Citations

Abstract Erdheim-Chester disease (ECD) and Rosai-Dorfman disease (RDD) are rare non-Langerhans cell histiocytoses (non-LCHs), for which therapeutic options are limited. MAPK pathway activation through BRAFV600E mutation or other genomic alterations is a histiocytosis hallmark and correlates with a favorable response to BRAF inhibitors and the MEK inhibitor cobimetinib. However, there has been no systematic evaluation of alternative MEK inhibitors. To assess the efficacy and safety of the MEK inhibitor trametinib, we retrospectively analyzed the outcomes of 26 adult patients (17 with ECD, 5 with ECD/RDD, 3 with RDD, and 1 with ECD/LCH) treated with orally administered trametinib at 4 major US care centers. The most common treatment-related toxicity was rash (27% of patients). In most patients, the disease was effectively managed at low doses (0.5-1.0 mg trametinib daily). The response rate of the 17 evaluable patients was 71% (73% [8/11] without a detectable BRAFV600E achieving response). At a median follow-up of 23 months, treatment effects were durable, with a median time-to-treatment failure of 37 months, whereas the median progression-free and overall survival were not reached (at 3 years, 90.1% of patients were alive). Most patients harbored mutations in BRAF (either classic BRAFV600E or other BRAF alterations) or alterations in other genes involved in the MAPK pathway, eg, MAP2K, NF1, GNAS, or RAS. Most patients required lower than standard doses of trametinib but were responsive to lower doses. Our data suggest that the MEK inhibitor trametinib is an effective treatment for ECD and RDD, including those without the BRAFV600E mutation.

Background Although there has been a decrease in the incidence of ST‐segment–elevation myocardial infarction (STEMI) in the United States, this trend might be stagnant or increasing in young women. We assessed the trends, characteristics, and outcomes of STEMI in women aged 18 to 55 years. Methods and Results We identified 177 602 women aged 18 to 55 with the primary diagnosis of STEMI from the National Inpatient Sample during years 2008 to 2019. We performed trend analyses to assess hospitalization rates, cardiovascular disease (CVD) risk factor profile, and in‐hospital outcomes stratified by three age subgroups (18–34, 35–44, and 45–55 years). We found STEMI hospitalization rates were decreased in the overall study cohort from 52 per 100 000 hospitalizations in 2008 to 36 per 100 000 in 2019. This was driven by decreased proportion of hospitalizations in women aged 45 to 55 years (74.2% to–71.7%; P <0.001). Proportion of STEMI hospitalizationincreased in women aged 18–34 (4.7%–5.5%; P <0.001) and 35–44 years (21.2%–22.7%; P <0.001). The prevalence of traditional and non‐traditional female‐specific or female‐predominant CVD risk factors increased in all age subgroups. The adjusted odds of in‐hospital mortality in the overall study cohort and age subgroups were unchanged throughout the study period. Additionally, we observed an increase in the adjusted odds of cardiogenic shock, acute stroke, and acute kidney injury in the overall cohort over the study period. Conclusions STEMI hospitalizations are increasing among women aged <45 years, and in‐hospital mortality has not changed over the past 12 years in women aged <55 years. Future studies on the optimization of risk assessment and management of STEMI in young women are urgently needed.

Insulin acts centrally to stimulate sympathetic vasoconstrictor outflow to skeletal muscle and peripherally to promote vasodilation. Given these divergent actions, the “net effect” of insulin on the transduction of muscle sympathetic nerve activity (MSNA) into vasoconstriction and thus, blood pressure (BP) remains unclear. We hypothesized that sympathetic transduction to BP would be attenuated during hyperinsulinemia compared with baseline. In 22 young healthy adults, MSNA (microneurography), and beat-to-beat BP (Finometer or arterial catheter) were continuously recorded, and signal-averaging was performed to quantify the mean arterial pressure (MAP) and total vascular conductance (TVC; Modelflow) responses following spontaneous bursts of MSNA at baseline and during a euglycemic-hyperinsulinemic clamp. Hyperinsulinemia significantly increased MSNA burst frequency and mean burst amplitude (baseline: 46 ± 6 au; insulin: 65 ± 16 au, P < 0.001) but did not alter MAP. The peak MAP (baseline: 3.2 ± 1.5 mmHg; insulin: 3.0 ± 1.9 mmHg, P = 0.67) and nadir TVC ( P = 0.45) responses following all MSNA bursts were not different between conditions indicating preserved sympathetic transduction. However, when MSNA bursts were segregated into quartiles based on their amplitudes at baseline and compared with similar amplitude bursts during hyperinsulinemia, the peak MAP and TVC responses were blunted (e.g., largest burst quartile: MAP, baseline: Δ4.4 ± 1.7 mmHg; hyperinsulinemia: Δ3.0 ± 0.8 mmHg, P = 0.02). Notably, ∼15% of bursts during hyperinsulinemia exceeded the size of any burst at baseline, yet the MAP/TVC responses to these larger bursts (MAP, Δ4.9 ± 1.4 mmHg) did not differ from the largest baseline bursts ( P = 0.47). These findings indicate that increases in MSNA burst amplitude contribute to the overall maintenance of sympathetic transduction during hyperinsulinemia.

ImportanceGlaucoma can develop following cataract removal in children.ObjectiveTo assess the cumulative incidence of glaucoma-related adverse events (defined as glaucoma or glaucoma suspect) and factors associated with risk of these adverse events in the first 5 years after lensectomy prior to 13 years of age.Design, Setting, and ParticipantsThis cohort study used longitudinal registry data collected at enrollment and annually for 5 years from 45 institutional and 16 community sites. Participants were children aged 12 years or younger with at least 1 office visit after lensectomy from June 2012 to July 2015. Data were analyzed from February through December 2022.ExposuresUsual clinical care after lensectomy.Main Outcomes and MeasuresThe main outcomes were cumulative incidence of glaucoma-related adverse events and baseline factors associated with risk of these adverse events.ResultsThe study included 810 children (1049 eyes); 443 eyes of 321 children (55% female; mean [SD] age, 0.89 [1.97] years) were aphakic after lensectomy, and 606 eyes of 489 children (53% male; mean [SD] age, 5.65 [3.32] years) were pseudophakic. The 5-year cumulative incidence of glaucoma-related adverse events was 29% (95% CI, 25%-34%) in 443 eyes with aphakia and 7% (95% CI, 5%-9%) in 606 eyes with pseudophakia; 7% (95% CI, 5%-10%) of aphakic eyes and 3% (95% CI, 2%-5%) of pseudophakic eyes were diagnosed as glaucoma suspect. Among aphakic eyes, a higher risk for glaucoma-related adverse events was associated with 4 of 8 factors, including age less than 3 months (vs ≥3 months: adjusted hazard ratio [aHR], 2.88; 99% CI, 1.57-5.23), abnormal anterior segment (vs normal: aHR, 2.88; 99% CI, 1.56-5.30), intraoperative complications at time of lensectomy (vs none; aHR, 2.25; 99% CI, 1.04-4.87), and bilaterality (vs unilaterality: aHR, 1.88; 99% CI, 1.02-3.48). Neither of the 2 factors evaluated for pseudophakic eyes, laterality and anterior vitrectomy, were associated with risk of glaucoma-related adverse events.Conclusions and RelevanceIn this cohort study, glaucoma-related adverse events were common after cataract surgery in children; age less than 3 months at surgery was associated with elevated risk of the adverse events in aphakic eyes. Children with pseudophakia, who were older at surgery, less frequently developed a glaucoma-related adverse event within 5 years of lensectomy. The findings suggest that ongoing monitoring for the development of glaucoma is needed after lensectomy at any age.

Evaluate the quantitative, subjective (Deauville score [DS]) and reader agreement differences between standard ordered subset expectation maximization (OSEM) and Bayesian penalized likelihood (BPL) positron emission tomography (PET) reconstruction methods. A retrospective review of 104 F-18 fluorodeoxyglucose PET/computed tomography (CT) exams among 52 patients with diffuse large B-cell lymphoma. An unblinded radiologist moderator reviewed both BPL and OSEM PET/CT exams. Four blinded radiologists then reviewed the annotated cases to provide a visual DS for each annotated lesion. Significant (P < .001) differences in BPL and OSEM PET methods were identified with greater standard uptake value (SUV) maximum and SUV mean for BPL. The DS was altered in 25% of cases when BPL and OSEM were reviewed by the same radiologist. Interobserver DS agreement was higher for OSEM (>1 cm lesion = 0.89 and ≤1 cm lesion = 0.84) compared to BPL (>1 cm lesion = 0.85 and ≤1 cm lesion = 0.81). Among the 4 readers, average intraobserver visual DS agreement between OSEM and BPL was 0.67 for lesions >1cm and 0.4 for lesions ≤1 cm. F-18 Fluorodeoxyglucose PET/CT of diffuse large B-cell lymphoma reconstructed with BPL has higher SUV values, altered DSs and reader agreement when compared to OSEM. This report finds volumetric PET measurements such as metabolic tumor volume to be similar between BPL and OSEM PET reconstructions. Efforts such as adoption of European Association Research Ltd accreditation should be made to harmonize PET data with an aim at balancing the need for harmonization and sensitivity for lesion detection.

Abstract Introduction Vaccinations against preventable respiratory infections such as Streptococcus pneumoniae and influenza are important in immunosuppressed solid organ transplant (SOT) recipients. Little is known about the role of age, race, ethnicity, sex, and sociodemographic factors including rurality, or socioeconomic status (SES) associated with vaccine uptake in this population. Methods We conducted a population‐based study using the Rochester Epidemiology Project, a medical records linkage system, to assess socioeconomic and demographic factors associated with influenza and pneumococcal vaccination rates among adult recipients of solid organ transplantation (aged 19–64 years) living in four counties in southeastern Minnesota. Vaccination data were obtained from the Minnesota Immunization Information Connection from June 1, 2010 to June 30, 2020. Vaccination rate was assessed with Poisson and logistic regression models. Results A total of 468 SOT recipients were identified with an overall vaccination rate of 57%–63% for influenza and 56% for pneumococcal vaccines. As expected, vaccination for pneumococcal vaccine positively correlated with influenza vaccination. Rural patients had decreased vaccination in both compared to urban patients, even after adjusting for age, sex, race, ethnicity, and SES. Although the population was mostly White and non‐Hispanic, neither vaccination differed by race or ethnicity, but influenza vaccination did by SES. Among organ transplant groups, liver and lung recipients were least vaccinated for influenza, and heart recipients were least up‐to‐date on pneumococcal vaccines. Conclusions Rates of vaccination were below national goals. Rurality was associated with undervaccination. Further investigation is needed to understand and address barriers to vaccination among transplant recipients. image

Prostate cancer is a disease of older adults that has undergone a significant therapeutic paradigm shift in the last decade with the emergence of novel androgen receptor pathway inhibitors (ARPis). One of the more commonly used ARPis is enzalutamide. This drug, along with darolutamide and apalutamide, initially received approvals in the metastatic castrate-resistant prostate cancer setting but is now utilized frequently in the metastatic castrate-sensitive and non-metastatic castration-resistant settings. Landmark phase III data illustrating ARPi efficacy in older adults are limited to those with excellent performance status. However, its role in unfit older prostate cancer patients remains to be explored in the context of a narrative review. This first-of-its-kind drug review aims to shed light on the most up-to-date evidence behind the unique toxicity profile of ARPis in the context of geriatric vulnerabilities such as cognitive and functional impairment, along with potential solutions and supporting evidence that exists to circumvent these issues in the vulnerable older adult.

TPS629 Background: The anti–PD-L1 antibody ATEZO prevents PD-L1 from interacting with PD-1 and B7.1, thus reinvigorating antitumor T cell activity. Anti-VEGF BEV can increase dendritic cell maturation, enhance T cell infiltration, and reduce myeloid-derived suppressor cells and regulatory T-cells in tumors. This combination has been FDA approved for first-line treatment of advanced HCC based on the IMbrave150 study. On the other hand, locoregional radiotherapy (e.g., Y90 TARE) enhances the diversity of the intratumoral T cell receptor repertoire. It is the standard of care for pts with intermediate-stage HCC (iHCC). Based on preclinical and clinical data, we hypothesize that the combination of Y90 TARE, BEV, and ATEZO induces synergistic tumor-killing. Methods: This is an open-label, multicenter, randomized phase II study of Y90 TARE and BEV plus ATEZO compared with Y90 TARE alone in pts with unresectable IHCC (NCT04541173). The primary study objective is to assess and compare the progression-free survival (PFS) (per mRECIST 1.1) of pts in each arm. The main secondary objective is to determine the safety and tolerability (CTCAE v5) of TARE combined with ATEZO and BEV in pts with HCC. Exploratory objectives are to assess the role of the immunoscore and PD-L1 expression levels in the prediction of improved clinical outcome in pts receiving Y-90 TARE and BEV plus ATEZO; the composition of tumor-infiltrating immune cell subtypes in predicting response to a chosen therapy; how Y90 therapy affects the proportion of antigen-presenting cells in the tumor; and symptoms experienced by pts receiving TARE and BEV plus ATEZO treatment, using patient-reported outcomes. Eligible pts have either HCC that is not amenable to surgical resection, confirmed by pathology review, or at least BCLC stage B HCC outside of downstaging criteria. Other standard eligibility criteria apply. Pts must have a pretreatment liver biopsy taken and then be randomized 1:1 to TARE (Arm A) or TARE followed by ATEZO and BEV (Arm B). Pts will have TARE mapping during week (wk) 1 and TARE treatment during wk 2. In Arm B, pts will start BEV plus ATEZO 4 wks (±1 wk) after TARE treatment. Pts will have abdominal MRI or CT scans every 12 weeks, CT scans of the chest every 24 wks. Disease progression will be captured by both RECIST 1.1 and mRECIST. We plan to assess the safety of TARE with BEV and ATEZO in the first 10 pts randomized to Arm B for two cycles. If there are no Grade ≥ 3 unexpected toxicities possibly, probably or definitely related to combined TARE plus BEV plus ATEZO, the study will continue to accrue 128 pts in total. Pts will continue study treatment (Arm B) for a total of 24 months from initiation of TARE or until intolerable toxicity or disease progression occur, whichever is earlier. Clinical trial information: NCT04541173 .

80 Background: Incidence of colorectal cancer (CRC) among adolescents and young adults (AYA) is increasing. A significant proportion of adolescents and young adults (AYA) with colorectal cancer (CRC) lack traceable genetic risk factors. We sought to study the impact of lifestyle-related risk factors on the incidence and mortality of CRC in these patients. Methods: We extracted data on crude incidence and mortality rates of CRC (reported per 100,000 population) for ages 15-39 years in all 50 U.S. states and District of Columbia from the Center for Disease Control (CDC) WONDER database (1999-2018). Data on risk factors such as obesity, physical activity, alcohol and tobacco abuse and nutrition were obtained from the Behavioral Risk Factor Surveillance System (BRFSS, 2020). Correlations were analyzed using Pearson’s co-efficient. p < 0.05 was considered statistically significant. Statistical analysis was performed using VassarStats. Results: Median crude incidence and mortality rates of CRC in AYA in the US from 1999-2018 were 3.8 (IQR 3.2, 4.4) and 0.7 (IQR 0.5,0.9) per 100,000 population respectively. States with higher age-adjusted prevalence of obesity per 100,000 had higher incidence (r = 0.36, p = 0.01) and mortality rates (r = 0.49, p = 0.0002) of CRC in AYA population. States with a higher age-adjusted prevalence of adherence to recommended weekly aerobic activity had lower incidence (r = -0.4515, p = 0.001) and mortality (r = -0.569, p < 0.0001) rates. While states with higher age-adjusted prevalence of tobacco abuse had higher incidence rate of CRC (r = 0.33, p = 0.02), there was no correlation with mortality rates (r = 0.24, p = 0.09). Higher prevalence of alcohol consumption was associated with decreased mortality rate (r = -0.44, p = 0.001), with no impact on incidence rate (r = -0.16, p = 0.26). States with lower daily consumption of fruits had higher incidence (r = 0.37, p = 0.01) and mortality rates (r = 0.59, p < 0.0001). No correlation of daily consumption of vegetables with incidence (r = -0.1516, p = 0.29) and mortality (r = 0.18, p = 0.22) rates was noted. Conclusions: In the current analysis, higher prevalence of obesity, lower rates of aerobic activity and lower daily consumption of fruits were strongly associated with increased incidence and mortality rates. The impact of tobacco abuse and alcohol consumption was more variable. Apart from improving access to genetic testing and counseling, efforts aimed at mitigating the rise of CRC incidence among AYA should also focus on traditional lifestyle-related risk factors.