Perioperative nivolumab versus observation in patients with renal cell carcinoma undergoing nephrectomy (PROSPER ECOG-ACRIN EA8143): an open-label, randomised, phase 3 study.

BACKGROUND: The standard of care for patients with intermediate-to-high risk renal cell carcinoma is partial or radical nephrectomy followed by surveillance. We aimed to investigate use of nivolumab before nephrectomy followed by adjuvant nivolumab in patients with high-risk renal cell carcinoma to determine recurrence-free survival compared with surgery only. METHODS: In this open-label, randomised, phase 3 trial (PROSPER EA8143), patients were recruited from 183 community and academic sites across the USA and Canada. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1, with previously untreated clinical stage T2 or greater or Tany N+ renal cell carcinoma of clear cell or non-clear cell histology planned for partial or radical nephrectomy. Selected patients with oligometastatic disease, who were disease free at other disease sites within 12 weeks of surgery, were eligible for inclusion. We randomly assigned (1:1) patients using permuted blocks (block size of 4) within stratum (clinical TNM stage) to either nivolumab plus surgery, or surgery only followed by surveillance. In the nivolumab group, nivolumab 480 mg was administered before surgery, followed by nine adjuvant doses. The primary endpoint was investigator-reviewed recurrence-free survival in patients with renal cell carcinoma assessed in all randomly assigned patients regardless of histology. Safety was assessed in all randomly assigned patients who started the assigned protocol treatment. This trial is registered with ClinicalTrials.gov, NCT03055013, and is closed to accrual. FINDINGS: Between Feb 2, 2017, and June 2, 2021, 819 patients were randomly assigned to nivolumab plus surgery (404 [49%]) or surgery only (415 [51%]). 366 (91%) of 404 patients assigned to nivolumab plus surgery and 387 (93%) of 415 patients assigned to surgery only group started treatment. Median age was 61 years (IQR 53-69), 248 (30%) of 819 patients were female, 571 (70%) were male, 672 (88%) were White, and 77 (10%) were Hispanic or Latino. The Data and Safety Monitoring Committee stopped the trial at a planned interim analysis (March 25, 2022) because of futility. Median follow-up was 30·4 months (IQR 21·5-42·4) in the nivolumab group and 30·1 months (21·9-41·8) in the surgery only group. 381 (94%) of 404 patients in the nivolumab plus surgery group and 399 (96%) of 415 in the surgery only group had renal cell carcinoma and were included in the recurrence-free survival analysis. As of data cutoff (May 24, 2023), recurrence-free survival was not significantly different between nivolumab (125 [33%] of 381 had recurrence-free survival events) versus surgery only (133 [33%] of 399; hazard ratio 0·94 [95% CI 0·74-1·21]; one-sided p=0·32). The most common treatment-related grade 3-4 adverse events were elevated lipase (17 [5%] of 366 patients in the nivolumab plus surgery group vs none in the surgery only group), anaemia (seven [2%] vs nine [2%]), increased alanine aminotransferase (ten [3%] vs one [<1%]), abdominal pain (four [1%] vs six [2%]), and increased serum amylase (nine [2%] vs none). 177 (48%) patients in the nivolumab plus surgery group and 93 (24%) in the surgery only group had grade 3-5 adverse events due to any cause, the most common of which were anaemia (23 [6%] vs 19 [5%]), hypertension (27 [7%] vs nine [2%]), and elevated lipase (18 [5%] vs six [2%]). 48 (12%) of 404 patients in the nivolumab group and 40 (10%) of 415 in the surgery only group died, of which eight (2%) and three (1%), respectively, were determined to be treatment-related. INTERPRETATION: Perioperative nivolumab before nephrectomy followed by adjuvant nivolumab did not improve recurrence-free survival versus surgery only followed by surveillance in patients with high-risk renal cell carcinoma. FUNDING: US National Institutes of Health National Cancer Institute and Bristol Myers Squibb.

Treatment of Non-Metastatic Muscle-Invasive Bladder Cancer: AUA/ASCO/SUO Guideline (2017; Amended 2020, 2024).

PURPOSE: Although representing approximately 25% of patients diagnosed with bladder cancer, muscle-invasive bladder cancer (MIBC) carries a significant risk of death that has not significantly changed in decades. Increasingly, clinicians and patients recognize the importance of multidisciplinary collaborative efforts that take into account survival and quality of life concerns. This guideline provides a risk-stratified, clinical framework for the management of muscle-invasive urothelial bladder cancer. METHODOLOGY/METHODS: In 2024, the MIBC guideline was updated through the AUA amendment process in which newly published literature is reviewed and integrated into previously published guidelines in an effort to maintain currency. The amendment allowed for the incorporation of additional literature released since the previous 2020 amendment. The updated search gathered literature from May 2020 to November 2023. This review identified 3739 abstracts, of which 46 met inclusion criteria.When sufficient evidence existed, the body of evidence was assigned a strength rating of A (high), B (moderate), or C (low) for support of Strong, Moderate, or Conditional Recommendations. In the absence of sufficient evidence, additional information is provided as Clinical Principles and Expert Opinions. RESULTS: Updates were made regarding neoadjuvant/adjuvant chemotherapy, radical cystectomy, pelvic lymphadenectomy, multi-modal bladder preserving therapy, and future directions. Further revisions were made to the methodology and reference sections as appropriate. CONCLUSIONS: This guideline seeks to improve clinicians' ability to evaluate and treat patients with MIBC based on currently available evidence. Future studies will be essential to further support or refine these statements to improve patient care.

Diagnosis and Treatment of Non-Muscle Invasive Bladder Cancer: AUA/SUO Guideline: 2024 Amendment.

PURPOSE: The purpose of this American Urological Association (AUA)/Society of Urologic Oncology (SUO) guideline amendment is to provide a useful reference on the effective evidence-based treatment strategies for non-muscle invasive bladder cancer (NMIBC). MATERIALS AND METHODS: In 2023, the NMIBC guideline was updated through the AUA amendment process in which newly published literature is reviewed and integrated into previously published guidelines in an effort to maintain currency. The amendment allowed for the incorporation of additional literature released since the previous 2020 amendment. The updated search gathered literature from July 2019 to May 2023. This review identified 1918 abstracts, of which 75 met inclusion criteria.When sufficient evidence existed, the body of evidence was assigned a strength rating of A (high), B (moderate), or C (low) in support of Strong, Moderate, or Conditional Recommendations. In the absence of sufficient evidence, additional information is provided as Clinical Principles and Expert Opinions. RESULTS: Updates were made to statements on variant histologies, urine markers after diagnosis of bladder cancer, intravesical therapy, BCG maintenance, enhanced cystoscopy, and future directions. Further revisions were made to the methodology and reference sections as appropriate. CONCLUSIONS: This guideline seeks to improve clinicians' ability to evaluate and treat patients with NMIBC based on currently available evidence. Future studies will be essential to further support or refine these statements to improve patient care.

Multifocal pupillographic objective perimetry for assessment of early diabetic retinopathy and generalised diabetes-related tissue injury in persons with type 1 diabetes.

BACKGROUND: To examine the potential utility of five multifocal pupillographic objective perimetry (mfPOP) protocols, in the assessment of early diabetic retinopathy (DR) and generalised diabetes-related tissue injury in subjects with type 1 diabetes (T1D). METHODS: Twenty-five T1D subjects (age 41.8 ± 12.1 (SD) years, 13 male) with either no DR (n = 13) or non-proliferative DR (n = 12), and 23 age and gender-matched control subjects (age 39.7 ± 12.9 years, 9 male) were examined by mfPOP using five different stimulus methods differing in visual field eccentricity (central 30° and 60°), and colour (blue, yellow or green test-stimuli presented on, respectively, a blue, yellow or red background), each assessing 44 test-locations per eye. In the T1D subjects, we assessed 16 metabolic status and diabetes complications variables. These were summarised as three principal component analysis (PCA) factors. DR severity was assessed using Early Treatment of Diabetic Retinopathy Study (ETDRS) scores. Area under the curve (AUC) from receiver operator characteristic analyses quantified the diagnostic power of mfPOP response sensitivity and delay deviations for differentiating: (i) T1D subjects from control subjects, (ii) T1D subjects according to three levels of the identified PCA-factors from control subjects, and (iii) TID subjects with from those without non-proliferative DR. RESULTS: The two largest PCA-factors describing the T1D subjects were associated with metabolic variables (e.g. body mass index, HbA1c), and tissue-injury variables (e.g. serum creatinine, vibration perception). Linear models showed that mfPOP per-region response delays were more strongly associated than sensitivities with the metabolic PCA-factor and ETDRS scores. Combined mfPOP amplitude and delay measures produced AUCs of 90.4 ± 8.9% (mean ± SE) for discriminating T1D subjects with DR from control subjects, and T1D subjects with DR from those without of 85.9 ± 8.8%. The yellow and green stimuli performed better than blue on most measures. CONCLUSIONS/INTERPRETATION: In T1D subjects, mfPOP testing was able to identify localised visual field functional abnormalities (retinal/neural reflex) in the absence or presence of mild DR. mfPOP responses were also associated with T1D metabolic status, but less so with early stages of non-ophthalmic diabetes complications.

Demographic disparities of penile cancer in Appalachian Kentucky.

INTRODUCTION: Appalachian Kentucky is a region characterized by poor healthcare literacy and access. We investigate the disparities in demographic distribution and outcomes of penile squamous cell carcinoma (pSCC) in rural Kentucky. MATERIALS AND METHODS: Data were retrieved for patients with pSCC from 1995-2015 from the Kentucky Cancer Registry and the Surveillance, Epidemiology and End Results Program (SEER) and were used to investigate differences between Appalachian Kentucky and the remainder of the state and country. RESULTS: The incidence of pSCC from 1995-2015 in Appalachian Kentucky was over 60% higher than non-Appalachian regions (2.6 vs. 1.6 cases/100,000 people). Nearly 40% were from Appalachian counties. They presented with similar grade and pT stage at diagnosis but were more likely to have pN+ disease (p < 0.001). Rates of cancer-specific mortality (CSM) were similar between the two regions, but patients with CSM exhibited shorter survival interval from diagnosis in Appalachia (median 20 vs. 26 months, p = 0.016). Compared to national SEER data, patients from Appalachian Kentucky presented with similar grade and stage but exhibited higher rates of CSM (24.0% vs. 20.1%, p = 0.029). African Americans (AA) comprised only 5% of patients but exhibited high pathologic stage at presentation (p = 0.041) and shorter survival intervals (median 12 vs. 23 months, p = 0.023) compared to Caucasians. CONCLUSIONS: There is a disproportionately high rate of pSCC in Appalachian Kentucky. Both Appalachian and AA men exhibited more advanced disease at presentation and shorter survival, identifying socioeconomic and racial disparities which can be targeted to improve outcomes in high risk individuals.

From evoked potentials to cortical currents: Resolving V1 and V2 components using retinotopy constrained source estimation without fMRI.

Despite evoked potentials' (EP) ubiquity in research and clinical medicine, insights are limited to gross brain dynamics as it remains challenging to map surface potentials to their sources in specific cortical regions. Multiple sources cancellation due to cortical folding and cross-talk obscures close sources, e.g. between visual areas V1 and V2. Recently retinotopic functional magnetic resonance imaging (fMRI) responses were used to constrain source locations to assist separating close sources and to determine cortical current generators. However, an fMRI is largely infeasible for routine EP investigation. We developed a novel method that replaces the fMRI derived retinotopic layout (RL) by an approach where the retinotopy and current estimates are generated from EEG or MEG signals and a standard clinical T1-weighted anatomical MRI. Using the EEG-RL, sources were localized to within 2 mm of the fMRI-RL constrained localized sources. The EEG-RL also produced V1 and V2 current waveforms that closely matched the fMRI-RL's (n = 2) r(1,198) = 0.99, P < 0.0001. Applying the method to subjects without fMRI (n = 4) demonstrates it generates waveforms that agree closely with the literature. Our advance allows investigators with their current EEG or MEG systems to create a library of brain models tuned to individual subjects' cortical folding in retinotopic maps, and should be applicable to auditory and somatosensory maps. The novel method developed expands EP's ability to study specific brain areas, revitalizing this well-worn technique. Hum Brain Mapp 37:1696-1709, 2016. © 2016 Wiley Periodicals, Inc.

Root Causes and Modifiability of 30-Day Hospital Readmissions after Radical Cystectomy for Bladder Cancer.

PURPOSE: Radical cystectomy is associated with high complication and rehospitalization rates. An understanding of the root causes of hospital readmissions and the modifiability of factors contributing to readmissions may decrease the morbidity associated with radical cystectomy. We characterize the indications for rehospitalization following radical cystectomy, and determine whether these indications represent immutable patient disease and procedure factors or whether they are modifiable. MATERIALS AND METHODS: From MarketScan® databases we identified patients younger than 65 years with a diagnosis of bladder cancer who underwent radical cystectomy between 2008 and 2011 and were readmitted to the hospital within 30 days of radical cystectomy. All associated ICD-9 codes in the index admission, subsequent outpatient claims and readmission claims were independently reviewed by 3 surgeons to determine a root cause of rehospitalization. Causes were broadly categorized as medical, surgical or infectious, and reviewers determined whether the readmission was modifiable. Multivariate logistical regression models were used to identify factors associated with rehospitalization. RESULTS: A total of 1,163 patients were included in the study and 242 (21%) were readmitted to the hospital within 30 days. Of these readmissions 26% were considered modifiable (kappa=0.71). Of the nonmodifiable readmissions an infectious cause accounted for 52% and a medical cause accounted for 48%, whereas of the modifiable readmissions 62% were due to surgical causes, 30% to medical and 8% to infectious causes. On multivariate analysis only discharge to a skilled nursing facility was associated with modifiable (OR 6.12, 95% CI 2.32-16.14) or nonmodifiable (OR 3.27, 95% CI 1.63-6.53) hospital readmissions. CONCLUSIONS: The majority of rehospitalizations after radical cystectomy are attributable its inherent morbidity. However, optimization of aspects of peri-cystectomy care could minimize the morbidity of radical cystectomy.

Overuse of antimicrobial prophylaxis in community practice urology.

PURPOSE: We examined index urological surgeries to assess utilization patterns of antimicrobial prophylaxis in a large, community based population. MATERIALS AND METHODS: From the Premier Perspectives Database we identified patients who underwent inpatient urological surgeries that are considered index procedures by the ABU (American Board of Urology), including radical prostatectomy, partial or radical nephrectomy, radical cystectomy, ureteroscopy, shock wave lithotripsy, transurethral resection of the prostate, percutaneous nephrostolithotomy, transvaginal surgery, inflatable penile prosthesis, brachytherapy, transurethral resection of bladder tumor and cystoscopy. Procedures were identified based on ICD-9 procedure codes for 2007 to 2012. Antimicrobial administration, class and duration were abstracted from patient billing data. The class and duration of antimicrobials concordant with the 2008 AUA Best Practice Policy Statement was used to determine compliance. RESULTS: The overall compliance rate was 53%, ranging from 0.6% for radical cystectomy to 97% for shock wave lithotripsy. Antimicrobial use consistent with AUA Best Practices included the appropriate class in 67% of cases (range 34% to 80%) and the recommended duration in 78% (range 1.2% to 98%). Average prophylaxis duration for procedures for which it is recommended ranged from 1.1 days after brachytherapy to 10.3 days after radical cystectomy. The compliance rate increased from 46% overall in 2007 to 59% overall in 2012. CONCLUSIONS: We documented considerable variation in antimicrobial prophylaxis for urological surgery. Compliance with AUA Best Practices increased with time but overall rates remain less than 60%. Efforts are needed to better understand the reasons for variation from recommended antimicrobial prophylaxis for common inpatient urological procedures to help decrease resultant complications and improve outcomes.

Use and outcomes of extended antibiotic prophylaxis in urological cancer surgery.

PURPOSE: Although perioperative antibiotic prophylaxis prevents postoperative infectious complications, national guidelines recommend cessation of antibiotics within 24 hours after the procedure. Extended antibiotic prophylaxis beyond 24 hours may contribute to hospital acquired infections such as Clostridium difficile colitis. We evaluated practice patterns of antibiotic prophylaxis in genitourinary cancer surgery and assessed the impact of antibiotic prophylaxis on hospital acquired C. difficile infections. MATERIALS AND METHODS: We identified 59,184 patients treated with radical prostatectomy, 27,921 who underwent partial or radical nephrectomy, and 5,425 treated with radical cystectomy for prostate, kidney and bladder cancers, respectively, from the Premier Perspective Database (Premier Inc., Charlotte, North Carolina) from 2007 to 2012. We constructed hierarchical linear regression models to identify patient and hospital factors associated with extended antibiotic prophylaxis. We evaluated the association between extended antibiotic prophylaxis and C. difficile infections for patients who underwent partial or radical nephrectomy and radical cystectomy with multivariate logistic regression. RESULTS: Surgery specific models demonstrated that hospital identity was associated with a substantial proportion of the variation in extended antibiotic prophylaxis (20% to 35% for radical prostatectomy, partial or radical nephrectomy, and radical cystectomy). Postoperative C. difficile colitis occurred in 0.02% of patients treated with radical prostatectomy, 0.23% of those treated with partial or radical nephrectomy and 1.7% of those treated with radical cystectomy. On multivariate analysis extended antibiotic prophylaxis was associated with higher odds of C. difficile infection after partial or radical nephrectomy (OR 3.79, 95% CI 2.46-5.84) and radical cystectomy (OR 1.64, 95% CI 1.12-2.39). CONCLUSIONS: Antibiotics may be overused after genitourinary cancer surgery and this overuse is associated with hospital acquired C. difficile colitis. Efforts are needed to encourage greater compliance with evidence-based approaches to postoperative care.

Neobladders and continent catheterizable stomas for the bladder cancer survivor.

PURPOSE OF REVIEW: Health-related quality of life (HRQOL) following radical cystectomy for bladder cancer is an important outcome measure following radical cystectomy. Understanding HRQOL issues related to continent urinary diversion is crucial in the care and counseling of patients undergoing radical cystectomy. The goals of this review are to give a broad overview of the major types of continent urinary diversions and to review recent literature examining HRQOL in patients undergoing orthotopic neobladders and continent catheterizable urinary reservoirs following radical cystectomy. RECENT FINDINGS: Generic questionnaires that broadly address physical, social, and mental functioning and bladder cancer-specific questionnaires that more specifically address urinary, bowel, and sexual function have been utilized to measure HRQOL following radical cystectomy. Although existing studies indicate that overall quality of life may be similar in patients with continent and noncontinent urinary diversions, more specific comparisons of urinary and sexual function are conflicting and complicated by sex-specific concerns. Uterine preservation may improve urinary function in women with continent urinary diversions. SUMMARY: Although the development of disease-specific validated questionnaires has improved our understanding of HRQOL following radical cystectomy, a lack of prospective studies limits conclusions regarding the superiority of diversion type. Appropriate preoperative consultation may facilitate realistic expectations, thereby optimizing outcomes.

Visual evoked potential and psychophysical contrast thresholds in glaucoma.

PURPOSE: We compared the diagnostic power of electrophysiologically and psychophysically measured contrast thresholds for the diagnosis of glaucoma. Additionally, we investigated whether combining results from the two methods improved diagnostic power. METHODS: Seven-eight subjects between 40 and 88 years formed the main study group: 21 normal controls (9 males) and 57 glaucoma patients (30 males) were tested. Twenty-two younger control subjects were also tested. Contrast thresholds were determined for a 1 cpd sinusoidal grating, subtending 41° × 52° modulated at 14.3 rps. The thresholds were based on the same staircase method applied to visual evoked potential (VEP) and psychophysical responses (Psyc). Diagnostic power was assessed by the percent area under the curve (%AUC) of receiver operating characteristic plots. RESULTS: Psyc showed significant age dependence, -0.10 ± 0.02 dB, while VEPs did not. Diagnostic performance for moderate and severe eyes combined was modest: Psyc 74 ± 9.0 % and VEP 72 ± 9.1 %, but improved significantly (p < 0.05) for a simple combined method, up to 90 ± 6.0 % for moderate disease. The combined method improved %AUC for all severities on average (p < 0.03). Canonical correlation analysis indicated that the four threshold measures contained independent information and that these independent dimensions were each correlated with glaucoma severity (p < 0.0015). CONCLUSION: Combining the VEP and Psyc thresholds appeared to improve diagnostic power. Canonical correlation analysis indicated that they measured statistically independent aspects of glaucoma possibly related to disease severity. Adding the 20-s psychophysical test to a VEP test produced a significant benefit for a small time cost.

Multifocal pupillography in early age-related macular degeneration.

PURPOSE: To investigate the potential of multifocal pupillographic objective perimetry to assess changes in retinal function with clinical severity of age-related macular degeneration (AMD). METHODS: Pupil responses were recorded from 40 subjects with AMD and 23 normal control subjects (mean ± SD age, 71.3 ± 5.1 years). Age-related macular degeneration subjects were classified according to the Age-Related Eye Disease Study (AREDS) classification system and allocated into one of four AMD severity groups. Three multifocal pupillographic objective perimetry stimulus variants that were identical in luminance but varied in spatiotemporal sequence were used. In one of the three protocols, stimuli were presented with a pedestal flicker for 266 milliseconds at 15 Hz. RESULTS: On average, response amplitudes demonstrated a significant change in sensitivity with progression from early-stage (0.32 ± 0.08 dB, t = 3.88) to late-stage (-1.60 ± 0.12 dB, t = -12.7) age-related macular degeneration. Response delays followed a similar trend with the longest delays in AREDS4 (57.2 ± 1.9 milliseconds, t = 29.5). Ring analysis identified the largest mean effect on responses within the central 6 degrees of fixation. The NewStimuli protocol achieved the best diagnostic accuracy across all severity groups with area under the curve values of 0.85 ± 0.066 (AREDS1), 0.908 ± 0.085 (AREDS2), 0.929 ± 0.040 (AREDS3), and 1.0 ± 0.0 (AREDS4). CONCLUSIONS: The mean effect of AMD on contraction amplitudes and response delays reflected the severity of disease, and the NewStimuli protocol achieved good diagnostic accuracy across all AMD severity groups. Multifocal pupillographic objective perimetry may potentially be a useful method in monitoring progression of AMD and assessing change in retinal function with novel interventions in early AMD. Longitudinal studies are required to identify biomarkers that predict eyes at risk of progression.

Luminance and colour variant pupil perimetry in glaucoma.

BACKGROUND: This study investigated the diagnostic utility for glaucoma of multifocal pupillographic objective perimetry stimuli targeting different components of the pupillary response: cortically derived colour responses and subcortical luminance responses. DESIGN: Observational cross-sectional study undertaken at the Australian National University. PARTICIPANTS: Thirty-five eyes of 24 glaucoma subjects and 46 eyes of 23 normal subjects. METHODS: Subjects were tested with three multifocal pupillographic objective perimetry stimulus variants. The luminance-only variant (YYbal) utilized yellow stimuli on a yellow background; mixed colour and luminance protocols utilized green stimuli on a red background (RGbal, RG). Stimuli of 33 ms duration were presented at mean intervals of 4 s/region. MAIN OUTCOME MEASURES: Pupil constriction amplitude and time to peak. Area under the receiver operating characteristic curve was the main measure of sensitivity and specificity for glaucoma. RESULTS: Colour and luminance protocols were more accurate at differentiating glaucoma subjects from normal subjects than the luminance-only protocol, and produced the largest reductions in amplitudes. This type of protocol also produced the highest overall sensitivity and specificity for glaucoma (receiver operating characteristic % area under the curve: severe, 100%; moderate, 94.4%; mild, 71.0%). Pattern deviations tended to produce higher area under the receiver operating characteristic curves in eyes classified as mild. Significant differences in the means of the six worst amplitude deviations were observed between normal and severe glaucoma subjects only. CONCLUSIONS: Stimuli targeting both cortical pupillary colour response and subcortical pupillary luminance response components produced higher diagnostic accuracy than stimuli targeting subcortical pupillary luminance responses alone. Inclusion of constriction latencies further improved accuracy.

Dichoptic multifocal visual evoked potentials identify local retinal dysfunction in age-related macular degeneration.

PURPOSE: To evaluate the ability of multifocal visual evoked potentials (mfVEPs) to identify functional loss in patients with early and exudative age-related macular degeneration (AMD). A dichoptic multifocal stimulus presentation was employed to investigate the regional effects of AMD and the potential diagnostic utility in macular disease. METHODS: MfVEP responses were recorded from 19 unilateral exudative AMD patients with non-exudative (n = 15) or normal (n = 4) presentations in the fellow eye and 28 age-matched controls. Root mean square (RMS) waveforms were pooled across selected EEG channels to produce global field RMS (gfRMS) waveforms. GfRMS amplitudes and response delays were analysed by multivariate linear models, and diagnostic capacity was measured using areas under the curve (AUC) of receiver operator characteristic plots. RESULTS: The mean gfRMS amplitude of the exudative eye of AMD patients was significantly reduced compared with the controls (-2.03 ± 0.08 dB, t = -12.9). Fellow non-exudative AMD eyes were less effected but still significantly reduced (-0.84 ± 0.07 dB, t = -11.5). No significant difference in mean gfRMS delay of AMD eyes across the central 46° was observed. AUC values of 100 ± 0.0% (mean ± SE) for exudative and 79.7 ± 6.5% for non-exudative eyes were obtained for response amplitudes. CONCLUSION: The study demonstrated that mfVEP identified retinal dysfunction in both exudative AMD and fellow non-exudative AMD eyes, but mostly affecting the macular field. The reduced testing duration and good diagnostic accuracy suggest that dichoptic mfVEPs may be a sensitive tool for monitoring progression in AMD.

Multifocal pupillography identifies retinal dysfunction in early age-related macular degeneration.

BACKGROUND: Early age-related macular degeneration (AMD) is common among the elderly. While only a small number progress to sight-threatening stages of AMD, identifying prognostic functional markers remains paramount. Here, we objectively evaluate retinal function in patients with large drusen by multifocal pupillographic objective perimetry (mfPOP). Different temporal presentation rates and luminances were compared to optimize parameters for high signal to noise ratios (SNR) and diagnosticity for early AMD. METHODS: Pupil responses were recorded from 19 early AMD patients (30 eyes) and 29 age-matched control subjects. We compared a luminance-balanced stimulus ensemble and two unbalanced stimulus variants, each consisting of 44 independent stimulus regions per eye extending from fixation to 15˚ eccentricity. Video cameras recorded pupil responses for each eye under infrared illumination. The amplitudes and delays of the peak responses were analysed by multivariate linear models. The diagnostic accuracy of the stimulus variants was compared using areas under the curve (AUC) of receiver operator characteristic (ROC) plots. RESULTS: Early AMD eyes differed significantly from normal in their mean constriction amplitudes (-2.22 ± 0.15 dB, t = -14.8) and delays (17.92 ± 1.2 ms, t = 14.9). The brightest stimulus ensembles produced the highest median SNRs of 3.45 z-score units; however, the balanced method was found to be the most diagnostic. AUC values of 0.95 ± 0.03 (mean ± SE) for early AMD were obtained when the asymmetry of response amplitudes between eyes was considered. CONCLUSIONS: The mfPOP responses of early AMD eyes showed significant abnormality in response amplitudes and peak time. The ROC AUCs of 95 % suggest that mfPOP is a sensitive tool for detecting early abnormalities in AMD and longitudinal studies measuring progression of retinal dysfunction are warranted.

High- versus low-density multifocal pupillographic objective perimetry in glaucoma.

BACKGROUND: Multifocal pupillographic objective perimetry was compared using 24 and 44 regions per visual field. DESIGN: Experimental design in a university setting. PARTICIPANTS: Twenty-seven normal control and 36 age-matched glaucoma patients. METHODS: The four test variants differed in the mean interval between stimuli: 4, 1 or 0.25 s; and the number of visual field regions tested within the central 60 degrees: 24 or 44. All subjects had their diagnostic status confirmed by optical coherence tomography, two forms of perimetry and slit-lamp biomicroscopy. Both eyes were measured concurrently in 2.73 ± 0.45 min/eye (mean ± standard deviation), and tests were repeated about 2 weeks apart. MAIN OUTCOME MEASURES: The main outcome measures were: (i) mean change in light sensitivity due glaucoma; and (ii) areas under Receiver Operator Characteristic plots for detecting glaucoma. RESULTS: For all four variants, consensual responses, female gender and age produced small but significant sensitivity differences, and sensitivity declined with age by ≤-0.27 dB/decade (all P < 0.0003). The best diagnostic accuracy (area under curve 93.2 ± 3.89%) was produced by the one-presentation/s 44-region protocol. Across the four protocols, the effect of repeat testing was small (all methods ≤0.15 dB). CONCLUSIONS: Presentation rate had little effect, but increasing the tested density from 24 to 44 regions/field improved diagnostic power. Given that multifocal pupillographic objective perimetry also provides information on response delay and afferent versus efferent defects at every visual field region, it may be a useful adjunct to perimetry.

Genome-wide in silico identification of GPI proteins in Mycosphaerella fijiensis and transcriptional analysis of two GPI-anchored ß-1,3-glucanosyltransferases.

The hemibiotrophic fungus Mycosphaerella fijiensis is the causal agent of black Sigatoka (BS), the most devastating foliar disease in banana (Musa spp.) worldwide. Little is known about genes that are important during M. fijiensis-Musa sp. interaction. The fungal cell wall is an attractive area of study because it is essential for maintenance of cellular homeostasis and it is the most external structure in the fungal cell and therefore mediates the interaction of the pathogen with the host. In this manuscript we describe the in silico identification of glycosyl phosphatidylinositol-protein (GPI) family in M. fijiensis, and the analysis of two ß-1,3-glucanosyltrans-ferases (Gas), selected by homology with fungal pathogenicity factors. Potential roles in pathogenesis were evaluated through analyzing expression during different stages of black Sigatoka disease, comparing expression data with BS symptoms and fungal biomass inside leaves. Real-time quantitative RT-PCR showed nearly constant expression of MfGAS1 with slightly increases (about threefold) in conidia and at speck-necrotrophic stage during banana-pathogen interaction. Conversely, MfGAS2 expression was increased during biotrophy (about seven times) and reached a maximum at speck (about 23 times) followed by a progressive decrease in next stages, suggesting an active role in M. fijiensis pathogenesis.

Association of CD47 Expression with Clinicopathologic Characteristics and Survival Outcomes in Muscle Invasive Bladder Cancer.

OBJECTIVE: CD47 is an antiphagocytic molecule that plays a critical role in immune surveillance. A variety of malignancies have been shown to evade the immune system by increasing the expression of CD47 on the cell surface. As a result, anti-CD47 therapy is under clinical investigation for a subset of these tumors. Interestingly, CD47 overexpression is associated with negative clinical outcomes in lung and gastric cancers; however, the expression and functional significance of CD47 in bladder cancer is not fully understood. MATERIALS AND METHODS: We retrospectively studied patients with muscle invasion bladder cancer (MIBC) who underwent a transurethral resection of bladder tumor (TURBT) and subsequently underwent radical cystectomy (RC) with or without neoadjuvant chemotherapy (NAC). CD47 expression was examined by IHC in both TURBT and matched RC specimens. The difference in CD47 expression levels between TURBT and RC was also compared. The association of CD47 levels (TURBT) with clinicopathological parameters and survival outcomes was evaluated by Pearson's chi-squared tests and the Kaplan-Meier method, respectively. RESULTS: A total of 87 MIBC patients were included. The median age was 66 (39-84) years. Most patients were Caucasian (95%), male (79%), and aged >60 (63%) and most often (75%) underwent NAC prior to RC. Of those who received NAC, 35.6% were responders and 64.4% were non-responders. The final reported stages as per AJCC for all patients were as follows: stage 0 (32%), stage 1 (1%), stage 2 (20%), stage 3 (43%), and stage 4a (5%). A total of 60% of patients were alive; of those, 30% had disease recurrence and 40% died from bladder cancer at a median follow-up of 3.1 (0.2-14.2) years. CD47 levels were detectable in 38 (44%) TURBT samples. There was no association between CD47 levels and clinicopathological parameters such as age, gender, race, NAC, final stage, disease recurrence, and overall survival (OS). Patients aged >60 (p = 0.006), non-responders (p = 0.002), and at stage ≥ 3 (p < 0.001) were associated with worse OS by a univariate analysis and stage ≥ 3 remained significant even after a multivariate analysis. In patients managed with NAC, there were decreased CD47 levels in RC specimens compared to the TURBT specimens, but this did not reach statistical significance. CONCLUSION: CD47 expression was not a predictive nor prognostic marker for MIBC patients. However, expression of CD47 was detected in nearly half of MIBCs, and future studies are needed to explore the potential role of anti-CD47 therapy in these patients. Furthermore, there was a slight positive trend in decreased CD47 levels (from TURBT to RC) in patients receiving NAC. As a result, more research is needed to understand how NAC may modify immune surveillance mechanisms in MIBC.

A Phase I Dose Escalation and Expansion Study of Epidiolex (Cannabidiol) in Patients with Biochemically Recurrent Prostate Cancer.

PURPOSE: Cannabinoids (CBD) have anti-tumor activity against prostate cancer (PCa). Preclinical studies have demonstrated a significant decrease in prostate specific antigen (PSA) protein expression and reduced tumor growth in xenografts of LNCaP and DU-145 cells in athymic mice when treated with CBD. Over-the-counter CBD products may vary in activity without clear standardization, and Epidiolex is a standardized FDA-approved oral CBD solution for treatment of certain types of seizures. We aimed to assess the safety and preliminary anti-tumor activity of Epidiolex in patients with biochemically recurrent (BCR) PCa. EXPERIMENTAL DESIGN: This was an open-label, single center, phase I dose escalation study followed by a dose expansion in BCR patients after primary definitive local therapy (prostatectomy +/- salvage radiotherapy or primary definitive radiotherapy). Eligible patients were screened for urine tetrahydrocannabinol prior to enrollment. The starting dose level of Epidiolex was 600 mg by mouth once daily and escalated to 800 mg daily with the use of a Bayesian optimal interval design. All patients were treated for 90 days followed by a 10-day taper. The primary endpoints were safety and tolerability. Changes in PSA, testosterone levels, and patient-reported health-related quality of life were studied as secondary endpoints. RESULTS: Seven patients were enrolled into the dose escalation cohort. There were no dose-limiting toxicities at the first two dose levels (600 mg and 800 mg). An additional 14 patients were enrolled at the 800 mg dose level into the dose expansion cohort. The most common adverse events were 55% diarrhea (grade 1-2), 25% nausea (grade 1-2), and 20% fatigue (grade 1-2). The mean PSA at baseline was 2.9 ng/mL. At the 12-week landmark time-point, 16 out of 18 (88%) had stable biochemical disease, one (5%) had partial biochemical response with the greatest measurable decline being 41%, and one (5%) had PSA progression. No statistically significant changes were observed in patient-reported outcomes (PROs), but PROs changed in the direction of supporting the tolerability of Epidiolex (e.g., emotional functioning improved). CONCLUSION: Epidiolex at a dose of 800 mg daily appears to be safe and tolerable in patients with BCR prostate cancer supporting a safe dose for future studies.

Clustered Volleys Stimulus Presentation for Multifocal Objective Perimetry.

PURPOSE: Multifocal pupillographic objective perimetry (mfPOP) is being developed as an alternative to subjective threshold perimetry for the management of visual and neurological disorders. Here, we evaluate, in normal subjects, differences in signal quality between the original mfPOP method of spatially sparse Continuous stimulus presentation and the new Clustered Volleys (CVs) method. We hypothesized that the CVs method would lead to increased signal-to-noise ratios (SNRs) over the original method due to the stabilization of gain within the pupillary system. METHODS: Data were collected from six separate studies where otherwise-identical pairs of mfPOP tests using either the original Continuous stimulus presentation method or the new CVs method were undertaken; 440 6-minute tests from 96 normal subjects of varying ages were included. Per-region SNRs were compared between the two methods. RESULTS: Mean SNRs for the CVs mfPOP variants were between 35% and 57% larger than the original Continuous mfPOP variants (P < 0.001 in five of six studies). Similarly, the goodness-of-fit measure (r2) demonstrated large and significant fold increases of between 2.3× and 3.4× over the original method (all P < 0.001). Significant improvements in SNRs were present in all of the 88 test regions (44/eye), ranging between 8.4% and 93.7%; mean SNRs were significantly larger in 98% of test subjects. CONCLUSIONS: The CVs mfPOP stimulus presentation method produced substantial increases in signal quality over the original method. This is likely due to the stabilization of pupillary gain during stimulus presentation. TRANSLATIONAL RELEVANCE: These improvements increase diagnostic accuracy and have enabled shorter, 80-second mfPOP tests to be developed.