A Measurement Invariance Analysis of the Anxiety Scale for Autism-Adults in a Sample of Autistic and Non-Autistic Men and Women.

The Anxiety Scale for Autism-Adults (ASA-A) captures the autistic anxiety experience, but we do not know whether it is structurally equivalent for men and women, or non-autistic people. Measurement invariance analysis considered gender and diagnostic status (342 cis-gender autistic men (N = 105) and women (N = 237), 316 cis-gender non-autistic men (N = 104) and women (N = 212)). Strict invariance was achieved between autistic men and women and between non-autistic men and women, but the ASA-A structure is quantitatively different in autistic compared to non-autistic adults. Therefore, this tool cannot be used to directly compare anxiety between these groups. Autistic women scored significantly higher on the ASA-A than autistic men and Uncertainty was the highest scoring factor for autistic participants. Future research should include alternative gender identities.

Assessment of efficacy and safety of dose-dense doxorubicin and cyclophosphamide (ddAC) in combination with immunotherapy in early-stage triple-negative breast cancer.

PURPOSE: This study aimed to assess safety and efficacy of a modified KEYNOTE 522 protocol, which incorporated pembrolizumab every 6 weeks, allowing for concomitant dose-dense (14 day) doxorubicin and cyclophosphamide (ddAC). By optimizing this dosing, the intention of this modified protocol was to improve pathologic complete response (pCR) rates in a population associated with a poorer prognosis. METHODS: This was a retrospective, single-center, cohort study. Patients were included if they had early stage, triple-negative breast cancer, and received at least one dose of AC. The entire cohort received neoadjuvant chemotherapy including weekly carboplatin and paclitaxel with pembrolizumab every 3 weeks for 12 weeks (4 cycles). The group then received either ddAC with pembrolizumab 400 mg every 6 weeks, or AC with pembrolizumab 200 mg every 3 weeks. The primary objective was pCR rate at time of surgery. RESULTS: This study assessed outcomes in 25 patients over 34 months. The pCR rate in the pembrolizumab, AC 3-week cohort was 64.3% versus 81.8% in the ddAC and 6-week pembrolizumab group. No pembrolizumab-associated grade 3-4 adverse events occurred in the either cohort. Despite seeing an increased incidence of grade 3-4 toxicities in the ddAC arm, this did not result in additional chemotherapy delays or dose reductions. CONCLUSION: This study demonstrated tolerability and a potential for favorable outcomes with this patient population, making this modified KEYNOTE 522 protocol a reasonable treatment approach. Larger, prospective studies are warranted to assess the feasibility of this dosing and true optimization of patient outcomes given the small sample size of this study.

Generalisation of Social Communication Skills by Autistic Children During Play-Based Assessments Across Home, School and an Unfamiliar Research Setting.

We investigated autistic children's generalisation of social communication over time across three settings during a play-based assessment with different adults and explore the potential moderating effects on generalisation of age, nonverbal IQ and level of restricted and repetitive behaviours. The social communication abilities of 248 autistic children (2-11 years, 21% female, 22% single parent, 60% white) from three UK sites were assessed from 1984 video interactions in three contexts with three different interaction partners (parent/home, teaching assistant/school, researcher/clinic) at baseline, midpoint (+ 7m) and endpoint (+ 12m) within the Paediatric Autism Communication Trial-Generalised (PACT-G), a parent-mediated social communication intervention. Children's midpoint social communication at home generalised to school at midpoint and to clinic at endpoint. Generalisation was stronger from home to school and clinic than school to home and clinic. Generalisation was not moderated by age, nonverbal IQ or restricted and repetitive behaviour. Broader child development did not explain the pattern of results. The current study is the largest study to date to explore generalisation with autistic children and provides novel insight into their generalisation of social communication skills. Further research is needed to gain a more comprehensive understanding of facilitators of generalisation across settings and interaction partners in order to develop targeted strategies for interventions to enhance outcomes for young autistic children.

Vaccination of Adults With Cancer: ASCO Guideline.

PURPOSE: To guide the vaccination of adults with solid tumors or hematologic malignancies. METHODS: A systematic literature review identified systematic reviews, randomized controlled trials (RCTs), and nonrandomized studies on the efficacy and safety of vaccines used by adults with cancer or their household contacts. This review builds on a 2013 guideline by the Infectious Disease Society of America. PubMed and the Cochrane Library were searched from January 1, 2013, to February 16, 2023. ASCO convened an Expert Panel to review the evidence and formulate recommendations. RESULTS: A total of 102 publications were included in the systematic review: 24 systematic reviews, 14 RCTs, and 64 nonrandomized studies. The largest body of evidence addressed COVID-19 vaccines. RECOMMENDATIONS: The goal of vaccination is to limit the severity of infection and prevent infection where feasible. Optimizing vaccination status should be considered a key element in the care of patients with cancer. This approach includes the documentation of vaccination status at the time of the first patient visit; timely provision of recommended vaccines; and appropriate revaccination after hematopoietic stem-cell transplantation, chimeric antigen receptor T-cell therapy, or B-cell-depleting therapy. Active interaction and coordination among healthcare providers, including primary care practitioners, pharmacists, and nursing team members, are needed. Vaccination of household contacts will enhance protection for patients with cancer. Some vaccination and revaccination plans for patients with cancer may be affected by the underlying immune status and the anticancer therapy received. As a result, vaccine strategies may differ from the vaccine recommendations for the general healthy adult population vaccine.Additional information is available at www.asco.org/supportive-care-guidelines.

Giredestrant for Estrogen Receptor-Positive, HER2-Negative, Previously Treated Advanced Breast Cancer: Results From the Randomized, Phase II acelERA Breast Cancer Study.

PURPOSE: To compare giredestrant and physician's choice of endocrine monotherapy (PCET) for estrogen receptor-positive, HER2-negative, advanced breast cancer (BC) in the phase II acelERA BC study (ClinicalTrials.gov identifier: NCT04576455). METHODS: Post-/pre-/perimenopausal women, or men, age 18 years or older with measurable disease/evaluable bone lesions, whose disease progressed after 1-2 lines of systemic therapy (≤1 targeted, ≤1 chemotherapy regimen, prior fulvestrant allowed) were randomly assigned 1:1 to giredestrant (30 mg oral once daily) or fulvestrant/aromatase inhibitor per local guidelines (+luteinizing hormone-releasing hormone agonist in pre-/perimenopausal women, and men) until disease progression/unacceptable toxicity. Stratification was by visceral versus nonvisceral disease, prior cyclin-dependent kinase 4/6 inhibitor, and prior fulvestrant. The primary end point was investigator-assessed progression-free survival (INV-PFS). RESULTS: At clinical cutoff (February 18, 2022; median follow-up: 7.9 months; N = 303), the INV-PFS hazard ratio (HR) was 0.81 (95% CI, 0.60 to 1.10; P = .1757). In the prespecified secondary end point analysis of INV-PFS by ESR1 mutation (m) status in circulating tumor DNA-evaluable patients (n = 232), the HR in patients with a detectable ESR1m (n = 90) was 0.60 (95% CI, 0.35 to 1.03) versus 0.88 (95% CI, 0.54 to 1.42) in patients with no ESR1m detected (n = 142). Related grade 3-4 adverse events (AEs), serious AEs, and discontinuations due to AEs were balanced across arms. CONCLUSION: Although the acelERA BC study did not reach statistical significance for its primary INV-PFS end point, there was a consistent treatment effect with giredestrant across most key subgroups and a trend toward favorable benefit among patients with ESR1-mutated tumors. Giredestrant was well tolerated, with a safety profile comparable to PCET and consistent with known endocrine therapy risks. Overall, these data support the continued investigation of giredestrant in other studies.

CDK4/6i-treated HR+/HER2- breast cancer tumors show higher ESR1 mutation prevalence and more altered genomic landscape.

As CDK4/6 inhibitor (CDK4/6i) approval changed treatment strategies for patients with hormone receptor-positive HER2-negative (HR+/HER2-) breast cancer (BC), understanding how exposure to CDK4/6i affects the tumor genomic landscape is critical for precision oncology. Using real-world data (RWD) with tumor genomic profiling from 5910 patients with metastatic HR+/HER2- BC, we investigated the evolution of alteration prevalence in commonly mutated genes across patient journeys. We found that ESR1 is more often altered in tumors exposed to at least 1 year of adjuvant endocrine therapy, contrasting with TP53 alterations. We observed a similar trend after first-line treatments in the advanced setting, but strikingly exposure to aromatase inhibitors (AI) combined with CDK4/6i led to significantly higher ESR1 alteration prevalence compared to AI alone, independent of treatment duration. Further, CDK4/6i exposure was associated with higher occurrence of concomitant alterations in multiple oncogenic pathways. Differences based on CDK4/6i exposure were confirmed in samples collected after 2L and validated in samples from the acelERA BC clinical trial. In conclusion, our work uncovers opportunities for further treatment personalization and stresses the need for effective combination treatments to address the altered tumor genomic landscape following AI+CDK4/6i exposure. Further, we demonstrated the potential of RWD for refining patient treatment strategy and guiding clinical trial design.

UGT1A4 Polymorphism is not Associated with a Clinically Relevant Change in Giredestrant Exposure.

PURPOSE: Giredestrant is a potent, orally bioavailable, small-molecule selective estrogen receptor antagonist and degrader (SERD) that is being developed for the treatment of patients with estrogen receptor (ER)-positive breast cancer. In vitro, giredestrant was primarily metabolized by UGT1A4. The goal of this study was to investigate if UGT1A4 polymorphism had a clinically relevant impact on giredestrant exposure. METHODS: Genotyping and pharmacokinetic data were obtained from 118 and 61 patients in two clinical studies, GO39932 [NCT03332797] and acelERA Breast Cancer [NCT04576455], respectively. RESULTS: The overall allelic frequencies of UGT1A4*2 and UGT1A4*3 were 3.3% and 11%, respectively. Giredestrant exposure was consistent between patients with wild-type UGT1A4 and UGT1A4*2 and *3 polymorphisms, with no clinically relevant difference observed. In addition, haplotype analysis indicated that no other UGT1A4 variants were significantly associated with giredestrant exposure. CONCLUSION: Therefore, this study indicates that UGT1A4 polymorphism status is unlikely a clinically relevant factor to impact giredestrant exposure and giredestrant can be administered at the same dose level regardless of patients' UGT1A4 polymorphism status.

Managing hyperglycemia and rash associated with alpelisib: expert consensus recommendations using the Delphi technique.

Hyperglycemia and rash are expected but challenging adverse events of phosphatidylinositol-3-kinase inhibition (such as with alpelisib). Two modified Delphi panels were conducted to provide consensus recommendations for managing hyperglycemia and rash in patients taking alpelisib. Experts rated the appropriateness of interventions on a 1-to-9 scale; median scores and dispersion were used to classify the levels of agreement. Per the hyperglycemia panel, it is appropriate to start alpelisib in patients with HbA1c 6.5% (diabetes) to <8%, or at highest risk for developing hyperglycemia, if they have a pre-treatment endocrinology consult. Recommend prophylactic metformin in patients with baseline HbA1c 5.7% to 6.4%. Metformin is the preferred first-line anti-hyperglycemic agent. Per the rash panel, initiate prophylactic nonsedating H1 antihistamines in patients starting alpelisib. Nonsedating H1 antihistamines and topical steroids are the preferred initial management for rash. In addition to clinical trial evidence, these recommendations will help address gaps encountered in clinical practice.

Phase Ia/b Study of Giredestrant ± Palbociclib and ± Luteinizing Hormone-Releasing Hormone Agonists in Estrogen Receptor-Positive, HER2-Negative, Locally Advanced/Metastatic Breast Cancer.

PURPOSE: Giredestrant is an investigational next-generation, oral, selective estrogen receptor antagonist and degrader for the treatment of estrogen receptor-positive (ER+) breast cancer. We present the primary analysis results of the phase Ia/b GO39932 study (NCT03332797). PATIENTS AND METHODS: Patients with ER+, HER2-negative locally advanced/metastatic breast cancer previously treated with endocrine therapy received single-agent giredestrant (10, 30, 90, or 250 mg), or giredestrant (100 mg) ± palbociclib 125 mg ± luteinizing hormone-releasing hormone (LHRH) agonist. Detailed cardiovascular assessment was conducted with giredestrant 100 mg. Endpoints included safety (primary), pharmacokinetics, pharmacodynamics, and efficacy. RESULTS: As of January 28, 2021, with 175 patients enrolled, no dose-limiting toxicity was observed, and the MTD was not reached. Adverse events (AE) related to giredestrant occurred in 64.9% and 59.4% of patients in the single-agent ± LHRH agonist and giredestrant + palbociclib ± LHRH agonist cohorts, respectively (giredestrant-only-related grade 3/4 AEs were reported in 4.5% of patients across the single-agent cohorts and 3.1% of those with giredestrant + palbociclib). Dose-dependent asymptomatic bradycardia was observed, but no clinically significant changes in cardiac-related outcomes: heart rate, blood pressure, or exercise duration. Clinical benefit was observed in all cohorts (48.6% of patients in the single-agent cohort and 81.3% in the giredestrant + palbociclib ± LHRH agonist cohort), with no clear dose relationship, including in patients with ESR1-mutated tumors. CONCLUSIONS: Giredestrant was well tolerated and clinically active in patients who progressed on prior endocrine therapy. Results warrant further evaluation of giredestrant in randomized trials in early- and late-stage ER+ breast cancer.

Exploring the mediating effect of camouflaging and the moderating effect of autistic identity on the relationship between autistic traits and mental wellbeing.

Mental health difficulties are prevalent among autistic adults. Camouflaging (behaving differently to fit in) may be a mechanism by which autistic traits and mental health difficulties relate to each other, but little research has considered the role of different facets of camouflaging. Additionally, autistic identity might buffer against camouflaging and mental health difficulties. This research aims to explore the mediating effects of camouflaging behaviours on the relationship between autistic traits and both positive and negative mental wellbeing, as well as how autistic identity might moderate the relationship between autistic traits and camouflaging, and also mental health. Data were available for 627 autistic adults, recruited through volunteer databases and social media. Participants completed measures of autistic traits, anxiety, depression, positive wellbeing, camouflaging behaviours (compensating for difficulties, masking, and assimilating/putting on an act) and autistic identity. Mediation and moderated mediation models were tested, applying 95% bootstrapped CIs (10,000 resamples) and including age, gender and diagnosis as covariates. There were no significant direct effects between autistic traits and mental wellbeing. Assimilation was a significant mediator of all mental wellbeing measures, and compensation was a significant mediator of positive wellbeing only. Autistic identity was not a significant moderator. Assimilation and compensation should be considered when offering psychological interventions to support mental wellbeing of autistic people. Additional research into external drivers of camouflaging (e.g. stigma) and mechanisms by which camouflaging impacts mental wellbeing, such as autonomy, authenticity, skill mastery and community, may identify other areas of support. Concurrently, societal change is necessary to reduce the need to camouflage.

Inclusion of person-centred care in UK postgraduate medical education curricula: Interviews and documentary analysis.

BACKGROUND: Person-centred care (PCC) involves placing people at the centre of their healthcare decision making to ensure it meets their needs, values, and personal circumstances. Increasingly, PCC is promoted in healthcare policy and guidance, but little is known about how this is embedded in postgraduate medical training. The aim of this research was to understand how PCC is embedded in UK postgraduate medical training and explore factors influencing inclusion of PCC in curricula content. METHODS: To explore this, we interviewed senior professionals with key roles in the curricula from four UK Royal Colleges (Psychiatrists; Physicians; Surgeons; and GPs) and used framework analysis on interviews and relevant curricula documents to identify themes. RESULTS: Legislation and professional/educational guidance influenced inclusion. PCC definitions and terminology differed and placement within curricula was variable. Royal Colleges defined the curriculum and provided training to ensure competence, but local deaneries independently implemented the curriculum. Trainer engagement was greater than trainee buy in. Quality assurance focused on feedback from trainers and trainees rather than patients, and patient and public involvement in curriculum development, teaching, and assessment was limited. CONCLUSIONS: There is a need for cross-organisation collaboration to develop a PCC competence framework that defines the skills and level of competence required at different points in training, with clarity around the differences between undergraduate and postgraduate requirements. Greater auditing and quality assurance of programme delivery would help identify successful practices to share within and across Royal Colleges, while still maintaining the flexibility of local provision. Engagement with patients and the public in this work can only strengthen provision.

Neoadjuvant palbociclib plus either giredestrant or anastrozole in oestrogen receptor-positive, HER2-negative, early breast cancer (coopERA Breast Cancer): an open-label, randomised, controlled, phase 2 study.

BACKGROUND: The development of more potent selective oestrogen receptor antagonists and degraders (SERDs) that can be orally administered could help to address the limitations of current endocrine therapies. We report the primary and final analyses of the coopERA Breast Cancer study, designed to test whether giredestrant, a highly potent, non-steroidal, oral SERD, would show a stronger anti-proliferative effect than anastrozole after 2 weeks for oestrogen receptor-positive, HER2-negative, untreated early breast cancer. METHODS: In this open-label, randomised, controlled, phase 2 study, postmenopausal women were eligible if they were aged 18 years or older; had clinical T stage (cT)1c to cT4a-c (≥1·5 cm within cT1c) oestrogen receptor-positive, HER2-negative, untreated early breast cancer; an Eastern Cooperative Oncology Group performance status of 0-1; and baseline Ki67 score of at least 5%. The study was conducted at 59 hospital or clinic sites in 11 countries globally. Participants were randomly assigned (1:1) to giredestrant 30 mg oral daily or anastrozole 1 mg oral daily on days 1-14 (window-of-opportunity phase) via an interactive web-based system with permuted-block randomisation with block size of four. Randomisation was stratified by cT stage, baseline Ki67 score, and progesterone receptor status. A 16-week neoadjuvant phase comprised the same regimen plus palbociclib 125 mg oral daily on days 1-21 of a 28-day cycle, for four cycles. The primary endpoint was geometric mean relative Ki67 score change from baseline to week 2 in patients with complete central Ki67 scores at baseline and week 2 (window-of-opportunity phase). Safety was assessed in all patients who received at least one dose of study drug. The study is registered with ClinicalTrials.gov (NCT04436744) and is complete. FINDINGS: Between Sept 4, 2020, and June 22, 2021, 221 patients were enrolled and randomly assigned to the giredestrant plus palbociclib group (n=112; median age 62·0 years [IQR 57·0-68·5]) or anastrozole plus palbociclib group (n=109; median age 62·0 [57·0-67·0] years). 15 (7%) of 221 patients were Asian, three (1%) were Black or African American, 194 (88%) were White, and nine (4%) were unknown races. At data cutoff for the primary analysis (July 19, 2021), the geometric mean relative reduction of Ki67 from baseline to week 2 was -75% (95% CI -80 to -70) with giredestrant and -67% (-73 to -59) with anastrozole (p=0·043), meeting the primary endpoint. At the final analysis (data cutoff Nov 24, 2021), the most common grade 3-4 adverse events were neutropenia (29 [26%] of 112 in the giredestrant plus palbociclib group vs 29 [27%] of 109 in the anastrozole plus palbociclib group) and decreased neutrophil count (17 [15%] vs 16 [15%]). Serious adverse events occurred in five (4%) patients in the giredestrant plus palbociclib group and in two (2%) patients in the anastrozole plus palbociclib group. There were no treatment-related deaths. One patient died due to an adverse event in the giredestrant plus palbociclib group (myocardial infarction). INTERPRETATION: Giredestrant offers encouraging anti-proliferative and anti-tumour activity and was well tolerated, both as a single agent and in combination with palbociclib. Results justify further investigation in ongoing trials. FUNDING: F Hoffmann-La Roche.

Inspired to Garden: A Qualitative Study of Participants' Experiences in an Academic Medical Center Garden.

Introduction Gardening is a healthy activity that promotes nutrition and satisfaction, with positive impacts on patients with chronic diseases, including patients with obesity, diabetes, and cardiovascular disease. Hospital-based gardening programs may provide opportunities to introduce patients to gardening. However, few studies have included participant experience as a metric of evaluation. The objective of this study was to explore participant experience in a hospital-based gardening intervention designed for individuals with metabolic syndrome. Methods This study was a qualitative evaluation of free text responses from four questions included in post-participation questionnaires from 59 community-dwelling adults who participated in a hospital-based garden program located at the University of Vermont Medical Center in 2020 and 2021. Eligible participants included a convenience sample of novice gardeners with self-reported hypertension, diabetes, pre-diabetes, or overweight/obesity. We used an interpretative phenomenological approach to analyze the questionnaire data. The phenomenological cycle for each of the questions included: 1) reading and re-reading participant responses, 2) exploratory noting, 3) constructing experimental statements, 4) searching for connections across statements, and 5) naming the themes. This process also involved working with individual question-level themes to develop group themes across questions. Results This dataset was one of positivity about gardening, new information gleaned, and the quality of instruction. Several themes and codes emerged: program implementation (new knowledge, new skills, new connections, instructor ability, climate), self-efficacy (confidence, vicarious experience, mastery experience, verbal persuasion), and future change (behavior change, future issues/problem-solving, passing it on). Conclusion This study supports analyzing participant experience as part of hospital-based gardening interventions. We found positivity around program implementation, increased self-efficacy, and intentions to change behavior in ways that support healthy lifestyles.

An Open-label Phase I Study of GDC-0927 in Postmenopausal Women with Locally Advanced or Metastatic Estrogen Receptor-Positive Breast Cancer.

PURPOSE: GDC-0927 is a novel, potent, nonsteroidal, orally bioavailable, selective estrogen receptor (ER) degrader that induces tumor regression in ER+ breast cancer xenograft models. PATIENTS AND METHODS: This phase I dose-escalation multicenter study enrolled postmenopausal women with ER+/HER2- metastatic breast cancer to determine the safety, pharmacokinetics, and recommended phase II dose of GDC-0927. Pharmacodynamics was assessed with [18F]-fluoroestradiol (FES) PET scans. RESULTS: Forty-two patients received GDC-0927 once daily. The MTD was not reached. The most common adverse events (AE) regardless of causality were nausea, constipation, diarrhea, arthralgia, fatigue, hot flush, back pain, and vomiting. There were no deaths, grade 4/5 AEs, or treatment-related serious AEs. Two patients experienced grade 2 AEs of special interest of deep vein thrombosis and jugular vein thrombosis, both considered unrelated to GDC-0927. Following dosing, approximately 1.6-fold accumulation was observed, consistent with the observed half-life and dosing frequency. There were no complete or partial responses. Pharmacodynamics was supported by >90% reduction in FES uptake and an approximately 40% reduction in ER expression, suggesting ER degradation is not the mechanistic driver of ER antagonism. Twelve patients (29%) achieved clinical benefit; 17 patients (41%) showed a confirmed best overall response of stable disease. Baseline levels of ER and progesterone receptor protein and mutant ESR1 circulating tumor DNA did not correlate with clinical benefit. CONCLUSIONS: GDC-0927 appeared to be well tolerated with pharmacokinetics supporting once-daily dosing. There was evidence of target engagement and preliminary evidence of antitumor activity in heavily pretreated patients with advanced/metastatic ER+/HER2- breast cancer with and without ESR1 mutations.

Real-World Perspectives and Practices for Pneumonitis/Interstitial Lung Disease Associated With Trastuzumab Deruxtecan Use in Human Epidermal Growth Factor Receptor 2-Expressing Metastatic Breast Cancer.

Trastuzumab deruxtecan (T-DXd) is an antibody drug conjugate with a topoisomerase I payload that targets the human epidermal growth factor receptor 2 (HER2). T-DXd is approved for patients with previously treated HER2-positive or HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+/ISH-) metastatic/unresectable breast cancer (BC). In a second-line HER2-positive metastatic BC (mBC) population (DESTINY-Breast03 [ClinicalTrials.gov identifier: NCT03529110]), T-DXd demonstrated significantly improved progression-free survival (PFS) over ado-trastuzumab emtansine (12-month rate: 75.8% v 34.1%; hazard ratio, 0.28; P < .001), and in patients with HER2-low mBC treated with one prior line of chemotherapy (DESTINY-Breast04 [ClinicalTrials.gov identifier: NCT03734029]), T-DXd demonstrated significantly longer PFS and overall survival than physician's choice chemotherapy (10.1 v 5.4 months; hazard ratio, 0.51; P < .001, and 23.4 v 16.8 months; hazard ratio, 0.64; P < .001, respectively).Interstitial lung disease (ILD) is an umbrella term used for a group of diseases characterized by lung injury including pneumonitis, which can lead to irreversible lung fibrosis. ILD is a well-described adverse event associated with certain anticancer therapies, including T-DXd. An important part of T-DXd therapy for mBC consists of monitoring for and managing ILD. Although information on ILD management strategies is included in the prescribing information, additional information on patient selection, monitoring, and treatment can be beneficial in routine clinical practice. The objective of this review is to describe real-world, multidisciplinary clinical practices and institutional protocols used for patient selection/screening, monitoring, and management related to T-DXd-associated ILD.

Evaluation of alpelisib-induced hyperglycemia prophylaxis and associated risk factors in PIK3CA-mutated hormone-receptor positive, human epidermal growth factor-2 negative advanced breast cancer.

PURPOSE: SOLAR-1 investigated alpelisib-fulvestrant (ALP + FLV) in patients with HR + /HER2-, PIK3CA-mutated advanced breast cancer and demonstrated a clinically significant increase in all-grade and grade (G) 3-4 hyperglycemia (HG) compared to placebo-fulvestrant. Given high rates of HG, a preventative protocol and identification of associated risk factors was implemented. METHODS: This single-center, retrospective study included patients receiving ALP + FLV. One week before ALP initiation, patients started an insulin-sensitizer. Patients had fasting plasma glucose (FPG) levels drawn day 8, 15, 28, then monthly. Primary outcome was incidence of G2-4 HG by day 28. Risk factors assessed included age, BMI, FPG, and HbA1c. Number of risk factors were compared between patients with and without HG. RESULTS: Sixteen women were included with median age of 59 years. The cohort was 69% White, 25% Black, 75% with BMI ≥ 25 kg/m2, and 50% with history of diabetes. By day 28, 9 patients (56%) had G2-4 HG, with only 3 (19%) G3 and zero G4. Patients with G2-4 HG had a median of 2 risk factors compared to only 1 if no HG (p = 0.03). 5 patients (31%) required a temporary hold of ALP and 3 (19%) required dose reduction due to HG. 13 patients permanently discontinued ALP-9 due to disease progression and 4 from an adverse event (only 1 HG). CONCLUSION: Implementation of a HG prophylaxis protocol with ALP in a single-center study demonstrated fewer G3-4 HG events compared to that seen in SOLAR-1 (19% vs 36.6%). An increase in HG-associated risk factors correlated with a higher incidence of G2-4 HG.

The oral selective estrogen receptor degrader GDC-0810 (ARN-810) in postmenopausal women with hormone receptor-positive HER2-negative (HR + /HER2 -) advanced/metastatic breast cancer.

PURPOSE: GDC-0810 (ARN-810) is a novel, non-steroidal, orally bioavailable, selective estrogen receptor degrader (SERD) that potentially inhibits ligand-dependent and ligand-independent estrogen receptor (ER)-mediated signaling. METHODS: A phase Ia/Ib/IIa dose escalation, combination treatment with palbociclib or a luteinizing hormone-releasing hormone, and expansion study determined the safety, pharmacokinetics, and recommended phase 2 dose (RP2D) of GDC-0810 in postmenopausal women with ER + (HER2 -) locally advanced or metastatic breast cancer (MBC). Baseline plasma ctDNA samples were analyzed to determine the ESR1 mutation status. RESULTS: Patients (N = 152) received GDC-0810 100-800 mg once daily (QD) or 300-400 mg twice daily, in dose escalation, expansion, as single agent or combination treatment. Common adverse events regardless of attribution to study drug were diarrhea, nausea, fatigue, vomiting, and constipation. There was one dose-limiting toxicity during dose escalation. The maximum tolerated dose was not reached. GDC-0810 600 mg QD taken with food was the RP2D. Pharmacokinetics were predictable. FES reduction (> 90%) highlighting pharmacodynamic engagement of ER was observed. Outcomes for the overall population and for patients with tumors harboring ESR1 mutations included partial responses (4% overall; 4% ESR1), stable disease (39% overall; 42% ESR1), non-complete response/non-progressive disease (13% overall; 12% ESR1), progressive disease (40% overall; 38% ESR1), and missing/unevaluable (5% overall; 5% ESR1). Clinical benefit (responses or SD, lasting ≥ 24 weeks) was observed in patients in dose escalation (n = 16, 39%) and expansion (n = 24, 22%). CONCLUSION: GDC-0810 was safe and tolerable with preliminary anti-tumor activity in heavily pretreated patients with ER + advanced/MBC, with/without ESR1 mutations, highlighting the potential for oral SERDs. Clinical Trial and registration date April 4, 2013. NCT01823835 .

What is the concordance between parent- and education professional-reported adaptive functioning in autistic children using the VABS-II?

Adaptive functioning of autistic children is traditionally measured through informant-report, often from parents. Behaviour varies across settings though, and context-specific reports should be considered. Limited and inconsistent results show low parent-education professional concordance, but no research has yet explored item level response variation. We investigated Vineland Adaptive Behaviour Scales-II concordance using 233 lower ability autistic children from the PACT-G sample. Domain and item level agreement was low, but better on objectively measured behaviours. Higher child nonverbal ability improved concordance. Where disagreements occurred, education professionals identified emergent skills more and parents were more likely to rate present/absent. Parents and education professionals view the adaptive abilities of autistic children differently and both should be considered when developing personalised interventions and support.

Preclinical and Clinical Efficacy of Trastuzumab Deruxtecan in Breast Cancer Brain Metastases.

PURPOSE: Brain metastases can occur in up to 50% of patients with metastatic HER2-positive breast cancer. Because patients with active brain metastases were excluded from previous pivotal clinical trials, the central nervous system (CNS) activity of the antibody-drug conjugate trastuzumab deruxtecan (T-DXd) is not well characterized. EXPERIMENTAL DESIGN: We studied how T-DXd affects growth and overall survival in orthotopic patient-derived xenografts (PDX) of HER2-positive and HER2-low breast cancer brain metastases (BCBM). Separately, we evaluated the effects of T-DXd in a retrospective cohort study of 17 patients with stable or active brain metastases. RESULTS: T-DXd inhibited tumor growth and prolonged survival in orthotopic PDX models of HER2-positive (IHC 3+) and HER2-low (IHC 2+/FISH ratio < 2) BCBMs. T-DXd reduced tumor size and prolonged survival in a T-DM1-resistant HER2-positive BCBM PDX model. In a retrospective multi-institutional cohort study of 17 patients with predominantly HER2-positive BCBMs, the CNS objective response rate (ORR) was 73% (11/15) while extracranial response rate was 45% (5/11). In the subset of patients with untreated or progressive BCBM at baseline, the CNS ORR was 70% (7/10). The median time on treatment with T-DXd was 8.9 (1.3-16.2) months, with 42% (7/17) remaining on treatment at data cutoff. CONCLUSIONS: T-DXd demonstrates evidence of CNS activity in HER2-positive and HER2-low PDX models of BCBM and preliminary evidence of clinical efficacy in a multi-institution case series of patients with BCBM. Prospective clinical trials to further evaluate CNS activity of T-DXd in patients with active brain metastases are warranted. See related commentary by Soffietti and Pellerino, p. 8.

Planning and licensing for marine aquaculture.

Marine aquaculture has the potential to increase its contribution to the global food system and provide valuable ecosystem services, but appropriate planning, licensing and regulation systems must be in place to enable sustainable development. At present, approaches vary considerably throughout the world, and several national and regional investigations have highlighted the need for reforms if marine aquaculture is to fulfil its potential. This article aims to map and evaluate the challenges of planning and licensing for growth of sustainable marine aquaculture. Despite the range of species, production systems and circumstances, this study found a number of common themes in the literature; complicated and fragmented approaches to planning and licensing, property rights and the licence to operate, competition for space and marine spatial planning, emerging species and diversifying marine aquaculture production (seaweed production, Integrated Multi-Trophic Aquaculture [IMTA], nutrient and carbon offsetting with aquaculture, offshore aquaculture and co-location and multiuse platforms), and the need to address knowledge gaps and use of decision-support tools. Planning and licensing can be highly complicated, so the UK is used as a case study to show more detailed examples that highlight the range of challenges and uncertainty that industry, regulators and policymakers face across interacting jurisdictions. There are many complexities, but this study shows that many countries have undergone, or are undergoing, similar challenges, suggesting that lessons can be learned by sharing knowledge and experiences, even across different species and production systems, rather than having a more insular focus.