Citations

3579 Background: Fruquintinib (F) is a highly selective, oral tyrosine kinase inhibitor of all 3 VEGF receptors. Based on FRESCO (NCT02314819) and FRESCO-2 (NCT04322539) data, F was approved by the US FDA for previously treatedmetastatic colorectal cancer (mCRC). Efficacy and safety of F + best supportive care (BSC) vs placebo (P) + BSC were analyzed according to prior treatment (tx) sequence using FRESCO and FRESCO-2 data. Methods: In FRESCO and FRESCO-2, patients (pts) were randomized 2:1 to receive F 5 mg or matching P, PO daily x 21 days every 28 days. In FRESCO, eligible pts had received ≥2 prior chemotherapy regimens and were permitted to have received prior anti-VEGF and/or anti-EGFR therapies, whereas in FRESCO-2, in addition to standard chemotherapies, anti-VEGF, and anti-EGFR therapies if indicated, prior exposure to trifluridine/tipiracil (TAS) and/or regorafenib (rego) was required. FRESCO-2 pts must have also received a BRAF inhibitor and/or immunotherapy, if indicated and available in their country. Results: In FRESCO (F n=278 vs P n=138), no pts had received rego and 16/416 pts (4%) had received TAS. InFRESCO-2, prior therapies were balanced between F vs P arms; pts had received prior TAS or rego in these sequences: prior TAS only (n=240 vs n=121); prior rego only (n=40 vs n=18); prior rego then TAS (n=84 vs n=45); prior TAS then rego (n=95 vs n=44). Improvements in OS and PFS were seen with F vs P regardless of prior tx sequence (Table), with similar magnitudes of benefit for OS (HRs 0.53–0.77) and PFS (HRs 0.25–0.37). F safety profile was consistent regardless of prior tx sequence (Table). Conclusions: F is effective in mCRC with a manageable safety profile regardless of prior TAS or rego tx and sequence. Improvement with F was similar for OS and PFS despite the number and sequence of prior regimens. F provides a new tx option for pts with previously treated mCRC regardless of prior TAS or rego exposure. Clinical trial information: NCT04322539 . [Table: see text]

Abstract Sex and gender—biological and social constructs—significantly impact the prevalence of protective and risk factors, influencing the burden of Alzheimer's disease (AD; amyloid beta and tau) and other pathologies (e.g., cerebrovascular disease) which ultimately shape cognitive trajectories. Understanding the interplay of these factors is central to understanding resilience and resistance mechanisms explaining maintained cognitive function and reduced pathology accumulation in aging and AD. In this narrative review, the ADDRESS! Special Interest Group (Alzheimer's Association) adopted a multidisciplinary approach to provide the foundations and recommendations for future research into sex‐ and gender‐specific drivers of resilience, including a sex/gender‐oriented review of risk factors, genetics, AD and non‐AD pathologies, brain structure and function, and animal research. We urge the field to adopt a sex/gender‐aware approach to resilience to advance our understanding of the intricate interplay of biological and social determinants and consider sex/gender‐specific resilience throughout disease stages. Highlights Sex differences in resilience to cognitive decline vary by age and cognitive status. Initial evidence supports sex‐specific distinctions in brain pathology. Findings suggest sex differences in the impact of pathology on cognition. There is a sex‐specific change in resilience in the transition to clinical stages. Gender and sex factors warrant study: modifiable, immune, inflammatory, and vascular.

ImportanceSince 2021, American College of Surgeons Commission on Cancer (CoC) accreditation standards require providing a survivorship program for patients with adult-onset cancer treated with curative intent. Since more than 70% of all patients with cancer in the US are treated at CoC-accredited facilities, this presents an opportunity for a landscape analysis of survivorship care availability.ObjectiveTo determine the prevalence, types, and outcomes of cancer survivorship services at CoC-accredited facilities.Design, Setting, and ParticipantsThis survey study used an anonymous, online, cross-sectional survey conducted from May 4 to 25, 2023. Participants were CoC-accredited facilities in the US representing diverse CoC program categories, institutional characteristics, geographic regions, and practice types. Department of Veterans Affairs cancer programs were excluded due to data usage restrictions. Data were analyzed from July to October 2023.ExposureCoC Survivorship Standard 4.8 was released in October 2019 and programs were expected to adhere to the Standard beginning January 1, 2021.Main Outcomes and MeasuresQuestions included self-reported survivorship program characteristics, availability of services aligned to CoC Survivorship Standard 4.8, and perceived program impacts. Response frequencies and proportions were determined in aggregate and by CoC program category.ResultsThere were 1400 eligible programs, and 384 programs participated (27.4% response rate). All regions and eligible program categories were represented, and most had analytic caseloads of 500 to 4999 patients in 2021. Most survivorship program personnel included nurses (334 programs [87.0%]) and social workers (278 programs [72.4%]), while physical (180 programs [46.9%]) and occupational (87 programs [22.7%]) therapists were less common. Services most endorsed as available for all survivors were screening for new cancers (330 programs [87.5%]), nutritional counseling (325 programs [85.3%]), and referrals to specialists (320 programs [84.7%]), while treatment summaries (242 programs [64.7%]), and survivorship care plans (173 programs [43.0%]), sexual health (217 programs [57.3%]), and fertility (214 programs [56.9%]) were less common. Survivorship services were usually delivered by cancer treatment teams (243 programs [63.3%]) rather than specialized survivorship clinics (120 programs [31.3%]). For resources needed, additional advanced practice clinicians with dedicated survivorship effort (205 programs [53.4%]) and electronic health record enhancements (185 programs [48.2%]) were most endorsed. Lack of referrals and low patient awareness were endorsed as the primary barriers. A total of 335 programs (87.2%) agreed that Survivorship Standard 4.8 helped advance their programs.Conclusions and RelevanceThese findings of this survey study of CoC-accredited programs establish a benchmark for survivorship care delivery in the US, identify gaps in specific services and opportunities for intervention, contribute to longitudinal reevaluation for tracking progress nationally, and suggest the value of survivorship care standards.

3020 Background: Radioligand therapy (RLT) use has been increasing with the approval of 177Lu-Dotatate for metastatic neuroendocrine tumors (NET) & 177Lu-PSMA-617 for metastatic castration resistant prostate cancer (mCRPC). Therapy-related myeloid neoplasms [tMN, including myelodysplastic syndrome (MDS) & acute myeloid leukemia, (AML)] have been reported after 177Lutetium (177Lu) for NET with rates of 2-20% & median time from first 177Lu to tMN of 2.8yrs [4-12]. Clonal hematopoiesis (CH) is a risk factor for tMN, with the spectrum of CH depending on selection pressures. To describe the prevalence of therapy selected CH & tMN, we performed a retrospective analysis of patients (pts) who had a bone marrow biopsy (BMB) post-177Lu. Methods: After IRB approval, we queried the electronic health record for pts with BMB post-177Lu. Pt demographics, treatment history, labs & BMB results were collected. Results: Fifty-seven pts met criteria, 41 (72%) with NET & 16 (28%) with mCRPC. . Median age at BMB was 68yrs (range, 28-85). Of the 57pts, prior treatments included: radiation (RT) in 21 (37%), temozolomide in 14 (25%), taxane in 15 (26%), & platinum agents in 10 (18%). The median number of 177Lu cycles was 4 (range, 1-11).Cytogenetics were available in 84% (n = 48) & were normal in 60% (n = 29). Of those with abnormal cytogenetics (n = 18, 38%), the most common abnormalities involved chromosome (chr) 7 (n = 12, 26%), chr 5 (n = 7, 15%), chr 20 (n = 5, 11%) and complex karyotypes in 7 (15%), with 3 (17%) of these patients having no mutations. Diagnoses were assessable in 49 (86%) pts: 15 (31%) with undefined cytopeniasand 16 (33%) with tMDS. Metastatic carcinoma was identified in 17 Fifty-one percent (n = 29), at a median of 0.5yrs (range, 0.04-2.6) after hematologic diagnosis. Conclusions: The enrichment of CH involving the DDR pathway in recipients of 177Lu underscores the impact of RLT on bone marrow progenitors.

3016 Background: PN in patients (pts) with NF1 can cause pain, disfigurement, impaired quality of life (QoL), and can undergo malignant transformation. ReNeu (NCT03962543), a multicenter, open-label, Phase 2b study, evaluated efficacy and safety of the highly selective, oral, investigational MEK1/2 inhibitor mirdametinib in adult (≥18 y) and pediatric (2-17 y) pts with inoperable NF1 PN causing significant morbidities. Methods: Mirdametinib was administered as a capsule or dispersible tablet (2 mg/m 2 BID, max 4 mg BID) without regard to food in 3 wk on/1 wk off 28-d cycles. The primary endpoint was confirmed objective response rate (ORR; percentage of pts with MRI-assessed ≥20% reduction of target PN volume by blinded independent central review [BICR] within the 24-cycle treatment phase). The minimum clinically relevant ORR (null) was defined as 23% for adults and 20% for pediatrics. Ptscould continue treatment in an optional long-term follow-up (LTFU) phase. Additional key endpoints were duration of response (DoR), time to response (TTR), change from baseline (BL) in target PN volume, pain severity (Numerical Rating Scale-11 [NRS-11]), pain interference (Pain Interference Index [PII]), health-related (HR) QoL (PedsQL), and safety. Results: All114 pts (58 adult, 56 pediatric) received mirdametinib. As of the 20 Sept 2023 data cutoff (DCO), BICR-confirmed ORR during the treatment phase was 41% (95% CI, 29-55; P<.001 vs null) in adults and 52% (95% CI, 38-65; P<.001 vs null) in pediatric pts. Two adult pts and 1 pediatric pt also had a confirmed response in the ongoing LTFU. Median (min, max) target PN volumetric best response from BL was -41% (-90, 13) and -42% (-91, 48) in adult and pediatric pts, respectively. As of the DCO, median treatment duration was 22 mo for each cohort and median DoR was not reached. Median (range) TTR was 7.8 (4-19) mo in adult pts and 7.9 (4-19) mo in pediatric pts. Adult and pediatric pts had statistically significant improvements from BL to cycle 13 in NRS-11, PII, and key PedsQL measures. Most frequent (≥35% pts) treatment-emergent adverse events (TEAEs) were dermatitis acneiform, diarrhea, nausea, and vomiting in adults and diarrhea, dermatitis acneiform, and vomiting in pediatric pts. 16% and 25% of adult and pediatric pts, respectively, had grade ≥3 treatment-related AEs, and 22% and 9%, respectively, discontinued due to TEAEs. Conclusions: In ReNeu, the largest multicenter NF1 PN trial reported to date, mirdametinib demonstrated a statistically significant ORR by BICR, with deep and durable PN volume reductions, significant improvements in pain severity, pain interference, and HRQoL, and a manageable safety profile in both adults and children. Together with a dispersible tablet formulation, these results underscore mirdametinib’s potential to become an important new treatment option for NF1 PN pts across all ages. Clinical trial information: NCT03962543 .

AbstractObjectiveWe performed a pilot stroke incidence study, focused on feasibility and inclusion of the CONSIDER reporting guidelines, to model the design of a future population‐based study aiming to definitively determine stroke incidence, antecedents, treatment, and outcomes.Study designProspective stroke incidence study (pilot study).Setting, participantsAll people aged 15 years or older who lived in postcode‐defined areas of South Australia and Northern Territory (885 472 people, including 45 127 Aboriginal people [5.1%]) diagnosed with stroke for the first time during 1 October – 31 December 2015 and admitted to public hospitals or stroke and transient ischaemic attack clinics.Main outcome measuresFeasibility of a prospective population‐based stroke incidence study.ResultsOf the 123 participants with first strokes, ten were Aboriginal (8%); the median age of Aboriginal people was 45 years (interquartile range [IQR], 33–55 years), of non‐Indigenous people 73 years (IQR, 62–84 years). For Aboriginal people, the age‐standardised incidence of stroke was 104 (95% confidence interval [CI], 84–124) per 100 000 person‐years, for non‐Indigenous people 33 (95% CI, 22–44) per 100 000 person‐years. We found that a prospective population‐based stroke incidence study in Aboriginal people was feasible, including with respect to establishing an adequate sample size, diagnostic confirmation, identification of incident stroke, confirming stroke subtypes, establishing a stable statistical population, standardising data reporting for comparison with other stroke incidence studies, and ethical research reporting that conforms to CONSIDER guidelines.ConclusionsA larger, population‐based study of the incidence of stroke in Aboriginal people is both feasible and needed to provide robust estimates of stroke incidence, antecedents, treatments and outcomes to help guide strategies for reducing the risk of and outcomes of stroke in Aboriginal people.

7011 Background: Monoclonal B-cell lymphocytosis (MBL) is a precursor to chronic lymphocytic leukemia (CLL) but also a risk factor for other lymphoid malignancies. Clonal hematopoiesis (CH), originally defined as the presence of mutations in myeloid driver genes, is a precursor to myeloid malignancies. Recently, CH that includes genes associated with lymphoid malignancies has been reportedly associated with risk of lymphoid malignancies, and particularly CLL. Little is known about the association between CH and MBL and their joint effects on risk of hematological malignancies (HM). Methods: Study participants were from the Mayo Clinic Biobank, a large-scale biorepository of patients who provided a peripheral blood sample. CH at enrollment was determined using whole-exome sequencing (50x coverage). Myeloid-CH (M-CH) was based on mutations located in 56 genes associated with myeloid malignancies. Lymphoid-CH (L-CH) was based on 235 genes associated with lymphoid malignancies. Individuals were screened for MBL using eight-color flow cytometry in two different cohorts of Biobank participants. Cohort 1 (N=3883) included participants who had available sample for MBL screening at enrollment. Cohort 2 (N=5684) were participants recontacted to provide a sample for MBL screening. Incident HM were identified using ICD codes and confirmed via medical record review. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Cox regression was used to estimate hazard ratios (HR), with time defined as date between MBL sample and the first of incident HM, death, or 9/30/2023. Analyses were adjusted for age at MBL screening and sex. Results: In total, 9567 individuals (39% male, median age 66 years) were screened for MBL with available CH, of whom 17% were positive for MBL, 7% were positive for M-CH, and 2% were positive for L-CH. We found no evidence of an association between M-CH and MBL (OR=1.11, 95% CI:0.91-1.34) nor L-CH and MBL (OR=1.05, 95% CI:0.70-1.55). When subset to Cohort 1, where the same sample was used for both CH and MBL screening, the results held (M-CH OR=1.11, 95% CI: 0.83-1.48; L-CH OR=0.82, 95% CI:0.40-1.53). Next, we investigated the effect of each of these precursors with incident HM. Median follow-up was 4 years, and 78 individuals developed incident HM (31 myeloid, 49 lymphoid overall, 8 CLL). When modeling both precursors, both L-CH (HR=6.23, 95% CI:2.46-15.79) and MBL (HR=3.89, 95% CI:2.17-6.99) were independently associated with incident lymphoid malignancy. When excluding CLL events, the association held (L-CH: HR=5.94, 95% CI:2.11-16.77; MBL: HR=2.95, 95% CI:1.54-5.66). Only M-CH was significantly associated with incident myeloid malignancies. Conclusions: In the largest cohort with MBL and CH precursors measured, we found no evidence of an association between them. However, both MBL and L-CH were strong independent risk factors for incident lymphoid malignancies.

World record speeds at different distances for men and women in different age categories are used to develop a model to predict running performance as a function of race distance, age, and sex. This empirical model quantifies the decline in running speed with distance and age in a way that provides insight into the aerobic and anaerobic contributions to running speed and may help with developing training strategies for different age groups at various distances.

8602 Background: LCNECs are a rare subtype of lung cancer, with limited clinical trial data and an unclear consensus on first-line treatment. Even less is known about the optimal treatment approach for pts with mixed LCNECs, a pathologic subtype where tumors contain both LCNEC histology as well as features of adenocarcinoma, squamous cell, or small cell lung cancer. Methods: We conducted an international multi-institutional retrospective analysis (n=13 institutions) of pts with advanced or metastatic mixed LCNECs who received 1st-line systemic therapy with either chemotherapy alone (chemo) or chemo-immunotherapy (chemoIO) between 2010-2023. Clinical outcomes included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and treatment-related adverse events (trAEs). Survival comparisons were made via the log-rank test. Results: Seventy-three pts with mixed LCNECs received either chemo (n=42, 57.5%) or chemoIO (n=31, 42.5%). The most common chemo regimens were carboplatin/etoposide (n=27) and cisplatin/etoposide (n=8), while the most common chemoIO was carboplatin/etoposide/atezolizumab (n=19). Median age at 1st-line therapy initiation was 65 (IQR: 60-72). 64% of pts were male (n=47). The majority were former smokers (n=41, 56.2%), with 22 current smokers (30.1%), and 10 non-smokers (13.7%). Mixed histologies included LCNEC/NSCLC (n=45, 56.2%), LCNEC/SCLC (n=17), LCNEC/carcinoid (n=1), and unspecified mixed LCNEC (n=10). Median PFS for chemo was 5 months (95% CI 2.7-9.2) vs. 6 months (95% CI 4.4-8.3) for chemoIO ( p=0.86). Median OS for chemo was 14.2 months (95% CI 10.4-22.5) vs. 17.2 months (95% CI 9.4-27.2) for chemoIO ( p=0.66). The ORR did not differ between chemo (n=18, 45%) and chemoIO (n=15, 48.4%) ( p=0.81). In the chemo group, 60% (n=25) experienced trAEs of any grade, with 23.8% (n=10) experiencing grade 3+ events and four requiring hospitalizations. For chemoIO pts, 61% (n=19) experienced trAEs, with 25.8% (n=8) experiencing grade 3+ events and six requiring hospitalizations. Neutropenia was the most common grade 3+ trAE for both chemo (n=5) and chemoIO (n=4). Overall, there were no significant differences between chemo or chemoIO groups for ORR ( p=0.81), all-grade trAEs ( p=0.88), grade 3+ trAEs ( p=0.84), PFS ( p=0.86), or median OS ( p=0.66). There were no significant differences in median PFS ( p=0.46) or OS ( p=0.99) for pts with mixed LCNEC/NSCLC vs. LCNEC/SCLC. Conclusions: For mixed LCNECs, there was no significant difference in PFS or OS between first-line treatment with chemo vs. chemoIO, suggesting limited benefit from immunotherapy for these pts. Additionally, survival outcomes did not differ between mixed LCNEC/NSCLC and LCNEC/SCLC, suggesting a biology primarily driven by their neuroendocrine component.

Abstract Background White matter (WM) abnormalities have been implicated in clinically relevant functional decline in multiple system atrophy (MSA). Objective To identify the WM and gray matter (GM) abnormalities in MSA and assess the utility of longitudinal structural and diffusion changes as surrogate markers for tracking disease progression in MSA. Methods Twenty‐seven participants with early MSA [15 with clinically predominant cerebellar (MSA‐C) and 12 with clinically predominant parkinsonian features (MSA‐P)] and 14 controls were enrolled as a part of our prospective, longitudinal study of synucleinopathies. Using structural magnetic resonance imaging (MRI) and diffusion MRI (diffusion tensor and neurite orientation and dispersion density imaging), we analyzed whole and regional brain changes in these participants. We also evaluated temporal imaging trajectories based on up to three annual follow‐up scans and assessed the impact of baseline diagnosis on these imaging biomarkers using mixed‐effect models. Results MSA patients exhibited more widespread WM changes than GM, particularly in the cerebellum and brainstem, with greater severity in MSA‐C. Structural and diffusion measures in the cerebellum WM and brainstem deteriorated with disease progression. Rates of progression of these abnormalities were similar in both MSA subtypes, reflecting increasing overlap of clinical features over time. Conclusion WM abnormalities are core features of MSA disease progression and advance at similar rates in clinical MSA subtypes. Multimodal MRI imaging reveals novel insights into the distribution and pattern of brain abnormalities and their progression in MSA. Selected structural and diffusion measures may be useful for tracking disease progression in MSA clinical trials.