Meaningful Work, Career Fit, and Professional Well-Being of Pediatric Academicians in the United States.

OBJECTIVE: Examine associations between time spent in academic activities perceived as meaningful and professional well-being among academic pediatrics faculty. METHODS: The sample comprised 248 full-time pediatric faculty (76% female, 81% white, non-Hispanic, 41% instructor or assistant professor) across the United States who completed an online survey in November 2019. Survey items included sociodemographic and professional characteristics, professional well-being measures (Stanford Professional Fulfillment Index; Maslach Burnout Inventory; Intention to Leave Academic Medicine), perceived meaningfulness of academic activities and assigned time to those activities. We defined global career fit as total percentage time assigned to professional activities considered meaningful by individuals, and activity-specific career fit as percentage time assigned to each meaningful professional activity. RESULTS: As global career fit scores increased, professional fulfillment increased (r = 0.45, P < .001), whereas burnout (r = -0.29, P < .001) and intention to leave (r = -0.22, P < .001) decreased. Regarding activity-specific career fit, for individuals who considered patient care meaningful, as assigned time to patient care increased, professional fulfillment decreased (r = -0.14, P = .048) and burnout (r = 0.16, P = .02) and intention to leave (r = 0.26, P < .001) increased. There was no significant correlation between assigned time for teaching, research, or advocacy and professional well-being. Faculty were less likely to intend to leave academic medicine as assigned time increased for administrative or leadership activities if considered meaningful (r = -0.24, P = .01). CONCLUSIONS: Time assigned to meaningful work activities may relate to professional well-being of academic pediatrics faculty. More time assigned to patient care, despite being meaningful, was associated with poor self-reported professional well-being. Effort allocation among diverse academic activities needs to be optimized to improve faculty well-being.

Post hospital admission blood lactate measurements are associated with mortality but not neurologic morbidity in children with cerebral malaria.

BACKGROUND: In children with cerebral malaria (CM) admission blood lactate has previously guided intravenous fluid therapy and been validated as a prognostic biomarker associated with death. The usefulness of post-admission measurements of blood lactate in children with CM is less clear. The strength of association between blood lactate and neurological sequelae in CM survivors, as well as the optimal duration of post-admission measurements of blood lactate to identify children at higher risk of adverse outcomes is unknown. METHODS: A retrospective cohort study of 1674 Malawian children with CM hospitalized from 2000 to 2018 who had blood lactate measurements every 6 h for the first 24 h after admission was performed. The strength of association between admission lactate or values measured at any time point in the first 24 h post-admission and outcomes (mortality and neurological morbidity in survivors) was estimated. The duration of time after admission that lactate remained a valid prognostic biomarker was assessed. RESULTS: When lactate is analysed as a continuous variable, children with CM who have higher values at admission have a 1.05-fold higher odds (95% CI 0.99-1.11) of death compared to those with lower lactate values. Children with higher blood lactate at 6 h have 1.16-fold higher odds (95% CI 1.09-1.23) of death, compared to those with lower values. If lactate levels are dichotomized into hyperlactataemic (lactate > 5.0 mmol/L) or not, the strength of association between admission lactate and mortality increases (OR = 2.49, 95% CI 1.47-4.22). Blood lactate levels obtained after 18 h post-admission are not associated with outcomes. Similarly, the change in lactate concentrations through time during the first 24 h of hospital admission is not associated with outcomes. Blood lactate during hospitalization is not associated with adverse neurologic outcomes in CM survivors. CONCLUSIONS: In children with CM, blood lactate is associated with death but not neurologic morbidity in survivors. To comprehensively estimate prognosis, blood lactate in children with CM should be assessed at admission and for 18 h afterwards.

Loss to Hospital Follow-Up in Pediatric Cerebral Malaria Survivors: A Case-Control Study.

Children surviving central nervous system (CNS) infections are at high risk of neurological, behavioral, and cognitive sequalae. Early identification, characterization, and treatment of these sequelae may improve child and family health. In Africa, it is unclear if there are demographic or clinical factors that increase the risk of post-hospital loss to follow-up in children with CNS infections. If these factors exist, targeted educational efforts to increase rates of post-hospital retention could be focused on families at highest risk. We performed a case-control study of Malawian children with cerebral malaria, a locally common CNS infection, previously admitted to a specialized research unit in Blantyre, Malawi. Routine survivor post-hospital follow-up was scheduled for 1 month, 6 months, and 12 months. We compared demographic and clinical characteristics between 84 children who missed one or more of these post-hospital visits with 120 children who attended all visits. There were no statistically significant differences in demographic or clinical characteristics between children whose families returned for all follow-up visits and those who did not. Specifically, when comparing these groups, we found no differences in age (P = 00.646), sex (P = 0.789), duration of hospitalization (P = 0.903), distance from home to hospital (P = 0.355), type or severity of neurological sequelae (P = 0.837), guardian literacy (P = 0.057), or number of discharge medications (P = 0.464). No factors assessed in this study were associated with higher risk of loss to follow-up in Malawian child survivors of CNS infections. During hospitalization, educational efforts to increase post-hospital retention should focus on all families.

Health-related quality of life in a systematically assessed cohort of children and adults with urea cycle disorders.

PURPOSE: Individuals with urea cycle disorders (UCDs) may develop recurrent hyperammonemia, episodic encephalopathy, and neurological sequelae which can impact Health-related Quality of Life (HRQoL). To date, there have been no systematic studies of HRQoL in people with UCDs. METHODS: We reviewed HRQoL and clinical data for 190 children and 203 adults enrolled in a multicenter UCD natural history study. Physical and psychosocial HRQoL in people with UCDs were compared to HRQoL in healthy people and people with phenylketonuria (PKU) and diabetes mellitus. We assessed relationships between HRQoL, UCD diagnosis, and disease severity. Finally, we calculated sample sizes required to detect changes in these HRQoL measures. RESULTS: Individuals with UCDs demonstrated worse physical and psychosocial HRQoL than their healthy peers and peers with PKU and diabetes. In children, HRQoL scores did not differ by diagnosis or severity. In adults, individuals with decreased severity had worse psychosocial HRQoL. Finally, we show that a large number of individuals would be required in clinical trials to detect differences in HRQoL in UCDs. CONCLUSION: Individuals with UCDs have worse HRQoL compared to healthy individuals and those with PKU and diabetes. Future work should focus on the impact of liver transplantation and other clinical variables on HRQoL in UCDs.

Temporal Trends of Blood Glucose in Children with Cerebral Malaria.

Hypoglycemia, defined as a blood glucose < 2.2 mmol/L, is associated with death in pediatric cerebral malaria (CM). The optimal duration of glucose monitoring in CM is unknown. We collected data from 1,674 hospitalized Malawian children with CM to evaluate the association between hypoglycemia and death or neurologic disability in survivors. We assessed the optimal duration of routine periodic measurements of blood glucose. Children with hypoglycemia at admission had a 2.87-fold higher odds (95% CI: 1.35-6.09) of death and, if they survived, a 3.21-fold greater odds (95% CI: 1.51-6.86) of sequelae at hospital discharge. If hypoglycemia was detected at 6 hours but not at admission, there was a 7.27-fold higher odds of death (95% CI: 1.85-8.56). The presence of newly developed hypoglycemia after admission was not independently associated with neurological sequelae in CM survivors. Among all new episodes of blood sugar below a treatment threshold of 3.0 mmol/L, 94.7% occurred within 24 hours of admission. In those with blood sugar below 3.0 mmol/L in the first 24 hours, low blood sugar persisted or recurred for up to 42 hours. Hypoglycemia at admission or 6 hours afterward is strongly associated with mortality in CM. Children with CM should have 24 hours of post-admission blood glucose measurements. If a blood glucose less than the treatment threshold of 3.0 mmol/L is not detected, routine assessments may cease. Children who have blood sugar values below the treatment threshold detected within the first 24 hours should continue to have periodic glucose measurements for 48 hours post-admission.

Clinical outcomes of children and adolescents with sickle cell disease and COVID-19 infection: A year in review at a metropolitan tertiary pediatric hospital.

Background: COVID-19 was declared a global pandemic in March 2020. Early reports were primarily in adults, and sickle cell disease (SCD) was classified as a risk factor for severe COVID-19 disease. However, there are a limited number of primarily multi-center studies reporting on the clinical course of pediatric patients with SCD and COVID-19. Methods: We conducted an observational study of all patients with SCD diagnosed with COVID-19 at our institution between March 31, 2020, and February 12, 2021. Demographic and clinical characteristics of this group were collected by retrospective chart review. Results: A total of 55 patients were studied, including 38 children and 17 adolescents. Demographics, acute COVID-19 clinical presentation, respiratory support, laboratory findings, healthcare utilization, and SCD modifying therapies were comparable between the children and adolescents. Seventy-three percent (N = 40) of all patients required emergency department care or hospitalization. While 47% (N = 26) were hospitalized, only 5% (N = 3) of all patients required intensive care unit admission. Patients frequently had concurrent vaso-occlusive pain crisis (VOC) (N = 17, 43%) and acute chest syndrome (ACS) (N = 14, 35%). Those with ACS or an oxygen requirement had significantly higher white blood cell count, lower nadir hemoglobin, and higher D-dimers, supporting a pro-inflammatory and coagulopathic picture. Non-hospitalized patients were more likely to be on hydroxyurea than hospitalized patients (79 vs. 50%, p = 0.023). Conclusion: Children and adolescent patients with SCD and acute COVID-19 often present with ACS and VOC pain requiring hospital-level care. Hydroxyurea treatment appears to be protective. We observed no mortality despite variable morbidity.

Changes in HDL cholesterol, particles, and function associate with pediatric COVID-19 severity.

Background: Myriad roles for high-density lipoprotein (HDL) beyond atheroprotection include immunologic functions implicated in the severity of coronavirus disease-2019 (COVID-19) in adults. We explored whether there is an association between HDL and COVID-19 severity in youth. Methods: A pediatric cohort (N = 102), who tested positive for COVID-19 across a range of disease manifestations from mild or no symptoms, to acute severe symptoms, to the multisystem inflammatory syndrome of children (MIS-C) was identified. Clinical data were collected from the medical record and reserve plasma aliquots were assessed for lipoproteins by NMR spectroscopy and assayed for HDL functional cholesterol efflux capacity (CEC). Findings were compared by COVID-19 status and symptom severity. Lipoprotein, NMR spectroscopy and CEC data were compared with 30 outpatient COVID negative children. Results: Decreasing HDL cholesterol (HDL-c), apolipoprotein AI (ApoA-I), total, large and small HDL particles and HDL CEC showed a strong and direct linear dose-response relationship with increasing severity of COVID-19 symptoms. Youth with mild or no symptoms closely resembled the uninfected. An atypical lipoprotein that arises in the presence of severe hepatic inflammation, lipoprotein Z (LP-Z), was absent in COVID-19 negative controls but identified more often in youth with the most severe infections and the lowest HDL parameters. The relationship between HDL CEC and symptom severity and ApoA-I remained significant in a multiply adjusted model that also incorporated age, race/ethnicity, the presence of LP-Z and of GlycA, a composite biomarker reflecting multiple acute phase proteins. Conclusion: HDL parameters, especially HDL function, may help identify youth at risk of more severe consequences of COVID-19 and other novel infectious pathogens.

First STEPS: Primary Outcomes of a Randomized, Stepped-Care Behavioral Clinical Trial for Parents of Young Children With New-Onset Type 1 Diabetes.

OBJECTIVE: Despite the emotional challenges of parental adjustment to a child's type 1 diabetes diagnosis and the unique complexities of early childhood, there are few programs designed to meet the needs of parents of young children at new onset. This study evaluated First STEPS (Study of Type 1 in Early childhood and Parenting Support), a stepped-care behavioral intervention designed to support parents' psychosocial functioning and promote children's glycemic outcomes. RESEARCH DESIGN AND METHODS: Using a two-site randomized clinical trial design, parents (n = 157) of children aged 1-6 years completed baseline data within 2 months of diabetes diagnosis and were randomly assigned to intervention (n = 115) or usual care (n = 42) for 9 months. Intervention steps included: 1) peer parent coaching, with step-ups to 2) structured behavioral counseling and 3) professional consultations with a diabetes educator and psychologist, based on parent mood and child HbA1c. Participants completed follow-ups at 9 and 15 months postrandomization. Primary outcomes were parent depressive symptoms and child HbA1c. RESULTS: Depressive symptoms improved in both groups, and intervention parents had significantly lower depressive symptoms at the 9- and 15-month follow-ups compared with usual care. HbA1c decreased in both groups, but there were no between-group differences at 9 or 15 months. CONCLUSIONS: First STEPS improved parents' mood following young children's type 1 diabetes diagnosis. Results indicate likely benefits of parent coach support, supplemented by intervention intensifications, including behavioral intervention and diabetes education. This model has high potential for patient engagement. The absence of a medical intervention component may explain null findings for HbA1c; incorporating targeted behavioral support for intensive diabetes treatment may maximize intervention impact.

An educational intervention to facilitate appropriate subspecialty referrals: a study assessing resident communication skills.

BACKGROUND: Our goal was to improve pediatric residents' advanced communication skills in the setting of referral to address the entrustable professional activity of subspecialty referral identified by the American Board of Pediatrics. To accomplish this aim, we created a referral and consultation curriculum to teach and assess core communication skills in subspecialty referral involving an adolescent with syncope, an anxiety-provoking symptom that is rarely associated with serious pathology. METHODS: We utilized blended multimodal educational interventions to improve resident communication skills in referral of patients. Trainees participated in 1) an interactive online module on syncope focusing on "red-flag" symptoms that would warrant a subspecialty cardiology referral and 2) a 4-h intervention with Standardized Parents (SPs), focusing on the case-based application of communication skills. Communication skills were assessed by two pre- and post- Objective Structured Clinical Examination encounters of patients with syncope, with an SP evaluation using a 20-item checklist. Analysis was performed with Sign test and McNemar's test. Trainees provided feedback on a Critical Incident Questionnaire, which was analyzed qualitatively. RESULTS: Sixty-four residents participated. There was an overall improvement in communication skills based on SP scores (82.7 ± 10.9% to 91.7 ± 5.0%, p < 0.001), and 13/20 items demonstrated significant improvement post-intervention. Residents' improved performance enabled them to address patient/family emotions, explain referral logistics, and clarify concerns to agree on a plan. CONCLUSIONS: By participating in this curriculum, residents' communication skills improved immediately post-intervention. Further research is needed to assess if this intervention improves patient care by providing residents with enduring skills to judiciously manage the referral process.

The prostate tissue-based telomere biomarker as a prognostic tool for metastasis and death from prostate cancer after prostatectomy.

Current biomarkers are inadequate prognostic predictors in localized prostate cancer making treatment decision-making challenging. Previously, we observed that the combination of more variable telomere length among prostate cancer cells and shorter telomere length in prostate cancer-associated stromal cells - the telomere biomarker - is strongly associated with progression to metastasis and prostate cancer death after prostatectomy independent of currently used pathologic indicators. Here, we optimized our method allowing for semi-automated telomere length determination in single cells in fixed tissue, and tested the telomere biomarker in five cohort studies of men surgically treated for clinically localized disease (N = 2,255). We estimated the relative risk (RR) of progression to metastasis (N = 311) and prostate cancer death (N = 85) using models appropriate to each study's design adjusting for age, prostatectomy stage, and tumor grade, which then we meta-analyzed using inverse variance weights. Compared with men who had less variable telomere length among prostate cancer cells and longer telomere length in prostate cancer-associated stromal cells, men with the combination of more variable and shorter telomere length had 3.76 times the risk of prostate cancer death (95% confidence interval [CI] 1.37-10.3, p = 0.01) and had 2.23 times the risk of progression to metastasis (95% CI 0.99-5.02, p = 0.05). The telomere biomarker was associated with prostate cancer death in men with intermediate risk disease (grade groups 2/3: RR = 9.18, 95% CI 1.14-74.0, p = 0.037) and with PTEN protein intact tumors (RR = 6.74, 95% CI 1.46-37.6, p = 0.015). In summary, the telomere biomarker is robust and associated with poor outcome independent of current pathologic indicators in surgically treated men.

Effects of Isocaloric Fructose Restriction on Ceramide Levels in Children with Obesity and Cardiometabolic Risk: Relation to Hepatic De Novo Lipogenesis and Insulin Sensitivity.

Sugar intake, particularly fructose, is implicated as a factor contributing to insulin resistance via hepatic de novo lipogenesis (DNL). A nine-day fructose reduction trial, controlling for other dietary factors and weight, in children with obesity and metabolic syndrome, decreased DNL and mitigated cardiometabolic risk (CMR) biomarkers. Ceramides are bioactive sphingolipids whose dysregulated metabolism contribute to lipotoxicity, insulin resistance, and CMR. We evaluated the effect of fructose reduction on ceramides and correlations between changes observed and changes in traditional CMR biomarkers in this cohort. Analyses were completed on data from 43 participants. Mean weight decreased (-0.9 ± 1.1 kg). The majority of total and subspecies ceramide levels also decreased significantly, including dihydroceramides, deoxyceramides and ceramide-1-phoshates. Change in each primary ceramide species correlated negatively with composite insulin sensitivity index (CISI). Change in deoxyceramides positively correlated with change in DNL. These results suggest that ceramides decrease in response to dietary fructose restriction, negatively correlate with insulin sensitivity, and may represent an intermediary link between hepatic DNL, insulin resistance, and CMR.

Multinational Analysis of Children Transfused With Pathogen Inactivated Platelets.

BACKGROUND: Pathogen inactivated (PI) platelets are a technological advancement in blood safety; however, the pediatric experience is not well characterized. We studied pediatric patients who received transfusions of PI platelets across several centers and countries to determine if transfusion reaction rates differed when compared with conventional platelets. METHODS: This is a retrospective multisite study conducted during 2 time periods. The study period started at the time each site began using PI platelets on a widespread basis, and the control period was a similar timespan before PI introduction. Suspected acute transfusion reactions were compared. RESULTS: The study included 3839 pediatric patients who were 0 to 18 years of age who received >7930 platelet transfusions, in total, across 4 centers in 3 countries between 2013 and 2019. The age distribution of patients in the study and control period was not significantly different (P = .190). There was not a difference in the percentage of patients who had any type of transfusion reaction between the time periods (1.0% and 1.1%, P = .803). There were fewer patients with mild allergic reactions in the study period compared with the control period (0.2% and 0.7% of patients with reactions, respectively, P = .018). CONCLUSIONS: Pediatric patients have the same rate of acutely suspected transfusion reactions when receiving PI or conventional platelet transfusions. Subgroup analysis found fewer mild allergic reactions in the study period, which was contemporaneous to the addition of using platelet additive solution more broadly. Future studies of PI platelets should include children to better assess transfusion efficacy and hemostatic outcomes.

Lipid-Lowering Drug Use and Cancer Incidence and Mortality in the ARIC Study.

Background: Lipid-lowering drugs, particularly statins, are associated with reduced incidence of certain cancers in some studies. Associations with cancer mortality are not well studied, and whether associations are similar across race is unknown. Methods: We conducted a prospective analysis of 12 997 cancer-free participants in the Atherosclerosis Risk in Communities Study who were never users at visit 1 (1987-1989). Ever use, duration of use, and age at first use were modeled as time-dependent variables using Cox regression to estimate associations with total, obesity- and smoking-associated, bladder, breast, colorectal, lung, and prostate cancer incidence and mortality. Results: We ascertained 3869 cancer cases and 1661 cancer deaths in 237 999 or more person-years. At 6 years of follow-up, 70.8% of lipid-lowering drug use was a statin. Compared with never use, ever use was associated with lower total, obesity- and smoking-associated cancer mortality and with colorectal cancer mortality (hazard ratio [HR] = 0.50, 95% confidence interval [CI] = 0.32 to 0.79) and incidence (HR = 0.69, 95% CI = 0.53 to 0.92). Inverse associations were consistent by sex and race. Shorter-term use was associated with bladder cancer incidence in men (<10 years: HR = 1.67, 95% CI = 1.02 to 2.73). First use at age 60 years or older was inversely associated with: total mortality, obesity- and smoking-associated mortality, and colorectal cancer mortality; and total incidence, obesity- and smoking-associated incidence, and breast, colorectal, and prostate cancer incidence. Conclusions: This study provides additional evidence for inverse associations between lipid-lowering drug use and cancer incidence and mortality but a positive association with bladder cancer incidence in men. Evaluation of the impact of chemoprevention strategies that include lipid-lowering drugs on population-level cancer burden is needed.

Predictors of mood, diabetes-specific and COVID-19-specific experiences among parents of early school-age children with type 1 diabetes during initial months of the COVID-19 pandemic.

OBJECTIVE: The current study explored pre-pandemic sociodemographics, medical characteristics, social/family support, and mood symptoms, and current COVID-19 experiences as predictors of mood, positive/negative diabetes-specific experiences, and COVID-19-specific distress among parents of children with type 1 diabetes during the COVID-19 pandemic. We hypothesized that parents from marginalized backgrounds, youth with higher pre-pandemic A1c and no CGM use, parents with lower pre-pandemic social/family support and more pre-pandemic mood/anxiety symptoms, and those with more negative COVID-19 experiences would have more depressive symptoms, fewer positive and more negative diabetes-specific experiences, and more COVID-19-specific distress during the initial months of the pandemic. RESEARCH DESIGN AND METHODS: Participants were parents of early school-age children with type 1 diabetes (n = 100; 65% non-Hispanic, white, 92% mothers, 75% married; Mchild age  = 6.74 ± 1.59 years) who had completed a behavioral intervention trial ≥6 months ago and were re-contacted in June/July 2020 to report on their COVID-19 pandemic experiences and parent psychosocial outcomes. Pre-pandemic parent mood/anxiety symptoms, family/social support, and children's medical characteristics (CGM use; MA1C  = 8.17% ± 1.40%) were assessed M = 1.45 ± 0.59 years prior. RESULTS: More pre-pandemic social support predicted fewer depressive symptoms, more positive diabetes-specific experiences, and less COVID-19-specific distress during the pandemic. More pre-pandemic depressive symptoms predicted more depressive symptoms during the pandemic. More life disruptions due to the pandemic were associated with more negative diabetes-specific experiences and more COVID-19-specific distress. Parents of color had more negative diabetes-specific experiences. CONCLUSIONS: Social support may be particularly important to assess and address through intervention. Pediatric diabetes care providers should monitor parent experiences in relation to children's diabetes management. ClinicalTrials.gov identifier: NCT02527525.

Obesity is Associated with Shorter Telomere Length in Prostate Stromal Cells in Men with Aggressive Prostate Cancer.

In our prior studies, obesity was associated with shorter telomeres in prostate cancer-associated stromal (CAS) cells, and shorter CAS telomeres were associated with an increased risk of prostate cancer death. To determine whether the association between obesity and shorter CAS telomeres is replicable, we conducted a pooled analysis of 790 men who were surgically treated for prostate cancer, whose tissue samples were arrayed on five tissue microarray (TMA) sets. Telomere signal was measured using a quantitative telomere-specific FISH assay and normalized to 4',6-diamidino-2-phenylindole for 351 CAS cells (mean) per man; men were assigned their median value. Weight and height at surgery, collected via questionnaire or medical record, were used to calculate body mass index (BMI; kg/m2) and categorize men as normal (<25), overweight (25 ≤ BMI < 30), or obese (≥30). Analyses were stratified by grade and stage. Men were divided into tertiles of TMA- (overall) or TMA- and disease aggressiveness- (stratified) specific distributions; short CAS telomere status was defined by the bottom two tertiles. We used generalized linear mixed models to estimate the association between obesity and short CAS telomeres, adjusting for age, race, TMA set, pathologic stage, and grade. Obesity was not associated with short CAS telomeres overall, or among men with nonaggressive disease. Among men with aggressive disease (Gleason≥4+3 and stage>T2), obese men had a 3-fold increased odds of short CAS telomeres (OR: 3.06; 95% confidence interval: 1.07-8.75; P trend = 0.045) when compared with normal weight men. Telomere shortening in prostate stromal cells may be one mechanism through which lifestyle influences lethal prostate carcinogenesis. PREVENTION RELEVANCE: This study investigates a potential mechanism underlying the association between obesity and prostate cancer death. Among men with aggressive prostate cancer, obesity was associated with shorter telomeres prostate cancer associated stromal cells, and shorter CAS telomeres have been associated with an increased risk of prostate cancer death.

The association between serum sex steroid hormone concentrations and intraprostatic inflammation in men without prostate cancer and irrespective of clinical indication for biopsy in the placebo arm of the Prostate Cancer Prevention Trial.

BACKGROUND: Intraprostatic inflammation is an emerging prostate cancer risk factor. Estrogens are pro-inflammatory while androgens are anti-inflammatory. Thus, we investigated whether serum sex steroid hormone concentrations are associated with intraprostatic inflammation to inform mechanistic links among hormones, inflammation, and prostate cancer. METHODS: We conducted a cross-sectional study among 247 men in the placebo arm of the Prostate Cancer Prevention Trial who had a negative end-of-study biopsy, most (92.7%) performed without clinical indication per trial protocol. Serum estradiol, estrone, and testosterone were previously measured by immunoassay in pooled baseline and Year 3 serum. Free estradiol and free testosterone were calculated. Inflammation was visually assessed (median of three prostate biopsy cores per man). Polytomous or logistic regression was used to estimate the odds ratio (OR) and 95% confidence interval (CI) of some or all cores inflamed (both vs none) or any core inflamed (vs none) by hormone tertile, adjusting for age, race, and family history. We evaluated effect modification by waist circumference and body mass index (BMI). RESULTS: In all, 51.4% had some and 26.3% had all cores inflamed. Free (P-trend = .11) but not total estradiol was suggestively inversely associated with all cores inflamed. In men with waist circumference greater than or equal to 102 cm (P-trend = .021) and BMI ≥ 27.09 kg/m2 (P-trend = .0037) free estradiol was inversely associated with any core inflamed. Estrone was inversely associated with all cores inflamed (T3: OR = 0.36, 95% CI 0.14-0.95, P-trend = .036). Total (T3: OR = 1.91, 95% CI 0.91-4.02, P-trend = .11) and free (T3: OR = 2.19, 95% CI 1.01-4.74, P-trend = .05) testosterone were positively associated with any core inflamed, especially free testosterone in men with waist circumference less than 102 cm (T3: OR = 3.51, 95% CI 1.03-12.11, P-trend = .05). CONCLUSIONS: In this first study in men without prostate cancer and irrespective of clinical indication for biopsy, contrary to the hypothesis, circulating estrogens appeared to be inversely associated, especially in heavy men, whereas androgens appeared to be positively associated with intraprostatic inflammation.

Clinical stage provides useful prognostic information even after pathological stage is known for prostate cancer in the PSA era.

BACKGROUND: Pathological and clinical stage are associated with prostate cancer-specific survival after prostatectomy. With PSA screening, the post-surgery prognostic utility of clinical stage is debatable in studies seeking to identify new biomarkers. Few studies have investigated clinical stage and lethal prostate cancer association after accounting for pathological stage. We hypothesize that clinical stage provides prognostic information beyond pathological stage in the PSA era. METHODS: Cox regression models tested associations between clinical and pathological stage and lethal prostate cancer among 3,064 participants from the Health Professionals Follow-Up Study and Physicians' Health Study (HPFS/PHS) who underwent prostatectomy. Likelihood ratio tests and c-statistics were used to assess the models' prognostic utility. Equivalent analyses were performed in 16,134 men who underwent prostatectomy at Johns Hopkins. RESULTS: Independently, clinical and pathological stage were associated (p<0.0001 for both) with rate of lethal prostate cancer in HPFS/PHS. The model with clinical and pathological stage fit significantly better than the model with only pathological stage in all men (p = 0.01) and in men diagnosed during the PSA era (p = 0.04). The mutually adjusted model also improved discriminatory ability. In the Johns Hopkins cohort, the model with clinical and pathological stage improved discriminatory ability and fit significantly better overall (p<0.0001) and in the PSA era (p<0.0001). CONCLUSIONS: Despite stage migration resulting from widespread PSA screening, clinical stage remains associated with progression to lethal prostate cancer independent of pathological stage. Future studies evaluating associations between new factors and poor outcome following prostatectomy should consider including both clinical and pathological stages since the data is already available.

High Extratumoral Mast Cell Counts Are Associated with a Higher Risk of Adverse Prostate Cancer Outcomes.

BACKGROUND: Given our previous findings that low intratumoral and high extratumoral mast cell numbers are associated with higher risk of biochemical recurrence after radical prostatectomy, we now assessed this relationship with race and the development of metastases. METHODS: We stained for mast cell tryptase via IHC and fluorescent immunolabeling in 885 men across multiple tissue microarray sets designed to assess biomarkers in association with race and prostate cancer outcomes (median follow-up, 7.0 years). RESULTS: Intratumoral and extratumoral mast cell counts were significantly lower in tissues from African-American compared with European-American men, but not within strata of cancer grade. There was no association between mast cell counts and ERG positivity, PTEN loss, or TP53 missense mutation. Higher minimum extratumoral mast cells were associated with an increased risk of biochemical recurrence [comparing highest with lowest tertiles: HR, 1.61; 95% confidence interval (CI), 1.12-2.29; P trend = 0.01]; this pattern was similar among European-American and African-American men and by grade of disease. There was no significant association between minimum intratumoral mast cell count and biochemical recurrence, overall or within strata of race and grade. Finally, high minimum number of extratumoral mast cells was associated with prostate cancer metastases (comparing highest with lowest tertiles: HR, 2.12; 95% CI, 1.24-3.63; P trend = 0.01). CONCLUSIONS: High extratumoral mast cell numbers are associated with biochemical recurrence and the development of metastases after radical prostatectomy. IMPACT: Higher numbers of benign tissue mast cells are associated with a higher risk of adverse outcomes after radical prostatectomy, including metastatic prostate cancer.

Racial Difference in Prostate Cancer Cell Telomere Lengths in Men with Higher Grade Prostate Cancer: A Clue to the Racial Disparity in Prostate Cancer Outcomes.

BACKGROUND: Black men have worse prostate cancer outcomes following treatment than White men even when accounting for prognostic factors. However, biological explanations for this racial disparity have not been fully identified. We previously showed that more variable telomere lengths among cancer cells and shorter telomere lengths in cancer-associated stromal (CAS) cells individually and together ("telomere biomarker") are associated with prostate cancer-related death in surgically treated men independent of currently used prognostic indicators. Here, we hypothesize that Black-White differences in the telomere biomarker and/or in its components may help explain the racial disparity in prostate cancer outcomes. METHODS: Black [higher grade (Gleason ≥4+3) = 34 and lower grade = 93] and White (higher grade = 34 and lower grade = 89) surgically treated men were frequency matched on age, pathologic stage, and grade. We measured telomere lengths in cancer and CAS cells using a robust telomere-specific FISH assay. Tissue microarray and grade-specific distributional cutoff points without regard to race were evaluated. RESULTS: Among men with higher grade disease, the proportion of Black men (47.1%) with more variable cancer cell telomere lengths was 2.3-times higher (P = 0.02) than that in White men (20.6%). In contrast, among men with lower grade disease, cancer cell telomere length variability did not differ by race. The proportion of men with shorter CAS cell telomeres did not differ by race for either higher or lower grade disease. CONCLUSIONS: A greater proportion of Black men with higher grade disease have an adverse prostate cancer cell telomere phenotype than White men with higher grade disease. IMPACT: Our findings suggest a possible explanation for the racial disparity in prostate cancer outcomes.