Publications by authors named "Paul A Decker"

202 Publications

Adhesion pathway proteins and risk of atrial fibrillation in the Multi-Ethnic Study of Atherosclerosis.

BMC Cardiovasc Disord 2021 Sep 14;21(1):436. Epub 2021 Sep 14.

Department of Quantitative Health Sciences, Mayo Clinic, 200 First Street Southwest, Rochester, MN, USA.

Background: The cellular adhesion pathway has been suggested as playing an important role in the pathogenesis of atrial fibrillation (AF). However, prior studies that have investigated the role of adhesion pathway proteins in risk of AF have been limited in the number of proteins that were studied and in the ethnic and racial diversity of the study population. Therefore we aimed to study the associations of fifteen adhesion pathway proteins with incident AF in a large, diverse population.

Methods: Multi-Ethnic Study of Atherosclerosis participants from four races/ethnicities (n = 2504) with protein levels measured were followed for incident AF (n = 253). HGF protein was measured on Exam 1 samples (N = 6669; AF n = 851). Cox proportional hazards regression was used to assess the association of AF with 15 adhesion pathway proteins. Bonferroni correction was applied to account for multiple comparisons.

Results: After adjusting for potential confounding variables (age, sex, race/ethnicity, height, body mass index, systolic blood pressure, antihypertension therapy, diabetes status, current smoker, current alcohol use, and total and HDL cholesterol), and accounting for multiple testing (P < 0.05/15 = 0.0033), circulating levels of the following proteins were positively associated with a higher risk of AF: MMP-2 (HR per standard deviation increment, 1.27; 95% CI 1.11‒1.45), TIMP-2 (HR 1.28; 95% CI 1.12‒1.46), VCAM-1 (HR 1.32; 95% CI 1.16‒1.50), and SLPI (HR 1.22; 95% CI 1.07‒1.38). The association between proteins and AF did not differ by race/ethnicity.

Conclusions: Circulating levels of MMP-2, TIMP-2, VCAM-1, and SLPI were positively associated with an increased risk of incident AF in a diverse population. Our findings suggest that adhesion pathway proteins may be important risk predictors of AF.
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http://dx.doi.org/10.1186/s12872-021-02241-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8442417PMC
September 2021

Factors associated with willingness to wear a mask to prevent the spread of COVID-19 in a Midwestern Community.

Prev Med Rep 2021 Dec 2;24:101543. Epub 2021 Sep 2.

Behavioral Health Research Program, Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, United States.

Objective: To identify motivators and barriers to wearing a mask to prevent COVID-19.

Participants And Methods: An anonymous, online survey of adults from Southeastern Minnesota conducted August 2020. We assessed willingness to wear a mask and its associations with socio-demographics, COVID-19-related factors and prevention behaviors using multivariable ordinal logistic regression.

Results: Of 7,786 respondents (78% women, 51% rural), 9% reported 'not at all willing', 27% 'willing', and 64% 'very willing' to wear a mask. Factors independently associated with willingness to wear a mask were: urban residence (OR = 1.23, 95% CI 1.05-1.44, p = 0.009); college degree or greater (OR 1.42, CI 1.05-1.93, p = 0.025); age (18-29 years OR 1.29, CI 01.02-1.64, p = 0.038; 30-39 OR = 1.37, CI 1.12-1.69, p = 0.003; 60-69 OR = 1.44, CI 1.09-1.91, p = 0.011; 70-89 OR 2.09, CI 1.32-3.37, p = 0.002; 40-49 reference group); and (all p < 0.001) democratic party affiliation (OR 1.79, CI 1.40-2.29), correct COVID-19 knowledge (OR 1.50, CI 1.28-1.75), 5 + COVID-19 prevention behaviors (OR 2.74, CI 1.98-3.81), positive perceived impacts for wearing a mask (OR 1.55, 1.52-1.59), perceived COVID-19 severity (OR 2.1, CI 1.44-3.1), and greater stress (OR 1.03, CI 1.02-1.04), and trust in the Centers for Disease Control (CDC) (OR 1.78, CI 1.45 -2.19).

Conclusion: Results from this sample of SEMN residents suggest interventions to enhance COVID-19 knowledge, positive expectations for mask wearing, and trust in the CDC are warranted. Research is needed to understand cultural and other barriers and facilitators among sub-populations, e.g., rural residents less willing to wear a mask.
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http://dx.doi.org/10.1016/j.pmedr.2021.101543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8411589PMC
December 2021

Derivation and validation of a prediction model for histopathologic fibrotic hypersensitivity pneumonitis.

Respir Med 2021 Oct 30;187:106598. Epub 2021 Aug 30.

Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA. Electronic address:

Background: Clinical differentiation of fibrotic hypersensitivity pneumonitis (f-HP) remains challenging given variable and overlapping presentations with other fibrotic interstitial lung disease (f-ILD).

Objective: We derived a multivariable model for predicting histopathologic f-HP to better inform multidisciplinary team discussion (MDD) diagnosis, particularly when biopsy may be unsafe or cannot be achieved.

Methods: Patients with histopathologically-defined f-HP and other overlapping f-ILD were reviewed for distinguishing clinical and radiological variables. Using elastic net logistic regression, a penalized regression approach to minimize overfitting, a clinical model built on non-invasive assessments was derived for the prediction of histopathologic f-HP. This model was then validated in an independently derived external cohort from three sites.

Results: The derivation and validation cohorts consisted of 248 (84 cHP and 164 other f-ILD) and 157 (82 f-HP and 75 other f-ILD) histopathologically-defined patients, respectively (total study N = 405). Variables retained from the elastic net model included age in years (regression coefficient 0.033), male sex (-1.109), positive exposure history (1.318), percent predicted forced vital capacity (-0.021), radiologic peribronchovascular axial ILD distribution (0.199), mid (-0.22) or lower lobe (-0.839) craniocaudal or patchy (0.287) ILD distribution, upper (1.188) or equivalent upper and lower lobe (0.237) traction bronchiectasis, mosaic attenuation (1.164), and centrilobular nodules (2.045). Bias corrected AUC was 0.84 (standard error = 0.02) for the derivation cohort and 0.80 (CI 0.73-0.87) for the validation cohort.

Conclusions: This multivariable model demonstrated good predictive performance for delineating histopathologically-defined f-HP from other f-ILD as a means of avoiding or justifying biopsy and supporting MDD diagnostic confidence.
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http://dx.doi.org/10.1016/j.rmed.2021.106598DOI Listing
October 2021

Association of gastric emptying with postprandial appetite and satiety sensations in obesity.

Obesity (Silver Spring) 2021 09 27;29(9):1497-1507. Epub 2021 Jul 27.

Precision Medicine for Obesity Program, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA.

Objective: Satiety, defined as the duration of the sensation of fullness, is usually measured by validated visual analog scales (VAS) for appetite. Gastric function plays a key role in food intake regulation. However, the association between gastric emptying (GE) and VAS appetite is unknown.

Methods: In this cross-sectional study, 134 participants (mean [SEM] age = 39 [0.8] years, mean [SEM] BMI = 38 [0.5] kg/m , 67% females) completed simultaneous measurements of GE and VAS appetite. After a 320-kcal meal, GE was measured by scintigraphy and appetite by validated 100-mm VAS for 240 minutes. Satiation was defined as calories consumed to terminate meal and was measured by an ad libitum meal. GE, VAS, and ad libitum meal tests were measured on the same day. Percent of meal retention in the stomach, VAS area under curve (AUC ), and overall appetite score (OAS) were calculated. Pearson correlation (ρ) determined the association of GE with VAS appetite and satiation. Appetite components were also analyzed by quartiles based on GE .

Results: GE was correlated with sensation of VAS hunger (ρ = 0.24, p = 0.004), fullness (ρ = 0.16, p = 0.05), and OAS (ρ = 0.20, p = 0.02). Patients with rapid GE had a mean increase in VAS hunger by 32 mm/min (15.62%, p = 0.03) compared with normal/slow GE .

Conclusions: GE is associated with the sensations of appetite, and rapid GE is associated with increased appetite, which may contribute to weight gain.
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http://dx.doi.org/10.1002/oby.23204DOI Listing
September 2021

Preclinical modeling in GBM PDX xenografts to guide clinical development of lisavanbulin - a novel tumor checkpoint controller targeting microtubules.

Neuro Oncol 2021 Jul 7. Epub 2021 Jul 7.

Department of Radiation Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.

Background: Glioblastoma (GBM) is an incurable disease with few approved therapeutic interventions. Radiation therapy (RT) and temozolomide (TMZ) remain the standards of care. The efficacy and optimal deployment schedule of the orally bioavailable small-molecule tumor checkpoint controller lisavanbulin alone, and in combination with, standards of care were assessed using a panel of IDH-wildtype GBM patient-derived xenografts.

Methods: Mice bearing intracranial tumors received lisavanbulin +/- RT +/- TMZ and followed for survival. Lisavanbulin concentrations in plasma and brain were determined by liquid chromatography with tandem mass spectrometry, while flow cytometry was used for cell cycle analysis.

Results: Lisavanbulin monotherapy showed significant benefit (p<0.01) in 9 of 14 PDXs tested (median survival extension 9-84%) and brain-to-plasma ratios of 1.3 and 1.6 at 2- and 6-hours post-dose, respectively, validating previous data suggesting significant exposure in the brain. Prolonged lisavanbulin dosing from RT start until moribund was required for maximal benefit (GBM6: median survival lisavanbulin/RT 90 vs. RT alone 69 days, p=0.0001; GBM150: lisavanbulin/RT 143 days vs. RT alone 73 days, p=0.06). Similar observations were seen with RT/TMZ combinations (GBM39: RT/TMZ/lisavanbulin 502 days vs. RT/TMZ 249 days, p=0.0001; GBM26: RT/TMZ/lisavanbulin 172 days vs. RT/TMZ 121 days, p=0.04). Immunohistochemical analyses showed a significant increase in phospho-histone H3 with lisavanbulin treatment (p=0.01).

Conclusions: Lisavanbulin demonstrated excellent brain penetration, significant extension of survival alone or in RT or RT/TMZ combinations and was associated with mitotic arrest. These data provide a strong clinical rationale for testing lisavanbulin in combination with RT or RT/TMZ in GBM patients.
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http://dx.doi.org/10.1093/neuonc/noab162DOI Listing
July 2021

Clinical utility of brain biopsy for presumed CNS relapse of systemic lymphoma.

J Neurosurg 2021 Jul 2:1-10. Epub 2021 Jul 2.

1Department of Neurosurgery and.

Objective: The objective of this study was to determine the frequency with which brain biopsy for presumed CNS relapse of systemic hematological malignancies yields new, actionable diagnostic information. Hematological malignancies represent a disparate group of genetic and histopathological disorders. Proclivity for brain involvement is dependent on the unique entity and may occur synchronously or metasynchronously with the systemic lesion. Diffuse large B-cell lymphomas (DLBCLs) have a high propensity for brain involvement. Patients in remission from systemic DLBCL may present with a lesion suspicious for brain relapse. These patients often undergo brain biopsy. The authors' a priori hypothesis was that brain biopsy in patients with a history of systemic DLBCL and a new brain MRI lesion would have lower diagnostic utility compared with patients with non-DLBCL systemic malignancies.

Methods: The authors performed a retrospective review of patients who underwent brain biopsy between 2000 and 2019. Inclusion criteria were patients ≥ 18 years of age with a prior systemic hematological malignancy in remission presenting with a new brain MRI lesion concerning for CNS relapse. Patients with a history of any CNS neoplasms, demyelinating disorders, or active systemic disease were excluded. The main outcome was the proportion of patients with a distinct histopathological brain diagnosis compared with the systemic malignancy. The authors secondarily assessed overall survival, procedure-related morbidity, and 30-day mortality.

Results: Sixty patients met inclusion criteria (40 males and 20 females); the median age at brain biopsy was 67 years (range 23-88 years). The median follow-up was 8.5 months (range 0.1-231 months). Thirty-nine (65.0%) patients had DLBCL and 21 (35%) had non-DLBCL malignancies. Thirty-five of 36 (97.2%) patients with prior systemic DLBCL and a diagnostic biopsy had histopathological confirmation of the original systemic disease versus 0 of 21 patients with non-DLBCL systemic malignancies (p < 0.001). Morbidity and 30-day mortality were 8.3% and 10.0%, respectively; 2 of 6 30-day mortalities were directly attributable to the biopsy. The median overall survival following brain biopsy was 10.8 months.

Conclusions: Patients with a history of systemic DLBCL and presumed CNS relapse gained minimal clinical benefit from brain biopsy but were at high risk of morbidity and mortality. In patients with a history of non-DLBCL systemic malignancies, brain biopsy remained critical given the high likelihood for discovery of distinct diagnostic entities. It was determined that patients with a prior systemic DLBCL and presumed brain relapse should likely receive empirical therapy obviating treatment delay and the risks of brain biopsy.
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http://dx.doi.org/10.3171/2020.12.JNS202517DOI Listing
July 2021

Experimental Design of Preclinical Experiments: Number of PDX Lines versus Subsampling within PDX Lines.

Neuro Oncol 2021 Jun 9. Epub 2021 Jun 9.

Department of Radiation Oncology, Mayo Clinic, Rochester, MN.

Background: Appropriately designed preclinical patient-derived xenograft (PDX) experiments are important to accurately inform human clinical trials. There is little experimental design guidance regarding choosing the number of PDX lines to study, and the number of mice within each PDX line.

Methods: Retrospective data from IDH-wildtype glioblastoma preclinical experiments evaluating a uniform regimen of fractionated radiation (RT), temozolomide (TMZ) chemotherapy, and concurrent RT/TMZ across 27 PDX lines were used to evaluate experimental designs and empirically estimate statistical power for analysis of variance (ANOVA) and Cox regression.

Results: Increasing the number of PDX lines resulted in more precise and reproducible estimates of effect size. To achieve 80% statistical power using ANOVA, experiments using a single PDX line required subsampling six mice per PDX for each treatment group to detect a difference in survival of 135 days, and nine mice per PDX to detect a difference of 100 days. Alternatively, a design that used 10 PDX lines had greater than 80% power to detect a difference of 135 days with a single mouse per PDX per treatment group, a difference of 100 days with two mice per PDX per treatment, and 35 days with more than 10 mice per PDX per treatment. Power for Cox regression was slightly smaller than ANOVA for very small experiments regardless of effect size, and slightly higher than ANOVA for detecting a smaller effect size of 35 days difference in survival for moderate-to-large experiments.

Conclusions: Experimental designs using few mice across many PDX lines can provide robust results and account for inter-tumor variability.
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http://dx.doi.org/10.1093/neuonc/noab137DOI Listing
June 2021

Longitudinal cohorts for harnessing the electronic health record for disease prediction in a US population.

BMJ Open 2021 06 8;11(6):e044353. Epub 2021 Jun 8.

Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota, USA

Purpose: The depth and breadth of clinical data within electronic health record (EHR) systems paired with innovative machine learning methods can be leveraged to identify novel risk factors for complex diseases. However, analysing the EHR is challenging due to complexity and quality of the data. Therefore, we developed large electronic population-based cohorts with comprehensive harmonised and processed EHR data.

Participants: All individuals 30 years of age or older who resided in Olmsted County, Minnesota on 1 January 2006 were identified for the discovery cohort. Algorithms to define a variety of patient characteristics were developed and validated, thus building a comprehensive risk profile for each patient. Patients are followed for incident diseases and ageing-related outcomes. Using the same methods, an independent validation cohort was assembled by identifying all individuals 30 years of age or older who resided in the largely rural 26-county area of southern Minnesota and western Wisconsin on 1 January 2013.

Findings To Date: For the discovery cohort, 76 255 individuals (median age 49; 53% women) were identified from which a total of 9 644 221 laboratory results; 9 513 840 diagnosis codes; 10 924 291 procedure codes; 1 277 231 outpatient drug prescriptions; 966 136 heart rate measurements and 1 159 836 blood pressure (BP) measurements were retrieved during the baseline time period. The most prevalent conditions in this cohort were hyperlipidaemia, hypertension and arthritis. For the validation cohort, 333 460 individuals (median age 54; 52% women) were identified and to date, a total of 19 926 750 diagnosis codes, 10 527 444 heart rate measurements and 7 356 344 BP measurements were retrieved during baseline.

Future Plans: Using advanced machine learning approaches, these electronic cohorts will be used to identify novel sex-specific risk factors for complex diseases. These approaches will allow us to address several challenges with the use of EHR.
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http://dx.doi.org/10.1136/bmjopen-2020-044353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190051PMC
June 2021

Heterogeneous delivery across the blood-brain barrier limits the efficacy of an EGFR-targeting antibody drug conjugate in glioblastoma.

Neuro Oncol 2021 May 29. Epub 2021 May 29.

Department of Radiation Oncology, Mayo Clinic, Rochester, MN.

Background: Antibody drug conjugates (ADCs) targeting the epidermal growth factor receptor (EGFR), such as depatuxizumab mafodotin (Depatux-M), is a promising therapeutic strategy for glioblastoma (GBM) but recent clinical trials did not demonstrate a survival benefit. Understanding the mechanisms of failure for this promising strategy is critically important.

Methods: PDX models were employed to study efficacy of systemic vs intracranial delivery of Depatux-M. Immunofluorescence and MALDI-MSI were performed to detect drug levels in the brain. EGFR levels and compensatory pathways were studied using quantitative flow cytometry, Western blots, RNAseq, FISH and phosphoproteomics.

Results: Systemic delivery of Depatux-M was highly effective in nine of 10 EGFR-amplified heterotopic PDXs with survival extending beyond one year in eight PDXs. Acquired resistance in two PDXs (GBM12 and GBM46) was driven by suppression of EGFR expression or emergence of a novel short-variant of EGFR lacking the epitope for the Depatux-M antibody. In contrast to the profound benefit observed in heterotopic tumors, only two of seven intrinsically sensitive PDXs were responsive to Depatux-M as intracranial tumors. Poor efficacy in orthotopic PDXs was associated with limited and heterogeneous distribution of Depatux-M into tumor tissues, and artificial disruption of the BBB or bypass of the BBB by direct intracranial injection of Depatux-M into orthotopic tumors markedly enhanced the efficacy of drug treatment.

Conclusions: Despite profound intrinsic sensitivity to Depatux-M, limited drug delivery into brain tumor may have been a key contributor to lack of efficacy in recently failed clinical trials.
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http://dx.doi.org/10.1093/neuonc/noab133DOI Listing
May 2021

Efficacy of Tesevatinib in -Amplified Patient-Derived Xenograft Glioblastoma Models May Be Limited by Tissue Binding and Compensatory Signaling.

Mol Cancer Ther 2021 06 30;20(6):1009-1018. Epub 2021 Mar 30.

Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota.

Tesevatinib is a potent oral brain penetrant EGFR inhibitor currently being evaluated for glioblastoma therapy. Tesevatinib distribution was assessed in wild-type (WT) and triple knockout (TKO) FVB mice after dosing orally or via osmotic minipump; drug-tissue binding was assessed by rapid equilibrium dialysis. Two hours after tesevatinib dosing, brain concentrations in WT and TKO mice were 0.72 and 10.03 μg/g, respectively. Brain-to-plasma ratios (Kp) were 0.53 and 5.73, respectively. With intraperitoneal infusion, brain concentrations were 1.46 and 30.6 μg/g (Kp 1.16 and 25.10), respectively. The brain-to-plasma unbound drug concentration ratios were substantially lower (WT mice, 0.03-0.08; TKO mice, 0.40-1.75). Unbound drug concentrations in brains of WT mice were 0.78 to 1.59 ng/g. cytotoxicity and EGFR pathway signaling were evaluated using -amplified patient-derived glioblastoma xenograft models (GBM12, GBM6). pharmacodynamics and efficacy were assessed using athymic nude mice bearing either intracranial or flank tumors treated by oral gavage. Tesevatinib potently reduced cell viability [IC GBM12 = 11 nmol/L (5.5 ng/mL), GBM6 = 102 nmol/L] and suppressed EGFR signaling However, tesevatinib efficacy compared with vehicle in intracranial (GBM12, median survival: 23 vs. 18 days, = 0.003) and flank models (GBM12, median time to outcome: 41 vs. 33 days, = 0.007; GBM6, 44 vs. 33 days, = 0.007) was modest and associated with partial inhibition of EGFR signaling. Overall, tesevatinib efficacy in -amplified PDX GBM models is robust but relatively modest , despite a high brain-to-plasma ratio. This discrepancy may be explained by drug-tissue binding and compensatory signaling.
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http://dx.doi.org/10.1158/1535-7163.MCT-20-0640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172524PMC
June 2021

Natural Language Processing and Machine Learning for Identifying Incident Stroke From Electronic Health Records: Algorithm Development and Validation.

J Med Internet Res 2021 03 8;23(3):e22951. Epub 2021 Mar 8.

Department of Health Sciences Research, Mayo Clinic, Rochester, MN, United States.

Background: Stroke is an important clinical outcome in cardiovascular research. However, the ascertainment of incident stroke is typically accomplished via time-consuming manual chart abstraction. Current phenotyping efforts using electronic health records for stroke focus on case ascertainment rather than incident disease, which requires knowledge of the temporal sequence of events.

Objective: The aim of this study was to develop a machine learning-based phenotyping algorithm for incident stroke ascertainment based on diagnosis codes, procedure codes, and clinical concepts extracted from clinical notes using natural language processing.

Methods: The algorithm was trained and validated using an existing epidemiology cohort consisting of 4914 patients with atrial fibrillation (AF) with manually curated incident stroke events. Various combinations of feature sets and machine learning classifiers were compared. Using a heuristic rule based on the composition of concepts and codes, we further detected the stroke subtype (ischemic stroke/transient ischemic attack or hemorrhagic stroke) of each identified stroke. The algorithm was further validated using a cohort (n=150) stratified sampled from a population in Olmsted County, Minnesota (N=74,314).

Results: Among the 4914 patients with AF, 740 had validated incident stroke events. The best-performing stroke phenotyping algorithm used clinical concepts, diagnosis codes, and procedure codes as features in a random forest classifier. Among patients with stroke codes in the general population sample, the best-performing model achieved a positive predictive value of 86% (43/50; 95% CI 0.74-0.93) and a negative predictive value of 96% (96/100). For subtype identification, we achieved an accuracy of 83% in the AF cohort and 80% in the general population sample.

Conclusions: We developed and validated a machine learning-based algorithm that performed well for identifying incident stroke and for determining type of stroke. The algorithm also performed well on a sample from a general population, further demonstrating its generalizability and potential for adoption by other institutions.
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http://dx.doi.org/10.2196/22951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985804PMC
March 2021

Developing a Social Media Intervention to Connect Alaska Native People Who Smoke with Resources and Support to Quit Smoking: The Connecting Alaska Native Quit Study.

Nicotine Tob Res 2021 05;23(6):1002-1009

Department of Psychiatry and Psychology and Behavioral Health Research Program, Mayo Clinic, Rochester, MN, USA.

Background: Face-to-face tobacco cessation has had limited reach and efficacy in Alaska Native (AN) communities. We describe our two-phased approach to develop content for Connecting Alaska Native People to Quit Smoking, a Facebook group intervention to reduce barriers to evidence-based smoking cessation treatment for AN people in Alaska.

Methods: Phase 1 included semi-structured telephone interviews with 30 AN people who smoke and ten stakeholders. They provided feedback on existing content from the Centers for Disease Control and Prevention Tips campaign and AN digital stories. Phase 2 included an online survey with a new group of 40 AN smokers who provided feedback on existing content via a measure of perceived effectiveness and cultural relevance.

Results: Phase I results revealed participants evaluated content based upon story strength, relevance to AN culture, emotional appeal, relatability to AN people, and favorite video. No single posting was rated highly across all themes. All perceived effectiveness (PE) and cultural relevance median scores fell between 3.5 and 4.4 (range 1-5). PE scores varied across participant demographic groups.

Conclusions: Content embodying characteristics perceived to be most appealing, effective, and culturally relevant were selected for the private Facebook group content library with refinements made to incorporate images of AN people engaged in AN activities. PE scores indicate a need for a wide variety of content that moderators could pull from when conducting the intervention.

Implications: Social media content targeting specific population sectors, such as American Indian/AN people for tobacco cessation needs to be culturally tailored. Our approach provides a model others can follow to determine what is appealing, relevant, and effective messaging.

Clinical Trial Registration: NCT03645941.
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http://dx.doi.org/10.1093/ntr/ntaa253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248946PMC
May 2021

PLEKHA7, an Apical Adherens Junction Protein, Suppresses Inflammatory Breast Cancer in the Context of High E-Cadherin and p120-Catenin Expression.

Int J Mol Sci 2021 Jan 28;22(3). Epub 2021 Jan 28.

Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA.

Inflammatory breast cancer is a highly aggressive form of breast cancer that forms clusters of tumor emboli in dermal lymphatics and readily metastasizes. These cancers express high levels of E-cadherin, the major mediator of adherens junctions, which enhances formation of tumor emboli. Previous studies suggest that E-cadherin promotes cancer when the balance between apical and basolateral cadherin complexes is disrupted. Here, we used immunohistochemistry of inflammatory breast cancer patient samples and analysis of cell lines to determine the expression of PLEKHA7, an apical adherens junction protein. We used viral transduction to re-express PLEKHA7 in inflammatory breast cancer cells and examined their aggressiveness in 2D and 3D cultures and in vivo. We determined that PLEKHA7 was deregulated in inflammatory breast cancer, demonstrating improper localization or lost expression in most patient samples and very low expression in cell lines. Re-expressing PLEKHA7 suppressed proliferation, anchorage independent growth, spheroid viability, and tumor growth in vivo. The data indicate that PLEKHA7 is frequently deregulated and acts to suppress inflammatory breast cancer. The data also promote the need for future inquiry into the imbalance between apical and basolateral cadherin complexes as driving forces in inflammatory breast cancer.
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http://dx.doi.org/10.3390/ijms22031275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865280PMC
January 2021

Healthy Pregnancies Project: Cluster Randomized Controlled Trial of a Community Intervention to Reduce Tobacco Use among Alaska Native Women.

Int J Environ Res Public Health 2020 12 12;17(24). Epub 2020 Dec 12.

Yukon-Kuskokwim Health Corporation, 528 Chief Eddie Hoffman Hwy, Bethel, AK 99559, USA.

Substantial gaps remain in the evidence base for prenatal tobacco use interventions among Indigenous women. Using a cluster randomized controlled trial (RCT), the Healthy Pregnancies Project evaluated a community-level intervention for Alaska Native (AN) women in rural western Alaska. Sixteen villages were randomly assigned to usual care (control, = 8 villages) or usual care plus a community-level intervention delivered by local AN "Native Sisters" ( = 8 villages). Outcomes were tobacco use rate at delivery and at 2 and 6 months postpartum, with biochemical confirmation obtained at 6 months. The program had high reach, enrolling 73% of all eligible women screened. Of the 352 participants, 67% used tobacco at baseline. No significant differences emerged between study groups on follow-up in tobacco use rates. More intervention than control participants made a quit attempt at 2 months postpartum (70% vs. 51%, respectively, = 0.012). Participants in both study groups reported the program helped to raise awareness of healthy pregnancies in the study villages. This trial supports the reach of a community-level intervention, but not its efficacy for reducing tobacco use during pregnancy or postpartum. Efforts to sustain early quit attempts appear warranted. The community involvement, and reported impact on raising awareness of the importance of healthy pregnancies, supports the value of the research program in this community.
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http://dx.doi.org/10.3390/ijerph17249302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764642PMC
December 2020

8q24 clear cell renal cell carcinoma germline variant is associated with VHL mutation status and clinical aggressiveness.

BMC Urol 2020 Oct 29;20(1):173. Epub 2020 Oct 29.

Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL, USA.

Background: The four most commonly-mutated genes in clear cell renal cell carcinoma (ccRCC) tumors are BAP1, PBRM1, SETD2 and VHL. And, there are currently 14 known RCC germline variants that have been reproducibly shown to be associated with RCC risk. However, the association of germline genetics with tumor genetics and clinical aggressiveness are unknown.

Methods: We analyzed 420 ccRCC patients from The Cancer Genome Atlas. Molecular subtype was determined based on acquired mutations in BAP1, PBRM1, SETD2 and VHL. Aggressive subtype was defined clinically using Mayo SSIGN score and molecularly using the ccA/ccB gene expression subtype. Publically-available Hi-C data were used to link germline risk variants with candidate target genes.

Results: The 8q24 variant rs35252396 was significantly associated with VHL mutation status (OR = 1.6, p = 0.0037) and SSIGN score (OR = 1.9, p = 0.00094), after adjusting for multiple comparisons. We observed that, while some germline variants have interactions with nearby genes, some variants demonstrate long-range interactions with target genes.

Conclusions: These data further demonstrate the link between rs35252396, HIF pathway and ccRCC clinical aggressiveness, providing a more comprehensive picture of how germline genetics and tumor genetics interact with respect to tumor development and progression.
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http://dx.doi.org/10.1186/s12894-020-00745-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7597051PMC
October 2020

Bronchoscopic Cryobiopsy and Forceps Biopsy for the Diagnostic Evaluation of Diffuse Parenchymal Lung Disease in Clinical Practice.

Mayo Clin Proc Innov Qual Outcomes 2020 Oct 6;4(5):565-574. Epub 2020 Oct 6.

Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic, Rochester, MN.

Objective: To assess the contribution and safety of bronchoscopic cryobiopsy vs traditional forceps biopsy used in clinical practice for diagnosing diffuse parenchymal lung disease (DPLD).

Patients And Methods: We identified 271 patients who underwent bronchoscopic biopsy for DPLD at Mayo Clinic, MN (June 1, 2013, through September 30, 2017). Medical records were reviewed including prebiopsy clinical and radiographic impressions. was assessed in terms of a specific histologic pattern resulting in a diagnosis when combined with the clinical-radiologic context. was defined as a biopsy result deemed useful in patient management.

Results: The cohort included 120 cryobiopsy and 151 forceps biopsy cases with mean age 61±14 years and 143 (53%) men. Diagnostic yield (55% vs 41%; odds ratio [OR], 1.73; 95% CI, 1.07 to 2.83; =.026) and clinical utility (60% vs 40%; OR, 2.21; 95% CI, 1.36 to 3.63; =.001) were higher for the cryobiopsy group, and the association remained after control for prebiopsy clinical impressions (OR, 2.21; 95% CI, 1.22 to 4.08; =.010 and OR, 3.23; 95% CI, 1.76 to 6.10; <.001, respectively). However, pneumothorax (5.4% vs 0.7%; =.022) and serious bleeding (7.1% vs 0%; =.001) rates were higher for the cryobiopsy group. Thirty-day mortality was 1.6% in the cryobiopsy group vs 0% for the forceps biopsy group (=.20).

Conclusion: Bronchoscopic cryobiopsy revealed higher diagnostic yield and clinical utility than did forceps biopsy. However, procedure-related complications were higher in the cryobiopsy group. The choice of bronchoscopic biopsy procedure for patients with DPLD depends on the clinicalradiologic context.
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http://dx.doi.org/10.1016/j.mayocpiqo.2020.05.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7560571PMC
October 2020

Atherosclerotic Cardiovascular Disease Risk Stratification Based on Measurements of Troponin and Coronary Artery Calcium.

J Am Coll Cardiol 2020 07;76(4):357-370

Department of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota. Electronic address:

Background: Low values of high-sensitivity cardiac troponin (hs-cTn) and coronary artery calcium (CAC) scores of zero are associated with a low risk for atherosclerotic cardiovascular disease (ASCVD).

Objectives: The purpose of this study was to evaluate baseline hs-cTnT and CAC in relation to ASCVD.

Methods: Baseline hs-cTnT (limit of detection [LoD] 3 ng/l) and CAC measurements were analyzed across participants age 45 to 84 years without clinical cardiovascular disease from the prospective MESA (Multi-Ethnic Study of Atherosclerosis) in relationship to incident ASCVD.

Results: Among 6,749 participants, 1,002 ASCVD events occurred during a median follow-up of 15 years. Participants with detectable CAC (20.1 vs. 5.0 events per 1,000 person-years; adjusted hazard ratio [HR]: 2.35; 95% confidence interval [CI]: 2.0 to 2.76; p < 0.001) and detectable hs-cTnT (15.4 vs. 5.2 per 1,000 person-years; adjusted HR: 1.47; 95% CI: 1.21 to 1.77; p < 0.001) had higher rates of ASCVD than those with undetectable results. Individuals with undetectable hs-cTnT (32%) had similar risk for ASCVD as did those with a CAC of zero (50%) (5.2 vs. 5.0 per 1,000 person-years). Together, hs-cTnT and CAC (discordance 38%) resulted in the following ASCVD event rates: hs-cTnT < LoD/CAC = 0: 2.8 per 1,000 person-years (reference), hs-cTnT ≥ LoD/CAC = 0: 6.8 per 1,000 person-years (HR: 1.59; 95% CI: 1.17 to 2.16; p = 0.003), hs-cTnT < LoD/CAC > 0: 11.1 per 1,000 person-years (HR: 2.74; 95% CI: 1.96 to 3.83; p < 0.00001), and hs-cTnT ≥ LoD/CAC > 0: 22.6 per 1,000 person-years (HR: 3.50; 95% CI: 2.60 to 4.70; p < 0.00001).

Conclusions: An undetectable hs-cTnT identifies patients with a similar, low risk for ASCVD as those with a CAC score of zero. The increased risk among those with discordant results supports their conjoined use for risk prediction.
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http://dx.doi.org/10.1016/j.jacc.2020.05.057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7513421PMC
July 2020

Adult diffuse glioma GWAS by molecular subtype identifies variants in D2HGDH and FAM20C.

Neuro Oncol 2020 11;22(11):1602-1613

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.

Background: Twenty-five germline variants are associated with adult diffuse glioma, and some of these variants have been shown to be associated with particular subtypes of glioma. We hypothesized that additional germline variants could be identified if a genome-wide association study (GWAS) were performed by molecular subtype.

Methods: A total of 1320 glioma cases and 1889 controls were used in the discovery set and 799 glioma cases and 808 controls in the validation set. Glioma cases were classified into molecular subtypes based on combinations of isocitrate dehydrogenase (IDH) mutation, telomerase reverse transcriptase (TERT) promoter mutation, and 1p/19q codeletion. Logistic regression was applied to the discovery and validation sets to test for associations of variants with each of the subtypes. A meta-analysis was subsequently performed using a genome-wide P-value threshold of 5 × 10-8.

Results: Nine variants in or near D-2-hydroxyglutarate dehydrogenase (D2HGDH) on chromosome 2 were genome-wide significant in IDH-mutated glioma (most significant was rs5839764, meta P = 2.82 × 10-10). Further stratifying by 1p/19q codeletion status, one variant in D2HGDH was genome-wide significant in IDH-mutated non-codeleted glioma (rs1106639, meta P = 4.96 × 10-8). Further stratifying by TERT mutation, one variant near FAM20C (family with sequence similarity 20, member C) on chromosome 7 was genome-wide significant in gliomas that have IDH mutation, TERT mutation, and 1p/19q codeletion (rs111976262, meta P = 9.56 × 10-9). Thirty-six variants in or near GMEB2 on chromosome 20 near regulator of telomere elongation helicase 1 (RTEL1) were genome-wide significant in IDH wild-type glioma (most significant was rs4809313, meta P = 2.60 × 10-10).

Conclusions: Performing a GWAS by molecular subtype identified 2 new regions and a candidate independent region near RTEL1, which were associated with specific glioma molecular subtypes.
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http://dx.doi.org/10.1093/neuonc/noaa117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690366PMC
November 2020

Association of Maximal Extent of Resection of Contrast-Enhanced and Non-Contrast-Enhanced Tumor With Survival Within Molecular Subgroups of Patients With Newly Diagnosed Glioblastoma.

JAMA Oncol 2020 04;6(4):495-503

Department of Neurological Surgery, University of California, San Francisco.

Importance: Per the World Health Organization 2016 integrative classification, newly diagnosed glioblastomas are separated into isocitrate dehydrogenase gene 1 or 2 (IDH)-wild-type and IDH-mutant subtypes, with median patient survival of 1.2 and 3.6 years, respectively. Although maximal resection of contrast-enhanced (CE) tumor is associated with longer survival, the prognostic importance of maximal resection within molecular subgroups and the potential importance of resection of non-contrast-enhanced (NCE) disease is poorly understood.

Objective: To assess the association of resection of CE and NCE tumors in conjunction with molecular and clinical information to develop a new road map for cytoreductive surgery.

Design, Setting, And Participants: This retrospective, multicenter cohort study included a development cohort from the University of California, San Francisco (761 patients diagnosed from January 1, 1997, through December 31, 2017, with 9.6 years of follow-up) and validation cohorts from the Mayo Clinic (107 patients diagnosed from January 1, 2004, through December 31, 2014, with 5.7 years of follow-up) and the Ohio Brain Tumor Study (99 patients with data collected from January 1, 2008, through December 31, 2011, with a median follow-up of 10.9 months). Image accessors were blinded to patient groupings. Eligible patients underwent surgical resection for newly diagnosed glioblastoma and had available survival, molecular, and clinical data and preoperative and postoperative magnetic resonance images. Data were analyzed from November 15, 2018, to March 15, 2019.

Main Outcomes And Measures: Overall survival.

Results: Among the 761 patients included in the development cohort (468 [61.5%] men; median age, 60 [interquartile range, 51.6-67.7] years), younger patients with IDH-wild-type tumors and aggressive resection of CE and NCE tumors had survival similar to that of patients with IDH-mutant tumors (median overall survival [OS], 37.3 [95% CI, 31.6-70.7] months). Younger patients with IDH-wild-type tumors and reduction of CE tumor but residual NCE tumors fared worse (median OS, 16.5 [95% CI, 14.7-18.3] months). Older patients with IDH-wild-type tumors benefited from reduction of CE tumor (median OS, 12.4 [95% CI, 11.4-14.0] months). The results were validated in the 2 external cohorts. The association between aggressive CE and NCE in patients with IDH-wild-type tumors was not attenuated by the methylation status of the promoter region of the DNA repair enzyme O6-methylguanine-DNA methyltransferase.

Conclusions And Relevance: This study confirms an association between maximal resection of CE tumor and OS in patients with glioblastoma across all subgroups. In addition, maximal resection of NCE tumor was associated with longer OS in younger patients, regardless of IDH status, and among patients with IDH-wild-type glioblastoma regardless of the methylation status of the promoter region of the DNA repair enzyme O6-methylguanine-DNA methyltransferase. These conclusions may help reassess surgical strategies for individual patients with newly diagnosed glioblastoma.
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http://dx.doi.org/10.1001/jamaoncol.2019.6143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042822PMC
April 2020

Development and Evaluation of a Cancer Literacy Intervention to Promote Mammography Screening Among Navajo Women: A Pilot Study.

Am J Health Promot 2020 07 27;34(6):681-685. Epub 2020 Jan 27.

Diné College, Tsaile, AZ, USA.

Purpose: Develop and evaluate a mammography intervention that provides hope about cancer prevention and treatment.

Design: Pilot randomized controlled trial.

Setting: Two communities on the Navajo Nation.

Participants: Navajo women and support persons.

Intervention: Both groups received standard care: one home visit discussing mammography pros/cons and barriers. The treatment group received an intervention based on Navajo language via an additional home visit with health education materials (written and oral) in English and Navajo, including a Navajo Cancer Glossary with a new descriptive phrase for cancer.

Analysis: Between control and intervention conditions, we compared baseline sociodemographics; changes from baseline to 3 months on mammography completion and breast cancer literacy scores.

Measures: (1) intervention feasibility; (2) self- and clinic-reported mammography screening completion; (3) breast cancer literacy.

Results: A total of 25 participants were randomly assigned (13 treatment, 12 control), with 7 support persons in each arm. Mean age was 53 years, 90% had a high school degree or higher, 86% spoke Navajo and English. At 3 months, 44% had a clinically verified mammogram. Mammography completion was 57% among those with a support person and 27% among those without ( = .14). Intervention women reported more breast cancer beliefs consistent with mammography ( = .015).

Conclusions: Increases in breast cancer beliefs consistent with mammography show promise. Findings highlight a need to tailor education materials to Navajo culture/language and focus on enhancing support.
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http://dx.doi.org/10.1177/0890117119900592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571462PMC
July 2020

Diagnostic Yield and Bleeding Complications Associated With Bronchoscopic Biopsy of Endobronchial Carcinoid Tumors.

J Bronchology Interv Pulmonol 2020 Jul;27(3):184-189

Division of Pulmonary and Critical Care Medicine.

Background: Bronchial carcinoid often appears hypervascular on bronchoscopic visualization and may be associated with hemoptysis. The diagnostic yield and bleeding complications associated with bronchoscopic biopsy of bronchial carcinoid tumors remain unclear.

Materials And Methods: Patients with bronchial carcinoid tumors that were bronchoscopically visualized and biopsied at our tertiary referral medical center, over an 8-year period from 2010 to 2017, were retrospectively identified and reviewed to assess diagnostic yield and bleeding complications. Correlations with patient characteristics and carcinoid tumor features were analyzed.

Results: Forty-nine patients were included (57% female). Tumors were predominantly (71%) located in proximal airways (mainstem and lobar bronchi). Bronchoscopic biopsy was diagnostic in 45 patients (92%). Thirteen patients (27%) experienced moderate (n=12, 25%) or severe (n=1, 2%) bleeding. Among these, 6 tumors (46%) had a vascular appearance and 4 patients (31%) had experienced recent hemoptysis. However, neither vascularity nor hemoptysis was associated with bleeding at biopsy (P=0.68 and 0.73, respectively). Carcinoid tumors were classified as typical in 79% and atypical in 21% with no difference in diagnostic yield or bleeding risk (P=0.28 and 0.92, respectively). Tumor size was also not associated with increased diagnostic yield or bleeding risk (P=0.54 and 0.39, respectively).

Conclusion: Bronchoscopic biopsy of endobronchial carcinoid is associated with a high diagnostic yield and severe bleeding is rarely encountered. Diagnostic yield and bleeding seemed independent of vascular tumor appearance or history of recent hemoptysis.
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http://dx.doi.org/10.1097/LBR.0000000000000639DOI Listing
July 2020

Genomic and Phenotypic Characterization of a Broad Panel of Patient-Derived Xenografts Reflects the Diversity of Glioblastoma.

Clin Cancer Res 2020 03 18;26(5):1094-1104. Epub 2019 Dec 18.

Mayo Clinic Arizona, Scottsdale, Arizona.

Purpose: Glioblastoma is the most frequent and lethal primary brain tumor. Development of novel therapies relies on the availability of relevant preclinical models. We have established a panel of 96 glioblastoma patient-derived xenografts (PDX) and undertaken its genomic and phenotypic characterization.

Experimental Design: PDXs were established from glioblastoma, IDH-wildtype ( = 93), glioblastoma, IDH-mutant ( = 2), diffuse midline glioma, H3 K27M-mutant ( = 1), and both primary ( = 60) and recurrent ( = 34) tumors. Tumor growth rates, histopathology, and treatment response were characterized. Integrated molecular profiling was performed by whole-exome sequencing (WES, = 83), RNA-sequencing ( = 68), and genome-wide methylation profiling ( = 76). WES data from 24 patient tumors was compared with derivative models.

Results: PDXs recapitulate many key phenotypic and molecular features of patient tumors. Orthotopic PDXs show characteristic tumor morphology and invasion patterns, but largely lack microvascular proliferation and necrosis. PDXs capture common and rare molecular drivers, including alterations of , and , most at frequencies comparable with human glioblastoma. However, amplification was absent. RNA-sequencing and genome-wide methylation profiling demonstrated broad representation of glioblastoma molecular subtypes. promoter methylation correlated with increased survival in response to temozolomide. WES of 24 matched patient tumors showed preservation of most genetic driver alterations, including amplification. However, in four patient-PDX pairs, driver alterations were gained or lost on engraftment, consistent with clonal selection.

Conclusions: Our PDX panel captures the molecular heterogeneity of glioblastoma and recapitulates many salient genetic and phenotypic features. All models and genomic data are openly available to investigators.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-0909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056576PMC
March 2020

Social Media Intervention to Promote Smoking Treatment Utilization and Cessation Among Alaska Native People Who Smoke: Protocol for the Connecting Alaska Native People to Quit Smoking (CAN Quit) Pilot Study.

JMIR Res Protoc 2019 Nov 22;8(11):e15155. Epub 2019 Nov 22.

Department of Psychiatry and Psychology and Behavioral Health Research Program, Mayo Clinic, Rochester, MN, United States.

Background: Despite the high prevalence of tobacco use among Alaska Native (AN) people, tobacco cessation interventions developed specifically for this group are lacking. Social media hold promise as a scalable intervention strategy to promote smoking treatment utilization and cessation, given the barriers to treatment delivery (ie, geographic remoteness, limited funding, climate, and travel costs) in the state of Alaska (AK). Building on a longstanding tobacco control research partnership with the AK Tribal Health System, in this study, we are developing and pilot-testing a culturally relevant, Facebook (FB)-delivered intervention that incorporates a digital storytelling approach adapted from the effective Centers for Disease Control Tips from Former Smokers campaign.

Objective: This study aims to promote evidence-based smoking treatment (eg, state quitline and Tribal cessation programs) uptake and cessation among AN people.

Methods: This study fulfills the objectives for stage 1 of the National Institute on Drug Abuse behavioral integrative treatment development program. In stage 1a, we will use a mixed method approach to develop the FB intervention. Cultural variance and surface/deep structure frameworks will address the influence of culture in designing health messages. These developmental activities will include qualitative and quantitative assessments, followed by beta testing of proposed intervention content. In stage 1b, we will conduct a randomized pilot trial enrolling 60 AN adults who smoke. We will evaluate the feasibility, uptake, consumer response, and potential efficacy of the FB intervention compared with a control condition (quitline/treatment referral only). Primary outcome measures include feasibility and biochemically verified smoking abstinence at 1-, 3-, and 6-month follow-ups. Secondary outcomes will include self-reported smoking cessation treatment utilization and abstinence from tobacco/nicotine products. We will also explore interdependence (relationship orientation and collaborative efforts in lifestyle change) as a culturally relevant mediator of intervention efficacy.

Results: The study enrolled 40 participants for phase 1, with data saturation being achieved at 30 AN people who smoke and 10 stakeholders. For phase 2, we enrolled 40 participants. Qualitative assessment of proposed intervention content was completed with 30 AN smokers and 10 stakeholders. We are currently analyzing data from the quantitative assessment with 40 participants in preparation for the beta testing, followed by the randomized pilot trial.

Conclusions: The project is innovative for its use of social media communication tools that are culturally relevant in a behavioral intervention designed to reach AN people statewide to promote smoking treatment utilization and cessation. The study will further advance tobacco cessation research in an underserved disparity group. If the pilot intervention is successful, we will have a blueprint to conduct a large randomized controlled efficacy trial. Our approach could be considered for other remote AN communities to enhance the reach of evidence-based tobacco cessation treatments.

International Registered Report Identifier (irrid): DERR1-10.2196/15155.
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http://dx.doi.org/10.2196/15155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6898890PMC
November 2019

Comparative Age-Based Prospective Multi-Institutional Observations of 12,367 Patients Enrolled to the American College of Surgeons Oncology Group (ACOSOG) Z901101 Trials (Alliance).

Ann Surg Oncol 2019 Dec 11;26(13):4213-4221. Epub 2019 Oct 11.

Alliance Statistics and Data Center, Mayo Clinic, Rochester, MN, USA.

Background: The risk of surgery, particularly for older cancer patients with serious, extensive comorbidities, can make this otherwise curative modality precarious. Leveraging data from the American College of Surgeons Oncology Group, this study sought to characterize age-based comparative demographics, adverse event rates, and study completion rates to define how best to conduct research in older cancer patients.

Methods: This study relied on clinical data from 21 completed studies to assess whether older patients experienced more grade 3 or worse adverse events and were more likely to discontinue study participation prematurely than their younger counterparts.

Results: The study enrolled 12,367 patients. The median age was 60 years, and 36% of the patients were 65 years of age or older. Among 4008 patients with adverse event data, 1067 (27%) had experienced a grade 3 or worse event. The patients 65 years or older had higher rates of grade 3 or worse adverse events compared to younger patients [32% vs. 24%; odds ratio (OR), 1.5; 95% confidence interval (CI), 1.3-1.7; p < 0.0001]. This association was not observed in multivariate analyses. The study protocol was completed by 97% of the patients. No association was observed between age and trial completion (OR 0.8; 95% CI 0.7-1.1; p = 0.14). Only the older gastrointestinal cancer trial patients were less likely to complete their studies compared to younger patients (OR 0.50; 95% CI 0.30-0.70; p < 0.0001).

Conclusion: Despite higher rates of adverse events, the older patients typically completed the study protocol, thereby contributing relevant data on how best to render care to older cancer patients and affirming the important role of enrolling these patients to surgical trials.
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http://dx.doi.org/10.1245/s10434-019-07851-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6868343PMC
December 2019

Association of Tobacco Use During Pregnancy, Perceived Stress, and Depression Among Alaska Native Women Participants in the Healthy Pregnancies Project.

Nicotine Tob Res 2020 10;22(11):2104-2108

Native American Cancer Initiatives, Inc., Pine, CO.

Introduction: In general population samples, higher levels of stress and depression have been associated with increased prevalence of smoking in pregnancy. Little is known about the association of prenatal tobacco use, stress, and depression among American Indian or Alaska Native (AI/AN) women.

Methods: The Healthy Pregnancies Project is a cluster-randomized controlled trial, evaluating a community-level intervention compared with usual care, for reducing tobacco use during pregnancy and postpartum among AN women in 16 villages in western Alaska. This cross-sectional study analyzed baseline data from enrolled pregnant women. Baseline measures included the self-reported, 7-day, point-prevalence current use of any tobacco, Perceived Stress Scale (PSS), and the Center for Epidemiological Studies-Depression (CES-D). Generalized estimating equations (GEE) analyses adjusted for village, participant age, and gestational age.

Results: Participants (N = 352) were on average (SD) 25.8 (5.0) years of age and at 26.8 (9.8) weeks gestation. 66.5% were current tobacco users, of which 77% used Iqmik, a homemade form of smokeless tobacco. Compared with nonusers, tobacco users reported lower PSS score (p = .020) and less clinical levels of depression (CES-D ≥ 16) (18.1% vs. 9.3%, p = .21). Findings were not accounted for by nicotine dependence severity or self-reported tobacco use before pregnancy.

Conclusions: In this sample of pregnant AN women, tobacco users report less stress and clinical levels of depression than nonusers. A potential challenge with tobacco treatment for pregnant AN women is to provide alternative ways of deescalating stress and affect management instead of using tobacco.

Implications: This study contributes novel information on the association of tobacco use, perceived stress, and depression among Alaska Native women enrolled in a clinical trial to promote healthy pregnancies. Most prior studies addressing this topic were conducted among general population samples of pregnant women who smoked cigarettes. Little is known about these associations with prenatal smokeless tobacco, or among American Indian or Alaska Native women. The results are contrary to findings reported previously, because current tobacco use was associated with less stress and depression than nonuse. The study findings have implications for cessation treatment for this tobacco-use disparity group.
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http://dx.doi.org/10.1093/ntr/ntz189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593352PMC
October 2020

Postpartum Tobacco Use and Perceived Stress among Alaska Native Women: MAW Phase 4 Study.

Int J Environ Res Public Health 2019 08 21;16(17). Epub 2019 Aug 21.

Clinical and Research Services, Division of Community Health Services, Alaska Native Tribal Health Consortium, 4000 Ambassador Dr., Anchorage, AK 99508, USA.

Prior research explored reasons for tobacco use among pregnant Alaska Native (AN) women but did not address the postpartum period. This study followed up with AN women one to three years postpartum who had participated in a prenatal smoking cessation intervention study (Motivate Alaska Women (MAW) Phase 3) and had consented to be re-contacted for future studies. Of 47 eligible women, 32 (68%) participated. A semi-structured phone interview was conducted a mean of 2.0 years after delivery (range 1.6-2.8). Measures assessed self-reported tobacco use status in the 12 months after delivery, at 12 months postpartum, and at the time of the interview; reasons for maintaining abstinence, continued use, or relapse; and included the Perceived Stress Scale (PSS) and Negative Affect (NA) scale. Content analysis was used to generate themes from open-ended response items. Tobacco use was reported by 23 women (72%) at delivery, 30 (94%) within the 12 months after delivery, 27 (84%) at 12 months postpartum, and 29 (91%) at the time of the interview. Among nine women not using tobacco at delivery, seven (78%) relapsed during the 12 months after delivery. Of the 29 current tobacco users, 28 (97%) smoked cigarettes. Twenty-seven participants (84%) reported stress and 15 (52%) indicated addiction as reasons for continuing, starting, or resuming tobacco use. Types of stressors were related to parenting and traumatic experiences. Among current tobacco users, mean NA score (18.7) was significantly higher ( = 0.01) than the normative mean (14.8), but no differences were detected for PSS score. In this sample of AN women, postpartum tobacco use was highly prevalent, and stress was a primary reason that women endorsed for using tobacco. These preliminary results have several practice and research implications for exploring ways to support non-tobacco use among postpartum AN women.
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http://dx.doi.org/10.3390/ijerph16173024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6747207PMC
August 2019

Molecular profiling of long-term IDH-wildtype glioblastoma survivors.

Neuro Oncol 2019 11;21(11):1458-1469

Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota.

Background: Glioblastoma (GBM) represents an aggressive cancer type with a median survival of only 14 months. With fewer than 5% of patients surviving 5 years, comprehensive profiling of these rare patients could elucidate prognostic biomarkers that may confer better patient outcomes. We utilized multiple molecular approaches to characterize the largest patient cohort of isocitrate dehydrogenase (IDH)-wildtype GBM long-term survivors (LTS) to date.

Methods: Retrospective analysis was performed on 49 archived formalin-fixed paraffin embedded tumor specimens from patients diagnosed with GBM at the Mayo Clinic between December 1995 and September 2013. These patient samples were subdivided into 2 groups based on survival (12 LTS, 37 short-term survivors [STS]) and subsequently examined by mutation sequencing, copy number analysis, methylation profiling, and gene expression.

Results: Of the 49 patients analyzed in this study, LTS were younger at diagnosis (P = 0.016), more likely to be female (P = 0.048), and MGMT promoter methylated (UniD, P = 0.01). IDH-wildtype STS and LTS demonstrated classic GBM mutations and copy number changes. Pathway analysis of differentially expressed genes showed LTS enrichment for sphingomyelin metabolism, which has been linked to decreased GBM growth, invasion, and angiogenesis. STS were enriched for DNA repair and cell cycle control networks.

Conclusions: While our findings largely report remarkable similarity between these LTS and more typical STS, unique attributes were observed in regard to altered gene expression and pathway enrichment. These attributes may be valuable prognostic markers and are worth further examination. Importantly, this study also underscores the limitations of existing biomarkers and classification methods in predicting patient prognosis.
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http://dx.doi.org/10.1093/neuonc/noz129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6827834PMC
November 2019

Increased hepatocyte growth factor levels over 2 years are associated with coronary heart disease: the Multi-Ethnic Study of Atherosclerosis (MESA)

Am Heart J 2019 07 13;213:30-34. Epub 2019 Apr 13.

Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN. Electronic address:

Hepatocyte growth factor (HGF) is associated with subclinical and clinical atherosclerosis. However, the significance of change in HGF and development of atherosclerotic disease is unknown. In a large and diverse population-based cohort, we report that change in the biomarker HGF is an independent predictor of incident CHD.
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http://dx.doi.org/10.1016/j.ahj.2019.03.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581609PMC
July 2019

PARP Inhibitors for Sensitization of Alkylation Chemotherapy in Glioblastoma: Impact of Blood-Brain Barrier and Molecular Heterogeneity.

Front Oncol 2018 22;8:670. Epub 2019 Jan 22.

Departments of Radiation Oncology, Mayo Clinic, Rochester, MN, United States.

Prognosis of patients with glioblastoma (GBM) remains dismal despite maximal surgical resection followed by aggressive chemo-radiation therapy. Almost every GBM, regardless of genotype, relapses as aggressive recurrent disease. Sensitization of GBM cells to chemo-radiation is expected to extend survival of patients with GBM by enhancing treatment efficacy. The PARP family of enzymes has a pleiotropic role in DNA repair and metabolism and has emerged as an attractive target for sensitization of cancer cells to genotoxic therapies. However, despite promising results from a number of preclinical studies, progress of clinical trials involving PARP inhibitors (PARPI) has been slower in GBM as compared to other malignancies. Preclinical studies have uncovered limitations of PARPI-mediated targeting of base excision repair, considered to be the likely mechanism of sensitization for temozolomide (TMZ)-resistant GBM. Nevertheless, PARPI remain a promising sensitizing approach for at least a subset of GBM tumors that are inherently sensitive to TMZ. Our PDX preclinical trial has helped delineate promoter hyper-methylation as a biomarker of the PARPI veliparib-mediated sensitization. In clinical trials, promoter hyper-methylation now is being studied as a potential predictive biomarker not only for response to TMZ therapy alone, but also PARPI-mediated sensitization of TMZ therapy. Besides the combination approach being investigated, IDH1/2 mutant gliomas associated with 2-hydroxygluterate (2HG)-mediated homologous recombination (HR) defect may potentially benefit from PARPI monotherapy. In this article, we discuss existing results and provide additional data in support of potential alternative mechanisms of sensitization that would help identify potential biomarkers for PARPI-based therapeutic approaches to GBM.
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http://dx.doi.org/10.3389/fonc.2018.00670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6349736PMC
January 2019
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