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Background: As outcomes improve in early-stage breast cancer, clinical trials are undergoing a paradigm shift from intensification trials (more therapy) to improve survival to optimization trials, which assess the potential for using less toxic therapy while preserving survival outcomes. However, little is known about physician perspectives in community and academic settings about possible barriers and facilitators that could impact accrual to optimization clinical trials and about the generalizability of future findings. Methods: We conducted a qualitative study with semi-structured interviews of medical oncologists from different academic and community practices to assess their perspectives on optimization trials. Interviews were audio-recorded and transcribed. Three independent coders utilized a content analysis approach to analyze transcripts using NVivo. Major themes and exemplary quotes were extracted. Results: Forty-six physicians were approached from 3/31/21-11/5/21; 39 oncologists from different oncology practices across 17 states completed interviews, 7 either declined or did not respond to email requests. Physician characteristics were balanced: men vs. women (49% vs 51%) and community oncologist vs. academic oncologist (49% vs 51%); and time practicing as medical oncologist (31% 0-9 years; 33% 10-19 years; 36% 20+ years). All 39 physicians reported that they would enroll patients in optimization clinical trials. Oncologists reported the need for treatment optimization, with one oncologist noting “historically, we’ve given way too much treatment to patients.” Oncologists highlighted specific reasons to consider optimization trials. They included quality of life improvement by reducing toxicity; reduction in financial toxicity; fertility preservation; ability to avoid chemotherapy; minimization of overtreatment in patients with comorbid conditions; personalized treatment; opportunities to test novel therapies; and leveraging the availability of targeted therapies. At the same time, there was hesitancy amongst some oncologists with this approach, “All my life I’ve worked to try to improve things and so I am not totally philosophically comfortable with the notion that I’m going to be happy with a result that says, we haven’t improved it but we can get by with less.” In addition, oncologists also identified accrual barriers, like tumor-specific biology, individual (host) factors (e.g. disease characteristics, patient demographics, patient psychological state, patient preferences), prognostic markers of risk, access to therapies, provider experience, and system constraints. They voiced recommendations regarding preliminary data, trial design, and tools to support communication about and enrollment in optimization trials. Conclusions: While optimization clinical trials are generally accepted to be beneficial by oncologists, barriers impact their acceptance. Scientifically robust design and education to overcome barriers are needed to support future enrollment on trials tailoring therapy based on risk and potential benefit to allow true personalization of treatment. Citation Format: Gabrielle B. Rocque, Andrews Courtney, Rachel M. Frazier, Lawhon Valerie, Stacey A. Ingram, Mary Lou Smith, Lynne I. Wagner, Lisa Zubkoff, Nadine Tung, Lauren P. Wallner, Antonio C. Wolff. Oncologist-reported Barriers and Facilitators to enrolling patients in optimization trials that test less intense cancer treatment [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-09-04.

Fear of recurrence (FoR) is prevalent among breast cancer survivors (BCS) and may be exacerbated by avoidance coping. This study examined BCS with avoidance coping and their engagement in a FoR eHealth intervention (FoRtitude).BCS (N = 196) with elevated FoR participated in FoRtitude. Patient-reported measures assessed avoidance coping with FoR and baseline emotional and behavioral health. Intervention engagement was measured quantitatively (e.g., website logins, telecoaching attendance) and qualitatively (i.e., telecoaching notes).38 BCS (19%) endorsed avoidance coping, which was associated with more severe post-traumatic anxiety-related symptoms and worse global mental health (ps .05), but not anxiety (p = .19), depression (p = .11), physical health (p = .12), alcohol consumption (p = .85), or physical activity (p = .39). Avoidance coping was not associated with engagement levels (ps .05) but did characterize engagement-related motivators and barriers.Avoidance coping was not a barrier to FoRtitude engagement. eHealth delivery is a promising modality for engaging survivors with avoidance coping in FoR interventions.

The theory of transient cognitive impairment in epilepsy posits that lapses in attention result from ephemeral disruption of attentional circuitry by interictal events. Eye movements are intimately associated with human attention and can be monitored in real time using eye-tracking technologies. Here, we sought to characterize the associations between interictal epileptiform discharges (IEDs), gaze, and attentional behavior in children with epilepsy.Eleven consecutive children undergoing invasive monitoring with stereotactic electrodes for localization-related epilepsy performed an attentional set-shifting task while tandem intracranial electroencephalographic signals and eye-tracking data were recorded. Using an established algorithm, IEDs were detected across all intracranial electrodes on a trial-by-trial basis. Hierarchical mixed-effects modeling was performed to delineate associations between trial reaction time (RT), eye movements, and IEDs.Hierarchical mixed-effects modeling revealed that both the presence of an IED (β ± SE = 72.74 ± 24.21 ms, p = .003) and the frequency of epileptiform events (β ± SE = 67.54 ± 17.30 ms, p .001) were associated with prolonged RT on the attentional set-shifting task. IED occurrence at the time of stimulus presentation was associated with delays in gaze initiation toward the visual targets (p = .017).The occurrence of epileptiform activity in close temporal association with stimulus presentation is associated with delays in target-directed gaze and prolonged response time, hallmarks of momentary lapses in attention. These findings provide novel insights into the mechanisms of transient impairments in children and support the use of visual tracking as a correlate of higher order attentional behavior.

Supplementary Table 4 - Summary of SNPs with p

Supplementary Table 3 - Summary of SNPs with p

Supplementary Figure 1. Principal component analysis for patients in ECOG-5103 Supplementary Figure 2. Regional association (locuszoom) plots of rs3125923.

Purpose: Taxane-induced peripheral neuropathy (TIPN) is an important survivorship issue for many cancer patients. Currently, there are no clinically implemented biomarkers to predict which patients might be at increased risk for TIPN. We present a comprehensive approach to identification of genetic variants to predict TIPN.Experimental Design: We performed a genome-wide association study (GWAS) in 3,431 patients from the phase III adjuvant breast cancer trial, ECOG-5103 to compare genotypes with TIPN. We performed candidate validation of top SNPs for TIPN in another phase III adjuvant breast cancer trial, ECOG-1199.Results: When evaluating for grade 3–4 TIPN, 120 SNPs had a P value of −4 from patients of European descent (EA) in ECOG-5103. Thirty candidate SNPs were subsequently tested in ECOG-1199 and SNP rs3125923 was found to be significantly associated with grade 3–4 TIPN (P = 1.7 × 10−3; OR, 1.8). Race was also a major predictor of TIPN, with patients of African descent (AA) experiencing increased risk of grade 2–4 TIPN (HR, 2.1; P = 5.6 × 10−16) and grade 3–4 TIPN (HR, 2.6; P = 1.1 × 10−11) compared with others. An SNP in FCAMR, rs1856746, had a trend toward an association with grade 2–4 TIPN in AA patients from the GWAS in ECOG-5103 (OR, 5.5; P = 1.6 × 10−7).Conclusions: rs3125923 represents a validated SNP to predict grade 3-4 TIPN. Genetically determined AA race represents the most significant predictor of TIPN. Clin Cancer Res; 21(22); 5082–91. ©2015 AACR.

Supplementary Table 5 - Summary of SNPs with p

GWAS with E5103 samples and OpenArray Genotyping with E1199 samples.

Supplementary Table 2 - Summary of evaluated candidate SNPs in patients with NE in E1199 or E5103.

PURPOSE: Advances in genomic techniques have led to increased use of next-generation sequencing (NGS). We evaluated the extent to which these tests guide treatment decisions. METHODS: We developed and distributed a survey assessing NGS use and outcomes to a survey pool of ASCO members. Comparisons between groups were performed with Wilcoxon two-sample, chi-square, and Fisher's exact tests. RESULTS: Among 178 respondents, 62% were male, 54% White, and 67% affiliated with academic centers. More than half (56%) indicated that NGS provided actionable information to a moderate or great extent. Use was highest (median ≥ 70% of cases) for lung and gastric cancer, and lowest (median < 25% of cases) in head and neck and genitourinary cancers. Approximately one third of respondents reported that, despite identification of an actionable molecular variant, patients were sometimes or often unable to access the relevant US Food and Drug Administration–approved therapy. When NGS did not provide actionable results, individuals reporting great or moderate guidance overall from NGS in treatment recommendations were more likely to request the compassionate use of an unapproved drug ( P < .001), enroll on a clinical trial ( P < .01), or treat off-label with a drug approved for another indication ( P = .02). CONCLUSION: When NGS identifies an actionable result, a substantial proportion of clinicians reported encountering challenges obtaining approved therapies on the basis of these results. Perceived overall impact of NGS appears associated with clinical behavior unrelated to actionable NGS test results, including pursuing off-label or compassionate use of unapproved therapies or referring to a clinical trial.

The NCCN Guidelines for Breast Cancer include up-to-date guidelines for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget disease, phyllodes tumor, inflammatory breast cancer, male breast cancer, and breast cancer during pregnancy. These guidelines are developed by a multidisciplinary panel of representatives from NCCN Member Institutions with breast cancer–focused expertise in the fields of medical oncology, surgical oncology, radiation oncology, pathology, reconstructive surgery, and patient advocacy. These NCCN Guidelines Insights focus on the most recent updates to recommendations for adjuvant systemic therapy in patients with nonmetastatic, early-stage, hormone receptor–positive, HER2-negative breast cancer.

Background Given excellent survival outcomes in breast cancer, there is interest in de‐escalating the amount of chemotherapy delivered to patients. This approach may be of even greater importance in the setting of the COVID‐19 pandemic. Methods This concurrent mixed methods study included (1) interviews with patients and patient advocates and (2) a cross‐sectional survey of women with breast cancer served by a charitable nonprofit organization. Questions evaluated interest in de‐escalation trial participation, perceived barriers/facilitators to participation, and language describing de‐escalation. Results Sixteen patient advocates and 24 patients were interviewed. Key barriers to de‐escalation included fear of recurrence, worry about decision regret, lack of clinical trial interest, and dislike for focus on less treatment. Facilitators included trust in physician recommendation, toxicity avoidance, monitoring for progression, perception of good prognosis, and impact on daily life. Participants reported that the COVID‐19 pandemic made them more likely to avoid chemotherapy if possible. Of 91 survey respondents, many (43%) patients would have been unwilling to participation in a de‐escalation clinical trial. The most commonly reported barrier to participation was fear of recurrence (85%). Few patients (19%) considered clinical trials themselves as a barrier to de‐escalation trial participation. The most popular terminology describing chemotherapy de‐escalation was “lowest effective chemotherapy dose” (53%); no patients preferred the term “de‐escalation.” Conclusions Fear of recurrence is a common concern among breast cancer survivors and patient advocates, contributing to resistance to de‐escalation clinical trial participation. Additional research is needed to understand how to engage patients in de‐escalation trials., Over 40% of patients would not be interested in participating in clinical trials testing de‐escalation, with the most common barriers being fear of recurrence. Common facilitators included toxicity avoidance, trust in the physician, and use of patient‐centric language to describe the trial.

Kathleen Beusterien,1 Martine C Maculaitis,2 Bernadette Hallissey,1 Michael M Gaschler,2 Mary Lou Smith,3 Ernest H Law4 1Kantar, Health Division, Horsham, PA, USA; 2Kantar, Health Division, New York, NY, USA; 3Research Advocacy Network, Plano, TX, USA; 4Pfizer Oncology, Pfizer Inc, New York, NY, USACorrespondence: Ernest H LawGlobal Health Economics & Outcomes Research (Breast) Oncology, Patient & Health Impact, Pfizer Inc., 235 E 42nd Street (Office: 219/06/86), New York, NY, 10017, USATel +1 212 733-0785Email ernest.law@pfizer.comPurpose: Several adjuvant phase III trials are evaluating cyclin-dependent kinase 4/6 inhibitors (CDK4/6is) in combination with endocrine therapy (ET) in hormonal receptor positive (HR+)/human epidermal growth factor receptor 2 negative (HER2-) early-stage breast cancer (eBC). This study examines preferences for this combination regimen and ET alone among patients, oncologists, and payers in the United States.Methods: A web-based questionnaire, including a discrete choice experiment (DCE), was administered to patients, practicing oncologists, and payers. In the DCE, respondents selected between hypothetical treatment profiles with attributes associated with ET monotherapy and CDK4/6i + ET regimens. Each treatment alternative was defined by the following attributes: 5-year invasive disease-free survival (iDFS), nausea, diarrhea, neutropenia, alopecia, dosing schedule, and electrocardiogram (ECG) monitoring. Payers had the additional attribute of annual per-patient treatment cost. Hierarchical Bayesian models were used to estimate relative preference weights for each attribute-level and relative attribute importance.Results: For patients (n=300) and oncologists (n=200), iDFS was most important (2 to 3 times more important than the next most important attribute), followed by neutropenia and diarrhea risks for patients and oncologists, respectively. Patients and oncologists required an improvement in iDFS of 8.0 and 5.6 percentage-points, respectively, to accept an increase in diarrhea risk from 11% to 81%. Payers (n=60) viewed annual per-patient cost as most important for treatment access decision-making, closely followed by iDFS. Payers required an improvement in iDFS of 21.8 percentage-points to accept an increase in cost from $5,100 to $149,400. Across all stakeholder groups, dosing schedule, alopecia risk, and ECG monitoring were perceived as least important.Conclusion: Patients, oncologists, and payers expect a large absolute risk reduction in efficacy to offset the potential risks and costs of adding a CDK4/6i to current standard of care. An open discussion between all stakeholders is necessary to ensure that decision-making, whether at patient- or system-level, is informed by preferences for novel treatments, like CDK4/6is.Keywords: cyclin-dependent kinase 4/6 inhibitors, endocrine therapy, treatment preferences, stage II/III breast cancer

Introduction: Given excellent survival outcomes in breast cancer and new methods to predict treatment response, oncologists are interested in de-escalating the amount of chemotherapy delivered to patients. This is particularly important in the setting of COVID-19, where patient perspectives of de-escalation may be altered by perception of COVID-19 risk.Methods: This concurrent mixed methods study included (1) semi-structured interview data from patients with breast cancer treated at the University of Alabama at Birmingham and patient advocates from nationally representative advocacy organizations (10/2019-5/2020) and (2) cross-sectional survey data from a nationwide sample of women with breast cancer (11/19-12/2019). Questions evaluated interest in de-escalation study participation, perceived barriers/facilitators to participation, and language describing de-escalation. Participant perspectives surrounding COVID-19 impact on de-escalation were elicited in interviews post 3/2020.Results: Quantitative and qualitative findings were synergistic. Interviews were conducted with 40 female participants (24 patients, 16 patient advocates). Participant ages ranged from 33-79 years old; 30% were minorities; 35% didn’t have a college degree. Common barriers to acceptance of de-escalation included fear of recurrence, worry about decision regret, lack of clinical trial interest, and dislike for the focus on less treatment. Fear of recurrence was the most commonly expressed barrier, with one participant stating, “I’m just afraid it wouldn’t get it all”. Common facilitators included trust in the physician, toxicity avoidance, monitoring with the option of increasing treatment intensity, perception of good prognosis, and impact on daily life. Participants interviewed during the COVID-19 pandemic (n=16) expressed substantial virus-related fear, including fear of exposure, fear of infecting their personal contacts or health care team, fear of cancer-related complications, and fear about their immunocompromised state. These fears contributed to participants perspective on de-escalation, as highlighted by participants stating, “I wouldn't worry about getting the chemo as much as I would worry about getting the virus” and “Less is more for me right now”.Of 91 survey respondents (69% response rate), median age was 58 years (interquartile range [IQR] 48-69), 86% had early stage breast cancer. Many (43%) patients were not interested in participation in a study testing lower doses of chemotherapy than standard of care. Patients not interested in participating were more often unmarried (55% vs. 32%, V=.23), disabled (56% vs. 40%, V=.17), or diagnosed with early stage cancer (45% vs. 22%, V=.14). Barriers to participation included fear of cancer recurrence (85%) and regret about the decision to receive less chemotherapy if the cancer were to recur (79%). Few patients (19%) considered clinical trials themselves as a barrier. Patients were interested in participation due to lessened physical side effects of treatment (82%), lessened long-term problems related to treatment (76%), and lessened impact on daily life (72%). The most popular terminology describing chemotherapy de-escalation was “lowest effective chemotherapy dose” (53%); no patients preferred the term “de-escalation.” Conclusion: Fear of recurrence is a common barrier to de-escalation clinical trial participation in patients with breast cancer. Fears may be altered for patients considering treatment during the COVID-19 pandemic. Trust in the physician and use of patient-generated language, such as “customized” instead of “de-escalation”, are potential areas for future interventions engaging patients in trials. Citation Format: Gabrielle Rocque, Courtney P. Williams, Courtney J. Andrews, Kathleen Gallagher, Timothy C. Childers, Kimberly D. Wiseman, Alan Balch, Stacey A. Ingram, Thelma Brown, Tara Kaufman, Nadine Tung, Mary Lou Smith, Antonio C. Wolff, Angela DeMichele, Lynn Wagner. Patient perspectives on chemotherapy de-escalation: “Don’t de-escalate! I don’t want to die!” [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD3-10.

Working memory deficits are prevalent in childhood epilepsy. Working memory processing is thought to be supported by the phase of hippocampal neural oscillations. Disruptions in working memory have previously been linked to the occurrence of transient epileptic activity. This study aimed to resolve the associations between oscillatory neural activity, transient epileptiform events, and working memory in children with epilepsy.Intracranial recordings were acquired from stereotactically implanted electrodes in the hippocampi, epileptogenic zones, and working memory-related networks of children with drug-resistant epilepsy during a 1-back working memory task. Interictal epileptic activity was captured using automated detectors. Hippocampal phase and interregional connectivity within working memory networks were indexed by Rayleigh Z and the phase difference derivative, respectively. Trials with and without transient epileptiform events were compared.Twelve children (mean age = 14.3 ± 2.8 years) with drug-resistant epilepsy were included in the study. In the absence of transient epileptic activity, significant delta and theta hippocampal phase resetting occurred in response to working memory stimulus presentation (Rayleigh z-score = 9, Rayleigh z-score = 8). Retrieval trials that were in phase with the preferred phase angle were associated with faster reaction times (p = .01, p = .03). Concurrently, delta and theta coordinated interactions between the hippocampi and working memory-related networks were enhanced (phase difference derivative [PDD] z-scores = 6-11). During retrieval trials with pre-encoding or pre-retrieval transient epileptic activity, phase resetting was attenuated (Rayleigh z-score = 5, Rayleigh z-score = 1), interregional connectivity was altered (PDD z-scores = 1-3), and reaction times were prolonged (p = .01, p = .03).This work highlights the role of hippocampal phase in working memory. We observe poststimulus hippocampal phase resetting coincident with enhanced interregional connectivity. The precision of hippocampal phase predicts optimal working memory processing, and transient epileptic activity prolongs working memory processing. These findings can help guide future treatments aimed at restoring memory function in this patient population.

As part of ongoing efforts to meaningfully improve recruitment, enrollment, and accrual of older adults into cancer clinical trials, the National Cancer Institute (NCI) sponsored a workshop with experts across the country entitled Engaging Older Adults in the NCI Clinical Trials Network: Challenges and Opportunities. Three working groups, including Study Design, Infrastructure, and Stakeholders, were formed, who worked together to offer synergistic improvements in the system. Here, we summarize the workshop discussions of the Infrastructure Working Group, whose goal was to address infrastructural challenges, identify underlying resources, and offer solutions to facilitate accrual of older adults into cancer clinical trials. Based on preconference work and workshop discussions, four key recommendations to strengthen NCI infrastructure were proposed: 1) further centralize resources and expertise; 2) provide training for clinical research staff; (3) develop common data elements; and 4) evaluate what works and does not work. These recommendations provide a strategy to improve the infrastructure to enroll more older adults in cancer clinical trials.

OBJECTIVE Pediatric drug-resistant epilepsy (DRE) is associated with poor health-related quality of life (HRQOL). Achieving seizure control, however, does not improve HRQOL in all children. This study sought to evaluate whether (1) baseline caregiver and family factors are associated with child HRQOL at 1-year follow-up over and above epilepsy characteristics, treatment, and seizure outcome; and (2) baseline family factors moderate the association between seizure outcome and child HRQOL at 1-year follow-up. METHODS This multicenter longitudinal cohort study recruited 152 children with DRE who were being evaluated for surgical candidacy. Child HRQOL was rated by caregivers using the Quality of Life in Childhood Epilepsy Questionnaire at baseline and 1-year follow-up. Additional data collected at baseline included child epilepsy characteristics, caregiver demographics, caregiver mood, and family environment. RESULTS Seizure freedom was achieved in 68% and 28% of patients 1 year after surgery and medical treatment, respectively. Caregiver and family factors were not associated with higher child HRQOL at follow-up after accounting for epilepsy characteristics, treatment, seizure outcome, and baseline child HRQOL, F11, 131 = 1.34, P = .21, ΔR2 = .04. Family resources moderated the association between seizure outcome and child HRQOL at follow-up (b = .41, 95% confidence interval [CI] = 0.09-0.74, P = .03); seizure freedom was strongly associated with higher HRQOL when family resources were high (b = 13.50, 95% CI = 8.35-18.54, P

Objective Seizure recurrence following surgery for temporal lobe (TL) epilepsy may be related to extratemporal epileptogenic foci, so-called temporal-plus (TL+) epilepsy. Here, we sought to leverage whole brain connectomic profiling in magnetoencephalography (MEG) to identify neural networks indicative of TL+ epilepsy in children. Methods Clinical and MEG data were analyzed for 121 children with TL and TL+ epilepsy spanning 20 years at the Hospital for Sick Children. Resting-state connectomes were derived using the weighted phase lag index from neuromagnetic oscillations. Multidimensional associations between patient connectomes, TL versus TL+ epilepsy, seizure freedom, and clinical covariates were performed using a partial least squares (PLS) analysis. Bootstrap resampling statistics were performed to assess statistical significance. Results A single significant latent variable representing 66% of the variance in the data was identified with significant contributions from extent of epilepsy (TL vs TL+), duration of illness, and underlying etiology. This component was associated with significant bitemporal and frontotemporal connectivity in the theta, alpha, and beta bands. By extracting a brain score, representative of the observed connectivity profile, patients with TL epilepsy were dissociated from those with TL+, independent of their postoperative seizure outcome. Significance By analyzing 121 connectomes derived from MEG data using a PLS approach, we find that connectomic profiling could dissociate TL from TL+ epilepsy. These findings may inform patient selection for resective procedures and guide decisions surrounding invasive monitoring.

Background Historically, clinical trials involved adding novel agents to standard of care to improve survival. There has been a shift to an individualized approach with testing less intense treatment, particularly in breast cancer where risk of recurrence is low. Little is known about physician perspectives on delivering less intense treatment for patients who are not well represented in clinical trials. Methods Open-ended, individual qualitative interviews with medical oncologists explored their perspectives on trials that test less intense treatment for patients with cancer, with a focus on breast cancer. Interviews were audio-recorded and transcribed. Four independent coders utilized a content analysis approach to analyze transcripts using NVivo. Major themes and exemplary quotes were extracted. Results Of the 39 participating physicians, 61.5% felt comfortable extrapolating, 30.8% were hesitant, and 7.7% would not feel comfortable extrapolating trial outcomes to underrepresented populations. Facilitators of comfort included the sentiment that “biology is biology” (such that the cancer characteristics were what mattered), the strength of the evidence, inclusion of subset analysis on underrepresented populations, and prior experience making decisions with limited data. Barriers to extrapolation included potential harm over the patient’s lifetime, concerns about groups that had minimal participants, application to younger patients, and extending findings to diverse populations. Universally, broader inclusion in trials testing lowering chemotherapy was desired. Conclusions The majority (92%) of physicians reported that they would de-implement treatment for patients poorly represented in clinical trials testing less treatment, while expressing concerns about applicability to specific subpopulations. Further work is needed to increase clinical trial representation of diverse populations to safely and effectively optimize treatment for patients with cancer. Trial registration NCT03248258

BackgroundCognitive flexibility encompasses the ability to efficiently shift focus and forms a critical component of goal-directed attention. The neural substrates of this process are incompletely understood in part due to difficulties in sampling the involved circuitry.MethodsStereotactic intracranial recordings that permit direct resolution of local-field potentials from otherwise inaccessible structures were employed to study moment-to-moment attentional activity in children with epilepsy during the performance of an attentional set-shifting task. A combined deep learning and model-agnostic feature explanation approach was used to analyze these data and decode attentionally-relevant neural features. Connectomic profiling of highly predictive attentional nodes was further employed to examine task-related engagement of large-scale functional networks.ResultsThrough this approach, we show that beta/gamma power within executive control, salience, and default mode networks accurately predicts single-trial attentional performance. Connectomic profiling reveals that key attentional nodes exclusively recruit dorsal default mode subsystems during attentional shifts.ConclusionsThe identification of distinct substreams within the default mode system supports a key role for this network in cognitive flexibility and attention in children. Furthermore, convergence of our results onto consistent functional networks despite significant inter-subject variability in electrode implantations supports a broader role for deep learning applied to intracranial electrodes in the study of human attention.FundingNo funds supported this specific investigation. Awards and grants supporting authors include: Canadian Institutes of Health Research (CIHR) Vanier Scholarship (NMW, HY); CIHR Frederick Banting and Charles Best Canada Graduate Scholarship Doctoral Award (SMW); CIHR Canada Graduate Scholarship Master’s Award (ONA); and a CIHR project grant (GMI).

ImportanceHealth-related quality of life (HRQOL) is regarded as a key outcome for evaluating treatment efficacy. However, it is uncertain how HRQOL evolves after epilepsy surgery compared with medical therapy, such as whether it continues to improve over time, improves and then remains stable, or deteriorates after a period of time.ObjectiveTo assess trajectory of HRQOL over 2 years in children with drug-resistant epilepsy (DRE) treated with surgery compared with medical therapy.Design, Setting, and ParticipantsProspective cohort study assessing HRQOL longitudinally over 2 years. Participants were children recruited from 8 epilepsy centers in Canada from 2014 to 2019 with suspected DRE aged 4 to 18 years who were evaluated for surgery. Data were analyzed from May 2014 to December 2021.ExposuresEpilepsy surgery or medical therapy.Main Outcomes and MeasuresHRQOL was measured using the Quality of Life in Childhood Epilepsy Questionnaire (QOLCE)-55. HRQOL and seizure frequency were assessed at baseline, 6-month, 1-year, and 2-year follow-ups. Clinical, parent, and family characteristics were assessed at baseline. A linear mixed model was used to evaluate HRQOL over time, adjusting for baseline clinical, parent, and family characteristics.ResultsThere were 111 surgical and 154 medical patients (mean [SD] age at baseline was 11.0 [4.1] years; 118 [45%] were female). At baseline, HRQOL was similar among surgical and medical patients. HRQOL of surgical patients was 3.0 (95% CI, −0.7 to 6.8) points higher at 6-month, 4.9 (95% CI, 0.7 to 9.1) points higher at 1-year, and 5.1 (95% CI, 0.7 to 9.5) points higher at 2-year follow-ups compared with medical patients. Surgical patients experienced greater improvements in social functioning relative to medical patients, but not for cognitive, emotional, and physical functioning. At 2-year follow-up, 72% of surgical patients were seizure-free, compared with 33% of medical patients. Seizure-free patients reported higher HRQOL than those who were not.Conclusions and RelevanceThis study provided evidence on the association between epilepsy surgery and children’s HRQOL, with improvement in HRQOL occurring within the first year and remaining stable 2 years after surgery. By demonstrating that surgery improved seizure freedom and HRQOL, which has downstream effects such as better educational attainment, reduced health care resource utilization, and health care cost, these findings suggest that the high costs of surgery are justified, and that improved access to epilepsy surgery is necessary.

Background: The high-level aims of the Advocate-BREAST study are to study and improve the overall experience of patients with breast cancer (BC) through education, shared decision making, and patient-centered clinical trials. Assessing areas of unmet need in care delivery and research as identified by patients with BC will direct future research and help us improve the patient experience. Methods: In April 2022, an electronic RedCap survey was circulated to 6,918 BC survivors (stage 0-4 disease) enrolled in the prospectively consented Mayo Clinic Breast Disease Registry (MCBDR), which includes rural-dwelling women often underrepresented in cancer care delivery research. The questionnaire asked about satisfaction with multiple aspects of cancer care delivery and the education and support patients receive(d) regarding practical, financial, emotional, societal and spiritual concerns linked to BC. Patients were also asked to rank potential Quality Improvement (QI) projects in order of the likelihood the proposal could improve quality of life for BC patients and their families. Questions regarding clinical trial participation, use of integrative medicine and perspectives on medical second opinions were also included. Responses were collected via anonymous local language questionnaires. Results: The survey received 2,451 responses from MCBDR enrollees. 13% of respondents had Ductal Carcinoma in Situ (DCIS), 83% had early breast cancer (EBC) (Stage 1-3) and 4% had metastatic breast cancer (MBC). Mean age was 64 (SD 11.9), and mean time in months since diagnosis was 93 (SD 1.42). 69.3 % of patients received all care at Mayo Clinic; 24.7% at Mayo and another healthcare organization, and 6% at a non-Mayo site. Although the overall experience of care was generally good/excellent (> 90 %), gaps were perceived in terms of information provision, continuity of care (including survivorship care after 5 years), navigating care transitions, and timely access to mental health resources. The main severe symptoms patients recalled in year 1 were hair loss, eyebrow/eyelash thinning, hot flashes, sexual dysfunction and cognitive issues. The main concerns patients recalled in the first year following diagnosis were fear of BC recurrence and spread as well as of dying, practical and emotional concerns for family members if they were to die of BC, and their emotional health. Patients were most dissatisfied with information and support related to management of lymphedema, sexual dysfunction, eyebrow/eyelash thinning, and peripheral neuropathy. Respondents overwhelmingly voiced the need for the following QI projects: i) lifetime access to online patient educational resources: including summary “cheat sheets”; ii) educational, practical, emotional and holistic support programs for MBC patients, and iii) BC Wellness Programs for EBC and MBC patients (endorsed by 82.6%; 82.4% and 81.9% of respondents, respectively). Predictors in terms of age, time since diagnosis, and cancer stage that may account for satisfaction with care, concerns, or QI preferences will be reported at the meeting. Of 20% of patients who saw an Integrative Medicine provider, 85% were satisfied/very satisfied with the care received. Of ~40% of patients who received a second opinion regarding their BC diagnosis and treatment plan, 96% found this beneficial. 47% of respondents had participated in a clinical trial, which is higher than seen in the general population such that conclusions may not be generalizable. Of those who had not participated in a study, 30% reported that they were unsure if they would participate in a trial if offered, and 9% reported that they would decline same. Conclusion: Understanding the lived experiences of persons with BC is essential to improve quality of care. Patients with early and advanced BC desire holistic care, continuity of care, concise educational resources and early psychological support. Citation Format: Kathryn Ruddy, Ciara C. O’Sullivan, Nicole Larson, Robert A. Vierkant, Mary Lou Smith, Cynthia Chauhan, Fergus J. Couch, Janet Olson. Advocate-BREAST: Advocates and Patients’ Advice to Enhance Breast Cancer Care Delivery, Patient Experience and Patient Centered Research by 2025 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-05-41.

Decelerated resting cortical oscillations, high-frequency activity, and enhanced cross-frequency interactions are features of focal epilepsy. The association between electrophysiological signal properties and neurocognitive function, particularly following resective surgery, is, however, unclear. In the current report, we studied intraoperative recordings from intracranial electrodes implanted in seven children with focal epilepsy and analyzed the spectral dynamics both before and after surgical resection of the hypothesized seizure focus. The associations between electrophysiological spectral signatures and each child's neurocognitive profiles were characterized using a partial least squares analysis. We find that extent of spectral alteration at the periphery of surgical resection, as indexed by slowed resting frequency and its acceleration following surgery, is associated with baseline cognitive deficits in children. The current report provides evidence supporting the relationship between altered spectral properties in focal epilepsy and neuropsychological deficits in children. In particular, these findings suggest a critical role of disrupted thalamocortical rhythms, which are believed to underlie the spectral alterations we describe, in both epileptogenicity and neurocognitive function.

The neural mechanisms that underlie selective attention in children are poorly understood. By administering a set-shifting task to children with intracranial electrodes stereotactically implanted within anterior cingulate cortex (ACC) for epilepsy monitoring, we demonstrate that selective attention in a set-shifting task is dependent upon theta-band phase resetting immediately following stimulus onset and that the preferred theta phase angle is predictive of reaction time during attentional shift. We also observe selective enhancement of oscillatory coupling between the ACC and the dorsal attention network and decoupling with the default mode network during task performance. When transient focal epileptic activity occurs around the time of stimulus onset, phase resetting is impaired, connectivity changes with attentional and default mode networks are abolished, and reaction times are prolonged. The results of the present work highlight the fundamental mechanistic role of oscillatory phase in ACC in supporting attentional circuitry and present novel opportunities to remediate attention deficits in children with epilepsy.

These NCCN Guidelines Insights highlight the updated recommendations for use of multigene assays to guide decisions on adjuvant systemic chemotherapy therapy for women with hormone receptor–positive, HER2-negative early-stage invasive breast cancer. This report summarizes these updates and discusses the rationale behind them.

Background Fear of recurrence (FoR) is a prevalent concern among breast cancer survivors (BCS), yet few accessible interventions exist. This study evaluated a targeted eHealth intervention, “FoRtitude,” to reduce FoR using cognitive behavioral skills training and telecoaching. Methods BCS (N = 196) were recruited from an academic medical center and 3 National Cancer Institute Community Oncology Research Program community sites, had stage 0-III breast cancer, were 1-10 years postprimary treatment, with moderate to high FoR and familiarity with the internet. Using the Multiphase Optimization Strategy, participants were independently randomly assigned to 3 cognitive behavioral skills (relaxation, cognitive restructuring, worry practice) vs an attention control condition (health management content [HMC]) and to telecoaching (motivational interviewing) vs no telecoaching. Website content was released across 4 weeks and included didactic lessons, interactive tools, and a text-messaging feature. BCS completed the Fear of Cancer Recurrence Inventory at baseline and at 4 and 8 weeks. Fear of Cancer Recurrence Inventory scores over time were compared using mixed-effects models. All statistical tests were 2-sided. Results FCRI scores [SD] decreased statistically significantly from baseline to postintervention (T0 = 53.1 [17.4], T2 = 41.9 [16.2], P Conclusions BCS experienced statistically significant reductions in FoR postintervention, but improvements were comparable between CBT and attention controls. Telecoaching improved adherence and retention. Future research is needed on optimal integration of CBT and HMC, dose, and features of eHealth delivery that contributed to reducing FoR. In the COVID-19 era, remote delivery has become even more essential for reaching survivors struggling with FoR.

Background As the combination of systemic and targeted chemotherapies is associated with severe adverse side effects and long-term health complications, there is interest in reducing treatment intensity for patients with early stage breast cancer (EBC). Clinical trials are needed to determine if it is feasible to reduce treatment intensity while maintaining 3-year recurrence-free survival of greater than 92%. In order to recruit patients for de-implementation trials, it is important to understand patient perspectives on barriers and facilitators to reducing treatment intensity. Methods We collected qualitative interview data from patients with Stage II-III breast cancer (N=24) and patient advocates (N=16). Interviews explored interest in de-implementation trial participation and identified potential barriers and facilitators to participation. 17 participants were asked about the potential impact of COVID-19 on de-implementation efforts. Interviews were audio-recorded and transcribed, and researchers used qualitative content analysis (NVIVO and Atlas.ti) to code for dominant themes. Results 17 participants (42.5%) expressed interest in participating in a trial of reduced chemotherapy. Barriers to reducing chemotherapy included (1) fear of recurrence and inefficacy, (2) preference for aggressive treatment, (3) disinterest in clinical trials, (4) lack of information about expected outcomes, (5) fear of regret, and (6) having young children. Facilitators included (1) avoiding physical toxicity, (2) understanding the scientific rationale of reducing chemotherapy, (3) confidence in providers, (4) consistent monitoring and the option to increase dosage, (5) fewer financial and logistical challenges, and (6) contributing to scientific knowledge. Of those asked, nearly all participants said they would be more motivated to reduce treatment intensity in the context of Covid-19, primarily in order to avoid exposure to the virus while receiving treatment. Conclusions We recommend framing de-implementation strategies and recruitment to trials in terms of customizing treatment to the individual patient and added benefit—reduced toxicities, higher quality of life during treatment and lower risk of long-term complications—rather than in terms of taking treatments away or doing less than the standard of care. Doctor-patient rapport and provider support will be crucial in this process.

Working memory (WM) deficits are pervasive co-morbidities of epilepsy. Although the pathophysiological mechanisms underpinning these impairments remain elusive, it is thought that WM depends on oscillatory interactions within and between nodes of large-scale functional networks. These include the hippocampus and default mode network as well as the prefrontal cortex and frontoparietal central executive network. Here, we review the functional roles of neural oscillations in subserving WM and the putative mechanisms by which epilepsy disrupts normative activity, leading to aberrant oscillatory signatures. We highlight the particular role of interictal epileptic activity, including interictal epileptiform discharges and high frequency oscillations (HFOs) in WM deficits. We also discuss the translational opportunities presented by greater understanding of the oscillatory basis of WM function and dysfunction in epilepsy, including potential targets for neuromodulation.

Aim To simultaneously evaluate long-term outcomes of children with drug-resistant epilepsy (DRE) across multiple cognitive domains and compare the characteristics of participants sharing a similar cognitive profile. Method Participants were adolescents and young adults (AYAs) diagnosed with DRE in childhood, who completed a comprehensive neuropsychological battery evaluating intelligence, memory, academic, and language skills at the time of surgical candidacy evaluation and at long-term follow-up (4-11y later). Hierarchical k-means clustering identified subgroups of AYAs showing a unique pattern of cognitive functioning in the long-term. Results Participants (n=93; mean age 20y 1mo [standard deviation {SD} 4y 6mo]; 36% male) were followed for 7 years (SD 2y 4mo), of whom 65% had undergone resective epilepsy surgery. Two subgroups with unique patterns of cognitive functioning were identified, which could be broadly categorized as 'impaired cognition' (45% of the sample) and 'average cognition' (55% of the sample); the mean z-score across cognitive measures at follow-up was -1.86 (SD 0.62) and -0.23 (SD 0.54) respectively. Surgical and non-surgical patients were similar with respect to seizure control and their long-term cognitive profile. AYAs in the average cognition cluster were more likely to have better cognition at baseline, an older age at epilepsy onset, and better seizure control at follow-up. Interpretation The underlying abnormal neural substrate and seizure control were largely associated with long-term outcomes across cognitive domains.

PURPOSE To identify factors that may influence physician participation in tumor profiling studies and to assess the routine use of tumor profiling in clinical practice. METHODS Physicians in the National Cancer Institute–Molecular Analysis for Therapy Choice (NCI-MATCH) were invited to participate in an electronic survey consisting of 73 questions related to participation in genomic profiling studies, tumor profiling practices and education during usual patient care, and physician background and practice characteristics. RESULTS The survey response rate was 8.9% (171 surveys returned of 1,931 sent). A majority of respondents practiced in academic medical centers (AMCs). Participation in NCI-MATCH increased workload and cost but resulted in increased professional satisfaction, confidence in treatment recommendation, and subsequent use of tumor profiling. Barriers to patient participation included length of wait time for results and lack of a therapeutic option from the testing. Physicians who worked in AMCs reported a higher use of tumor profiling than did those who worked in non-AMC settings (43% v 18%; P = .0009). Access to a molecular tumor board was perceived as valuable by 56%. The study identified a need for educational materials to guide both physicians and patients in the field of genomic profiling. CONCLUSION Physicians who participate in NCI-MATCH perceive value to patient treatment that outweighs the additional effort required; survey results help identify barriers that may limit participation. The current findings have implications for the design of future genomic and other profiling studies.

Objective This study estimated trajectories of health-related quality of life (HRQOL) over a 10-year period among children newly diagnosed with epilepsy. We also modeled the characteristics of children, parents, and families associated with each identified trajectory. Methods Data came from the HERQULES (Health-Related Quality of Life in Children With Epilepsy Study), a Canada-wide prospective cohort study of children (aged 4-12 years) with newly diagnosed epilepsy. Parents reported on their children's HRQOL at diagnosis, and at 0.5-, 1-, 2-, 8-, and 10-year follow-ups using the Quality of Life in Childhood Epilepsy Questionnaire-55. Trajectories of HRQOL were identified using latent class growth models. Characteristics of children, parents, and families at the time of diagnosis that were associated with each trajectory were identified using multinomial logistic regression. Results A total of 367 children were included. Four unique HRQOL trajectories were identified; 11% of the cohort was characterized by low and stable scores, 18% by intermediate and stable scores, 35% by intermediate scores that increased then plateaued, and 43% by high scores that increased then plateaued. Absence of comorbidities, less severe epilepsy, and better family environment (greater satisfaction with family relationships and fewer family demands) at the time of diagnosis were associated with better long-term HRQOL trajectories. Although the analyses used estimates for missing values and accounted for any nonrandom attrition, the proportion of children with poorer HRQOL trajectories may be underestimated. Significance Children with new onset epilepsy are heterogenous and follow unique HRQOL trajectories over the long term. Overall, HRQOL improves for the majority in the first 2 years after diagnosis, with these improvements sustained over the long term.

OBJECTIVE To evaluate longitudinal changes in caregiver depression, anxiety, and family relationships following resective surgery for pediatric drug-resistant epilepsy (DRE). METHODS This multicenter cohort study involved 177 caregivers of children with DRE aged 4-18 years (63 surgical and 114 nonsurgical). Caregivers completed measures of depression (Quick Inventory of Depressive Symptomatology), anxiety (Generalized Anxiety Disorder 7-item scale), and satisfaction with family relationships (Family Adaptability, Partnership, Growth, Affective, and Resolve scale) at baseline, 6 months, and 1 year. Additional data collected at baseline included child, caregiver, and family sociodemographic and clinical factors as well as family environment (demands and resources). RESULTS At 1 year, 64% and 27% of surgical and nonsurgical patients were seizure-free, respectively. Linear mixed-effects models found a reduction in caregiver depression (b = -0.85, P = .004) and anxiety (b = -1.09, P = .003), but not family satisfaction (b = 0.18, P = .31) over time. There was no effect of treatment. When seizure outcome was added to the model, seizure freedom was associated with fewer depressive symptoms (b = -1.15, P = .005) and greater family satisfaction (b = 0.65, P = .006), but not anxiety (b = -0.41, P = .42). A greater proportion of caregivers of patients who achieved seizure freedom (32%) versus continued seizures (18%) reported clinically meaningful improvement in depression at 1 year (P = .03). Lower baseline depression (β = 0.42, P

Objective To prospectively delineate self-reported health-related quality of life (HRQOL) of adolescents and young adults (AYAs) 8 and 10 years after an epilepsy diagnosis and evaluate the degree of AYA-parent agreement in ratings of AYA's HRQOL. Methods Data came from the Health-Related Quality of Life in Children with Epilepsy Study (HERQULES), a 10-year longitudinal study of children, aged 4-12 years, with newly diagnosed epilepsy. Epilepsy-specific HRQOL was self-reported by AYA 8 and 10 years after diagnosis and by parents at multiple time points throughout the 10-year follow-up. Measurers of HRQOL over time were analyzed using a linear mixed-effect model approach. AYA-parent agreement was evaluated using intraclass correlation coefficient (ICC) and Bland-Altman plots. Results A total of 165 AYAs participated at long-term follow-up. There was considerable heterogeneity among AYA's HRQOL, and as a group, there was no significant change in HRQOL from the 8- to 10-year follow-up. Household income at the time of diagnosis, seizure control at follow-up, and a history of emotional problems (anxiety/depression) were independent predictors of HRQOL at follow-up. AYA-parent agreement on AYA's HRQOL was moderate (ICC 0.62, 95% CI 0.51-0.71), although considerable differences were observed at the individual level. AYA-parent agreement varied with AYA's and parent's age, seizure control, and family environment. Significance In the long-term after a diagnosis of epilepsy, AYAs report stable HRQOL over time at the group level, although notable individual differences exist. Seizure control, anxiety/depression, and family environment meaningfully impact AYA's long-term HRQOL. AYA and parent reports on HRQOL are similar at the group level, although they cannot be used interchangeably, given the large individual differences observed.

BackgroundCombination antiretroviral therapy (cART) during pregnancy prevents vertical transmission, but many antiretrovirals cross the placenta and several can affect mitochondria. Exposure to maternal human immunodeficiency virus (HIV) and/or cART could have long-term effects on children who are HIV exposed and uninfected (CHEU). Our objective was to compare blood mitochondrial DNA (mtDNA) content in CHEU and children who are HIV unexposed and uninfected (CHUU), at birth and in early life.MethodsWhole-blood mtDNA content at birth and in early life (age 0–3 years) was compared cross-sectionally between CHEU and CHUU. Longitudinal changes in mtDNA content among CHEU was also evaluated.ResultsAt birth, CHEU status and younger gestational age were associated with higher mtDNA content. These remained independently associated with mtDNA content in multivariable analyses, whether considering all infants, or only those born at term. Longitudinally, CHEU mtDNA levels remained unchanged during the first 6 months of life, and gradually declined thereafter. A separate age- and sex-matched cross-sectional analysis (in 214 CHEU and 214 CHUU) illustrates that the difference in mtDNA between the groups remains detectable throughout the first 3 years of life.ConclusionThe persistently elevated blood mtDNA content observed among CHEU represents a long-term effect, possibly resulting from in utero stresses related to maternal HIV and/or cART. The clinical impact of altered mtDNA levels is unclear.