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Congenital lipomatous overgrowth with vascular, epidermal, and skeletal (CLOVES) anomalies and Klippel‐Trenaunay (KTS) syndromes are caused by somatic gain‐of‐function mutations in PIK3CA, encoding a catalytic subunit of phosphoinositide 3‐kinase. Affected tissue is needed to find mutations, as mutant alleles are not detectable in blood. Because some patients with CLOVES develop Wilms tumor, we tested urine as a source of DNA for mutation detection. We extracted DNA from the urine of 17 and 24 individuals with CLOVES and KTS, respectively, and screened 5 common PIK3CA mutation hotspots using droplet digital polymerase chain reaction. Six of 17 CLOVES participants (35%) had mutant PIK3CA alleles in urine. Among 8 individuals in whom a mutation had been previously identified in affected tissue, 4 had the same mutant allele in the urine. One study participant with CLOVES had been treated for Wilms tumor. We detected the same PIK3CA mutation in her affected tissue, urine, and tumor, indicating Wilms tumors probably arise from PIK3CA mutant cells in patients with CLOVES. No urine sample from a participant with KTS had detectable PIK3CA mutations. We suggest that urine, which has the advantage of being collected non‐invasively, is useful when searching for mutations in individuals with CLOVES syndrome. [ABSTRACT FROM AUTHOR]

Background: There seems to be an association between paracetamol consumption during late pregnancy and the prevalence of wheezing in infancy and childhood. The aim of the present study is to determine whether the aforementioned association is modified by the presence of asthma in the mother. Methods: A total of 1,741 children aged 3–5 years from an epidemiological survey performed in the province of Murcia (Spain) were included in the analysis. Data on paracetamol consumption (never, at least once during pregnancy or at least once per month during pregnancy), wheezing symptoms in the offspring (according to the International Study of Asthma and Allergies in Childhood protocol) and the presence of asthma in the mother, together with other known risk factors for asthma, were obtained by means of a questionnaire. Results: The mean age of the children was 4.08 ± 0.8 years and 51.1% were males. The overall prevalence of current wheezing was 20.2%. The frequency of paracetamol usage was similar among asthmatic and non-asthmatic mothers, and only a small proportion of them took this drug at least once a month (13.8% of asthmatics and 11.0% of non-asthmatics). Compared to the mothers who never took paracetamol, there was a significant association between the mother having taken paracetamol at least once per month during pregnancy and the offspring suffering from wheezing at preschool age, but only among non-asthmatic mothers (odds ratio 1.94, 95% confidence interval 1.34–2.79 vs. odds ratio 1.05, 95% confidence interval 0.21–5.08). This association was maintained after controlling for potential confounders (odds ratio 1.74, 95% confidence interval 1.15–2.61). Conclusions: The frequent usage of paracetamol during pregnancy is associated with the prevalence of wheezing in offspring during preschool years. Asthma in the mother might modify this association. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Sturge-Weber syndrome (SWS), a neurocutaneous disorder, is characterized by capillary malformations (CM) in the skin, brain, and eyes. Patients may suffer from seizures, strokes, and glaucoma, and only symptomatic treatment is available. CM are comprised of enlarged vessels with endothelial cells (ECs) and disorganized mural cells. Our recent finding indicated that the R183Q mutation in ECs leads to heightened signaling through phospholipase Cβ3 and protein kinase C, leading to increased angiopoietin-2 (ANGPT2). Furthermore, knockdown of ANGPT2, a crucial mediator of pro-angiogenic signaling, inflammation, and vascular remodeling, in EC-R183Q rescued the enlarged vessel phenotype in vivo. This prompted us to look closer at the microenvironment in CM-affected vascular beds. We analyzed multiple brain histological sections from patients with GNAQ-R183Q CM and found enlarged vessels devoid of mural cells along with increased macrophage-like cells co-expressing MRC1 (CD206, a mannose receptor), CD163 (a scavenger receptor and marker of the monocyte/macrophage lineage), CD68 (a pan macrophage marker), and LYVE1 (a lymphatic marker expressed by some macrophages). These macrophages were not found in non-SWS control brain sections. To investigate the mechanism of increased macrophages in the perivascular environment, we examined THP1 (monocytic/macrophage cell line) cell adhesion to EC-R183Q versus EC-WT under static and laminar flow conditions. First, we observed increased THP1 cell adhesion to EC-R183Q compared to EC-WT under static conditions. Next, using live cell imaging, we found THP1 cell adhesion to EC-R183Q was dramatically increased under laminar flow conditions and could be inhibited by anti-ICAM1. ICAM1, an endothelial cell adhesion molecule required for leukocyte adhesion, was strongly expressed in the endothelium in SWS brain histological sections, suggesting a mechanism for recruitment of macrophages. In conclusion, our findings demonstrate that macrophages are an important component of the perivascular environment in CM suggesting they may contribute to the CM formation and SWS disease progression., (© 2024. The Author(s).)

Objective: Determine the main asthma phenotypes in a population of asthmatic children in Cartagena, Colombia., Methods: 107 children (7 to 17 years old) with a previous diagnosis of asthma were recruited. Biomarkers of T2 inflammation were evaluated by measuring FeNO, eosinophil count in peripheral blood by hemocytometry, and determination of specific IgE to mite allergens by ELISA. The study was approved by the ethics committee of the University of Cartagena (SGR, Grant BPIN2020000100405)., Results: The average age of patients was 10,9 years. 19,6% of the children did not show elevation of any of the T2 inflammation biomarkers evaluated (FeNO<20ppb, eos<300/ul, negative specific IgE), so they were considered patients with non-allergic asthma (non-T2). 71,9% of all patients were sensitized to at least one allergen, this phenotype was considered allergic asthma. 30,8% of the patients presented the three elevated biomarkers (FeNO>20ppb + eos >300/ul + positive specific IgE), this phenotype was classified as high T2 allergic asthma. A moderate correlation (Spearman rho=0,44, p<0,0001) was found between FeNO values and eosinophil counts., Conclusion: In this study, the following phenotypes were found: allergic asthma, high T2 asthma, and non-allergic asthma. Most patients presented a type 2 inflammatory phenotype with allergic sensitization. In addition to the measurement of specific IgE, the use of FeNO and eosinophil count in peripheral blood help to accurately determine those patients with high T2 asthma phenotypes.

Rationale: Despite the importance of inflammation in chronic obstructive pulmonary disease (COPD), the immune cell landscape in the lung tissue of patients with mild-moderate disease has not been well characterized at the single-cell and molecular level. Objectives: To define the immune cell landscape in lung tissue from patients with mild-moderate COPD at single-cell resolution. Methods: We performed single-cell transcriptomic, proteomic, and T-cell receptor repertoire analyses on lung tissue from patients with mild-moderate COPD ( n  = 5, Global Initiative for Chronic Obstructive Lung Disease I or II), emphysema without airflow obstruction ( n  = 5), end-stage COPD ( n  = 2), control ( n  = 6), or donors ( n  = 4). We validated in an independent patient cohort ( N  = 929) and integrated with the Hhip +/- murine model of COPD. Measurements and Main Results: Mild-moderate COPD lungs have increased abundance of two CD8 +  T cell subpopulations: cytotoxic KLRG1 + TIGIT + CX3CR1 +  TEMRA (T effector memory CD45RA + ) cells, and DNAM-1 + CCR5 +  T resident memory (T RM ) cells. These CD8 +  T cells interact with myeloid and alveolar type II cells via IFNG and have hyperexpanded T-cell receptor clonotypes. In an independent cohort, the CD8 + KLRG1 + TEMRA cells are increased in mild-moderate COPD lung compared with control or end-stage COPD lung. Human CD8 + KLRG1 +  TEMRA cells are similar to CD8 +  T cells driving inflammation in an aging-related murine model of COPD. Conclusions: CD8 +  TEMRA cells are increased in mild-moderate COPD lung and may contribute to inflammation that precedes severe disease. Further study of these CD8 +  T cells may have therapeutic implications for preventing severe COPD.

Objective: Lymphangioleiomyomatosis (LAM) is a rare, destructive disease of the lungs with a limited number of determinants of disease activity, which are a critical need for clinical trials. FGF23 has been implicated in several chronic pulmonary diseases. We aimed to determine the association between serum FGF23 levels and pulmonary function in a cohort of patients with LAM., Methods: This was a descriptive single-center study in which subjects with LAM and controls with unreported lung disease were recruited. Serum FGF23 levels were measured in all subjects. Clinical data, including pulmonary function testing, were retrospectively obtained from electronic medical records of LAM subjects. Associations between FGF23 levels and clinical features of LAM were explored via nonparametric hypothesis testing., Results: The sample comprised 37 subjects with LAM and 16 controls. FGF23 levels were higher in the LAM group than in the control group. In the LAM group, FGF23 levels above the optimal cutoff point distinguished 33% of the subjects who had nondiagnostic VEGF-D levels. Lower FGF23 levels were associated with impaired DLCO (p = 0.04), particularly for those with isolated diffusion impairment with no other spirometric abnormalities (p = 0.04)., Conclusions: Our results suggest that FGF23 is associated with pulmonary diffusion abnormalities in LAM patients and elicit novel mechanisms of LAM pathogenesis. FGF23 alone or in combination with other molecules needs to be validated as a biomarker of LAM activity in future clinical research.

Neuroendocrine carcinomas of the lung are currently classified into two categories: small-cell lung carcinoma and large-cell neuroendocrine carcinoma. Diagnostic criteria for small-cell and large-cell neuroendocrine carcinoma are based solely on tumour morphology; however, overlap in histologic and immunophenotypic features between the two types of carcinomas can potentially make their classification challenging. Accurate diagnosis of pulmonary neuroendocrine carcinomas is paramount for patient management, as clinical course and treatment differ between small-cell and large-cell neuroendocrine carcinoma. Molecular-genetic, transcriptomic, and proteomic data published over the past decade suggest that small-cell and large-cell neuroendocrine carcinomas are not homogeneous categories but rather comprise multiple groups of distinctive malignancies. Nuances in the susceptibility of small-cell lung carcinoma subtypes to different chemotherapeutic regimens and the discovery of targetable mutations in large-cell neuroendocrine carcinoma suggest that classification and treatment of neuroendocrine carcinomas may be informed by ancillary molecular and protein expression testing going forward. This review summarizes the current diagnostic criteria, prognostic and predictive correlates of classification, and evidence of previously unrecognised subtypes of small-cell and large-cell neuroendocrine carcinoma., (© 2022 John Wiley & Sons Ltd.)

Activation of the stimulator of interferon genes (STING) pathway promotes antitumor immunity but STING agonists have yet to achieve clinical success. Increased understanding of the mechanism of action of STING agonists in human tumors is key to developing therapeutic combinations that activate effective innate antitumor immunity. Here, we report that malignant pleural mesothelioma cells robustly express STING and are responsive to STING agonist treatment ex vivo. Using dynamic single-cell RNA sequencing of explants treated with a STING agonist, we observed CXCR3 chemokine activation primarily in tumor cells and cancer-associated fibroblasts, as well as T-cell cytotoxicity. In contrast, primary natural killer (NK) cells resisted STING agonist-induced cytotoxicity. STING agonists enhanced migration and killing of NK cells and mesothelin-targeted chimeric antigen receptor (CAR)-NK cells, improving therapeutic activity in patient-derived organotypic tumor spheroids. These studies reveal the fundamental importance of using human tumor samples to assess innate and cellular immune therapies. By functionally profiling mesothelioma tumor explants with elevated STING expression in tumor cells, we uncovered distinct consequences of STING agonist treatment in humans that support testing combining STING agonists with NK and CAR-NK cell therapies., (©2022 American Association for Cancer Research.)

Background: Pro-inflammatory fibroblasts are critical for pathogenesis in rheumatoid arthritis, inflammatory bowel disease, interstitial lung disease, and Sjögren's syndrome and represent a novel therapeutic target for chronic inflammatory disease. However, the heterogeneity of fibroblast phenotypes, exacerbated by the lack of a common cross-tissue taxonomy, has limited our understanding of which pathways are shared by multiple diseases., Methods: We profiled fibroblasts derived from inflamed and non-inflamed synovium, intestine, lungs, and salivary glands from affected individuals with single-cell RNA sequencing. We integrated all fibroblasts into a multi-tissue atlas to characterize shared and tissue-specific phenotypes., Findings: Two shared clusters, CXCL10 + CCL19 + immune-interacting and SPARC + COL3A1 + vascular-interacting fibroblasts, were expanded in all inflamed tissues and mapped to dermal analogs in a public atopic dermatitis atlas. We confirmed these human pro-inflammatory fibroblasts in animal models of lung, joint, and intestinal inflammation., Conclusions: This work represents a thorough investigation into fibroblasts across organ systems, individual donors, and disease states that reveals shared pathogenic activation states across four chronic inflammatory diseases., Funding: Grant from F. Hoffmann-La Roche (Roche) AG., Competing Interests: Declaration of interests E.Y.K. is a member of the advisory board for Cell Reports Medicine. In disclosures unrelated to this work, E.Y.K. is a member of the Steering Committees for and receives no financial renumeration from NCT04409834 (Prevention of arteriovenous thrombotic events in critically ill COVID-19 patients, TIMI group) and REMAP-CAP ACE2 renin-angiotensin system (RAS) modulation domain. E.Y.K. receives unrelated research funding from Bayer AG. In the past, E.Y.K. received unrelated research funding from Windtree Therapeutics. T.T. receives unrelated support from the Zoll Foundation. K.W. is a consultant to Mestag and Gilead Sciences and reports grant support from Gilead Sciences. S.R. is a scientific advisor for Rheos Medicines, Janssen, and Pfizer and a founder of Mestag, Inc. Y.J. and H.A. receive unrelated support from Bayer AG. M.B.B. is a consultant to GSK and 4FO Ventures and a founder of Mestag Therapeutics. M.L.S. receives unrelated research funding and institution consulting fees from Genentech, institution consulting fees from Lilly, research funding from Bristol Myers Squibb, and personal consulting fees from GV20 Therapeutics. M.C. is a co-founder of Mestag Therapeutics and obtains grant funding from and has consulted for Hoffman La-Roche. S.B. has provided paid consultancy services regarding Sjögren’s syndrome clinical trial design for the following companies in the past 3 years: Abbvie, AstraZeneca, BMS, Galapagos, Novartis, and Resolve Pharma. A.F. has received personal renumerations from Abbvie, Roche, and Janssen in the last 2 years and institutional research funding from Roche, UCB, Nascient, Mestag, GSK, and Janssen. A.P.F. and K.G.L. reported being employees of F. Hoffmann-La Roche (Roche) AG., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

The digestion efficiency of liquid industrial wastes increases when using bioreactors colonized by microbial biofilms. High concentrations of proteins derived from the fish processing industry lead to the production of ammonia, which inhibits methane production. Two bioreactors were constructed to compare methanogenic activity: one enriched with mMPA (methylaminotrofic methane production archaea) consortia (control bioreactor), and the second with NH 3 tolerant consortia (treatment bioreactor). Ammonia tolerant activity was assessed by applying an ammonia shock (755 mg NH 3 /L). Methane production, consumption of total organic carbon (TOC) and the taxonomic composition of bacteria and archaea was evaluated using 16S rDNA in the acclimatization, ammonia shock, and recovery phases.The ammonia shock significantly affected both methane production and the consumption of TOC in the control reactor (p < 0.05) and taxonomical composition of the microbial consortia (OTU). These values remained constant in the treatment reactor. The analysis of biofilm composition showed a predominance of Methanosarcinaceae (Methanomethylovorans sp., and probably two different species of Methanosarcina sp.) in bioreactors. These results demonstrate that using acclimated biofilms enriched with ammonia tolerant methanogens control the inhibitory effect of ammonia on methanogenesis., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Neuroendocrine to nonneuroendocrine plasticity supports small cell lung cancer (SCLC) tumorigenesis and promotes immunogenicity. Approximately 20% to 25% of SCLCs harbor loss-of-function (LOF) NOTCH mutations. Previous studies demonstrated that NOTCH functions as a SCLC tumor suppressor, but can also drive nonneuroendocrine plasticity to support SCLC growth. Given the dual functionality of NOTCH, it is not understood why SCLCs select for LOF NOTCH mutations and how these mutations affect SCLC tumorigenesis. In a CRISPR-based genetically engineered mouse model of SCLC, genetic loss of Notch1 or Notch2 modestly accelerated SCLC tumorigenesis. Interestingly, Notch -mutant SCLCs still formed nonneuroendocrine subpopulations, and these Notch-independent, nonneuroendocrine subpopulations were driven by Runx2-mediated regulation of Rest. Notch2 -mutant nonneuroendocrine cells highly express innate immune signaling genes including stimulator of interferon genes (STING) and were sensitive to STING agonists. This work identifies a Notch-independent mechanism to promote nonneuroendocrine plasticity and suggests that therapeutic approaches to activate STING could be selectively beneficial for SCLCs with NOTCH2 mutations. SIGNIFICANCE: A genetically engineered mouse model of NOTCH -mutant SCLC reveals that nonneuroendocrine plasticity persists in the absence of NOTCH, driven by a RUNX2-REST-dependent pathway and innate immune signaling., (©2021 American Association for Cancer Research.)

Objective: To evaluate psychometric properties of the Voice Symptom Scale (VoiSS) - Chilean Spanish version., Study Design: Cross-sectional, nonrandomized, prospective study with controls., Methods: The validation of the Chilean Spanish VoiSS version met the criteria of the Scientific Advisory Committee of the Medical Outcomes Trust: Cultural and linguistic adaptation, by translation into Chilean Spanish and back-translation. Validity, employed external criteria (excellent, very good, fair, and poor). Reliability was made by test-retest and responsiveness to treatment, the initial voice and after vocal treatment of 12 dysphonic patients were analyzed, by GRBAS. The Chilean Spanish adapted VoiSS protocol, Escala de Síntomas Vocales (ESV-CL), was applied to 205 subjects, 89 with dysphonia and 116 of them vocally healthy. A cutoff value for the total score was determined by the efficiency characteristics., Results: The ESV-CL demonstrates high validity, reliability, and responsiveness. A cutoff score of 35.5 was determined by using the high sensitivity (90%) and specificity (75%) found in subjects with dysphonia compared to vocally healthy subjects., Conclusions: The results of the Chilean version of VoiSS, renamed the ESV-CL, revealed it to be culturally equivalent to the original version, and to be a valid, reliable, and responsive instrument for voice symptoms in the Chilean population. Chilean speech-language pathologists can benefit from this adapted protocol in clinical research and voice management., (Copyright © 2019 The Voice Foundation. Published by Elsevier Inc. All rights reserved.)

Identifying childhood cognitive processes that predict adolescent problem behaviors can help guide understanding and prevention of these behaviors. In a community sample of 313 youth recruited in a small Midwestern city between 2006 and 2012 (49% male, 64% European American), executive control and foundational cognitive abilities were assessed at age 5 in a lab setting with performance-based measures. In adolescence, youth provided self-report of problem behaviors in surveys administered annually between ages 14 and 16. Executive control was negatively associated with externalizing behavior problems and adolescents getting in trouble at school, accounting for foundational cognitive abilities and family background covariates. Executive control had negative, but nonsignificant, associations with internalizing problems and substance use initiation. The findings point to deficits in executive control as a childhood risk factor for later problems and a potential target for preventive interventions.

High-grade neuroendocrine carcinomas (NEC) of the endometrium are rare and account for <1% of all endometrial carcinomas. Both small cell neuroendocrine carcinoma (SCNEC) and large cell neuroendocrine carcinoma (LCNEC) morphologies have been reported. Little is known regarding the molecular features of endometrial NEC including how they compare to pulmonary NEC (the most common site for these neoplasms) and the more common endometrial carcinoma histotypes. In this study, we investigated the molecular alterations in a series of endometrial NEC using a targeted next generation sequencing panel (Oncopanel). Fourteen NEC were sequenced; pure NEC (n=4) and mixed (n=10) with endometrioid adenocarcinoma (n=9) or carcinosarcoma (n=1). The NEC components of mixed tumors comprised LCNEC (n=6) and SCNEC (n=4). The 4 pure NEC comprised LCNEC (n=2) and SCNEC (n=2). Molecular analysis classified tumors into the 4 The Cancer Genome Atlas groups: (1) POLE-mutated/ultramutated (1/14; 7%), (2) microsatellite instability/hypermutated (6/14; 43%), (3) TP53 mutated/copy number high (2/14; 14%), or (4) no specific molecular profile (5/14; 36%). Overall, 50% of cases were ultramutated or hypermutated. In 8 cases of mixed carcinomas, the different histologic components were macrodissected and separately sequenced; molecular alterations were nearly identical among the 2 components, with the non-NEC component harboring slightly increased tumor mutational burden. Only 2 carcinomas (both with pure SCNEC morphology) had a molecular profile that would be expected in typical pulmonary SCNEC (RB1 deletion and TP53 mutations). Our findings, similar to data from NECs of other anatomic sites, suggest that the molecular context may be important when selecting therapies for women with endometrial NEC. Immune checkpoint inhibition may be a reasonable approach to treatment of microsatellite instability-NEC and we thus recommend that all endometrial NEC be tested for mismatch repair abnormalities, either molecularly or by mismatch repair protein immunohistochemistry.

INSM1 is a diagnostic marker for neuroendocrine tumors originating in multiple anatomic sites. In the lung, INSM1 shows 76-97% sensitivity for neuroendocrine tumors overall. Our aim was to characterize INSM1 as a diagnostic marker for small cell carcinoma in the context of its epithelial, lymphoid, and mesenchymal morphologic mimics. Immunohistochemistry was performed on 231 tumors, including lung neuroendocrine tumors, nonneuroendocrine carcinomas of the thoracic cavity, diffuse large B-cell lymphomas, and small round cell sarcomas, using an anti-INSM1 mouse monoclonal antibody. Extent (0-100%) and intensity (1-3+) of nuclear INSM1 staining was multiplied in each case to calculate an H-score. Demographic and clinical information was obtained from the medical record. INSM1 had an overall sensitivity and specificity of 81.5% and 82.7% for small cell carcinoma, respectively, using a threshold established with a receiver operating characteristic curve. 40/48 (82.7%) small cell carcinomas were positive for INSM1, including 19/24 (79%) small cell carcinomas that were negative for chromogranin and synaptophysin. 5/5 carcinoids and 21/28 (75%) large cell neuroendocrine carcinomas showed INSM1 expression. Among nonneuroendocrine tumors, 7/38 (18%) lung adenocarcinomas, 2/17 (12%) lung squamous cell carcinomas, 4/10 (40%) thymic carcinomas, 4/12 (33%) adenoid cystic carcinomas, 1/19 (5%) diffuse large B-cell lymphomas, 4/11 (36%) alveolar rhabdomyosarcomas, and 4/23 (17%) Ewing sarcomas were positive for INSM1. No synovial sarcomas or desmoplastic small round cell tumors were positive. Weak, focal INSM1 expression alone is insufficient as a diagnostic marker for small cell carcinoma, but is sensitive and specific, easy to interpret in small biopsies, and makes a valuable addition to a diagnostic panel.

Metaplastic thymomas are rare biphasic thymic tumors that are characteristically well-circumscribed, confined to the thymus, and follow a benign to indolent clinical course. Their relationship to other thymic neoplasms remains unclear, and their molecular characteristics have not been defined. We report for the first time recurrent translocation events in metaplastic thymomas involving the Yes Associated Protein 1 (YAP1) and Mastermind Like Transcriptional Coactivator 2 (MAML2) genes. Eight metaplastic thymomas were retrieved from two institutions' archives over a 21-year period. Paraffin-embedded material from all cases underwent targeted DNA-based hybrid capture next-generation sequencing. Cases showing no somatic alterations subsequently underwent targeted RNA sequencing. Allele-specific real-time polymerase chain reaction was performed to detect GTF2I c.74146970T>A (p.L424H) mutations. All cases showed characteristic histologic features of metaplastic thymoma and demonstrated no local recurrence or distant metastatic disease at 1-22 years of follow-up. Six of eight cases were successfully sequenced, all showing YAP1-MAML2 fusions; in four cases the fusions were detected by DNA sequencing and in two cases by RNA sequencing. Two distinct products were identified: 5' YAP1 exon 1 fused to 3' MAML2 exons 2-5 or 5' YAP1 exons 1-5 fused to 3' MAML2 exons 2-5. All cases underwent allele-specific real-time polymerase chain reaction and demonstrated no GTF2I L424H mutations. Metaplastic thymoma is a distinct, clinically indolent thymic epithelial neoplasm characterized by YAP1-MAML2 fusion and lacking the GTF2I mutations found in Type A and AB thymomas.

Background: Optimal timing for resection of asymptomatic congenital lung malformations (CLMs) remains controversial. The aim of this study is to define optimal timing for surgical intervention of patients with CLMs and define clinical variables that affect surgical outcomes. Methods: An IRB-approved retrospective analysis was conducted for patients undergoing surgery for CLMs between 2012 and 2017. Subjects were divided into cohorts based on timing of operative intervention. "Early intervention" was defined as surgery within 4 months of birth; "intermediate intervention"-between 4 and 6 months; and "late intervention"-6-12 months. Surgical outcomes including intraoperative estimated blood loss (EBL), surgical time, post-operative pneumothorax, length of time chest tube stayed in, and hospital length of stay were compared among the three groups using Fisher's exact test or Chi-squared test for categorical variables and one-way analysis of variance test for continuous variables. Results: We analyzed 63 patients who underwent surgery for CLM. There were no significant differences in baseline characteristics. Timing of surgery did not significantly correlate with post-operative outcomes. Specifically, there was no difference in operative time, EBL, post-operative pneumothorax, or length of hospital stay among the early, intermediate, and late intervention groups. Even after controlling for cyst-volume ratio (CVR), timing of surgery still did not affect post-operative outcomes. Conclusions: Surgical outcomes for resection of CLMs are not significantly affected by timing of surgery. We advocate for early intervention to decrease the incidence of associated complications that can occur with later intervention., (Copyright © 2020 Duron, Zenilman, Griggs, DeFazio, Price, Fan, Vivero, Castrillon, Schmaedick, Iqbal and Rothenberg.)

Safe use of immune checkpoint blockade in patients with cancer and autoimmune disorders requires a better understanding of the pathophysiology of immunologic activation. We describe the immune correlates of reactivation of granulomatosis with polyangiitis (GPA)-an antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis-in a patient with metastatic urothelial carcinoma treated with pembrolizumab. After PD-1 blockade, an inflammatory pulmonary nodule demonstrated a granulomatous, CD4+ T-cell infiltrate, correlating with increased CD4+ and CD8+ naïve memory cells in the peripheral blood without changes in other immune checkpoint receptors. Placed within the context of the existing literature on GPA and disease control, our findings suggest a key role for PD-1 in GPA self-tolerance and that selective strategies for immunotherapy may be needed in patients with certain autoimmune disorders. We further summarize the current literature regarding reactivation of autoimmune disorders in patients undergoing immune checkpoint blockade, as well as potential immunosuppressive strategies to minimize the risks of further vasculitic reactivation upon rechallenge with anti-PD-1 blockade. KEY POINTS: Nonspecific imaging findings in patients with cancer and rheumatological disorders may require biopsy to distinguish underlying pathology.Patients with rheumatologic disorders have increased risk of reactivation with PD-(L)1 immune checkpoint blockade, requiring assessment of disease status before starting treatment.Further study is needed to evaluate the efficacy of treatment regimens in preventing and controlling disease reactivation., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2019.)

The prevalence of incidental nonneoplastic lung disease in patients undergoing resection for mass lesions is unknown. We determined the prevalence and characteristics of parenchymal findings in patients with lung nodules, aiming to increase awareness of findings that could potentially impact patient management. A total of 397 patients with benign or malignant mass lesions with available presurgical chest computed tomography scans resected between January 2001 and July 2015 were included. Retrospective histologic assessment of parenchymal abnormalities in at least 1 section of grossly normal lung was performed for each case by 2 pulmonary pathologists and correlated with original pathology reports, clinical history, and radiologic findings. A total of 233 women and 164 men underwent resections for carcinomas (78%) or benign nodules (22%). One hundred one (25%) patients showed parenchymal abnormalities, including 14 patients with multiple findings. The most common abnormal findings were fibrotic interstitial changes (10%), including usual interstitial pneumonia (1%), followed by granulomatous processes (8%). Other findings included aspiration (4%), intravascular thrombi (2%), Langerhans cell histiocytosis (1.5%), constrictive bronchiolitis (1%), atypical lymphoid infiltrates (1%), and amyloidosis (0.5%). Abnormalities were more likely to have been documented in the original pathology report by pulmonary pathologists (68%) than by general pathologists (15%) (P < .0001). Cases with histologic parenchymal abnormalities were more likely to show radiologic interstitial lung abnormalities than those without (16% versus 5%; P = .001). Evaluation of background lung parenchyma may yield valuable and unanticipated information in patients undergoing surgical resections for lung masses that may correlate with radiographic interstitial lung abnormalities and influence clinical management., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: To achieve a cross-cultural equivalence of the Chilean version of the V-RQOL protocol, through its cultural and linguistic adaptation., Methods: First, two bilingual speech therapists made a translation of the V-RQOL into Spanish. Second, a back-translation to English was performed by a speech therapist who did not participate in the previous stages. Then, a comparison between the original and the back-translation versions of the test was conducted. The existing discrepancies were modified by a committee of five speech therapists, translating the name of the Voice-Related Quality of Life (V-RQOL) instrument into Spanish as Medición de la Calidad de Vida en Relación a la Voz (MCV-RV), with 10 questions and 5 possible answers for each. In order to analyze cultural equivalence, the protocol was applied to 15 individuals with voice disorders. For each question, a 'Not applicable' option was added to the possible answers to determine which questions were not clearly understood by the individuals being tested. Two of the assessed individuals had difficulties in answering a distinct question, though only one of these two questions was modified. The final version of MCV-RV protocol was applied to five individuals with voice disorders who had no difficulty understanding the questions properly., Results: The MCV-RV reflects the original English version, both in the number and types of questions (including physical functioning and the social-emotional aspects)., Conclusion: A cross-cultural equivalence of the V-RQOL was achieved, thereby creating an adapted Chilean-Spanish version (MCV-RV). The validation of the MCV-RV protocol for Chilean Spanish is currently in progress.

Effusion cytology plays multiple roles in the management of benign and malignant disease, from primary diagnosis to tissue allocation for ancillary diagnostic studies and biomarker testing of therapeutic targets. This article summarizes recent advances in pleural effusion cytology, with a focus on the practical application of immunohistochemical markers, cytogenetic techniques, flow cytometry, and molecular techniques for the diagnosis and management of primary and secondary neoplasms of the pleura., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Programmed cell death protein 1 inhibitors increasingly are being used to treat patients with advanced lung carcinomas. Programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) in tumor cells (TCs) and tumor-infiltrating immune cells (ICs) is used to select patients for programmed cell death protein 1 inhibition, but few studies have evaluated PD-L1 IHC in cytology specimens. The objective of the current study was to compare PD-L1 IHC in cytology cell blocks and matched surgical specimens., Methods: A total of 56 cytology specimens obtained between 2013 and 2016 with matching surgical specimens were stained with anti-PD-L1. Membranous positivity was scored as a percentage of the TCs and ICs by 2 pathologists. Results were compared between cytology and surgical specimens, and interobserver concordance was assessed., Results: The average PD-L1 positivity rate was 28% in TCs and 5% in ICs in surgical specimens (standard deviations of 37% and 7%, respectively), and 21% in TCs and 8% in ICs in cytology specimens (standard deviations of 33% and 15%, respectively). Interobserver concordance was high for TCs in surgical and cytology specimens (intraclass correlation coefficients of 0.96 and 0.96, respectively), and was moderate for ICs in surgical and cytology specimens (intraclass correlation coefficients of 0.47 and 0.67, respectively). There was moderate to high correlation between PD-L1 positivity in TCs between surgical and cytology specimens (Spearman correlation coefficient [Spearman r], 0.69), particularly among fine-needle aspiration specimens (Spearman r, 0.78), but not between PD-L1 positivity in ICs in surgical and cytology specimens (Spearman r, 0.14), including among fine-needle aspiration specimens (Spearman r, 0.23)., Conclusions: Tumor PD-L1 IHC positivity in cytology specimens appears to correlate strongly with results obtained from matching surgical specimens. PD-L1 IHC in ICs within cytology specimens does not reflect results in matched surgical specimens and should not be used in clinical decision making. Cancer Cytopathol 2018;126:253-63. © 2018 American Cancer Society., (© 2018 American Cancer Society.)