PSA Stratification for Predicting Advanced Prostate Cancer Events in Men Approaching Age-Limits for Recommended Screening.

PURPOSE: To quantify the ability of various PSA values in predicting the likelihood of developing metastatic or fatal prostate cancer in older men. MATERIALS/METHODS: We used a random sample of patients in the United States Veterans Health Administration to identify 80,706 men who had received PSA testing between ages 70 to 75. Our primary endpoint was time to development of either metastatic prostate cancer or death from prostate cancer. We used cumulative/dynamic modeling to account for competing events (death from non-prostate cancer causes) in studying both the discriminative ability of PSA as well as for positive predictive value and negative predictive value at three time points. RESULTS: PSA demonstrated time-dependent predictive discrimination, with receiver operating characteristic area under the curve at 5, 10, and 14 years decreasing from 0.83 to 0.77 to 0.73, respectively, but without statistically significant difference when stratified by race. At PSA thresholds between 1 and 8 ng/mL, the positive predictive value of developing advanced prostate cancer was significantly greater in Black than White patients. For instance, at a PSA > 3, at 5, 10, and 14 years, White patients had 2.4%, 2.9%, and 3.7% risk of an event, whereas Black patients had 4.3%, 6.5%, and 8.3% risk. CONCLUSIONS: In men aged 70 to 75 deciding whether to cease PSA testing with borderline-elevated PSA values, the risk of developing metastatic or fatal prostate cancer is quantifiable and relatively low. Risk assessment in this setting must account for the higher incidence of prostate cancer in Black men.

A revised action spectrum for vitamin D synthesis by suberythemal UV radiation exposure in humans in vivo.

Action spectra are important biological weighting functions for risk/benefit analyses of ultraviolet (UV) radiation (UVR) exposure. One important human benefit of exposure to terrestrial solar UVB radiation (∼295 to 315 nm) is the cutaneous synthesis of vitamin D3 that is initiated by the photoconversion of 7-dehydrocholesterol to previtamin D3 An action spectrum for this process that is followed by other nonphotochemical steps to achieve biologically active vitamin D3 has been established from ex vivo data and is widely used, although its validity has been questioned. We tested this action spectrum in vivo by full- or partial-body suberythemal irradiation of 75 healthy young volunteers with five different polychromatic UVR spectra on five serial occasions. Serum 25-hydroxyvitamin D3 [25(OH)D3] levels, as the most accurate measure of vitamin D3 status, were assessed before, during, and after the exposures. These were then used to generate linear dose-response curves that were different for each UVR spectrum. It was established that the previtamin D3 action spectrum was not valid when related to the serum 25(OH)D3 levels, as weighting the UVR doses with this action spectrum did not result in a common regression line unless it was adjusted by a blue shift, with 5 nm giving the best fit. Such a blue shift is in accord with the published in vitro action spectra for vitamin D3 synthesis. Thus, calculations regarding the risk (typically erythema) versus the benefit of exposure to solar UVR based on the ex vivo previtamin D3 action spectrum require revision.

A randomized patient education trial investigating treatment-related distress and satisfaction with the use of an at-home gynecologic brachytherapy educational video.

BACKGROUND: Physician explanation of gynecologic brachytherapy can be overwhelming or induce patient anxiety, and may be time-constrained given clinical limitations. We report the first randomized trial of an educational video intervention in gynecologic brachytherapy on patient-reported outcomes. METHODS: Between February 2020 and January 2022, 80 gynecologic cancer patients prescribed brachytherapy were randomly assigned to either standard informed consent (Arm A) or a supplemental 16 min brachytherapy educational video (https://vimeo.com/403385455/d0716e3cc8) via the internet (Arm B). Primary outcome was treatment-related distress (National Comprehensive Cancer Network (NCCN) distress scale scored 0 (no distress) to 10 (maximum distress)). Secondary outcome was patient satisfaction (summated Likert-scale scored 11-55). Surveys were administered at baseline, after first treatment, and prior to brachytherapy completion. RESULTS: All patients completed the prescribed brachytherapy. In Arm B, 19/40 (48%) patients and 10/40 (25%) patients' family/friends viewed the video. For patients that completed all surveys (Arm A n=29, Arm B n=28), there was no difference between arms in the sociodemographic, clinical, or treatment variables. Distress scores were low at baseline (Arm A median 4, Arm B median 4, p=0.65) and there was no detectable change in distress between arms on surveys 1 and 2 (ß 0.36, p=0.67) or surveys 1 and 3 (ß -1.02, p=0.29) in multivariable analysis. Satisfaction scores were high at baseline (Arm A median 54, Arm B median 54.5, p=0.64) and there was no detectable change in satisfaction between arms on surveys 1 and 2 (ß 0.22, p=0.93) or surveys 1 and 3 (ß 0.63, p=0.85) in multivariable analysis. CONCLUSIONS: Among patients randomized to an educational video tool for gynecologic brachytherapy, approximately 50% of the cohort and 25% of the cohort's family/friends used the video. Overall, patients had low distress scores and high satisfaction scores with no significant differences between the standard and video intervention arms. Further work is needed to understand factors contributing to gynecologic brachytherapy anxiety. TRIAL REGISTRATION NUMBER: NCT04363957.

Differential regulation of TNFα and IL-6 expression contributes to immune evasion in prostate cancer.

BACKGROUND: The role of the inflammatory milieu in prostate cancer progression is not well understood. Differences in inflammatory signaling between localized and metastatic disease may point to opportunities for early intervention. METHODS: We modeled PCa disease progression by analyzing RNA-seq of localized vs. metastatic patient samples, followed by CIBERSORTx to assess their immune cell populations. The VHA CDW registry of PCa patients was analyzed for anti-TNF clinical outcomes. RESULTS: We observed statistically significant opposing patterns of IL-6 and TNFα expression between localized and metastatic disease. IL-6 was robustly expressed in localized disease and downregulated in metastatic disease. The reverse was observed with TNFα expression. Metastatic disease was also characterized by downregulation of adhesion molecule E-selectin, matrix metalloproteinase ADAMTS-4 and a shift to M2 macrophages whereas localized disease demonstrated a preponderance of M1 macrophages. Treatment with anti-TNF agents was associated with earlier stage disease at diagnosis. CONCLUSIONS: Our data points to clearly different inflammatory contexts between localized and metastatic prostate cancer. Primary localized disease demonstrates local inflammation and adaptive immunity, whereas metastases are characterized by immune cold microenvironments and a shift towards resolution of inflammation and tissue repair. Therapies that interfere with these inflammatory networks may offer opportunities for early intervention in monotherapy or in combination with immunotherapies and anti-angiogenic approaches.

ASTHMA - comparing the impact of vitamin D versus UVR on clinical and immune parameters.

The incidence of asthma has increased markedly since the 1960s and is currently estimated to affect more than 300 million individuals worldwide. A number of environmental factors are implicated in asthma pathogenesis, one of which is vitamin D. Vitamin D deficiency is a global health concern and has increased in parallel with asthma incidence. Epidemiological studies report associations between low vitamin D status, assessed as circulating levels of 25-hydroxyvitamin D, with asthma incidence, severity, exacerbations and responses to treatment. This has led to clinical studies to test whether increasing the levels of vitamin D improves asthma management. Despite being highly variable in dosing regimens, design and outcomes, meta-analyses suggest overall positive outcomes with respect to reduced asthma exacerbations and steroid requirements. The primary mechanism for increasing vitamin D levels in the body is through exposure of the skin to the ultraviolet B (UVB) component of ultraviolet radiation (UVR), most commonly from sun exposure. However, only a limited number of studies investigating the impact of UVR on the asthmatic response have been performed; these generally report on the impact of latitude as a surrogate of sun exposure, or address this in animal models. To the best of our knowledge no comprehensive trials to assess the impact of UVB radiation on asthma outcomes have been performed. Within this review we discuss observational and clinical studies in this field, and innate and adaptive immune mechanisms through which UVR and vitamin D may impact respiratory health, and asthma. We highlight the heterogeneity of asthmatic disease, which is likely to impact upon the efficacy of interventional studies, and briefly overview more recent findings relating to the impact of vitamin D/UVR on the development of asthma.

A functional siRNA screen identifies genes modulating angiotensin II-mediated EGFR transactivation.

The angiotensin type 1 receptor (AT1R) transactivates the epidermal growth factor receptor (EGFR) to mediate cellular growth, however, the molecular mechanisms involved have not yet been resolved. To address this, we performed a functional siRNA screen of the human kinome in human mammary epithelial cells that demonstrate a robust AT1R-EGFR transactivation. We identified a suite of genes encoding proteins that both positively and negatively regulate AT1R-EGFR transactivation. Many candidates are components of EGFR signalling networks, whereas others, including TRIO, BMX and CHKA, have not been previously linked to EGFR transactivation. Individual knockdown of TRIO, BMX or CHKA attenuated tyrosine phosphorylation of the EGFR by angiotensin II stimulation, but this did not occur following direct stimulation of the EGFR with EGF, indicating that these proteins function between the activated AT1R and the EGFR. Further investigation of TRIO and CHKA revealed that their activity is likely to be required for AT1R-EGFR transactivation. CHKA also mediated EGFR transactivation in response to another G protein-coupled receptor (GPCR) ligand, thrombin, indicating a pervasive role for CHKA in GPCR-EGFR crosstalk. Our study reveals the power of unbiased, functional genomic screens to identify new signalling mediators important for tissue remodelling in cardiovascular disease and cancer.

Opioid tapering in older cancer survivors does not increase psychiatric or drug hospitalization rates.

BACKGROUND: Opioid tapering in the general population is linked to increases in hospitalizations or emergency department visits related to psychiatric or drug-related diagnoses. Cancer survivors represent a unique population with different opioid indications, prescription patterns, and more frequent follow-up care. This study sought to describe patterns of opioid tapering among older cancer survivors and to test the hypothesis of whether older cancer survivors face increased risks of adverse events with opioid tapering. METHODS: Using the Surveillance, Epidemiology and End Results Medicare-linked database, we identified 15 002 Medicare-beneficiary cancer survivors diagnosed between 2010 and 2017 prescribed opioids consistently for at least 6 months after their cancer diagnosis. Tapering was defined as a binary time-varying event occurring with any monthly oral morphine equivalent reduction of 15% or more from the previous month. Primary diagnostic billing codes associated with emergency room or hospital admissions were used for the composite endpoint of psychiatric- or drug-related event(s). RESULTS: There were 3.86 events per 100 patient-months, with 97.8% events being mental health emergencies, 1.91% events being overdose emergencies, and 0.25% involving both. Using a generalized estimating equation for repeated measure time-based analysis, opioid tapering was not statistically associated with acute events in the 3-month posttaper period (odds ratio [OR] = 1.02; P = .62) or at any point in the future (OR = 0.96; P = .46). CONCLUSIONS: Opioid tapering in older cancer survivors does not appear to be linked to a higher risk of acute psychiatric- or drug-related events, in contrast to prior research in the general population.

Androgen Deprivation Therapy and Outcomes After Radiation Therapy in Black Patients With Prostate Cancer.

Importance: Prostate cancer in Black men compared with White men may be more sensitive to radiation therapy resulting in better outcomes in equal-access settings. The outcomes of androgen-deprivation therapy (ADT) vs radiation therapy itself remains uncharacterized. Objectives: To quantify any outcome modification by receipt of ADT on the association between Black race and prostate cancer outcomes following radiation therapy. Design, Setting, and Participants: This was a retrospective, nationwide cohort study of Black and White patients treated in the US Veterans Healthcare system between 2000 and 2020 receiving definitive radiation for localized prostate cancer. Data were analyzed from January 2000 to December 2020. Exposure: Patient self-identified race and use of ADT defined as any gonadotrophin-releasing hormone agonist or antagonist prescription within 6 months of radiation. Main Outcomes and Measures: Biochemical recurrence (BCR) from time of completion of radiation therapy (prostate-specific antigen nadir plus 2 ng/mL) and development of metastatic disease or prostate cancer mortality (PCSM) from time of recurrence. Results: A total of 26 542 patients (8716 Black men with median [IQR] age of 64 [59-69] years and 17 826 White men with median [IQR] age of 67 [62-72] years) received definitive radiation therapy for nonmetastatic prostate cancer and had complete staging and follow-up data. A total of 5144 patients experienced BCR (3384 White and 1760 Black patients). The cumulative incidence of BCR at 10 years was not significantly different between Black and White men (1602 [22.14%] vs 3099 [20.13%], respectively) with multivariable hazard ratio (HR) of 1.03 (95% CI, 0.97-1.09; P = .33). In men receiving ADT, Black men had an HR for BCR of 0.90 (95% CI, 0.82-0.99; P = .03) compared with White men, and in men not receiving ADT, Black men had an HR of 1.13 (95% CI, 1.05-1.22; P = .002). Black race was associated with a decreased risk of developing metastatic disease (HR, 0.90; 95% CI, 0.82-0.98; P = .02) or PCSM (subdistribution HR, 0.72; 95% CI, 0.63-0.82; P < .001) from time of biochemical recurrence. Conclusions and Relevance: Black patients treated with radiation appear to specifically benefit from the addition of ADT with regard to biochemical control. Additionally, BCR in Black men results in a lower rate of metastatic disease and death from prostate cancer. Future analyses of radiosensitivity in Black men should evaluate for the possibility of outcome modification by ADT.

The Role of Radical Cystectomy in Clinically Node Positive Bladder Cancer: A US Veterans Health Administration Study.

INTRODUCTION: The role of local definitive therapy in addition to systemic treatment in clinically positive regional lymph node (cN+) bladder cancer is yet to be determined. Herein, we sought to investigate the role of radical cystectomy (RC) in management of patients with cN+ bladder cancer at US Veterans Health Administration Facilities. METHODS: We identified patients diagnosed with cN+ bladder cancer between 2000-2017 using the Department of Veterans Affairs (VA) Informatics and Computing Infrastructure (VINCI). We employed a combination of database/registry coded values and chart review for data collection. To minimize mortality bias, we excluded patients who died within 90 days of diagnosis. We divided the patients into cystectomy (C) versus "no cystectomy" (NOC) cohorts. Propensity score matching was performed based on predictors of undergoing RC. Multivariable Cox models and Kaplan-Meier survival curves were used to estimate overall survival (OS) and cancer specific survival (CCS). RESULT: After matching, 158 patients were included in the C and NOC groups. In the C-group, 85(54%) patients received pre-cystectomy chemotherapy, and 73(46%) patients underwent post-cystectomy chemotherapy. In the C-group, 65(41%) patients and in the NOC-group, 66(42%) patients had clinical N1 disease (P = .77). In multivariable Cox model, undergoing RC was associated with improved OS (HR0.62; 95%CI 0.47-0.81), P < .001) and CSS (HR0.58; 95%CI 0.42-0.80; P < .001). CONCLUSION: As part of multimodal treatment, undergoing RC was associated with improved OS and CSS in subset of patients with cN+ bladder cancer. Prospective randomized trials are warranted to further investigate the role of local definitive therapy in this specific patient population.

Racial disparities in colorectal cancer outcomes and access to care: a multi-cohort analysis.

Introduction: Non-Hispanic Black (NHB) Americans have a higher incidence of colorectal cancer (CRC) and worse survival than non-Hispanic white (NHW) Americans, but the relative contributions of biological versus access to care remain poorly characterized. This study used two nationwide cohorts in different healthcare contexts to study health system effects on this disparity. Methods: We used data from the Surveillance, Epidemiology, and End Results (SEER) registry as well as the United States Veterans Health Administration (VA) to identify adults diagnosed with colorectal cancer between 2010 and 2020 who identified as non-Hispanic Black (NHB) or non-Hispanic white (NHW). Stratified survival analyses were performed using a primary endpoint of overall survival, and sensitivity analyses were performed using cancer-specific survival. Results: We identified 263,893 CRC patients in the SEER registry (36,662 (14%) NHB; 226,271 (86%) NHW) and 24,375 VA patients (4,860 (20%) NHB; 19,515 (80%) NHW). In the SEER registry, NHB patients had worse OS than NHW patients: median OS of 57 months (95% confidence interval (CI) 55-58) versus 72 months (95% CI 71-73) (hazard ratio (HR) 1.14, 95% CI 1.12-1.15, p = 0.001). In contrast, VA NHB median OS was 65 months (95% CI 62-69) versus NHW 69 months (95% CI 97-71) (HR 1.02, 95% CI 0.98-1.07, p = 0.375). There was significant interaction in the SEER registry between race and Medicare age eligibility (p < 0.001); NHB race had more effect in patients <65 years old (HR 1.44, 95% CI 1.39-1.49, p < 0.001) than in those ≥65 (HR 1.13, 95% CI 1.11-1.15, p < 0.001). In the VA, age stratification was not significant (p = 0.21). Discussion: Racial disparities in CRC survival in the general US population are significantly attenuated in Medicare-aged patients. This pattern is not present in the VA, suggesting that access to care may be an important component of racial disparities in this disease.

ATRX interacts with H3.3 in maintaining telomere structural integrity in pluripotent embryonic stem cells.

ATRX (alpha thalassemia/mental retardation syndrome X-linked) belongs to the SWI2/SNF2 family of chromatin remodeling proteins. Besides the ATPase/helicase domain at its C terminus, it contains a PHD-like zinc finger at the N terminus. Mutations in the ATRX gene are associated with X-linked mental retardation (XLMR) often accompanied by alpha thalassemia (ATRX syndrome). Although ATRX has been postulated to be a transcriptional regulator, its precise roles remain undefined. We demonstrate ATRX localization at the telomeres in interphase mouse embryonic stem (ES) cells in synchrony with the incorporation of H3.3 during telomere replication at S phase. Moreover, we found that chromobox homolog 5 (CBX5) (also known as heterochromatin protein 1 alpha, or HP1 alpha) is also present at the telomeres in ES cells. We show by coimmunoprecipitation that this localization is dependent on the association of ATRX with histone H3.3, and that mutating the K4 residue of H3.3 significantly diminishes ATRX and H3.3 interaction. RNAi-knockdown of ATRX induces a telomere-dysfunction phenotype and significantly reduces CBX5 enrichment at the telomeres. These findings suggest a novel function of ATRX, working in conjunction with H3.3 and CBX5, as a key regulator of ES-cell telomere chromatin.

The effect of music on brain wave functioning during an acute psychotic episode: a pilot study.

This pilot study compared the differences in the quantified electroencephalogram (qEEG) between two conditions; eyes closed resting and eyes closed listening to music of 15 subjects currently experiencing an acute psychotic episode. The results showed a significant decrease in delta, alpha and beta waves when listening to music compared to resting condition.

Melanin has a Small Inhibitory Effect on Cutaneous Vitamin D Synthesis: A Comparison of Extreme Phenotypes.

Epidemiology suggests that melanin inhibits cutaneous vitamin D3 synthesis by UVR. Laboratory investigations assessing the impact of melanin on vitamin D production have produced contradictory results. We determined the effect of melanin on vitamin D3 photosynthesis in healthy young volunteers (n = 102) of Fitzpatrick skin types II-VI (white to black). Participants, irrespective of skin type, were exposed to the same suberythemal UVR dose, to 85% body surface area, using solar simulated UVR or narrowband UVB (311 nm). This was repeated five times with intervals of 3-4 days between UVR exposures. Blood was taken before, during, and after the irradiation and assessed for serum 25-hydroxyvitamin D3 (25[OH]D3) as a marker of vitamin D3 status. Linear UVR dose-dependent increases in 25(OH)D3 were highly significant (P ≤ 7.7 x 10-11). The ratios of regression slopes of the different skin type groups were compared, and only skin type II was significantly steeper than the other groups. Comparisons between extreme skin types II and VI showed melanin inhibition factors of approximately 1.3-1.4, depending on the UVR source. We conclude that the inhibitory effect of melanin on vitamin D3 synthesis is small, compared with erythema, but that this difference may be sufficient to explain the epidemiological data.

The singer or the singing: who sings individually to persons with dementia and what are the effects?

''Live'' singing to persons with dementia (PWDs) may be an underused but highly accessible resource for their caregivers, regardless of qualifications. A systematic literature review sought to illuminate who sings to PWDs, and with what objectives and effects, to address the question of whether it is the singer or the singing which is effective. The literature revealed that music therapists seek to address cognitive, behavioral, physiological, and social factors through one-to-one singing, whereas other caregivers are more broadly concerned with quality of life, often through facilitating activities of daily living. All included studies concurred that individual singing to PWDs can be effective in a variety of ways, depending on contexts and goals. PWD's perceptions of situations may influence the effectiveness of singing interventions. Music therapists are urged to empower professional caregivers to sing sensitively to PWDs during caregiving activities.