P4‐564: Short‐Term Outcomes Of A Randomized Controlled Trial Of Amyloid Pet Results Disclosure In Mild Cognitive Impairment

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152786/1/alzjjalz201908111.pd

Rental Housing Deposits and Health Care Use

ImportanceHousing deposits and tenancy supports have become new Medicaid benefits in multiple states; however, evidence on impacts from these specific housing interventions is limited.ObjectiveTo evaluate the association of rental housing deposits and health care use among Medicaid beneficiaries receiving social needs case management as part of a Whole-Person Care (Medicaid 1115 waiver) pilot program in California.Design, setting, and participantsThis cohort study compared changes in health care use among a group of adults who received a housing deposit between October 2018 and December 2021 along with case management vs a matched comparison group who received case management only in Contra Costa County, California, a large county in the San Francisco Bay Area. All participants were enrolled in health and social needs case management based on elevated risk of acute care use. Data analysis took place from March 2023 to June 2024.ExposureRental housing deposit funds that covered 1-time moving transition costs. Funds averaged $1750 per recipient.Main outcomes and measuresChanges in hospitalizations, emergency department visits, primary care visits, specialty care visits, behavioral health visits, psychiatric emergency services, or detention intakes during the 6 months before vs 6 months after deposit receipt. Changes 12 months before and after deposit receipt were examined as a sensitivity analysis.ResultsOf 1690 case management participants, 845 received a housing deposit (362 [42.8%] <40 years old; 422 [49.9%] male) and 845 received case management only (367 [43.4%] <40 years old; 426 [50.4%] male). In adjusted analyses, deposit recipients had no statistically significant differential changes in health care use for any measure compared to participants who received case management alone. Twelve-month sensitivity analyses yielded consistent results.Conclusions and relevanceIn this cohort study, compared to case management only, housing deposits with case management were not associated with short-term changes in health care use. There may be other unmeasured health benefits or downstream benefits from greater case management engagement. States considering housing deposits as an expanded Medicaid benefit may need to temper expectations about short-term health care use impacts

FOLFIRINOX for advanced pancreatic cancer:The Princess Margaret Cancer Centre experience

BACKGROUND: FOLFIRINOX has been shown to significantly increase both overall survival (OS) and progression-free survival (PFS) in metastatic pancreas cancer. There is limited data regarding the treatment of locally advanced pancreatic cancer. We present a retrospective study of patients with both locally advanced and metastatic pancreas cancer using FOLFIRINOX as first-line therapy in our centre. METHODS: This is a retrospective review of patients treated with FOLFIRINOX for pancreatic cancer at Princess Margaret Cancer Centre, between December 2011 and July 2014. The primary objective was to evaluate the efficacy and safety of FOLFIRINOX when used with dose modifications. RESULTS: One hundred two patients were identified; 66 metastatic and 36 locally advanced. Sixty-eight per cent of patients initiated treatment with a dose reduction. The median (95% CI) OS in the metastatic group was 13.1 (6.3–16.1) months with full dose and 12.9 (10.3–30.1) months with modified dose. The median (95% CI) OS in the locally advanced group was 11.1 (6.1–not reached) months with full dose and 23 (not reached–not reached) months with modified dose. The median (95% CI) PFS in the metastatic group was 6.2 (4.9–15.2) months with full dose and 8.7 (5.7–12.9) months with modified dose. The median (95% CI) PFS in the locally advanced group was 11.1 (3.1–not reached) months with full dose and 10.4 (6.8–not reached) months with modified dose. Grade 3/4 haematologic adverse events were observed in 43% of patients. Grade 3/4 non-haematologic adverse events were observed in 28% of patients. Patient well-being significantly improved from baseline to cycle 4 (P=0.002). CONCLUSIONS: Efficacy was achievable with dose-modified FOLFIRINOX in daily setting. The safety of FOLFIRINOX remains a concern with a high rate of grades 3 and 4 neutropaenia despite dose reduction

Vegetation demographics in Earth System Models: A review of progress and priorities

Numerous current efforts seek to improve the representation of ecosystem ecology and vegetation demographic processes within Earth System Models (ESMs). These developments are widely viewed as an important step in developing greater realism in predictions of future ecosystem states and fluxes. Increased realism, however, leads to increased model complexity, with new features raising a suite of ecological questions that require empirical constraints. Here, we review the developments that permit the representation of plant demographics in ESMs, and identify issues raised by these developments that highlight important gaps in ecological understanding. These issues inevitably translate into uncertainty in model projections but also allow models to be applied to new processes and questions concerning the dynamics of real-world ecosystems. We argue that stronger and more innovative connections to data, across the range of scales considered, are required to address these gaps in understanding. The development of first-generation land surface models as a unifying framework for ecophysiological understanding stimulated much research into plant physiological traits and gas exchange. Constraining predictions at ecologically relevant spatial and temporal scales will require a similar investment of effort and intensified inter-disciplinary communication

KRAS Allelic Variants in Biliary Tract Cancers

IMPORTANCE: Biliary tract cancers (BTCs) contain several actionable molecular alterations, including FGFR2, IDH1, ERBB2 (formerly HER2), and KRAS. KRAS allelic variants are found in 20% to 30% of BTCs, and multiple KRAS inhibitors are currently under clinical investigation. OBJECTIVES: To describe the genomic landscape, co-sequence variations, immunophenotype, genomic ancestry, and survival outcomes of KRAS-mutated BTCs and to calculate the median overall survival (mOS) for the most common allelic variants. DESIGN, SETTING, AND PARTICIPANTS: This retrospective, multicenter, pooled cohort study obtained clinical and next-generation sequencing data from multiple databases between January 1, 2017, and December 31, 2022. These databases included Princess Margaret Cancer Centre, MD Anderson Cancer Center, Foundation Medicine, American Association for Cancer Research Project GENIE, and cBioPortal for Cancer Genomics. The cohort comprised patients with BTCs who underwent genomic testing. MAIN OUTCOME AND MEASURE: The main outcome was mOS, defined as date of diagnosis to date of death, which was measured in months. RESULTS: A total of 7457 patients (n = 3773 males [50.6%]; mean [SD] age, 63 [5] years) with BTCs and genomic testing were included. Of these patients, 5813 had clinical outcome data available, in whom 1000 KRAS-mutated BTCs were identified. KRAS allelic variants were highly prevalent in perihilar cholangiocarcinoma (28.6%) and extrahepatic cholangiocarcinoma (36.1%). Thirty-six KRAS allelic variants were identified, and the prevalence rates in descending order were G12D (41%), G12V (23%), and Q61H (8%). The variant G12D had the highest mOS of 25.1 (95% CI, 22.0-33.0) months compared with 22.8 (95% CI, 19.6-31.4) months for Q61H and 17.8 (95% CI, 16.3-23.1) months for G12V variants. The majority of KRAS-mutated BTCs (98.9%) were not microsatellite instability-high and had low tumor mutational burden (ranging from a median [IQR] of 1.2 (1.2-2.5) to a mean [SD] of 3.3 [1.3]). Immune profiling through RNA sequencing of KRAS and NRAS-mutated samples showed a pattern toward a more immune-inflamed microenvironment with higher M1 macrophage activation (0.16 vs 0.12; P = .047) and interferon-γ expression compared with wild-type tumors. The G12D variant remained the most common KRAS allelic variant in all patient ancestries. Patients with admixed American ancestry had the highest proportion of G12D variant (45.0%). CONCLUSIONS AND RELEVANCE: This cohort study found that KRAS allelic variants were relatively common and may be potentially actionable genomic alterations in patients with BTCs, especially perihilar cholangiocarcinoma and extrahepatic cholangiocarcinoma. The findings add to the growing data on genomic and immune landscapes of KRAS allelic variants in BTCs and are potentially of value to the planning of specific therapies for this heterogeneous patient group

A randomized controlled trial of amyloid positron emission tomography results disclosure in mild cognitive impairment

IntroductionRecent studies suggest that Alzheimer’s disease (AD) biomarker disclosure has no discernable psychological impact on cognitively healthy persons. Far less is known about how such results affect symptomatic individuals and their caregivers.MethodsRandomized controlled trial of 82 mild cognitive impairment (MCI) patient and caregiver dyads (total n = 164) to determine the effect of receiving amyloid positron emission tomography results on understanding of, and perceived efficacy to cope with, MCI over 52 weeks of follow‐up.ResultsGains in the primary outcomes were not consistently observed. Amyloid negative patients reported greater perceived ambiguity regarding MCI at follow‐up, while moderate and sustained emotional distress was observed in patients, and to a lesser extent, caregivers, of those who were amyloid positive. There was no corresponding increase in depressive symptoms.DiscussionThese findings point to the possibility that both MCI patients and caregivers may need emotional support after the disclosure of amyloid scan results.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163444/2/alz12129_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163444/1/alz12129.pd

Efficacy and Safety of Nivolumab Plus Ipilimumab in Patients With Advanced Hepatocellular Carcinoma Previously Treated With Sorafenib The CheckMate 040 Randomized Clinical Trial

IMPORTANCE Most patients with hepatocellular carcinoma (HCC) are diagnosed with advanced disease not eligible for potentially curative therapies; therefore, new treatment options are needed. Combining nivolumab with ipilimumab may improve clinical outcomes compared with nivolumab monotherapy. OBJECTIVE To assess efficacy and safety of nivolumab plus ipilimumab in patients with advanced HCC who were previously treated with sorafenib. DESIGN, SETTING, AND PARTICIPANTS CheckMate 040 is a multicenter, open-label, multicohort, phase 1/2 study. In the nivolumab plus ipilimumab cohort, patients were randomized between January 4 and September 26, 2016. Treatment group information was blinded after randomization. Median follow-up was 30.7 months. Data cutoff for this analysis was January 2019. Patients were recruited at 31 centers in 10 countries/territories in Asia, Europe, and North America. Eligible patients had advanced HCC (with/without hepatitis B or C) previously treated with sorafenib. A total of 148 patients were randomized (50 to arm A and 49 each to arms B and C). INTERVENTIONS Patients were randomized 1:1:1 to either nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, administered every 3 weeks (4 doses), followed by nivolumab 240 mg every 2 weeks (arm A); nivolumab 3 mg/kg plus ipilimumab 1 mg/kg, administered every 3 weeks (4 doses), followed by nivolumab 240 mg every 2 weeks (arm B); or nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks (arm C). MAIN OUTCOMES AND MEASURES Coprimary end points were safety, tolerability, and objective response rate. Duration of response was also measured (investigator assessed with the Response Evaluation Criteria in Solid Tumors v1.1). RESULTS Of 148 total participants, 120 were male (81%). Median (IQR) age was 60 (52.5-66.5). At data cutoff (January 2019), the median follow-up was 30.7 months (IQR, 29.9-34.7). Investigator-assessed objective response rate was 32% (95% CI, 20%-47%) in arm A, 27% (95% CI, 15%-41%) in arm B, and 29% (95% CI, 17%-43%) in arm C. Median (range) duration of response was not reached (8.3-33.7+) in arm A and was 15.2 months (4.2-29.9+) in arm B and 21.7 months (2.8-32.7+) in arm C. Any-grade treatment-related adverse events were reported in 46 of 49 patients (94%) in arm A, 35 of 49 patients (71%) in arm B, and 38 of 48 patients (79%) in arm C; there was 1 treatment-related death (arm A; grade 5 pneumonitis). CONCLUSIONS AND RELEVANCE In this randomized clinical trial, nivolumab plus ipilimumab had manageable safety, promising objective response rate, and durable responses. The arm A regimen (4 doses nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks then nivolumab 240 mg every 2 weeks) received accelerated approval in the US based on the results of this study. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0165887

BRAFΔβ3−αC^{Δβ3-αC} in-frame deletion mutants differ in their dimerization propensity, HSP90 dependence, and druggability

In-frame BRAF exon 12 deletions are increasingly identified in various tumor types. The resultant BRAF$^{Δβ3-αC}$ oncoproteins usually lack five amino acids in the β3-αC helix linker and sometimes contain de novo insertions. The dimerization status of BRAF$^{Δβ3-αC}$ oncoproteins, their precise pathomechanism, and their direct druggability by RAF inhibitors (RAFi) has been under debate. Here, we functionally characterize BRAF$^{ΔLNVTAP>F}$ and two novel mutants, BRAF$^{delinsFS}$ and BRAF$^{ΔLNVT>F}$, and compare them with other BRAF$^{Δβ3-αC}$ oncoproteins. We show that BRAF$^{Δβ3-αC}$ oncoproteins not only form stable homodimers and large multiprotein complexes but also require dimerization. Nevertheless, details matter as aromatic amino acids at the deletion junction of some BRAF$^{Δβ3-αC}$ oncoproteins, e.g., BRAF$^{ΔLNVTAP>F}$, increase their stability and dimerization propensity while conferring resistance to monomer-favoring RAFi such as dabrafenib or HSP 90/CDC37 inhibition. In contrast, dimer-favoring inhibitors such as naporafenib inhibit all BRAF$^{Δβ3-αC}$ mutants in cell lines and patient-derived organoids, suggesting that tumors driven by such oncoproteins are vulnerable to these compounds