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Endothelin-1 (ET-1) contributes to declines in endothelial function in postmenopausal women. To our knowledge, we show for the first time that aerobic exercise reduces ET-1-mediated vasoconstriction in previously sedentary postmenopausal women. Moreover, aerobic exercise improved endothelial-dependent dilation due in part to the reductions in ET-1-mediated vasoconstriction.

Background: Medulloblastomas (MB) are the most common malignant brain tumors in the pediatric age. In 2021, WHO categorized medulloblastomas into two groups: molecularly defined and histologically defined medulloblastomas. Molecularly defined medulloblastomas are divided into WNTactivated medulloblastoma, SHH-activated and TP53-wildtype medulloblastoma, SHH-activated, and TP53-mutant and non-WNT/non-SHH medulloblastoma, which include Group 3 (MYC) and Group 4 (CDK6 and MYCN). In this paper, we will focus on molecularly defined medulloblastomas. Objective: This paper aims to review the literature in order to describe the molecular structure of the medulloblastoma groups and to emphasize the importance of genetic predictors in medulloblastoma that can be used in clinical practice, either as a prognostic tool or as a therapeutic target in the future. Results: Each molecular subtype of medulloblastoma presents a different prognosis, and the molecular subtype with the best prognosis is medulloblastoma-activated WNT. It has even been observed that a reduction in the intensity of the combined treatment does not modify the prognosis of the patients, resulting in even fewer adverse effects due to the treatment. On the other hand, it was observed that the subtypes with the worst prognosis are medulloblastomas with activated MYC and medulloblastomas with activated SHH and mutated TP53, due to their high capacity to metastasize or to their radio-resistance. However, a new target therapy has emerged that could help improve the prognosis in these patients. Conclusion: The deeper knowledge of the molecular pathways involved in the appearance and progression of medulloblastomas will allow us to offer a prognosis at the time of diagnosis and more specific treatments through the development of the targeted therapy.

Bullying is a type of youth violence and an adverse childhood experience that can result in trauma and have immediate and long-term consequences for all involved. It can happen at school or elsewhere - including online entertainment and social and learning environments. Some children are at increased risk for bullying victimization, such as those targeted because of their racial/ethnic background or cultural identity. This study assessed U.S. parents and caregivers' self-reported changes in concern about their children's involvement in bullying during Fall 2020 compared to the prior year, which was marked by extraordinary historical circumstances (e.g., COVID-19 pandemic, heightened awareness of racial inequities, schools transitioning to virtual learning). Secondary analyses of data from the 2020 Fall ConsumerStyles and

Background: Different studies, mostly with limited cohorts, have suggested the effects of patients’ characteristics on levodopa (LD) pharmacokinetics. Objective: We primarily aimed at investigating in a large population the relationship between patients’ features and LD kinetic variables, to assess the main demographic and clinical predictors of LD clinical pharmacokinetics. Methods: The study was retrospective, based on data collected from subjects with parkinsonism on chronic LD undergoing LD therapeutic monitoring (TM). LD TM includes serial quantitative motor tests and blood samples to measure plasma drug concentrations after each subject’s chronically taken first-morning LD dose intake. Results: Five hundred patients, 308 males (61.6%), mean (SD) age of 65 (10.1) years were included. Parkinsonian symptoms and LD therapy lasted 5.5 (4.5) and 3.4 (3.9) years, respectively. MDS-UPDRS part III “off” score was 28.8 (15.2). LD dose was 348.2 (187.1) mg/day. From multiple linear regression analysis, test dose, sex, type of LD decarboxylase inhibitor, weight and MDS-UPDRS part III score were linear predictors of both LD peak plasma concentration (Cmax) (R2 = 0.52) and area under the 3-h plasma concentration-time curve (AUC) (R2 = 0.71), while age was a further predictor only for AUC. Besides test dose, sex was the strongest independent contributing variable to LD AUC, which resulted 27% higher in females compared to males. Conclusion: This is the largest collection of data on the relationship between demographic and clinical-therapeutic variables and LD kinetics in patients with parkinsonian symptoms. As a main clinically practical finding, women might require a 25% reduced weight-normalized LD dose compared with men to achieve the same LD bioavailability.

Despite becoming increasingly represented in academic departments, women scholars face a critical lack of support as they navigate demands pertaining to pregnancy, motherhood, and child caregiving. In addition, cultural norms surrounding how faculty and academic leaders discuss and talk about tenure, promotion, and career success have created pressure for women who wish to grow their family and care for their children, leading to questions about whether it is possible for these women to have a family and an academic career. This paper is a call to action for academia to build structures that support professors who are women as they navigate the complexities of pregnancy, the postpartum period, and the caregiving demands of their children. We specifically call on those of us in I-O psychology, management, and related departments to lead the way. In making this call, we first present the realistic, moral, and financial cases for why this issue needs to be at the forefront of discussions surrounding success in the academy. We then discuss how, in the U.S. and elsewhere, an absence of policies supporting women places two groups of academics—department heads (as the leaders of departments who have discretion outside of formal policies to make work better for women) and other faculty members (as potential allies both in the department and within our professional organizations)—in a critical position to enact support and change. We conclude with our boldest call—to make a cultural shift that shatters the assumption that having a family is not compatible with academic success. Combined, we seek to launch a discussion that leads directly to necessary and overdue changes in how women scholars are supported in academia.

This position paper explores the needs of rural families of children, adolescents, and adults with autism spectrum disorder (ASD) during the COVID-19 pandemic. Prior to COVID-19, literature portrays elevated stress in families of individuals with ASD and health and socioeconomic disparities for rural and underserved populations. These disparities were exacerbated due to COVID-19 and subsequent lockdowns and economic turmoil. Academic and adaptive skills training were particularly impacted due to school closures, with parents tasked with taking some responsibility for training these skills. Our goals for this article focus on special considerations for rural families regarding (a) neurobiological and developmental impacts of stressful experiences like COVID-19, (b) delineation of the impacts on individuals with ASD and other comorbid and related conditions, and (c) education and intervention needs during these times. Finally, we offer suggestions for future care during pandemic events, including recommendations for improving service delivery under such conditions.

TCR diversity measures are often used to understand the immune response in cancer. Traditional measures of diversity rely on bulk RNA sequencing (RNAseq) of the β-chain variable regions. However, the full αβ TCR repertoire is a combination of both the α- and β-chains, which are encoded by separate genes. In contrast with bulk RNAseq, single-cell RNAseq (scRNAseq) allows paired chain analyses, yielding a more accurate measure of the repertoire. Interestingly, ∼30% of mature peripheral T cells express multiple TCR alleles (e.g., two α-chains) and may exhibit dual Ag specificity. scRNAseq has become increasingly common, and data from both human and animal studies are publicly available. However, routine workflows discard secondary TCR alleles and focus on a single TCR clone per cell. This perspectives piece emphasizes why this may not be good practice and highlights unanswered questions in the field of T cell dual specificity.

White dwarfs that accrete from non-degenerate companions show anomalous carbon and nitrogen abundances in the photospheres of their stellar components have been postulated to be descendants of supersoft X-ray binaries. Measuring the carbon-to-nitrogen abundance ratio may provide constraints on their past evolution. We fit far-ultraviolet spectroscopy of the cataclysmic variable HS 0218 + 3229 taken with the Cosmic Origins Spectrograph using Markov chain Monte Carlo methods, and found the carbon-to-nitrogen ratio is about one tenth of the Solar value $(\rm{\log \mathrm{[C/N]}}=-0.56\pm 0.15)$. We also provide estimates of the silicon and aluminium abundances, and upper limits for iron and oxygen. Using the parameters we derived for HS 0218 + 3229 we reconstruct its past. We calculated a grid of mesa models and implemented Gaussian process fits in order to determine its most likely initial binary configuration. We found that an initial mass of the donor of $M_{\rm donor;i}=0.90-0.98,\rm{\mathrm{M}_{\odot }}$ and an initial orbital period of Porb; i = 2.88 d (Porb; i = 3.12–3.16 d) for an assumed initial white dwarf mass of $\rm{M_{\mathrm{WD}}}_\mathrm{;i}=0.83\, \rm{\mathrm{M}_{\odot }}$$(\rm{M_{\mathrm{WD}}}_{\rm ;i}=0.60\, \rm{\mathrm{M}_{\odot }})$ can replicate the measured parameters. The low mass ratio, $M_{\rm donor;i} / \rm{M_{\mathrm{WD}}}_{\rm ;i} =1.08-1.18\, (1.5-1.63)$, suggests that the system did not go through a phase of hydrogen-burning on the white dwarf’s surface. However, we can not exclude a phase of thermal time-scale mass transfer in the past. We predict that HS 0218 + 3229 will evolve below the ≃ 76.2 ± 1 min period minimum for normal cataclysmic variables.

Purpose Patients with breast cancer (BC) face complex medical information and decisions. The Outcomes4Me mobile app provides evidence-based BC education, symptom management tracking and clinical trial matching. This study sought to evaluate the feasibility of introducing this app into routine BC care. Methods In this pilot study among BC patients undergoing therapy at an academic cancer center, patients were followed for 12 weeks with survey administration and electronic health record (EHR) abstraction at baseline and completion. Feasibility was defined as 40% of patients engaging with the app 3 or more times during the study. Additional endpoints included app usability (system usability scale), patient care experience, symptom evaluation, and clinical trial matching. Results The study enrolled 107 patients from 6/01/2020 to 3/31/2021. Utilization of the app was deemed feasible with 60% of patients engaging with the app at least 3 times. SUS score of 70 indicated above average usability. New diagnosis and higher education level was associated with greater app engagement, with usability similar across all age groups. 41% of patients found the app helped track symptoms. Cognitive and sexual symptoms were infrequently reported, but were more frequently captured in the app than in the EHR. After using the app, 33% of patients reported increased interest in clinical trial enrollment. Conclusion Introducing the Outcomes4Me patient navigation app into routine BC care is feasible and may improve the patient experience. These results support further evaluation of this mobile technology platform to improve BC education, symptom management, and decision making. Clinical trial registry Clinicaltrials.gov registration #: NCT04262518

Introduction MRI of excised hearts at ultra-high field strengths ($${\mathrm{B}}_{0}$$ B 0 ≥7 T) can provide high-resolution, high-fidelity ground truth data for biomedical studies, imaging science, and artificial intelligence. In this study, we demonstrate the capabilities of a custom-built, multiple-element transceiver array customized for high-resolution imaging of excised hearts. Method A dedicated 16-element transceiver loop array was implemented for operation in parallel transmit (pTx) mode (8Tx/16Rx) of a clinical whole-body 7 T MRI system. The initial adjustment of the array was performed using full-wave 3D-electromagnetic simulation with subsequent final fine-tuning on the bench. Results We report the results of testing the implemented array in tissue-mimicking liquid phantoms and excised porcine hearts. The array demonstrated high efficiency of parallel transmits characteristics enabling efficient pTX-based B1+-shimming. Conclusion The receive sensitivity and parallel imaging capability of the dedicated coil were superior to that of a commercial 1Tx/32Rx head coil in both SNR and T2*-mapping. The array was successfully tested to acquire ultra-high-resolution (0.1 × 0.1 × 0.8 mm voxel) images of post-infarction scar tissue. High-resolution (isotropic 1.6 mm3 voxel) diffusion tensor imaging-based tractography provided high-resolution information about normal myocardial fiber orientation.

Background Biallelic deletions at 15q15.3, including STRC and CATSPER2, cause autosomal recessive deafness-infertility syndrome (DIS), while biallelic deletions of STRC alone cause nonsyndromic hearing loss. These deletions are among the leading genetic causes of mild–moderate hearing loss, but their detection using chromosomal microarray (CMA) is impeded by a tandem duplication containing highly homologous pseudogenes. We sought to assess copy number variant (CNV) detection in this region by a commonly-employed CMA platform. Methods Twenty-two specimens with known 15q15.3 CNVs, determined by droplet digital PCR (ddPCR), were analyzed by CMA. To investigate the impact of pseudogene homology on CMA performance, a probe-level analysis of homology was performed, and log2 ratios of unique and pseudogene-homologous probes compared. Results Assessment of 15q15.3 CNVs by CMA compared to ddPCR revealed 40.9% concordance, with frequent mis-assignment of zygosity by the CMA automated calling software. Probe-level analysis of pseudogene homology suggested that probes with high homology contributed to this discordance, with significant differences in log2 ratios between unique and pseudogene-homologous CMA probes. Two clusters containing several unique probes could reliably detect CNVs involving STRC and CATSPER2, despite the noise of surrounding probes, discriminating between homozygous vs heterozygous losses and complex rearrangements. CNV detection by these probe clusters showed 100% concordance with ddPCR. Conclusions Manual analysis of clusters containing unique CMA probes without significant pseudogene homology improves CNV detection and zygosity assignment in the highly homologous DIS region. Incorporation of this method into CMA analysis and reporting processes can improve DIS diagnosis and carrier detection.

Background Encephalitis and myelitis have been linked to both COVID-19 vaccination and infection, causing symptoms such as reduced consciousness, mental state alterations and seizures. Remarkably, most cases do not show significant structural alterations on MRI scans, which poses a diagnostic challenge. Methods We present the diagnostic workup and clinical course of a patient who developed a progressive brainstem syndrome two weeks after COVID-19 vaccination and subsequent infection. We used translocator protein (TSPO)-PET scans for the first time to investigate COVID-related neuroinflammation. Results The patient developed oculomotor disorder, dysarthria, paresthesia in all distal limbs and spastic-atactic gait. CSF analysis revealed mild lymphocytic pleocytosis with normal protein levels. Brain and spinal cord MRI scans were negative, but TSPO/PET scans showed increased microglia activity in the brainstem, which correlated with the clinical course. Steroid treatment led to clinical improvement, but relapse occurred during prednisone taper after four weeks. Plasmapheresis had no significant effect; however, complete remission was achieved with cyclophosphamide and methotrexate, with normal TSPO signal ten months after onset. Conclusions TSPO-PET can be a valuable tool in the diagnostic and therapeutic monitoring of COVID-19-related encephalitis, particularly in cases where MRI scans are negative. Aggressive immunosuppressive therapy can lead to sustained remission.

Background: Children’s movement behaviors have been affected by the COVID-19 pandemic; however, little is known regarding movement behavior patterns over time by government-issued lockdowns. Our primary objective was to evaluate how children’s movement behaviors changed by stages of lockdown/reopening in Ontario, Canada, from 2020 to 2021. Methods: A longitudinal cohort study with repeated measures of exposure and outcomes was conducted. The exposure variables were dates from before and during COVID-19 when child movement behavior questionnaires were completed. Lockdown/reopening dates were included as knot locations in the spline model. The outcomes were daily screen, physical activity, outdoor, and sleep time. Results: A total of 589 children with 4805 observations were included (53.1% boys, 5.9 [2.6] y). On average, screen time increased during the first and second lockdowns and decreased during the second reopening. Physical activity and outdoor time increased during the first lockdown, decreased during the first reopening, and increased during the second reopening. Younger children (Conclusions: Policy makers should consider the impact of lockdowns on child movement behaviors, especially in younger children.

An asymmetric bis(silyl) niobocene hydride complex, namely, bis(η5-cyclopentadienyl)(fluorodimethylsilyl)hydrido(iododimethylsilyl)niobium, [Nb(C5H5)2(C2H6FSi)(C2H6ISi)H] or Cp2NbH(SiIMe2)(SiFMe2), has been studied to determine the effect of the silyl ligand on the position of the hydride attached to the Nb atom. It has been shown that when a Group 17 atom is substituted onto one of the silyl ligands, there is a greater interaction between the hydride and this ligand, as demonstrated by a shorter Si...H distance. In the present work, we have investigated the effect when the silyl ligands are substituted by different Group 17 atoms. We present here the structure and DFT calculations of Cp2NbH(SiIMe2)(SiFMe2), showing that the position of the hydride is located between the two silyl ligands. The results from our investigation show that the hydride is closer to the silyl ligand that is substituted by fluorine.

Intellectual disability (ID) is an early onset impairment in cognitive functioning and adaptive behavior, affecting approximately 1% of the population worldwide. Extreme deviations of X-chromosome inactivation (XCI) can be related to ID phenotypes caused by pathogenic variants in the X-chromosome. We analyzed the blood pattern of XCI in 194 women with idiopathic ID, using the androgen receptor gene (AR) methylation assay. Among the 136 patients who were informative, 11 patients (8%) presented with extreme or total XCI deviation (≥90%), which was significantly higher than the deviation expected by chance. Whole-exome data obtained from these 11 patients revealed the presence of dominant pathogenic variants in eight of them, all sporadic cases, resulting in a molecular diagnosis rate of 73%. All variants were mapped to ID-related genes with dominant phenotypes: four variants in the X-linked genes DDX3X (two patients), WDR45 and PDHA1), of which one is an XCI escape gene (DDX3X), and four variants in autosomal genes (KCNB1, CTNNB1, YY1, ANKRD11). Three of the autosomal genes had no obvious correlation with the observed XCI skewing. However, YY1 is a known transcriptional repressor that acts in the binding of the XIST long noncoding RNA on the inactive X chromosome, providing a mechanistic link between the pathogenic variant and the detected skewed XCI in the carrier. These data confirm that extreme XCI skewing in females with ID is highly indicative of causative X-linked pathogenic variants and point to the possibility of identifying causative variants in autosomal genes with a role in XCI.

ObjectiveTo determine whether frailty is associated with post-operative complications following surgery for vulvar cancer.MethodsThis retrospective study used a multi-institutional dataset from the National Surgical Quality Improvement Program (NSQIP) database (2014–2020) to analyze the relationship between frailty, procedure type, and post-operative complications. Frailty was determined using the modified frailty index-5 (mFI-5). Univariate and multivariable-adjusted logistic regression analyses were performed.ResultsOf 886 women, 49.9% underwent radical vulvectomy alone, and 19.5% and 30.6% underwent concurrent unilateral or bilateral inguinofemoral lymphadenectomy, respectively; 24.5% had mFI ≥2 and were considered frail. Compared with non-frail women, those with an mFI ≥2 were more likely to have an unplanned readmission (12.9% vs 7.8%, p=0.02), wound disruption (8.3% vs 4.2%, p=0.02), and deep surgical site infection (3.7% vs 1.4%, p=0.04). On multivariable-adjusted models, frailty was a significant predictor for minor (OR 1.58, 95% CI 1.09 to 2.30) and any complications (OR 1.46, 95% CI 1.02 to 2.08). Specifically, for radical vulvectomy with bilateral inguinofemoral lymphadenectomy, frailty was significantly associated with major (OR 2.13, 95% CI 1.03 to 4.40) and any complications (OR 2.10, 95% CI 1.14 to 3.87).ConclusionIn this analysis of the NSQIP database, nearly 25% of women undergoing radical vulvectomy were considered frail. Frailty was associated with increased post-operative complications, especially in women concurrently undergoing bilateral inguinofemoral lymphadenectomy. Frailty screening prior to radical vulvectomy may assist in patient counseling and improve post-operative outcomes.

Correctly spelling an English word requires a high-quality orthographic representation. When faced with spelling a complex word without a high-quality representation, spellers often rely on other knowledge sources (e.g., incomplete stored orthographic forms, phonological to orthographic relationships) to spell it. For bilinguals, another potentially facilitative source is knowledge of a word's lexical and sublexical representations in another language. In the current study we considered simultaneous effects of word-level (e.g., frequency, cognate status) and person-level (e.g., English spelling skill, prompting, bilingual status) predictors on college students’ complex English word spelling. Monolinguals (English; n = 42) significantly outperformed bilinguals (Spanish and English; n = 76) on non-cognate spelling; no group differences emerged for cognate spelling accuracy. Within bilinguals, significantly higher spelling performance on cognates compared to non-cognates suggests cognate facilitation, with no prompting effects. Findings expand an interdisciplinary framework of understanding bilinguals’ activation and use of cross-linguistic representations in spelling.

Background: The introduction of immune checkpoint inhibitors (ICI) to standard neoadjuvant chemotherapy regimens has been shown to significantly improve outcomes in patients with triple negative breast cancer and is being investigated for high-risk hormone receptor-positive (HR+)/human epidermal growth factor-2 negative (HER2-) breast cancer. Preclinical evidence suggests radiation therapy (RT) can stimulate intra-tumoral T cell infiltration and enhance the expression and immune detection of tumor-specific neoantigens. This phase II pilot randomized study (NCT04443348) aims to evaluate the safety and efficacy of two different doses of preoperative primary tumor RT boost when combined with neoadjuvant pembrolizumab, then followed by standard neoadjuvant chemotherapy. Dual co-primary endpoints include determining the pathologic complete response (pCR) rate in the non-irradiated and pathologically confirmed metastatic axillary lymph node(s) in each treatment arm and quantifying tumor-infiltrating T lymphocytes in on-treatment (C1D14) tumor biopsies. We hypothesize that high-dose RT will increase the proportion of tumors with high T cell infiltration (i.e., top quartile) from 25% to 55%. Secondary endpoints include measuring residual cancer burden, evaluating tolerability of the regimen, and assessing quality of life. Exploratory endpoints include evaluation of treatment-associated changes in the tumor immune microenvironment, circulating immune cell analyses, and circulating tumor DNA kinetics. Methods: The study plans to enroll 128 participants with either triple negative (n=80) or high-risk HR=/HER2- (n=48) breast cancer who will be randomized to receive no, low (9 Gy), or high (24 Gy) dose of preoperative RT boost, after which 24 participants of either breast cancer subtype will be enrolled to an exploratory high dose proton therapy boost cohort. The eligibility criteria include patients who have biopsy-proven, axillary lymph node-positive breast cancer that is either triple negative (defined as ER< 10%, PR< 10%, and HER2-negative) or high-risk HR+/HER2- (grade III or having a high-risk genomic assay score). Study treatment is given in 6-week cycles, with 400 mg Pembrolizumab given on day 1 of each cycle. For those participants randomized to receive a preoperative RT boost, treatment is delivered in 3 fractions (3 × 3 Gy or 3 × 8 Gy) over consecutive business days, where one of the fractions is given on the same day as C1D1 Pembrolizumab. Standard neoadjuvant chemotherapy begins on C1D15 with paclitaxel (plus carboplatin for triple negative) administered weekly for 12 weeks, and then starting on C3D15, dose-dense doxorubicin/cyclophosphamide is administered every 2 weeks for 8 weeks. Following neoadjuvant treatment, participants will receive standard breast surgery (including removal of the pathologically confirmed metastatic lymph node) followed by adjuvant pembrolizumab, radiation therapy, and standard-of-care systemic therapy as clinically indicated. Tissue samples from the primary tumor and biopsy-proven lymph node are taken at baseline, C1D14, and at the time of surgery. There are eleven blood collection timepoints throughout the neoadjuvant and adjuvant settings. Participants will be followed for 2 years after surgery to assess safety and durability of responses. Results: This study has accrued 12 participants to date, including 10 with triple negative breast cancer and 2 with high-risk HR+/HER2- breast cancer. Formal results for this study are forthcoming, as the trial is actively accruing at 6 institutions, with plans to open at 3 more within the year. For persons with a specific interest in this trial, please contact Joseph Connolly, Multi-Center Coordinator, at jconnolly28@mgh.harvard.edu. Citation Format: Joseph J. Connolly, Laura M. Spring, Alphonse G. Taghian, Michele Gadd, Laura Warren, Ana C. Garrido-Castro, Tari King, Elizabeth A. Mittendorf, Jose P. Leone, Dana L. Casey, Lisa Carey, Tiffany A. Traina, Yara Abdou, Atif Khan, George Plitas, Jean Wright, Cesar Augusto Santa-Maria, Lisa Jacobs, Rachel Blitzblau, E Shelley Hwang, Carey Anders, Ian Krop, Antonio C. Wolff, Alastair M. Thompson, Elyssa Denault, Gaorav Gupta, Alice Ho. TBCRC-053: P-RAD: A Randomized Study of Preoperative Chemotherapy, Pembrolizumab and No, Low or High Dose RADiation in Node-Positive, HER2-Negative Breast Cancer [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 OT3-15-01.

Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) provide significant clinical benefit in patients with HR+/HER2- metastatic breast cancer (MBC) and have become a standard of care treatment. Prior insights from tumor profiling and preclinical analyses suggest that AKT1 activation can induce CDK4/6i resistance. We hypothesized that targeting AKT1 following CDK4/6i progression may be an effective therapeutic strategy and conducted a clinical trial to evaluate both doublet (ET+AKTi) and triplet (ET+AKTIi+CDK 4/6i) therapy in the ≥ 2nd line MBC setting. Methods: TAKTIC is an open-label phase Ib clinical trial (clinicaltrials.gov NCT03959891) evaluating the combination of the AKT inhibitor ipatasertib (ipat) with fulvestrant (Arm A), an aromatase inhibitor (Arm B), or the triplet combination (Arm C) with fulvestrant + palbociclib (palbo). The primary objective is to evaluate the safety (NCI CTCAE 5.0) and tolerability of ipat in combination with endocrine therapy +/- CDK4/6i. Secondary objectives include clinical efficacy, as determined by objective response rate (RECIST v1.1), clinical benefit rate (CBR), progression-free survival (PFS), and overall survival (OS). Key inclusion criteria include unresectable HR+/HER2- MBC; at least 1 prior therapy for MBC including any CDK4/6i; up to 2 prior lines of chemotherapy for MBC (no limit on prior endocrine therapy). Here, we present an updated interim analysis from all study arms. Results: The trial completed accrual with 77 pts enrolled from June 2019 – February 2022, including 19 on Arm A, 16 on Arm B, and 42 on Arm C. Median age was 62 (range 32-88) and 65/77 pts (84%) received prior CDK4/6i (median no. of prior lines = 3, range 1-13). 56/77 pts (73%) had measurable disease at baseline and 50/77 pts (65%) had visceral metastases in the liver/lung (68% Arm A, 44% Arm B, 71% Arm C). Pts enrolled on Arms A and B received ipat at 400mg in combination with fulvestrant or an aromatase inhibitor, respectively. In Arm C, 27/42 pts enrolled into the dose escalation phase and received ipat + palbo at varying doses in combination with fulvestrant. Two DLTs were observed in the 300mg ipat + 125mg palbo cohort (grade 4 neutropenia ≥ 7 days). ET+400mg ipat + 100mg palbo was determined to be the recommended phase 2 dose (R2PD), and the remaining 15/42 pts on Arm C were treated at this dose level in the expansion phase. Treatment was well tolerated in all arms. Grade 3 and 4 toxicities included neutropenia (39/77, 50.6%), leukopenia (15/77, 19.5%), diarrhea (11/77, 14/3%), transaminitis (7/77, 9.1%), lymphopenia (6/77, 7.8%), rash (6/77, 7.8%), and thrombocytopenia (3/77, 3.9%). As of 6/28/2022, 16/77 pts remain on treatment. The median treatment duration for all pts is estimated at 6 months (range 0.5-39). Among the 56 pts with measurable disease, 11 had partial response (PR) and 32 had stable disease (SD) as the best response. CBR, defined as percentage of pts who achieved PR or SD > 6 months, was 48% across the study (53% Arm A, 31% Arm B, 57% Arm C). The median PFS was 5.5 months (95% confidence interval [CI]: 3.8 – 7.4) and the median OS was 24.5 months (95% CI: 17.1 – 33.9). Conclusions: The combination of ipat with endocrine therapy +/- palbo is well tolerated in heavily pre-treated pts, with preliminary evidence of clinical activity. This trial demonstrates how molecular insights related to CDK4/6i resistance inform potential therapy combinations. Further studies are needed to evaluate AKTi-based combinations in pts with HR+ MBC. Citation Format: Seth A. Wander, Jennifer C. Keenan, Andrzej Niemierko, Dejan Juric, Laura M. Spring, Jeffrey Supko, Neelima Vidula, Steven J. Isakoff, Lianne Ryan, Sarah Padden, Elizabeth Fisher, Amber Newton, Beverly Moy, Leif Ellisen, Douglas S. Micalizzi, Aditya Bardia. PD13-07 Combination therapy with the AKT inhibitor, ipatasertib, endocrine therapy, and a CDK4/6 inhibitor for hormone receptor positive (HR+)/HER2 negative metastatic breast cancer (MBC): results from the phase I TAKTIC trial [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 PD13-07.

Background: The gut microbiome modulates response and resistance to immune checkpoint inhibitors (ICI) across different cancer types. The objective of this study was to explore the association between fecal microbiome profiles and clinical outcomes in patients with hormone receptor-positive (HR+) metastatic breast cancer (MBC) treated with eribulin (E) + pembrolizumab (P) or E alone as part of a randomized phase II study (NCT03051659). Patients and Methods: Metagenomic shotgun sequencing was performed on fecal samples collected prior to randomization from a subset of 26 participating patients (E+P, n = 15; E, n = 11) collected prior to randomization. Sequencing data were processed with MetaPhlAn3 to obtain diversity scores and taxonomic composition profiles. Associations between microbiome diversity, taxonomic composition, and clinical outcomes including survival metrics were assessed using Kaplan-Meier estimation methods and Cox proportional hazard models. Results: In this subset, median follow-up was 21.6 months and median overall survival (OS) was 17.9 months. OS was not statistically significant between two treatment arms as observed in the overall cohort. Metagenomic microbiome analysis revealed higher alpha diversity by inverse Simpson Index values associated with longer survival among all patients (p = 0.004), and in patients in the E + P arm (p = 0.006) but not in the E arm (p = 0.2). At the taxonomic level, longer OS among all patients was associated with a baseline lower relative abundance of Blautia wexlerae (≤0.2%vs >0.2%) (22.1 vs 16.6 months; p = 0.01) and a higher relative abundance of Odoribacter splanchnicus, a common short-chain fatty acid producing gut bacterium (>0.35% vs ≤0.35%) (22.3 vs 11.3 months; p < 0.0001). These associations remained significant after controlling for age, ECOG-PS status, and use or not of prior lines of chemotherapy in the metastatic setting. Conclusions: These results suggest high diversity and composition of the gut microbiome are associated with prolonged OS in HR+ MBC pts receiving eribulin with pembrolizumab. Additional and larger clinical studies are needed to validate these findings and preclinical models are needed to interrogate the mechanisms by which gut microbiome diversity and composition may impact therapeutic response and clinical outcomes in this patient population. Citation Format: Romualdo Barroso-Sousa, Tianyu Li, Ashish V. Damania, Molly K. DiLullo, Tanya Keenan, Gerburg M. Wulf, Laura M. Spring, Elizabeth A. Mittendorf, Jennifer A. Ligibel, Nadim J. Ajami, Jennifer Wargo, Nabihah Tayob, Sara Tolaney. PD11-05 Gut microbiome signatures correlate with overall survival among patients receiving eribulin with or without pembrolizumab for hormone receptor-positive metastatic breast cancer [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 PD11-05.

Increased access to legalized non-medical cannabis has led to growing concern over the potential adverse health impacts of cannabis consumption among youth and emerging adults. This study explored emerging adult perceptions of cannabis consumption and if perceptions changed based on the age and sex of the cannabis consumer.Canadian emerging adults between the ages of 18 and 25 years (N = 1,424, Mean = 21.23) were randomly assigned to one of six vignettes that varied by age (14 years, 21 years, and 28 years) or sex (male, female) of the cannabis consumer. Participants were asked to rate seven single-item measures on perceived dangerousness, problematic consumption, negative impacts, and level of disapproval related to the vignette character's almost daily cannabis consumption.The results of seven 2 × 3 factorial analyses of variance revealed a main effect of age on six of seven items, no main effects of sex, and no interactions. Except for social life, participants noted significant differences in harms of cannabis consumption by 14-year-olds, compared to 21-year-olds and 28-year-olds. There were no significant differences in overall perceived dangerousness, problematic consumption, or impact on mental or cognitive health between 21-year-olds and 28-year-olds. Participants perceived cannabis consumption by a 21-year-old to be more harmful to brain development and reported greater disapproval than consumption by a 28-year-old.Emerging adults may appreciate the impacts of cannabis consumption within their age cohort on brain development and perceive greater risks for youth. Further education should focus on the potential cognitive and mental health impacts of cannabis in emerging adults.

Background: Clinical outcomes in breast cancer differ across racial and ethnic populations. We have previously demonstrated that receipt of genotype-matched therapy targeted to an actionable mutation may potentially improve patient outcomes (Vidula, CCR, 2021). We evaluated the impact of race on clinical, socioeconomic, and genomic characteristics, clinical trial participation, and receipt of genotype-matched therapy among patients with metastatic breast cancer (MBC). Methods: We conducted a retrospective study of patients with MBC at an academic institution who underwent cell-free DNA testing (cfDNA, Guardant360, 74 gene panel) as part of routine clinical care from 11/29/2016-11/2/2020. Patient demographics (including self-reported race and ethnicity) and clinical trial enrollment (at same institution) were determined by retrospective data collection. Mutations identified in cfDNA were characterized as actionable based on the variant interpretation performed by Guardant360 using vetted genomic databases, and receipt of genotype-matched therapy targeted to an actionable mutation was determined as previously described (Vidula, CCR, 2021). Pearson’s chi-squared and Wilcoxon rank-sum tests were used to compare categorical and continuous variables between groups, with p< 0.05 indicating statistical significance. Results: Four hundred and twenty-five patients with MBC and cfDNA results were identified, of which 369 were White (87%), 27 Black (6.4%), 15 Hispanic (3.5%), and 14 Asian (3.3%). There were no significant differences in median age at MBC diagnosis (p=0.064), disease subtype distribution (p=0.74), proportions of de-novo/recurrent MBC (p=0.95), presence of visceral metastases (p=0.84), Charleston comorbidity index (p=0.93), menopausal status (p=0.3), and level of education (p=0.44) across racial groups. Higher proportions of non-primary English speakers were seen in Hispanic (80%) and Asian (29%) races (p< 0.001). Median distance traveled to the institution also varied based on race, with White patients traveling further (White: 39.1 miles, Black: 21.8 miles, Hispanic 9.4 miles, Asian 9.1 miles, p< 0.001). In addition, type of insurance varied based on race, with White patients having the highest rates of commercial insurance and Medicare, Black patients having the highest rate of state-supported insurance, and Asian patients having the highest uninsured rates (p< 0.001). Clinical trial enrollment rates did not significantly differ by race (White: 44%, Black: 37%, Hispanic: 47%, and Asian 21%, p=0.34), but patients without insurance were significantly less likely to be enrolled on a trial than those with commercial insurance (p=0.03). The proportion of patients with ≥1 actionable mutation in cfDNA did not vary significantly by race (White: 78%, Black: 56%, Hispanic: 73%, Asian 86%, p=0.18) and the median number of actionable mutations found in cfDNA was similar across races (p=0.31). However, receipt of genotype-matched therapy targeted to an actionable mutation varied by race, with the highest rates of matched therapy in White patients (White: 28%, Black: 11%, Hispanic 13%, Asian 14%, p< 0.001). After multivariable logistic regression adjusting for subtype, commercial insurance versus other insurance types, and proximity to the center, White patients remained significantly more likely to receive matched therapy (p=0.029). Conclusions: We observed significant race-based differences in non-English speaking status, insurance type, and median distance traveled to the institution. Racial/ethnic minority patients were less likely to receive genotype-matched therapy than White patients. Further research is needed to identify barriers and reduce disparities in access to precision medicine. Citation Format: Rupali Sood, Lianne Ryan, Andrzej Niemierko, Laura M. Spring, Dejan Juric, Steven J. Isakoff, Seth A. Wander, Jennifer Shin, Naomi Ko, Leif Ellisen, Beverly Moy, Aditya Bardia, Neelima Vidula. Impact of Race on Clinical, Socioeconomic, and Genomic Characteristics, Clinical Trial Participation, and Receipt of Genotype-matched Therapy Among Patients with Metastatic Breast Cancer [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 PD1-10.