Adjuvant Chemotherapy and Survival After Radical Cystectomy in Histologic Subtype Bladder Cancer.

OBJECTIVES: Patients with histologic subtype bladder cancer (HSBC) suffer worse outcomes than those with conventional urothelial carcinoma (UC). We sought to characterize the use of adjuvant chemotherapy (AC) in HSBC after radical cystectomy (RC) using the National Cancer Database (NCDB). MATERIALS AND METHODS: We retrospectively queried the NCDB (2006-2019) for patients with non-metastatic bladder cancer (BC) who underwent RC (N = 45,797). Patients were stratified by histologic subtype and receipt of AC. Multivariable logistic regression determined associations of demographic and clinicopathologic features with receipt of AC. Multivariable Cox regression evaluated associations between receipt of any AC and overall survival (OS). RESULTS: We identified 4,469 patients with HSBC classified as squamous, adenocarcinoma, small cell, sarcomatoid, micropapillary, or plasmacytoid. Squamous comprised 31% of the HSBC cohort, followed by small cells and micropapillary. Black patients were presented with a higher prevalence of adenocarcinoma (119/322, 37.0%). Use of AC was highest in plasmacytoid and small cell (30% each) and lowest in squamous (11%). Neuroendocrine histology was independently associated with greater odds of receiving AC (HR 1.6, 95% CI 1.37-1.87), while squamous cell histology was associated with lower odds (HR 0.61, 95% CI 0.53-0.71). On multivariable Cox regression analysis, treatment with AC was associated with significantly longer OS (HR 0.69, 95% CI 0.59-0.81) and for squamous, sarcomatoid, and micropapillary cohorts after stratified by subtype. CONCLUSIONS: AC was variably used among patients with HSBC and was associated with OS benefit in such patients.

Characteristic BOLD signals are detectable in white matter of the spinal cord at rest and after a stimulus.

We report the reliable detection of reproducible patterns of blood-oxygenation-level-dependent (BOLD) MRI signals within the white matter (WM) of the spinal cord during a task and in a resting state. Previous functional MRI studies have shown that BOLD signals are robustly detectable not only in gray matter (GM) in the brain but also in cerebral WM as well as the GM within the spinal cord, but similar signals in WM of the spinal cord have been overlooked. In this study, we detected BOLD signals in the WM of the spinal cord in squirrel monkeys and studied their relationships with the locations and functions of ascending and descending WM tracts. Tactile sensory stimulus -evoked BOLD signal changes were detected in the ascending tracts of the spinal cord using a general-linear model. Power spectral analysis confirmed that the amplitude at the fundamental frequency of the response to a periodic stimulus was significantly higher in the ascending tracts than the descending ones. Independent component analysis of resting-state signals identified coherent fluctuations from eight WM hubs which correspond closely to the known anatomical locations of the major WM tracts. Resting-state analyses showed that the WM hubs exhibited correlated signal fluctuations across spinal cord segments in reproducible patterns that correspond well with the known neurobiological functions of WM tracts in the spinal cord. Overall, these findings provide evidence of a functional organization of intraspinal WM tracts and confirm that they produce hemodynamic responses similar to GM both at baseline and under stimulus conditions.

TARGETING SOLUBLE AMYLOID-BETA OLIGOMERS WITH A NOVEL NANOBODY.

The classical amyloid cascade hypothesis postulates that the aggregation of amyloid plaques and the accumulation of intracellular hyperphosphorylated Tau tangles, together, lead to profound neuronal death. However, emerging research has demonstrated that soluble amyloid-ß oligomers (SAßOs) accumulate early, prior to amyloid plaque formation. SAßOs induce memory impairment and disrupt cognitive function independent of amyloid-ß plaques, and even in the absence of plaque formation. This work describes the development and characterization of a novel anti-SAßO (E3) nanobody generated from an alpaca immunized with SAßO. In-vitro assays and in-vivo studies using 5XFAD mice indicate that the fluorescein (FAM)-labeled E3 nanobody recognizes both SAßOs and amyloid-ß plaques. The E3 nanobody traverses across the blood-brain barrier and binds to amyloid species in the brain of 5XFAD mice. Imaging of mouse brains reveals that SAßO and amyloid-ß plaques are not only different in size, shape, and morphology, but also have a distinct spatial distribution in the brain. SAßOs are associated with neurons, while amyloid plaques reside in the extracellular matrix. The results of this study demonstrate that the SAßO nanobody can serve as a diagnostic agent with potential theragnostic applications in Alzheimer's disease.

Phase 1/2 Randomized Clinical Trial of In-clinic acupuncture Prior to Bacillus Calmette-Guérin in Patients with High-risk Non-muscle-invasive Bladder Cancer.

BACKGROUND: Treatment-related dose-limiting dysuria and irritative bladder symptoms are common in patients receiving intravesical bacillus Calmette-Guérin (BCG) to treat non-muscle-invasive bladder cancer (NMIBC). Acupuncture has been shown to reduce pain and urinary urgency/frequency in other patient populations. OBJECTIVE: To evaluate the feasibility, safety, and tolerability of weekly in-clinic preprocedural acupuncture among patients receiving induction BCG. DESIGN, SETTING, AND PARTICIPANTS: Patients with high-risk NMIBC undergoing induction BCG were randomized 2:1 to a standardized acupuncture protocol (acupuncture) versus the standard-of-care control arm. INTERVENTION: In-office acupuncture prior to each BCG instillation. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES: Feasibility was assessed via recruitment, retention, and intervention adherence. Acupuncture safety and tolerability were assessed via physician-reported Common Terminology Criteria for Adverse Events version 5.0 and adverse events (AEs). Secondary endpoints included BCG treatment adherence, patient-reported BCG-related toxicity, and bladder cancer-specific and generic (European Organisation for Research and Treatment of Cancer [EORTC]-QLQ-NMIBC-24 and EORTC-QLQ-NMIBC-C30) quality of life (QOL). Subjective assessments of acupuncture acceptability were performed through patient surveys. RESULTS AND LIMITATIONS: A total of 43 individuals were randomized 2:1 to the acupuncture (n = 28) versus control (n = 15) group. The median age was 70.3 yr, and 76% were male. Week 7 follow-up surveys were completed by 93%; six participants withdrew early due to disease progression, refractory gross hematuria, or preference. Acupuncture was delivered successfully prior to each BCG treatment, with no acupuncture-related AEs or interruptions to induction BCG. BCG-attributed AEs were reported by 91% acupuncture and 100% control individuals, including pain (28% vs 43%, p = 0.34) and urinary symptoms (62% vs 79%, p = 0.31). Comparing acupuncture patients with controls, change in QOL over the study period demonstrated greater improvements in median urinary symptoms (9.5, interquartile range [IQR] 0.0-19.0 vs 0.0, IQR -14.3 to 7.1; p = 0.02) among patients in the acupuncture arm. Of the acupuncture patients, 96% reported that acupuncture was "very/extremely helpful," and 91% would recommend acupuncture to other patients. Limitations include modest sample size and single-institution design. CONCLUSIONS: Acupuncture prior to induction BCG treatments is feasible and safe. In this phase 1/2 trial, improved urinary function scores were observed among patients undergoing acupuncture. Patients receiving acupuncture reported high degrees of satisfaction with treatments. PATIENT SUMMARY: We evaluated the safety and feasibility of delivering acupuncture in a urology clinic prior to weekly intravesical bladder cancer treatments with bacillus Calmette-Guérin (BCG) in a randomized controlled trial. We found that acupuncture could be delivered safely prior to weekly BCG instillations and that the use of acupuncture was associated with high patient satisfaction and a decrease in patient-reported urinary symptoms compared with usual care.

Urgent versus elective surgical disparities among American Indian and Alaska Native patients.

BACKGROUND: American Indian and Alaska Native (AIAN) health issues are understudied despite documentation of lower-than-average life expectancy. Urgent surgery is associated with higher rates of postsurgical complications and postoperative death. We assess whether American Indian and Alaska Native (AIAN) patients in Washington State are at greater risk of requiring urgent rather than elective surgery compared with non-Hispanic Whites (NHW). METHODS: We accessed data for the period 2009-2014 from the Washington State Comprehensive Hospital Abstract Reporting System (CHARS) database, which captures all statewide hospital admissions, to examine three common surgeries that are performed both urgently and electively: hip replacements, aortic valve replacements, and spinal fusions. We extracted patient race, age, insurance status, comorbidity, admission type, and procedures performed. We then constructed multivariable logistic regression models to identify factors associated with use of urgent surgical care. RESULTS: AIAN patients had lower mean age at surgery for all three surgeries compared with NHW patients. AIAN patients were at higher risk for urgent surgery for hip replacements (OR = 1.49, 95% CI 1.19-1.88), spinal fusions (OR = 1.39, 95% CI 1.04-1.87), and aortic valve replacements (OR = 2.06, 95% CI 1.12-3.80). CONCLUSION: AIAN patients were more likely to undergo urgent hip replacement, spinal fusion, and aortic valve replacement than NHW patients. AIAN patients underwent urgent surgery at younger ages. Medicaid insurance conferred higher risks for urgent surgery across all surgeries studied. Further research is warranted to more clearly identify the factors contributing to disparities among AIAN patients undergoing urgent surgery.

Impact of Dobbs v. Jackson Women's Health Organization on Professional Decision-Making Among Urology Applicants.

MATERIALS AND METHODS: An Institutional Review Board-exempt REDCap survey was distributed through the Society of Academic Urologists to all 508 applicants registered for the 2023 Urology Match following the rank list submission deadline on January 10, 2023. The survey closed on February 1, 2023. Responses were anonymized, aggregated, and characterized using descriptive statistics. Thematic mapping of open text comments was performed by 2 reviewers. RESULTS: The response rate was 42% (215/508). Eighty-eight percent of respondents disapproved of the Dobbs ruling. Twenty percent of respondents (15% male/24% female) eliminated programs in states where abortion is illegal. Fifty-nine percent (51% male/70% female) would be concerned for their or their partner's health if they matched in a state where abortion was illegal, and 66% (55% male/82% female) would want their program to assist them or their partner if they required abortion care during residency. Due to the competitive nature of Urology, 68% of applicants reported feeling at least somewhat obligated to apply in states where abortion legislation conflicts with their beliefs. Of the 65 comments provided by respondents, 4 common themes emerged: (1) avoidance of states with restrictive abortion laws; (2) inability to limit applications because of the competitiveness of urology; (3) impacts on personal health care; and (4) desire for advocacy from professional urology organizations. CONCLUSION: The Dobbs ruling will impact the urology workforce by affecting urology applicants' decision-making regarding residency selection and ranking. Although the competitiveness of the Urology Match pressures applicants to apply broadly, many are taking reproductive health care access into consideration.

Telemedicine for Multidisciplinary Urologic Cancer Care: A Prospective Single Institution Study.

BACKGROUND: We rapidly implemented a telemedicine Multidisciplinary Urologic Cancer Clinic (MDUCC) at the University of Washington/Seattle Cancer Care Alliance during the peak of the COVID-19 Public Health Emergency to maintain our ability to provide multidisciplinary cancer care. We report our experiences though assessment of patient-reported outcomes from our telemedicine MDUCC. METHODS: Video visits with a urologic oncologist, medical oncologist, and radiation oncologist were conducted in the same format as our in-person MDUCC. We prospectively collected patient demographic and clinical data. Patients were invited to complete a post-visit survey that assessed satisfaction, provider trust, travel time, and costs of the telemedicine visit. We estimated travel distances and times from each patient's home to our clinic. RESULTS: Among invited patients, twenty-four patients completed a survey after their telemedicine MDUCC visit. Twenty patients (83%) were at home during the visit. Most (85%) were men, Caucasian (79%), and were being seen in our Bladder Cancer MDUCC (83%). All twenty-four patients responded that they would be willing to have future appointments via telemedicine; eighteen patients (75%) strongly agreed that the encounter was high quality; 19 patients strongly agreed that they were satisfied with their visit. Patients saved an estimated average one-way travel distance of 145 miles and one-way travel time of 179 minutes to convene a telemedicine visit. CONCLUSIONS: Telemedicine MDUCCs are feasible and effective in providing access to multidisciplinary urologic cancer care. Patient satisfaction was high, and many patients were spared a substantial travel burden. Telemedicine may continue to be leveraged to improve access to multidisciplinary urologic cancer care.

Quantification of mediation effects of white matter functional characteristics on cognitive decline in aging.

Cognitive decline with aging involves multifactorial processes, including changes in brain structure and function. This study focuses on the role of white matter functional characteristics, as reflected in blood oxygenation level-dependent signals, in age-related cognitive deterioration. Building on previous research confirming the reproducibility and age-dependence of blood oxygenation level-dependent signals acquired via functional magnetic resonance imaging, we here employ mediation analysis to test if aging affects cognition through white matter blood oxygenation level-dependent signal changes, impacting various cognitive domains and specific white matter regions. We used independent component analysis of resting-state blood oxygenation level-dependent signals to segment white matter into coherent hubs, offering a data-driven view of white matter's functional architecture. Through correlation analysis, we constructed a graph network and derived metrics to quantitatively assess regional functional properties based on resting-state blood oxygenation level-dependent fluctuations. Our analysis identified significant mediators in the age-cognition relationship, indicating that aging differentially influences cognitive functions by altering the functional characteristics of distinct white matter regions. These findings enhance our understanding of the neurobiological basis of cognitive aging, highlighting the critical role of white matter in maintaining cognitive integrity and proposing new approaches to assess interventions targeting cognitive decline in older populations.

Primary Palliative Care in Urology: Quality Improvement Summit 2021-2022.

INTRODUCTION: The AUA convened a 2021-2022 Quality Improvement Summit to bring together interdisciplinary providers to inform the current state and to discuss potential strategies for integrating primary palliative care into urology practice. We hypothesized that the Summit findings would inform a scalable primary palliative care model for urology. METHODS: The 3-part summit reached a total of 160 interdisciplinary health care professionals. Webinar 1, "Building a Primary Palliative Care Model for Urology," focused on a urologist's role in palliative care. Webinar 2, "Perspectives on Increasing the Use of Palliative Care in Advanced Urologic Disease," addressed barriers to possible implementation of a primary palliative care model. The in-person Summit, "Laying the Foundation for Primary Palliative Care in Urology," focused on operationalization of primary palliative care, clinical innovations needed, and relevant metrics. RESULTS: Participants agreed that palliative care is needed early in the disease course for patients with advanced disease, including those with benign and malignant conditions. The group agreed about the important domains that should be addressed as well as the interdisciplinary providers who are best suited to address each domain. There was consensus that a primary "quarterback" was needed, encapsulated in a conceptual model-UroPal-with a urologist at the hub of care. CONCLUSIONS: The Summit provides the field of urology with a framework and specific steps that can be taken to move urology-palliative care integration forward. Urologists are uniquely positioned to provide primary palliative care for their many patients with serious illness, both in the surgical and chronic care contexts.

Identification of functional white matter networks in BOLD fMRI.

White matter signals in resting state blood oxygen level dependent functional magnetic resonance (BOLD-fMRI) have been largely discounted, yet there is growing evidence that these signals are indicative of brain activity. Understanding how these white matter signals capture function can provide insight into brain physiology. Moreover, functional signals could potentially be used as early markers for neurological changes, such as in Alzheimer's Disease. To investigate white matter brain networks, we leveraged the OASIS-3 dataset to extract white matter signals from resting state BOLD-FMRI data on 711 subjects. The imaging was longitudinal with a total of 2,026 images. Hierarchical clustering was performed to investigate clusters of voxel-level correlations on the timeseries data. The stability of clusters was measured with the average Dice coefficients on two different cross fold validations. The first validated the stability between scans, and the second validated the stability between subject populations. Functional clusters at hierarchical levels 4, 9, 13, 18, and 24 had local maximum stability, suggesting better clustered white matter. In comparison with JHU-DTI-SS Type-I Atlas defined regions, clusters at lower hierarchical levels identified well defined anatomical lobes. At higher hierarchical levels, functional clusters mapped motor and memory functional regions, identifying 50.00%, 20.00%, 27.27%, and 35.14% of the frontal, occipital, parietal, and temporal lobe regions respectively.

The Prostate Cancer Active Lifestyle Study (PALS): A randomized controlled trial of diet and exercise in overweight and obese men on active surveillance.

BACKGROUND: Active surveillance (AS) is increasingly used to monitor patients with lower risk prostate cancer (PCa). The Prostate Cancer Active Lifestyle Study (PALS) was a randomized controlled trial to determine whether weight loss improves obesity biomarkers on the causal pathway to progression in patients with PCa on AS. METHODS: Overweight/obese men (body mass index >25 kg/m2) diagnosed with PCa who elected AS were recruited. The intervention was a 6-month, individually delivered, structured diet and exercise program adapted from the Diabetes Prevention Program with a 7% weight loss goal from baseline. Control participants attended one session reviewing the US Dietary and Physical Activity Guidelines. The primary outcome was change in glucose regulation from baseline to the end of the 6-month intervention, which was measured by fasting plasma glucose, C-peptide, insulin, insulin-like growth factor 1, insulin-like growth factor binding protein-3, adiponectin, and homeostatic model assessment for insulin resistance. RESULTS: Among 117 men who were randomized, 100 completed the trial. The mean percentage weight loss was 7.1% and 1.8% in the intervention and control arms, respectively (adjusted between-group mean difference, -6.0 kg; 95% confidence interval, -8.0, -4.0). Mean percentage changes from baseline for insulin, C-peptide, and homeostatic model assessment for insulin resistance in the intervention arm were -23%, -16%, and -25%, respectively, compared with +6.9%, +7.5%, and +6.4%, respectively, in the control arm (all p for intervention effects ≤ .003). No significant between-arm differences were detected for the other biomarkers. CONCLUSIONS: Overweight/obese men with PCa undergoing AS who participated in a lifestyle-based weight loss intervention successfully met weight loss goals with this reproducible lifestyle intervention and experienced improvements in glucose-regulation biomarkers associated with PCa progression.

Influence of preprocessing, distortion correction and cardiac triggering on the quality of diffusion MR images of spinal cord.

Diffusion MRI of the spinal cord (SC) is susceptible to geometric distortion caused by field inhomogeneities, and prone to misalignment across time series and signal dropout caused by biological motion. Several modifications of image acquisition and image processing techniques have been introduced to overcome these artifacts, but their specific benefits are largely unproven and warrant further investigations. We aim to evaluate two specific aspects of image acquisition and processing that address image quality in diffusion studies of the spinal cord: susceptibility corrections to reduce geometric distortions, and cardiac triggering to minimize motion artifacts. First, we evaluate 4 distortion preprocessing strategies on 7 datasets of the cervical and lumbar SC and find that while distortion correction techniques increase geometric similarity to structural images, they are largely driven by the high-contrast cerebrospinal fluid, and do not consistently improve the geometry within the cord nor improve white-to-gray matter contrast. We recommend at a minimum to perform bulk-motion correction in preprocessing and posit that improvements/adaptations are needed for spinal cord distortion preprocessing algorithms, which are currently optimized and designed for brain imaging. Second, we design experiments to evaluate the impact of removing cardiac triggering. We show that when triggering is foregone, images are qualitatively similar to triggered sequences, do not have increased prevalence of artifacts, and result in similar diffusion tensor indices with similar reproducibility to triggered acquisitions. When triggering is removed, much shorter acquisitions are possible, which are also qualitatively and quantitatively similar to triggered sequences. We suggest that removing cardiac triggering for cervical SC diffusion can be a reasonable option to save time with minimal sacrifice to image quality.

NCCN Guidelines® Insights: Kidney Cancer, Version 2.2024.

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for diagnostic workup, staging, and treatment of patients with renal cell carcinoma (RCC). These NCCN Guidelines Insights focus on the systemic therapy options for patients with advanced RCC and summarize the new clinical data evaluated by the NCCN panel for the recommended therapies in Version 2.2024 of the NCCN Guidelines for Kidney Cancer.

Assessing White Matter Engagement in Brain Networks through Functional and Structural Connectivity Mapping.

Understanding the intricate interplay between gray matter (GM) and white matter (WM) is crucial for deciphering the complex activities of the brain. While diffusion tensor imaging (DTI) has advanced the mapping of these structural pathways, the relationship between structural connectivity (SC) and functional connectivity (FC) remains inadequately understood. This study addresses the need for a more integrative approach by mapping the importance of the inter-GM functional link to its structural counterparts in WM. This mapping yields a spatial distribution of engagement that is not only highly reproducible but also aligns with direct structural, functional, and bioenergetic measures within WM, illustrating a notable interdependence between the function of GM and the characteristics of WM. Additionally, our research has uncovered a set of unique engagement modes through a clustering analysis of window-wise engagement maps, highlighting the dyanmic nature of the engagement. The engagement along with their temporal variations revealed significant differences across genders and age groups. These findings suggest the potential of WM engagement as a biomarker for neurological and cognitive conditions, offering a more nuanced understanding of individualized brain activity and connectivity patterns.

Isolating the Drivers of Racial Inequities in Prostate Cancer Treatment.

BACKGROUND: Black individuals in the United States are less likely than White individuals to receive curative therapies despite a 2-fold higher risk of prostate cancer death. While research has described treatment inequities, few studies have investigated underlying causes. METHODS: We analyzed a cohort of 40,137 Medicare beneficiaries (66 and older) linked to the Surveillance Epidemiology and End Results (SEER) cancer registry who had clinically significant, non-metastatic (cT1-4N0M0, grade group 2-5) prostate cancer (diagnosed 2010-2015). Using the Kitagawa-Oaxaca-Blinder decomposition, we assessed the contributions of patient health and health care delivery on the racial difference in localized prostate cancer treatments (radical prostatectomy or radiation). Patient health consisted of comorbid diagnoses, tumor characteristics, SEER site, diagnosis year, and age. Health care delivery was captured as a prediction model with these health variables as predictors of treatment, reflecting current treatment patterns. RESULTS: A total of 72.1% and 78.6% of Black and White patients received definitive treatment, respectively, a difference of 6.5 percentage points. An estimated 15% [95% confidence interval (CI): 6-24] of this treatment difference was explained by measured differences in patient health, leaving the remaining estimated 85% (95% CI: 74-94) attributable to a potentially broad range of health care delivery factors. Limitations included insufficient data to explore how specific health care delivery factors, including structural racism and social determinants, impact differential treatment. CONCLUSIONS: Our results show the inadequacy of patient health differences as an explanation of the treatment inequity. IMPACT: Investing in studies and interventions that support equitable health care delivery for Black individuals with prostate cancer will contribute to improved outcomes.

The missing third dimension-Functional correlations of BOLD signals incorporating white matter.

Correlations between magnetic resonance imaging (MRI) blood oxygenation level-dependent (BOLD) signals from pairs of gray matter areas are used to infer their functional connectivity, but they are unable to describe how white matter is engaged in brain networks. Recently, evidence that BOLD signals in white matter are robustly detectable and are modulated by neural activities has accumulated. We introduce a three-way correlation between BOLD signals from pairs of gray matter volumes (nodes) and white matter bundles (edges) to define the communication connectivity through each white matter bundle. Using MRI images from publicly available databases, we show, for example, that the three-way connectivity is influenced by age. By integrating functional MRI signals from white matter as a third component in network analyses, more comprehensive descriptions of brain function may be obtained.

Tumor therapy by targeting extracellular hydroxyapatite using novel drugs: A paradigm shift.

BACKGROUND: It has been shown that tumor microenvironment (TME) hydroxyapatite (HAP) is typically associated with many malignancies and plays a role in tumor progression and growth. Additionally, acidosis in the TME has been reported to play a key role in selecting for a more aggressive tumor phenotype, drug resistance and desensitization to immunotherapy for many types of cancers. TME-HAP is an attractive target for tumor detection and treatment development since HAP is generally absent from normal soft tissue. We provide strong evidence that dissolution of hydroxyapatite (HAP) within the tumor microenvironment (TME-HAP) using a novel therapeutic can be used to kill cancer cells both in vitro and in vivo with minimal adverse effects. METHODS: We developed an injectable cation exchange nano particulate sulfonated polystyrene solution (NSPS) that we engineered to dissolve TME-HAP, inducing localized acute alkalosis and inhibition of tumor growth and glucose metabolism. This was evaluated in cell culture using 4T1, MDA-MB-231 triple negative breast cancer cells, MCF10 normal breast cells, and H292 lung cancer cells, and in vivo using orthotopic mouse models of cancer that contained detectable microenvironment HAP including breast (MMTV-Neu, 4T1, and MDA-MB-231), prostate (PC3) and colon (HCA7) cancer using 18 F-NaF for HAP and 18 F-FDG for glucose metabolism with PET imaging. On the other hand, H292 lung tumor cells that lacked detectable microenvironment HAP and MCF10a normal breast cells that do not produce HAP served as negative controls. Tumor microenvironment pH levels following injection of NSPS were evaluated via Chemical Exchange Saturation (CEST) MRI and via ex vivo methods. RESULTS: Within 24 h of adding the small concentration of 1X of NSPS (~7 µM), we observed significant tumor cell death (~ 10%, p < 0.05) in 4T1 and MDA-MB-231 cell cultures that contain HAP but ⟨2% in H292 and MCF10a cells that lack detectable HAP and in controls. Using CEST MRI, we found extracellular pH (pHe) in the 4T1 breast tumors, located in the mammary fat pad, to increase by nearly 10% from baseline before gradually receding back to baseline during the first hour post NSPS administration. in the tumors that contained TME-HAP in mouse models, MMTV-Neu, 4T1, and MDA-MB-231, PC3, and HCA7, there was a significant reduction (p<0.05) in 18 F-Na Fuptake post NSPS treatment as expected; 18 F- uptake in the tumor = 3.8 ± 0.5 %ID/g (percent of the injected dose per gram) at baseline compared to 1.8 ±0.5 %ID/g following one-time treatment with 100 mg/kg NSPS. Of similar importance, is that 18 F-FDG uptake in the tumors was reduced by more than 75% compared to baseline within 24 h of treatment with one-time NSPS which persisted for at least one week. Additionally, tumor growth was significantly slower (p < 0.05) in the mice treated with one-time NSPS. Toxicity showed no evidence of any adverse effects, a finding attributed to the absence of HAP in normal soft tissue and to our therapeutic NSPS having limited penetration to access HAP within skeletal bone. CONCLUSION: Dissolution of TME-HAP using our novel NSPS has the potential to provide a new treatment paradigm to enhance the management of cancer patients with poor prognosis.

Detection of Treatment Response in Triple-Negative Breast Tumors to Paclitaxel Using MRI Cell Size Imaging.

BACKGROUND: Breast cancer treatment response evaluation using the response evaluation criteria in solid tumors (RECIST) guidelines, based on tumor volume changes, has limitations, prompting interest in novel imaging markers for accurate therapeutic effect determination. PURPOSE: To use MRI-measured cell size as a new imaging biomarker for assessing chemotherapy response in breast cancer. STUDY TYPE: Longitudinal; animal model. STUDY POPULATION: Triple-negative human breast cancer cell (MDA-MB-231) pellets (4 groups, n = 7) treated with dimethyl sulfoxide (DMSO) or 10 nM of paclitaxel for 24, 48, and 96 hours, and 29 mice with MDA-MB-231 tumors in right hind limbs treated with paclitaxel (n = 16) or DMSO (n = 13) twice weekly for 3 weeks. FIELD STRENGTH/SEQUENCE: Oscillating gradient spin echo and pulsed gradient spin echo sequences at 4.7 T. ASSESSMENT: MDA-MB-231 cells were analyzed using flowcytometry and light microscopy to assess cell cycle phases and cell size distribution. MDA-MB-231 cell pellets were MR imaged. Mice were imaged weekly, with 9, 6, and 14 being sacrificed for histology after MRI at weeks 1, 2, and 3, respectively. Microstructural parameters of tumors/cell pellets were derived by fitting diffusion MRI data to a biophysical model. STATISTICAL TESTS: One-way ANOVA compared cell sizes and MR-derived parameters between treated and control samples. Repeated measures 2-way ANOVA with Bonferroni post-tests compared temporal changes in MR-derived parameters. A P-value <0.05 was considered statistically significant. RESULTS: In vitro experiments showed that the mean MR-derived cell sizes of paclitaxel-treated cells increased significantly with a 24-hours treatment and decreased (P = 0.06) with a 96-hour treatment. For in vivo xenograft experiments, the paclitaxel-treated tumors showed significant decreases in cell size at later weeks. MRI observations were supported by flowcytometry, light microscopy, and histology. DATA CONCLUSIONS: MR-derived cell size may characterize the cell shrinkage during treatment-induced apoptosis, and may potentially provide new insights into the assessment of therapeutic response. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 4.

Interruptions in bladder cancer care during the COVID-19 public health emergency.

BACKGROUND: Academic and community urology centers participating in a pragmatic clinical trial in non-muscle-invasive bladder cancer completed monthly surveys assessing restrictions in aspects of bladder cancer care due to the COVID-19 Public Health Emergency. Our objective was to describe pandemic-related restrictions on bladder cancer care. METHODS: We invited 32 sites participating in a multicenter pragmatic bladder cancer trial to complete monthly surveys distributed through REDCap beginning in May 2020. These surveys queried sites on whether they were experiencing restrictions in the use of elective surgery, transurethral resection of bladder tumors (TURBT), radical cystectomy, office cystoscopy, and intravesical bacillus Calmette-Guerin (BCG) availability. Responses were collated with descriptive statistics. RESULTS: Of 32 eligible sites, 21 sites had at least a 50% monthly response rate over the study period and were included in the analysis. Elective surgery was paused at 76% of sites in May 2020, 48% of sites in January 2021, and 52% of sites in January 2022. Over those same periods, coinciding with COVID-19 incidence waves, TURBT was restricted at 10%, 14%, and 14% of sites, respectively, radical cystectomy was restricted at 10%, 14%, and 19% of sites, respectively, and cystoscopy was restricted at 33%, 0%, and 10% of sites, respectively. CONCLUSIONS: Bladder cancer care was minimally restricted compared with more pronounced restrictions seen in general elective surgeries during the COVID-19 pandemic.

Model-based parcellation of diffusion MRI of injured spinal cord predicts hand use impairment and recovery in squirrel monkeys.

A mathematical model-based parcellation of magnetic resonance diffusion tensor images (DTI) has been developed to quantify progressive changes in three types of tissues - grey (GM), white matter (WM), and damaged spinal cord tissue, along with behavioral assessments over a 6 month period following targeted spinal cord injuries (SCI) in monkeys. Sigmoid Gompertz function based fittings of DTI metrics provide early indicators that correlate with, and predict, recovery of hand grasping behavior. Our three tissue pool model provided unbiased, data-driven segmentation of spinal cord images and identified DTI metrics that can serve as reliable biomarkers of severity of spinal cord injuries and predictors of behavioral outcomes.