Ethno-racial differences in depressive symptom endorsement: Evaluation of brief forms of the Geriatric Depression Scale in older adults.

BACKGROUND: Depression among older adults is a pressing public health concern, necessitating accurate assessment tools. The Geriatric Depression Scale (GDS) offers a brief and efficient means of screening depressive symptoms, yet its performance across ethno-racial groups remains understudied. This study aimed to compare the ability of various brief forms of the GDS to detect depressive symptoms and to assess potential ethno-racial differences in symptom endorsement among White, Black/African-American, and American Indian/Alaska Native older adults. METHODS: Data were obtained from the Wisconsin Alzheimer's Disease Research Center (ADRC) clinical cohort, comprising 555 cognitively healthy individuals at risk for dementia. We used participants' baseline data for this cross-sectional analysis. Depressive symptoms were assessed using multiple brief forms of the GDS, derived from a systematic review and meta-analysis. We examined internal consistency and correlations with global Clinical Dementia Rating (CDR) scores. We conducted Kruskal-Wallis tests and post hoc pairwise comparisons to assess ethno-racial group differences in symptom endorsement. RESULTS: Descriptive statistics revealed a predominance of female and White participants, with notable representation from Black and American Indian/Alaska Native groups. All GDS versions demonstrated moderate to high internal consistency. Significant positive correlations were observed between GDS scores and global CDR scores. Ethno-racial group differences in depressive symptom endorsement were evident, with Black participants consistently reporting higher levels of symptoms across most GDS versions. However, American Indian/Alaska Native participants endorsed significantly fewer symptoms than Black participants in one GDS version. CONCLUSION: The study highlights the importance of considering ethno-racial differences in depressive symptomatology when assessing older adults. While the GDS demonstrates overall reliability, variations in symptom endorsement across different ethno-racial groups underscore the need for culturally sensitive assessment tools and interventions. Future research should further explore these group differences and develop tailored approaches to depression screening and treatment in diverse older adult populations.

COVID-19 outcomes among patients with dementia and age-matched controls who were hospitalized in 21 US health-care systems.

INTRODUCTION: COVID-19 had devastating impacts worldwide. However, most research examining the impact of dementia on COVID-19 outcomes has been conducted in Europe and Asia and has not examined dementia subtypes. METHODS: A retrospective analysis of electronic health record data from 21 US health-care systems examined relationships of all-cause dementia, Alzheimer's disease (AD), and vascular dementia with in-hospital mortality, intensive care unit (ICU) admission, and hospital stay duration. RESULTS: All-cause dementia, but not AD or vascular dementia independently, was associated with increased mortality risk, the inclusion of discharge to hospice as a mortality equivalent increased risk for mortality for all-cause dementia, and AD and vascular dementia. Patients with all-cause dementia and AD were less likely to be admitted to the ICU than patients without. Patients with any form of dementia had longer hospital stays than patients without. DISCUSSION: Dementia was associated with increased mortality or hospice discharge, decreased ICU admissions, and longer hospital stays. HIGHLIGHTS: Only all-cause dementia was associated with increased mortality risk. This risk was lower than what has been published in previous research. Combining mortality and hospice discharge increased risk for all dementia subtypes. All-cause and Alzheimer's disease (AD) dementia were associated with decreased intensive care unit admissions. All-cause, vascular, and AD dementia were associated with longer hospital stays.

Post-therapy emergence of an NBN reversion mutation in a patient with pancreatic acinar cell carcinoma.

Pancreatic acinar cell carcinoma (PACC) is a rare form of pancreatic cancer that commonly harbors targetable alterations, including activating fusions in the MAPK pathway and loss-of-function (LOF) alterations in DNA damage response/homologous recombination DNA repair-related genes. Here, we describe a patient with PACC harboring both somatic biallelic LOF of NBN and an activating NTRK1 fusion. Upon disease progression following 13 months of treatment with folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX), genomic analysis of a metastatic liver biopsy revealed the emergence of a novel reversion mutation restoring the reading frame of NBN. To our knowledge, genomic reversion of NBN has not been previously reported as a resistance mechanism in any tumor type. The patient was treated with, but did not respond to, targeted treatment with a selective NTRK inhibitor. This case highlights the complex but highly actionable genomic landscape of PACC and underlines the value of genomic profiling of rare tumor types such as PACC.

Loss of the DNA Repair Gene RNase H2 Identifies a Unique Subset of DDR-Deficient Leiomyosarcomas.

Targeting the DNA damage response (DDR) pathway is an emerging therapeutic approach for leiomyosarcoma (LMS), and loss of RNase H2, a DDR pathway member, is a potentially actionable alteration for DDR-targeted treatments. Therefore, we designed a protein- and genomic-based RNase H2 screening assay to determine its prevalence and prognostic significance. Using a selective RNase H2 antibody on a pan-tumor microarray (TMA), RNase H2 loss was more common in LMS (11.5%, 9/78) than across all tumors (3.8%, 32/843). In a separate LMS cohort, RNase H2 deficiency was confirmed in uterine LMS (U-LMS, 21%, 23/108) and soft-tissue LMS (ST-LMS; 30%, 39/102). In the TCGA database, RNASEH2B homozygous deletions (HomDels) were found in 6% (5/80) of LMS cases, with a higher proportion in U-LMS (15%; 4/27) compared with ST-LMS (2%; 1/53). Using the SNiPDx targeted-NGS sequencing assay to detect biallelic loss of function in select DDR-related genes, we found RNASEH2B HomDels in 54% (19/35) of U-LMS cases with RNase H2 loss by IHC, and 7% (3/43) HomDels in RNase H2 intact cases. No RNASEH2B HomDels were detected in ST-LMS. In U-LMS patient cohort (n = 109), no significant overall survival difference was seen in patients with RNase H2 loss versus intact, or RNASEH2B HomDel (n = 12) versus Non-HomDel (n = 37). The overall diagnostic accuracy, sensitivity, and specificity of RNase H2 IHC for detecting RNA-SEH2B HomDels in U-LMS was 76%, 93%, and 71%, respectively, and it is being developed for future predictive biomarker driven clinical trials targeting DDR in U-LMS.

Qualitative Message Development to Motivate Quitting Smoking in Older Adults: Dementia May Motivate Quitting.

Compared to younger adults, older adults who smoke cigarettes are half as likely to make a quit attempt, but more likely to maintain abstinence using evidence-based smoking treatments (EBSTs), illustrating the need for motivational messages to promote cessation through EBSTs. It is unclear whether messaging regarding the association between smoking and dementia might motivate older adults to quit. We conducted 90-min semi-structured qualitative interviews and surveys via telephone with 24 U.S. older adults who smoke (ages 50-75) with no cognitive impairment history. Rapid content analysis revealed the most reported health-related concern of aging was dementia/cognitive loss/loss of functioning. However, most participants were unaware of the association between cognitive decline and smoking. Participants had seen previous smoking cessation advertisements, but most did not feel motivated to quit by them. The majority found a message about smoking raising dementia risk and quitting decreasing that risk to be motivational for cessation. Exact message content preference varied, but 2 broad categories arose: hope- and fear-based messages. Most participants stated willingness to use some cessation pharmacotherapy and half were willing to use cessation counseling. Participants preferred messages to come from older adults who were successful quitters. To our knowledge, this was the first study to explore potential motivational messages targeting older adult smokers, including the potential acceptability of a dementia-related message in this context. This work supports patient desire for targeted motivational messages for older adult smokers. Messages highlighting the link between smoking and dementia are perceived to be motivational for this group; future work should compare a hope- to fear-based messages.

Explaining COVID-19 related mortality disparities in American Indians and Alaska Natives.

American Indian and Alaska Native (AI/AN) individuals are more likely to die with COVID-19 than other groups, but there is limited empirical evidence to explain the cause of this inequity. The objective of this study was to determine whether medical comorbidities, area socioeconomic deprivation, or access to treatment can explain the greater COVID-19 related mortality among AI/AN individuals. The design was a retrospective cohort study of harmonized electronic health record data of all inpatients with COVID-19 from 21 United States health systems from February 2020 through January 2022. The mortality of AI/AN inpatients was compared to all Non-Hispanic White (NHW) inpatients and to a matched subsample of NHW inpatients. AI/AN inpatients were more likely to die during their hospitalization (13.2% versus 7.1%; odds ratio [OR] = 1.98, 95% confidence interval [CI] = 1.48, 2.65) than their matched NHW counterparts. After adjusting for comorbidities, area social deprivation, and access to treatment, the association between ethnicity and mortality was substantially reduced (OR 1.59, 95% CI 1.15, 2.22). The significant residual relation between AI/AN versus NHW status and mortality indicate that there are other important unmeasured factors that contribute to this inequity. This will be an important direction for future research.

Plasma Aß42/40 and cognitive variability are associated with cognitive function in Black Americans: Findings from the AA-FAIM cohort.

Introduction: It is critical to develop more inclusive Alzheimer's disease (AD) research protocols to ensure that historically excluded groups are included in preclinical research and have access to timely diagnosis and treatment. If validated in racialized groups, plasma AD biomarkers and measures of subtle cognitive dysfunction could provide avenues to expand diversity in preclinical AD research. We sought to evaluate the utility of two easily obtained, low-burden disease markers, plasma amyloid beta (Aß)42/40, and intra-individual cognitive variability (IICV), to predict concurrent and longitudinal cognitive performance in a sample of Black adults. Methods: Two hundred fifty-seven Black participants enrolled in the African Americans Fighting Alzheimer's in Midlife (AA-FAIM) study underwent at least one cognitive assessment visit; a subset of n = 235 had plasma samples. Baseline IICV was calculated as the standard deviation across participants' z scores on five cognitive measures: Rey Auditory Verbal Learning Test Delayed Recall, Trail Making Test Parts A and B (Trails A and B), and Boston Naming Test. Using mixed effects regression models, we compared concurrent and longitudinal models to baseline plasma Aß42/40 or IICV by age interactions. PrecivityAD assays quantified baseline plasma Aß42/40. Results: IICV was associated with concurrent/baseline performance on several outcomes but did not modify associations between age and cognitive decline. In contrast, plasma Aß42/40 was unrelated to baseline cognitive performance, but a pattern emerged in interactions with age in longitudinal models of Trails A and B and Rey Auditory Verbal Learning Test total learning trials. Although not significant after correcting for multiple comparisons, low Aß42/40 was associated with faster cognitive declines over time. Discussion: Our results are promising as they extend existing findings to an Black American sample using low-cost, low-burden methods that can be implemented outside of a research center, thus supporting efforts for inclusive AD biomarker research.

Effect of Metabolic Syndrome Risk Factors on Processing Speed and Executive Function in Three Racialized Groups.

BACKGROUND: Metabolic syndrome (MetS) has been associated with increased risk for Alzheimer's disease and related dementias (ADRD). Understanding the association of MetS risk factors to processing speed and executive function in the pre-clinical stages of ADRD in under-represented groups would offer insight on potential mechanisms through which MetS associates with ADRD risk. OBJECTIVE: Examine association of MetS features and processing speed and executive function across three racial groups. METHODS: Cognitively unimpaired adults from the Wisconsin Alzheimer's Disease Research Center and the Wisconsin Registry for Alzheimer's Disease Prevention completed blood-draws and neuropsychological testing. Six cognitive outcomes were assessed in association to MetS risk factors: Trailmaking Tests A and B, Animal Fluency, Digit Symbol, and composite scores for Processing Speed and Executive Function. Linear mixed effect models were used to assess the relationship between MetS risk factor count and longitudinal cognitive performance across three racialized groups. RESULTS: Participant sample sizes varied by outcome analyzed (N = 714-1,088). African American and Native American groups exhibited higher rates of MetS than non-Hispanic Whites. MetS was associated with processing speed and executive function across all racialized groups. Three-way interaction by racialized group was limited to one cognitive outcome: Trailmaking Test A. CONCLUSION: Metabolic dysfunction incrementally affects cognitive trajectory, with generally similar associations across racial groups. Since racialized groups exhibit higher levels of both MetS and ADRD, MetS may represent a driving factor for increased ADRD risk experience by racialized group and an important and modifiable target through which to reduce risk of ADRD.

Wisconsin Healthcare Utilization Cost Among American Indians/Alaska Natives with and without Alzheimer's Disease and Related Dementias.

Individuals with Alzheimer's disease and related dementias (ADRD) accrue higher healthcare utilization costs than peers without ADRD, but incremental costs of ADRD among American Indians/Alaska Natives (AI/AN) is unknown. State-wide paid electronic health record data were retrospectively analyzed using percentile-based bootstrapped 95% confidence intervals of the weighted mean difference of total 5-year billed costs to compare total accrued for non-Tribal and Indian Health Service utilization costs among Medicaid and state program eligible AI/AN, ≥40 years, based on the presence/absence of ADRD (matching by demographic and medical factors). AI/AN individuals with ADRD accrued double the costs compared to those without ADRD, costing an additional $880.45 million to $1.91 billion/year.

Evolution of antibiotic resistance impacts optimal temperature and growth rate in Escherichia coli and Staphylococcus epidermidis.

AIMS: Bacterial response to temperature changes can influence their pathogenicity to plants and humans. Changes in temperature can affect cellular and physiological responses in bacteria that can in turn affect the evolution and prevalence of antibiotic-resistance genes. Yet, how antibiotic-resistance genes influence microbial temperature response is poorly understood. METHODS AND RESULTS: We examined growth rates and physiological responses to temperature in two species-E. coli and Staph. epidermidis-after evolved resistance to 13 antibiotics. We found that evolved resistance results in species-, strain- and antibiotic-specific shifts in optimal temperature. When E. coli evolves resistance to nucleic acid and cell wall inhibitors, their optimal growth temperature decreases, and when Staph. epidermidis and E. coli evolve resistance to protein synthesis and their optimal temperature increases. Intriguingly, when Staph. epidermidis evolves resistance to Teicoplanin, fitness also increases in drug-free environments, independent of temperature response. CONCLUSION: Our results highlight how the complexity of antibiotic resistance is amplified when considering physiological responses to temperature. SIGNIFICANCE: Bacteria continuously respond to changing temperatures-whether through increased body temperature during fever, climate change or other factors. It is crucial to understand the interactions between antibiotic resistance and temperature.

Understanding what changes adults in a smoking cessation study believe they need to make to quit smoking: A qualitative analysis of pre- and post-quit perceptions.

OBJECTIVE: Most individuals who try to quit smoking will not succeed even if they use evidence-based treatment. Qualitative methods can help identify cessation treatments' limitations and suggest adaptations to increase treatment success. METHOD: Rapid qualitative analysis was conducted on data from 125 adults who smoked daily (48% female; 44% White) and participated in a smoking cessation trial and completed qualitative interviews 2 weeks prequit, reporting on changes they needed to make to quit, and 100 adults (50% female; 49% White) who completed a second interview 2 weeks postquit, reporting changes they had made. RESULTS: The anticipated changes reported prequit (in order of frequency) were as follows: identify smoking triggers (without a coping plan), focus on benefits of quitting, reduce exposure to others smoking, make other health changes, reduce exposure to nonsocial smoking cues, and reduce alcohol consumption. Many participants were unable to identify specific changes that would aid their cessation success. Changes reported postquit included the following: use the 4 D strategies (delay, drink water, deep breathing, distract), reduce exposure to nonsocial smoking cues, focus on benefits of quitting, change daily routine, make other health changes, reduce exposure to others smoking, and get support from loved ones. Most changes reported postquit were consistent with clinical practice guidelines; however, use of cessation medication was the least reported theme. CONCLUSION: Prior to quitting, over a third of participants were unable to identify changes to increase cessation success. Those who could focus on triggers and cues for smoking. Postquit, participants reported using cessation strategies encouraged during study cessation counseling. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Racial Differences in Associations of Cognitive Health Status With Happiness, Helplessness, and Hopelessness Among Older Adults: An Exploratory Study.

Background: The relationship between healthy and positive aging and dementia and cognitive impairment has received limited attention in the field of aging. Affect impacts cognitive changes and processes, and cognitive impairment is associated with affective comorbidities. The purpose of the study was to examine (a) whether happiness, helplessness, and hopelessness are linked to cognitive health status, and (b) whether these associations differ by race. Methods: Participants were enrollees in the Wisconsin Alzheimer's Disease Research Center's Clinical Core (ADRC). Average age at baseline was 60.85 (SD = 8.65), 73.70 (SD = 8.02), and 73.80 (SD = 9.59) years for cognitively normal individuals, individuals with MCI, and individuals with dementia, respectively. Results: In the full sample, chi-square test results revealed associations between Cognitive Health Status (CHS) and (a) happiness, χ2(2) = 6.06, p < 0.05, (b) helplessness, χ2(2) = 6.44, p < 0.05, and (c) hopelessness, χ2(2) = 14.11, p < 0.01. Conclusion: This study provides support for the association of both positive and negative affect with cognitive health status in middle- to older-aged adults.

Alzheimer's disease biomarkers in Black and non-Hispanic White cohorts: A contextualized review of the evidence.

Black Americans are disproportionately affected by dementia. To expand our understanding of mechanisms of this disparity, we look to Alzheimer's disease (AD) biomarkers. In this review, we summarize current data, comparing the few studies presenting these findings. Further, we contextualize the data using two influential frameworks: the National Institute on Aging-Alzheimer's Association (NIA-AA) Research Framework and NIA's Health Disparities Research Framework. The NIA-AA Research Framework provides a biological definition of AD that can be measured in vivo. However, current cut-points for determining pathological versus non-pathological status were developed using predominantly White cohorts-a serious limitation. The NIA's Health Disparities Research Framework is used to contextualize findings from studies identifying racial differences in biomarker levels, because studying biomakers in isolation cannot explain or reduce inequities. We offer recommendations to expand study beyond initial reports of racial differences. Specifically, life course experiences associated with racialization and commonly used study enrollment practices may better account for observations than exclusively biological explanations.

Cigarette Smoking Status, Cigarette Exposure, and Duration of Abstinence Predicting Incident Dementia and Death: A Multistate Model Approach.

BACKGROUND: To fully characterize the risk for dementia associated with cigarette smoking, studies must consider competing risks that hinder the observation of dementia or modify the chance that dementia occurs (i.e., death). Extant research examining the competing risks fails to account for the occurrence of death following dementia, limiting our understanding of the relation between smoking and dementia. OBJECTIVE: Examine the impact of smoking status, lifetime smoking exposure, and duration of abstinence on incident dementia, death following dementia, and death without dementia. METHODS: Multi-state models estimated hazard ratios (HR) for 95% confidence interval (CI) of 10,681 cognitively healthy adults for transition from baseline to dementia, baseline to death, and dementia to death based on smoking status, lifetime cigarette exposure, and abstinence duration. RESULTS: Compared to never smokers, current smokers had increased risk of dementia (HR = 1.66; 95% CI 1.18- 2.32; p = 0.004), and death from baseline (HR = 2.98; 95% CI 2.24- 3.98; p < 0.001) and incident dementia (HR = 1.88; 95% CI 1.08- 3.27; p = 0.03). Pack years increased risk of death from baseline (HR = 1.01; 95% CI 1.00- 1.01; p < 0.001), but not dementia risk (HR = 1.00; 95% CI 1.00- 1.00; p = 0.78) or death following dementia (HR = 1.01; 95% CI 1.00- 1.01; p = 0.05). Recent quitters (quit < 10 years), compared to never smokers, had increased risk of death after baseline (HR = 2.31; 95% CI 1.55- 3.43; p < 0.001), but not dementia (HR = 1.17; 95% CI 0.73- 1.88; p = 0.52) or death following dementia (HR = 1.01; 95% CI 0.42- 2.41; p = 0.99). CONCLUSION: Current smoking increases the risk for dementia and death, but dementia is better attributed to smoking recency than lifetime exposure. Smoking cessation at any age might reduce these risks for cognitively healthy individuals.

Smokers with and without Epilepsy show Similar Smoking Rate, Dependence Level, Cessation Attempts, and Motives.

BACKGROUND: Individuals with epilepsy are up to twice as likely to be current cigarette smokers compared to those without. Moreover, one study showed current smoking is associated with an increased likelihood of seizures. However, outside of this one study, there is limited data on the presentation of specific smoking-related behaviors and cognitions in people with epilepsy, inhibiting our understanding of the severity of this behavior and our ability to formulate effective treatments for this population. PURPOSE: The current study examined smoking-related behaviors and cognitions among smokers with epilepsy compared to smokers without epilepsy. METHODS: Participants were 43 smokers with (Mage = 43.4, SD = 11.6) and 43 smokers without (Mage = 45.5, SD = 8.8) epilepsy recruited from an urban, academic setting within the U.S. Separate Analyses of Covariance (ANCOVAs) were conducted to evaluate differences between smokers with and without epilepsy in terms of smoking behavior (i.e., daily smoking rate, nicotine dependence, number of quit attempts, smoking duration, age of smoking onset) and smoking-related cognitive processes (i.e., smoking motives, perceived barriers to smoking cessation, cessation motives) after controlling for race and problematic alcohol use. RESULTS: Smokers with epilepsy did not differ from smokers without epilepsy in terms of smoking rate (p = .51, ηp2 = .01), nicotine dependence (p = .12, ηp2 = .03), age of smoking onset (p = .42, ηp2 = .01), number of quit attempts (p = .43, ηp2 = .01), barriers to cessation (p = .30 to .80, ηp2 = .00 to .01), or cessation motives (p = .28 to .60, ηp2 = .00 to .02). Smokers without epilepsy reported higher levels of smoking for sensorimotor manipulation reasons (p = .03, ηp2 = .06) and longer smoking duration (p = .03, ηp2 = .06) than smokers with epilepsy. CONCLUSIONS: Smokers with epilepsy do not appear to differ significantly from smokers without epilepsy in terms of smoking-related behaviors and cognitions, and may therefore benefit from current evidence-based treatments for smoking cessation that are not contraindicated for epilepsy (i.e., bupropion, varenicline).

Provider perspectives on a clinical demonstration project to transition patients with stable mental health conditions to primary care.

Research to improve access to mental healthcare often focuses on increasing timely referrals from primary care (PC) to specialty mental health (SMH). However, timely and appropriate transitions back to PC are indispensable for increasing access to SMH for new patients. We developed and implemented a formalized process to identify patients eligible for transition from SMH to PC. The FLOW intervention was piloted at a Veterans Health Administration community-based outpatient clinic. Qualitatively examine provider perspectives regarding patient transitions at initiation and termination of the FLOW project. Sixteen mental health providers and three PC staff completed qualitative interviews about the benefits and drawbacks of FLOW at initiation. Ten mental health providers and one PC staff completed interviews at 12-month follow-up. Primary benefits anticipated at initiation were that FLOW would increase access to SMH, provide acknowledgment of veterans' recovery, and differentiate between higher and lower intensity mental health services. SMH providers reported additional perceived benefits at 12-month follow-up, including decreased stress over their caseloads and increased ability to deliver efficient, effective treatment. Anticipated drawbacks at initiation were that veterans would get inconsistent care, PC could not offer the same level of care as SMH, and veterans might view transition as a rejection by their SMH provider. Perceived drawbacks were similar at 12-month follow-up, but there was less frequent endorsement. Findings highlight need for sustained and frequent provider education regarding (i) the appropriate characteristics of individuals eligible for transition and (ii) established procedures to ensure care coordination during and after transition.

Perspectives of Veterans Affairs mental health providers on working with older adults with dementia and their caregivers.

Continuing education directed at building providers' skills and knowledge in geriatrics represents a practical approach to addressing the geriatric mental health (MH) care workforce shortage. To inform the development of professional training curricula, we surveyed MH providers (N = 65) at a Veterans Affairs medical center on working with older persons with dementia (PwD) and informal caregivers. Providers rated service provision to PwD and caregivers as highly important but endorsed modest self-efficacy. Half of respondents were minimally confident in managing risk of harm to self or others in a PwD. Respondents believed PwD can benefit from MH treatments, yet identified several barriers to providing care, including inadequate time and staffing resources. Interest in geriatric training topics was high. Findings demonstrate that MH providers at this site value care provision to PwD and caregivers, and desire additional training to serve this population. System-level barriers to MH care for PwD should also be identified and addressed.

The Exceptional Responders Initiative: Feasibility of a National Cancer Institute Pilot Study.

BACKGROUND: Tumor molecular profiling from patients experiencing exceptional responses to systemic therapy may provide insights into cancer biology and improve treatment tailoring. This pilot study evaluates the feasibility of identifying exceptional responders retrospectively, obtaining pre-exceptional response treatment tumor tissues, and analyzing them with state-of-the-art molecular analysis tools to identify potential molecular explanations for responses. METHODS: Exceptional response was defined as partial (PR) or complete (CR) response to a systemic treatment with population PR or CR rate less than 10% or an unusually long response (eg, duration >3 times published median). Cases proposed by patients' clinicians were reviewed by clinical and translational experts. Tumor and normal tissue (if possible) were profiled with whole exome sequencing and, if possible, targeted deep sequencing, RNA sequencing, methylation arrays, and immunohistochemistry. Potential germline mutations were tracked for relevance to disease. RESULTS: Cases reflected a variety of tumors and standard and investigational treatments. Of 520 cases, 476 (91.5%) were accepted for further review, and 222 of 476 (46.6%) proposed cases met requirements as exceptional responders. Clinical data were obtained from 168 of 222 cases (75.7%). Tumor was provided from 130 of 168 cases (77.4%). Of 117 of the 130 (90.0%) cases with sufficient nucleic acids, 109 (93.2%) were successfully analyzed; 6 patients had potentially actionable germline mutations. CONCLUSION: Exceptional responses occur with standard and investigational treatment. Retrospective identification of exceptional responders, accessioning, and sequencing of pretreatment archived tissue is feasible. Data from molecular analyses of tumors, particularly when combining results from patients who received similar treatments, may elucidate molecular bases for exceptional responses.

Molecular Features of Cancers Exhibiting Exceptional Responses to Treatment.

A small fraction of cancer patients with advanced disease survive significantly longer than patients with clinically comparable tumors. Molecular mechanisms for exceptional responses to therapy have been identified by genomic analysis of tumor biopsies from individual patients. Here, we analyzed tumor biopsies from an unbiased cohort of 111 exceptional responder patients using multiple platforms to profile genetic and epigenetic aberrations as well as the tumor microenvironment. Integrative analysis uncovered plausible mechanisms for the therapeutic response in nearly a quarter of the patients. The mechanisms were assigned to four broad categories-DNA damage response, intracellular signaling, immune engagement, and genetic alterations characteristic of favorable prognosis-with many tumors falling into multiple categories. These analyses revealed synthetic lethal relationships that may be exploited therapeutically and rare genetic lesions that favor therapeutic success, while also providing a wealth of testable hypotheses regarding oncogenic mechanisms that may influence the response to cancer therapy.

Targetable BRAF and RAF1 Alterations in Advanced Pediatric Cancers.

RAF family protein kinases signal through the MAPK pathway to orchestrate cellular proliferation, survival, and transformation. Identifying BRAF alterations in pediatric cancers is critically important as therapeutic agents targeting BRAF or MEK may be incorporated into the clinical management of these patients. In this study, we performed comprehensive genomic profiling on 3,633 pediatric cancer samples and identified a cohort of 221 (6.1%) cases with known or novel alterations in BRAF or RAF1 detected in extracranial solid tumors, brain tumors, or hematological malignancies. Eighty percent (176/221) of these tumors had a known-activating short variant (98, 55.7%), fusion (72, 40.9%), or insertion/deletion (6, 3.4%). Among BRAF altered cancers, the most common tumor types were brain tumors (74.4%), solid tumors (10.8%), hematological malignancies (9.1%), sarcomas (3.4%), and extracranial embryonal tumors (2.3%). RAF1 fusions containing intact RAF1 kinase domain (encoded by exons 10-17) were identified in seven tumors, including two novel fusions TMF1-RAF1 and SOX6-RAF1. Additionally, we highlight a subset of patients with brain tumor with positive clinical response to BRAF inhibitors, demonstrating the rationale for incorporating precision medicine into pediatric oncology. IMPLICATIONS FOR PRACTICE: Precision medicine has not yet gained a strong foothold in pediatric cancers. This study describes the landscape of BRAF and RAF1 genomic alterations across a diverse spectrum of pediatric cancers, primarily brain tumors, but also encompassing melanoma, sarcoma, several types of hematologic malignancy, and others. Given the availability of multiple U.S. Food and Drug Administration-approved BRAF inhibitors, identification of these alterations may assist with treatment decision making, as described here in three cases of pediatric cancer.