Applications of the partial-order continual reassessment method in the early development of treatment combinations.

Combination therapy is increasingly being explored as a promising approach for improving cancer treatment outcomes. However, identifying effective dose combinations in early oncology drug development is challenging due to limited sample sizes in early-phase clinical trials. This task becomes even more complex when multiple agents are being escalated simultaneously, potentially leading to a loss of monotonic toxicity order with respect to the dose. Traditional single-agent trial designs are insufficient for this multi-dimensional problem, necessitating the development and implementation of dose-finding methods specifically designed for drug combinations. While, in practice, approaches to this problem have focused on preselecting combinations with a known toxicity order and applying single-agent designs, this limits the number of combinations considered and may miss promising dose combinations. In recent years, several novel designs have been proposed for exploring partially ordered drug combination spaces with the goal of identifying a maximum tolerated dose combination, based on safety, or an optimal dose combination, based on toxicity and efficacy. However, their implementation in clinical practice remains limited. In this article, we describe the application of the partial order continual reassessment method and its extensions for combination therapies in early-phase clinical trials. We present completed trials that use safety endpoints to identify maximum tolerated dose combinations and adaptively use both safety and efficacy endpoints to determine optimal treatment strategies. We discuss the effectiveness of the partial-order continual reassessment method and its extensions in identifying optimal treatment strategies and provide our experience with executing these novel adaptive designs in practice. By utilizing innovative dose-finding methods, researchers and clinicians can more effectively navigate the challenges of combination therapy development, ultimately improving patient outcomes in the treatment of cancer.

Predictors of U.S. Adults' Opinion Toward an R-Rating Policy for Movies With Cigarette Smoking.

Recently, multiple health organizations and advocacy groups have pushed for giving an R-rating for movies depicting tobacco imagery. This study examined several predictors of U.S. adults' opinion toward an R-rating policy for movies depicting cigarette smoking. We used data from the Health Information National Trends Survey (2020 cycle), for a nationally representative sample of 3,865 US adults (aged ≥ 18). The outcome variable was opinion toward an R-rating policy (support, neutral, and oppose) for movies depicting cigarette smoking. A weighted adjusted multinomial logistic regression analysis with comparisons of support versus oppose, support versus neutral, and neutral versus oppose was performed. About 48.2% of respondents were supportive of, 31.1% were neutral toward, and 20.7% were opposed to an R-rating policy. Adults aged 50 to 64 years (adjusted odds ratio [aOR] = 2.28, p = .008) and ≥65 years (aOR = 4.54, p <.001) (vs. 18-34 years) were more likely to support the R-rating policy than oppose it. Non-Hispanic Black respondents (vs. non-Hispanic Whites) were 1.74 times more likely to support than oppose the policy (aOR = 1.74, p = .04), whereas adults with a household annual income of US$75,000 or more (vs. <$20,000) and those with moderate (vs. liberal) political viewpoints were more likely to be neutral than oppose the policy. Former and current e-cigarette users (vs. never users) were less likely to support than oppose the policy. Tailored messaging addressing the rationale behind R-rating policy should be directed towards communities based on age, race/ethnicity, household income, e-cigarette usage, and political ideologies.

Slimmer's Palsy Following Weight Loss Associated With Metastatic Breast Cancer: A Case Report.

Common peroneal neuropathy (CPN), also known as Slimmer's Palsy, is an isolated peripheral neuropathy typically associated with rapid weight loss resulting in loss of adipose tissue and subsequent nerve compression at the fibular head and is up to three times more common in individuals with malignancy. In this case report, we describe the diagnosis of CPN in a 54-year-old female with a 2.5-month history of atraumatic left foot drop and left ankle paresthesias, preceded by a 35-40 pound weight loss over the prior 3.5 month period in the setting of metastatic breast cancer.

A Pilot Study of the Combination of Entinostat with Capecitabine in Advanced Breast Cancer.

Background: Breast cancer has an unacceptably high recurrence rate when any residual disease is found following neoadjuvant treatment of high-risk disease. Based on clinical data suggesting an adjuvant role for epigenetic modifying agents in breast cancer and preclinical data suggesting synergistic activity of entinostat combined with capecitabine, we conducted a phase I, open-label study of these agents in metastatic breast cancer (MBC). Both agents have published doses for use in combination therapy, but the agents had not previously been combined with each other in a human trial. Methods: A multisite phase I dose escalation study was performed at two academic centers. Patients with pretreated, HER2-negative MBC, and measurable disease were enrolled. Dual dose escalation was performed via a Bayesian partial order continual assessment method. Dose levels ranged from entinostat 3 mg to 5 mg and capecitabine 800 mg/m2 to 1000 mg/m2. Results: Thirteen patients with MBC and a median of 4 lines of prior therapy were enrolled across four dose level combinations. The most common toxicities were neutropenia, thrombocytopenia, and palmar-plantar dysesthesia, which were expected toxicities. No new safety signals were observed. One dose-limiting toxicity was observed, which did not exceed a prespecified toxicity rate of 25%. The median treatment duration was 2.37 months. No partial nor complete responses were observed. The study was halted early prior to entering an expansion phase, due to drug supply limitations. Conclusion: The tested dosing combinations of entinostat and capecitabine are likely safe in heavily pretreated metastatic breast cancer. This study's clinical investigation of entinostat in breast cancer was halted, but drug development of this agent continues outside the US. There remains a need for postoperative adjuvant drug therapy for the subpopulation of breast cancer patients with high-risk residual cancer after curative therapy. This trial is registered with NCT03473639.

Phase I study targeting newly diagnosed grade 4 astrocytoma with bispecific antibody armed T cells (EGFR BATs) in combination with radiation and temozolomide.

PURPOSE: The purpose of this study was to determine the safety, feasibility, and immunologic responses of treating grade 4 astrocytomas with multiple infusions of anti-CD3 x anti-EGFR bispecific antibody (EGFRBi) armed T cells (EGFR BATs) in combination with radiation and chemotherapy. METHODS: This phase I study used a 3 + 3 dose escalation design to test the safety and feasibility of intravenously infused EGFR BATs in combination with radiation and temozolomide (TMZ) in patients with newly diagnosed grade 4 astrocytomas (AG4). After finding the feasible dose, an expansion cohort with unmethylated O6-methylguanine-DNA methyltransferase (MGMT) tumors received weekly EGFR BATs without TMZ. RESULTS: The highest feasible dose was 80 × 109 EGFR BATs without dose-limiting toxicities (DLTs) in seven patients. We could not escalate the dose because of the limited T-cell expansion. There were no DLTs in the additional cohort of three patients with unmethylated MGMT tumors who received eight weekly infusions of EGFR BATs without TMZ. EGFR BATs infusions induced increases in glioma specific anti-tumor cytotoxicity by peripheral blood mononuclear cells (p < 0.03) and NK cell activity (p < 0.002) ex vivo, and increased serum concentrations of IFN-γ (p < 0.03), IL-2 (p < 0.007), and GM-CSF (p < 0.009). CONCLUSION: Targeting AG4 with EGFR BATs at the maximum feasible dose of 80 × 109, with or without TMZ was safe and induced significant anti-tumor-specific immune responses. These results support further clinical trials to examine the efficacy of this adoptive cell therapy in patients with MGMT-unmethylated GBM. CLINICALTRIALS: gov Identifier: NCT03344250.

Predictors of Adolescents' Transition Through the Stages of Change for Quitting E-Cigarettes: Findings From the Population Assessment of Tobacco and Health Study.

PURPOSE: To identify predictive factors associated with US adolescents' transition through the stages of change for potentially quitting e-cigarettes using the Trans-theoretical model of behavior change. DESIGN: Prospective cohort study. SETTING: United States. SUBJECTS: We utilized data from adolescents (12-17 years) in Wave 3 of the Population Assessment of Tobacco and Health study who used e-cigarettes exclusively over the past 30 days (n = 177) and were followed up with in Wave 4. MEASURES: Outcome variables were 3 transition categories: those who remained stagnant, those who progressed, and those who regressed in their stage of quitting e-cigarettes. Predictor variables were socio-demographics, e-cigarette harm perception, e-cigarette use at home or by important people, social norms, e-cigarette and anti-tobacco advertisements, and e-cigarette health warnings. ANALYSIS: Weighted-adjusted multinomial regression analysis was performed to determine the association between predictor and outcome variables. RESULTS: From Wave 3 to Wave 4, 19% of adolescents remained stagnant; 73.3% progressed; and 7.7% regressed. Adolescents were less likely to progress in their stage of change if they perceived nicotine in e-cigarettes to be "not at all/slightly harmful" (AOR = .26 [95% CI: .25, .27], P < .001); reported important people's use of e-cigarettes (AOR = .18 [95% CI: .05, .65, P = .009); and "rarely" noticed e-cigarette health warnings (AOR = .28 [95% CI: .08, .98, P = .054). CONCLUSION: Intervention efforts must target specific predictive factors that may help adolescents quit e-cigarettes.

Disparities in E-Cigarette Harm and Addiction Perceptions Among Adolescents in the United States: a Systematic Review of the Literature.

BACKGROUND: Health disparities associated with e-cigarette use are increasingly apparent among US adolescents. Perceptions of e-cigarette harm and addiction play an important role in understanding adolescents' e-cigarette use behavior. The objective of this systematic review is to examine racial/ethnic and socio-economic disparities in e-cigarette harm and addiction perceptions among US adolescents. METHODS: We searched five databases to identify cross-sectional or longitudinal studies that focused on adolescents (≤ 18 years of age) who were ever, current, or never e-cigarettes users; we then examined how race/ethnicity and/or socio-economic status (SES) impacted e-cigarette harm and/or addiction perceptions. Two co-authors independently identified relevant studies, extracted data, and assessed the risk of bias. RESULTS: Adhering to PRISMA guidelines, eight of 226 identified studies met the inclusion criteria. These eight studies examined either perceptions regarding absolute e-cigarette harm and/or addiction (i.e., assessing perception of only e-cigarette) or relative e-cigarette harm and/or addiction (i.e., comparative perceptions to traditional cigarettes) by race and ethnicity. Two of the eight studies assessed absolute harm and/or addiction perceptions of e-cigarettes by SES. Our results indicate that, compared to all other racial/ethnic groups, relative e-cigarette harm and addiction perceptions were lower among Non-Hispanic White adolescents; however, absolute e-cigarette harm perception was higher among these groups. No clear patterns of racial/ethnic differences in absolute e-cigarette addiction perceptions and SES differences in absolute e-cigarette harm perceptions were reported. CONCLUSION: More research is needed to explicitly assess perceptions of e-cigarette harm and addiction among US adolescents by race/ethnicity and SES to develop subgroup appropriate public health messaging.

mHealth Apps Use and Their Associations With Healthcare Decision-Making and Health Communication Among Informal Caregivers: Evidence From the National Cancer Institute's Health Information National Trends Survey.

PURPOSE: The current study investigates associations between mHealth apps and healthcare decision-making and health communication among informal caregivers in the US. DESIGN: Cross-sectional study employing secondary data. SETTING: The Health Information National Trends Survey (HINTS5, Cycles 2 through 4, 2018 - 2020). SAMPLE: Self-identified informal caregivers (n = 1386; had mHealth apps = 61.3%, female = 63.2%, some college or more in education = 80.3%) who reported owning at least a smartphone or a tablet computer (i.e., ownership of a "smart device"). MEASURES: Sociodemographic characteristics, reports of having mHealth apps, smart device utilization in healthcare decision-making and health communication. ANALYSIS: Accounting for the complex design features of the HINTS data, we constructed multiple hierarchical logistic regressions to compute adjusted odds ratios (aOR) and their 95% confidence intervals (CI). RESULTS: Compared to caregivers without mHealth apps, those with the apps had higher odds of utilizing their smart devices to make a health-related decision, such as how to treat a disease or a medical condition (aOR = 1.65; 95% CI: 1.13-2.39, P < .01), or engage in health-related discussions with a healthcare provider (aOR = 2.36; 95% CI: 1.54-3.61, P < .001). CONCLUSION: Having mHealth apps was associated with a higher likelihood of using smart devices in healthcare decision-making and health communication by informal caregivers. Empowering caregivers to make informed health-related decisions and communicate effectively with healthcare providers are both crucial to health promotion and well-being. Future studies should investigate facilitators as well as barriers to using mHealth apps and smart devices in health-promoting strategies involving informal caregivers.

Diagnostic Performance of Magnetic Resonance Imaging for Pediatric Ovarian Neoplasms: A Multi-Institutional Review.

STUDY OBJECTIVE: To assess the diagnostic performance of MRI to predict ovarian malignancy alone and compared with other diagnostic studies. METHODS: A retrospective analysis was conducted of patients aged 2-21 years who underwent ovarian mass resection between 2009 and 2021 at 11 pediatric hospitals. Sociodemographic information, clinical and imaging findings, tumor markers, and operative and pathology details were collected. Diagnostic performance for detecting malignancy was assessed by calculating sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for MRI with other diagnostic modalities. RESULTS: One thousand and fifty-three patients, with a median age of 14.6 years, underwent resection of an ovarian mass; 10% (110/1053) had malignant disease on pathology, and 13% (136/1053) underwent preoperative MRI. MRI sensitivity, specificity, PPV, and NPV were 60%, 94%, 60%, and 94%. Ultrasound sensitivity, specificity, PPV, and NPV were 31%, 99%, 73%, and 95%. Tumor marker sensitivity, specificity, PPV, and NPV were 90%, 46%, 22%, and 96%. MRI and ultrasound concordance was 88%, with sensitivity, specificity, PPV, and NPV of 33%, 99%, 75%, and 94%. MRI sensitivity in ultrasound-discordant cases was 100%. MRI and tumor marker concordance was 88% with sensitivity, specificity, PPV, and NPV of 100%, 86%, 64%, and 100%. MRI specificity in tumor marker-discordant cases was 100%. CONCLUSION: Diagnostic modalities used to assess ovarian neoplasms in pediatric patients typically agree. In cases of disagreement, MRI is more sensitive for malignancy than ultrasound and more specific than tumor markers. Selective use of MRI with preoperative ultrasound and tumor markers may be beneficial when the risk of malignancy is uncertain. CONCISE ABSTRACT: This retrospective review of 1053 patients aged 2-21 years who underwent ovarian mass resection between 2009 and 2021 at 11 pediatric hospitals found that ultrasound, tumor markers, and MRI tend to agree on benign vs malignant, but in cases of disagreement, MRI is more sensitive for malignancy than ultrasound.

Cryotherapy for prevention of chemotherapy induced peripheral neuropathy in breast cancer.

Peripheral neuropathy is a well-described complication of chemotherapy. There are no known treatments to reverse peripheral neuropathy. Chemotherapy-induced peripheral neuropathy is a dose-limiting toxicity in cancer treatment and is debilitating. Cryotherapy, or the use of cold garments/ice bags applied to extremities during chemotherapy, is a method to prevent or minimize treatment related neuropathy. There is no standard method of providing cryotherapy currently. A review of the literature was performed revealing that a variety of cryotherapy methods exist. While small studies suggest potential preventive effect of some forms of cryotherapy, consistent results from well-designed randomized studies are lacking. A small benefit from the use of cryotherapy to prevent peripheral neuropathy might exist, but conflicting studies exist. In light of the low cost to implement ice bags during chemotherapy and the low risk of toxicity, the use of ice bags may be reasonable during taxane chemotherapy for the treatment of breast cancer.

Estrogen receptor positive breast cancer: contemporary nuances to sequencing therapy.

The treatment landscape of hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer has evolved dramatically in recent years. While the combination of endocrine therapy and a cyclin-dependent kinase 4/6 inhibitor is accepted as standard first-line treatment in most settings without visceral crisis, newer therapies have challenged traditional treatment models where cytotoxic chemotherapy was previously felt to be the only second-line option at time of progression. The incorporation of next-generation sequencing has led to the identification of molecular targets for therapeutic agents, including phosphatidylinositol 3-kinase and ESR1, though similar pathways can be targeted even in the absence of a mutation, such as with use of inhibitors of mammalian target of rapamycin. Current data also supports the use of cyclin-dependent kinase inhibitors beyond progression, even prior to the patient's first introduction to chemotherapy. The abundance of therapeutic options not only delay time to cytotoxic chemotherapy and antibody-drug conjugate initiation, but has resulted in improvement in breast cancer survivorship. Many unanswered questions remain, however, as to the most efficacious way to sequence these novel agents. To assist in this decision-making, we will review the existing data on systemic therapy and propose a treatment paradigm.

Reducing Unnecessary Oophorectomies for Benign Ovarian Neoplasms in Pediatric Patients.

Importance: Although most ovarian masses in children and adolescents are benign, many are managed with oophorectomy, which may be unnecessary and can have lifelong negative effects on health. Objective: To evaluate the ability of a consensus-based preoperative risk stratification algorithm to discriminate between benign and malignant ovarian pathology and decrease unnecessary oophorectomies. Design, Setting, and Participants: Pre/post interventional study of a risk stratification algorithm in patients aged 6 to 21 years undergoing surgery for an ovarian mass in an inpatient setting in 11 children's hospitals in the United States between August 2018 and January 2021, with 1-year follow-up. Intervention: Implementation of a consensus-based, preoperative risk stratification algorithm with 6 months of preintervention assessment, 6 months of intervention adoption, and 18 months of intervention. The intervention adoption cohort was excluded from statistical comparisons. Main Outcomes and Measures: Unnecessary oophorectomies, defined as oophorectomy for a benign ovarian neoplasm based on final pathology or mass resolution. Results: A total of 519 patients with a median age of 15.1 (IQR, 13.0-16.8) years were included in 3 phases: 96 in the preintervention phase (median age, 15.4 [IQR, 13.4-17.2] years; 11.5% non-Hispanic Black; 68.8% non-Hispanic White); 105 in the adoption phase; and 318 in the intervention phase (median age, 15.0 [IQR, 12.9-16.6)] years; 13.8% non-Hispanic Black; 53.5% non-Hispanic White). Benign disease was present in 93 (96.9%) in the preintervention cohort and 298 (93.7%) in the intervention cohort. The percentage of unnecessary oophorectomies decreased from 16.1% (15/93) preintervention to 8.4% (25/298) during the intervention (absolute reduction, 7.7% [95% CI, 0.4%-15.9%]; P = .03). Algorithm test performance for identifying benign lesions in the intervention cohort resulted in a sensitivity of 91.6% (95% CI, 88.5%-94.8%), a specificity of 90.0% (95% CI, 76.9%-100%), a positive predictive value of 99.3% (95% CI, 98.3%-100%), and a negative predictive value of 41.9% (95% CI, 27.1%-56.6%). The proportion of misclassification in the intervention phase (malignant disease treated with ovary-sparing surgery) was 0.7%. Algorithm adherence during the intervention phase was 95.0%, with fidelity of 81.8%. Conclusions and Relevance: Unnecessary oophorectomies decreased with use of a preoperative risk stratification algorithm to identify lesions with a high likelihood of benign pathology that are appropriate for ovary-sparing surgery. Adoption of this algorithm might prevent unnecessary oophorectomy during adolescence and its lifelong consequences. Further studies are needed to determine barriers to algorithm adherence.

Complete Response of Triple-Negative Metaplastic Carcinoma of the Breast Using Pembrolizumab.

Metaplastic breast cancer (MpBC) is a rare form of breast malignancy with a poor prognosis and limited treatment guidance. Here, we report on a case of triple-negative MpBC that was successfully treated following the Keynote-522 clinical algorithm using pembrolizumab, paclitaxel, carboplatin, adriamycin, and cyclophosphamide in a neo-adjuvant fashion. The radiographic and histologic findings of the tumor are reviewed here along with the treatment regimen and response. No major toxicities associated with pembrolizumab were observed in this case. This case report serves as an example of complete pathological response of triple-negative MpBC with pembrolizumab plus chemotherapy and demonstrates the need for further research on chemoimmunotherapy for MpBC.

Systematic review of the management of brain metastases from hormone receptor positive breast cancer.

INTRODUCTION: Brain metastases are a common cause of morbidity and mortality in patients with breast cancer. Local central nervous system (CNS) directed therapies are usually the first line treatment for breast cancer brain metastases (BCBM), but those must be followed by systemic therapies to achieve long-term benefit. Systemic therapy for hormone receptor (HR+) breast cancer has evolved in the last 10 years, but their role when brain metastases occur is uncertain. METHODS: We performed a systematic review of the literature focused on management of HR+ BCBM by searching Medline/PubMed, EBSCO, and Cochrane databases. The PRISMA guidelines were used for systematic review. RESULTS: Out of 807 articles identified, 98 fulfilled the inclusion criteria in their relevance to the management of HR+ BCBM. CONCLUSIONS: Similar to brain metastases from other neoplasms, local CNS directed therapies are the first line treatment for HR+ BCBM. Although the quality of evidence is low, after local therapies, our review supports the combination of targeted and endocrine therapies for both CNS and systemic management. Upon exhaustion of targeted/endocrine therapies, case series and retrospective reports suggest that certain chemotherapy agents are active against HR+ BCBM. Early phase clinical trials for HR+ BCBM are ongoing, but there is a need for prospective randomized trials to guide management and improve patients' outcome.

Desmoid Tumor and Implant-Based Breast Reconstruction.

Desmoid tumors are rare locally aggressive myelodysplastic tumors that are usually abdominally based. They account for 0.2% of breast tumors. Certain factors like prior surgery, familial adenomatous polyposis, pregnancy, and high estrogen states are associated with chest wall desmoid tumor occurrence. We present a patient with a history of intraductal carcinoma of the left breast who underwent mastectomy with implant-based reconstruction who had a desmoid tumor of the breast detected during workup for cardiac transplantation for chemotherapy-induced heart failure. The tumor was originally thought to be recurrent breast cancer during workup with imaging obscured by the implant. Excisional biopsy demonstrated a desmoid tumor with a positive deep margin requiring rib resection, synthetic mesh, and pectoralis major flap reconstruction. Breast desmoid tumors are reactive malignancies that have been diagnosed after prior breast implant surgery but without an established risk associated with breast implants. Excision with microscopically negative margins and chest wall reconstruction when indicated is the current established treatment protocol; however, recent paradigm shifts include "watchful waiting" and medical management among treatment strategies.

Food security status and breast cancer screening among women in the United States: Evidence from the Health and Retirement Study and Health Care and Nutrition Study.

PURPOSE: To assess the impact of food insecurity on biennial breast cancer screenings (i.e., mammography or breast X-ray) among older women in the United States (US). METHODS: Data from the 2014 and 2016 waves of the Health and Retirement Study and the 2013 Health Care and Nutrition Study were used. The analyses were limited to a nationally representative sample of 2,861 women between 50 and 74 years of age, residing in the US. We employed a propensity score weighting method to balance observed confounders between food-secure and food-insecure women and fit a binary logistic regression to investigate population-level estimates for the association between food security and breast cancer screening. RESULTS: Food insecurity was significantly associated with failure to obtain a mammogram or breast X-ray within the past two years. Food-insecure women had 54% lower odds of reporting breast cancer screening in the past 2 years (adjusted OR = 0.46; 95% CI 0.30-0.70, p-value < 0.001) as compared to food-secure women. Additional factors associated with a higher likelihood of receiving breast cancer screenings included greater educational attainment, higher household income, regular access to health care/advice, not smoking, and not being physically disabled or experiencing depressive symptoms. CONCLUSION: Results demonstrate a socioeconomic gradient existing in regard to the utilization of regular breast cancer screenings among women. Those who tend to have lower education, lower income, and lack of reliable healthcare access are more likely to be food insecure. Thus, more likely to face the financial, logistical, or environmental barriers in obtaining screening services that accompany food insecurity.

Use and Accuracy of Intraoperative Frozen Section Analysis for Ovarian Masses in Children and Adolescents.

STUDY OBJECTIVE: Describe the current practice patterns and diagnostic accuracy of frozen section (FS) pathology for children and adolescents with ovarian masses DESIGN: Prospective cohort study from 2018 to 2021 SETTING: Eleven children's hospitals PARTICIPANTS: Females age 6-21 years undergoing surgical management of an ovarian mass INTERVENTIONS: Obtaining intraoperative FS pathology MAIN OUTCOME MEASURE: Diagnostic accuracy of FS pathology RESULTS: Of 691 patients who underwent surgical management of an ovarian mass, FS was performed in 27 (3.9%), of which 9 (33.3%) had a final malignant pathology. Among FS patients, 12 of 27 (44.4%) underwent ovary-sparing surgery, and 15 of 27 (55.5%) underwent oophorectomy with or without other procedures. FS results were disparate from final pathology in 7 of 27 (25.9%) cases. FS had a sensitivity of 44.4% and specificity of 94.4% for identifying malignancy, with a c-statistic of 0.69. Malignant diagnoses missed on FS included serous borderline tumor (n = 1), mucinous borderline tumor (n = 2), mucinous carcinoma (n = 1), and immature teratoma (n = 1). FS did not guide intervention in 10 of 27 (37.0%) patients: 9 with benign FS underwent oophorectomy, and 1 with malignant FS did not undergo oophorectomy. Of the 9 patients who underwent oophorectomy with benign FS, 5 (55.6%) had benign and 4 (44.4%) had malignant final pathology. CONCLUSIONS: FSs are infrequently utilized for pediatric and adolescent ovarian masses and could be inaccurate for predicting malignancy and guiding operative decision-making. We recommend continued assessment and refinement of guidance before any standardization of use of FS to assist with intraoperative decision-making for surgical resection and staging in children and adolescents with ovarian masses.

Wearable Activity Tracker Use and Physical Activity Among Informal Caregivers in the United States: Quantitative Study.

BACKGROUND: With an increase in aging population and chronic medical conditions in the United States, the role of informal caregivers has become paramount as they engage in the care of their loved ones. Mounting evidence suggests that such responsibilities place substantial burden on informal caregivers and can negatively impact their health. New wearable health and activity trackers (wearables) are increasingly being used to facilitate and monitor healthy behaviors and to improve health outcomes. Although prior studies have examined the efficacy of wearables in improving health and well-being in the general population, little is known about their benefits among informal caregivers. OBJECTIVE: This study aimed to examine the association between use of wearables and levels of physical activity (PA) among informal caregivers in the United States. METHODS: We used data from the National Cancer Institute's Health Information National Trends Survey 5 (cycle 3, 2019 and cycle 4, 2020) for a nationally representative sample of 1273 community-dwelling informal caregivers-aged ≥18 years, 60% (757/1273) female, 75.7% (990/1273) had some college or more in education, and 67.3% (885/1273) had ≥1 chronic medical condition-in the United States. Using jackknife replicate weights, a multivariable logistic regression was fit to assess an independent association between the use of wearables and a binary outcome: meeting or not meeting the current World Health Organization's recommendation of PA for adults (≥150 minutes of at least moderate-intensity PA per week). RESULTS: More than one-third (466/1273, 37.8%) of the informal caregivers met the recommendations for adult PA. However, those who reported using wearables (390/1273, 31.7%) had slightly higher odds of meeting PA recommendations (adjusted odds ratios 1.1, 95% CI 1.04-1.77; P=.04) compared with those who did not use wearables. CONCLUSIONS: The results demonstrated a positive association between the use of wearables and levels of PA among informal caregivers in the United States. Therefore, efforts to incorporate wearable technology into the development of health-promoting programs or interventions for informal caregivers could potentially improve their health and well-being. However, any such effort should address the disparities in access to innovative digital technologies, including wearables, to promote health equity. Future longitudinal studies are required to further support the current findings of this study.

Replicative Instability Drives Cancer Progression.

In the past decade, defective DNA repair has been increasingly linked with cancer progression. Human tumors with markers of defective DNA repair and increased replication stress exhibit genomic instability and poor survival rates across tumor types. Seminal studies have demonstrated that genomic instability develops following inactivation of BRCA1, BRCA2, or BRCA-related genes. However, it is recognized that many tumors exhibit genomic instability but lack BRCA inactivation. We sought to identify a pan-cancer mechanism that underpins genomic instability and cancer progression in BRCA-wildtype tumors. Methods: Using multi-omics data from two independent consortia, we analyzed data from dozens of tumor types to identify patient cohorts characterized by poor outcomes, genomic instability, and wildtype BRCA genes. We developed several novel metrics to identify the genetic underpinnings of genomic instability in tumors with wildtype BRCA. Associated clinical data was mined to analyze patient responses to standard of care therapies and potential differences in metastatic dissemination. Results: Systematic analysis of the DNA repair landscape revealed that defective single-strand break repair, translesion synthesis, and non-homologous end-joining effectors drive genomic instability in tumors with wildtype BRCA and BRCA-related genes. Importantly, we find that loss of these effectors promotes replication stress, therapy resistance, and increased primary carcinoma to brain metastasis. Conclusions: Our results have defined a new pan-cancer class of tumors characterized by replicative instability (RIN). RIN is defined by the accumulation of intra-chromosomal, gene-level gain and loss events at replication stress sensitive (RSS) genome sites. We find that RIN accelerates cancer progression by driving copy number alterations and transcriptional program rewiring that promote tumor evolution. Clinically, we find that RIN drives therapy resistance and distant metastases across multiple tumor types.