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Importance The choice of induction agent during rapid sequence intubation (RSI) of critically ill adults may affect clinical outcomes. Although ketamine and etomidate are frequently used for RSI, their comparative effectiveness remains controversial. Objective To compare the safety of etomidate vs ketamine for emergency RSI in critically ill adults. Design, Setting, and Participants This cohort study used a target trial emulation with observational data collected between March 1, 2022, and April 30, 2024, from 18 emergency departments across Brazil, with data from the Brazilian Airway Registry Cooperation. Adults who underwent RSI and received either etomidate or ketamine as a sole hypnotic agent were included; those with preintubation cardiac arrest or immediate postintubation transfer were excluded. Exposure Administration of etomidate or ketamine as the induction agent for RSI. Main Outcomes and Measures The primary outcome was 28-day in-hospital mortality. Secondary outcomes included 7-day in-hospital mortality, first-attempt intubation success, and major adverse events (new hemodynamic instability, severe hypoxemia, and cardiac arrest) within 30 minutes after intubation. Inverse probability of treatment weighting was used to adjust for confounding. Risk ratios (RRs) and risk differences (RDs) with 95% CIs were used to compare outcomes between groups. Results Among 1810 patients (median age, 64 years [IQR, 50-74 years]; 1048 men [57.9%]), 514 received ketamine and 1296 received etomidate. The median shock index was higher in the ketamine group than the etomidate group (0.81 [IQR, 0.65-1.01] vs 0.76 [IQR, 0.59-0.99]), and preintubation vasopressor use was more common in the ketamine group than the etomidate group (191 of 514 [37.2%] vs 391 of 1296 [30.2%]). Weighted 28-day mortality was higher with etomidate than ketamine (60.5% [95% CI, 57.2%-63.8%] vs 54.4% [95% CI, 45.0%-63.9%]; RR, 1.14 [95% CI, 1.03-1.27]; RD, 7.6% [95% CI, 2.0%-13.3%]). Seven-day mortality was also higher with etomidate than ketamine (35.2% [95% CI, 32.0%-38.3%] vs 30.1% [95% CI, 23.5%-36.7%]; RR, 1.19 [95% CI, 1.04-1.35]). New hemodynamic instability within 30 minutes after intubation was more frequent with ketamine (24.2% [95% CI, 20.4%-28.0%] vs 18.9% [95% CI, 16.7%-21.0%]; RR, 0.78 [0.64-0.95]). There were no statistically significant differences in the other secondary outcomes. Conclusions and Relevance In this cohort study of critically ill adults undergoing RSI, etomidate use was associated with higher in-hospital mortality at 7 and 28 days compared with ketamine. These findings highlight the need for definitive randomized clinical trials to compare both agents.

Background: Body contouring is an increasingly common trend in aesthetic plastic surgery. In the pursuit of ideal body proportions, anterior thoracic cage deformities, especially lower rib cartilage prominence have emerged as a frequent source of dissatisfaction. To address this concern, the anterior aesthetic rib cage remodeling with osteosynthesis (ARCO) technique was developed as an innovative method to reshape the anterior rib cage. Methods: A retrospective study was conducted in Colombia on patients who underwent the ARCO procedure. Preoperative and postoperative rib cage perimeter measurements were recorded. Spirometry was performed preoperatively and during long-term follow-up to assess potential changes in respiratory volumes. Intraoperative peak pressure and pulmonary compliance values were monitored to evaluate procedural safety. Postoperative satisfaction was assessed using the BODY-Q questionnaire, and all complications were documented. Results: A total of 34 patients were included, with a mean age of 34 years. A significant reduction in the inferior rib cage perimeter at the level of the eighth rib was observed (Mann-Whitney U =190, P < 0.001), with a mean decrease of 2 cm. Intraoperative peak inspiratory pressure and pulmonary compliance remained stable across all procedural stages. Spirometric analyses revealed no restrictive changes in respiratory volumes. Conclusions: The ARCO technique offers an effective approach for reducing chest circumference and enhancing the aesthetic contour of the anterior rib margin while achieving high patient satisfaction. It involves a controlled greenstick fracture followed by osteosynthesis to create a stable and natural rib curvature, reducing the risk of malunion and eliminating the need for postoperative corsets.

Abstract BTK degraders promote proteasomal degradation of BTK and can overcome resistance to covalent and noncovalent BTK inhibitors in patients with relapsed CLL. Currently the molecular basis for BTK degrader resistance is unknown. We therefore set out to understand BTK degrader resistance based on observations from the phase 1 trial of zelebrudomide (NX-2127) (NCT04830137), the first BTK degrader to enter clinical studies. Targeted 500-gene sequencing was performed on blood and/or tissue from four CLL patients treated with zelebrudomide. In one patient previously treated with chemoimmunotherapy, ibrutinib, venetoclax, and pirtobrutinib, BTK A428D was detected in the baseline blood sample with variant allele frequency (VAF) of &lt;2%, along with BTK V416L (13%) and mutations in TP53 (60%) and SF3B1 (37%). Following daily treatment with 100mg zelebrudomide and subsequent dose escalation to 200mg, at 6 months the VAF of all four mutations increased, with BTK A428D VAF increasing to 6% in the blood and 29% in a lymph node. BTK A428D was detected at baseline but not at progression in a second patient. To evaluate the impact of BTK A428D on drug response, we transduced BTK-dependent TMD8 cells with BTK WT, C481S, L528W, and A428D, and found that BTK A428D uniquely conferred resistance to all FDA-approved BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib, pirtobrutinib) as well as three BTK degraders under clinical evaluation (zelebrudomide, bexobrutideg, BGB-16673). To model the subclonal nature of BTK A428D we conducted a competition assay in which TMD8 cells expressing GFP + BTK A428D (5%) were mixed with TMD8 cells expressing mCherry + BTK WT (95%); over 9 days the GFP + BTK A428D expanded from 5% to 88-97% with all four BTKi and all three BTK degraders. In vitro kinase assays revealed that the BTK A428D mutant protein lacks kinase activity yet facilitates calcium flux and ERK/AKT signaling upon B-cell receptor activation, suggesting a scaffolding effect similar to other kinase deficient BTK mutations. To determine whether BTK A428D affects BTK degradation, we developed a reporter that fuses the BTK kinase domain to GFP. BTK A428D showed minimal degradation following 20 hours of treatment with a titration of all three BTK degraders. Similarly, we knocked BTK A428D into the endogenous BTK locus of HBL1 cells and confirmed a lack of degradation at doses up to 1 µM of all 3 degraders. Consistent with these findings, surface plasmon resonance revealed that the FDA-approved BTK inhibitors as well as zelebrudomide, bexobrutideg, BGB-16673, and AbbVie-1 (Compound 1 from WO 2023183811) are unable to bind to BTK A428D. Additionally, an in-cell NanoBRET assay demonstrated that zelebrudomide was unable to mediate the interaction between cereblon and BTK A428D. Strikingly, NanoBRET also demonstrated that a panel of promiscuous kinase-binding compounds was unable to bind to BTK A428D. The lack of binding of both selective and promiscuous kinase binders to BTK A428D led us to speculate that the mutation disrupted the ATP binding pocket to an unusual degree. We therefore solved the crystal structure of apo BTK A428D and found that, in addition to its predicted steric clash with ligand binding in the hinge region, the mutation led the protein to crystallize with its activation loop occupying the catalytic cleft, rendering it inaccessible. This is the first apo BTK structure observed in this autoinhibited conformation, and explains the observed binding profile. We hypothesized that the addition of a second targeted agent such as venetoclax might mitigate expansion of the A428D subclone. To test this, we introduced the BTK A428D mutation into the endogenous BTK gene in 3% of TMD8 cells and then exposed them to 0.1µM of zelebrudomide, bexobrutideg, or BGB-16673 +/- venetoclax 0.1µM. Combining the BTK degraders with venetoclax slowed the emergence of the BTK A428D resistant population and, in the case of zelebrudomide, eradicated both the wild-type and A428D clones. In summary, we identified and validated BTK A428D as a clinically relevant acquired pan-resistance mutation that confers resistance by blocking access to the ATP binding pocket. This mechanism differs from other kinase dead BTK mutations in which the kinase's enzymatic pocket remained accessible.These data also provide rationale for combining BTK degraders with BCL2 inhibitors, particularly in patients with BTK A428D mutations, or high-risk mutations such as in TP53.

Abstract Copy Number Alterations (CNAs), including chromosomal gains and losses, shape the genetics and clinical management of acute myeloid leukemia (AML), particularly in complex karyotypes (e.g. CK-AML). Traditionally, AML associated CNAs have been studied using cytogenetic approaches, i.e., karyotyping, that are limited in resolution and sensitivity. Here, low-coverage, sparse whole genome sequencing followed by machine learning applied to over 600 AML patient samples (ECOG-ARCIN trials: E1900, E3999) reveals novel genetic, biologic, and clinical correlates in AML disease. We find that multi-variate Cox-regression analysis applied to the data identifies select patients exhibiting focal and cryptic hemizygous deletions at 17q, 21q, and 3p, in otherwise diploid genomes, associate with inferior survival compared to other patients (median overall survival; OS = 65.5 compared to 421 days, Chi-square test pval=6x10-11), independent of factors such as age, treatment, and karyotype complexity status. In addition, we confirm that amplifications at 11q23, encoding the KM2TA gene, are associated with inferior outcome, and further identify unique breakpoint event features as well as transcriptional signatures suggestive of distinctive KM2TA-translocation independent biology. Applying machine learning approaches to the data, more specifically Non-negative Matrix Factorization (NMF), we develop a prognostic model that captures clinically adverse, cryptic variation such as focal 5q deletions, missed by conventional chromosome analysis and thereby, adds novel, complementary information to traditional, cytogenetic based risk-stratification (e.g. ELN). The model also associates gain of chromosome 8 in Intermediate risk patients with worse outcome compared to other Intermediate risk patients (median OS = 186 compared to 446 days, Chi-square test pval=0.005) and identifies a subgroup of patients within the adverse risk category that lack deletions on chromosomes 5, 7, and 17, and that fare better than the rest of the adverse risk patients (median OS = 188 compared to 97.5 days, Chi-square test pval=0.02), likely reflecting previously identified “atypical” CK-AML patients. Last, we develop a prognostic classifier based on a combination of Neural-Network and Random-Forest based learning, that predicts disease outcome with high accuracy and is based on a three genomic feature list on chromosome bands 5q31.2, 7q31.33, and 8q24, suggesting potential for clinical implementation. Altogether, our results show that low coverage, sparse whole genome sequencing combined with advanced learning methods can be applied clinically to support the diagnosis and clinical management of AML disease as well as serve as a powerful tool to further a basic understanding of the genetics and biology of CNAs in myeloid neoplasms and other cancers.

Abstract Background: Population registries and the Alliance co-operative group database have highlighted racial disparities in AML survival attributed to differential prevalence and impact of oncogenic drivers on disease biology. However, the small number of Black patients with well-annotated genomic profiles limits the validity of these findings. The current study leverages ECOG-ACRIN cytogenetic and outcomes data from newly diagnosed adult AML patients treated on intensive chemotherapy-based clinical trials over three decades. Methods: Self-reported race was categorized as White, Black or Other. Descriptive statistics were used to summarize baseline characteristics using the Wilcoxon rank-sum and Fisher's exact tests. Multivariable Cox proportional hazards regression models evaluated the association between race and survival outcomes adjusting for age, hemoglobin, platelet count, white blood cell count, blast percentage, performance status and ELN cytogenetic risk score (RS). All Cox models were stratified by protocol. Subgroup analyses of overall survival (OS) and disease-free survival (DFS) were performed using Kaplan-Meier curves stratified by race using log-rank tests. All statistical tests were two-sided. Analyses included only patients with complete data for the variables of interest. Results: Data was collected across 10 phase II and III interventional trials for newly diagnosed adult AML that accrued patients between 1984 and 2019. The study population included 3469 White, 184 Black, and 156 Other patients with a Black representation of 1.1-11% across trials. Blacks were significantly younger at diagnosis with a median age of 47.9 years compared to 53.5 years in Whites (p&lt;0.001). Racial groups were well matched for gender and performance status. Black race was an independent prognostic factor for inferior OS (HR 1.212, CI 1.01 – 1.453; p = 0.0383) and DFS (HR 1.313, CI 1.05-1.641; p = 0.017). Complete cytogenetic results were available for 117 Black and 2162 White patients and revealed no significant racial differences in the distribution of ELN 2017 cytogenetic RS, although core binding factor AML was non-significantly enriched in Black patients (12.8% vs 8.3%). No difference was observed between Blacks and Whites in the prevalence of complex karyotype (CK), CK with -5/del(5q), -7/del(7q), or -17/del(17p), and AML-MRC including +8 and del(20q). Notably, the ELN 2017 cytogenetic RS effectively predicted OS in Black (57.8 vs 14.2 vs 5.8 months in favorable, intermediate and adverse RS, p = 0.018), and White patients (60.1 vs 15.2 vs 7.1 months, p &lt; 0.0004 for Whites) but only predicted DFS for White AML patients (p &lt; 0.0001 for Whites, p=0.48 for Blacks). In patients with molecular data for FLT3-ITD (n=1218), CEBPA (n=576), TP53 (n=572), or NPM1(n=683), no racial difference in the prevalence of these mutations was observed. However, NPM1 mutations were associated with inferior OS in Blacks compared to Whites (19.1 vs 8.9 months; p = 0.0095). Black and White AML patients had similar responses with complete remission rates of 58.2% vs 57.5%, p=0.55, and treatment tolerability with 30-day mortality of 7.1% vs 8.9%, p=0.50. However, consolidation approaches differed significantly. Among patients that underwent stem cell transplant (SCT), a significantly higher percentage of White patients received allogenic SCT compared to Blacks (48.5% versus 37.1%, p &lt;0.01). Conclusions: This study represents one of the largest race-based comparisons of cytogenetic abnormalities and clinical outcomes in prospective trials of intensive chemotherapy in AML . Our data confirms the independent prognostic relevance of race in AML survival and validates the predictive ability of the ELN 2017 cytogenetic RS for OS across racial groups. There is ancestry-based attenuation of the survival benefit of NPM1 mutations as previously reported, underscoring the need to tailor the current treatment approach to NPM1 mutated AML based on race. The availability of NGS data limited the genomic analysis to a subset of patients. Future studies should examine the depth of treatment response incorporating MRD biomarkers and explore the effect of race on co-occurring mutations and the leukemic stem cell transcriptome to better explain the observed disparities. Finally, persistent disparities in access to allo-SCT even within the context of clinical trials reinforces the need to address diversity in the stem cell donor pool and social barriers to transplant.

Abstract Introduction Nadir bone marrow biopsies (BM Bx) are routinely performed around day 14 to assess early response to AML intensive induction therapy. The presence of residual disease prompts initiation of reinduction therapy, often with another cycle of intensive chemotherapy. Whether there are characteristics of nadir BM Bx that predict for response to intensive reinduction is unknown. To evaluate this, we analyzed data from ECOG-ACRIN clinical trials in AML of intensive induction chemotherapy with nadir biopsy information available to determine predictors of outcomes after reinduction. Methods We included patients from ECOG-ACRIN E1900 (Fernandez NEJM 2009) and arm A of E2906 (Foran ASH 2015) who received induction therapy with daunorubicin and cytarabine (7+3), had residual disease (blasts ≥5% or cellularity ≥20%) at nadir BM Bx and received reinduction chemotherapy. Nadir BM Bx characteristics that were evaluated included blast percentage and cellularity as well as both absolute and relative (percentage change, e.g. 20% to 10% = -50%) differences calculated between diagnosis and nadir for each parameter. Complete remission (CR) after reinduction therapy, disease free survival (DFS) and overall survival (OS) were outcomes for all analyses. Logistic regression models were used to evaluate associations with CR, and Cox proportional hazards models were used for DFS and OS. For models evaluating changes in blast percentage or cellularity as predictors, baseline blast percentage or cellularity was included as a covariate, respectively. Results Of 1013 patients identified, 750 (74%) had a nadir biopsy, 233 (23%) had evidence of residual disease, received reinduction therapy, and were included in the primary analysis. The median age was 58 and 42% were female. Cytogenetic risk category (by ELN2017) was adverse in 31%, intermediate in 66% and favorable in 3%. The median nadir BM Bx blast was 30% (range 0 to +97%) and cellularity was 20% (0 to +100%). The median absolute difference in blast percentage between baseline and nadir BM Bx was -15% (-95% to +66%) with a median relative difference of -36% (-100% to +400%). After reinduction, 118 patients (52%) achieved a CR. Neither absolute difference in blast percentage (OR 0.99, 95%CI 0.98-1.00, p=0.20) nor relative difference (OR 1.00, 95%CI 0.99-1.00, p=0.33) predicted CR. There was similarly no association with DFS (HR = 1.00, 95%CI: 0.99-1.01, p=0.65) or OS (HR = 1.00, 95%CI 0.99-1.01, p=0.76). Blast reduction ≥50% similarly did not predict these outcomes. We also evaluated the impact of any reduction in blast percentage (responders) from baseline to nadir and again found no association with CR (OR 1.65, 95%CI 0.90-3.03, p=0.11). Similarly, there was no association with DFS (HR 0.74, 95%CI 0.51-1.09, p=0.13) or OS (HR 0.81, 95%CI 0.58-1.13, p=0.21) in responders vs nonresponders. No association with CR, DFS or OS were identified when performing the same analysis in intermediate and adverse cytogenetic subgroups. We found no association with CR when nadir cellularity was assessed as a continuous variable (OR 0.99, 95%CI 0.98-1.00, p=0.10) or by relative difference (OR 0.99, 95%CI 0.99-1.00, p=0.10). There was a trend towards association with absolute reduction in cellularity from baseline to nadir and CR (OR 0.99, 95%CI 0.98-1.00, p=0.06). No association was identified between relative difference in cellularity and DFS and OS, nor was there an association among cytogenetic risk subgroups with any outcome. Discussion In intensively treated patients with residual disease at nadir BM Bx (i.e. day 14) who received intensive reinduction, the likelihood of achieving a CR was not influenced by the magnitude of disease reduction nor the extent of disease at the time of nadir biopsy. Similarly, there were no nadir biopsy features that predicted DFS or OS after intensive reinduction therapy. Given alternative reinduction therapies such as hypomethylating agents and venetoclax are available, these results suggest that the decision to attempt a second intensive induction cycle following the unequivocal presence of residual disease should not be influenced by characteristics of the nadir BM Bx. Although patient-specific factors such as patient fitness may favor a switch to less intensive options, these results support consideration of intensive reinduction therapy in patients with residual disease at nadir biopsy, even without changes in blasts or cellularity.

Background: Pericarotid adipose tissue (PCAT) characteristics and systemic inflammation may play an important role in carotid endarterectomy (CEA) outcomes. This study explores the association between PCAT Hounsfield Unit (HU) ranges, radiomic features, and systemic inflammatory markers in patients undergoing carotid endarterectomy (CEA). Methods: Twenty patients undergoing CEA were included in this cross-sectional study. PCAT was analyzed using preoperative computed tomography angiography (CTA) images, with regions of interest defined around the carotid arteries. PCAT was categorized into three HU ranges: −190 to −120, −119 to −70, and −69 to −30. Radiomics features were extracted using PyRadiomics. The primary outcome was the correlation of PCAT imaging with preoperative neutrophil-to-lymphocyte ratios (NLRs). The secondary outcome was the association of PCAT imaging with the red cell distribution width (RDW-CV). Linear regression was used to evaluate associations between PCAT characteristics and inflammatory markers. Results: Distinct HU ranges in PCAT imaging showed strong correlations with the preoperative NLR. The −190 to −120 HU range demonstrated a negative association (β = −3.809, p < 0.001), whereas the −119 to −70 HU range showed a positive correlation (β = 3.814, p < 0.001). PCAT uniformity was positively associated with RDW-CV (β = 0.494, p = 0.027). Other radiomics features, such as contrast, showed trends but did not reach statistical significance. A larger outer area of PCAT was inversely associated with the NLR (β = −0.677, p < 0.001). Conclusions: Specific PCAT HU ranges and radiomics features are significantly associated with systemic inflammatory markers in CEA patients. These findings suggest that HU-based segmentation and radiomics analysis of PCAT may offer valuable insights into the relationship between local adipose tissue characteristics and systemic inflammation.

Abstract Glioblastoma (GBM), the most common malignant primary brain tumor in adults, has a median survival of 15 months and 5-year survival rate of only 6.9%. Standard of care, including radiation and chemotherapy, can induce cellular senescence in the brain. The senescence-associated secretory phenotype (SASP) significantly affects glioma microenvironment as these secreted factors exhibit both anti-and pro-tumorigenic effects. However, it is currently unknown whether senescence in the surrounding GBM microenvironment could be beneficial or detrimental to tumor outcomes. Using cell-specific proteomics, we identified upregulation of cathepsin B (CTSB) expression in patient-derived brain tumor initiating cells (BTICs) co-cultured with human fetal neural progenitor cells (NPCs). In matched patient tumor biopsies, sequencing of lateral ventricle (LV)-proximal regions revealed increased CTSB expression compared to LV-distal counterparts. Remarkably, LV-proximal GBMs induced a senescent phenotype and reduced differentiation in subventricular zone (SVZ) NPCs through CTSB secretion. We hypothesize that senescent NPCs in the SVZ contribute to a pro-tumorigenic microenvironment that promotes tumor aggressiveness in LV-proximal GBM. To model this in vitro, senescence was induced in NPCs using recombinant CTSB (100 nM) and hydrogen peroxide (250 µM, 2 hours). Treated NPCs showed increased β-galactosidase activity and increased expression of SASP factors IL-1α, IL-6, and CTSB. Senescent NPCs significantly increased BTIC migration and proliferation (p&lt;0.05) both in co-culture and through conditioned media, suggesting this effect may be mediated by soluble factors. These findings support the hypothesis that senescent NPCs promote BTIC malignancy in LV-proximal GBM and identify CTSB as a potential mediator of this interaction.

Abstract Glioblastoma (GBM), the most aggressive primary brain tumor in adults, presents significant challenges due to its universal recurrence and limited survival rates, exacerbated when proximal to the lateral ventricles (LV). The subpopulation of brain tumor-initiating cells (BTICs) plays a pivotal role in tumor initiation and invasiveness, interacting with the microenvironment, particularly the cellular components in the subventricular zone (SVZ), like Neural Progenitor Cells (NPCs). Mechanisms of intercellular communication present in the SVZ include paracrine, autocrine, direct cell contact, and more recently extracellular vesicles (EVs). EVs are membrane-bound particles released by cells that are central to intercellular communication. They carry bioactive proteins, RNA, and other molecules that influence recipient cell behavior. This study investigates the role of EVs in GBM’s communication with non-cancer cells. Our findings indicate that BTIC-derived EVs promote migration and proliferation (*p &lt; 0.02, ****p &lt;0.001) in NPCs in vitro, highlighting the EVs’ role in altering the microenvironment. Additionally, we leverage a multi-omic approach to profile the small RNA and protein cargo of BTIC-EVs while also evaluating changes in the transcriptome of NPCs after BTIC-EV treatment. To identify the protein cargo contained in GBM-derived EVs, we utilized the innovative proximity-labeling system TurboID. We successfully induced TurboID expression in primary-cultured human BTICs from GBM patients, enabling the unbiased biotinylation of proteins in EVs. This method marks the first implementation of TurboID for unbiased global labeling of EV protein cargo in primary GBM cells. We identified unique miRNAs to be regulators of NPC’s transcriptome, and ontogenic analysis revealed upregulation of pathways involved in maintaining stem-like state, and upregulating PI3k-AKT, mTOR, and WNT signaling. This approach facilitates the investigation of EV-mediated communication and potential therapeutic targets, contributing to the understanding of GBM’s complex interactions with the brain’s microenvironment and the identification of biomarkers for improved diagnosis and treatment response.

Abstract BACKGROUND Understanding long-term sequelae of cancer care is critical. Cognitive impairment is a common and disabling survivorship issue. Because sex influences tumor biology, therapy exposure, and dementia risk, we examined whether cancer care for a prior malignancy alters late-life cognitive outcomes differently in males and females. METHODS We assessed adults ≥50 years, cognitively normal at study entry, from a longitudinal, population-based cohort (Mayo Clinic Study of Aging). Participants were linked to our institutional cancer registry (excluding non-melanoma skin cancers). Mild cognitive impairment (MCI) and dementia were adjudicated by consensus. We fitted multivariable Cox proportional-hazards models to estimate how prevalent cancer diagnosis influenced the risk of developing MCI/dementia. Sex-specific effects were determined by incorporating a cancer×sex interaction term and by generating separate hazard ratios. Analyses were controlled for age, APOE4 status, education, and presence of vascular/metabolic conditions. RESULTS 5793 MCSA participants (female: 49.4%, APOE4 positive: 27.5%) were included in the study, with a mean age of 73 years at study entry. Incident MCI was recorded in 866 participants, and 737 were diagnosed with incident dementia. About 20% (n=1176) of the cohort had a cancer diagnosis, most commonly prostate (n=423) and breast (n=277). There was no independent relationship between history of cancer and risk for MCI or dementia. We found that males with cancer had an increased risk for MCI (HR 1.28, 95% CI 1.04-1.57, p=0.003) and dementia (HR 1.29, 95% CI 1.04-1.6, p=0.053). Conversely, females with cancer had a lower risk for MCI (HR 0.79, 95% CI 0.61-1.01, p=0.063), although this was not statistically significant. CONCLUSIONS Our data suggests male cancer survivors may be more susceptible to cognitive impairment, independent of age, APOE4 status, education, and vascular/metabolic burden. Elucidating the hormonal, treatment-related, and systemic pathways driving this should be a priority for future mechanistic studies.