Poor Concordance between Sequential Transbronchial Lung Cryobiopsy and Surgical Lung Biopsy in the Diagnosis of Diffuse Interstitial Lung Diseases.

Rationale: The diagnostic concordance between transbronchial lung cryobiopsy (TBLC)-versus surgical lung biopsy (SLB) as the current gold standard-in interstitial lung disease (ILD) cases requiring histology remains controversial. Objectives: To assess diagnostic concordance between TBLC and SLB sequentially performed in the same patients, the diagnostic yield of both techniques, and subsequent changes in multidisciplinary assessment (MDA) decisions. Methods: A two-center prospective study included patients with ILD with a nondefinite usual interstitial pneumonia pattern (on high-resolution computed tomography scan) confirmed at a first MDA. Patients underwent TBLC immediately followed by video-assisted thoracoscopy for SLB at the same anatomical locations. After open reading of both sample types by local pathologists and final diagnosis at a second MDA (MDA2), anonymized TBLC and SLB slides were blindly assessed by an external expert pathologist (T.V.C.). Kappa-concordance coefficients and percentage agreement were computed for: TBLC versus SLB, MDA2 versus TBLC, MDA2 versus SLB, and blinded pathology versus routine pathology. Measurements and Main Results: Twenty-one patients were included. The median TBLC biopsy size (longest axis) was 7 mm (interquartile range, 5-8 mm). SLB biopsy sizes averaged 46.1 ± 13.8 mm. Concordance coefficients and percentage agreement were: TBLC versus SLB: κ = 0.22 (95% confidence interval [CI], 0.01-0.44), percentage agreement = 38% (95% CI, 18-62%); MDA2 versus TBLC: κ = 0.31 (95% CI, 0.06-0.56), percentage agreement = 48% (95% CI, 26-70)%; MDA2 versus SLB: κ = 0.51 (95% CI, 0.27-0.75), percentage agreement = 62% (95% CI, 38-82%); two pneumothoraces (9.5%) were recorded during TBLC. TBLC would have led to a different treatment if SLB was not performed in 11 of 21 (52%) of cases. Conclusions: Pathological results from TBLC and SLB were poorly concordant in the assessment of ILD. SLBs were more frequently concordant with the final diagnosis retained at MDA.

Outcome after mechanical thrombectomy using a stent retriever under conscious sedation: comparison between tandem and single occlusion of the anterior circulation.

BACKGROUND AND PURPOSE: In acute ischemic stroke patients, internal carotid artery/middle cerebral artery (ICA/MCA) occlusion in tandem predicts a poor outcome after systemic thrombolysis. This study aimed to compare outcomes after mechanical thrombectomy for tandem and single occlusions of the anterior circulation. MATERIALS AND METHODS: This prospective study included consecutive patients with acute ischemic stroke of the anterior circulation who had undergone mechanical thrombectomy performed with a stent retriever under conscious sedation within 6h of symptom onset. Data on clinical, imaging and endovascular findings were collected. In cases of tandem occlusion, distal thrombectomy (retrograde approach) was performed first whenever possible. Tandem and single occlusions were compared in terms of functional outcome and mortality at 3 months. RESULTS: From May 2010 to April 2012, 42 patients with acute ischemic stroke attributable to MCA and/or ICA occlusion were treated. Eleven patients (26.2%) presented with tandem occlusions and 31 patients (73.8%) had a single anterior circulation occlusion. Baseline characteristics were similar between the two groups. Recanalization status also did not differ significantly (P=0.76), but patients with tandem occlusions had poorer functional outcomes (18.2% vs. 67.7% for single occlusions; P=0.01), a higher mortality rate at 3 months (45.5% vs. 12.9%, respectively; P=0.03) and more symptomatic intracranial hemorrhages at 24h (9.7% vs. 0%, respectively; P=0.01). A high rate of early proximal re-occlusion or severe residual stenosis (66%) was also observed in the tandem group. CONCLUSION: Tandem occlusions had poor clinical outcomes after mechanical thrombectomy compared with single occlusions. The retrograde approach (treatment of distal occlusion first) used in patients under conscious sedation may have contributed to these poor outcomes.

Multiplexed Profiling of CDK Kinase Activities in Tumor Biopsies with Fluorescent Peptide Biosensors.

Detection of disease biomarkers constitutes a major challenge for the development of personalized and predictive diagnostics as well as companion assays. Protein kinases (PKs) involved in the coordination of cell cycle progression and proliferation that are hyperactivated in human cancers constitute attractive pharmacological targets and relevant biomarkers. Although it is relatively straightforward to assess the relative abundance of PKs in a biological sample, there is not always a direct correlation with enzymatic activity, which is regulated by several posttranslational mechanisms. Studies of relative abundance therefore convey limited information, and the lack of selective, sensitive, and standardized tools together with the inherent complexity of biological samples makes it difficult to quantify PK activities in physio-pathological tissues. To address this challenge, we have developed a toolbox of fluorescent biosensors that report on CDK activities in a sensitive, selective, dose-dependent, and quantitative fashion, which we have implemented to profile CDK activity signatures in cancer cell lines and biopsies from human tumors. In this study, we report on a standardized and calibrated biosensing approach to quantify CDK1,2,4, and 6 activities simultaneously through a combination of four different biosensors in a panel of 40 lung adenocarcinoma and 40 follicular lymphoma samples. CDK activity profiling highlighted two major patterns which were further correlated with age, sex of patients, tumor size, grade, and genetic and immunohistochemical features of the biopsies. Multiplex CDKACT biosensing technology provides new and complementary information relative to current genetic and immunohistochemical characterization of tumor biopsies, which will be useful for diagnostic purposes, potentially guiding therapeutic decision. These fluorescent peptide biosensors offer promise for personalized diagnostics based on kinase activity profiling.

Can diffusion-weighted imaging-fluid-attenuated inversion recovery mismatch (positive diffusion-weighted imaging/negative fluid-attenuated inversion recovery) at 3 Tesla identify patients with stroke at <4.5 hours?

BACKGROUND AND PURPOSE: At 1.5 T, diffusion-weighted imaging-fluid-attenuated inversion recovery (DWI-FLAIR) mismatch helps identify strokes within 4.5 hours of onset. However, at 3T, studies have found divergent results. The goal of this study was to determine whether DWI-FLAIR mismatch at 3T would also be helpful for identifying patients within 4.5 hours of symptom onset. METHODS: All patients presenting with an ischemic stroke in the middle cerebral artery territory and explored with 3T MRI within 12 hours between November 2007 and April 2012 were included in this retrospective study. Two readers analyzed the DWI and FLAIR images. Logistic regression was performed to determine independent predictors of FLAIR visibility. Also, the predictive values of a mismatch for identifying patients with stroke onset ≤4.5 hours were estimated. RESULTS: The study included 194 patients. The only predictive factor of FLAIR visibility was delayed MRI acquisition. The DWI-FLAIR mismatch was able to identify patients within 4.5 hours of stroke onset with relatively low sensitivity (0.55; 95% confidence interval, 0.48-0.63), low specificity (0.60; 95% confidence interval, 0.42-0.77), high positive predictive value (0.88; 95% confidence interval, 0.82-0.94), and very low negative predictive value (0.19; 95% confidence interval, 0.11-0.28). In addition, 44.5% of patients had a positive FLAIR sequence within 4.5 hours. CONCLUSIONS: This study improves our understanding of DWI-FLAIR mismatch as an imaging biomarker for wake-up management of patients with stroke. At 3T, the presence of a DWI-FLAIR mismatch was able to identify stroke onset of <4.5 hours. However, 44.5% of such stroke cases demonstrated FLAIR signal changes.

Predictive factors of outcome and hemorrhage after acute ischemic stroke treated by mechanical thrombectomy with a stent-retriever.

INTRODUCTION: The study attempts to identify notable factors predicting poor outcome, death, and intracranial hemorrhage in patients with acute ischemic stroke undergoing mechanical thrombectomy with stent retriever. These data could be useful to improve the selection of patients for thrombectomy. METHODS: Patients with acute ischemic stroke treated with the Solitaire FR device were retrospectively analyzed from a prospectively collected database. We assessed the effect of selected demographic characteristics, clinical and imaging factors on poor outcome at 3 months (modified Rankin score 3-6), mortality at 3 months, and hemorrhage at day 1 (symptomatic and asymptomatic). RESULTS: From May 2010 to April 2012, 59 consecutive patients with an acute ischemic stroke underwent mechanical thrombectomy. At 3 months, 57.6% of the patients were functionally independent (modified Rankin Scale 0-2) and mortality was 20.4%. Multivariate analyses revealed that a thrombus length > 14 mm (p = 0.02; OR 7.55; 95% CI 1.35-42.31) and longer endovascular procedure duration (p = 0.01; OR 1.04; 95% CI 1.01-1.07) were independently associated with poor outcome. A higher baseline Alberta Stroke Program Early CT (ASPECT) score (p = 0.04; OR 0.79 per point; 95% CI 0.63-0.99) and successful recanalization (p = 0.02; OR 0.07; 95% CI 0.01-0.72) were independent predictors of good functional outcome. Baseline ASPECT score (p < 0.01; OR 0.65; 95% CI 0.54-0.78) independently predicted symptomatic intracranial hemorrhage at day 1. CONCLUSION: Absolute baseline ASPECT score reflects early symptomatic hemorrhage risk and functional outcome at 3 months. Thrombus length measured on MRI play an important role on functional outcome at 3 months after thrombectomy. Further analyses are needed to determine its importance in the selection of patients for mechanical thrombectomy.

Delayed pulmonary arterial hypertension in relation to pulmonary damage score after pneumonectomy under protective ventilation: experimental study.

OBJECTIVE: To characterize pulmonary hemodynamic changes in relation to lung injury at 2 time points [48 h (H48) and 168 h (H168)] after pneumonectomy under intraoperative protective ventilation in order to improve postpneumonectomy pulmonary edema (PPE) prevention. METHOD: Fifteen pigs (25 ± 1.9 kg) were randomly allocated to nonsurgical (control, n = 5) and surgical (H48 and H168) groups. A left pneumonectomy under volume-controlled one-lung ventilation (OLV) (low tidal volume, positive end-expiratory pressure = 4 cm H2O, inspired oxygen fraction = 50%) was performed in surgical animals. Mean pulmonary artery pressure (MPAP) and pulmonary artery occlusion pressure were recorded. Pulmonary vascular resistance (PVR) was calculated. Pulmonary damage score (PDS) and bronchoalveolar albumin level were evaluated. Data were collected after induction (T0), after OLV (T1), after left pneumonectomy (T2), and at H48 or H168 (T3). RESULTS: Pneumonectomy caused precapillary pulmonary arterial hypertension (PAH) measured at T3 H48 (36.2 ± 3.67 mm Hg). PAH was delayed temporarily (both after OLV and after pneumonectomy) (p < 0.001), and linked with PVR (r = 0.93; p < 0.05). PDS and bronchoalveolar albumin level varied with MPAP (r = 0.76; p < 0.001 and r = 0.55; p < 0.05). CONCLUSION: Given that PAH is delayed and related to PVR increase, indicating secondary pulmonary vascular bed adaptation limits, pharmacological treatment should focus on a delayed failure in pulmonary capacitance in patients at risk of PPE.

Brief Report: A Multidisciplinary Initial Workup for Suspected Lung Cancer as Fast-Track Intervention to Histopathologic Diagnosis.

Guidelines for optimal timing of lung cancer diagnosis and treatment have been implemented in many countries, but the effect of fast-track interventions on the shortening of time interval is still debatable. In this study, the delay from the first specialist visit to the histopathologic diagnosis was compared between two patient cohorts: before (n = 280) and after (n = 247) implementation of a fast-track multidisciplinary diagnosis program. The cumulative incidence function curves were compared, and hazard ratio was adjusted in the Cox model. The implementation allowed a statistically significant increase in the cumulative incidence of the lung cancer histopathologic diagnosis over time. Adjusted hazard ratio for patients accrued in the post-implementation cohort was 1.22 (1.03-1.45) (p = 0.023), corresponding to a reduction of this waiting period by 18%. In conclusion, a multidisciplinary approach of the diagnostic process implemented at the initial visit allows a significant reduction of the timeline until the histopathologic diagnosis of lung cancer.

Prognosis of immune checkpoint inhibitors-induced myocarditis: a case series.

BACKGROUND: Immune checkpoint inhibitors (ICI) have transformed cancer treatment over the last decade. Alongside this therapeutic improvement, a new variety of side effects has emerged, called immune-related adverse events (irAEs), potentially affecting any organ. Among these irAEs, myocarditis is rare but life-threatening. METHODS: We conducted a multicenter cross-sectional retrospective study with the aim of better characterizing ICI-related myocarditis. Myocarditis diagnosis was based on the recent consensus statement of the International Cardio-Oncology Society. RESULTS: Twenty-nine patients were identified, from six different referral centers. Most patients (55%) were treated using anti-programmed-death 1, rather than ICI combination (35%) or anti-programmed-death-ligand 1 (10%). Transthoracic echocardiography was abnormal in 52% of them, and cardiac magnetic resonance showed abnormal features in 14/24 patients (58%). Eleven patients (38%) were classified as severe. Compared with other patients, they had more frequently pre-existing systemic autoimmune disease (45% vs 6%, p=0.018), higher troponin level on admission (42-fold the upper limit vs 3.55-fold, p=0.001), and exhibited anti-acetylcholine receptor autoantibodies (p=0.001). Seven patients (24%) had myocarditis-related death, and eight more patients died from cancer progression during follow-up. Twenty-eight patients received glucocorticoids, 10 underwent plasma exchanges, 8 received intravenous immunoglobulins, and 5 other immunosuppressants. ICI rechallenge was performed in six patients, with only one myocarditis relapse. DISCUSSION: The management of ICI-related myocarditis may be challenging and requires a multidisciplinary approach. Prognostic features are herein described and may help to allow ICI rechallenge for some patients with smoldering presentation, after an accurate evaluation of benefit-risk balance.

Can renal biopsy accurately predict histological subtype and Fuhrman grade of renal cell carcinoma?

PURPOSE: We determined the accuracy of renal biopsy in predicting histological subtype and final Fuhrman nuclear grade in small (4 cm or smaller) renal cancers, and evaluated the concordance between renal biopsy and surgery for these 2 criteria. MATERIALS AND METHODS: A total of 187 percutaneous needle biopsies of small renal tumors, guided by computerized tomography with gauge needles and a coaxial technique, were consecutively performed between 2006 and 2011. Renal cell carcinoma was diagnosed in 132 tumors. Partial or radical nephrectomy was performed for 61 of these carcinomas. Preoperative biopsy results for the operative specimens were compared with respect to histological subtype and Fuhrman nuclear grade. In addition, Kappa values were calculated as a measure of agreement between biopsy and surgical specimens, with correction for chance agreement to evaluate the concordance between biopsy and surgical classification for these criteria. RESULTS: Biopsy accuracy and the concordance between biopsy and surgery were excellent for determining histological subtype. The biopsy correctly identified the grade in 75% of cases, and in 93% when pooling renal cell carcinoma in low (1 or 2) and high (3 or 4) grade cases. The agreement between biopsy and surgery for Fuhrman nuclear grade was moderate (Kappa = 0.52) and substantial (Kappa = 0.71) when pooling low and high grade carcinoma, respectively. CONCLUSIONS: Although the concordance between grading on biopsy and with surgical specimens was moderate, likely because of the reproducibility of the grading system, the accuracy of biopsy for differentiating high and low grade small renal tumors was high, which may greatly impact decision making in cases of small renal cancer.

Characterization of small solid renal lesions: can benign and malignant tumors be differentiated with CT?

OBJECTIVE: The purpose of this study was to evaluate the diagnostic performance of CT in determining whether a small solid renal enhancing mass is benign or malignant. MATERIALS AND METHODS: Ninety-nine biopsies of enhancing solid renal masses 4 cm or smaller without fat on CT scans were performed under CT fluoroscopic guidance. The growth pattern, interface with parenchyma, presence of a scar and segmental inversion enhancement, unenhanced CT histogram, and pattern and degree of enhancement on triphasic MDCT images were independently evaluated by two radiologists. Biopsy and pathology reports were used as the reference standard, and imaging follow-up of benign lesions was performed for at least 1 year. Statistical analysis was performed to determine the significance of CT criteria in differentiating malignant from benign lesions. RESULTS: Of the 99 lesions, 74 (75%) were malignant at biopsy, and 25 (25%) were benign. Lesions with gradual enhancement were more likely to be benign. No significant correlation was found between other CT features and a malignant or benign diagnosis. The sensitivity, specificity, and positive and negative predictive values of progressive enhancement for a diagnosis of benignity were 60%, 73%, 43%, and 84%. CONCLUSION: In the evaluation of enhancing small solid renal lesions without fat, no CT criteria were of substantial help in differentiating malignant from benign lesions.

EGFR-dependent mechanisms of resistance to osimertinib determined by ctDNA NGS analysis identify patients with better outcome.

BACKGROUND: Osimertinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that is highly selective for EGFR T790M subclones in patients with EGFR sensitizing non-small cell lung cancer (NSCLC). Unfortunately, all patients develop resistance through EGFR-dependent or EGFR-independent pathways. Recently, circulating tumoral DNA (ctDNA) analysis has highlighted the usefulness of plasma genotyping for exploring patient survival outcomes after disease progression under osimertinib. METHODS: Plasma samples from patients treated with osimertinib as a second-line therapy were collected and the presence of molecular alterations of acquired resistance was evaluated after relapse under osimertinib using ctDNA molecular profiling by next-generation sequencing (NGS) assays. The clinical implications of these genomic alterations for the efficiency of the third-generation TKI were further assessed. RESULTS: Our ctDNA molecular profiling of plasma samples highlighted large number of actionable genomic alterations. According to ctDNA NGS results, patients were classified as having developed an EGFR-dependent or EGFR-independent mechanism of resistance. Thus, patients who developed an EGFR-dependent mechanism of resistance responded longer to osimertinib (13.8 vs. 4.6 months; P<10-4) and have a better post-osimertinib clinical outcome than EGFR-independent resistant patients. Moreover, the development of an EGFR-dependent mechanism of osimertinib resistance was identified as the best fit to determine patients' clinical outcome compared with EGFR T790M status alone (P=0.003). CONCLUSIONS: Our study highlights the potential of ctDNA NGS to rapidly select the appropriate drug after osimertinib failure and to determine clinical outcomes of patients. We suggest that ctDNA NGS should be more intensively used in clinical practice to follow patients under third-generation TKIs.

Complication and lung function impairment prediction using perfusion and computed tomography air trapping (CLIPPCAIR): protocol for the development and validation of a novel multivariable model for the prediction of post-resection lung function.

BACKGROUND: Recent advancements in computed tomography (CT) scanning and post processing have provided new means of assessing factors affecting respiratory function. For lung cancer patients requiring resection, and especially those with respiratory comorbidities such as chronic obstructive pulmonary disease (COPD), the ability to predict post-operative lung function is a crucial step in the lung cancer operability assessment. The primary objective of the CLIPPCAIR study is to use novel CT data to develop and validate an algorithm for the prediction of lung function remaining after pneumectomy/lobectomy. METHODS: Two sequential cohorts of non-small cell lung cancer patients requiring a pre-resection CT scan will be recruited at the Montpellier University Hospital, France: a test population (N=60) on which predictive models will be developed, and a further model validation population (N=100). Enrolment will occur during routine pre-surgical consults and follow-up visits will occur 1 and 6 months after pneumectomy/lobectomy. The primary outcome to be predicted is forced expiratory volume in 1 second (FEV1) six months after lung resection. The baseline CT variables that will be used to develop the primary multivariable regression model are: expiratory to inspiratory ratios of mean lung density (MLDe/i for the total lung and resected volume), the percentage of voxels attenuating at less than ‒950 HU (PVOX‒950 for the total lung and resected volume) and the ratio of iodine concentrations for the resected volume over that of the total lung. The correlation between predicted and real values will be compared to (and is expected to improve upon) that of previously published methods. Secondary analyses will include the prediction of transfer factor for carbon monoxide (TLCO) and complications in a similar fashion. The option to explore further variables as predictors of post-resection lung function or complications is kept open. DISCUSSION: Current methods for estimating post-resection lung function are imperfect and can add assessments (such as scintigraphy) to the pre-surgical workup. By using CT imaging data in a novel fashion, the results of the CLIPPCAIR study may not only improve such estimates, it may also simplify patient pathways. TRIAL REGISTRATION: Clinicaltrials.gov (NCT03885765).

Club Cell Loss as a Feature of Bronchiolization in ILD.

Background: Distal airway metaplasia may precede honeycombing in progressive fibrosing interstitial lung disease (ILD). The SCGB1A1+ bronchiolar-specific club cell may play a role in this aberrant regenerative process. Objective: To assess the presence of club cells in the small airways of patients suffering from ILD. Methods: Small airways (internal diameter <2 mm) in lung samples [surgical lung biopsy (SLB) and/or transbronchial lung cryobiopsy (TBLC)] from 14 patients suffering from ILD and 10 controls were morphologically assessed and stained for SCGB1A1. SCGB1A1 was weighted by epithelial height as a marker of airway generation (SCGB1A1/EH). Correlations between clinical, functional, and high-resolution CT (HRCT) prognostic factors and histomorphometry were assessed. Results: Small airways from samples with ILD patterns were significantly less dense in terms of SCGB1A1+ cells [0.064 (0.020-0.172)] as compared to controls' sample's small airways [0.393 (0.082-0.698), p < 0.0001]. Usual interstitial pneumonia (UIP) patterns most frequently contained small airways with limited or absent SCGB1A1 expression (SCGB1A1/EH <0.025): UIP (18/33; 55%) as compared with non-UIP patterns (4/31; 13%) or controls (0/29; 0%): p < 0.0001. In addition, correlations with HRCT indicated a significant negative relationship between SCGB1A1 and bronchiectasis as a feature of bronchiolization (Rho -0.63, p < 0.001) and a positive relationship with both forced vital capacity (FVC) and Hounsfield unit (HU)-distribution pattern in kurtosis (Rho 0.38 and 0.50, respectively, both p < 0.001) as markers of fibrotic changes. Conclusion: Compared with controls, the small airways of patients with ILD more often lack SCGB1A1, especially so in UIP. Low densities of SCGB1A1-marked cells correlate with bronchiectasis and fibrotic changes. Further research investigating SCGB1A1 staining as a pathological feature of the bronchiolization process is merited.

Combination of tissue and liquid biopsy molecular profiling to detect transformation to small cell lung carcinoma during osimertinib treatment.

BACKGROUND: Histological transformation of advanced non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) is one of the mechanisms of resistance to third-generation tyrosine kinase inhibitors (TKIs), such as osimertinib. This acquired TKI resistance is linked to the high degree of tumor heterogeneity and adaptive cellular signaling pathways, including epidermal growth factor receptor (EGFR)-dependent pathways, observed in NSCLC. METHODS: Here, we investigated a series of paired pre- and post-histological transformation biopsies obtained from three patients initially having a NSCLC with an EGFR activating mutation treated with first-generation TKI, who then received osimertinib as second-line after EGFR T790M resistance and, lastly, developed a histological transformation to SCLC. Both tissue and liquid biopsies were analyzed using large panel sequencing approaches at various time points to reconstruct the clonal evolutionary history of the tumor. RESULTS: Our complementary analysis of tumor tissue and circulating tumor DNA samples allowed us to better characterize the histological and molecular alterations associated with resistance to osimertinib. SCLC transformation was linked to the presence of several concomitant gene alterations, including EGFR, TP53 and RB1, but also to specific signal bypass, such as EGFR and MET amplifications and activation of the PI3K/AKT/mTOR pathway. CONCLUSION: Our report emphasizes the mutational landscape of SCLC histological transformation and highlights the importance of combining tissue and liquid biopsy profiling before and during osimertinib treatment to predict such histological transformation.

Homoplasmic deleterious MT-ATP6/8 mutations in adult patients.

To address the frequency of complex V defects, we systematically sequenced MT-ATP6/8 genes in 512 consecutive patients. We performed functional analysis in muscle or fibroblasts for 12 out of 27 putative homoplasmic mutations and in cybrids for four. Fibroblasts, muscle and cybrids with known deleterious mutations underwent parallel analysis. It included oxidative phosphorylation spectrophotometric assays, western blots, structural analysis, ATP production, glycolysis and cell proliferation evaluation. We demonstrated the deleterious nature of three original mutations. Striking gradation in severity of the mutations consequences and differences between muscle, fibroblasts and cybrids implied a likely under-diagnosis of human complex V defects.

Can early neurological improvement after mechanical thrombectomy be used as a surrogate for final stroke outcome?

BACKGROUND AND PURPOSE: We aimed to identify the best definition of early neurological improvement (ENI) at 2 and 24 hours after mechanical thrombectomy (MT) and determine its ability to predict a good functional outcome at 3 months. METHODS: This retrospective analysis was based on a prospectively collected registry of patients treated by MT for ischemic stroke from May 2010 to March 2017. We included patients treated with stent-retrievers with National Institute of Health Stroke Scale (NIHSS) score before treatment and at 2 and/or 24 hours after treatment and modified Rankin Score (mRS) at 3 months. Receiver operating characteristic curve analysis was performed to estimate optimal thresholds for ENI at 2 and 24 hours. The relationship between optimal ENI definitions and good outcome at 3 months (mRS 0-2) was assessed by logistic regression. RESULTS: The analysis included 246 patients. At 2 hours, the optimal threshold to predict a good outcome at 3 months was improvementin the NIHSS score of >1 point (AUC 0.83,95% CI 0.77 to 0.87), with sensitivity and specificity 78.3% (62.2-85.7%) and 84.6% (77.2-90.3%), respectively, and OR 12.67 (95% CI 4.69 to 31.10, p<0.0001). At 24 hours, the optimal threshold was an improvementin the NIHSS score of >4 points (AUC 0.93, 95% CI 0.89 to 0.96), with sensitivity and specificity 93.8% (87.7-97.5%) and 83.2% (75.7-89.2%), respectively, and OR 391.32 (95% CI 44.43 to 3448.35, p<0.0001). CONCLUSIONS: ENI 24 hours after thrombectomy appears to be a straightforward surrogate of long-term endpoints and may have value in future research.

SMARCA4-deficient Thoracic Sarcomas: Clinicopathologic Study of 30 Cases With an Emphasis on Their Nosology and Differential Diagnoses.

SMARCA4-deficient thoracic sarcoma (SMARCA4-DTS) is a recently described entity with an aggressive clinical course and specific genetic alterations of the BAF chromatin remodeling complex. In the present study, we reviewed the clinical and pathologic features of 30 cases of SMARCA4-DTS, discussed its main differential diagnoses and the challenging diagnostic scenarios that the average pathologist may face. In addition, we tested the specificity of the "SMARCA4-DTS immunohistochemical signature" (co-loss of SMARCA4 and SMARCA2 with overexpression of SOX2) in a large cohort of intrathoracic malignancies. Patients ranged from 28 to 90 years of age (median: 48 y), with a marked male predominance (male:female=9:1) and they were usually smokers. Tumors were generally large compressive masses located in the mediastinum (n=13), pleura (n=5), lung (n=2) or in 2 or more of these topographies (n=10). Treatment strategies were varied, including 1 case treated with EZH2 inhibitors. Median overall survival was 6 months. Histologically, tumors were poorly differentiated frequently showing rhabdoid features. A subset of cases showed a focal myxoid stroma (7%, n=2/30) and rare cases displayed a previously unreported pattern simulating desmoplastic small round cell tumors (7%, n=2/30). Making a diagnosis was challenging when dealing with biopsy material from massively necrotic tumors and in this setting the expression of SOX2, CD34, and SALL4 proved useful. All tested cases displayed concomitant loss of SMARCA4 and SMARCA2 and most tumors expressed epithelial markers (Pan-keratin or EMA) (n=29/30), SOX2 (n=26/27), and CD34 (n=17/27). SMARCB1 expression was retained in all cases (23/23). SALL4 and Claudin-4 were expressed in a subset of cases (n=7/21 and 2/19, respectively). TTF-1 and P63 were focally expressed in 1 case each. P40 and NUT were not expressed (0/23 and 0/20, respectively) The SMARCA4-DTS immunohistochemical signature was both sensitive and specific, with only a subset of small cell carcinoma of the ovary hypercalcemic type showing overlapping phenotypes. Our study confirms and expands the specific features of SMARCA4-DTS, emphasizing the fact that they can be straightforwardly identified by pathologists.

Childhood pulmonary Langerhans cell histiocytosis: a comprehensive clinical-histopathological and BRAFV600E mutation study from the French national cohort.

Childhood pulmonary Langerhans cell histiocytosis (PLCH) is a rare disease. Its pulmonary histopathology, according to comprehensive clinical-radiological findings and BRAFV600E mutation status, has not yet been thoroughly documented. From the 167 childhood PLCH cases entered in the French National Histiocytosis Registry (1983-2016), we retrieved lung biopsies from a consecutive retrospective series of 17 patients, diagnosed when they were 2 weeks to 16 years old (median, 9.4 years), and report the clinical and histopathological findings herein. Histological analyses of biopsies (16 surgical and 1 postmortem) found the following features, alone or associated: Langerhans cell (LC) nodules with cavitation (9/17), cysts (14/17), fibrotic scars (2/17), peribronchiolar topographic distribution of the lesions (10/17), and accessory changes, like stretch emphysema (7/17). Those characteristics closely resemble those describing adult PLCH. However, unusual findings observed were 2 large nodules and a diffuse interstitial LC infiltrate. BRAFV600E mutation was detected in 4 of 12 samples tested, notably in the 3 with unusual features. In conclusion, childhood PLCH mostly shares the common histology features already described in adult PLCH, regardless of age. Because smoking is considered the major trigger in PLCH pathogenesis, the findings based on this series suggest other inducers of bronchiolar LC recruitment, especially in very young patients.

Myocardial expression of a dominant-negative form of Daxx decreases infarct size and attenuates apoptosis in an in vivo mouse model of ischemia/reperfusion injury.

BACKGROUND: Apoptosis has been described extensively in acute myocardial infarction and chronic heart failure. Because Daxx (death-associated protein) appears to be essential for stress-induced cell death and acts as an antisurvival molecule, we tested the hypothesis that Daxx is involved in myocardial ischemia/reperfusion-induced cell death in vivo. METHODS AND RESULTS: Transgenic mice overexpressing a dominant-negative form of Daxx (Daxx-DN) under the control of the beta-actin promoter and control wild-type mice underwent an ischemia/reperfusion protocol: 40 minutes of left coronary artery occlusion and 60 minutes of reperfusion. Area at risk and infarct size were measured after dual staining by triphenyltetrazolium chloride and phthalocyanine blue dye. Apoptosis was measured in the ischemic versus the nonischemic part of the left ventricle by terminal deoxynucleotidyl transferase-mediated dUTP biotin nick end labeling staining, enzyme-linked immunosorbent assay, and Western blotting of caspase-3, caspase-8, and poly(ADP-ribose) polymerase. The mitogen-activated protein kinase status was investigated by Western blot analysis. Comparison between groups was assessed by ANOVA or Student t test (statistical significance: P<0.05). Left ventricle tissues from transgenic mice expressed Daxx-DN at the protein level. Area at risk/left ventricle values were comparable among groups. Infarct size/area at risk was 45% reduced in Daxx-DN versus wild-type mice (P<0.001). This cardioprotection was maintained for a 4-hour reperfusion. Ischemia/reperfusion-induced apoptosis was significantly decreased and ERK1/2 prosurvival pathway was activated in ischemic Daxx-DN hearts. CONCLUSIONS: Our study clearly indicates that Daxx participates in myocardial ischemia/reperfusion proapoptotic signaling in vivo.