Disparate Outcomes, Biologic and Therapeutic Differences in Pediatric versus Adult Patients with Ewing Sarcoma.

INTRODUCTION: Ewing sarcoma (ES) is a small blue round cell sarcoma affecting a wide age spectrum. Clinical advances predominately stem from pediatric research consortia clinical trials. In most series, adults have poorer outcomes when compared to children. The aim of this study was to perform a detailed evaluation of factors potentially accounting for this difference. METHODS: A single institution retrospective chart review was conducted on patients with ES diagnosed from 2005 to 2015, identified using a free-text search engine with the keywords "Ewing sarcoma" as well as a corresponding pathologic database. Data were analyzed based on age, pediatric (age <18) and adult (age >18 years), using a multivariate analysis model. RESULTS: Eighty-eight ES patients (34 pediatric, 54 adult) were identified with a median age of 13 (range 3-18) and 31 (range 19-70) in their respective cohorts. Five-year overall survival (OS) was higher in pediatric patients (73.5% vs. 48.1%, p = 0.0213). By stage, 5-year OS in pediatric versus adult patients was 65% versus 20% (p = 0.0530) in metastatic (n = 32) and 68.1% versus 58.8% (p = 0.278) in localized (n = 56) patients. Lung-only metastases were present in 83% of metastatic pediatric patients versus 35% of adult metastatic patients. Pediatric patients received more cycles of first-line chemotherapy (13.8 vs. 11.4, p = 0.001), independent of stage. More cycles of chemotherapy correlated with improved OS (HR: 0.864, CI: 0.773-0.967) and progression-free survival (HR: 0.897, CI: 0.808-0.996). CONCLUSIONS: Outcome differences were most notable in patients with metastatic disease, although not statistically significant. Our series found differences in presentation between pediatric and adult populations with adult patients receiving fewer cycles of chemotherapy. This may suggest that both variations in underlying disease biology and potentially differences in treatment may account for outcome disparities.

A Phase II Trial of Pevonedistat and Docetaxel in Patients With Previously Treated Advanced Non-Small-Cell Lung Cancer.

BACKGROUND: Postimmunotherapy (IO) treatment options for stage IV non-small-cell lung cancer (NSCLC) remain limited. Docetaxel alone or in combination with ramucirumab remains a standard of care, but response rates and survival benefit are suboptimal. Cullin-RING ligases (CRL) catalyze degradation of tumor suppressor proteins and are overactivated in NSCLC. Neddylation, which is catalyzed by the NEDD8 activating enzyme (NAE), is required for the activation of CRLs. Pevonedistat, a first-in-class small molecule NAE inhibitor, exerted antitumor activity when combined with docetaxel in preclinical studies. METHODS: We conducted a phase II, single-arm, investigator-initiated study evaluating the efficacy of pevonedistat plus docetaxel in patients with relapsed/refractory stage IV NSCLC. Patients received docetaxel 75 mg/m2 on day 1 and pevonedistat 25 mg/m2 on days 1, 3 and 5 of a 21-day cycle. The primary endpoint was objective response rate (ORR). RESULTS: From March 5, 2018 to January 26, 2021, we enrolled 31 patients. The ORR was 22% (1 CR, 5 PR), median PFS was 4.1 months, and median OS was 13.2 months. The incidence of Grade ≥3 adverse events (AE) was 53% in patients (n = 30) who received at least 1 dose of both drugs, with the most frequent being neutropenia and AST/ALT elevation. One patient was taken off study for a Grade 4 transaminase elevation. There were no Grade 5 toxicities. CONCLUSION: Our data suggest that the combination of docetaxel and pevonedistat is safe and exerts activity in patients with relapsed NSCLC. These encouraging results suggest that the neddylation pathway is an antitumor pathway that should be further studied.

Sex Differences in Presentation and Surgical Outcomes From a Prospective Multicenter Chronic Rhinosinusitis Study.

OBJECTIVE: Despite extensive research into chronic rhinosinusitis (CRS) epidemiology, presentation, and outcomes, there is scant knowledge on sex-specific differences. The objective of this study was to identify differences between male and female patients with CRS in baseline disease severity at presentation, choice for surgery vs continued medical treatment, and postoperative response. STUDY DESIGN: We evaluated data on demographic and health characteristics, clinical objective disease measures, and sinus-specific and general health patient-reported outcome measures. SETTING: Secondary analysis of prospective multicenter outcome study. METHODS: Comparison of cohort characteristics and baseline and postoperative measures was performed with a t test, chi-square test of independence, or Fisher exact test. Within-subject improvement was compared between sexes with a linear mixed model. RESULTS: Females reported worse quality of life on presentation and postsurgery, despite experiencing less severe disease by standard clinical measures. Overall, females and males showed similar within-subject improvement after surgery. However, certain quality of life domains and disease measures showed sex-specific improvement. Females demonstrated greater within-subject improvement in SF6D-derived health utility and the SNOT-22 ear and facial, psychological, and sleep subdomains, although this did not reach statistical significance for the overall cohort. CONCLUSION: Incorporating data on sex-specific differences may be important to personalize CRS treatment decision making. The discordance between patient-reported and clinical measures in CRS has been demonstrated in other pathologies and appears to be exaggerated by sex. Biological and psychological bases for sex-specific differences in CRS manifestations are an intriguing topic for further research.

IMAGINE: A Trial of Messaging Strategies for Social Needs Screening and Referral.

INTRODUCTION: Health-related social needs are associated with poor health outcomes. Many primary care practices now screen and refer patients with health-related social needs to assistance organizations, but some patients decline screening or assistance. Improving communication about health-related social needs screening and referral could increase screening response and assistance acceptance rates. STUDY DESIGN: This is a pragmatic, nonrandomized 3-stage trial of messages and communication strategies for health-related social needs screening and referral. Messages and strategies were informed by qualitative analysis of stakeholder interviews and were developed through an iterative, patient-, and stakeholder-engaged process. SETTING/PARTICIPANTS: Settings included 3 primary care clinics serving primarily low-income patients in western Colorado. INTERVENTION: Stage 1 includes usual clinic processes for health-related social needs screening (form given to patients at the front desk without additional explanation), Stage 2 includes adding written patient-friendly messages regarding the purpose of health-related social needs screening and referral to usual clinic processes, and Stage 3 includes adding verbal messages delivered by a medical assistant (form given to patients by a medical assistant during the rooming process). MAIN OUTCOME MEASURES: Primary outcomes include (1) screening form response rate and (2) acceptance of referral for assistance rate among patients with health-related social needs. Secondary outcomes include (1) comfort with screening, (2) perceived helpfulness of screening, and (3) receipt of explanation about screening. RESULTS: All data collection and analysis occurred in 2021. Study Stage 2 was not associated with significant changes in any outcomes. Stage 3 was associated with decreased odds of screening form response at 2 of the 3 clinics relative to those of Stage 1 (OR=0.1, 95% CI=0.1, 0.3; OR=0.4, 95% CI=0.2, 0.7) but with increased odds of assistance acceptance (OR=2.1, 95% CI=1.1, 4.0) among patients with needs who responded to the screening form. Stage 3 was also associated with higher odds of patients perceiving screening as helpful and receiving an explanation about screening. CONCLUSIONS: Altering practice workflows to provide verbal explanations of health-related social needs screening may reduce response rates but may encourage responders to accept assistance referrals. Optimal communication strategies and workflows will likely differ depending on the intended goals of health-related social needs screening and referral.

Screening for chronic diseases: optimizing lead time through balancing prescribed frequency and individual adherence.

Screening for chronic diseases, such as cancer, is an important public health priority, but traditionally only the frequency or rate of screening has received attention. In this work, we study the importance of adhering to recommended screening policies and develop new methodology to better optimize screening policies when adherence is imperfect. We consider a progressive disease model with four states (healthy, undetectable preclinical, detectable preclinical, clinical), and overlay this with a stochastic screening-behavior model using the theory of renewal processes that allows us to capture imperfect adherence to screening programs in a transparent way. We show that decreased adherence leads to reduced efficacy of screening programs, quantified here using elements of the lead time distribution (i.e., the time between screening diagnosis and when diagnosis would have occurred clinically in the absence of screening). Under the assumption of an inverse relationship between prescribed screening frequency and individual adherence, we show that the optimal screening frequency generally decreases with increasing levels of non-adherence. We apply this model to an example in breast cancer screening, demonstrating how accounting for imperfect adherence affects the recommended screening frequency.

Application of gap time analysis with flexible hazards to pulmonary exacerbations in the EPIC observational study.

Cystic fibrosis and other chronic lung disease clinical trials often use time to first pulmonary exacerbation (PEx) or total PEx count as endpoints. The use of these outcomes may fail to capture patterns or timing of multiple exacerbations and how covariates influence the risk of future exacerbations. Analysis of gap times between PEx provides a useful framework to understand risks of subsequent events, particularly to assess if there is a temporary increase in a hazard of a subsequent PEx following the occurrence of a PEx. This may be useful for estimating the amount of time needed to follow patients after a PEx and predicting which patients are more likely to have multiple PEx. We propose a smoothed hazard for gap times to account for elevated hazards after exacerbations. A simulation study was conducted to explore model performance and was able to appropriately estimate parameters in all situations with an underlying change point with independent or correlated recurrent events. Models with different change-point structures and trends are compared using Early Pseudomonas Infection Control (EPIC) observational study data, using a quasi-likelihood modification of the Akaike information criterion; a model with a change-point provided a better fit than a model without one. The analysis suggests that the change point may be 1.8 years (SE 0.09) after the end of a PEx. Models including covariates in the hazard function revealed that having one or two copies of the Δ$\Delta$ F508 mutation, female sex, and higher numbers of previous PEx were significantly associated with increased risk of another PEx.

Examination of Sex Differences in a Chronic Rhinosinusitis Surgical Cohort.

OBJECTIVE: Sex discrepancies have been reported in chronic rhinosinusitis (CRS), but limited data exist exploring sex-specific biological processes and sinonasal quality of life. STUDY DESIGN: Prospective cohort. SETTING: Academic medical center. METHODS: Demographics, clinical data, and sinonasal mucus were collected from patients with CRS presenting for surgical consideration over a 5-year period. A random forest model and linear regression were used to assess predictor variables for the 22-item Sino-Nasal Outcome Test (SNOT-22) and subdomains. Enzyme-linked immunosorbent assays were used to measure substance P and tryptase in a subset of mucus samples to explore biological differences by sex. RESULTS: In total, 520 patients were studied (mean age 48.3 years, 50.9% female). Males were older (50.1 vs 46.6 years, P = .008), had more polyp disease (48.2% vs 35.5%, P = .004), and had higher mean Lund-Mackay CT score (11.3 vs 9.5, P = .004). Females had a higher overall mean SNOT-22 (40.9 vs 46.9, P = .001) and higher scores in ear/facial, psychological, and sleep domains (P < .01). Age, objective disease measures, and sex were top predictors for total SNOT-22. Neither mucus substance P or tryptase, alone or paired with sex, correlated with total SNOT-22. Analysis of mucus biomarkers by sex revealed correlation between mucus tryptase in females with the extranasal subdomain (P = .01). CONCLUSION: Sex differences exist in CRS disease manifestations and presentation for surgical consideration. Detection of mucus (substance P and tryptase) was reliable, but in this exploratory study, we were not able to establish neurogenic or allergic inflammatory processes as a large source of differential disease features between sexes.

A quasiexperimental study of targeted normoxia in critically ill trauma patients.

BACKGROUND: Avoidance of hypoxia and hyperoxia may reduce morbidity and mortality in critically ill civilian and military trauma patients. The objective of this study was to determine if a multimodal quality improvement intervention increases adherence to a consensus-based, targeted normoxia strategy. We hypothesized that this intervention would safely improve compliance with targeted normoxia. METHODS: This is a pre/postquasiexperimental pilot study to improve adherence to normoxia, defined as a pulse oximetry (SpO2) of 90% to 96% or an arterial partial pressure oxygen (PaO2) of 60 to 100 mm Hg. We used a multimodal informatics and educational intervention guiding clinicians to safely titrate supplemental oxygen to normoxia based on SpO2 monitoring in critically ill trauma patients admitted to the surgical-trauma or neurosurgical intensive care unit within 24 hours of emergency department arrival. The primary outcome was effectiveness in delivering targeted normoxia (i.e., an increase in the probability of being in the targeted normoxia range and/or a reduction in the probability of being on a higher fraction-inspired oxygen concentration [FiO2]). RESULTS: Analysis included 371 preintervention subjects and 201 postintervention subjects. Preintervention and postintervention subjects were of similar age, race/ethnicity, and sex and had similar comorbidities and Acute Physiologic and Chronic Health Evaluation II scores. Overall, the adjusted probability of being hyperoxic while on supplemental oxygen was reduced during the postintervention period (adjusted odds ratio, 0.74; 95% confidence interval, 0.57-0.97). There was a higher probability of being on room air (FiO2, 0.21) in the postintervention period (adjusted odds ratio, 1.38; 95% confidence interval, 0.83-2.30). In addition, there was a decreased amount of patient time spent on higher levels of FiO2 (FiO2, >40%) without a concomitant increase in hypoxia. CONCLUSION: A multimodal intervention targeting normoxia in critically ill trauma patients increased normoxia and lowered the use of supplemental oxygen. A large clinical trial is needed to validate the impact of this protocol on patient-centered clinical outcomes. LEVEL OF EVIDENCE: Therapeutic/care management, level II.

High-fat diet induces an ovulatory defect associated with dysregulated endothelin-2 in mice.

High-fat diet (HFD) consumption in female rodents causes impaired estrous cyclicity, fewer pups per litter, and dysregulation of key ovulatory genes suggesting that HFD-induced subfertility may be due to ovulatory dysfunction. To test this hypothesis female mice were fed chow or HFD for 10 weeks at which point ovulation and ovarian gene expression of endothelin-2 (Edn2), a gene critical for ovulation, were assessed. After 10 weeks of HFD, both mice that remained lean and those that became obese had fewer ovulated oocytes than chow controls (P = 0.041, P = 0.0030, respectively). In chow controls, Edn2 was expressed as expected with basal levels during diestrus and proestrus, increased 11.6-fold during estrus, and decreased to basal levels during metestrus. In HFD mice, Edn2 was dysregulated across the entire estrous cycle as were other Edn2 system components (endothelin converting enzyme 1 (Ece-1), and the endothelin receptors (Ednra, Ednrb)). Interestingly, we found dysregulation of key ovarian steroidogenic genes after HFD. We also found that estradiol treatment in prepubertal mice increased Edn2 expression in the ovary (P = 0.030), suggesting that impaired steroidogenesis may be involved in the HFD-induced dysregulation of ovarian Edn2. In conclusion, HFD leads to ovulatory dysfunction regardless of the development of obesity, which appears to be mediated through dysregulation of ovarian Edn2 expression.

Engaging practices and communities in the development of interventions to promote HPV vaccine uptake: a protocol for implementing Boot Camp Translation in the private practice setting.

INTRODUCTION: The Healthy People 2020 report states a goal of 80% uptake of recommended vaccines among adolescents, including the human papillomavirus (HPV) vaccine. However, the rate of uptake of the HPV vaccine is estimated at 51% in 2018, which leaves young people vulnerable to morbidity and mortality from preventable, HPV-related cancers. Reasons for this are multifactorial and include factors at the level of the provider, primary care practice, patient and family, and community. The development of interventions that are responsive to these multifactorial barriers in real-world settings is a priority. Boot Camp Translation (BCT) is a community-engaged approach to message development for translating evidence-based practices into clinics and communities. This project aims to (1) Engage practices and communities in the development of interventions to promote HPV vaccine uptake and (2) Evaluate the impact of the BCT-designed intervention on practice-level HPV vaccine initiation rates. We hypothesise that the BCT-designed intervention will increase the rate of HPV vaccine initiation in the practices. METHODS AND ANALYSIS: This study will implement HPV-focused BCT in three counties in Colorado with a below average county-level vaccination rate. Each BCT group will design a multipronged intervention targeted at patients, parents, providers and the general community to then be disseminated in the participating practices and communities over the subsequent 6-month period. The long-term goal is to develop a replicable approach and low-cost method of increasing HPV vaccine uptake that is easily adaptable to different settings and sociodemographic contexts. ETHICS AND DISSEMINATION: This study is approved by the Colorado Multiple Institutional Review Board. Results will be disseminated through peer-reviewed manuscripts and conference presentations, as well as within Colorado practice-based research networks. TRIAL REGISTRATION NUMBER: NCT04279964.

Prevalence and characteristics of HPV vaccine hesitancy among parents of adolescents across the US.

BACKGROUND: While many clinicians encounter parents or adolescents who refuse HPV vaccine, little is known about the prevalence of hesitancy for HPV vaccine nationally or its association with vaccination. METHODS: In April 2019, we surveyed families with adolescents 11-17 years using a national online panel (Knowledge Panel®) as the sampling frame. We assessed the prevalence of HPV vaccine hesitancy with the validated 9-item Vaccine Hesitancy Scale (VHS). We used multivariate analyses to assess demographic factors associated with HPV vaccine hesitancy. We also assessed practical barriers to receipt of HPV vaccine and the relationship between barriers and hesitancy. Finally, we evaluated the association between both HPV vaccine hesitancy and practical barriers on HPV vaccine receipt or refusal. RESULTS: 2,177 parents out of 4,185 sampled (52%) completed the survey, 2,020 qualified (lived with adolescent). Using a VHS cut-off score > 3 out of 5 points, 23% of US parents were hesitant about HPV vaccine. Hesitancy was lower among those with Hispanic ethnicity. At least one out of five parents disagreed that the HPV vaccine is beneficial for their adolescent, that the vaccine is effective, protects against HPV-related cancers, or that they followed their adolescent's health-care provider's recommendation about the vaccine. Many were concerned about vaccine side effects and the novelty of the vaccine. Adolescents living with vaccine-hesitant parents were less than one-third as likely to have received the vaccine (RR = 0.29, 95% CI 0.24, 0.35) or completed the vaccine series (RR = 0.29, 95% CI 0.23, 0.36), and were 6-fold more likely to have refused the vaccine because of parental vaccine-related concerns (RR = 6.09, 95% CI = 5.26, 7.04). Most practical barriers were independently associated with vaccine receipt but not with vaccine refusal. CONCLUSIONS: HPV vaccine hesitancy is common nationally and strongly related to both under-vaccination and vaccine refusal.

Modeling the rate of HIV testing from repeated binary data amidst potential never-testers.

Many longitudinal studies with a binary outcome measure involve a fraction of subjects with a homogeneous response profile. In our motivating data set, a study on the rate of human immunodeficiency virus (HIV) self-testing in a population of men who have sex with men (MSM), a substantial proportion of the subjects did not self-test during the follow-up study. The observed data in this context consist of a binary sequence for each subject indicating whether or not that subject experienced any events between consecutive observation time points, so subjects who never self-tested were observed to have a response vector consisting entirely of zeros. Conventional longitudinal analysis is not equipped to handle questions regarding the rate of events (as opposed to the odds, as in the classical logistic regression model). With the exception of discrete mixture models, such methods are also not equipped to handle settings in which there may exist a group of subjects for whom no events will ever occur, i.e. a so-called "never-responder" group. In this article, we model the observed data assuming that events occur according to some unobserved continuous-time stochastic process. In particular, we consider the underlying subject-specific processes to be Poisson conditional on some unobserved frailty, leading to a natural focus on modeling event rates. Specifically, we propose to use the power variance function (PVF) family of frailty distributions, which contains both the gamma and inverse Gaussian distributions as special cases and allows for the existence of a class of subjects having zero frailty. We generalize a computational algorithm developed for a log-gamma random intercept model (Conaway, 1990. A random effects model for binary data. Biometrics46, 317-328) to compute the exact marginal likelihood, which is then maximized to obtain estimates of model parameters. We conduct simulation studies, exploring the performance of the proposed method in comparison with competitors. Applying the PVF as well as a Gaussian random intercept model and a corresponding discrete mixture model to our motivating data set, we conclude that the group assigned to receive follow-up messages via SMS was self-testing at a significantly lower rate than the control group, but that there is no evidence to support the existence of a group of never-testers.

Semiparametric time-to-event modeling in the presence of a latent progression event.

In cancer research, interest frequently centers on factors influencing a latent event that must precede a terminal event. In practice it is often impossible to observe the latent event precisely, making inference about this process difficult. To address this problem, we propose a joint model for the unobserved time to the latent and terminal events, with the two events linked by the baseline hazard. Covariates enter the model parametrically as linear combinations that multiply, respectively, the hazard for the latent event and the hazard for the terminal event conditional on the latent one. We derive the partial likelihood estimators for this problem assuming the latent event is observed, and propose a profile likelihood-based method for estimation when the latent event is unobserved. The baseline hazard in this case is estimated nonparametrically using the EM algorithm, which allows for closed-form Breslow-type estimators at each iteration, bringing improved computational efficiency and stability compared with maximizing the marginal likelihood directly. We present simulation studies to illustrate the finite-sample properties of the method; its use in practice is demonstrated in the analysis of a prostate cancer data set.

Locally Weighted Score Estimation for Quantile Classification in Binary Regression Models.

One common use of binary response regression methods is classification based on an arbitrary probability threshold dictated by the particular application. Since this is given to us a priori, it is sensible to incorporate the threshold into our estimation procedure. Specifically, for the linear logistic model, we solve a set of locally weighted score equations, using a kernel-like weight function centered at the threshold. The bandwidth for the weight function is selected by cross validation of a novel hybrid loss function that combines classification error and a continuous measure of divergence between observed and fitted values; other possible cross-validation functions based on more common binary classification metrics are also examined. This work has much in common with robust estimation, but diers from previous approaches in this area in its focus on prediction, specifically classification into high- and low-risk groups. Simulation results are given showing the reduction in error rates that can be obtained with this method when compared with maximum likelihood estimation, especially under certain forms of model misspecification. Analysis of a melanoma data set is presented to illustrate the use of the method in practice.

Validation of statistical predictive models meant to select melanoma patients for sentinel lymph node biopsy.

INTRODUCTION: To identify melanoma patients at sufficiently low risk of nodal metastases who could avoid sentinel lymph node biopsy (SLNB), several statistical models have been proposed based upon patient/tumor characteristics, including logistic regression, classification trees, random forests, and support vector machines. We sought to validate recently published models meant to predict sentinel node status. METHODS: We queried our comprehensive, prospectively collected melanoma database for consecutive melanoma patients undergoing SLNB. Prediction values were estimated based upon four published models, calculating the same reported metrics: negative predictive value (NPV), rate of negative predictions (RNP), and false-negative rate (FNR). RESULTS: Logistic regression performed comparably with our data when considering NPV (89.4 versus 93.6%); however, the model's specificity was not high enough to significantly reduce the rate of biopsies (SLN reduction rate of 2.9%). When applied to our data, the classification tree produced NPV and reduction in biopsy rates that were lower (87.7 versus 94.1 and 29.8 versus 14.3, respectively). Two published models could not be applied to our data due to model complexity and the use of proprietary software. CONCLUSIONS: Published models meant to reduce the SLNB rate among patients with melanoma either underperformed when applied to our larger dataset, or could not be validated. Differences in selection criteria and histopathologic interpretation likely resulted in underperformance. Statistical predictive models must be developed in a clinically applicable manner to allow for both validation and ultimately clinical utility.