Androgen deprivation therapy for prostate cancer and neurocognitive disorders: a systematic review and meta-analysis.

BACKGROUND: Prostate cancer is a prevalent disease that urgently needs to address its treatment-related complications. By examining existing evidence on the association between Androgen Deprivation Therapy (ADT) and dementia, this study contributes to the understanding of potential risks. We sought to analyze the currently available evidence regarding the risk of dementia, Alzheimer's disease (AD), vascular dementia, and Parkinson's disease (PD) in patients undergoing ADT. METHODS: A systematic search of PubMed, EMBASE, Scopus, and Google Scholar was performed to identify studies published from the databases' inception to April 2023. Studies were identified through systematic review to facilitate comparisons between studies with and without some degree of controls for biases affecting distinctions between ADT receivers and non-ADT receivers. This review identified 305 studies, with 28 meeting the inclusion criteria. Heterogeneity was assessed using Higgins I2%. Variables with an I2 over 50% were considered heterogeneous and analyzed using a Random-Effects model. Otherwise, a Fixed-Effects model was employed. RESULTS: A total of 28 studies were included for analysis. Out of these, only 1 study did not report the number of patients. From the remaining 27 studies, there were a total of 2,543,483 patients, including 900,994 with prostate cancer who received ADT, 1,262,905 with prostate cancer who did not receive ADT, and 334,682 patients without prostate cancer who did not receive ADT. This analysis revealed significantly increased Hazard Ratios (HR) of 1.20 [1.11, 1.29], p < 0.00001 for dementia, HR 1.26 [1.10, 1.43], p = 0.0007 for Alzheimer's Disease, HR 1.66 [1.40, 1.97], p < 0.00001 for depression, and HR 1.57 [1.31, 1.88], p < 0.00001 for Parkinson's Disease. The risk of vascular dementia was HR 1.30 [0.97, 1.73], p < 0.00001. CONCLUSION: Based on the analysis of the currently available evidence, it suggests that ADT significantly increases the risk of dementia, AD, PD, and depression.

Dissecting the immune suppressive human prostate tumor microenvironment via integrated single-cell and spatial transcriptomic analyses.

The treatment of low-risk primary prostate cancer entails active surveillance only, while high-risk disease requires multimodal treatment including surgery, radiation therapy, and hormonal therapy. Recurrence and development of metastatic disease remains a clinical problem, without a clear understanding of what drives immune escape and tumor progression. Here, we comprehensively describe the tumor microenvironment of localized prostate cancer in comparison with adjacent normal samples and healthy controls. Single-cell RNA sequencing and high-resolution spatial transcriptomic analyses reveal tumor context dependent changes in gene expression. Our data indicate that an immune suppressive tumor microenvironment associates with suppressive myeloid populations and exhausted T-cells, in addition to high stromal angiogenic activity. We infer cell-to-cell relationships from high throughput ligand-receptor interaction measurements within undissociated tissue sections. Our work thus provides a highly detailed and comprehensive resource of the prostate tumor microenvironment as well as tumor-stromal cell interactions.

Mucinous adenocarcinoma of the prostatic urethra after brachytherapy for prostatic adenocarcinoma: a case series.

Mucinous adenocarcinoma of the urethra is extremely rare, even more so in a setting of postradiation therapy, with only 3 cases reported up to date including the first case published by our group in 2011. In the present study, we included the long-term follow-up on our previously reported case and report 3 additional cases. This is the first case series to date of this rare disease entity. The aim of this study is to review the clinicopathologic features of mucinous adenocarcinoma of the prostatic urethra in patients after receiving brachytherapy for prostatic adenocarcinoma. We identified 4 patients with a mean age of 72 years, and a mean interval of 14.8 years from brachytherapy for prostate carcinoma (grade group 1). Patients presented with hematuria or urinary retention. A colonoscopy was performed in three-fourth of patients and was within normal limits. Three patients underwent cystoprostatectomy and 1 had a transurethral resection of the prostate. On gross examination, only tumor formed a 3.5 cm tan-gray, ulcerated, friable, and necrotic mass and 2 displayed either irregular red granular or thickened areas within the prostatic urethra. Abundant extracellular mucin pools dissecting the prostatic stroma were present in all tumors, with clusters of tumor cells floating in the mucin. The mucin pools were lined by pleomorphic pseudostratified columnar mucinous epithelium. Tumors were diffusely positive for CK20, CDX2 (4/4), and AMACR (2/2); they focally expressed CK7 (2/4), and lacked nuclear ß-catenin expression (3/3). PSA, PSAP, NKX3.1, p63, and GATA3 were negative in the tumors tested. Among the 3 patients who underwent radical surgery, 2 had stage 2 tumors (confined to the prostatic urethra and prostate), and 1 had a stage 3 tumor, with seminal vesicle involvement. All 4 patients were alive without disease with a mean follow-up of 4.9 years. In conclusion, brachytherapy-associated mucinous adenocarcinoma of the prostatic urethra displays intestinal-type features as its non-radiation-related counterpart. It appears to lack a villous adenoma component, displays a different immunohistochemical profile with diffuse CK20 and CDX2 positivity, and is associated with lower stage and less aggressive behavior.

Immunotherapy and Checkpoint Inhibitors in Urologic Cancer.

Cancer immunotherapy has transformed urologic oncology by expanding the arsenal of available treatment options and improving outcomes. The number of patients eligible for immune-based cancer treatment continues to increase as indications for currently approved therapies expand with new agents being developed and studied. In this review the authors discuss the major recent clinical developments in immunotherapy for the treatment of urologic cancers.

Do improvements in upper extremity motor function affect changes in bladder management after cervical spinal cord injury?

INTRODUCTION: One of the most important predictors of clean intermittent catheterization (CIC) adoption after spinal cord injury (SCI) is upper extremity (UE) motor function at discharge from rehabilitation. It is not clear however if post-discharge improvements in UE motor function affect future bladder management decisions. METHODS: We assessed persons with cervical SCI in the National Spinal Cord Injury Dataset for the years 2000-2016 who underwent motor examination at discharge from rehabilitation and again at 1-year follow-up. Individuals were stratified based on a previously described algorithm which categorizes the ability to independently perform CIC based upon UE motor scores. Improvements in the predicted ability to self-catheterize over the first year after rehabilitation discharge were evaluated in relation to bladder management. RESULTS: Despite 15% of our SCI cohort improving from "less than able to independently catheterize" to "able to independently catheterize", more patients in the overall cohort dropped out of CIC (175/643 = 27.2%) than adopted CIC (68/548 = 12.4%) (P < .001). We found that in those initially categorized as "less than able to independently catheterize" at the time of rehabilitation discharge, CIC adoption was not significantly different at 1-year follow-up whether or not there was motor improvement to "able to independently catheterize" (12.7% vs 9.2% respectively, P = 0.665). Between these two groups, CIC dropout was also equivalent (34.3% vs 30.0% respectively, P = 0.559). CONCLUSIONS: In the first year after rehabilitation, more overall SCI patients transition away from CIC than convert to CIC. Significant improvements in UE motor function during the first year after rehabilitation discharge do not appear to affect bladder management decisions.

Incorporating PSMA-Targeting Theranostics Into Personalized Prostate Cancer Treatment: a Multidisciplinary Perspective.

Recent developments in prostate-specific membrane antigen (PSMA) targeted diagnostic imaging and therapeutics (theranostics) promise to advance the management of primary, biochemically recurrent, and metastatic prostate cancer. In order to maximize the clinical impact of PSMA-targeted theranostics, a coordinated approach between the clinical stakeholders involved in prostate cancer management is required. Here, we present a vision for multidisciplinary use of PSMA theranostics from the viewpoints of nuclear radiology, medical oncology, urology, and radiation oncology. We review the currently available and forthcoming PSMA-based imaging and therapeutics and examine current and potential impacts on prostate cancer management from early localized disease to advanced treatment-refractory disease. Finally, we highlight the clinical and research opportunities related to PSMA-targeted theranostics and describe the importance of multidisciplinary collaboration in this space.

Demographics, Usage Patterns, and Safety of Male Users of Clomiphene in the United States.

PURPOSE: The aim of this study was to characterize the demographics, usage patterns and complication rates of clomiphene use in male patients. MATERIALS AND METHODS: We retrospectively analyzed male patients from ages 20 to 55 years old who were prescribed clomiphene citrate from 2001 to 2014 using the Truven Health MarketScan, a US claims database. We collected data regarding associated medical diagnoses, diagnostic testing, duration of use, and reported side effects including thrombotic events, vision problems, gynecomastia, mental disorders, liver disease, nausea, or skin problems. RESULTS: In total, 12,318 men took clomiphene and represented the primary study cohort, with a mean age of 37.8 years. The percentage of men prescribed clomiphene increased over the study period, as did the average age of clomiphene users. Associated diagnoses included male infertility (52.0%), testicular hypofunction (13.5%), erectile dysfunction (2.4%), and low libido (0.4%). Associated testing included semen analysis (43.7%), testosterone (23.5%), luteinizing hormone (19.3%), and follicle-stimulating hormone (21.1%) levels. The median time of clomiphene use was 3.6 months, with 63% of men stopping within 6 months. No increased risk of reported clomiphene side effects were apparent in men taking the medication. CONCLUSIONS: There is a rising prevalence of clomiphene usage without associated adverse side effects in the US. The variability in associated diagnoses, diagnostic testing, and duration of use suggest a need for greater awareness of the proper evaluation and treatment of the men who are prescribed clomiphene.

Cognitive Correlates of Hippocampal Atrophy and Ventricular Enlargement in Adults with or without Mild Cognitive Impairment.

We analyzed structural magnetic resonance imaging data from 58 cognitively normal and 101 mild cognitive impairment subjects. We used a general linear regression model to study the association between cognitive performance with hippocampal atrophy and ventricular enlargement using the radial distance method. Bilateral hippocampal atrophy was associated with baseline and longitudinal memory performance. Left hippocampal atrophy predicted longitudinal decline in visuospatial function. The multidomain ventricular analysis did not reveal any significant predictors.

Optical biopsy of penile cancer with in vivo confocal laser endomicroscopy.

INTRODUCTION: Surgical management of penile cancer depends on accurate margin assessment and staging. Advanced optical imaging technologies may improve penile biopsy and organ-sparing treatment. We evaluated the feasibility of confocal laser endomicroscopy for intraoperative assessment of benign and malignant penile tissue. PATIENTS AND METHODS: With institutional review board approval, 11 patients were recruited, 9 with suspected penile cancer, and 2 healthy controls. Confocal laser endomicroscopy using a 2.6-mm fiber-optic probe was performed at 1 or 2 procedures on all subjects, for 13 imaging procedures. Fluorescein was administered intravenously approximately 3 minutes prior to imaging for contrast. Video sequences from in vivo (n = 12) and ex vivo (n = 6) imaging were obtained of normal glans, suspicious lesions, and surgical margins. Images were processed, annotated, characterized, and correlated with standard hematoxylin and eosin histopathology. RESULTS: No adverse events related to imaging were reported. Distinguishing features of benign and malignant penile tissue could be identified by confocal laser endomicroscopy. Normal skin had cells of uniform size and shape, with distinct cytoplasmic membranes consistent with squamous epithelium. Malignant lesions were characterized by disorganized, crowded cells of various size and shape, lack of distinct cytoplasmic membranes, and hazy, moth-eaten appearance. The transition from normal to abnormal squamous epithelium could be identified. CONCLUSIONS: We report the initial feasibility of intraoperative confocal laser endomicroscopy for penile cancer optical biopsy. Pending further evaluation, confocal laser endomicroscopy could serve as an adjunct or replacement to conventional frozen section pathology for management of penile cancer.

Do appreciable changes in the upper extremity motor capability to perform clean intermittent catheterization come about with time after traumatic spinal cord injury?

INTRODUCTION: Bladder dysfunction after spinal cord injury (SCI) often requires clean intermittent catheterization (CIC) or other management strategies. A common dilemma in those desiring to perform CIC independently but lacking the appropriate upper extremity (UE) motor function is the timing of reconstructive surgery. METHODS: We assessed the National Spinal Cord Injury Data Set for the years 2000-2016. Our cohort consisted of persons with cervical SCI, who underwent complete motor examination upon discharge from rehabilitation and at 1-year follow-up. Using a previously published algorithm, UE motor scores were transformed to predict a patient's ability to independently perform CIC. Improvements in the predicted ability to self-catheterize were evaluated. RESULTS: Of the 1428 individuals meeting the inclusion criteria, improvements in the predicted UE motor function necessary to independently self-catheterize were observed in 39%, 42%, and 38% of those deemed possibly able, only able with surgical assistance, or unable to self-catheterize at rehabilitation discharge, respectively. On multivariate analysis, only increasing Association Impairment Scale (AIS) classification and AIS classification improvement over the first year were associated with an increased odds of improving predicted CIC ability (odds ratio [OR] = 1.44 for AIS C and 1.97 for AIS D compared with AIS A, and OR = 1.90 for AIS classification improvement versus stable AIS classification, P < 0.05 for each). CONCLUSION: Improvements in UE motor function to independently perform CIC occur in approximately 40% of persons with cervical SCI in the first year after rehabilitation discharge. Those with incomplete injuries are more likely to improve. These findings should enhance patient bladder management counseling and guide surgeons in determining an appropriate timeline for offering reconstruction.

Examining the relationship between complications and perioperative mortality following radical cystectomy: a population-based analysis.

OBJECTIVE: To examine the incidence of perioperative complications after radical cystectomy (RC) and assess their impact on 90-day postoperative mortality during the index stay and upon readmission. PATIENTS AND METHODS: A total of 57 553 patients with bladder cancer (unweighted cohort: 9137 patients) treated with RC, at 360 hospitals in the USA between 2005 and 2013 within the Premier Healthcare Database, were used for analysis. The 90-day perioperative mortality was the primary outcome. Multivariable regression was used to predict the probability of mortality; models were adjusted for patient, hospital, and surgical characteristics. RESULTS: An increase in the number of complications resulted in an increasing predicted probability of mortality, with a precipitous increase if patients had four or more complications compared to one complication during hospitalisation following RC (index stay; 1.0-9.7%, P < 0.001) and during readmission (2.0-13.1%, P < 0.001). A readmission complication nearly doubled the predicted probability of postoperative mortality as compared to an initial complication (3.9% vs 7.4%, P < 0.001). During the initial hospitalisation cardiac- (odds ratio [OR] 3.1, 95% confidence interval [CI] 1.9-5.1), pulmonary- (OR 4.8, 95% CI 2.8-8.4), and renal-related (OR 3.6, 95% CI 2-6.7) complications had the most significant impact on the odds of mortality across categories examined. CONCLUSIONS: The number and nature of complications have a distinct impact on mortality after RC. As complications increase there is an associated increase in perioperative mortality.

Volitional Voiding of the Bladder after Spinal Cord Injury: Validation of Bilateral Lower Extremity Motor Function as a Key Predictor.

PURPOSE: In many individuals with spinal cord injury a return of volitional bladder voiding is considered more important than regaining motor function. Recently a predictive model using only composite bilateral lower extremity motor scores for levels L2-S1 (range 0 to 50) was proposed by the EMSCI (European Multicenter Study about Spinal Cord Injury) group. The model showed exceptional predictive power with an AUC of 0.912. We sought to further validate the EMSCI model in a national spinal cord injury cohort. MATERIALS AND METHODS: We created models of volitional voiding using the United States NSCID (National Spinal Cord Injury Database) for 2007 to 2016. In addition to testing lower extremity motor scores, we evaluated other patient variables that we hypothesized might affect volitional voiding. RESULTS: Volitional voiding was present in 1,333 of the cohort of 4,327 individuals (30.8%) at 1-year followup. While younger age, female gender, increased sacral sparing, improved AIS (American Spinal Injury Association Impairment Scale) classification and a more caudal sensory level predicted volitional voiding, lower extremity motor scores were most predictive (AUC 0.919). Adding the other patient characteristics did little to improve model performance (full model AUC 0.932). Further analysis of the predictive power of lower extremity motor scores suggested that while the AUC appeared to decrease in persons who were most likely to void volitionally, the performance of the predictive model remained outstanding with a combined AIS C and D AUC of 0.792. CONCLUSIONS: Our study verifies the validity of the EMSCI predictive model of volitional voiding after spinal cord injury. The differing performance of lower extremity motor scores in various AIS classifications should be noted.

Orthotopic Urinary Diversion for Women.

Orthotopic neobladder is a viable option for women undergoing cystectomy for bladder cancer, with excellent oncologic outcomes and a low incidence of urethral recurrence. Careful patient selection is important, as is developing a clear understanding by the patient and her family in what to expect with an orthotopic diversion. Surgical technique is also important in optimizing functional outcomes, such as continence, sexual function, and decreased rate of vaginal fistula formation, and urinary retention.

Predictors of long-term bladder management in spinal cord injury patients-Upper extremity function may matter most.

INTRODUCTION: Clean intermittent catheterization (CIC) is the gold standard for neurogenic bladder management in most patients with spinal cord injury (SCI). There is nonetheless a lack of long-term adherence to CIC, with up to 50% discontinuance at 5-year follow-up. We hypothesize that limitations in upper extremity (UE) motor function represent a strong predictor for long-term CIC adoption. METHODS: We assessed Forms I and II data from the 2000-2013 National SCI Database. Bladder management was determined at initial discharge and 1-year follow-up. Upper extremity (UE) motor scores were transformed using a previously published algorithm to predict a patient's ability to independently self-catheterize. Uni- and multivariable logistic regression modeling was performed to assess risk factors affecting: a) a lack of CIC adoption at rehabilitation discharge, b) CIC discontinuance by 1-year follow-up (CIC "dropout"), and c) adherence to management with an indwelling catheter rather than conversion to CIC at 1-year follow-up. RESULTS: For all three modeled scenarios, UE motor function represented the most significant predictor for lack of CIC adoption (OR range 2.1-6.3, P ≤ 0.003 for all). Other predictors included increasing age (OR 1.01-1.02, P ≤ 0.001 for all models) and female gender (OR 1.6-1.7, P < 0.001 for lack of CIC adoption at discharge). CONCLUSIONS: Among physically limiting factors, impairment in UE motor function appears to be the most significant predictor of a lack of long-term CIC adoption at 1-year follow-up.

3D reconstruction of cystoscopy videos for comprehensive bladder records.

White light endoscopy is widely used for diagnostic imaging of the interior of organs and body cavities, but the inability to correlate individual 2D images with 3D organ morphology limits its utility for quantitative or longitudinal studies of disease physiology or cancer surveillance. As a result, most endoscopy videos, which carry enormous data potential, are used only for real-time guidance and are discarded after collection. We present a computational method to reconstruct and visualize a 3D model of organs from an endoscopic video that captures the shape and surface appearance of the organ. A key aspect of our strategy is the use of advanced computer vision techniques and unmodified, clinical-grade endoscopy hardware with few constraints on the image acquisition protocol, which presents a low barrier to clinical translation. We validate the accuracy and robustness of our reconstruction and co-registration method using cystoscopy videos from tissue-mimicking bladder phantoms and show clinical utility during cystoscopy in the operating room for bladder cancer evaluation. As our method can powerfully augment the visual medical record of the appearance of internal organs, it is broadly applicable to endoscopy and represents a significant advance in cancer surveillance opportunities for big-data cancer research.

Multimodal 3D cancer-mimicking optical phantom.

Three-dimensional (3D) organ-mimicking phantoms provide realistic imaging environments for testing various aspects of optical systems, including for evaluating new probe designs, characterizing the diagnostic potential of new technologies, and assessing novel image processing algorithms prior to validation in real tissue. We introduce and characterize the use of a new material, Dragon Skin (Smooth-On Inc.), and fabrication technique, air-brushing, for fabrication of a 3D phantom that mimics the appearance of a real organ under multiple imaging modalities. We demonstrate the utility of the material and technique by fabricating the first 3D, hollow bladder phantom with realistic normal and multi-stage pathology features suitable for endoscopic detection using the gold standard imaging technique, white light cystoscopy (WLC), as well as the complementary imaging modalities of optical coherence tomography and blue light cystoscopy, which are aimed at improving the sensitivity and specificity of WLC to bladder cancer detection. The flexibility of the material and technique used for phantom construction allowed for the representation of a wide range of diseased tissue states, ranging from inflammation (benign) to high-grade cancerous lesions. Such phantoms can serve as important tools for trainee education and evaluation of new endoscopic instrumentation.