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.

Examination of a hope- and fear-based message targeting older adults who smoke: A randomized trial.

Older adults who smoke are half as likely to make a quit attempt, but more likely to maintain abstinence using evidence-based treatments. Awareness of the increased risk of dementia among people who currently smoke may motivate cessation in this population, but messages have not been tested. 820 adults who smoke, ages 50-80, with no history of dementia completed an online survey examining one of three randomly assigned messages (Control N = 266, Fear N = 274, Hope N = 280) on motivation and intentions to quit. Fear and Hope messages were based on the link between smoking and dementia. Fear increased motivation to quit [t(813) = 2.818, p = 0.005] more than Control. Hope did not differ from Control [t(813) = 1.908, p = 0.057] or Fear [t(813) = 0.937, p = 0.349] in change in motivation to quit. There were no differences between messages in change in intention to quit, F(2, 817) = 0.825, p = 0.439. Future work should examine feasibility and acceptability of fear-based motivational messages on quitting success.

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.

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.

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.

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 role of cigarette smoking in epilepsy severity and epilepsy-related quality of life.

Empirical evidence suggests that cigarette smoking is common among individuals with epilepsy. However, little is known about relationship between smoking and clinical features of epilepsy. Thus, the aim of the current study was to examine the differences between smokers (n = 43; 58.1% female, Mage = 43.4 years, SD = 11.6) and nonsmokers (n = 49; 63.3% female, Mage = 48.5 years, SD = 15.9) with epilepsy in terms of epilepsy severity (i.e., presence of seizures in the past year, refractory epilepsy status) and epilepsy-related quality of life. As hypothesized, smokers with epilepsy, compared with nonsmokers with epilepsy, were at an increased risk to have experienced seizures in the past year after controlling for the effect of Medicaid status as a proxy for socioeconomic status (odds ratio [OR] = 3.61). Positive smoking status was also associated with lower levels of epilepsy-related quality of life; however, this finding did not remain significant when Medicaid status was taken into consideration. Contrary to the hypotheses, smokers with epilepsy were not at an increased risk of having refractory epilepsy compared with nonsmokers with epilepsy. These findings suggest that cigarette smoking is associated with at least one aspect of epilepsy severity. Thus, in addition to the broader health benefits, smokers with epilepsy should be advised of the increased seizure risk associated with current cigarette smoking. Future work should examine the longitudinal impact of smoking on epilepsy severity, including whether successful smoking cessation ameliorates the seizure risk found in this cross-sectional study.

The role of anxiety sensitivity-physical concerns in terms of quit day withdrawal symptoms and cravings: A pilot test among smokers with asthma.

OBJECTIVE: The aim of the current study was to conduct secondary analyses of data collected from a study examining a self-guided quit attempt of smokers with and without asthma in order to examine the unique predictive ability of precessation (i.e., baseline) anxiety sensitivity physical concerns in terms of quit day withdrawal symptoms and cravings among abstinent smokers with asthma. METHODS: Participants were 24 regular cigarette smokers with asthma (50% female, Mage = 37.63 years, SD = 12.20) who participated in a self-guided-quit attempt and were able to maintain abstinence on their quit day. RESULTS: After controlling for the effects of the cognitive and social concerns domains of anxiety sensitivity, anxiety sensitivity-physical concerns significantly predicted greater quit day withdrawal symptoms (20.8% unique variance) and urges to smoke (38.0% unique variance). CONCLUSIONS: These findings suggest that smokers with asthma who fear anxiety-related sensations due to their feared physical consequences are more likely to experience intense withdrawal symptoms and desire to smoke at the beginning of a quit attempt. Clinically, smokers with higher levels of anxiety sensitivity physical concerns may benefit from smoking cessation interventions that specifically target anxiety sensitivity as well as prolonged use of nicotine replacement therapies to target withdrawal symptoms and cravings.

Hybrid Capture-Based Comprehensive Genomic Profiling Identifies Lung Cancer Patients with Well-Characterized Sensitizing Epidermal Growth Factor Receptor Point Mutations That Were Not Detected by Standard of Care Testing.

BACKGROUND: In our recent study, of cases positive for epidermal growth factor receptor (EGFR) exon 19 deletions using comprehensive genomic profiling (CGP), 17/77 (22%) patients with prior standard of care (SOC) EGFR testing results available were previously negative for exon 19 deletion. Our aim was to compare the detection rates of CGP versus SOC testing for well-characterized sensitizing EGFR point mutations (pm) in our 6,832-patient cohort. MATERIALS AND METHODS: DNA was extracted from 40 microns of formalin-fixed paraffin-embedded sections from 6,832 consecutive cases of non-small cell lung cancer (NSCLC) of various histologies (2012-2015). CGP was performed using a hybrid capture, adaptor ligation-based next-generation sequencing assay to a mean coverage depth of 576×. Genomic alterations (pm, small indels, copy number changes and rearrangements) involving EGFR were recorded for each case and compared with prior testing results if available. RESULTS: Overall, there were 482 instances of EGFR exon 21 L858R (359) and L861Q (20), exon 18 G719X (73) and exon 20 S768I (30) pm, of which 103 unique cases had prior EGFR testing results that were available for review. Of these 103 cases, CGP identified 22 patients (21%) with sensitizing EGFR pm that were not detected by SOC testing, including 9/75 (12%) patients with L858R, 4/7 (57%) patients with L861Q, 8/20 (40%) patients with G719X, and 4/7 (57%) patients with S768I pm (some patients had multiple EGFR pm). In cases with available clinical data, benefit from small molecule inhibitor therapy was observed. CONCLUSION: CGP, even when applied to low tumor purity clinical-grade specimens, can detect well-known EGFR pm in NSCLC patients that would otherwise not be detected by SOC testing. Taken together with EGFR exon 19 deletions, over 20% of patients who are positive for EGFR-activating mutations using CGP are previously negative by SOC EGFR mutation testing, suggesting that thousands of such patients per year in the U.S. alone could experience improved clinical outcomes when hybrid capture-based CGP is used to inform therapeutic decisions. IMPLICATIONS FOR PRACTICE: This study points out that genomic profiling, as based on hybrid capture next-generation sequencing, can identify lung cancer patients with point mutation in epidermal growth factor receptor (EGFR) missed by standard molecular testing who can likely benefit from anti-EGFR targeted therapy. Beyond the specific findings regarding false-negative point mutation testing for EGFR, this study highlights the need for oncologists and pathologists to be cognizant of the performance characteristics of testing deployed and the importance of clinical intuition in questioning the results of laboratory testing.

Panic and epilepsy in adults: A systematic review.

The purpose of the current paper was to review the empirical literature on the cooccurrence of panic and epilepsy, in order to determine whether there is an increased risk of panic attacks and panic disorder among adults with epilepsy and an increased risk of epilepsy among adults with panic disorder. Given the overlap between panic and ictal fear, a preliminary aim of the current review was to critically evaluate the methodology used to differentiate between diagnoses of panic disorder and epilepsy in existing research. A literature search was conducted in relevant electronic databases, and articles that directly focused on panic and epilepsy among adults were selected for the current review (n = 17). Overall, results suggest that rates of epilepsy are elevated among individuals with panic disorder and that panic attacks are elevated among individuals with epilepsy, but rates of panic disorder among people with epilepsy are inconsistent. However, most studies did not use sufficiently rigorous methods to differentiate between panic disorder and epilepsy. Therefore, a critical next step in this area of research is to develop a standard procedure for differentiating ictal fear from panic attacks and panic disorder.

Pediatric, Adolescent, and Young Adult Thyroid Carcinoma Harbors Frequent and Diverse Targetable Genomic Alterations, Including Kinase Fusions.

BACKGROUND: Thyroid carcinoma, which is rare in pediatric patients (age 0-18 years) but more common in adolescent and young adult (AYA) patients (age 15-39 years), carries the potential for morbidity and mortality. METHODS: Hybrid-capture-based comprehensive genomic profiling (CGP) was performed prospectively on 512 consecutively submitted thyroid carcinomas, including 58 from pediatric and AYA (PAYA) patients, to identify genomic alterations (GAs), including base substitutions, insertions/deletions, copy number alterations, and rearrangements. This PAYA data series includes 41 patients with papillary thyroid carcinoma (PTC), 3 with anaplastic thyroid carcinoma (ATC), and 14 with medullary thyroid carcinoma (MTC). RESULTS: GAs were detected in 93% (54/58) of PAYA cases, with a mean of 1.4 GAs per case. In addition to BRAF V600E mutations, detected in 46% (19/41) of PAYA PTC cases and in 1 of 3 AYA ATC cases, oncogenic fusions involving RET, NTRK1, NTRK3, and ALK were detected in 37% (15/41) of PAYA PTC and 33% (1/3) of AYA ATC cases. Ninety-three percent (13/14) of MTC patients harbored RET alterations, including 3 novel insertions/deletions in exons 6 and 11. Two of these MTC patients with novel alterations in RET experienced clinical benefit from vandetanib treatment. CONCLUSION: CGP identified diverse clinically relevant GAs in PAYA patients with thyroid carcinoma, including 83% (34/41) of PTC cases harboring activating kinase mutations or activating kinase rearrangements. These genomic observations and index cases exhibiting clinical benefit from targeted therapy suggest that young patients with advanced thyroid carcinoma can benefit from CGP and rationally matched targeted therapy. The Oncologist 2017;22:255-263 IMPLICATIONS FOR PRACTICE: The detection of diverse clinically relevant genomic alterations in the majority of pediatric, adolescent, and young adult patients with thyroid carcinoma in this study suggests that comprehensive genomic profiling may be beneficial for young patients with papillary, anaplastic, or medullary thyroid carcinoma, particularly for advanced or refractory cases for which clinical trials involving molecularly targeted therapies may be appropriate.

Comprehensive Genomic Profiling of 282 Pediatric Low- and High-Grade Gliomas Reveals Genomic Drivers, Tumor Mutational Burden, and Hypermutation Signatures.

BACKGROUND: Pediatric brain tumors are the leading cause of death for children with cancer in the U.S. Incorporating next-generation sequencing data for both pediatric low-grade (pLGGs) and high-grade gliomas (pHGGs) can inform diagnostic, prognostic, and therapeutic decision-making. MATERIALS AND METHODS: We performed comprehensive genomic profiling on 282 pediatric gliomas (157 pHGGs, 125 pLGGs), sequencing 315 cancer-related genes and calculating the tumor mutational burden (TMB; mutations per megabase [Mb]). RESULTS: In pLGGs, we detected genomic alterations (GA) in 95.2% (119/125) of tumors. BRAF was most frequently altered (48%; 60/125), and FGFR1 missense (17.6%; 22/125), NF1 loss of function (8.8%; 11/125), and TP53 (5.6%; 7/125) mutations were also detected. Rearrangements were identified in 35% of pLGGs, including KIAA1549-BRAF, QKI-RAF1, FGFR3-TACC3, CEP85L-ROS1, and GOPC-ROS1 fusions. Among pHGGs, GA were identified in 96.8% (152/157). The genes most frequently mutated were TP53 (49%; 77/157), H3F3A (37.6%; 59/157), ATRX (24.2%; 38/157), NF1 (22.2%; 35/157), and PDGFRA (21.7%; 34/157). Interestingly, most H3F3A mutations (81.4%; 35/43) were the variant K28M. Midline tumor analysis revealed H3F3A mutations (40%; 40/100) consisted solely of the K28M variant. Pediatric high-grade gliomas harbored oncogenic EML4-ALK, DGKB-ETV1, ATG7-RAF1, and EWSR1-PATZ1 fusions. Six percent (9/157) of pHGGs were hypermutated (TMB >20 mutations per Mb; range 43-581 mutations per Mb), harboring mutations deleterious for DNA repair in MSH6, MSH2, MLH1, PMS2, POLE, and POLD1 genes (78% of cases). CONCLUSION: Comprehensive genomic profiling of pediatric gliomas provides objective data that promote diagnostic accuracy and enhance clinical decision-making. Additionally, TMB could be a biomarker to identify pediatric glioblastoma (GBM) patients who may benefit from immunotherapy. IMPLICATIONS FOR PRACTICE: By providing objective data to support diagnostic, prognostic, and therapeutic decision-making, comprehensive genomic profiling is necessary for advancing care for pediatric neuro-oncology patients. This article presents the largest cohort of pediatric low- and high-grade gliomas profiled by next-generation sequencing. Reportable alterations were detected in 95% of patients, including diagnostically relevant lesions as well as novel oncogenic fusions and mutations. Additionally, tumor mutational burden (TMB) is reported, which identifies a subpopulation of hypermutated glioblastomas that harbor deleterious mutations in DNA repair genes. This provides support for TMB as a potential biomarker to identify patients who may preferentially benefit from immune checkpoint inhibitors.

The role of mindfulness skills in terms of anxiety-related cognitive risk factors among college students with problematic alcohol use.

BACKGROUND: The aim of the current study was to examine the associations between the specific mindfulness skills of observing, describing, awareness, nonjudgment, and nonreactivity in terms of anxiety sensitivity (AS), distress tolerance (DT), and intolerance of uncertainty (IU) among college students with problematic alcohol use. METHODS: Participants were 202 (69.3% male; Mage = 18.96, SD = 2.24, range = 18-45 years) undergraduate college students with problematic alcohol use who completed self-report measures for course credit. RESULTS: Results indicated that after controlling for the effects of gender, smoking status, marijuana use status, and negative affectivity, greater use of the mindfulness skill of observing was associated with higher AS, greater describing was associated with lower AS and higher DT, greater nonjudgment was associated with lower AS and IU and higher DT, and greater nonreactivity was associated with increased DT. Awareness did not significantly predict any of the examined risk factors. CONCLUSIONS: These results suggest that specific mindfulness skills are associated with a greater tolerance of physiological, emotional, and uncertain states. An important next step will be to examine whether mindfulness skills are associated with decreased problematic alcohol use due to improvements in these anxiety-related risk factors.

Differences in panic psychopathology between smokers with and without asthma.

Cigarette smoking is more common among individuals with asthma compared to those without, resulting in increased risk of morbidity and mortality. However, there has been little exploration of psychological factors that differ between smokers with and without asthma. Thus, the aim of the current study was to examine differences between smokers with and without asthma in terms of anxiety sensitivity, panic symptoms, lifetime history of panic attacks, and lifetime history of panic disorder. Participants were 115 smokers with asthma (55.3% male, Mage = 38.4 years, SD = 11.9) and 120 smokers without asthma (70.6% male, Mage = 37.0 years, SD = 12.8) who were administered a structured diagnostic interview and completed self-report measures. As hypothesized, after controlling for the effects of cigarettes per day, gender, race, and education, smokers with asthma reported higher levels of anxiety sensitivity and panic symptoms and were at an increased risk for having a lifetime history of panic attacks (OR = 3.01) and panic disorder (OR = 2.96) compared to smokers without asthma. Further, group differences in anxiety sensitivity and panic symptoms remained even after removing participants with a lifetime history of panic attacks or panic disorder. These findings suggest that smokers with asthma are a particularly 'at-risk' population for panic psychopathology and likely in need of specialized smoking-related prevention and intervention efforts.

The distribution of BRAF gene fusions in solid tumors and response to targeted therapy.

Although the BRAF V600E base substitution is an approved target for the BRAF inhibitors in melanoma, BRAF gene fusions have not been investigated as anticancer drug targets. In our study, a wide variety of tumors underwent comprehensive genomic profiling for hundreds of known cancer genes using the FoundationOne™ or FoundationOne Heme™ comprehensive genomic profiling assays. BRAF fusions involving the intact in-frame BRAF kinase domain were observed in 55 (0.3%) of 20,573 tumors, across 12 distinct tumor types, including 20 novel BRAF fusions. These comprised 29 unique 5' fusion partners, of which 31% (9) were known and 69% (20) were novel. BRAF fusions included 3% (14/531) of melanomas; 2% (15/701) of gliomas; 1.0% (3/294) of thyroid cancers; 0.3% (3/1,062) pancreatic carcinomas; 0.2% (8/4,013) nonsmall-cell lung cancers and 0.2% (4/2,154) of colorectal cancers, and were enriched in pilocytic (30%) vs. nonpilocytic gliomas (1%; p < 0.0001), Spitzoid (75%) vs. nonSpitzoid melanomas (1%; p = 0.0001), acinar (67%) vs. nonacinar pancreatic cancers (<1%; p < 0.0001) and papillary (3%) vs. nonpapillary thyroid cancers (0%; p < 0.03). Clinical responses to trametinib and sorafenib are presented. In conclusion, BRAF fusions are rare driver alterations in a wide variety of malignant neoplasms, but enriched in Spitzoid melanoma, pilocytic astrocytomas, pancreatic acinar and papillary thyroid cancers.

Evaluation of 122 advanced-stage cutaneous squamous cell carcinomas by comprehensive genomic profiling opens the door for new routes to targeted therapies.

BACKGROUND: The authors hypothesized that comprehensive genomic profiling of advanced-stage cutaneous squamous cell carcinoma (cSCC) could identify genomic-derived drug targets of therapy for patients with conventional therapy-resistant disease. METHODS: Comprehensive genomic profiling of 315 cancer genes was applied to 50 ng of DNA from 122 cSCC cases for the evaluation of all classes of genomic alterations (GAs). Clinically relevant genomic alterations (CRGAs) were defined as those identifying anticancer drugs on the market or in registered clinical trials. RESULTS: There were 21 women (17%) and 101 men (83%) with a median age of 64.9 years (range, 21-87 years). Eleven cSCC cases (9%) were histologic AJCC grade 1, 69 (57%) were grade 2, and 42 (34%) were grade 3. The primary cSCC was used for sequencing in 77 cases (63%). Metastatic lesions were sequenced in 37% of cases. There were 1120 total GAs identified (average of 9.2 GAs per tumor), with 100% of cases harboring at least 1 alteration. Of the 122 cSCCs, 107 (88%) harbored at least 1 CRGA (2.5 CRGAs per cSCC) includingNOTCH1 (43%); patched 1 (PTCH1) (11%); BRCA2 (10%); HRAS (8%); ataxia telangiectasia mutated (ATM) (7%); erb-B2 receptor tyrosine kinase 4 (ERBB4) (7%); neurofibromatosis type 1 (NF1) (7%); erb-B2 receptor tyrosine kinase 2 (ERBB2) (6%); phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) (6%); cyclin D1 (CCND1) (6%); epidermal growth factor receptor (EGFR) (5%); and F-box and WD repeat domain containing 7, E3 ubiquitin protein ligase (FBXW7) (5%). CONCLUSIONS: In the current study, approximately 88% of patients with cSCC were found to harbor clinically relevant GAs that have the potential to guide the treatment of patients with advanced-stage tumors with targeted therapeutic agents. Cancer 2016;122:249-257. © 2015 American Cancer Society.

Comprehensive Genomic Profiling Facilitates Implementation of the National Comprehensive Cancer Network Guidelines for Lung Cancer Biomarker Testing and Identifies Patients Who May Benefit From Enrollment in Mechanism-Driven Clinical Trials.

BACKGROUND: The National Comprehensive Cancer Network (NCCN) guidelines for patients with metastatic non-small cell lung cancer (NSCLC) recommend testing for EGFR, BRAF, ERBB2, and MET mutations; ALK, ROS1, and RET rearrangements; and MET amplification. We investigated the feasibility and utility of comprehensive genomic profiling (CGP), a hybrid capture-based next-generation sequencing (NGS) test, in clinical practice. METHODS: CGP was performed to a mean coverage depth of 576× on 6,832 consecutive cases of NSCLC (2012-2015). Genomic alterations (GAs) (point mutations, small indels, copy number changes, and rearrangements) involving EGFR, ALK, BRAF, ERBB2, MET, ROS1, RET, and KRAS were recorded. We also evaluated lung adenocarcinoma (AD) cases without GAs, involving these eight genes. RESULTS: The median age of the patients was 64 years (range: 13-88 years) and 53% were female. Among the patients studied, 4,876 (71%) harbored at least one GA involving EGFR (20%), ALK (4.1%), BRAF (5.7%), ERBB2 (6.0%), MET (5.6%), ROS1 (1.5%), RET (2.4%), or KRAS (32%). In the remaining cohort of lung AD without these known drivers, 273 cancer-related genes were altered in at least 0.1% of cases, including STK11 (21%), NF1 (13%), MYC (9.8%), RICTOR (6.4%), PIK3CA (5.4%), CDK4 (4.3%), CCND1 (4.0%), BRCA2 (2.5%), NRAS (2.3%), BRCA1 (1.7%), MAP2K1 (1.2%), HRAS (0.7%), NTRK1 (0.7%), and NTRK3 (0.2%). CONCLUSION: CGP is practical and facilitates implementation of the NCCN guidelines for NSCLC by enabling simultaneous detection of GAs involving all seven driver oncogenes and KRAS. Furthermore, without additional tissue use or cost, CGP identifies patients with "pan-negative" lung AD who may benefit from enrollment in mechanism-driven clinical trials. IMPLICATIONS FOR PRACTICE: National Comprehensive Cancer Network guidelines for patients with metastatic non-small cell lung cancer (NSCLC) recommend testing for several genomic alterations (GAs). The feasibility and utility of comprehensive genomic profiling were studied in NSCLC and in lung adenocarcinoma (AD) without GAs. Of patients with NSCLC, 71% harbored at least one GA to a gene listed in the guidelines or KRAS; 273 cancer-related genes were altered in at least 0.1% of the AD cases. Although logistical and administrative hurdles limit the widespread use of next-generation sequencing, the data confirm the feasibility and potential utility of comprehensive genomic profiling in clinical practice.

Clinically advanced and metastatic pure mucinous carcinoma of the breast: a comprehensive genomic profiling study.

PURPOSE: Pure mucinous breast carcinoma (pmucBC) is a distinctive variant of breast cancer (BC) featuring an excellent overall prognosis. However, on rare occasions, pmucBC pursues an aggressive clinical course. We queried whether comprehensive genomic profiling (CGP) would uncover clinically relevant genomic alterations (CRGA) that could lead to targeted therapy treatment for patients with an advanced and metastatic form of pmucBC. METHODS: From a series of 51,238 total cancer samples, which included 5605 cases of clinically advanced BC and 22 cases of stage IV pmucBC, DNA was extracted from 40 microns of FFPE sections. Comprehensive genomic profiling was performed using a hybrid-capture, adaptor ligation-based next generation sequencing assay to a mean coverage depth of 564X. The results were analyzed for all classes of genomic alterations (GA) including base substitutions, insertions and deletions, select rearrangements, and copy number changes. Clinically relevant genomic alterations were defined as those indicating possible treatment with anti-cancer drugs on the market or in registered clinical trials. RESULTS: Samples were obtained from breast (11), lymph nodes (3), chest wall (2), liver (2), soft tissue (2), bone (1), and pleura (1). The median age of the 22 pmucBC patients was 57 years (range 32-79 years). Three pmucBCs were grade 1, 17 were grade 2, and 2 were grade 3. Twenty-one (95 %) pmucBC were ER+, 18 (82 %) were PR+, and 3 (14 %) were HER2+ by IHC and/or FISH. A total of 132 GA were identified (6.0 GA per tumor), including 53 CRGA, for a mean of 2.4 GA per tumor. Amplification of FGFR1 or ZNF703, located within the same amplicon, was found in 8 of 22 cases (36 %). This enrichment of FGFR1 amplification in 36 % of pmucBC versus 11 % of non-mucinous ER+ BC (601 cases) was significant (p < 0.005). Other frequently altered genes of interest in pmucBC were CCND1 and the FGF3/FGF4/FGF19 amplicon (27 %), often co-amplified together. ERBB2/HER2 alterations were identified in 5 pmucBC (23 %): ERBB2 amplification was found in 3 of 3 cases (100 %) that were HER2+ by IHC and/or FISH; 1 pmucBC was negative for HER2 overexpression by IHC, but positive for amplification by CGP; and 2 pmucBC harbored the ERBB2 substitutions D769Y and V777L (one sample also featured ERBB2 amplification). The enrichment of ERBB2 GA in metastatic pmucBC versus non-metastatic primary pmucBC was significant (p = 0.03). CRGA were also found in 20 additional genes including PIK3CA (5), BRCA1 (1), TSC2 (1), STK11 (1), AKT3 (1), and ESR1 (1). CONCLUSIONS: Metastatic pmucBC is a distinct form of breast cancer that features a relatively high frequency of CRGA, including a significant enrichment of FGFR1 alterations and a high frequency of ERBB2 alterations when compared with non-metastatic pmucBC. These findings suggest that CGP can identify a variety of known and emerging therapy targets that have the potential to improve outcomes for patients with clinically advanced and metastatic forms of this disease.

Evaluating the role of anxiety sensitivity in barriers to cessation and reasons for quitting among smokers with asthma.

The aim of the present study was to examine the unique predictive ability of anxiety sensitivity (AS) in terms of perceived barriers to cessation and smoking cessation motives among daily smokers with asthma (n = 125, 54% male, Mage = 37.7 years, SD = 12.1). As hypothesized, after controlling for the effects of race, asthma control, negative affect, and smoking rate, AS significantly predicted greater barriers to cessation, and reasons for quitting related to health concerns and self-control. Contrary to hypotheses, AS did not significantly predict external reasons for quitting. These findings suggest that smokers with asthma who are fearful of physiological arousal may be a particularly 'at-risk' population for smoking cessation difficulties due, in part, to greater perceived barriers to cessation. Interventions focused on enhancing intrinsic motivation for quitting and reducing AS may be most effective for this population.