Comparison and Validation of Rapid Molecular Testing Methods for Theranostic Epidermal Growth Factor Receptor Alterations in Lung Cancer: Idylla versus Digital Droplet PCR.

Targeting EGFR alterations, particularly the L858R (Exon 21) mutation and Exon 19 deletion (del19), has significantly improved the survival of lung cancer patients. From now on, the issue is to shorten the time to treatment. Here, we challenge two well-known rapid strategies for EGFR testing: the cartridge-based platform Idylla™ (Biocartis) and a digital droplet PCR (ddPCR) approach (ID_Solution). To thoroughly investigate each testing performance, we selected a highly comprehensive cohort of 39 unique del19 (in comparison, the cbioportal contains 40 unique del19), and 9 samples bearing unique polymorphisms in exon 19. Additional L858R (N = 24), L861Q (N = 1), del19 (N = 63), and WT samples (N = 34) were used to determine clear technical and biological cutoffs. A total of 122 DNA samples extracted from formaldehyde-fixed samples was used as input. No false positive results were reported for either of the technologies, as long as careful droplet selection (ddPCR) was ensured for two polymorphisms. ddPCR demonstrated higher sensitivity in detecting unique del19 (92.3%, 36/39) compared to Idylla (67.7%, 21/31). However, considering the prevalence of del19 and L858R in the lung cancer population, the adjusted theranostic values were similar (96.51% and 95.26%, respectively). ddPCR performs better for small specimens and low tumoral content, but in other situations, Idylla is an alternative (especially if a molecular platform is absent).

Complex Compound Inheritance of Lethal Lung Developmental Disorders Due to Disruption of the TBX-FGF Pathway.

Primary defects in lung branching morphogenesis, resulting in neonatal lethal pulmonary hypoplasias, are incompletely understood. To elucidate the pathogenetics of human lung development, we studied a unique collection of samples obtained from deceased individuals with clinically and histopathologically diagnosed interstitial neonatal lung disorders: acinar dysplasia (n = 14), congenital alveolar dysplasia (n = 2), and other lethal lung hypoplasias (n = 10). We identified rare heterozygous copy-number variant deletions or single-nucleotide variants (SNVs) involving TBX4 (n = 8 and n = 2, respectively) or FGF10 (n = 2 and n = 2, respectively) in 16/26 (61%) individuals. In addition to TBX4, the overlapping ∼2 Mb recurrent and nonrecurrent deletions at 17q23.1q23.2 identified in seven individuals with lung hypoplasia also remove a lung-specific enhancer region. Individuals with coding variants involving either TBX4 or FGF10 also harbored at least one non-coding SNV in the predicted lung-specific enhancer region, which was absent in 13 control individuals with the overlapping deletions but without any structural lung anomalies. The occurrence of rare coding variants involving TBX4 or FGF10 with the putative hypomorphic non-coding SNVs implies a complex compound inheritance of these pulmonary hypoplasias. Moreover, they support the importance of TBX4-FGF10-FGFR2 epithelial-mesenchymal signaling in human lung organogenesis and help to explain the histopathological continuum observed in these rare lethal developmental disorders of the lung.

Role of the occupational disease consultant in the multidisciplinary discussion of interstitial lung diseases.

BACKGROUND: Diffuse interstitial lung diseases (ILD) constitute a heterogeneous group of conditions with complex etiological diagnoses requiring a multidisciplinary approach. Much is still unknown about them, particularly their relationship with occupational exposures. The primary objective of this study was to investigate the distribution of occupational exposures according to type of ILD. The secondary objectives were to estimate the proportion of ILDs possibly related to occupational exposure and to evaluate the added value of the participation of an occupational disease consultant in ILD multidisciplinary discussions (MDD). METHODS: From May to December 2020, all consecutive patients with ILD whose cases were reviewed during a MDD in a referral centre for ILD were prospectively offered a consultation with an occupational disease consultant. RESULTS: Of the 156 patients with ILD whose cases were reviewed in MDD during the study period, 141 patients attended an occupational exposure consultation. Occupational exposure was identified in 97 patients. Occupational exposure to asbestos was found in 12/31 (38.7%) patients with idiopathic pulmonary fibrosis (IPF) and in 9/18 (50.0%) patients with unclassifiable fibrosis. Occupational exposure to metal dust was found in 13/31 (41.9%) patients with IPFs and 10/18 (55.6%) patients with unclassifiable fibrosis. Silica exposure was found in 12/50 (24.0%) patients with autoimmune ILD. The link between occupational exposure and ILD was confirmed for 41 patients after the specialist occupational consultation. The occupational origin had not been considered (n = 9) or had been excluded or neglected (n = 4) by the MDD before the specialised consultation. A total of 24 (17%) patients were advised to apply for occupational disease compensation, including 22 (15.6%) following the consultation. In addition, a diagnosis different from the one proposed by the MDD was proposed for 18/141 (12.8%) patients. CONCLUSIONS: In our study, we found a high prevalence of occupational respiratory exposure with a potential causal link in patients with ILD. We suggest that a systematic specialised consultation in occupational medicine could be beneficial in the ILD diagnostic approach.

In Vivo Molecular K-Edge Imaging of Atherosclerotic Plaque Using Photon-counting CT.

Background Macrophage burden is a major factor in the risk of atherosclerotic plaque rupture, and its evaluation remains challenging with molecular noninvasive imaging approaches. Photon-counting CT (PCCT) with k-edge imaging aims to allow for the specific detection of macrophages using gold nanoparticles. Purpose To perform k-edge imaging in combination with gold nanoparticles to detect and quantify the macrophage burden within the atherosclerotic aortas of rabbits. Materials and Methods Atherosclerotic and control New Zealand white rabbits were imaged before and at several time points up to 2 days after intravenous injection of gold nanoparticles (3.5 mL/kg, 65 mg gold per milliliter). Aortic CT angiography was performed at the end of the follow-up using an intravenous injection of an iodinated contrast material. Gold k-edge and conventional CT images were reconstructed for qualitative and quantitative assessment of the macrophage burden. PCCT imaging results were compared with findings at histologic examination, quantitative histomorphometry, transmission electron microscopy, and quantitative inductively coupled plasma optical emission spectrometry. Pearson correlations between the macrophage area measured in immunostained sections and the concentration of gold and attenuation measured in the corresponding PCCT sections were calculated. Results Seven rabbits with atherosclerosis and four control rabbits without atherosclerosis were analyzed. In atherosclerotic rabbits, calcifications were observed along the aortic wall before injection. At 2 days after injection of gold nanoparticles, only gold k-edge images allowed for the distinction of plaque enhancement within calcifications and for lumen enhancement during angiography. A good correlation was observed between the gold concentration measured within the wall and the macrophage area in 35 plaques (five per rabbit) (r = 0.82; 95% CI: 0.67, 0.91; P < .001), which was higher than that observed on conventional CT images (r = 0.41; 95% CI: 0.09, 0.65; P = .01). Transmission electron microscopy and inductively coupled plasma optical emission spectrometry analyses confirmed the gold k-edge imaging findings. Conclusion Photon-counting CT with gold nanoparticles allowed for the noninvasive evaluation of both molecular and anatomic information in vivo in rabbits with atherosclerotic plaques. Published under a CC BY 4.0 license. Online supplemental material is available for this article. See also the editorial by Leiner in this issue.

Progressive fibrosing interstitial lung disease: a clinical cohort (the PROGRESS study).

In patients with chronic fibrosing interstitial lung disease (ILD), a progressive fibrosing phenotype (PF-ILD) may develop, but information on the frequency and characteristics of this population outside clinical trials is lacking.We assessed the characteristics and outcomes of patients with PF-ILD other than idiopathic pulmonary fibrosis (IPF) in a real-world, single-centre clinical cohort. The files of all consecutive adult patients with fibrosing ILD (2010-2017) were examined retrospectively for pre-defined criteria of ≥10% fibrosis on high-resolution computed tomography and progressive disease during overlapping windows of 2 years. Baseline was defined as the date disease progression was identified. Patients receiving nintedanib or pirfenidone were censored from survival and progression analyses.In total, 1395 patients were screened; 617 had ILD other than IPF or combined pulmonary fibrosis and emphysema, and 168 had progressive fibrosing phenotypes. In 165 evaluable patients, median age was 61 years; 57% were female. Baseline mean forced vital capacity (FVC) was 74±22% predicted. Median duration of follow-up was 46.2 months. Annualised FVC decline during the first year was estimated at 136±328 mL using a linear mixed model. Overall survival was 83% at 3 years and 72% at 5 years. Using multivariate Cox regression analysis, mortality was significantly associated with relative FVC decline ≥10% in the previous 24 months (p<0.05), age ≥50 years (p<0.01) and diagnosis subgroup (p<0.01).In this cohort of patients with PF-ILD not receiving antifibrotic therapy, the disease followed a course characterised by continued decline in lung function, which predicted mortality.

Estimates of epidemiology, mortality and disease burden associated with progressive fibrosing interstitial lung disease in France (the PROGRESS study).

BACKGROUND: There is a paucity of data on the epidemiology, survival estimates and healthcare resource utilisation and associated costs of patients with progressive fibrosing interstitial lung disease (PF-ILD) in France. An algorithm for extracting claims data was developed to indirectly identify and describe patients with PF-ILD in the French national administrative healthcare database. METHODS: The French healthcare database, the Système National des Données de Santé (SNDS), includes data related to ambulatory care, hospitalisations and death for 98.8% of the population. In this study, algorithms based on age, diagnosis and healthcare consumption were created to identify adult patients with PF-ILD other than idiopathic pulmonary fibrosis between 2010 and 2017. Incidence, prevalence, survival estimates, clinical features and healthcare resource usage and costs were described among patients with PF-ILD. RESULTS: We identified a total of 14,413 patients with PF-ILD. Almost half of them (48.1%) were female and the mean (± standard deviation) age was 68.4 (± 15.0) years. Between 2010 and 2017, the estimated incidence of PF-ILD ranged from 4.0 to 4.7/100,000 person-years and the estimated prevalence from 6.6 to 19.4/100,000 persons. The main diagnostic categories represented were exposure-related ILD other than hypersensitivity pneumonitis (n = 3486; 24.2%), idiopathic interstitial pneumonia (n = 3113; 21.6%) and rheumatoid arthritis-associated ILD (n = 2521; 17.5%). Median overall survival using Kaplan-Meier estimation was 3.7 years from the start of progression. During the study, 95.2% of patients had ≥ 1 hospitalisation for respiratory care and 34.3% were hospitalised in an intensive care unit. The median (interquartile range) total specific cost per patient during the follow-up period was €25,613 (10,622-54,287) and the median annual cost per patient was €18,362 (6856-52,026), of which €11,784 (3003-42,097) was related to hospitalisations. Limitations included the retrospective design and identification of cases through an algorithm in the absence of chest high-resolution computed tomography scans and pulmonary function tests. CONCLUSIONS: This large, real-world, longitudinal study provides important insights into the characteristics, epidemiology and healthcare resource utilisation and costs associated with PF-ILD in France using a comprehensive and exhaustive database, and provides vital evidence that PF-ILD represents a high burden on both patients and healthcare services. Trial registration ClinicalTrials.gov, NCT03858842. ISRCTN, ISRCTN12345678. Registered 3 January 2019-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03858842.

[Thymoma and squamous thymic carcinoma diagnosis; experience from the RYTHMIC network]. / Diagnostic des thymomes et carcinomes thymiques malpighiens ; expérience du réseau RYTHMIC.

The RYTHMIC network, supported by the French National Cancer Institute is dedicated to the management of patients with thymic epithelial tumors through regional and national multidisciplinary tumor boards. Tumor board decisions are based on the initial pathology diagnoses. However, following clinical inclusion in the network, a central pathology review is organized, implicating a panel of pathologists, for histotype and stage classification, which is different from a classical second opinion from pathologist to pathologist for a difficult case. Thanks to the participation of all French pathologists, more than 1000 cases have been reviewed by the panel. The aim of this review is to share with the French pathology community, the experience of the group. It underlines the importance of macroscopy and surgeon-pathologist involvement to allow a good central review, the main histopathological and immunophenotypical patterns of the most frequent thymomas and thymic carcinoma types, the differential diagnoses, as well as the difficulties for the panel to reproducibly assess on slides, stage, for some cases.

Impact of Lung Biopsy on Lung Function in Idiopathic Pulmonary Fibrosis.

BACKGROUND: Video-assisted surgical lung biopsy (SLB) is performed in 10-30% of cases to establish the diagnosis of idiopathic pulmonary fibrosis (IPF). OBJECTIVES: The aim of the study was to analyze the impact of SLB on lung function in patients eventually diagnosed with IPF. METHODS: This is an observational, retrospective, monocentric study of all consecutive patients eventually diagnosed with IPF in multidisciplinary discussion who underwent SLB over 10 years in a specialized center. The primary end point was the variation in forced vital capacity (FVC) before and after the SLB. The secondary end points were the variations in forced expiratory volume in one second (FEV1), total lung capacity (TLC), carbon monoxide diffusion capacity (DLCO), and morbidity and mortality associated with the SLB. RESULTS: In 118 patients who underwent SLB and were diagnosed with IPF, a relative decrease in FVC of 4.8% (p < 0.001) was found between measurements performed before and after the procedure. The mean FVC decrease was 156 ± 386 mL in an average period of 185 days, representing an annualized decline of 363 ± 764 mL/year. A significant decrease was also observed after SLB in FEV1, TLC, and DLCO. Complications within 30 days of SLB occurred in 14.4% of patients. Two patients (1.7%) died within 30 days, where one of them had poor lung function. Survival at 1 year was significantly poorer in patients with FVC <50% at baseline. CONCLUSION: In this uncontrolled study in patients ultimately diagnosed with IPF, SLB was followed by a significant decline in FVC, which appears to be numerically greater than the average decline in the absence of treatment in the literature. Summary at a Glance: This study evaluated the change in lung function in 118 consecutive patients diagnosed with idiopathic pulmonary fibrosis by surgical lung biopsy. Forced vital capacity decreased by 156 ± 386 mL in a mean of 185 days between the last measurement before and first measurement after biopsy, representing an annualized decline of 363 ± 764 mL/year.

[Multiple lung carcinoma: Primary or intrapulmonary metastasis?] / Adénocarcinomes pulmonaires multiples : primitifs ou métastases ?

Multiple lung carcinomas are 5 to 11,5% of lung carcinomas. The distinction between primary lung carcinomas from carcinomas with intrapulmonary metastasis is essential for optimal patient management. The histopathological analysis is very useful but it has to be completed by genotypic assessment using molecular biology (NGS). Molecular biology can also identify genetic alterations with therapeutic implications. We present the case of a patient with a history of surgery for multiple lung carcinomas diagnosed from 2013 to 2017.

Primary cardiac lymphoma: diagnosis, treatment and outcome in a modern series.

Primary cardiac lymphoma (PCL) represents a rare subset of extranodal lymphomas for which the primary lesion arises from the heart and/or the pericardium. Fundamental characteristics of PCL remain uncertain, regarding optimal diagnosis strategy, pathological features, treatments, as well as prognostic factors. This is a single-institution retrospective study of patients with histologically proven lymphoma, presenting with exclusive or predominant myocardial invasion at time of diagnosis. Thirteen patients were included, all of whom had symptoms related to cardiac tumour location with chronic chest pain in six (46%), dyspnea in seven (54%) and arythmia in three (23%). Sub-acute and acute congestive heart failure were noticed in respectively nine (70%) and one (9%). PCL was identified at transthoracic echocardiography and computed tomography scan in 80 and 100% of patients, respectively. Most frequent location was the right atrium in 10 (77%) patients. Pericardial effusion was identified in 10 (77%). Pathological diagnosis-diffuse large B-cell lymphoma in 12 cases and Burkitt in 1 case-was made on cardiac surgical biopsies in 9 cases and by intravascular procedure in 2 cases. All patients received first-line chemotherapy, with a complete response rate of 62%. Recurrences occurred in 55% of patients, mostly at extracardiac extranodal sites. Our data confirm that PCL harbours specific clinical and anatomical features. The aggressiveness of PCL mainly results from the possible onset of acute cardiac events. Further molecular characterization may help to further individualize PCL among diffuse and intrathoracic lymphomas. Copyright © 2016 John Wiley & Sons, Ltd.

[About a case of a recurrent glandular cardiac myxoma in a child]. / À propos d'un cas de myxome cardiaque avec éléments glandulaires récidivant chez un enfant.

Primary cardiac tumors are extremely rare and mainly benign. The majority of these are myxomas (40%). Myxoma are generally sporadic tumors which occur most commonly in adult females between 30 and 40 years, and are seldom found in the paediatric population (5%). Seven percent are associated with igenetic diseases. We report the case of an eight-year-old boy presenting a recurrent glandular cardiac myxoma. In 2011, he presented a deterioration of the general state. An echocardiography highlighted a left atrial mass on the interatrial septum, with a pedicular insertion. On the microscope, it consisted of a proliferation of stellate cells isolated or clustered in rudimentary vessels in a myxoid stroma presenting haemorrhage changes. These cells expressed CD34 and calretinine. Glandular elements without atypia were clustered within the myxomatous proliferation. They expressed cytokeratin (CK) 7. Surgical resection was macroscopically complete. In 2014, the boy had a sudden neurological deficit during a football match. An echocardiography revealed a recurrence at the same location. The lesion was excised and addressed in several fragments. Classical myxoma was associated with glands without atypia. This last component expressed CKAE1/AE3 and CK7. Ki67 index of proliferation was low. The surgical reintervention was macroscopically complete. The final diagnosis was glandular cardiac myxoma. A genetic survey was conducted, showing the presence of Carney complex. This is the first description in the litterature of a recurrent glandular cardiac myxoma occuring in a child.

[BRCA1 associated protein 1 (BAP1) expression in pleural diffuse malignant mesothelioma: A comparative cytological and histological analyses on 50 patients]. / Apport de l'expression protéique de BRCA1 associated protein 1 (BAP1) dans le diagnostic des mésothéliomes malins diffus pleuraux : une analyse cytologique et histologique comparative sur une série de 50 patients.

INTRODUCTION: Diffuse malignant mesothelioma (MMD) is a rare disease. The diagnosis is difficult and needs an antibody panel. The tumor suppressor gene BRCA1 associated protein 1 (BAP1) is involved in several cancers, including MMD. Loss of BAP1 expression is correlated with BAP1 somatic or constitutional genetic defects. Our work assesses the value of integrating BAP1 in the panel of antibodies used for the diagnosis of MMD. MATERIALS AND METHODS: Immunohistochemical techniques were performed on cytological and histological specimens of MMD and adenocarcinoma pleural metastasis. RESULTS: Of the 26 patients with MMD and the 24 patients with adenocarcinoma pleural metastasis, loss of BAP1 expression was observed in 11 (48%) and one adenocarcinoma (6%) on cytological specimens and in 12 MMD (48%) and in one adenocarcinoma (5%) on biopsy specimens. The concordance between immunocytochemistry and immunohistochemistry was 100%. The specificity of BAP1 was 100% on cytological and biopsy specimen for the diagnosis of malignancy in case of mesothelial proliferation. DISCUSSION AND CONCLUSION: Loss of BAP1 expression is an indicator of MMD in a context of mesothelial proliferation. This immunohistochemistry could be integrated in the panel of immunostaining used for MMD diagnosis, either on histological or cytological samples. Furthermore, loss of BAP1 expression guides the patient to an oncology genetic counseling in order to eliminate a MMD developed as part of a constitutional genetic defect.

Usual interstitial pneumonia end-stage features from explants with radiologic and pathological correlations.

Idiopathic pulmonary fibrosis (IPF) is the most frequent and severe idiopathic interstitial pneumonia, with typical high-resolution computed tomography (HRCT) features and histologic pattern of usual interstitial pneumonia (UIP); its main differential diagnosis is fibrotic nonspecific interstitial pneumonia (F-NSIP). Usual interstitial pneumonia was mainly described from lung biopsies, and little is known on explants. Twenty-two UIP/IPF explants were analyzed histologically and compared with previous open lung biopsies (OLBs; n = 11) and HRCT (n = 19), when available. Temporospatial heterogeneity and subpleural and paraseptal fibrosis were similarly found in UIP/IPF explants and OLB (91%-95%). Fibroblastic foci were found in 82% of OLBs and 100% of explants, with a higher mean score in explants (P = .023). Honeycombing was present in 64% of OLBs and 95% of explants, with a higher mean score in explants (P = .005). Almost 60% of UIP/IPF explants showed NSIP areas and 41% peribronchiolar fibrosis; inflammation, bronchiolar metaplasia, and vascular changes were more frequent in UIP/IPF explants; and Desquamative Interstitial Pneumonia (DIP)-like areas were not common (18%-27%). Numerous large airspace enlargements with fibrosis were frequent in UIP/IPF explants (59%). On HRCT, honeycombing was observed in 95% of the cases and ground-glass opacities in 53%, correlating with NSIP areas or acute exacerbation at histology. Six patients had combined IPF and emphysema. Lesions were more severe in UIP/IPF explants, reflecting the worsening of the disease. Usual interstitial pneumonia/IPF explants more frequently presented with confounding lesions such as NSIP areas, peribronchiolar fibrosis, and airspace enlargements with fibrosis sometimes associated with emphysema.

[About a case of calcifying fibrous tumor of the pleura]. / À propos d'un cas de tumeur calcifiante de la plèvre.

Calcifying fibrous tumor is a rare soft tissue benign tumor (OMS 2002). Some pleural localisations are described, which affect slightly older individuals than the other soft tissue forms. The calcifying fibrous tumor is included in the 2004 World Health Organization classification of pleural tumors. A pleural tumor located in the right inferior pulmonary lobe is diagnosed in a 59-year-old man. This pleural tumor is macroscopically well-circumscribed. Histologically, the rare spindle tumoral cells are located between bundles of a collagenous tissue, sometimes hyalinized, with psammomatous or dystrophic calcifications. The tumoral cells have a fibrohistiocytic origin. They stain positively for antibodies against vimentin, factor XIIIa, CD68, CD163, CD34. Antibodies against smooth muscle actin, desmin, PS100, ALK1 and EBV are negative. Main differencial diagnoses are other benign pleural tumors (solitary fibrous tumor, inflammatory myofibroblastique tumor), some malignant tumors (desmoplastic malignant pleural mesothelioma) and pleural pseudotumors (calcified pleural plaques, chronic fibrous pleuritis, amylose, hyalinizing granuloma). Our case is the 15th pleural calcifying fibrous tumor being reported.

[Rythmic-pathology: the French national pathology network for thymic epithelial tumours]. / Rythmic-Pathologie : le groupe français de relecture des tumeurs épithéliales thymiques du réseau clinique Rythmic.

Epithelial thymic tumours are rare and sometimes difficult to classify. Since 2010, the French National Cancer Institute supports a French national network, called Rythmic, devoted to the treatment of these tumours through regional and national multidisciplinary conferences using the web. All the tumours are secondarily reviewed by a French pathology national network for classification and staging. This review focuses on the presentation of the Rythmic network, and mainly to the Pathology review process.

Micronodular thymic epithelial tumors with lymphoid hyperplasia and mimicking lesions.

Micronodular arrangement of epithelial cells and lymphoid B-cell hyperplasia with follicles are both peculiar histological features in thymic tissue. Such features may especially occur in thymic epithelial tumors. The most common form is called micronodular thymoma with lymphoid stroma. We have recently described some characteristics of thymic micronodular carcinoma with lymphoid hyperplasia, highlighting how this carcinomatous counterpart should not be misdiagnosed as a thymoma. In this review, we discuss these two entities but also other mimics, which may occur in the anterior mediastinum. These mimics include various types of cellular micronodules and lymphoid backgrounds encompassing a wide range of mediastinal lesions. Non-neoplastic lesions, such as thymic nodular epithelial hyperplasia, thymic lymphoid hyperplasia, or sarcoidosis, as well as tumors of very varying aggressiveness, such as micronodular thymic epithelial tumors, low-grade lymphoma, seminoma, or lymphoepithelial carcinoma, are discussed. We show how these lesions may be misleading and we describe how a correct diagnostic may be obtained in current practice.

International reproducibility study of thymic epithelial tumors staging: pT stage is an issue. proposals for improvement. A RYTHMIC/ITMIG study.

INTRODUCTION: Pathologists are staging thymic epithelial tumors (TET) according to the 8th UICC/AJCC TNM system. Within the French RYTHMIC network, dedicated to TET, agreement on pathologic tumor stage (pT) among the pathology panelists was difficult. The aim of our study was to determine the interobserver reproducibility of pT at an international level, to explore the source of discrepancies and potential interventions to address these. METHODS: An international panel of pathologists was recruited through the International Thymic Malignancy Interest Group (ITMIG). The study focused on invasion of mediastinal pleura, pericardium, and lung. From a cohort of cases identified as challenging within the RYTHMIC network, we chose a series of test and validation cases (n = 5 and 10, respectively). RESULTS: Reproducibility of the pT stage was also challenging at an international level as none of the 15 cases was classified as the same pT stage by all ITMIG pathologists. The agreement rose from slight (κ = 0.13) to moderate (κ = 0.48) between test and validation series. Discussion among the expert pathologists pinpointed two major reasons underlying discrepancies: 1) Thymomas growing with their "capsule" and adhering to the pleurae, pericardium, or lung were often misinterpreted as invading these structures. 2) Recognition of the mediastinal pleura was identified as challenging. CONCLUSION: Our study underlines that the evaluation of the pT stage of TET is problematic and needs to be addressed in more detail in an upcoming TNM classification. The publication of histopathologic images of landmarks, including ancillary tests could improve reproducibility for future TNM classifications.

Recommendations for Post-Operative RadioTherapy After Complete Resection of Thymoma-a French DELPHI Consensus Initiative.

INTRODUCTION: Thymomas are rare intrathoracic malignancies that can relapse after surgery. Whether or not Post-Operative RadioTherapy (PORT) should be delivered after surgery remains a major issue. RADIORYTHMIC is an ongoing, multicenter, randomized phase 3 trial addressing this question in patients with completely R0 resected Masaoka-Koga stage IIb/III thymoma. Experts in the field met to develop recommendations for PORT. METHODS: A scientific committee from the RYTHMIC network identified key issues regarding the modalities of PORT in completely resected thymoma. A DELPHI method was used to question 24 national experts, with 115 questions regarding the following: (1) imaging techniques, (2) clinical target volume (CTV) and margins, (3) dose constraints to organs at risk, (4) dose and fractionation, and (5) follow-up and records. Consensus was defined when opinions reached more than or equal to 80% agreement. RESULTS: We established the following recommendations: preoperative contrast-enhanced computed tomography (CT) scan is recommended (94% agreement); optimization of radiation delivery includes either a four-dimensional CT-based planning (82% agreement), a breath-holding inspiration breath-hold-based planning, or daily control CT imaging (81% agreement); imaging fusion based on cardiovascular structures of preoperative and planning CT scan is recommended (82% agreement); right coronary and left anterior descending coronary arteries should be delineated as cardiac substructures (88% agreement); rotational RCMI/volumetric modulated arc therapy is recommended (88% agreement); total dose is 50 Gy (81% agreement) with 1.8 to 2 Gy per fraction (94% agreement); cardiac evaluation and follow-up for patients with history of cardiovascular disease are recommended (88% agreement) with electrocardiogram and evaluation of left ventricular ejection fraction at 5 years and 10 years. CONCLUSION: This is the first consensus for PORT in thymoma. Implementation will help to harmonize practices.

Idiopathic pulmonary fibrosis with benign SFTPC variant and pathogenic MARS1 mutations: can't see the forest for the trees!

Even in the absence of liver disease, MARS1 screening should be considered in severe lung fibrosis of young individuals. Interpretation of the genetic variants can evolve with improvement of knowledge (databases, bioinformatic tools) over time. https://bit.ly/45OxF5E.