Decisional Conflict Among Patients Newly Diagnosed With Clinical T1 Renal Masses: A Prospective Study.

PURPOSE: Because multiple management options exist for clinical T1 renal masses, patients may experience a state of uncertainty about the course of action to pursue (ie, decisional conflict). To better support patients, we examined patient, clinical, and decision-making factors associated with decisional conflict among patients newly diagnosed with clinical T1 renal masses suspicious for kidney cancer. MATERIALS AND METHODS: From a prospective clinical trial, participants completed the Decisional Conflict Scale (DCS), scored 0 to 100 with < 25 associated with implementing decisions, at 2 time points during the initial decision-making period. The trial further characterized patient demographics, health status, tumor burden, and patient-centered communication, while a subcohort completed additional questionnaires on decision-making. Associations of patient, clinical, and decision-making factors with DCS scores were evaluated using generalized estimating equations to account for repeated measures per patient. RESULTS: Of 274 enrollees, 250 completed a DCS survey; 74% had masses ≤ 4 cm in size, while 11% had high-complexity tumors. Model-based estimated mean DCS score across both time points was 17.6 (95% CI 16.0-19.3), though 50% reported a DCS score ≥ 25 at least once. On multivariable analysis, DCS scores increased with age (+2.64, 95% CI 1.04-4.23), high- vs low-complexity tumors (+6.50, 95% CI 0.35-12.65), and cystic vs solid masses (+9.78, 95% CI 5.27-14.28). Among decision-making factors, DCS scores decreased with higher self-efficacy (-3.31, 95% CI -5.77 to -0.86]) and information-seeking behavior (-4.44, 95% CI -7.32 to -1.56). DCS scores decreased with higher patient-centered communication scores (-8.89, 95% CI -11.85 to -5.94). CONCLUSIONS: In addition to patient and clinical factors, decision-making factors and patient-centered communication relate with decisional conflict, highlighting potential avenues to better support patient decision-making for clinical T1 renal masses.

Efficient computation of high-dimensional penalized generalized linear mixed models by latent factor modeling of the random effects.

Modern biomedical datasets are increasingly high-dimensional and exhibit complex correlation structures. Generalized linear mixed models (GLMMs) have long been employed to account for such dependencies. However, proper specification of the fixed and random effects in GLMMs is increasingly difficult in high dimensions, and computational complexity grows with increasing dimension of the random effects. We present a novel reformulation of the GLMM using a factor model decomposition of the random effects, enabling scalable computation of GLMMs in high dimensions by reducing the latent space from a large number of random effects to a smaller set of latent factors. We also extend our prior work to estimate model parameters using a modified Monte Carlo Expectation Conditional Minimization algorithm, allowing us to perform variable selection on both the fixed and random effects simultaneously. We show through simulation that through this factor model decomposition, our method can fit high-dimensional penalized GLMMs faster than comparable methods and more easily scale to larger dimensions not previously seen in existing approaches.

Effect of an mHealth intervention on physical activity outcomes among young adult cancer survivors: The IMPACT randomized controlled trial.

BACKGROUND: Physical inactivity is common in young adult cancer survivors (YACS), but evidence regarding effects of physical activity (PA) interventions among YACS is limited. The IMproving Physical Activity after Cancer Treatment (IMPACT) trial evaluated a theory-based mobile PA intervention on total PA minutes/week (primary) and secondary outcomes (moderate-to-vigorous PA [MVPA], light PA, steps, sedentary behaviors) at 6 months in YACS. METHODS: YACS (N = 280) were randomized to an intervention group or self-help group. All participants received digital tools (activity tracker, smart scale, access to arm-specific Facebook group) and an individual video chat session. Intervention participants also received a 6-month program with behavioral lessons, adaptive goal-setting, tailored feedback, tailored text messages, and Facebook prompts. PA was assessed via accelerometry and questionnaires at baseline and 6 months. Generalized estimating equation analyses tested between-group differences in changes over time. RESULTS: Of 280 YACS, 251 (90%) completed the 6-month accelerometry measures. Accelerometer-measured total PA minutes/week changed from 1974.26 at baseline to 2024.34 at 6 months in the intervention (mean change, 55.14 [95% CI, -40.91 to 151.19]) and from 1814.93 to 1877.68 in the self-help group (40.94 [95% CI, -62.14 to 144.02]; between-group p = .84). Increases in MVPA were +24.67 minutes/week (95% CI, 14.77-34.57) in the intervention versus +11.41 minutes/week in the self-help (95% CI, 1.44-21.38; between-group p = .07). CONCLUSION: Although the intervention did not result in significant differences in total PA, the increase in MVPA relative to the self-help group might be associated with important health benefits. Future research should examine moderators to identify for whom, and under what conditions, the intervention might be effective. CLINICALTRIALS: gov Identifier: NCT03569605. PLAIN LANGUAGE SUMMARY: Physical inactivity is common in young adult cancer survivors. However, few interventions have focused on helping young adult cancer survivors to get more physical activity. The IMproving Physical Activity after Cancer Treatment trial compared a mobile health physical activity intervention with a self-help group on total amount of physical activity at 6 months in a nationwide sample of young adult cancer survivors. Intervention participants did not improve their total amount of physical activity, but they did increase their moderate-to-vigorous intensity physical activity by twice as much as the self-help participants. This increase in activity may be associated with health benefits.

A phase 2 study of neoadjuvant chemotherapy plus durvalumab in resectable locally advanced head and neck squamous cell carcinoma.

BACKGROUND: Patients with locally advanced head and neck squamous cell cancer (HNSCC) are treated with surgery followed by adjuvant (chemo) radiotherapy or definitive chemoradiation, but recurrence rates are high. Immune checkpoint blockade improves survival in patients with recurrent/metastatic HNSCC; however, the role of chemo-immunotherapy in the curative setting is not established. METHODS: This phase 2, single-arm, multicenter study evaluated neoadjuvant chemo-immunotherapy with carboplatin, nab-paclitaxel, and durvalumab in patients with resectable locally advanced HNSCC. The primary end point was a hypothesized pathologic complete response rate of 50%. After chemo-immunotherapy and surgical resection, patients received study-defined, pathologic risk adapted adjuvant therapy consisting of either durvalumab alone (low risk), involved field radiation plus weekly cisplatin and durvalumab (intermediate risk), or standard chemoradiation plus durvalumab (high risk). RESULTS: Between December 2017 and November 2021, 39 subjects were enrolled at three centers. Oral cavity was the most common primary site (69%). A total of 35 of 39 subjects underwent planned surgical resection; one subject had a delay in surgery due to treatment-related toxicity. The most common treatment-related adverse events were cytopenias, fatigue, and nausea. Post treatment imaging demonstrated an objective response rate of 57%. Pathologic complete response and major pathologic response were achieved in 29% and 49% of subjects who underwent planned surgery, respectively. The 1-year progression-free survival was 83.8% (95% confidence interval, 67.4%-92.4%). CONCLUSIONS: Neoadjuvant carboplatin, nab-paclitaxel, and durvalumab before surgical resection of HNSCC were safe and feasible. Although the primary end point was not met, encouraging rates of pathologic complete response and clinical to pathologic downstaging were observed.

Physical Activity Intervention in Patients with Metastatic Breast Cancer During Active Treatment: Quality of Life and Function.

BACKGROUND: In this study, we explore recruitment, retention, and potential quality of life (QoL) and function benefits from a self-directed, home-based walking intervention in women during active treatment for metastatic breast cancer (MBC). METHODS: In this single-arm pilot study, women with stage IV BC wore an activity tracker (FitbitTM) to measure steps per week throughout the intervention study. Participants were asked to walk 150 min per week at a comfortable and safe pace. Patient-reported outcome measures (PRO) were collected at baseline and follow-up. RESULTS: Target recruitment of 60 patients was achieved. In 52 patients who completed all baseline measures, mean age was 55 (SD 11.1), 23% were pre-menopausal, and 19% non-White. Forty patients (77%) were retained at 3 months and 29 (56%) at 6 months. Baseline walking was the strongest predictor of retention at 3 months (P = .02). For 24 patients (46%) with analyzable Fitbit data at 3 months, mean steps/week rose from 19,175 to 31,306. Higher number of steps correlated with larger improvements FACT-G General well-being (FACT-G, rho = 0.55, P = .01), FACT-G Physical well-being (rho = 0.48, P = .03), and PROMIS Mental Health (rho = 0.55, P = .01). CONCLUSION: Recruitment into a walking intervention is feasible (a priory target of N = 60) in women during treatment for MBC, but retention at 3 months follow-up fell short (77% versus a priori 80%), yet there were potential benefits in general and physical well-being and mental health. CLINICALTRIALS.GOV IDENTIFIER: NCT02682836.

Estimating cell type composition using isoform expression one gene at a time.

Human tissue samples are often mixtures of heterogeneous cell types, which can confound the analyses of gene expression data derived from such tissues. The cell type composition of a tissue sample may itself be of interest and is needed for proper analysis of differential gene expression. A variety of computational methods have been developed to estimate cell type proportions using gene-level expression data. However, RNA isoforms can also be differentially expressed across cell types, and isoform-level expression could be equally or more informative for determining cell type origin than gene-level expression. We propose a new computational method, IsoDeconvMM, which estimates cell type fractions using isoform-level gene expression data. A novel and useful feature of IsoDeconvMM is that it can estimate cell type proportions using only a single gene, though in practice we recommend aggregating estimates of a few dozen genes to obtain more accurate results. We demonstrate the performance of IsoDeconvMM using a unique data set with cell type-specific RNA-seq data across more than 135 individuals. This data set allows us to evaluate different methods given the biological variation of cell type-specific gene expression data across individuals. We further complement this analysis with additional simulations.

Tolerability of palbociclib in younger and older patients with advanced breast cancer.

INTRODUCTION: Palbociclib is a small-molecule cyclin-dependent kinase 4/6 inhibitor used to treat hormone receptor-positive, human epidermal growth factor receptor-2 negative advanced breast cancer. Patient-specific factors impacting dose reductions or discontinuations are unknown. METHODS: The primary objective was to evaluate the association of age (<60 vs. ≥60 years) with palbociclib dose reductions or discontinuations secondary to neutropenia. This single-center, retrospective chart review included hormone receptor-positive, human epidermal growth factor receptor-2 negative advanced breast cancer patients ≥18 years treated with palbociclib between April 2015 and May 2020. Patients <60 years at the time of palbociclib initiation were in the younger group and patients ≥60 years were in the older group. RESULTS: Among the 107 patients included, younger patients were less likely than older patients to have a palbociclib starting dose <125 mg (0% vs. 11.9%, p = 0.02). Differences in palbociclib dose reductions or treatment discontinuations secondary to neutropenia were not detected (35.4% vs. 42.4%, p = 0.55). Neither the total number of palbociclib dose reductions (none: 54.2% vs. 49.1%, one: 33.3% vs. 42.4%, two: 12.5% vs. 8.5%, p = 0.61), nor the final dose of palbociclib (125 mg: 54.2% vs. 40.7%, 100 mg: 29.2% vs. 27.1%, 75 mg: 16.7% vs. 32.2%, p = 0.17) differed between younger and older patients. CONCLUSIONS: Age (<60 vs. ≥60 years) was not associated with the rate of palbociclib dose reductions or discontinuations secondary to neutropenia. Older (≥60 years) patients were more likely to start palbociclib at lower doses which may impact neutropenia and non-neutropenic intolerance.

Frail young adult cancer survivors experience poor health-related quality of life.

BACKGROUND: Young adult cancer survivors experience frailty and decreased muscle mass at rates equivalent to much older noncancer populations, which indicate accelerated aging. Although frailty and low muscle mass can be identified in survivors, their implications for health-related quality of life are not well understood. METHODS: Through a cross-sectional analysis of young adult cancer survivors, frailty was assessed with the Fried frailty phenotype and skeletal muscle mass in relation to functional and quality of life outcomes measured by the Medical Outcomes Survey Short-Form 36 (SF-36). z tests compared survivors with US population means, and multivariable linear regression models estimated mean SF-36 scores by frailty and muscle mass with adjustments made for comorbidities, sex, and time from treatment. RESULTS: Sixty survivors (median age, 21 years; range, 18-29) participated in the study. Twenty-five (42%) had low muscle mass, and 25 were either frail or prefrail. Compared with US population means, survivors reported worse health and functional impairments across SF-36 domains that were more common among survivors with (pre)frailty or low muscle mass. In multivariable linear modeling, (pre)frail survivors (vs nonfrail) exhibited lower mean scores for general health (-9.1; P = .05), physical function (-14.9; P < .01), and overall physical health (-5.6; P = .02) independent of comorbid conditions. CONCLUSIONS: Measures of frailty and skeletal muscle mass identify subgroups of young adult cancer survivors with significantly impaired health, functional status, and quality of life independent of medical comorbidities. Identifying survivors with frailty or low muscle mass may provide opportunities for interventions to prevent functional and health declines or to reverse this process. LAY SUMMARY: Young adult cancer survivors age more quickly than peers without cancer, which is evidenced by a syndrome of decreased resilience known as frailty. The relationship between frailty (and one of its common components, decreased muscle mass) and quality of life among young adult cancer survivors was examined. Measuring decreased muscle mass and frailty identifies young survivors with poor quality of life, including worse general health, fatigue, physical function, and overall physical health, compared with nonfrail survivors. Interventions to address components of frailty (low muscle mass and weakness) may improve function and quality of life among young adult cancer survivors.

Families Addressing Cancer Together (FACT): feasibility and acceptability of a web-based psychosocial intervention for parents with cancer.

PURPOSE: Although parents with cancer report that talking with their children about cancer and dying is distressing, accessible support is rare. We assessed the feasibility, acceptability, and preliminary effects of Families Addressing Cancer Together (FACT), a web-based, tailored psychosocial intervention to help parents talk about their cancer with their children. METHODS: This pilot study used a pre-posttest design. Eligible participants were parents with new or metastatic solid tumors who had minor (ages 3-18) children. Participants who completed baseline assessments received online access to FACT. We assessed feasibility through enrollment and retention rates and reasons for study refusal. Acceptability was evaluated by satisfaction ratings. We examined participants' selection of intervention content and preliminary effects on communication self-efficacy and other psychosocial outcomes (depression and anxiety symptoms, health-related quality of life, family functioning) at 2- and 12-week post-intervention. RESULTS: Of 68 parents we approached, 53 (78%) agreed to participate. Forty-six parents completed baseline assessments and received the FACT intervention. Of the 46 participants, 35 (76%) completed 2-week assessments, and 25 (54%) completed 12-week assessments. Parents reported that FACT was helpful (90%), relevant (95%), and easy to understand (100%). Parents' psychosocial outcomes did not significantly improve post-intervention, but parents endorsed less worry about talking with their child (46% vs. 37%) and reductions in the number of communication concerns (3.4 to 1.8). CONCLUSION: The FACT intervention was feasible, acceptable, and has potential to address communication concerns of parents with cancer. A randomized trial is needed to test its efficacy in improving psychological and parenting outcomes. TRIAL REGISTRATION: This study was IRB-approved and registered with clinicaltrials.gov (NCT04342871).

Randomly organized lipids and marginally stable proteins: a coupling of weak interactions to optimize membrane signaling.

Eukaryotic lipids in a bilayer are dominated by weak cooperative interactions. These interactions impart highly dynamic and pliable properties to the membrane. C2 domain-containing proteins in the membrane also interact weakly and cooperatively giving rise to a high degree of conformational plasticity. We propose that this feature of weak energetics and plasticity shared by lipids and C2 domain-containing proteins enhance a cell's ability to transduce information across the membrane. We explored this hypothesis using information theory to assess the information storage capacity of model and mast cell membranes, as well as differential scanning calorimetry, carboxyfluorescein release assays, and tryptophan fluorescence to assess protein and membrane stability. The distribution of lipids in mast cell membranes encoded 5.6-5.8bits of information. More information resided in the acyl chains than the head groups and in the inner leaflet of the plasma membrane than the outer leaflet. When the lipid composition and information content of model membranes were varied, the associated C2 domains underwent large changes in stability and denaturation profile. The C2 domain-containing proteins are therefore acutely sensitive to the composition and information content of their associated lipids. Together, these findings suggest that the maximum flow of signaling information through the membrane and into the cell is optimized by the cooperation of near-random distributions of membrane lipids and proteins. This article is part of a Special Issue entitled: Interfacially Active Peptides and Proteins. Guest Editors: William C. Wimley and Kalina Hristova.

Predictive potential of MRI in differentiating the predominant component in biphasic pleural mesothelioma.

PURPOSE: To assess the potential of apparent diffusion coefficient (ADC) values derived from diffusion weighted (DW) MRI preoperatively to predict the predominant histologic component among biphasic pleural mesothelioma (PM) tumors. METHODS: ADC maps were generated from DW MRI scans. Histology and predominant component of biphasic PM were confirmed following surgical resection. Statistical analyses were done with R (R Foundation for Statistical Computing, Vienna, Austria). Average ADC values corresponding to epithelioid- and sarcomatoid-predominant tumors were compared. ADC thresholding was accomplished by recursive partitioning and confirmed with ROC analysis. RESULTS: Eighty-four patients with biphasic PM's, 69 (82 %) epithelioid-predominant (BE) and 15(18 %) sarcomatoid-predominant (BS) tumors were evaluated. Thirty-eight (45 %) patients underwent extrapleural pneumonectomy (EPP), 39 (46 %) had extended pleural decortication (ePDC) and 7 (8 %) had pleural decortication (PDC). ADC values ranged between 0.696 x 10-3 to 1.921 x 10-3 mm2/s. BE tumors demonstrated significantly higher ADC values than BS tumors (p = 0.026). ADC values above 0.94 x 10-3 mm2/s were associated with a significant increase of relative risk of being in group BE over group BS (relative risk: 1.47, 95 %CI: 1.05-2.06, p = 0.027) CONCLUSION: Average ADC values of BE tumors were higher than BS tumors and the two groups can be separated by a cut off value of 0.94 X 10-3 mm2/s.

Trends in breast, colon, pancreatic, and uterine cancers in women during the COVID-19 pandemic in North Carolina.

IMPORTANCE: The COVID-19 pandemic led to reductions in primary care and cancer screening visits, which may delay detection of some cancers. The impact on incidence has not been fully quantified. We examined change in cancer incidence to determine how the COVID-19 pandemic may have altered the characteristics of cancers diagnosed among women. METHODS: This study included female patients aged ≥18 years and diagnosed with breast (n = 9489), colon (n = 958), pancreatic (n = 669), or uterine (n = 1991) cancer at three hospitals in North Carolina. Using interrupted time series, we compared incidence of cancers diagnosed between March 2020 and November 2020 (during pandemic) with cancers diagnosed between January 2016 and February 2020 (pre-pandemic). RESULTS: During the pandemic, incidence of breast and uterine cancers was significantly lower than expected compared to pre-pandemic (breast-18%, p = 0.03; uterine -20%, p = 0.05). Proportions of advanced pathologic stage and hormone receptor-negative breast cancers, and advanced clinical stage and large size uterine cancers were more prevalent during the pandemic. No significant changes in incidence were detected for pancreatic (-20%, p = 0.08) or colon (+14%, p = 0.30) cancers. CONCLUSION AND RELEVANCE: In women, the COVID-19 pandemic resulted in a significant reduction in the incidence of breast and uterine cancers, but not colon or pancreatic cancers. A change in the proportion of poor prognosis breast and uterine cancers suggests that some cancers that otherwise would have been diagnosed at an earlier stage will be detected in later years. Continued analysis of long-term trends is needed to understand the full impact of the pandemic on cancer incidence and outcomes.

Examining sociodemographic and health-related characteristics as moderators of an mHealth intervention on physical activity outcomes in young adult cancer survivors.

PURPOSE: This study explored whether sociodemographic and health-related characteristics moderated mHealth PA intervention effects on total and moderate-to-vigorous physical activity (MVPA) at 6 months, relative to a self-help condition among young adult cancer survivors (YACS). METHODS: We conducted exploratory secondary analyses of data from a randomized controlled trial among 280 YACS. All participants received digital tools; intervention participants also received lessons, adaptive goals, tailored feedback, text messages, and Facebook prompts. Potential moderators were assessed in baseline questionnaires. PA was measured at baseline and 6 months with accelerometers. Linear model repeated measures analyses examined within- and between-group PA changes stratified by levels of potential moderator variables. RESULTS: Over 6 months, the intervention produced MVPA increases that were ≥ 30 min/week compared with the self-help among participants who were males (28.1 vs. -7.7, p = .0243), identified with racial/ethnic minority groups (35.2 vs. -8.0, p = .0006), had baseline BMI of 25-30 (25.4 vs. -7.2, p = .0034), or stage III/IV cancer diagnosis (26.0 vs. -6.8, p = .0041). Intervention participants who were ages 26-35, college graduates, married/living with a partner, had a solid tumor, or no baseline comorbidities had modest MVPA increases over 6 months compared to the self-help (ps = .0163-.0492). Baseline characteristics did not moderate intervention effects on total PA. CONCLUSIONS: The mHealth intervention was more effective than a self-help group at improving MVPA among subgroups of YACS defined by characteristics (sex, race, BMI, cancer stage) that may be useful for tailoring PA interventions. IMPLICATIONS FOR CANCER SURVIVORS: These potential moderators can guide future optimization of PA interventions for YACS. GOV IDENTIFIER: NCT03569605.

Complete anatomic segmentectomy shows improved oncologic outcomes compared to incomplete anatomic segmentectomy.

OBJECTIVES: To compare oncologic outcomes after segmentectomy with division of segmental bronchus, artery and vein (complete anatomic segmentectomy) versus segmentectomy with division of <3 segmental structures (incomplete anatomic segmentectomy). METHODS: We conducted a single-centre, retrospective analysis of patients undergoing segmentectomy from March 2005 to May 2020. Operative reports were audited to classify procedures as complete or incomplete anatomic segmentectomy. Patients who underwent neoadjuvant therapy or pulmonary resection beyond indicated segments were excluded. Survival was estimated with Kaplan-Meier models and compared using log-rank tests. Cox proportional hazards models were used to estimate hazard ratios (HRs) for death. Cumulative incidence functions for loco-regional recurrence were compared with Gray's test, with death considered a competing event. Cox and Fine-Gray models were used to estimate cause-specific and subdistribution HRs, respectively, for loco-regional recurrence. RESULTS: Of 390 cases, 266 (68.2%) were complete and 124 were incomplete anatomic segmentectomy. Demographics, pulmonary function, tumour size, stage and perioperative outcomes did not significantly differ between groups. Surgical margins were negative in all but 1 case. Complete anatomic segmentectomy was associated with improved lymph node dissection (5 vs 2 median nodes sampled; P < 0.001). Multivariable analysis revealed reduced incidence of loco-regional recurrence (cause-specific HR = 0.42; 95% confidence interval 0.22-0.80; subdistribution HR = 0.43; 95% confidence interval 0.23-0.81), and non-significant improvement in overall survival (HR = 0.66; 95% confidence interval: 0.43-1.00) after complete versus incomplete anatomic segmentectomy. CONCLUSIONS: This single-centre experience suggests complete anatomic segmentectomy provides superior loco-regional control and may improve survival relative to incomplete anatomic segmentectomy. We recommend surgeons perform complete anatomic segmentectomy and lymph node dissection whenever possible.

Clinical Decision Support for Surgery: A Mixed Methods Study on Design and Implementation Perspectives From Urologists.

OBJECTIVE: To assess urologist attitudes toward clinical decision support (CDS) embedded into the electronic health record (EHR) and define design needs to facilitate implementation and impact. With recent advances in big data and artificial intelligence (AI), enthusiasm for personalized, data-driven tools to improve surgical decision-making has grown, but the impact of current tools remains limited. METHODS: A sequential explanatory mixed methods study from 2019 to 2020 was performed. First, survey responses from the 2019 American Urological Association Annual Census evaluated attitudes toward an automatic CDS tool that would display risk/benefit data. This was followed by the purposeful sampling of 25 urologists and qualitative interviews assessing perspectives on CDS impact and design needs. Bivariable, multivariable, and coding-based thematic analysis were applied and integrated. RESULTS: Among a weighted sample of 12,366 practicing urologists, the majority agreed CDS would help decision-making (70.9%, 95% CI 68.7%-73.2%), aid patient counseling (78.5%, 95% CI 76.5%-80.5%), save time (58.1%, 95% CI 55.7%-60.5%), and improve patient outcomes (42.9%, 95% CI 40.5%-45.4%). More years in practice was negatively associated with agreement (P <.001). Urologists described how CDS could bolster evidence-based care, personalized medicine, resource utilization, and patient experience. They also identified multiple implementation barriers and provided suggestions on form, functionality, and visual design to improve usefulness and ease of use. CONCLUSION: Urologists have favorable attitudes toward the potential for clinical decision support in the EHR. Smart design will be critical to ensure effective implementation and impact.

Mammalian SWI/SNF complex activity regulates POU2F3 and constitutes a targetable dependency in small cell lung cancer.

Small cell lung cancers (SCLC) are comprised of heterogeneous subtypes marked by lineage-specific transcription factors, including ASCL1, NEUROD1, and POU2F3. POU2F3-positive SCLC, ∼12% of all cases, are uniquely dependent on POU2F3 itself; as such, approaches to attenuate POU2F3 expression may represent new therapeutic opportunities. Here using genome-scale screens for regulators of POU2F3 expression and SCLC proliferation, we define mSWI/SNF complexes, including non-canonical BAF (ncBAF) complexes, as top dependencies specific to POU2F3-positive SCLC. Notably, clinical-grade pharmacologic mSWI/SNF inhibition attenuates proliferation of all POU2F3-positive SCLCs, while disruption of ncBAF via BRD9 degradation is uniquely effective in pure non-neuroendocrine POU2F3-SCLCs. mSWI/SNF maintains accessibility over gene loci central to POU2F3-mediated gene regulatory networks. Finally, chemical targeting of SMARCA4/2 mSWI/SNF ATPases and BRD9 decrease POU2F3-SCLC tumor growth and increase survival in vivo . Taken together, these results characterize mSWI/SNF-mediated global governance of the POU2F3 oncogenic program and suggest mSWI/SNF inhibition as a therapeutic strategy for SCLC.

glmmPen: High Dimensional Penalized Generalized Linear Mixed Models.

Generalized linear mixed models (GLMMs) are widely used in research for their ability to model correlated outcomes with non-Gaussian conditional distributions. The proper selection of fixed and random effects is a critical part of the modeling process, where model misspecification may lead to significant bias. However, the joint selection of fixed and random effects has historically been limited to lower dimensional GLMMs, largely due to the use of criterion-based model selection strategies. Here we present the R package glmmPen, one of the first to select fixed and random effects in higher dimension using a penalized GLMM modeling framework. Model parameters are estimated using a Monte Carlo expectation conditional minimization (MCECM) algorithm, which leverages Stan and RcppArmadillo for increased computational efficiency. Our package supports the Binomial, Gaussian, and Poisson families and multiple penalty functions. In this manuscript we discuss the modeling procedure, estimation scheme, and software implementation through application to a pancreatic cancer subtyping study. Simulation results show our method has good performance in selecting both the fixed and random effects in high dimensional GLMMs.

Accelerated epigenetic aging and myopenia in young adult cancer survivors.

BACKGROUND: Young adult cancer survivors experience early aging-related morbidities and mortality. Biological aging biomarkers may identify at-risk survivors and increase our understanding of mechanisms underlying this accelerated aging. METHODS: Using an observational study design, we cross-sectionally measured DNA methylation-based epigenetic age in young adult cancer survivors at a tertiary, academic state cancer hospital. Participants were a convenience sample of consecutively enrolled survivors of childhood, adolescent, and young adult cancers treated with either an anthracycline or alkylating agent, and who were at least 3 months post-treatment. Similarly aged healthy comparators were consecutively enrolled. Cancer treatment and treatment intensity were compared to DNA methylation-based epigenetic age and pace of aging. RESULTS: Sixty survivors (58 completing assessments, mean age 20.5 years, range 18-29) and 27 comparators (mean age 20 years, range 17-29) underwent DNA methylation measurement. Survivors were predominantly female (62%) and white (60%) and averaged nearly 6 years post-treatment (range 0.2-25 years). Both epigenetic age (AgeAccelGrim: 1.5 vs. -2.4, p < 0.0001; AgeAccelPheno 2.3 vs. -3.8, p = 0.0013) and pace of aging (DunedinPACE 0.99 vs. 0.83, p < 0.0001) were greater in survivors versus comparators. In case-case adjusted analysis, compared to survivors with normal muscle mass, myopenic survivors had higher AgeAccelGrim (2.2 years, 95% CI 0.02-4.33, p = 0.02), AgeAccelPheno (6.2 years, 2.36-10.09, p < 0.001), and DunedinPACE (0.11, 0.05-0.17, p < 0.001). CONCLUSIONS: Epigenetic age is older and pace of aging is faster in young adult cancer survivors compared to noncancer peers, which is evident in the early post-therapy period. Survivors with physiological impairment demonstrate greater epigenetic age advancement. Measures of epigenetic age may identify young adult survivors at higher risk for poor functional and health outcomes.

Patient-reported outcomes in CD30-directed CAR-T cells against relapsed/refractory CD30+ lymphomas.

Chimeric antigen receptor (CAR)-T cells targeting CD30 have demonstrated high response rates with durable remissions observed in a subset of patients with relapsed/refractory CD30+ hematologic malignancies, particularly classical Hodgkin lymphoma. This therapy has low rates of toxicity including cytokine release syndrome with no neurotoxicity observed in our phase 2 study. We collected patient-reported outcomes (PROs) on patients treated with CD30 directed CAR-T cells to evaluate the impact of this therapy on their symptom experience. We collected PROs including PROMIS (Patient-Reported Outcomes Measurement Information System) Global Health and Physical Function questionnaires and selected symptom questions from the NCI PRO-CTCAE in patients enrolled on our clinical trial of CD30-directed CAR-T cells at procurement, at time of CAR-T cell infusion, and at various time points post treatment. We compared PROMIS scores and overall symptom burden between pre-procurement, time of infusion, and at 4 weeks post infusion. At least one PRO measurement during the study period was found in 23 out of the 28 enrolled patients. Patient overall symptom burden, global health and mental health, and physical function were at or above baseline levels at 4 weeks post CAR-T cell infusion. In addition, PROMIS scores for patients who participated in the clinical trial were similar to the average healthy population. CD30 CAR-T cell therapy has a favorable toxicity profile with patient physical function and symptom burden recovering to at least their baseline pretreatment health by 1 month post infusion. Trial registration number: NCT02690545.