A Bayesian beta-binomial piecewise growth mixture model for longitudinal overdispersed binomial data.

In a recent 12-week smoking cessation trial, varenicline tartrate failed to show significant improvements in enhancing end-of-treatment abstinence when compared with placebo among adolescents and young adults. The original analysis aimed to assess the average effect across the entire population using timeline followback methods, which typically involve overdispersed binomial counts. We instead propose to investigate treatment effect heterogeneity among latent classes of participants using a Bayesian beta-binomial piecewise linear growth mixture model specifically designed to address longitudinal overdispersed binomial responses. Within each class, we fit a piecewise linear beta-binomial mixed model with random changepoints for each study group to detect critical windows of treatment efficacy. Using this model, we can cluster subjects who share similar characteristics, estimate the class-specific mean abstinence trends for each study group, and quantify the treatment effect over time within each class. Our analysis identified two classes of subjects: one comprising high-abstinent individuals, typically young adults and light smokers, in which varenicline led to improved abstinence; and another comprising low-abstinent individuals for whom varenicline showed no discernible effect. These findings highlight the importance of tailoring varenicline to specific participant subgroups, thereby advancing precision medicine in smoking cessation studies.

National Experience of Technology-based Eye Care Services (TECS): A Comprehensive Ophthalmology Telemedicine Initiative.

PURPOSE: Technology-Based Eye Care Services (TECS) is a tele-ophthalmology program operating in the Veterans' Administration since 2015. This study explores characteristics of the national TECS population, evaluates implementation and sustainability of TECS, and analyzes possible associations and effects of demographic characteristics and social determinants of health (SDOH) on being diagnosed with a vision threatening (VT) disease. DESIGN: Implementation and sustainability of TECS from 2015-2022 was examined along with the sociodemographic characteristics of Veterans served through TECS in 2021. PATIENTS/SUBJECTS: Veteran patients seen in TECS nationwide. MAIN OUTCOME MEASURES: Characteristics, disease prevalence and diagnoses, implementation success rate, sustainability rate, preliminary analysis of outcomes and disparity. METHODS: Per quarter from 2015-2022, TECS sites were classified as implementing, active, or sustained. Standard Query Language (SQL) was used to determine sociodemographic data and logistic regression models were used to identify risk factors associated with VT eye diagnosis. RESULTS: 21,712 Veterans, 52.1% rural or highly rural, were served by TECS in 2021. The average age was 64.7 years, with females comprising 10.9% of the population served. From 2015-2022, of the 67 TECS sites initiated, 6 were implementing with 51 of 61 initiated sites still operational in the first quarter (Q1) of 2022 (83.6% success rate).Macular degeneration (AMD) and cataracts were more prevalent in rural and highly rural populations (7.6% and 11.3%, and 48.8% and 55.0%, respectively) vs. urban populations; glaucoma and diabetic retinopathy (DR) had the opposite association. The prevalence of any type of VT eye disease was lowest in the Mountains/Central region (0.54%) and highest in the Southeast region (3.2%) of the US. Rural and highly rural residents were 1.3 and 2.5 times as likely, respectively, to be diagnosed with a VT eye disease than urban residents. CONCLUSIONS: Implementation and sustainability of TECS has been promising. The data provides key information that can be utilized to improve the deployment of TECS and similar programs, along with the possible future direction of TECS services. Moreover, experience from one national ocular telehealth program clearly illustrates that telemedicine can address eye care disparities in the Veteran population and may be utilized for other vulnerable groups as well.

A preoperative window-of-opportunity study of oral SERD, imlunestrant, in newly diagnosed ER-positive, HER2-negative early breast cancer: Results from EMBER-2 Study.

PURPOSE: Imlunestrant is an oral SERD with favorable safety and preliminary efficacy in patients with ABC. PD biomarker data can optimize drug dosing; herein is the PD data from the EMBER-2 study. METHODS: Postmenopausal women with untreated, operable ER-positive, HER2-negative EBC were randomized to 400mg vs 800mg of imlunestrant daily for ~2 weeks before surgery. A single arm testing 200mg daily was later accrued. PD biomarker changes (ER, PR, Ki-67 by IHC, and mRNA expression of ER-related genes) were evaluated in paired tumor samples (pre-/ post-treatment). Safety and PK were also assessed. RESULTS: Among evaluable paired samples (n=75), PD profiles demonstrated consistent ER targeting between 400 and 800mg doses with less toxicity at the 400mg dose. Although inducing the lowest rate of CCCA, PD and PK results were similar for the 200mg dose. CONCLUSION: EMBER-2 combined with existing phase 1 data has identified 400mg as the optimal imlunestrant dose.

Increasing Prevalence of Diagnosed Gestational Diabetes in South Carolina: 2015-2021.

Objective: To examine trends with a focus on racial and ethnic disparities in reported gestational diabetes mellitus (GDM) and related outcomes (macrosomia, large for gestational age infants) before and during the COVID-19 pandemic in South Carolina (SC). Methods: A retrospective cohort study of pregnancies resulting in livebirths from 2015 through 2021 was conducted in SC. Statewide maternal hospital and emergency department discharge codes were linked to birth certificate data. GDM was defined by ICD-9-CM (i.e., 648.01-648.02, 648.81-648.82) or ICD-10-CM codes (i.e., O24.4, O24.1, O24.9), or indication of GDM on the birth certificate without evidence of diabetes outside pregnancy (ICD-9-CM: 250.xx; ICD-10-CM: E10, E11, O24.0, O24.1, O24.3). Results: Our study included 194,777 non-Hispanic White (White), 108,165 non-Hispanic Black (Black), 25,556 Hispanic, and 16,344 other race-ethnic group pregnancies. The relative risk for GDM associated with a 1-year increase was 1.01 (95% confidence interval [CI]: 1.01-1.02) before the pandemic and 1.12 (1.09-1.14) during the pandemic. While there were race-ethnic differences in the prevalence of GDM, increasing trends were similar across all race-ethnic groups before and during the pandemic. From quarter 1, 2020, to quarter 4, 2021, the prevalence of reported GDM increased from 8.92% to 10.85% in White, from 8.04% to 9.78% in Black, from 11.2% to 13.65% in Hispanic, and from 13.3% to 16.16% in other race-ethnic women. Conclusion: An increasing prevalence of diagnosed GDM was reported during the COVID-19 pandemic. Future studies are needed to understand the mechanisms underlying increasing trends, to develop interventions, and to determine whether the increasing trend continues in subsequent years.

Patterns of Care and Outcomes of Patients with Small Gastrointestinal Stromal Tumors at a High-Volume Sarcoma Center.

BACKGROUND: The course of subclinical gastrointestinal stromal tumors (GISTs) is variable. The management of small GISTs is not well-defined. METHODS: Records of patients presenting with small GISTs with documented follow-up appointment at our institution between 2016 and 2022 were identified and reviewed. Comparative univariate analysis to compare patient and tumor characteristics and outcomes was performed. RESULTS: Eighty-six patients were followed for a median of 3.7 years (range 0.1-20 years). The median size at presentation was 1.7 (range 0.1-2.5) cm. A total of 51.2% (n = 44) underwent surgery before or immediately after initial presentation for pain (18.2%), bleeding (15.9%), or patient preference (6.8%). Another 17.4% (n = 15) had delayed surgery for tumor growth (40%), patient preference (2.7%), bleeding (6.7%), or pain (6.7%). The remaining 31.4% (n = 27) of patients never underwent surgery for reasons that included no growth/stability (44.4%), concomitant cancer diagnosis/treatment (29.6%), comorbidities (14.8%), and patient preference (3.7%). Patients who underwent surveillance without intervention compared with those who had delayed surgery were older (71.1 vs. 60.8 years, p < 0.001) with multiple comorbidities or a concurrent cancer diagnosis (70.3% vs. 20%, p = 0.005). There were no differences in survival or rate of distant metastases. Average time to surgery in the delayed group was 2 (range 0.1-10.3) years, and 86% of these patients underwent surgery by 5.5 years after diagnosis. CONCLUSIONS: In older patients with comorbidities or concurrent cancer diagnoses, opting out of surgery does not affect survival. Conversely, younger patients, free from significant comorbidities or other diagnoses, may consider surgery or active surveillance for up to 5 years, with comparable outcomes.

BRCA genetic testing and counseling in breast cancer: how do we meet our patients' needs?

BRCA1 and BRCA2 are tumor suppressor genes that have been linked to inherited susceptibility of breast cancer. Germline BRCA1/2 pathogenic or likely pathogenic variants (gBRCAm) are clinically relevant for treatment selection in breast cancer because they confer sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. BRCA1/2 mutation status may also impact decisions on other systemic therapies, risk-reducing measures, and choice of surgery. Consequently, demand for gBRCAm testing has increased. Several barriers to genetic testing exist, including limited access to testing facilities, trained counselors, and psychosocial support, as well as the financial burden of testing. Here, we describe current implications of gBRCAm testing for patients with breast cancer, summarize current approaches to gBRCAm testing, provide potential solutions to support wider adoption of mainstreaming testing practices, and consider future directions of testing.

Impact of Skin Care Products on Phthalates and Phthalate Replacements in Children: the ECHO-FGS.

BACKGROUND: Phthalates and their replacements have been implicated as developmental toxicants. Young children may be exposed to phthalates/replacements when using skin care products (SCPs). OBJECTIVES: Our objective is to assess the associations between use of SCPs and children's urinary phthalate/replacement metabolite concentrations. METHODS: Children (4-8 years old) from the Environmental Influences on Child Health Outcomes-Fetal Growth Study (ECHO-FGS) cohort provided spot urine samples from 2017 to 2019, and mothers were queried about children's SCP use in the past 24 h (n=906). Concentrations of 16 urinary phthalate/replacement metabolites were determined by liquid chromatography-tandem mass spectrometry (n=630). We used linear regression to estimate the child's use of different SCPs as individual predictors of urinary phthalate/replacement metabolites, adjusted for urinary specific gravity, age, sex assigned at birth, body mass index, and self-reported race/ethnic identity, as well as maternal education, and season of specimen collection. We created self-organizing maps (SOM) to group children into "exposure profiles" that reflect discovered patterns of use for multiple SCPs. RESULTS: Children had lotions applied (43.0%) frequently, but "2-in-1" hair-care products (7.5%), sunscreens (5.9%), and oils (4.3%) infrequently. Use of lotions was associated with 1.17-fold [95% confidence interval (CI): 1.00, 1.34] greater mono-benzyl phthalate and oils with 2.86-fold (95% CI: 1.89, 4.31) greater monoethyl phthalate (MEP), 1.43-fold (95% CI: 1.09, 1.90) greater monobutyl phthalate (MBP), and 1.40-fold (95% CI: 1.22, 1.61) greater low-molecular-weight phthalates (LMW). Use of 2-in-1 haircare products was associated with 0.84-fold (95% CI: 0.72, 0.97) and 0.78-fold (95% CI: 0.62, 0.98) lesser mono(3-carboxypropyl) phthalate (MCPP) and MBP, respectively. Child's race/ethnic identity modified the associations of lotions with LMW, oils with MEP and LMW, sunscreen with MCPP, ointments with MEP, and hair conditioner with MCPP. SOM identified four distinct SCP-use exposure scenarios (i.e., profiles) within our population that predicted 1.09-fold (95% CI: 1.03, 1.15) greater mono-carboxy isononyl phthalate, 1.31-fold (95% CI: 0.98, 1.77) greater mono-2-ethyl-5-hydroxyhexyl terephthalate, 1.13-fold (95% CI: 0.99, 1.29) greater monoethylhexyl phthalate, and 1.04-fold (95% CI: 1.00, 1.09) greater diethylhexyl phthalate. DISCUSSION: We found that reported SCP use was associated with urinary phthalate/replacement metabolites in young children. These results may inform policymakers, clinicians, and parents to help limit children's exposure to developmental toxicants. https://doi.org/10.1289/EHP13937.

Assessing Surgeon Familiarity with the Commission on Cancer Operative Standards for Cancer Surgery.

BACKGROUND: In response to growing evidence that proper performance of operative techniques during cancer surgery is associated with improved patient outcomes, the American College of Surgeons (ACS) implemented six operative standards as part of Commission on Cancer (CoC) accreditation. This study aimed to assess surgeon familiarity with these standards when first introduced and 2 years after their adoption. METHODS: The ACS Cancer Surgery Standards Program distributed an anonymous 36-question survey to CoC-accredited cancer programs in 2021 and 2023. Questions specific to operative techniques determined the Surgery Score, and those specific to the accreditation standards determined the Standards Score. Mean scores were compared using one-way analysis of variance (ANOVA) and t tests. RESULTS: The survey was completed by 376 surgeons in 2021 and 380 surgeons in 2023. The Surgery Scores were higher than the Standards Scores in 2021 and 2023. The surgeons who practiced at institutions with CoC accreditation had significantly higher Standards Scores than the surgeons at non-accredited institutions in 2021 (p = 0.005) and 2023 (p = 0.004), but not significantly different Surgery Scores. CONCLUSIONS: The baseline survey in 2021 demonstrated significant knowledge of technical aspects of cancer surgery among a broad surgeon base, but a need for greater understanding of the accreditation standards. The repeat survey distribution 2 years after rollout of the operative standards and associated educational programing showed increased awareness surrounding the operative standards in 2023 and a trend toward improvement in knowledge of the accreditation standards across all specialties. Further evaluation will be directed toward compliance with the accreditation standards.

Beyond surgery: the proper role and delivery of radiation therapy in the local-regional management of BIA-ALCL.

For localized breast implant-associated anaplastic large cell lymphoma (BIA-ALCL), surgical resection is crucial; however, radiation therapy (RT) can be utilized as local-regional therapy if surgery is incomplete or not recommended. We present the case of a woman with BIA-ALCL who received systemic therapy and consolidation RT.

Clinical Variables Influencing Outcomes in Patients with Atypical Intradermal Smooth Muscle Neoplasms (Formerly Cutaneous Leiomyosarcomas): Single-Institution Study of 95 Surgical Patients.

BACKGROUND: Atypical intradermal smooth muscle neoplasm, also commonly termed cutaneous leiomyosarcoma, is a soft tissue tumor with a low risk of aggressive behavior. These lesions arise in the dermis with possible superficial subcutaneous extension, demonstrate cytologic atypia, and often show mitotic activity. METHODS: A retrospective review of patient demographics, tumor characteristics, and treatment methods was conducted in a consecutive series of patients presenting to MD Anderson Cancer Center (MDACC) from 2002 to 2021 (n = 95). All pathology was reviewed by MDACC pathologists and determined to be atypical intradermal smooth muscle neoplasm. RESULTS: Median age at diagnosis was 58 years (range 22-86), and 74% were male. Ninety-five percent (n = 90) of patients identified as White, non-Hispanic. Most tumors were slow-growing, solitary, and painless nodules. Tumors were in the lower extremities (44.2%), followed by the upper extremity (28.4%), trunk (22.1%), and head and neck (5.2%). All patients (n = 44, 46.3%) who had a punch/incisional biopsy for diagnostic purposes had a subsequent tumor excision. Unplanned excision or excisional biopsy was performed on the remaining 46 (48%) patients. Of this subset, 41 of the 46 aforementioned patients (89%) had positive margins and underwent re-excision. Final pathology in 25/38 (66%) re-excision specimens was negative for residual tumor despite an initial positive margin. Two patients in the cohort had local recurrence 2 and 3 years after initial surgery. Both patients had positive margins, underwent excision of the recurrent tumor, and remain free of disease. After median follow-up of 6.9 years (range 1 day-18 years), 5-year recurrence-free survival was 96% and overall survival (OS) of the entire cohort was 78%. CONCLUSION: In this study of consecutive patients presenting with atypical intradermal smooth muscle neoplasm, we found good OS and local control after definitive surgical excision with negative margins, including excisional biopsy with close margins. Atypical intradermal smooth muscle neoplasm is unlikely to metastasize and has an excellent prognosis. Guidelines to determine optimal surveillance strategies for these patients should be revisited.

Low Molecular Weight Cyclin E Confers a Vulnerability to PKMYT1 Inhibition in Triple-Negative Breast Cancer.

Cyclin E is a regulatory subunit of CDK2 that mediates S phase entry and progression. Cleavage of full-length cyclin E (FL-cycE) to low molecular weight isoforms (LMW-E) dramatically alters the substrate specificity, promoting G1/S cell cycle transition and accelerating mitotic exit. Approximately 70% of triple-negative breast cancers (TNBC) express LMW-E, which correlates with poor prognosis. PKMYT1 also plays an important role in mitosis by inhibiting CDK1 to block premature mitotic entry, suggesting it could be a therapeutic target in TNBC expressing LMW-E. Here, analysis of TNBC patient tumor samples revealed that co-expression of LMW-E and PKMYT1-catalyzed CDK1 phosphorylation predicted poor response to neoadjuvant chemotherapy. Compared to FL-cycE, LMW-E specifically upregulated PKMYT1 expression and protein stability, elevating CDK1 phosphorylation. Inhibiting PKMYT1 with the selective inhibitor RP-6306 (lunresertib) elicited LMW-E dependent antitumor effects, accelerating premature mitotic entry, inhibiting replication fork restart, and enhancing DNA damage, chromosomal breaks, apoptosis, and replication stress. Importantly, TNBC cell line xenografts expressing LMW-E showed greater sensitivity to RP-6306 than tumors with empty vector or FL-cycE. Furthermore, RP-6306 exerted tumor suppressive effects in LMW-E transgenic murine mammary tumors and LMW-E-high TNBC patient-derived xenografts but not in the LMW-E null models examined in parallel. Lastly, transcriptomic and immune profiling demonstrated that RP-6306 treatment induced interferon responses and T-cell infiltration in the LMW-E-high tumor microenvironment, enhancing the antitumor immune response. These findings highlight the LMW-E/PKMYT1/CDK1 regulatory axis as a promising therapeutic target in TNBC, providing the rationale for further clinical development of PKMYT1 inhibitors in this aggressive breast cancer subtype.

Moderately hypofractionated, preoperative radiotherapy in patients with soft tissue sarcomas (HYPORT-STS): Updated local control, late toxicities, and patient-reported outcomes.

BACKGROUND: Moderately hypofractionated, preoperative radiotherapy in patients with soft tissue sarcomas (HYPORT-STS; ClinicalTrials.gov identifier NCT03819985) investigated a radiobiologically equivalent, moderately hypofractionated course of preoperative radiotherapy (RT) 15 × 2.85 Gy in patients with soft tissue sarcoma (STS). Here, the authors report longer term follow-up to update local control and report late toxicities, as well as functional and patient-reported outcomes. METHODS: HYPORT-STS was a single-center, open-label, single-arm, prospective phase 2 clinical trial that enrolled 120 eligible adult patients with localized STS of the extremities or superficial trunk between 2018 and 2021. Patients received a 3-week course of preoperative RT followed by surgery 4-8 weeks later. End points and follow-up were analyzed from the date of surgery. RESULTS: The median follow-up was 43 months (interquartile range, 37-52 months), and the 4-year local recurrence-free survival rate was 93%. Overall RT-related late toxicities improved with time from local therapy (p < .001), and few patients had grade ≥2 toxicities (9%; n = 8 of 88) at 2 years. These included: 2% grade ≥2 skin toxicity, 2% fibrosis, 3% lymphedema, and 1% joint stiffness. Four patients (3%) had bone fractures. Both functional outcomes, as measured by the Musculoskeletal Tumor Society Rating Scale (p < .001), and quality of life, as measured by the Functional Assessment of Cancer Therapy-General (p < .001), improved with time from treatment, and both measures were better in follow-up at 2 years compared with baseline. CONCLUSIONS: Long-term follow up suggests that moderately hypofractionated preoperative RT for patients with STS is safe and effective. Higher grade late toxicities affect a minority of patients. Late toxicities decrease over time, whereas functional outcomes and health-related quality of life seem to improve with more time from combined modality treatment.