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Background: Event monitors are being increasingly used in pediatric and adult congenital heart disease (ACHD) patients for arrhythmia evaluation. Data on their diagnostic yield are limited., Objectives: To evaluate the diagnostic yield of event monitors, patient characteristics associated with critical events, and clinical response to events., Methods: We retrospectively assessed event monitors prescribed to patients at our institution's Heart Center from 2017 to 2020. Thirty-day event monitor tracings were reviewed by an electrophysiologist (EP) to identify critical events defined as supraventricular tachycardia (SVT, re-entrant, atrial tachycardia, atrial flutter, and atrial fibrillation), ventricular tachycardia (VT), atrioventricular block, and pauses greater than 3 s. Patient characteristics and treatment data were collected. Characteristics associated with events were assessed using multivariable logistic regression. Trends in monitor prescription over time, diagnostic yield, and clinical response to events were analyzed., Results: 204/2330 (8.8%) event monitors had EP-confirmed critical events. Critical events included SVT (51.5%), VT (38.5%), atrioventricular block (4%), and pauses (6%). 129/198 (65%) patients with critical events underwent treatment. Event monitoring usage increased by 52% between 2017 and 2020 (p < 0.0001). Complex CHD (OR 2.1, 95% CI 1.3-3.4, p = 0.004), cardiomyopathy (OR 2.9, 95% CI 1.5-4.8, p < 0.001), and EP-ordered monitors (OR 1.6, 95% CI 1.2-2.1, p = 0.001) were more highly associated with critical events., Conclusion: Event monitor use is common, and critical events were captured in 8.8% of patients. The majority of patients with critical events underwent treatment. Factors associated with critical events include EPs as ordering providers, complex CHD, and cardiomyopathy., (© 2024 Wiley Periodicals LLC.)

Immunotherapy response is associated with the presence of conventional dendritic cells (cDCs). cDC type 1 (cDC1) is critically important for CD8+ T cell activation, cDC type 2 (cDC2) regulates CD4+ T cell responses, and mature regulatory cDCs may dampen T cell responses in the tumor microenvironment (TME). However, we lack a clear understanding of cDC distribution in the human TME, cDC prevalence in metastatic sites, and cDC differences in early- versus late-stage disease. Rapid autopsy specimens of 10 patients with lung adenocarcinoma were evaluated to detect cDCs and immune cells via multiplex immunofluorescence using 18 markers and 42 tumors. First, we found that T cells, cDC1, and cDC2 were confined to stroma, whereas mature regulatory DCs were enriched in tumor, suggesting unique localization-specific functions. Second, lung and lymph node tumors were more enriched in T cells and cDCs than liver tumors, underscoring differences in the TME of metastatic sites. Third, although the proportion of T cells and cDC1 did not differ in different stages, an increase in the proportion of cDC2 and macrophages in late stage suggests potential differences in regulation of T cell responses in different stages. Collectively, these findings provide new, to our knowledge, insights into cDC biology in human cancer that may have important therapeutic implications., (Copyright © 2024 by The American Association of Immunologists, Inc.)

Hematopoietic cell transplantation (HCT) is the only potentially curative treatment option for many patients with hematologic malignancies. While HCT outcomes have improved drastically over the years, patients and clinicians continue to face numerous survivorship challenges, such as relapse, graft-versushost disease, and secondary malignancies. Recent literature suggests that clonal hematopoiesis (CH), the presence of a recurrent somatic mutation in hematopoietic cells, in HCT patients or donors may be associated with outcomes in autologous and allogeneic HCT. Herein, we perform a review of the literature and summarize reported associations between CH and clinical outcomes in HCT. For commonly reported outcomes, we used meta-analysis methods to provide estimates of effect sizes when combining results. A total of 32 articles with relevant and independent contributions were included, covering both autologous (n = 19) and allogeneic (n = 13) HCT. The articles report variable risk for developing outcomes according to CH characteristics, patient disease status, and method of HCT. Using meta-analysis of available results, HCT outcomes with statistically significant effects by CH status include therapy-related myeloid neoplasms (OR 3.65, 95%CI 2.18-6.10) and overall survival (HR 1.38, 95%CI 1.20-1.58) in autologous HCT and relapse (HR 0.80, 95%CI 0.68-0.94) in allogeneic HCT. However, heterogeneity, biases, and limitations in the literature provide challenges for informing the translation of CH to clinical decision-making. We conclude with a call to action and discussion of next steps to build upon the current literature and provide granularity to the true clinical impact of CH in the setting of HCT.

Background: Aspirin use has been associated with reduced ovarian cancer risk, yet the underlying biological mechanisms are not fully understood. To gain mechanistic insights, we assessed the association between prediagnosis low and regular-dose aspirin use and gene expression profiles in ovarian tumors., Methods: RNA sequencing was performed on high-grade serous, poorly differentiated, and high-grade endometrioid ovarian cancer tumors from the Nurses' Health Study (NHS), NHSII, and New England Case-Control Study (n = 92 cases for low, 153 cases for regular-dose aspirin). Linear regression identified differentially expressed genes associated with aspirin use, adjusted for birth decade and cohort. False discovery rates (FDR) were used to account for multiple testing and gene set enrichment analysis was used to identify biological pathways., Results: No individual genes were significantly differentially expressed in ovarian tumors in low or regular-dose aspirin users accounting for multiple comparisons. However, current versus never use of low-dose aspirin was associated with upregulation of immune pathways (e.g., allograft rejection, FDR = 5.8 × 10 -10 ; interferon-gamma response, FDR = 2.0 × 10 -4 ) and downregulation of estrogen response pathways (e.g., estrogen response late, FDR = 4.9 × 10 -8 ). Ovarian tumors from current regular aspirin users versus never users were also associated with upregulation in interferon pathways (FDR <1.5 × 10 -4 ) and downregulation of multiple extracellular matrix (ECM) architecture pathways (e.g., ECM organization, 4.7 × 10 -8 )., Conclusion: Our results suggest low and regular-dose aspirin may impair ovarian tumorigenesis in part via enhancing adaptive immune response and decreasing metastatic potential supporting the likely differential effects on ovarian carcinogenesis and progression by dose of aspirin., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Proinflammatory chemokines/cytokines support development and maturation of tertiary lymphoid structures (TLS) within the tumor microenvironment (TME). In the current study, we sought to investigate the prognostic value of TLS-associated chemokines/cytokines (TLS-kines) expression levels in melanoma patients by performing serum protein and tissue transcriptomic analyses, and to then correlate these data with patients clinicopathological and TME characteristics., Methods: Levels of TLS-kines in patients' sera were quantitated using a custom Luminex Multiplex Assay. The Cancer Genomic Atlas melanoma cohort (TCGA-SKCM) and a Moffitt Melanoma cohort were used for tissue transcriptomic analyses. Associations between target analytes and survival outcomes, clinicopathological variables, and correlations between TLS-kines were statistically analyzed., Results: Serum of 95 patients with melanoma were evaluated; 48 (50%) female, median age of 63, IQR 51-70 years. Serum levels of APRIL/TNFSF13 were positively correlated with levels of both CXCL10 and CXCL13. In multivariate analyses, high levels of serum APRIL/TNFSF13 were associated with improved event-free survival after adjusting for age and stage (HR = 0.64, 95% CI 0.43-0.95; p = 0.03). High expression of APRIL/TNFSF13 tumor transcripts was significantly associated with improved OS in TCGA-SKCM (HR = 0.69, 95% CI 0.52-0.93; p = 0.01) and in Moffitt Melanoma patients (HR = 0.51, 95% CI: 0.32-0.82; p = 0.006). Further incorporation of CXCL13 and CXCL10 tumor transcript levels in a 3-gene index revealed that high APRIL/CXCL10/CXCL13 expression was associated with improved OS in the TCGA SKCM cohort (HR = 0.42, 95% CI 0.19-0.94; p = 0.035). Melanoma differentially expressed genes positively associated with high APRIL/CXCL10/CXCL13 tumor expression were linked to tumor infiltration by a diverse array of proinflammatory immune cell types., Conclusion: Serum protein and tumor transcript levels of APRIL/TNFSF13 are associated with improved survival outcomes. Patients exhibiting high coordinate expression of APRIL/CXCL10/CXCL13 transcripts in their tumors displayed superior OS. Further investigation of TLS-kine expression profiles related to clinical outcomes in larger cohort studies is warranted., Competing Interests: The authors report no competing interests relevant to this work. Outside of this work: JL reports the following disclosures: DSMB: Abbvie, Immutep, Evaxion; Scientific Advisory Board: no stock 7 Hills, Affivant, Bright Peak, Exo, Fstar, Inzen, RefleXion, Xilio stock Actym, Alphamab Oncology, Arch Oncology, Duke Street Bio, Kanaph, Mavu, NeoTx, Onc.AI, OncoNano, physIQ, Pyxis, Saros, STipe, Tempest; Consultancy with compensation: Abbvie, Agenus, Alnylam, Atomwise, Bayer, Bristol-Myers Squibb, Castle, Checkmate, Codiak, Crown, Cugene, Curadev, Day One, Eisai, EMD Serono, Endeavor, Flame, G1 Therapeutics, Genentech, Gilead, Glenmark, HotSpot, Kadmon, KSQ, Janssen, Ikena, Inzen, Immatics, Immunocore, Incyte, Instil, IO Biotech, Macrogenics, Merck, Mersana, Nektar, Novartis, Partner, Pfizer, Pioneering Medicines, PsiOxus, Regeneron, Replimmune, Ribon, Roivant, Servier, STINGthera, Synlogic, Synthekine; Research Support: all to institution for clinical trials unless noted AbbVie, Astellas, Astrazeneca, Bristol-Myers Squibb, Corvus, Day One, EMD Serono, Fstar, Genmab, Ikena, Immatics, Incyte, Kadmon, KAHR, Macrogenics, Merck, Moderna, Nektar, Next Cure, Numab, Palleon, Pfizer, Replimmune, Rubius, Servier, Scholar Rock, Synlogic, Takeda, Trishula, Tizona, Xencor; Patents: both provisional Serial #15/612,657 Cancer Immunotherapy, PCT/US18/36052 Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof. DDa reports the following disclosures: Arcus, Bristol-Myers Squibb, Checkmate Pharmaceuticals, CellSight Technologies, Merck, GlaxoSmithKline/Tesaro research support; Array Biopharma, Checkmate Pharmaceuticals, Finch, Incyte, Immunocore, Merck; Shionogi consulting; and Vedanta Biosciences scientific advisory board. YN reports the following disclosures: Merck, Pfizer, and Bristol-Myers Squibb research support. Array Biopharma, Merck, Novartis, InterVenn Bio consulting/scientific advisory board. Pfizer, Immunocore speaker’s bureau. CE Speakers’ Bureau: Medical Learning Group MLG. JK reports the following disclosures: Honoraria: Bristol Myers Squibb Consulting or Advisory Role: Novartis, Amgen, Harbor BioMed, Istari Oncology, Scopus BioPharma, Pfizer, AXIO Research, Immunocore, Natera, DermTech, Ankyra Therapeutics, Becker Pharmaceutical Consulting, Fenix Group International, IQVIA, Merck, Replimune, SR One Capital Management, Iovance Biotherapeutics, Checkmate Pharmaceuticals, OncoSec, OncoCyte, Cancer Network, Takeda, Applied Clinical Intelligence. Research Funding: Amgen Inst, Bristol Myers Squibb Inst, Checkmate Pharmaceuticals Inst, Immunocore Inst, Iovance Biotherapeutics Inst, Novartis Inst, ImmVira Inst, Harbor BioMed Inst, Takeda Inst, Verastem Inst. TB reports the following disclosures: Walking Fish Therapeutics Scientific Advisory Board. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer PK declared a past collaboration with the author WJS to the handling editor., (Copyright © 2023 Karapetyan, AbuShukair, Li, Knight, Al Bzour, MacFawn, Thompson, Chen, Yang, Dadey, Karunamurthy, De Stefano, Sander, Kunning, Najjar, Davar, Luke, Gooding, Bruno, Kirkwood and Storkus.)

Purpose: We studied 571 patients with intracranial meningioma for clinical characteristics and tumor location associated with high grade meningioma (WHO II/III)., Materials and Methods: Patients were participants in a multicentre epidemiologic study of risk factors for primary brain tumors including meningioma recruited from September 2005 to November 2019. We included patients 18 or older with a recent diagnosis of a primary intracranial meningioma of any subtype (ICD9/10: 9530-0, 9531-0, 9532-0, 9537-0, 9533-0, 9534-0, 9530-0, 9538-1, 9538-3) who were enrolled at neuro-oncology and neuro-surgery clinics in the southeastern U.S., Results: The median patient age was 58 years (IQR: 48-68) and the majority of patients were female ( n  = 415; 72.7%) and Caucasian ( n  = 516; 90.4%). Most patients were symptomatic ( n  = 460; 80.6%) and their tumours more commonly occurred in a non-skull base location ( n  = 298; 52.2%). A total of 86 patients (15.0%) had a WHO grade II/III meningioma. Compared to patients with WHO grade I tumours, patients with WHO II/III meningiomas were over 3-times more likely to be male (odds ratio (OR): 3.25; 95% confidence interval (CI): 1.98, 5.35) adjusting for age, race, symptomatic presentation, and skull-based location. Moreover, a WHO grade II/III meningioma was substantially less likely to be observed in asymptomatic patients (OR: 0.15, 95% CI: 0.04, 0.42), and in patients with a skull-based tumour (OR: 0.40, 95% CI: 0.24, 0.66), adjusting for other factors. Male gender, symptomatic tumour, and a non-skull base location were independently associated with WHO grade II/III meningioma., Conclusion: These findings may shed additional light on the underlying pathogenesis of meningioma.

Rationale: Adverse events (AEs) have been shown to have clinical associations, in addition to patient safety assessments of drugs of interest. However, due to their complex content and associated data structure, AE evaluation has been restricted to descriptive statistics and small AE subset for efficacy analysis, limiting the opportunity for global discovery. This study takes a unique approach to utilize AE-associated parameters to derive a set of innovative AE metrics. Comprehensive analysis of the AE-derived biomarkers enhances the chance of discovering new predictive AE biomarkers of clinical outcomes., Methods: We utilized a set of AE-associated parameters (grade, treatment relatedness, occurrence, frequency, and duration) to derive 24 AE biomarkers. We further innovatively defined early AE biomarkers by landmark analysis at an early time point to assess the predictive value. Statistical methods included the Cox proportional hazards model for progression-free survival (PFS) and overall survival (OS), two-sample t-test for mean difference of AE frequency and duration between disease control (DC: complete response (CR) + partial response (PR) + stable disease (SD)) versus progressive disease (PD), and Pearson correlation analysis for relationship of AE frequency and duration versus treatment duration. Two study cohorts (Cohort A: vorinostat + pembrolizumab, and B: Taminadenant) from two immunotherapy trials in late-stage non-small cell lung cancer were used to test the potential predictiveness of AE-derived biomarkers. Data from over 800 AEs were collected per standard operating procedure in a clinical trial using the Common Terminology Criteria for Adverse Events v5 (CTCAE). Clinical outcomes for statistical analysis included PFS, OS, and DC., Results: An early AE was defined as event occurrence at or prior to day 30 from initial treatment date. The early AEs were then used to calculate the 24 early AE biomarkers to assess overall AE, each toxicity category, and each individual AE. These early AE-derived biomarkers were evaluated for global discovery of clinical association. Both cohorts showed that early AE biomarkers were associated with clinical outcomes. Patients previously experienced with low-grade AEs (including treatment related AEs (TrAE)) had improved PFS, OS, and were associated with DC. The significant early AEs included low-grade TrAE in overall AE, endocrine disorders, hypothyroidism (pembrolizumab's immune-related adverse event (irAE)), and platelet count decreased (vorinostat related TrAE) for Cohort A and low-grade AE in overall AE, gastrointestinal disorders, and nausea for Cohort B. In contrast, patients with early development of high-grade AEs tended to have poorer PFS, OS, and correlated with PD. The associated early AEs included high-grade TrAE in overall AE, gastrointestinal disorders with two members, diarrhea and vomiting, for Cohort A and high-grade AE in overall AE, three toxicity categories, and five related individual AEs for Cohort B. One low-grade TrAE, alanine aminotransferase increased (vorinostat + pembrolizumab related), was an irAE and correlated with worse OS in Cohort A., Conclusions: The study demonstrated the potential clinical utility of early AE-derived biomarkers in predicting positive and negative clinical outcomes. It could be TrAEs or combination of TrAEs and nonTrAEs from overall AEs, toxicity category AEs, to individual AEs with low-grade event leaning to encouraging effect and high-grade event to undesirable impact. Moreover, the methodology of the AE-derived biomarkers could change current AE analysis practice from a descriptive summary into modern informative statistics. It modernizes AE data analysis by helping clinicians discover novel AE biomarkers to predict clinical outcomes and facilitate the generation of vast clinically meaningful research hypotheses in a new AE content to fulfill the demands of precision medicine.

Elevated cancer-specific mortality in PWH has been demonstrated for non-AIDS-defining malignancies. However, additional clinical endpoints of interest, including patient-reported outcomes (PROs), have not been systematically examined in PWH and cancer. We evaluated differences in patient-reported symptomology between cancer patients with versus without HIV using data from 12,529 patients at the Moffitt Cancer Center, including 55 with HIV. The symptoms were assessed using the Edmonton Symptom Assessment Scale (ESAS), which asks patients to rank 12 symptoms on a scale of 1−10, with scores ≥7 considered severe. The responses across all questions were summed to create a composite score. Vital status through t July 2021 was determined through linkage to the electronic health record. PWH reported a higher composite ESAS score on average (44.4) compared to HIV-uninfected cancer patients (30.7, p-value < 0.01). In zero-inflated negative binomial regression models adjusted for cancer site, sex, and race, the composite ESAS scores and the count of severe symptoms were 1.41 times (95% CI: 1.13−1.77) and 1.45 times (95% CI: 1.09−1.93) higher, respectively, in cancer patients with HIV. Among PWH, higher ESAS scores were associated with mortality (p-value = 0.02). This is the first demonstration of uniquely poor PROs in PWH and cancer and suggests that patient symptom monitoring to improve clinical endpoints deserves further study.

Although substantial progress has been made in treating patients with advanced melanoma with targeted and immuno-therapies, de novo and acquired resistance is commonplace. After treatment failure, therapeutic options are very limited and novel strategies are urgently needed. Combination therapies are often more effective than single agents and are now widely used in clinical practice. Thus, there is a strong need for a comprehensive computational resource to define rational combination therapies. We developed a Shiny app, DRepMel to provide rational combination treatment predictions for melanoma patients from seventy-three thousand combinations based on a multi-omics drug repurposing computational approach using whole exome sequencing and RNA-seq data in bulk samples from two independent patient cohorts. DRepMel provides robust predictions as a resource and also identifies potential treatment effects on the tumor microenvironment (TME) using single-cell RNA-seq data from melanoma patients. Availability: DRepMel is accessible online.

Background: Malignant gliomas are the most common primary adult brain tumors, with a poor prognosis and ill-defined etiology. Mitochondrial DNA (mtDNA) sequence variation has been linked with certain cancers; however, research on glioma is lacking., Methods: We examined the association of common (minor allele frequency ≥ 5%) germline mtDNA variants and haplogroups with glioma risk in 1,566 glioma cases and 1,017 controls from a US case-control study, and 425 glioma cases and 1,534 matched controls from the UK Biobank cohort (UKB). DNA samples were genotyped using the UK Biobank array that included a set of common and rare mtDNA variants. Risk associations were examined separately for glioblastoma (GBM) and lower grade tumors (non-GBM)., Results: In the US study, haplogroup W was inversely associated with glioma when compared with haplogroup H (OR = 0.43, 95%CI: 0.23-0.79); this association was not demonstrated in the UKB (OR = 1.07, 95%CI: 0.47-2.43). In the UKB, the variant m.3010G > A was significantly associated with GBM (OR = 1.32; 95%CI: 1.01-1.73; p = 0.04), but not non-GBM (1.23; 95%CI: 0.78-1.95; p = 0.38); no similar association was observed in the US study. In the US study, the variant m.14798 T > C, was significantly associated with non-GBM (OR = 0.72; 95%CI: 0.53-0.99), but not GBM (OR = 0.86; 95%CI: 0.66-1.11), whereas in the UKB, a positive association was observed between this variant and GBM (OR = 1.46; 95%CI: 1.06-2.02) but not non-GBM (OR = 0.92; 95%CI: 0.52-1.63). None of these associations were significant after adjustment for multiple testing., Conclusion: The association of inherited mtDNA variation, including rare and singleton variants, with glioma risk merits further study., (Copyright © 2022 Elsevier B.V. and Mitochondria Research Society. All rights reserved.)

Background: Risk factors for meningioma include female gender, African American race, high body mass index (BMI), and exposure to ionizing radiation. Although genome-wide association studies (GWAS) have identified two nuclear genome risk loci for meningioma (rs12770228 and rs2686876), the relation between mitochondrial DNA (mtDNA) sequence variants and meningioma is unknown., Methods: We examined the association of 42 common germline mtDNA variants (minor allele frequency ≥ 5%), haplogroups, and genes with meningioma in 1080 controls and 478 meningioma cases from a case-control study conducted at medical centers in the southeastern United States. Associations were examined separately for meningioma overall and by WHO grade (n = 409 grade I and n = 69 grade II/III)., Results: Overall, meningioma was significantly associated with being female (OR 2.85; 95% CI 2.21-3.69), self-reported African American race (OR 2.38, 95% CI 1.41-3.99), and being overweight (OR 1.48; 95% CI 1.11-1.97) or obese (OR 1.70; 95% CI 1.25-2.31). The variant m.16362T > C (rs62581341) in the mitochondrial control region was positively associated with grade II/III meningiomas (OR 2.33; 95% CI 1.14-4.77), but not grade I tumors (OR 0.99; 95% CI 0.64-1.53). Haplogroup L, a marker for African ancestry, was associated with meningioma overall (OR 2.92; 95% CI 1.01-8.44). However, after stratifying by self-reported race, this association was only apparent among the few self-reported Caucasians with this haplogroup (OR 6.35; 95% CI 1.56-25.9). No other mtDNA variant, haplogroup, or gene was associated with meningioma., Conclusion: Common mtDNA variants and major mtDNA haplogroups do not appear to have associations with the odds of developing meningioma., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Adoptive cell therapy using tumor-infiltrating lymphocytes (TILs) has shown activity in melanoma, but has not been previously evaluated in metastatic non-small cell lung cancer. We conducted a single-arm open-label phase 1 trial ( NCT03215810 ) of TILs administered with nivolumab in 20 patients with advanced non-small cell lung cancer following initial progression on nivolumab monotherapy. The primary end point was safety and secondary end points included objective response rate, duration of response and T cell persistence. Autologous TILs were expanded ex vivo from minced tumors cultured with interleukin-2. Patients received cyclophosphamide and fludarabine lymphodepletion, TIL infusion and interleukin-2, followed by maintenance nivolumab. The end point of safety was met according to the prespecified criteria of ≤17% rate of severe toxicity (95% confidence interval, 3-29%). Of 13 evaluable patients, 3 had confirmed responses and 11 had reduction in tumor burden, with a median best change of 35%. Two patients achieved complete responses that were ongoing 1.5 years later. In exploratory analyses, we found T cells recognizing multiple types of cancer mutations were detected after TIL treatment and were enriched in responding patients. Neoantigen-reactive T cell clonotypes increased and persisted in peripheral blood after treatment. Cell therapy with autologous TILs is generally safe and clinically active and may constitute a new treatment strategy in metastatic lung cancer., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Rationale: Recent studies have discovered several unique tumor response subgroups outside of response classification by Response Evaluation Criteria for Solid Tumors (RECIST), such as mixed response and oligometastasis. These subtypes have a distinctive property, lesion heterogeneity defined as diversity of tumor growth profiles in RECIST target lesions. Furthermore, many cancer clinical trials have been activated to evaluate various treatment options for heterogeneity-related subgroups (e.g., 29 trials so far listed in clinicaltrials.gov for cancer patients with oligometastasis). Some of the trials have shown survival benefit by tailored treatment strategies. This evidence presents the unmet need to incorporate lesion heterogeneity to improve RECIST response classification., Method: An approach for Lesion Heterogeneity Classification (LeHeC) was developed using a contemporary statistical approach to assess target lesion variation, characterize patient treatment response, and translate informative evidence to improving treatment strategy. A mixed effect linear model was used to determine lesion heterogeneity. Further analysis was conducted to classify various types of lesion variation and incorporate with RECIST to enhance response classification. A study cohort of 110 target lesions from 36 lung cancer patients was used for evaluation., Results: Due to small sample size issue, the result was exploratory in nature. By analyzing RECIST target lesion data, the LeHeC approach detected a high prevalence (n = 21; 58%) of lesion heterogeneity. Subgroup classification revealed several informative distinct subsets in a descending order of lesion heterogeneity: mix of progression and regression (n = 7), mix of progression and stability (n = 9), mix of regression and stability (n = 5), and non-heterogeneity (n = 15). Evaluation for association of lesion heterogeneity and RECIST best response classification showed lesion heterogeneity commonly occurred in each response group (stable disease: 16/27; 59%; partial response: 3/5; 60%; progression disease: 2/4; 50%). Survival analysis showed a differential trend of overall survival between heterogeneity and non-heterogeneity in RECIST response groups., Conclusion: This is the first study to evaluate lesion heterogeneity, an underappreciated metric, for RECIST application in oncology clinical trials. Results indicated lesion heterogeneity is not an uncommon event. The LeHeC approach could enhance RECIST response classification by utilizing granular lesion level discovery of heterogeneity., Competing Interests: The authors have read the journal’s policy and have the following competing interests: AC serves on Advisory Boards and/or Speaker Bureaus for Novartis, Merck, Genentech, Takeda, Jazz, Blueprint, Amgen and Pfizer and has research support from Bristol-Myers Squibb, and AstraZeneca. BC is an advisor or consultant with E.R. Squibb & Sons LLC, Celgene Corp, Gilead Sciences Inc., Achilles plc., Xilio Therapeutics, and KSQ Therapeutics. He is on the Speaker’s Bureau for Hoffman-LaRoche AG, E.R. Squibb & Sons LLC, AstraZeneca LLC. He has research support from Prometheus Inc., Iovance Biotherapeutics Inc., Adaptive Biotechnologies Corp. JEG serves in Advisory Board or consultant, or has research support from AstraZeneca, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, EMD Serono - Merck KGaA, Genetech, G 1 Therapeutics, Inivata, Merck, Novartis, Pfizer, and Ludwig Institute of Cancer Research. EH is advisory board or consultant for Ellipses, Janssen, Amgen and Revolution. AS has travel reimbursement or research support from Novartis, Daiichi Sankyo, Mersana, Genmab, AstraZeneca, and Turning Point Therapeutics, and Prime Oncology. AAB has research support from Bristol-Myers -Squib and serves on the advisory board of Memgen Inc. DTC has research from Bristol-Myers -Squib and Oncologies. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare.

Background: Radiotherapy may synergize with programmed cell death 1 (PD1)/PD1 ligand (PD-L1) blockade. The purpose of this study was to determine the recommended phase II dose, safety/tolerability, and preliminary efficacy of combining pembrolizumab, an anti-PD1 monoclonal antibody, with hypofractionated stereotactic irradiation (HFSRT) and bevacizumab in patients with recurrent high-grade gliomas (HGGs)., Methods: Eligible subjects with recurrent glioblastoma or anaplastic astrocytoma were treated with pembrolizumab (100 or 200 mg based on dose level Q3W) concurrently with HFSRT (30 Gy in 5 fractions) and bevacizumab 10 mg/kg Q2W., Results: Thirty-two patients were enrolled (bevacizumab-naïve, n = 24; bevacizumab-resistant, n = 8). The most common treatment-related adverse events (TRAEs) were proteinuria (40.6%), fatigue (25%), increased alanine aminotransferase (25%), and hypertension (25%). TRAEs leading to discontinuation occurred in 1 patient who experienced a grade 3 elevation of aspartate aminotransferase. In the bevacizumab-naïve cohort, 20 patients (83%) had a complete response or partial response. The median overall survival (OS) and progression-free survival (PFS) were 13.45 months (95% CI: 9.46-18.46) and 7.92 months (95% CI: 6.31-12.45), respectively. In the bevacizumab-resistant cohort, PR was achieved in 5 patients (62%). Median OS was 9.3 months (95% CI: 8.97-18.86) with a median PFS of 6.54 months (95% CI: 5.95-18.86). The majority of patients (n = 20/26; 77%) had tumor-cell/tumor-microenvironment PD-L1 expression <1%., Conclusions: The combination of HFSRT with pembrolizumab and bevacizumab in patients with recurrent HGG is generally safe and well tolerated. These findings merit further investigation of HFSRT with immunotherapy in HGGs., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: MUC16 is a mucin marker that is frequently mutated in melanoma, but whether MUC16 mutations could be useful as a surrogate biomarker for tumor mutation burden (TMB) remains unclear., Methods: This study rigorously evaluates the MUC16 mutation as a clinical biomarker in cutaneous melanoma by utilizing genomic and clinical data from patient samples from The Cancer Genome Atlas (TCGA) and two independent validation cohorts. We further extended the analysis to studies with patients treated with immunotherapies., Results: Analysis results showed that samples with MUC16 mutations had a higher TMB than the samples of wild-type, with strong statistical significance ( P < 0.001) in all melanoma cohorts tested. Associations between MUC16 mutations and TMB remained statistically significant after adjusting for potential confounding factors in the TCGA cohort [OR, 9.28 (95% confidence interval (CI), 5.18-17.39); P < 0.001], Moffitt cohort [OR, 31.95 (95% CI, 8.71-163.90); P < 0.001], and Yale cohort [OR, 8.09 (95% CI, 3.12-23.79); P < 0.01]. MUC16 mutations were also found to be associated with overall survival in the TCGA [HR, 0.62; (95% CI, 0.45-0.85); P < 0.01] and Moffitt cohorts [HR, 0.49 (95% CI, 0.28-0.87); P = 0.014]. Strikingly, MUC16 is the only top frequently mutated gene for which prognostic significance was observed. MUC16 mutations were also found valuable in predicting anti-CTLA-4 and anti-PD-1 therapy responses., Conclusions: MUC16 mutation appears to be a useful predictive marker of global TMB and patient survival in melanoma., Impact: This is, to the best of our knowledge, the first systematic evaluation of MUC16 mutation as a clinical biomarker and a predictive biomarker for immunotherapy in melanoma., (©2020 American Association for Cancer Research.)

Background: NLR, PLR, and LMR have been associated with pancreatic ductal adenocarcinoma (PDAC) survival. Prognostic value and optimal cutpoints were evaluated to identify underlying significance in surgical PDAC patients., Methods: NLR, PLR, and LMR preoperative values were available for 277 PDAC patients who underwent resection between 2007 and 2015. OS, RFS, and survival probability estimates were calculated by univariate, multivariable, and Kaplan-Meier analyses. Continuous and dichotomized ratio analysis determined best-fit cutpoints and assessed ratio components to determine primary drivers., Results: Elevated NLR and PLR and decreased LMR represented 14%, 50%, and 50% of the cohort, respectively. OS (P = .002) and RFS (P = .003) were significantly decreased in resected PDAC patients with NLR ≥5 compared to those with NLR < 5. Optimal prognostic OS and RFS cutpoints for NLR, PLR, and LMR were 4.8, 192.6, and 1.7, respectively. Lymphocytes alone were the primary prognostic driver of NLR, demonstrating identical survival to NLR., Conclusions: NLR is a significant predictor of OS and RFS, with lymphocytes alone as its primary driver; we identified optimal cutpoints that may direct future investigation of their prognostic value. This study contributes to the growing evidence of immune system influence on outcomes in early-stage pancreatic cancer.

Background: The American Thyroid Association (ATA) sonographic patterns stratify the risk of malignancy of cytologically indeterminate thyroid nodules (ITNs). This study aimed to (1) assess inter-observer agreement for sonographic features and patterns; (2) identify potential sources of disagreement; and (3) evaluate whether the number of suspicious features risk-stratifies non-ATA and high-suspicion patterns., Methods: Three observers independently reviewed the ultrasound images of 463 ITNs with histological follow-up consecutively evaluated between October 2008 and June 2015 at an academic cancer center. Each observer evaluated individual sonographic features. ATA sonographic patterns were derived from the interpretation of sonographic features. Nodules not fitting into any of the proposed patterns were clustered into a non-ATA pattern., Results: The inter-observer agreement for ATA sonographic patterns and echogenicity was fair, moderate for margins, good for composition and echogenic foci, and very good for extrathyroidal extension and lymph node metastasis. The interpretation of each sonographic feature was significantly different between observers, and there was complete disagreement in at least one of the features in 104 (22%) nodules. A total of 169 nodules (37%) were classified into the non-ATA pattern. The number of suspicious features allowed risk stratifying nodules with non-ATA and high-suspicion sonographic patterns. Most Non-invasive Follicular Thyroid Neoplasms with Papillary-like Nuclear Features had 0-1 suspicious features and none had >2., Conclusions: Echogenicity interpretation was the greatest source of disagreement. The number of suspicious features risk-stratifies ITNs with non-ATA or high-suspicion patterns. Future studies attempting to objectivize the interpretation of echogenicity and heterogeneity are needed.

HOXB13, a homeodomain transcription factor, is linked to recurrence following radical prostatectomy. While HOXB13 regulates Androgen Receptor (AR) functions in a context dependent manner, its critical effectors in prostate cancer (PC) metastasis remain largely unknown. To identify HOXB13 transcriptional targets in metastatic PCs, we performed integrative bioinformatics analysis of differentially expressed genes (DEGs) in the proximity of the human prostate tumor-specific AR binding sites. Unsupervised Principal Component Analysis (PCA) led to a focused core HOXB13 target gene-set referred to as HOTPAM9 (HOXB13 Targets separating Primary And Metastatic PCs). HOTPAM9 comprised 7 mitotic kinase genes overexpressed in metastatic PCs, TRPM8, and the heat shock protein HSPB8, whose levels were significantly lower in metastatic PCs compared to the primary disease. The expression of a two-gene set, CIT and HSPB8 with an overall balanced accuracy of 98.8% and a threshold value of 0.2347, was sufficient to classify metastasis. HSPB8 mRNA expression was significantly increased following HOXB13 depletion in multiple metastatic CRPC models. Increased expression of HSPB8 by the microtubule inhibitor Colchicine or by exogenous means suppressed migration of mCRPC cells. Collectively, our results indicate that HOXB13 promotes metastasis of PCs by coordinated regulation of mitotic kinases and blockade of a putative tumor suppressor gene.

Importance: Tens of thousands of unnecessary operations are performed each year for diagnostic purposes among patients with cytologically indeterminate thyroid nodules. Whereas a diagnostic lobectomy is recommended for most patients with solitary indeterminate thyroid nodules, a total thyroidectomy is preferred for nodules larger than 4 cm., Objective: To determine whether histologic or clinical outcomes of indeterminate thyroid nodules 4 cm or larger are worse than those for nodules smaller than 4 cm, thus justifying a more aggressive initial surgical approach., Design, Setting, and Participants: In this retrospective cohort study, 652 indeterminate thyroid nodules (546 nodules <4 cm and 106 nodules ≥4 cm) with surgical follow-up were consecutively evaluated at an academic cancer center from October 1, 2008, through April 30, 2016., Exposure: Tumor size., Main Outcomes and Measures: Differences in cancer rates, rates of invasive features, cancer aggressiveness, and response to therapy between indeterminate thyroid nodules smaller than 4 cm and 4 cm or larger., Results: A total of 652 indeterminate thyroid nodules (546 nodules <4 cm and 106 nodules ≥4 cm) from 589 patients (mean [SD] age, 53.1 [13.8] years; 453 [76.9%] female) were studied. No differences were found in the baseline characteristics of patients or nodules between the 2 size groups. Tumor size was not associated with the cancer rate as a categorical (140 of 546 [25.6%] for nodules <4 cm and 33 of 106 [31.1%] for nodules ≥4 cm; effect size, 0.05; 95% CI, 0.002-0.12) or continuous (odds ratio [OR], 1.03; 95% CI, 0.92-1.15) variable. No association was found between nodule size and prevalence of extrathyroidal extension, positive margins, lymphovascular invasion, lymph node metastasis, or distant metastasis. Most malignant tumors were low risk in both size groups (70% in the nodules <4 cm and 72% in the nodules ≥4 cm), and tumor size was not associated with tumor aggressiveness as a categorical (effect size, 0.10; 95% CI, 0.03-0.31) or continuous variable (OR for intermediate-risk cancer, 0.91; 95% CI, 0.72-1.14; OR for high-risk cancer, 1.43; 95% CI, 0.96-2.15). At the last follow-up visit, 88 of 105 patients (83.8%) with malignant tumors in the smaller than 4 cm group and 21 of 25 (84.0%) in the 4 cm or greater group had no evidence of disease, and tumor size was not associated with response to therapy (effect size, 0.13; 95% CI, 0.07-0.33)., Conclusions and Relevance: Most indeterminate thyroid nodules are benign or low-risk malignant tumors regardless of tumor size. In the absence of other indications for total thyroidectomy, this study suggests that a thyroid lobectomy is sufficient initial treatment for most solitary cytologically indeterminate thyroid nodules independent of the tumor size.

Background: The impact of oncogene panel results on the surgical management of indeterminate thyroid nodules (ITNs) is currently unknown., Methods: Surgical management of 649 patients consecutively evaluated from October 2008 to April 2016 with a single nodule biopsied and indeterminate cytology (193 evaluated with and 456 without oncogene panels) was assessed and compared. Histological features of 629 consecutively resected ITNs (164 evaluated with and 465 without oncogene panels) were also characterized and compared., Results: Oncogene panel evaluation was associated with higher rates of total thyroidectomy (45% vs 28%; P = .006), and central lymph node dissection (19% vs 12%; P = .03) without increasing the yield of malignancy or decreasing the rate of completion thyroidectomy. Most malignancies (64%), including 83% of those with driver mutation identified, were low-risk cancers for which a lobectomy could have been sufficient initial treatment., Conclusion: Current oncogene panel results seem insufficient to guide the surgical extent of solitary ITNs., (© 2018 Wiley Periodicals, Inc.)

Background: The 2015 American Thyroid Association (ATA) guidelines recommend using a classification based on sonographic patterns to set the size threshold for biopsies. Each pattern is associated with a distinct estimated rate of malignancy that it was hypothesized should stratify the risk of malignancy of cytologically indeterminate thyroid nodules (ITNs)., Methods: Ultrasound images of 463 ITNs (38% atypia/follicular lesions of undetermined significance; 62% follicular neoplasms) with histological follow-up consecutively evaluated between October 2008 and June 2015 at the authors' academic cancer center were independently evaluated by three observers and classified into one of the five sonographic patterns proposed by the ATA. Nodules with sonographic patterns not defined in the classification were grouped into a non-ATA pattern category. Differences in clinical and histological findings between the sonographic patterns were assessed. The prevalence of malignancy and odds ratio for malignancy were calculated for each sonographic pattern (low and intermediate patterns were collapsed for the analysis)., Results: The distribution of size and cytological diagnosis was significantly different between sonographic patterns (p < 0.001). The overall rate of malignancy was 27%. The rate of malignancy for the very low, low/intermediate, high, and non-ATA patterns were 0%, 19%, 56%, and 36%, respectively, and were all significantly different. Compared to the low/intermediate suspicion patterns, the odds ratios for malignancy were 2.35 for the non-ATA and 5.18 for the high suspicion patterns (p < 0.001). The odds ratio of the non-ATA pattern was 0.45 over the high suspicion pattern (p = 0.04). Results were similar in both cytological categories and for each observer separately. Sonographic patterns were associated with distinct histopathological profiles (p < 0.001)., Conclusions: ATA sonographic patterns are associated with distinct clinical features and pathological outcomes, and effectively stratify the cancer risk in ITNs. Thus, the ATA sonographic patterns should be used not only to set the size threshold for biopsy, but also to personalize management after the biopsy.

Gliomas are the most common type of malignant primary brain tumor and few risk factors have been linked to their development. Handedness has been associated with several pathologic neurological conditions such as schizophrenia, autism, and epilepsy, but few studies have evaluated a connection between handedness and risk of glioma. In this study, we examined the relationship between handedness and glioma risk in a large case-control study (1849 glioma cases and 1354 healthy controls) and a prospective cohort study (326,475 subjects with 375 incident gliomas). In the case-control study, we found a significant inverse association between left handedness and glioma risk, with left-handed persons exhibiting a 35% reduction in the risk of developing glioma [odds ratio (OR) = 0.65, 95% confidence interval (CI) 0.51-0.83] after adjustment for age, gender, race, education, and state of residence; similar inverse associations were observed for GBM (OR = 0.69, 95% CI 0.52-0.91), and non-GBM (OR = 0.59, 95% CI 0.42-0.82) subgroups. The association was consistent in both males and females, and across age strata, and was observed in both glioblastoma and in lower grade tumors. In the prospective cohort study, we found no association between handedness and glioma risk (hazards ratio = 0.92, 95% CI 0.67-1.28) adjusting for age, gender, and race. Further studies on this association may help to elucidate mechanisms of pathogenesis in glioma.

Background: Indeterminate categories of thyroid cytopathology (categories B-III and B-IV of the Bethesda system) are integrated by a heterogeneous spectrum of cytological scenarios that are generally clustered for analysis and management recommendations. It has been suggested that aspirates exhibiting nuclear atypia have a higher risk of malignancy. This study aimed to assess whether cytologically indeterminate thyroid nodules with nuclear atypia have a significantly higher cancer risk than those without nuclear atypia., Methods: On June 30, 2016, PubMed and EMBASE were searched for articles in English or Spanish using a search strategy developed by an endocrinologist and a librarian. Case reports were excluded, and no date limits were used. The references of all included studies were also screened for relevant missing studies. Studies were included if the prevalences of malignancy of cytologically indeterminate thyroid nodules with histological confirmation with and without nuclear atypia were reported. Studies were excluded if they had: (i) nodules suspicious for malignancy; (ii) nodules with non-indeterminate (B-III or B-IV) cytology on repeated biopsy, if performed; (iii) nodules not consecutively evaluated; or (iv) cohorts overlapping with another larger series. Two investigators independently assessed the eligibility and risk of bias of the studies. PRISMA and MOOSE guidelines were followed. Summary data were extracted from published reports by one investigator and independently reviewed by another. Data were pooled using a random-effects model. Heterogeneity was explored using subgroup analysis and mixed-effect model meta-regression. The odds ratio for malignancy of cytologically indeterminate thyroid nodules with nuclear atypia over cytologically indeterminate thyroid nodules without nuclear atypia was calculated., Results: Of 2571 retrieved studies, 20 were eligible. The meta-analysis was conducted on summary data of 3532 cytologically indeterminate thyroid nodules: 1162 with and 2370 without nuclear atypia. The odds ratio for malignancy in cytologically indeterminate thyroid nodules with nuclear atypia was 3.63 [confidence interval 3.06-4.35]. There was no evidence of publication bias, and heterogeneity was insignificant (I 2 < 0.01%, p = 0.40)., Conclusions: Nuclear atypia is a significant indicator of malignancy in cytologically indeterminate thyroid nodules and needs to be standardized and implemented into clinical practice.

Purpose To extract radiologic features from small pulmonary nodules (SPNs) that did not meet the original criteria for a positive screening test and identify features associated with lung cancer risk by using data and images from the National Lung Screening Trial (NLST). Materials and Methods Radiologic features in SPNs in baseline low-dose computed tomography (CT) screening studies that did not meet NLST criteria to be considered a positive screening examination were extracted. SPNs were identified for 73 incident case patients who were given a diagnosis of lung cancer at either the first or second follow-up screening study and for 157 control subjects who had undergone three consecutive negative screening studies. Multivariable logistic regression was used to assess the association between radiologic features and lung cancer risk. All statistical tests were two sided. Results Nine features were significantly different between case patients and control subjects. Backward elimination followed by bootstrap resampling identified a reduced model of highly informative radiologic features with an area under the receiver operating characteristic curve of 0.932 (95% confidence interval [CI]: 0.88, 0.96), a specificity of 92.38% (95% CI: 52.22%, 84.91%), and a sensitivity of 76.55% (95% CI: 87.50%, 95.35%) that included total emphysema score (odds ratio [OR] = 1.71; 95% CI: 1.39, 2.01), attachment to vessel (OR = 2.41; 95% CI: 0.99, 5.81), nodule location (OR = 3.25; 95% CI: 1.09, 8.55), border definition (OR = 7.56; 95% CI: 1.89, 30.8), and concavity (OR = 2.58; 95% CI: 0.89, 5.64). Conclusion A set of clinically relevant radiologic features were identified that that can be easily scored in the clinical setting and may be of use to determine lung cancer risk among participants with SPNs. © RSNA, 2017 Online supplemental material is available for this article.

Background: Management recommendations for thyroid nodules rely primarily on the cytological diagnosis. However, 25% of biopsies render an indeterminate cytology for which management decision is more challenging due to heterogeneity of the specimens. This study aimed to stratify the cancer risk through subcategorization of indeterminate cytology., Methods: The indeterminate cytological specimens (Bethesda-III or IV) of 518 thyroid nodules consecutively evaluated at our academic cancer center between October 2008 and September 2015, blinded to the histological outcome, were retrospectively reviewed. Cytological specimens were subclassified into four groups: aspirates exhibiting nuclear atypia (n = 158; 31%); architectural atypia (n = 222; 43%); oncocytic features (n = 120; 23%); or other types of atypia (n = 18; 3%). The prevalence of malignancy and odds ratio for malignancy were calculated in 323 nodules with histological confirmation., Results: The prevalence of malignancy was 26% overall (20% in Bethesda-III and 29% in Bethesda-IV; p = 0.07), and 47%, 12%, 24%, and 25% for aspirates with nuclear atypia, architectural atypia, oncocytic features, or other types of atypia, respectively. The OR of nuclear atypia over architectural atypia was 6.4 (3.4-12.2; p < 0.001), and 2.7 over oncocytic features (1.4-5.1; p = 0.01), whereas the OR of architectural atypia over oncocytic features was 0.4 (0.2-0.9; p = 0.03). Results were similar for Bethesda-III and IV aspirates when analyzed independently. Furthermore, cytological subcategories improved cytology-histology correlation, as they were associated with distinct profiles of histological diagnoses (p < 0.001)., Conclusions: Cytological subcategories can effectively stratify the risk of malignancy of thyroid nodules with indeterminate cytology and improve cytology-histology correlation.

Purpose: To examine the association of age when adult height was attained with glioma risk., Methods: We analyzed data from a US-based case-control study of glioma risk factors. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) associated between age at attainment of adult height and glioma risk. Multivariate models were adjusted for age, race, sex, education, and state of residence. We examined associations overall, and according to glioma grade, sex, and final adult height., Results: The study set included n = 951 controls and n = 776 cases, with a median age of 56 (18-92); the majority was male (53.8%) and identified as Caucasian. Older age at height completion was associated with an increased risk of glioma. A significant positive trend was observed both for glioblastoma (OR 1.10; 95% CI 1.04-1.17 per 1-year increase in age) and lower grade non-glioblastoma subtypes combined (OR 1.18; 95% CI 1.10-1.28 per year increase in age). The association was observed in men and women, and in all categories of final adult height., Conclusions: We observed for the first time a positive association between glioma risk and a prolonged adolescent growth phase. Our results suggest a role for factors governing the timing and intensity of growth in adolescence as risk-determining exposures in adult glioma.

ThyroSeq v2 claims high positive (PPV) and negative (NPV) predictive values in a wide range of pretest risks of malignancy in indeterminate thyroid nodules (ITNs) (categories B-III and B-IV of the Bethesda system). We evaluated ThyroSeq v2 performance in a cohort of patients with ITNs seen at our Academic Cancer Center from September 2014 to April 2016, in light of the new diagnostic criteria for non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). Our study included 182 patients (76% female) with 190 ITNs consecutively tested with ThyroSeq v2. Patient treatment followed our institutional thyroid nodule clinical pathway. Histologies of nodules with follicular variant papillary thyroid carcinoma or NIFTP diagnoses were reviewed, with reviewers blinded to molecular results. ThyroSeq v2 performance was calculated in nodules with histological confirmation. We identified a mutation in 24% ( n =  45) of the nodules. Mutations in RAS were the most prevalent ( n =  21), but the positive predictive value of this mutation was much lower (31%) than that in prior reports. In 102 resected ITNs, ThyroSeq v2 performance was as follows: sensitivity 70% (46-88), specificity 77% (66-85), PPV 42% (25-61) and NPV 91% (82-97). The performance in B-IV nodules was significantly better than that in B-III nodules (area under the curve 0.84 vs 0.57, respectively; P  = 0.03), where it was uninformative. Further studies evaluating ThyroSeq v2 performance are needed, particularly in B-III., (© 2017 Society for Endocrinology.)

Glioma and meningioma are uncommon tumors of the brain with few known risk factors. Regular use of aspirin has been linked to a lower risk of gastrointestinal and other cancers, though evidence for an association with brain tumors is mixed. We examined the association of aspirin and other analgesics with the risk of glioma and meningioma in a large US case-control study. Cases were persons recently diagnosed with glioma or meningioma and treated at medical centers in the southeastern US. Controls were persons sampled from the same communities as the cases combined with friends and other associates of the cases. Information on past use of analgesics (aspirin, other anti-inflammatory agents, and acetaminophen) was collected in structured interviews. Logistic regression was used to estimate odds ratios (ORs) and 95 % confidence intervals (CIs) for analgesic use adjusted for potential confounders. All associations were considered according to indication for use. A total of 1123 glioma cases, 310 meningioma cases and 1296 controls were included in the analysis. For indications other than headache, glioma cases were less likely than controls to report regular use of aspirin (OR 0.69; CI 0.56, 0.87), in a dose-dependent manner (P trend < 0.001). No significant associations were observed with other analgesics for glioma, or any class of pain reliever for meningioma. Results suggest that regular aspirin use may reduce incidence of glioma., Competing Interests: Potential conflicts of interest: The authors declare no conflicts of interest.

Lung cancer screening identifies cancers with heterogeneous behaviors. Some lung cancers will be identified among patients who had prior negative CT screens and upon follow-up scans develop a de novo nodule that was determined to be cancerous. Other lung cancers will be identified among patients who had one or more prior stable positive scans that were not determined to be lung cancer (indeterminate pulmonary nodules), but in follow-up scans was diagnosed with an incidence lung cancer. Using data from the CT arm of the National Lung Screening Trial, this analysis investigated differences in patient characteristics and survival endpoints between prevalence-, interval-, and screen-detected lung cancers, characterized based on sequence of screening results. Lung cancers immediately following a positive baseline (T0), and prior to the T1 screen, formed the prevalence cohort. Interval cancers were diagnosed following a negative screen at any time point prior to the next screening round. Two cohorts of screen-detected lung cancers (SDLC) were identified that had a baseline positive screen that was that was not determined to be lung cancer (i.e., an indeterminate pulmonary nodule), but in follow-up scans was diagnosed with an incidence lung cancer 12 (SDLC1) or 24 (SDLC2) months later. Two other incidence cohorts had screen-detected lung cancers that had baseline negative screen and upon follow-up scans developed a de novo nodule determined to be cancerous at 12 (SDLC3) or 24 (SDLC4) months later. Differences in patient characteristics, progression-free survival (PFS), and overall survival (OS) were assessed. The lung cancer-specific death rate was higher for SDLC3/SDLC4 compared to SDLC1/SDLC2 lung cancers (136.6/1,000 person-years vs. 71.3/1,000 person-years, P < 0.001). Moreover, PFS and OS were significantly lower for SDLC3/SDLC4 compared to SDLC1/SDLC2 (P < 0.004; P < 0.002, respectively). The findings were consistent when stratified by stage and histology. Multivariable Cox proportional models revealed that the SDLC3/SDLC4 case groups were associated with significantly poorer PFS (HR = 1.89; 95% CI 1.31-2.74) and OS (HR = 1.80; 95% CI 1.21-2.67) compared to SDLC1/SDLC2 lung cancers (HR = 1.00). Lung cancer patients who develop a de novo nodule that determined to be cancerous (i.e., at least one negative CT screen prior to cancer diagnosis) had poorer survival outcomes compared to patients who had at least one positive screen prior to cancer diagnosis. As such, the observation that de novo screen-detected are associated with poorer survival could be attributed to faster growing, more aggressive cancers that arose from a lung environment previously lacking focal abnormalities.

Background: The 2015 American Thyroid Association (ATA) thyroid nodule guidelines recommend selecting nodules for biopsy based on a sonographic pattern classification. These patterns were developed based on features of differentiated thyroid cancer. This study aimed to evaluate the performance and the inter-observer agreement of this classification system in medullary thyroid carcinoma (MTC)., Methods: The medical records of all patients with MTC evaluated at the authors' institution between 1998 and 2014 were retrospectively reviewed. Only patients with presurgical thyroid ultrasound available for review were included in the study. Five independent reviewers assessed the stored ultrasound images for composition, echogenicity, margins, presence of calcifications, and extrathyroidal extension for each nodule. The presence of suspicious lymph nodes was also evaluated when presurgical lateral neck ultrasound was available for review. Each nodule was classified according to the ATA sonographic patterns. Inter-observer agreement was calculated for each sonographic feature and for the sonographic patterns. To validate the findings, a systematic review of the literature and meta-analysis on the sonographic features of MTC was conducted., Results: In this institutional cohort, the inter-observer agreement for individual sonographic features was moderate to good (κ = 0.45-0.71), and for the ATA classification it was good (κ = 0.72). Ninety-seven percent (29/30) of the MTCs were classified in the intermediate or high suspicion patterns. A total of 249 MTCs were included in the meta-analysis. Based on pooled frequencies for solid composition and hypoechogenicity, >95% of MTCs would be classified at least in the intermediate suspicion pattern, warranting the lowest-size threshold for biopsy (≥1 cm)., Conclusions: The sonographic patterns proposed by the ATA perform well in MTC, and inter-observer agreement is good to very good.

Introduction: Ampullary adenocarcinoma (AAC) is a rare neoplasm. We sought to determine the clinicopathologic factors contributing to the overall survival (OS) and recurrence-free (RFS) survival., Methods: Patients (pts) with resected AAC were identified from 1996 to 2015 and reviewed for clinicopathologic factors and correlated with outcome., Results: We identified and evaluated 106 pts diagnosed with AAC. The median age was 70.2 years (range 41-86) and 60 (56.6%) were male. Overall, 105 pts (99.1%) had a pancreaticoduodenectomy. An R0 resection was achieved in 101 (95%) pts. Median follow-up was 19 months with a median OS of 49.3 months. Lymph node metastasis and poorly differentiated tumors adversely affected OS on multivariate analysis (MVA). Twenty patients (18.9%) developed recurrence. The median RFS was 27 months. RFS was adversely affected by lymph node count and metastasis, tumor differentiation, and histological subtype on MVA. Survival was not affected by the addition of adjuvant therapy. Retrieval of ≤12 lymph nodes and lymph node ratio ≥0.10 resulted in worse OS on Kaplan-Meier analysis., Conclusions: Our data show retrieval of ≤12 nodes, involvement of nodes with AAC, moderately or poorly differentiated tumors, and pancreaticobiliary subtype adversely affected survival, while the use of adjuvant therapy demonstrated no significant benefit. J. Surg. Oncol. 2016;114:170-175. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Background: The current NCCN recommendation for resection margins in patients with melanomas between 1.01 and 2 mm deep is a 1-2 cm radial margin. We sought to determine whether margin width had an impact on local recurrence (LR), disease-specific survival (DSS), and type of wound closure., Methods: Melanomas measuring 1.01-2.0 mm were evaluated at a single institution between 2008 and 2013. All patients had a 1 or 2 cm margin., Results: We identified 965 patients who had a 1 cm (n = 302, 31.3 %) or 2 cm margin (n = 663, 68.7 %). Median age was 64 years, and 592 (61.3 %) were male; 32.5 and 48.7 % of head and neck and extremity patients had a 1 cm margin versus 18.9 % of trunk patients (p < 0.001). LR was 2.0 and  2.1 % for a 1 and 2 cm margin, respectively (p = not significant). Five-year DSS was 87 % for a 1 cm margin and 85 % for a 2 cm margin (p = not significant). Breslow thickness, melanoma on the head and neck, lymphovascular invasion, and sentinel lymph node biopsy (SLNB) status significantly predicted LR on univariate analysis; however, only location and SLNB status were associated with LR on multivariate analysis. Margin width was not significant for LR or DSS. Wider margins were associated with more frequent graft or flap use only on the head and neck (p = 0.025)., Conclusions: Our data show that selectively using a narrower margin of 1 cm did not increase the risk of LR or decrease DSS. Avoiding a 2 cm margin may decrease the need for graft/flap use on the head and neck.

Background: The purpose is to determine the clinicopathologic factors related to survival and recurrence of primary resected pelvic soft tissue sarcomas (STS)., Methods: Demographic/clinical variables were recorded., Results: Thirty-five pts were identified. Median follow-up was 24.2 months. There were 23 (65.7%) high/intermediate-grade and 12 (34.3%) low-grade tumors included in the final analysis. Eight patients (22.9%) received neoadjuvant therapy. Margins were grossly negative in 27 (77.1%, 17-R0, 10-R1) and grossly positive (R2) in 8 (22.9%). Adjuvant therapy was used in 13 patients (37.1%). The 2- and 3-year RFS was 56.5% and 51.3%, with 14 patients recurring at a median time of 16 months (6-local, 8-distant). All distant recurrences were in high-grade tumors. There were no differences in RFS for margins (R0 vs. R1), neoadjuvant/adjuvant therapy, size (≥10 vs. <10 cm) or gender. High/intermediate-grade tumors had worse RFS (P < 0.008). The 2- and 3-year OS was 80.9%. OS was improved for R0/R1 resection (P < 0.001). Resection to R0/R1 margin was a significant predictor of improved OS (P = 0.001)., Conclusions: High/intermediate-grade lesions were associated with worse OS and RFS. Resection to gross negative margins was the only independent predictor of OS. Adjuvant therapy may be reserved for high-grade lesions due to increased metastatic potential. J, (© 2016 Wiley Periodicals, Inc.)

Introduction: Historically dermal melanoma (DM) has been labeled as either stage IIIB (in-transit) or stage IV (M1a) disease. We sought to investigate the natural history of DM and the utility and prognostic significance of sentinel lymph node biopsy (SLNB)., Methods: Patients with DM undergoing SLNB at a single center from 1998 to 2009 were identified., Results: Eighty-three patients met criteria, 10 (12%) patients had a positive SLNB. Of those, 5 (50%) recurred (all with distant disease). Twenty-one (29%) of the 73 SLNB negative patients recurred and of those, 15 (71%) developed distant metastases, whereas 6 (29%) developed local or regional recurrence, including two false-negative regional nodal recurrences. No in-transit recurrences were recorded. Five-year recurrence-free and disease-specific survival was significantly better for patients with a negative SLNB versus positive SLNB (56.8% vs. 22.2% P = 0.02, 81.1% vs. 61.0%, P = 0.05, respectively)., Conclusion: SLNB has prognostic significance for RFS and DSS, and should be utilized in the management of DM based on a >10% yield and low false-negative rate. Our data demonstrate patients with DM do not recur in an in-transit fashion, which along with the survival outcomes suggest the behavior of DM is consistent with primary cutaneous melanoma of similar thickness rather than an isolated in-transit or distant dermal metastasis from a regressed cutaneous primary., (© 2015 Wiley Periodicals, Inc.)

We demonstrate that high-field terahertz (THz) pulses trigger transient insulator-to-metal transition in a nanoantenna patterned vanadium dioxide thin film. THz transmission of vanadium dioxide instantaneously decreases in the presence of strong THz fields. The transient THz absorption indicates that strong THz fields induce electronic insulator-to-metal transition without causing a structural transformation. The transient phase transition is activated on the subcycle time scale during which the THz pulse drives the electron distribution of vanadium dioxide far from equilibrium and disturb the electron correlation. The strong THz fields lower the activation energy in the insulating phase. The THz-triggered insulator-to-metal transition gives rise to hysteresis loop narrowing, while lowering the transition temperature both for heating and cooling sequences. THz nanoantennas enhance the field-induced phase transition by intensifying the field strength and improve the detection sensitivity via antenna resonance. The experimental results demonstrate a potential that plasmonic nanostructures incorporating vanadium dioxide can be the basis for ultrafast, energy-efficient electronic and photonic devices.

Biomarkers based on germline DNA variations could have translational implications by identifying prognostic factors and sub-classifying patients to tailored, patient-specific treatment. To investigate the association between germline variations in interleukin (IL) genes and lung cancer outcomes, we genotyped 251 single nucleotide polymorphisms (SNPs) from 33 different IL genes in 651 non-small cell lung cancer (NSCLC) patients. Analyses were performed to investigate overall survival, disease-free survival, and recurrence. Our analyses revealed 24 different IL SNPs significantly associated with one or more of the lung cancer outcomes of interest. The GG genotype of IL16:rs7170924 was significantly associated with disease-free survival (HR = 0.65; 95% CI 0.50-0.83) and was the only SNP that produced a false discovery rate (FDR) of modest confidence that the association is unlikely to represent a false-positive result (FDR = 0.142). Classification and regression tree (CART) analyses were used to identify potential higher-order interactions. We restricted the CART analyses to the five SNPs that were significantly associated with multiple endpoints (IL1A:rs1800587, IL1B:rs1143634, IL8:s12506479, IL12A:rs662959, and IL13:rs1881457) and IL16:rs7170924 which had the lowest FDR. CART analyses did not yield a tree structure for overall survival; separate CART tree structures were identified for recurrence, based on three SNPs (IL13:rs1881457, IL1B:rs1143634, and IL12A:rs662959), and for disease-free survival, based on two SNPs (IL12A:rs662959 and IL16:rs7170924), which may suggest that these candidate IL SNPs have a specific impact on lung cancer progression and recurrence. These data suggest that germline variations in IL genes are associated with clinical outcomes in NSCLC patients., (© 2015 Wiley Periodicals, Inc.)

Objectives: Moderate alcohol consumption can impair host defence against viral infections. The objective of this cross-sectional analysis was to assess the association between alcohol intake and prevalent human papillomavirus (HPV) infection among US men enrolled in the HPV in Men (HIM) study using quantitative alcohol intake measured from a Food Frequency Questionnaire., Methods: The HIM study is a prospective, multinational study of the natural history of HPV infection. For this report, we restricted our analyses to men from the US cohort (N = 1313). Samples from the corona of glans penis, penile shaft and scrotum were combined for HPV DNA testing. Self-reported alcohol intake was quantified by grams of alcohol intake per day. Multivariable prevalence ratios (mPRs) were used to assess the association between alcohol intake and HPV infections., Results: Prevalent infections were significantly higher among men in the highest quartile of alcohol intake and multivariable models revealed that the highest quartile of alcohol intake was associated with significantly increased risks for any (mPR = 1.13; 95% CI 1.00 to 1.27) HPV types and oncogenic (mPR = 1.35; 95% CI 1.08 to 1.68) HPV types. The fourth quartile of alcohol intake was associated with elevated risks for prevalent HPV infection across all strata of number of sexual partners and among never-smokers and current smokers, but not among former smokers., Conclusions: These results demonstrate that high intake of alcohol is associated with an increased risk for prevalent HPV infections among men. The biological role that alcohol plays in genital HPV infection remains understudied and limited epidemiological data exist, especially among men., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Isolated limb infusion (ILI) with melphalan is a minimally invasive, effective treatment for in transit melanoma. We hypothesized that burden of disease (BOD) would correlate to treatment response., Methods: We retrospectively analyzed a prospectively collected database from two academic centers. BOD was stratified as high or low (low ≤ 10 lesions, none >2 cm). Response rates were measured 3 months post-ILI. Multivariable analysis (MV) was used to evaluate the association between the response and BOD. Kaplan-Meier methods with log-rank tests and MV Cox proportional hazard models were used to analyze overall survival (OS) and progression free survival (PFS)., Results: Sixty (38 %) patients had low and 100 (62 %) high BOD. Patients with low BOD had an overall response rate (ORR) of 73 % with 50 % CR, compared with an ORR of 47 % with 24 % CR in patients with high BOD (p = 0.002). MV analysis of preoperative, intraoperative, and postoperative parameters showed no significant impact on 3-month response. Patients with a CR at 3 months demonstrated improved PFS over the remainder of the cohort, but OS was similar. Low BOD patients had an increased median PFS of 6.9 versus 3.8 months (p = 0.047) and a increased median OS of 38.4 versus 30.9 months (p = 0.146)., Conclusions: Lower BOD is associated with an increased ORR and CR rate with statistically significantly improved PFS in patients undergoing ILI for in transit extremity melanoma. BOD provides useful prognostic information for patient counseling and serves as a marker to stratify patient risk groups.

Objectives: An assessment of temporal trends in patient survival is important to determine the progress toward patient outcomes and to reveal where advancements must be made. This study assessed temporal changes spanning 22years in demographics, clinical characteristics, and overall survival of small cell lung cancer (SCLC) patients., Materials and Methods: This analysis included 1032 SCLC patients spanning two time-periods from the H. Lee Moffitt Cancer Center and Research Institute: 1986-1999 (N=410) and 2000-2008 (N=622). Kaplan-Meier survival curves and log-rank statistics were used to assess survival rates across the two time-periods and multivariable Cox proportional hazards models were used to generate hazard ratios (HRs) and 95% confidence intervals (CIs)., Results: The overall 5-year survival rate significantly increased from 8.3% for the 1986-1999 time-period to 11.0% (P<0.001) for the 2000-2008 time-period, and the median survival time increased from 11.3months (95% CI 10.5-12.7) to 15.2months (95% CI 13.6-16.6). We also observed significant increases in stage-specific median survival times and survival rates across the two time-periods. A multivariable Cox proportional hazards model for the entire cohort revealed significant increased risk of death for patients diagnosed in 1986-1999 (HR=1.29; 95% CI 1.11-1.49), patients diagnosed between 60 and 69years of age (HR=1.33; 95% CI 1.04-1.49) and over 70years of age (HR=1.63; 95% CI 1.26-2.11), men (HR=1.33; 95% CI 1.16-1.53), patients with no first course treatment (HR=2.17; 95% CI 1.57-3.00) and extensive stage SCLC (HR=2.79; 95% CI 2.35-3.30)., Conclusion: This analysis demonstrated significant improvements in overall and stage-specific median survival times and survival rates of SCLC patients treated at the Moffitt Cancer Center from 1986 to 2008., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Gender-specific incidence patterns and the presence of hormonal receptors on tumor cells suggest that sex hormones may play a role in the onset of primary brain tumors. However, epidemiological studies on the relation of hormonal risk factors to the risk of brain tumors have been inconsistent. We examined the role of reproductive factors in the onset of glioma and meningioma in a case-control study conducted in the Southeastern US that included 507 glioma cases, 247 meningioma cases, and 695 community-based and friend controls. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI) adjusting for age, race, US state of residence, and education. An older age at menarche was associated with an increased risk of glioma (≥ 15 vs. ≤ 12 years: OR 1.65; 95% CI 1.11-2.45), with a stronger association observed in pre-menopausal (OR 2.22; 95% CI 1.12-4.39) than post-menopausal (OR 1.55; 95% CI 0.93-2.58) women. When compared to controls, meningioma cases were more likely to have undergone natural menopause (OR 1.52; 95% CI 1.04-2.21) whereas glioma cases were less likely to be long term users of oral contraceptives (OR 0.47; 95% CI 0.33-0.68). Increasing parity was not related to the risk of either tumor. Current findings are consistent with a limited role for hormones in the onset of brain tumors in women. Results contribute to a growing body of evidence that a later age at menarche increases the risk of glioma in women.

Background: An assessment of historical trends in patient survival is important to determine the progress toward patient outcomes and to reveal where advancements must be made. The goal of this study was to assess changes in demographics and overall survival of non-small-cell lung cancer (NSCLC) patients who were seen at Moffitt Cancer Center spanning 22 years., Methods: This analysis included 4,997 NSCLC patients who were treated at our institute over 5 time periods: 1986 to 1988, 1991 to 1993, 1996 to 1998, 2001 to 2003, and 2006 to 2008. Kaplan-Meier survival curves and the log-rank statistic were used to assess changes in 5-year survival rates over the 5 time periods, and multivariable hazard ratios were estimated from Cox proportional hazards models., Results: From 1986 to 2008 we observed statistically significant increases in the percentage of patients over the age of 70 years, women, never-smokers and former smokers, and patients with stage I tumors. Over the same time period the median survival time statistically significantly increased from 1.09 years (95% confidence interval [CI], 0.95-1.34, P < .001) to 2.27 years (95% CI, 2.07-2.46, P < .001), and the overall 5-year survival rate for all patients significantly increased from 14.7% to 31.1% (P < .001). Among stage I patients, the 5-year survival rate increased from 31.7% to 54.0% (P < .001), 13.3% to 36.0% for stage II (P < .001), 10.5% to 21.7% for stage III (P < .001), and 3.4% to 9.6% for stage IV (P < .001)., Conclusions: This analysis demonstrated important temporal changes in the demographics and improvements in overall survival of NSCLC patients treated at our institute from 1986 to 2008. The 5-year survival rates and median survival time of patients diagnosed with NSCLC has significantly improved across all stages, including patients with late-stage disease.

Presently, there are few validated biomarkers that can predict survival or treatment response for non-small cell lung cancer (NSCLC) and most are based on tumor markers. Biomarkers based on germ line DNA variations represent a valuable complementary strategy, which could have translational implications by subclassifying patients to tailored, patient-specific treatment. We analyzed single nucleotide polymorphisms (SNPs) in 53 inflammation-related genes among 651 NSCLC patients. Multivariable Cox proportional hazard models, adjusted for lung cancer prognostic factors, were used to assess the association of genotypes and haplotypes with overall survival. Four of the top 15 SNPs associated with survival were located in the TNF-receptor superfamily member 10b (TNFRSF10B) gene. The T-allele of the top ranked SNP (rs11785599) was associated with a 41% increased risk of death (95% confidence interval [CI] = 1.16-1.70) and the other three TNFRSF10B SNPs (rs1047275, rs4460370 and rs883429) exhibited a 35% (95% CI = 1.11-1.65), 29% (95% CI = 1.06-1.57) and 24% (95% CI = 0.99-1.54) increased risk of death, respectively. Haplotype analyses revealed that the most common risk haplotype (TCTT) was associated with a 78% (95% CI = 1.25-2.54) increased risk of death compared with the low-risk haplotype (CGCC). When the data were stratified by treatment, the risk haplotypes exhibited statistically significantly increased risk of death among patients who had surgery only and no statistically significant effects among patients who had surgery and adjuvant chemotherapy. These data suggest that possessing one or more risk alleles in TNFRSF10B is associated with an increased risk of death. Validated germ line biomarkers may have potential important clinical implications by optimizing patient-specific treatment.

Background and Objectives: Many clinicians have not received adequate training in smoking cessation. We examined the effects of a tobacco training program on clinician behavior, attitudes, knowledge, and comfort related to smoking cessation., Methods: In a prospective cohort study, family medicine residents and faculty completed a pretest, followed by an educational intervention that encompassed presentations on smoking cessation resources, motivational interviewing, and the neurobiology of addiction and pharmacotherapy. After 3 months, participants completed a postintervention survey. Results were analyzed using chi-square tests to examine the effects of training., Results: Thirty-three residents and faculty completed the pretraining survey and 25 completed the posttraining survey. Following training, participants were more familiar and comfortable with Public Health Service Clinical Practice Guidelines (P < .0001). No significant differences were found in performance of the 5 As (Ask, Advise, Assess, Assist, and Arrange) or other behaviors, including providing assistance with counseling, cessation plans, resources, or pharmacotherapy. There were no improvements in knowledge of specific intervention plans or attitudes related to identifying and counseling smokers., Conclusion: A multidisciplinary tobacco training program increases clinician familiarity and comfort with practice guidelines, and may contribute to improving care activities that promote a healthy lifestyle. Future research should explore other interventions that have the potential of changing practice patterns on a larger scale. Future studies should also assess the effect of training programs on patient-oriented outcomes.

Objective: Males with chronic obstructive pulmonary disease (COPD) are at increased risk for developing osteoporosis (OP) with subsequent vertebral compression fractures. Such fractures with resultant increased thoracic kyphotic angle (TKA) may interfere with these patients' already compromised pulmonary function. A retrospective cross-sectional study was performed to evaluate the recognition and treatment of vertebral fractures in male patients with COPD., Methods: The study population included male patients with COPD aged 55 years and older who had a lateral chest X-ray (index film) performed between January 1, 2001 and July 5, 2005. Vertebral fractures and the TKA were determined independently by two different radiologists. One radiologist (reviewer #1) used direct measurement including quantitative morphometric analysis to determine fractures and the TKA, whereas the second radiologist (reviewer #2) used visual inspection only. Inter-reader agreement for vertebral fractures and TKA was assessed. The computerized charts were reviewed to determine the initial recognition of vertebral fractures and the subsequent therapy. Logistic regression was employed to determine significant risk factors for vertebral fractures in this male population., Results: Three hundred and fifty male study subjects and their index lateral chest X-rays were reviewed. Ages ranged from 52 to 90 and 9/350 (2.6%) of the study subjects had vertebral fractures identified on the initial radiology report. None of these nine patients were subsequently treated with anti-osteoporotic agents other than calcium and vitamin D, and two of them had a follow-up central bone density. Reviewer #1 measured 361 fractures in 181 subjects and determined the mean TKA to be 31.43 (+/-8.62) degrees. Reviewer #2 identified 27 fractures in 19 subjects and with an estimated mean TKA of 24.84 (+/-8.53) degrees. There was little inter-observer agreement with vertebral fractures (kappa=0.07), but there was a strong positive correlation with the TKA (r=0.79). There was a weak to moderate correlation with the TKA and the presence of vertebral fractures (r=0.26). Significant risk factors for vertebral fractures included smoking status (odds ratio 1.84 [1.08-3.15]) and age (odds ratio 1.06 [1.03-1.09] for each year increase in age)., Conclusion: A large number of vertebral fractures in males with COPD goes undiagnosed. In those patients with diagnosed vertebral fractures, follow-up therapy is under-utilized. When analyzing lateral chest X-rays for vertebral fractures, visual inspection alone without direct measurement may not be an adequate technique for identifying fractures.