negotiated prices for all services (p < 0.001) other than prostate biopsy. The range of pricing was widest for self-pay prostatectomy, with a 32-fold difference from 90th to 10th percentile ($47,445 to $1476). Self-pay prices of total prostate-specific antigen, magnetic resonance imaging, biopsy, intensity-modulated radiation therapy, and prostatectomy were higher at academic vs. non-academic, for-profit vs. non-profit hospitals, and hospitals in the top quartile of gross annual revenue vs. the third and fourth quartiles (p < 0.01). Self-pay prices of prostate biopsy and prostatectomy were higher in urban vs. rural neighborhoods and neighborhoods with high vs. low hospital density (p < 0.001). CONCLUSIONS: Self-pay prices of prostate cancer services were generally higher than insurance-negotiated prices and were higher at for-profit hospitals, academic hospitals, and hospitals in the highest quartile of gross annual revenue. Higher neighborhood hospital density was not associated with higher likelihood of price disclosure nor lower pricing of services, suggesting that local competition does not lead to lower prices and may disincentivize disclosure of prices.

Clipless Robotic-assisted Radical Prostatectomy and Impact on Outcomes.

BACKGROUND: The use of surgical clips for athermal dissection of the lateral prostatic pedicles and ligation during pelvic lymph node dissection (PLND) while performing robotic-assisted radical prostatectomy (RARP) has been the gold standard. Clips are used to prevent thermal injury of the unmyelinated nerve fibers and lymphceles, respectively. OBJECTIVE: To compare oncological and functional outcomes of a new technique of clipless, lateral pedicle control and PLND with RARP with bipolar energy (RARP-bi) versus the standard RARP technique with clips (RARP-c). DESIGN, SETTING, AND PARTICIPANTS: A retrospective study was conducted among 338 men who underwent RARP between July 2018 and March 2020. SURGICAL PROCEDURE: RARP-c versus RARP-bi. MEASUREMENTS: We prospectively collected data and retrospectively compared demographic, clinicopathological, and functional outcome data. Urinary as well as sexual function was assessed using the Expanded Prostate Cancer Index for Clinical Practice, and complications were assessed using Clavien-Dindo grading. Multivariable regression modeling was used to examine whether the technical approach of RARP-bi versus RARP-c was associated with positive surgical margins (PSMs) or sexual and urinary function scores. RESULTS AND LIMITATIONS: A total of 144 (43%) and 194 (57%) men underwent RARP-bi and RARP-c, respectively. Overall, there were no differences in functional and oncological outcomes between the two approaches. On multivariable regression analysis, the RARP-bi technique was not associated with significant differences in PSMs (odds ratio [OR] = 1.04, 95% confidence interval [CI] 0.6-1.8; p = 0.9), sexual function (OR = 0.4, 95% CI 0.1-1.5; p = 0.8), or urinary function (OR = 0.5, 95% CI 0.2-1.4; p = 0.2). The overall 30-d complication rates (12% vs 16%, p = 0.5) and bladder neck contracture rates (2.1% vs 3.6%, p = 0.5) were similar between the two groups. There was no difference in lymphocele complications (1.4% vs 0.52%, p = 0.58). All complications were of Clavien-Dindo grade I-II. CONCLUSIONS: Despite the concerns for an increased risk of nerve injury secondary to the use of bipolar energy for prostatic pedicle dissection, we demonstrate that this technique is oncologically and functionally similar to the standard approach with surgical clips. There was no difference in complications or lymphocele formation for techniques with versus without clips. PATIENT SUMMARY: We describe a modified technique for prostatic pedicle dissection during robotic-assisted radical prostatectomy, which utilizes bipolar energy and is associated with shorter operative time, without compromising functional or oncological outcomes.

Endovascular management of a large renal artery aneurysm: a case report and review of the literature.

BACKGROUND: A renal artery aneurysm is a rare clinical presentation that can be found incidentally on imaging or during workup for refractory hypertension. Its presentation can be similar to that of a renal artery pseudoaneurysm, but the etiologies of the two vascular lesions differ. We present a patient who had an incidental finding of a large renal artery aneurysm that was managed with endovascular embolization. We also describe the literature surrounding the etiology, presentation and management of both renal artery aneurysms and renal artery pseudoaneurysms. CASE PRESENTATION: A 62-year-old man was referred to a urologic oncologist for workup of a newly found renal mass. Initial imaging with computed tomography showed a homogenous, well-circumscribed mass arising from the right kidney. Further evaluation with Doppler ultrasonography demonstrated pulsatile flow within the renal mass that was concerning for a renal artery pseudoaneurysm. The patient initially underwent a diagnostic angiogram by interventional radiology and was found to have a true renal artery aneurysm. Interventional radiology considered placement of a covered stent or angioembolization, but treatment was deferred due to concern for compromising the patient's renal function. Patient was subsequently transferred to a neighboring hospital for management by vascular surgery. After considering both open surgical and endovascular approaches, the patient ultimately underwent angioembolization of the renal artery aneurysm. Short-term follow-up showed successful exclusion of the aneurysm with minimal adverse effects to the patient. CONCLUSIONS: Our case report documents a unique case of an incidentally found large renal artery aneurysm that was successfully managed with endovascular embolization. Renal artery aneurysms and renal artery pseudoaneurysms, which can present similarly on imaging, are important diagnostic considerations in a patient presenting with a new renal mass. While open surgical approaches can be used to repair aneurysms, endovascular approaches using stenting or angioembolization are safe and effective options for treating renal aneurysms and renal pseudoaneurysms.

National practice patterns for lymph node irradiation in 197,000 men receiving external beam radiotherapy for localized prostate cancer.

PURPOSE: Controversy surrounds the benefit of pelvic lymph node irradiation (PLN-RT) in localized prostate cancer (CaP). Our objective was to determine the practice patterns and predictors of PLN-RT in a national cohort. MATERIALS AND METHODS: The National Cancer Data Base (2005-2015) was leveraged to obtain men diagnosed with nonmetastatic CaP treated with external beam radiotherapy (n = 197,378). Multivariable logistic regressions were used to assess temporal trends and factors associated with PLN-RT. RESULTS: PLN-RT occurred in 37% of patients overall, which increased to 41% by 2015. When stratified by risk group, there was no significant difference in PLN-RT over time in low, favorable intermediate, unfavorable intermediate, or high-risk CaP. PLN-RT increased for men with very high-risk disease (51%-60%; odds ratio per year 1.34, 95% confidence inrerval 1.06-1.70, P = 0.013). Increased odds of PLN-RT was associated with higher risk disease, addition of hormone therapy, treatment at community hospitals, and shorter patient travel distance to treatment facilities. Surprisingly, 26% and 34% of low and favorable intermediate risk CaP received PLN-RT, respectively. Predictors of PLN-RT among these patients included treatment at a community practice and use of brachytherapy or hormone therapy. CONCLUSIONS: PLN-RT occurred in about one-third of men receiving external beam radiotherapy and increased over time, mostly in men with very high-risk CaP for unclear reasons. Of concern, over one-quarter of low-risk men receive PLN-RT. Further work is needed to understand the heterogeneity in PLN-RT use. We await the completion of RTO G 09-24 to better understand the role of PLN-RT for men with localized CaP.

Neuronal-Targeted TFEB Accelerates Lysosomal Degradation of APP, Reducing Aß Generation and Amyloid Plaque Pathogenesis.

In AD, an imbalance between Aß production and removal drives elevated brain Aß levels and eventual amyloid plaque deposition. APP undergoes nonamyloidogenic processing via α-cleavage at the plasma membrane, amyloidogenic ß- and γ-cleavage within endosomes to generate Aß, or lysosomal degradation in neurons. Considering multiple reports implicating impaired lysosome function as a driver of increased amyloidogenic processing of APP, we explored the efficacy of targeting transcription factor EB (TFEB), a master regulator of lysosomal pathways, to reduce Aß levels. CMV promoter-driven TFEB, transduced via stereotactic hippocampal injections of adeno-associated virus particles in APP/PS1 mice, localized primarily to neuronal nuclei and upregulated lysosome biogenesis. This resulted in reduction of APP protein, the α and ß C-terminal APP fragments (CTFs), and in the steady-state Aß levels in the brain interstitial fluid. In aged mice, total Aß levels and amyloid plaque load were selectively reduced in the TFEB-transduced hippocampi. TFEB transfection in N2a cells stably expressing APP695, stimulated lysosome biogenesis, reduced steady-state levels of APP and α- and ß-CTFs, and attenuated Aß generation by accelerating flux through the endosome-lysosome pathway. Cycloheximide chase assays revealed a shortening of APP half-life with exogenous TFEB expression, which was prevented by concomitant inhibition of lysosomal acidification. These data indicate that TFEB enhances flux through lysosomal degradative pathways to induce APP degradation and reduce Aß generation. Activation of TFEB in neurons is an effective strategy to attenuate Aß generation and attenuate amyloid plaque deposition in AD. SIGNIFICANCE STATEMENT: A key driver for AD pathogenesis is the net balance between production and clearance of Aß, the major component of amyloid plaques. Here we demonstrate that lysosomal degradation of holo-APP influences Aß production by limiting the availability of APP for amyloidogenic processing. Using viral gene transfer of transcription factor EB (TFEB), a master regulator of lysosome biogenesis in neurons of APP/PS1 mice, steady-state levels of APP were reduced, resulting in decreased interstitial fluid Aß levels and attenuated amyloid deposits. These effects were caused by accelerated lysosomal degradation of endocytosed APP, reflected by reduced APP half-life and steady-state levels in TFEB-expressing cells, with resultant decrease in Aß production and release. Additional studies are needed to explore the therapeutic potential of this approach.

Enhancing astrocytic lysosome biogenesis facilitates Aß clearance and attenuates amyloid plaque pathogenesis.

In sporadic Alzheimer's disease (AD), impaired Aß removal contributes to elevated extracellular Aß levels that drive amyloid plaque pathogenesis. Extracellular proteolysis, export across the blood-brain barrier, and cellular uptake facilitate physiologic Aß clearance. Astrocytes can take up and degrade Aß, but it remains unclear whether this function is insufficient in AD or can be enhanced to accelerate Aß removal. Additionally, age-related dysfunction of lysosomes, the major degradative organelles wherein Aß localizes after uptake, has been implicated in amyloid plaque pathogenesis. We tested the hypothesis that enhancing lysosomal function in astrocytes with transcription factor EB (TFEB), a master regulator of lysosome biogenesis, would promote Aß uptake and catabolism and attenuate plaque pathogenesis. Exogenous TFEB localized to the nucleus with transcriptional induction of lysosomal biogenesis and function in vitro. This resulted in significantly accelerated uptake of exogenously applied Aß42, with increased localization to and degradation within lysosomes in C17.2 cells and primary astrocytes, indicating that TFEB is sufficient to coordinately enhance uptake, trafficking, and degradation of Aß. Stereotactic injection of adeno-associated viral particles carrying TFEB driven by a glial fibrillary acidic protein promoter was used to achieve astrocyte-specific expression in the hippocampus of APP/PS1 transgenic mice. Exogenous TFEB localized to astrocyte nuclei and enhanced lysosome function, resulting in reduced Aß levels and shortened half-life in the brain interstitial fluid and reduced amyloid plaque load in the hippocampus compared with control virus-injected mice. Therefore, activation of TFEB in astrocytes is an effective strategy to restore adequate Aß removal and counter amyloid plaque pathogenesis in AD.