Enzalutamide induces cytotoxicity in desmoplastic small round cell tumor independent of the androgen receptor.

Desmoplastic Small Round Cell Tumor (DSRCT) is a rare, pediatric cancer caused by the EWSR1::WT1 fusion protein. DSRCT predominantly occurs in males, which comprise 80-90% of the patient population. While the reason for this male predominance remains unknown, one hypothesis is that the androgen receptor (AR) plays a critical role in DSRCT and elevated testosterone levels in males help drive tumor growth. Here, we demonstrate that AR is highly expressed in DSRCT relative to other fusion-driven sarcomas and that the AR antagonists enzalutamide and flutamide reduce DSRCT growth. However, despite these findings, which suggest an important role for AR in DSRCT, we show that DSRCT cell lines form xenografts in female mice at the same rate as male mice and AR depletion does not significantly alter DSRCT growth in vitro. Further, we find that AR antagonists reduce DSRCT growth in cells depleted of AR, establishing an AR-independent mechanism of action. These findings suggest that AR dependence is not the reason for male predominance in DSRCT and that AR-targeted therapies may provide therapeutic benefit primarily through an AR-independent mechanism that requires further elucidation.

Recent Trends in "Manels" and Gender Representation Among Panelists at North American Annual Radiation Oncology Meetings.

PURPOSE: Achieving gender equity in radiation oncology is an important goal, as a smaller proportion of women enter radiation oncology residency compared with those graduating from medical school. As invited speaking opportunities at academic medical conferences are vital for promotion/tenure, we investigated the prevalence of all-men panels ("manels") at American Society for Radiation Oncology (ASTRO) and Canadian Society of Radiation Oncology (CARO) annual meetings. METHODS AND MATERIALS: Using ASTRO and CARO online meeting programs, 2018 to 2021 faculty information was obtained, including gender, panel role (chair vs nonchair), type of session, and topic. Primary outcomes included percentage of manels and proportion of female panelists over time. Representation of women among chairs was also evaluated. RESULTS: Over the 4-year study period across both conferences, a total of 765 panel sessions were held with 2973 faculty members, of whom 1287 (43.3%) were women. Of these sessions, 127 of 765 (16.6%) were manels. ASTRO meetings had 1169 of 2742 (42.6%) female faculty members and held 107 of 680 (15.7%) manels, whereas CARO meetings had 118 of 231 (51.1%) female faculty and held 20 of 85 manels (23.5%). From 2018 to 2021, the proportion of manels decreased at ASTRO and CARO meetings from 25.6% to 8.2% (P < .001) and from 29.6% to 15.0% (P = .130), respectively. The role of chair was majority male in every year from 2018 to 2021 at ASTRO meetings (58.6% overall), but more balanced at CARO meetings (48.0% overall). Among session types, the highest proportion of manels was observed for scientific sessions (19.1%, P = .011) at ASTRO meetings and leadership sessions (29.4%, P = .533) at CARO meetings. The lowest proportion of female panelists was on genitourinary cancer topics at ASTRO meetings (31.9%, P = .018) and physics topics at CARO meetings (40.4%, P = .085). CONCLUSIONS: During the study period, the proportion of female panelists increased with a corresponding decrease in manels. ASTRO and CARO should strive for further involvement of women and the elimination of manels whenever possible.

Comparison of ChatGPT and Traditional Patient Education Materials for Men's Health.

INTRODUCTION: ChatGPT is an artificial intelligence platform available to patients seeking medical advice. Traditionally, urology patients consulted official provider-created materials, particularly the Urology Care Foundation™ (UCF). Today, men increasingly go online due to the rising costs of health care and the stigma surrounding sexual health. Online health information is largely inaccessible to laypersons as it exceeds the recommended American sixth to eighth grade reading level. We conducted a comparative assessment of patient education materials generated by ChatGPT vs UCF regarding men's health conditions. METHODS: All 6 UCF men's health resources were identified. ChatGPT responses were generated using patient questions obtained from UCF. Adjusted ChatGPT responses were generated by prompting, "Explain it to me like I am in sixth grade." Textual analysis was performed using sentence, word, syllable, and complex word count. Six validated formulae were used for readability analysis. Two physicians independently scored responses for accuracy, comprehensiveness, and understandability. Statistical analysis involved Wilcoxon matched-pairs test. RESULTS: ChatGPT responses were longer and more complex. Both UCF and ChatGPT failed official readability standards, although ChatGPT performed significantly worse across all 6 topics (all P < .001). Conversely, adjusted ChatGPT readability typically surpassed UCF, even meeting the recommended level for 2 topics. Qualitatively, UCF and ChatGPT had comparable accuracy, although ChatGPT had better comprehensiveness and worse understandability. CONCLUSIONS: When comparing readability, ChatGPT-generated education is less accessible than provider-written content, although neither meets the recommended level. Our analysis indicates that specific artificial intelligence prompts can simplify educational materials to meet national standards and accommodate individual literacy.

Clinical Outcomes of De Novo Versus Relapsed Early Metastatic Testicular Seminoma Treated With Contemporary Radiation Therapy.

PURPOSE: Chemotherapy (CHT) or radiation therapy (RT) are first-line treatments for clinical stage II (CS-II) testicular seminoma. Historically, clinical stage I (CS-I) seminoma was also treated with CHT or RT, but in the past 2 decades practice has shifted toward active surveillance for CS-I with RT or CHT reserved for patients with progression to CS-II. Limited data exist on contemporary RT techniques and patient stratification (ie, de novo [CS-II at orchiectomy] vs relapsed [CS-II diagnosed during surveillance after orchiectomy for CS-I]). We investigated outcomes in CS-II patients treated with RT in the modern era across 2 institutions. METHODS AND MATERIALS: A retrospective review identified 73 patients treated with RT for CS-II A or B seminoma between 2001 and 2022. Recurrence-free survival (RFS) was calculated by the Kaplan-Meier method and univariate analyses were performed with log-rank or Cox proportional hazard regression. Recurrence was defined as biopsy-proven metastatic seminoma after RT completion. Second malignancies were defined as a biopsy-proven malignancy originating in the prior RT field. RESULTS: Thirty-eight (52%) patients presented with de novo CS-II and 35 (48%) patients had relapsed CS-II. Median follow-up was 4.8 years (IQR: 2.3-8.1). Five-year RFS was 82% overall (92% in relapsed patients and 73% in de novo patients). Relapsed CS-II disease had lower recurrence rates after RT compared with de novo CS-II disease. All recurrences occurred outside the prior RT field and were salvaged. Disease-specific survival was 100%. Two second malignancies occurred (prostate, colorectal cancer at 67 months and 119 months post-RT, respectively). CONCLUSIONS: In patients with CS-II seminoma treated with modern RT, there were no in-field recurrences. Presentation with de novo CS-II is associated with out-of-field recurrence. Subject to further larger-scale validation, our results suggest that compared with CS-II at time of relapse, de novo CS-II may portend more aggressive or micrometastatic disease beyond the retroperitoneum, raising the possibility of benefit from CHT after radiation.

Enzalutamide Induces Cytotoxicity in Desmoplastic Small Round Cell Tumor Independent of the Androgen Receptor.

Desmoplastic Small Round Cell Tumor (DSRCT) is a rare, pediatric cancer caused by the EWSR1::WT1 fusion protein. DSRCT predominantly occurs in males, which comprise 80-90% of the patient population. While the reason for this male predominance remains unknown, one hypothesis is that the androgen receptor (AR) plays a critical role in DSRCT and elevated testosterone levels in males help drive tumor growth. Here, we demonstrate that AR is highly expressed in DSRCT relative to other fusion-driven sarcomas and that the AR antagonists enzalutamide and flutamide reduce DSRCT growth. However, despite these findings, which suggest an important role for AR in DSRCT, we show that DSRCT cell lines form xenografts in female mice at the same rate as male mice and AR depletion does not significantly alter DSRCT growth in vitro. Further, we find that AR antagonists reduce DSRCT growth in cells depleted of AR, establishing an AR-independent mechanism of action. These findings suggest that AR dependence is not the reason for male predominance in DSRCT and that AR-targeted therapies may provide therapeutic benefit primarily through an AR-independent mechanism that requires further elucidation.

Disparities in testicular cancer incidence, mortality, and place of death trends from 1999 to 2020: A comprehensive cohort study.

BACKGROUND: Testicular cancer (TC) mortality rates have decreased over time, however it is unclear whether these improvements are consistent across all communities. AIMS: The aim of this study was to analyze trends in TC incidence, mortality, and place of death (PoD) in the United States between 1999-2020 and identify disparities across race, ethnicity, and geographic location. METHODS AND RESULTS: This cross-sectional study used CDC WONDER and NAACCR, to calculate age-adjusted rates of TC incidence and mortality, respectively. PoD data for individuals who died of TC were collected from CDC WONDER. Using Joinpoint analysis, longitudinal mortality trends were evaluated by age, race, ethnicity, US census region, and urbanization category. TC stage (localized vs metastatic) trends were also evaluated. Univariate and multivariate regression analysis identified demographic disparities for PoD. A total of 8,456 patients died of TC from 1999-2020. Average annual percent change (AAPC) of testicular cancer-specific mortality (TCSM) remained largely stable (AAPC, 0.4; 95% CI -0.2 to 0.9; p = 0.215). Men ages 25-29 experienced a significant increase in TCSM (AAPC, 1.3, p = 0.003), consistent with increased metastatic testicular cancer-specific incidence (TCSI) trend for this age group (AAPC, 1.6; p < 0.01). Mortality increased for Hispanic men (AAPC, 1.7, p < 0.001), with increased metastatic TCSI (AAPC, 2.5; p < 0.001). Finally, younger (<45), single, and Hispanic or Black men were more likely to die in medical facilities (all p < 0.001). The retrospective study design is a limitation. CONCLUSION: Significant increases in metastatic TC were found for Hispanic men and men aged 25-29 potentially driving increasing testicular cancer specific mortality in these groups. Evidence of racial and ethnic differences in place of death may also highlight treatment disparities.

Regional with urban-rural variation in low birth weight and its determinants of Indian children: findings from National Family Health Survey 5 data.

BACKGROUND: Low birth weight is a key indicator for child health, especially a concern in low-middle-income countries. However, health and medically-related reforms are being actively implemented in some middle-income countries like India. Identifying low birth weight (LBW) babies with their determinants across the whole country is essential to formulate regional and area-specific interventions. The objective of this study was to find out the burden and determinants of LBW on the regional and residential (rural-urban) divisions of India. METHODS: The present study was based on the NFHS-5 dataset (2019-21), a nationally representative survey in India. A total of 209,223 births were included in this study. A newborn weighing less than 2500 g was considered as LBW. According to the objectives, we used frequency distribution, chi-square test and binary logistic regression analysis for analysing the data. RESULTS: About 18.24% of the babies were LBW in India, significantly higher in rural areas than in urban areas (18.58% vs 17.36%). Regionally prevalence was more frequent in western (20.63%) and central (20.16%) rural areas. Regarding maternal concerns, in the eastern and southern regions of India, mothers aged 25-34 were less likely to have LBW children than mothers aged 35-49 years. It was found that the risk of LBW was more likely among the children born out of unintended pregnancies in almost all regions except for eastern part. In rural India, women who delivered children at home were more likely to have LBW children in India (AOR = 1.19, CI: 1.12-1.28, p < 0.001) and its central, northern, and southern regions than those who gave birth in institutions. The study indicates that LBW coexists with lower maternal education levels and poor household wealth index across all regions. About 58% and 57% of cumulative effects of independent variables on LBW can be distinguished in urban and rural India, respectively. CONCLUSIONS: Targeted-specific strategies need to be undertaken as per region and geographical variations. Then only India should be able to decline LBW as proposed by National Health Policy.

US Cancer Mortality Trends Among Hispanic Populations From 1999 to 2020.

Importance: Advances in cancer research and treatment access have led to decreasing cancer mortality in the US; however, cancer remains the leading cause of death among Hispanic individuals. Objective: To evaluate longitudinal cancer mortality trends from 1999 to 2020 among Hispanic individuals by demographic characteristics and to compare age-adjusted cancer death rates between the Hispanic population and other racial and ethnic populations during 2000, 2010, and 2020. Design, Setting, and Participants: This cross-sectional study obtained age-adjusted cancer death rates among Hispanic individuals of all ages between January 1999 and December 2020, using the Centers for Disease Control and Prevention WONDER database. Cancer death rates in other racial and ethnic populations were extracted for 2000, 2010, and 2020. Data were analyzed from October 2021 to December 2022. Exposures: Age, gender, race, ethnicity, cancer type, and US census region. Main Outcomes and Measures: Trends and average annual percent changes (AAPCs) in age-adjusted cancer-specific mortality (CSM) rates among Hispanic individuals were estimated by cancer type, age, gender, and region. Results: From 1999 to 2020, 12 644 869 patients died of cancer in the US, of whom 690 677 (5.5%) were Hispanic; 58 783 (0.5%) were non-Hispanic American Indian or Alaska Native; 305 386 (2.4%), non-Hispanic Asian or Pacific Islander; 1 439 259 (11.4%), non-Hispanic Black or African American; and 10 124 361 (80.1%), non-Hispanic White. For 26 403 patients (0.2%), no ethnicity was stated. The overall CSM rate among Hispanic individuals decreased by 1.3% (95% CI, 1.2%-1.3%) annually. Overall CSM rate decreased more for Hispanic men (AAPC, -1.6%; 95% CI, -1.7% to -1.5%) compared with women (AAPC, -1.0%; 95% CI, -1.0% to -0.9%). While death rates among Hispanic individuals decreased for most cancer types, mortality rates for liver cancer (AAPC, 1.0%; 95% CI, 0.6%-1.4%) increased among Hispanic men, and rates of liver (AAPC, 1.0%; 95% CI, 0.8%-1.3%), pancreas (AAPC, 0.2%; 95% CI, 0.1%-0.4%), and uterine (AAPC, 1.6%; 95% CI, 1.0%-2.3%) cancers increased among Hispanic women. Overall CSM rates increased for Hispanic men aged 25 to 34 years (AAPC, 0.7%; 95% CI, 0.3%-1.1%). By US region, liver cancer mortality rates increased significantly in the West for both Hispanic men (AAPC, 1.6%; 95% CI, 0.9%-2.2%) and Hispanic women (AAPC, 1.5%; 95% CI, 1.1%-1.9%). There were differential findings in mortality rates when comparing Hispanic individuals with individuals belonging to other racial and ethnic populations. Conclusions and Relevance: In this cross-sectional study, despite overall CSM decreasing over 2 decades among Hispanic individuals, disaggregation of data demonstrated that rates of liver cancer deaths among Hispanic men and women and pancreas and uterine cancer deaths among Hispanic women increased from 1999 to 2020. There were also disparities in CSM rates among age groups and US regions. The findings suggest that sustainable solutions need to be implemented to reverse these trends among Hispanic populations.

Peptidoglycan deacetylation controls type IV secretion and the intracellular survival of the bacterial pathogen Legionella pneumophila.

Peptidoglycan is a critical component of the bacteria cell envelope. Remodeling of the peptidoglycan is required for numerous essential cellular processes and has been linked to bacterial pathogenesis. Peptidoglycan deacetylases that remove the acetyl group of the N-acetylglucosamine (NAG) subunit protect bacterial pathogens from immune recognition and digestive enzymes secreted at the site of infection. However, the full extent of this modification on bacterial physiology and pathogenesis is not known. Here, we identify a polysaccharide deacetylase of the intracellular bacterial pathogen Legionella pneumophila and define a two-tiered role for this enzyme in Legionella pathogenesis. First, NAG deacetylation is important for the proper localization and function of the Type IVb secretion system, linking peptidoglycan editing to the modulation of host cellular processes through the action of secreted virulence factors. As a consequence, the Legionella vacuole mis-traffics along the endocytic pathway to the lysosome, preventing the formation of a replication permissive compartment. Second, within the lysosome, the inability to deacetylate the peptidoglycan renders the bacteria more sensitive to lysozyme-mediated degradation, resulting in increased bacterial death. Thus, the ability to deacetylate NAG is important for bacteria to persist within host cells and in turn, Legionella virulence. Collectively, these results expand the function of peptidoglycan deacetylases in bacteria, linking peptidoglycan editing, Type IV secretion, and the intracellular fate of a bacterial pathogen.

Recent trends of "manels": gender representation among invited panelists at an international oncology conference.

BACKGROUND: Gender disparities in academic medicine are a long-acknowledged concern, particularly at medical conferences. We investigated gender representation and prevalence of "manels" (all-men panels) among invited speakers at the 2018-2021 American Society of Clinical Oncology Annual Meetings. METHODS: Using American Society of Clinical Oncology online programs, 2018-2021 faculty information was obtained, including perceived or self-reported gender, medical specialty, session type, and topic. Primary outcomes were percentage of manels and proportion of women panelists over time; women representation among specialties and topics were evaluated. Cochran-Armitage and Fisher's exact tests were used to analyze trends in proportion of manels and women representation over time and to compare each session type, topic, or specialty with other categories combined, respectively. RESULTS: During 2018-2021, there were 670 sessions, 81 of which (12.1%) were manels. Among 2475 panelists, 1181 (47.7%) were women. Over time, the percentage of manels significantly decreased from 17.4% in 2018 to 9.9% in 2021 (P = .030). The highest proportion of manels was observed for leadership or special sessions (17.1%, P = .419). Women panelists were underrepresented for the topics of genitourinary cancers (38.6%, P = .029) and translational or preclinical sciences (36.7%, P < .001). There was a positive trend toward improved women representation among translational or preclinical sciences (27.4% in 2018 vs 41.8% in 2021, P = .031) but not among genitourinary cancers (41.1% in 2018 vs 40.7% in 2021, P = .969). CONCLUSIONS: The number of women panelists increased during the study period, with a corresponding decrease in the proportion of manels, specifically in education and leadership or special sessions. Ongoing underrepresentation of women in genitourinary cancers and translational or preclinical topics underscores the importance of annual meeting organizers continuing to strive for diverse gender representation.

Longitudinal Analysis of Bladder Cancer-Specific Mortality Trends in the United States.

BACKGROUND: Bladder cancer is the tenth leading cause of cancer death in the United States (US). Advances in diagnosis, imaging, and treatments have led to improvements in bladder cancer management. OBJECTIVE: To evaluate longitudinal bladder cancer mortality trends from 1999-2020 in the US by gender, race, ethnicity, age, geographic region, and urbanization category. METHODS: Age-adjusted bladder cancer death and incidence rates of individuals in the US of all ages between 1999-2020 were obtained using the CDC WONDER and NAACCR databases. Trends and average annual percent changes (AAPC) in age-adjusted Bladder Cancer-Specific Mortality (BCSM) and incidence rates were estimated. Data were analyzed from May 2023 to October 2023. RESULTS: From 1999-2020, overall BCSM decreased by 0.4% annually, with a dramatic decrease in deaths between 2015-2020 (AAPC: -2.0% [95% CI: -2.6,-1.3]). However, BCSM rates and metastatic malignant bladder cancer incidence rates from 1999-2020 increased for individuals≥85 years old (AAPC for BCSM: 0.8% [95% CI:0.5,1.1]; AAPC for metastatic malignant incidence: 2.5% [95% CI: 2.0,2.9]). Increases in BCSM were found for certain years in the South, in rural areas, and for Non-Hispanic White and Asian or Pacific Islander individuals. CONCLUSIONS: Overall mortality from bladder cancer has been decreasing in the US over two decades. Upon disaggregation, increasing trends were found for BCSM and for metastatic malignant bladder cancer incidence for individuals≥85 years old from 1999-2020. Further evaluation of these trends is essential to understand how to target specific populations to improve patient outcomes.

Association of the USPSTF Grade D Recommendation Against Prostate-Specific Antigen Screening With Prostate Cancer-Specific Mortality.

Importance: The 2012 US Preventive Services Task Force (USPSTF) Grade D recommendation against prostate-specific antigen (PSA) screening for all men has been controversial, with data documenting a shift to a higher stage of disease at diagnosis. The association between the Grade D recommendation and prostate cancer-specific mortality (PCSM) among contemporary cohorts, however, is unclear. Objective: To evaluate PCSM rates between 1999 and 2019, comparing trends in rates before and after the change in the 2012 USPSTF screening guideline to assess its association with PCSM. Exposure: The 2012 USPSTF Grade D recommendation against PSA screening for all men. Design, Setting, and Participants: This cross-sectional study used Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research maintained by the National Center for Health Statistics to collect data on cause of death for all individuals who died of prostate cancer in the US from 1999 to 2019. Analysis was performed from January to August 2021. Main Outcomes and Measures: Trends in PCSM rates were calculated from 1999 to 2012 and from 2014 to 2019, with a washout year of 2013, using linear regression, with year and binary indicator of pre-2013 and post-2013 status as interaction terms. Trends were further analyzed by age, race and ethnicity, urbanization category, and US Census region. Other measures included diagnosis of localized or metastatic prostate cancer and overall cancer mortality. Results: A total of 618 095 patients died of prostate cancer in the US from 1999 to 2019. Age-adjusted PCSM decreased linearly at a rate of -0.273 per 100 000 population per year from 1999 to 2012 and stalled at a rate of -0.009 per 100 000 per year from 2014 to 2019 (P < .001). This finding was significant among men aged 60 years or older, especially among men aged 60 to 69 years, men aged 80 years or older, and among Black men. Men aged 60 to 64 years had a decreasing, age-adjusted PCSM rate of -0.0088 per 100 000 population per year prior to 2013 followed by an increasing rate of 0.0014 per 100 000 per year. Men aged 65 to 69 years had a decreasing, age-adjusted PCSM rate of -0.024 per 100 000 population per year prior to 2013 followed by an increasing rate of 0.0011 per 100 000 population per year. Men aged 80 years or older had the largest absolute difference between rates before and after 2013 compared with all other age groups, with a difference of 0.06 for men aged 80 to 84 years and 0.07 for men 85 aged years or older. Black men had a decreasing, age-adjusted PCSM rate of -0.700 per 100 000 population per year prior to 2013 followed by a flattened rate of -0.091 per 100 000 population per year. Changes were observed across races and ethnicities, urbanization categories, and US Census regions and were accompanied by increased diagnoses of metastatic disease, which are inconsistent with mortality trends across all malignant neoplasms. Conclusions and Relevance: This cross-sectional study using comprehensive PCSM data through 2019 demonstrated decreasing PCSM rates that flattened or increased after the 2012 USPSTF Grade D recommendation, suggesting that decreased PSA screening may be a factor associated with this change. This change was seen across ages, races and ethnicities, urbanization categories, and US Census regions. The updated 2018 USPSTF guideline supporting shared decision-making may reverse these trends in the coming years.

Characterization of an Iodinated Rectal Spacer for Prostate Photon and Proton Radiation Therapy.

PURPOSE: Conventional rectal spacers (nonI-SPs) are low-contrast on computed tomography (CT), often necessitating magnetic resonance imaging for accurate delineation. A new formulation of spacers (I-SPs) incorporates iodine to improve radiopacity and CT visualization. We characterized placement, stability, and plan quality of I-SPs compared to nonI-SPs. METHODS AND MATERIALS: Patients with intact prostate cancer (n = 50) treated with I-SPs and photons were compared to randomly selected patients (n = 50) with nonI-SPs (photon or proton therapy). The I-SP was contoured on the planning CT and cone beam CTs at 3 timepoints: first, middle, and final treatment (n = 200 scans). I-SPs Hounsfield units (HU), volume, surface area (SA), centroid position relative to prostate centroid, and distance between prostate/rectum centroids were compared on the planning CTs between each cohort. I-SP changes were evaluated on cone beam CTs over courses of treatment. Dosimetric evaluations of plan quality and robustness were performed. I-SP was tested in a phantom to characterize its relative linear stopping power for protons. RESULTS: I-SPs yielded a distinct visible contrast on planning CTs compared to nonI-SPs (HU 138 vs 12, P < .001), allowing delineation on CT alone. The delineated volume and SA of I-SPs were smaller than nonI-SPs (volume 8.9 vs 10.6 mL, P < .001; SA 28 vs 35 cm2, P < .001), yet relative spacer position and prostate-rectal separation were similar (P = .79). No significant change in HU, volume, SA, or relative position of the I-SPs hydrogel occurred over courses of treatment (all P > .1). Dosimetric analysis concluded there were no significant changes in plan quality or robustness for I-SPs compared to nonI-SPs. The I-SP relative linear stopping power was 1.018, necessitating HU override for proton planning. CONCLUSIONS: I-SPs provide a manifest CT contrast, allowing for delineation on planning CT alone with no magnetic resonance imaging necessary. I-SPs radiopacity, size, and relative position remained stable over courses of treatment from 28 to 44 fractions. No changes in plan quality or robustness were seen comparing I-SPs and nonI-SPs.