Guidelines for Pathologic Diagnosis of Mesothelioma.

CONTEXT.­: Mesothelioma is an uncommon tumor that can be difficult to diagnose. OBJECTIVE.­: To provide updated, practical guidelines for the pathologic diagnosis of mesothelioma. DATA SOURCES.­: Pathologists involved in the International Mesothelioma Interest Group and others with expertise in mesothelioma contributed to this update. Reference material includes peer-reviewed publications and textbooks. CONCLUSIONS.­: There was consensus opinion regarding guidelines for (1) histomorphologic diagnosis of mesothelial tumors, including distinction of epithelioid, biphasic, and sarcomatoid mesothelioma; recognition of morphologic variants and patterns; and recognition of common morphologic pitfalls; (2) molecular pathogenesis of mesothelioma; (3) application of immunohistochemical markers to establish mesothelial lineage and distinguish mesothelioma from common morphologic differentials; (4) application of ancillary studies to distinguish benign from malignant mesothelial proliferations, including BAP1 and MTAP immunostains; novel immunomarkers such as Merlin and p53; fluorescence in situ hybridization (FISH) for homozygous deletion of CDKN2A; and novel molecular assays; (5) practical recommendations for routine reporting of mesothelioma, including grading epithelioid mesothelioma and other prognostic parameters; (6) diagnosis of mesothelioma in situ; (7) cytologic diagnosis of mesothelioma, including use of immunostains and molecular assays; and (8) features of nonmalignant peritoneal mesothelial lesions.

Fleischner Society: Glossary of Terms for Thoracic Imaging.

Members of the Fleischner Society have compiled a glossary of terms for thoracic imaging that replaces previous glossaries published in 1984, 1996, and 2008, respectively. The impetus to update the previous version arose from multiple considerations. These include an awareness that new terms and concepts have emerged, others have become obsolete, and the usage of some terms has either changed or become inconsistent to a degree that warranted a new definition. This latest glossary is focused on terms of clinical importance and on those whose meaning may be perceived as vague or ambiguous. As with previous versions, the aim of the present glossary is to establish standardization of terminology for thoracic radiology and, thereby, to facilitate communications between radiologists and clinicians. Moreover, the present glossary aims to contribute to a more stringent use of terminology, increasingly required for structured reporting and accurate searches in large databases. Compared with the previous version, the number of images (chest radiography and CT) in the current version has substantially increased. The authors hope that this will enhance its educational and practical value. All definitions and images are hyperlinked throughout the text. Click on each figure callout to view corresponding image. © RSNA, 2024 Supplemental material is available for this article. See also the editorials by Bhalla and Powell in this issue.

Pulmonary Pathology Society Survey on Practice Approaches in the Histologic Diagnosis of Fibrotic Interstitial Lung Disease: Consensus and Opportunities.

CONTEXT.­: The pathologic diagnosis of usual interstitial pneumonia (UIP) remains a challenging area, and application of histologic UIP guidelines has proved difficult. OBJECTIVE.­: To understand current practice approaches by pulmonary pathologists for the histologic diagnosis of UIP and other fibrotic interstitial lung diseases (ILDs). DESIGN.­: The Pulmonary Pathology Society (PPS) ILD Working Group developed and sent a 5-part survey on fibrotic ILD electronically to the PPS membership. RESULTS.­: One hundred sixty-one completed surveys were analyzed. Of the respondents, 89% reported using published histologic features in clinical guidelines for idiopathic pulmonary fibrosis (IPF) in their pathologic diagnosis; however, there was variability in reporting terminology, quantity and quality of histologic features, and the use of guideline categorization. Respondents were very likely to have access to pulmonary pathology colleagues (79%), pulmonologists (98%), and radiologists (94%) to discuss cases. Half of respondents reported they may alter their pathologic diagnosis based on additional clinical and radiologic history if it is pertinent. Airway-centered fibrosis, granulomas, and types of inflammatory infiltrates were considered important, but there was poor agreement on how these features are defined. CONCLUSIONS.­: There is significant consensus among the PPS membership on the importance of histologic guidelines/features of UIP. There are unmet needs for (1) consensus and standardization of diagnostic terminology and incorporation of recommended histopathologic categories from the clinical IPF guidelines into pathology reports, (2) agreement on how to incorporate into the report relevant clinical and radiographic information, and (3) defining the quantity and quality of features needed to suggest alternative diagnoses.

Modular antibodies reveal DNA damage-induced mono-ADP-ribosylation as a second wave of PARP1 signaling.

PARP1, an established anti-cancer target that regulates many cellular pathways, including DNA repair signaling, has been intensely studied for decades as a poly(ADP-ribosyl)transferase. Although recent studies have revealed the prevalence of mono-ADP-ribosylation upon DNA damage, it was unknown whether this signal plays an active role in the cell or is just a byproduct of poly-ADP-ribosylation. By engineering SpyTag-based modular antibodies for sensitive and flexible detection of mono-ADP-ribosylation, including fluorescence-based sensors for live-cell imaging, we demonstrate that serine mono-ADP-ribosylation constitutes a second wave of PARP1 signaling shaped by the cellular HPF1/PARP1 ratio. Multilevel chromatin proteomics reveals histone mono-ADP-ribosylation readers, including RNF114, a ubiquitin ligase recruited to DNA lesions through a zinc-finger domain, modulating the DNA damage response and telomere maintenance. Our work provides a technological framework for illuminating ADP-ribosylation in a wide range of applications and biological contexts and establishes mono-ADP-ribosylation by HPF1/PARP1 as an important information carrier for cell signaling.

Diffuse Pulmonary Meningotheliomatosis: Clinic-Pathologic Entity or Indolent Metastasis from Meningioma (or Both)?

Pulmonary minute meningothelial-like nodules (MMNs) are common incidental findings in surgical specimens, consisting of tiny proliferation (usually no larger than 5-6 mm) of bland-looking meningothelial cells showing a perivenular and interstitial distribution, sharing morphologic, ultrastructural, and immunohistochemical profiles with meningiomas. The identification of multiple bilateral MMNs leading to an interstitial lung disease characterized by diffuse and micronodular/miliariform patterns radiologically allows the diagnosis of diffuse pulmonary meningotheliomatosis (DPM). Nevertheless, the lung is the most common site of metastatic primary intracranial meningioma, and differential diagnosis with DPM may be impossible without clinic-radiologic integration. Herein, we report four cases (three females; mean age, 57.5 years) fitting the criteria of DPM, all incidentally discovered and histologically evidenced on transbronchial biopsy (2) and surgical resection (2). All cases showed immunohistochemical expression of epithelial membrane antigen (EMA), progesterone receptor, and CD56. Notably, three of these patients had a proven or radiologically suspected intracranial meningioma; in two cases, it was discovered before, and in one case, after the diagnosis of DPM. An extensive literature review (44 patients with DPM) revealed similar cases with imaging studies excluding intracranial meningioma in only 9% (4 of 44 cases studied). The diagnosis of DPM requires close correlation with the clinic-radiologic data since a subset of cases coexist with or follow a previously diagnosed intracranial meningioma and, thus, may represent incidental and indolent metastatic deposits of meningioma.

European Respiratory Society guidelines on transbronchial lung cryobiopsy in the diagnosis of interstitial lung diseases.

BACKGROUND: In patients with interstitial lung diseases (ILD), histopathological input is often required to obtain a diagnosis. Surgical lung biopsy (SLB) is considered the reference standard, but many patients are clinically unfit to undergo this invasive procedure, and adverse events, length of hospitalisation and costs are considerable. This European Respiratory Society (ERS) guideline provides evidence-based clinical practice recommendations for the role of transbronchial lung cryobiopsy (TBLC) in obtaining tissue-based diagnosis in patients with undiagnosed ILD. METHODS: The ERS Task Force consisted of clinical experts in the field of ILD and/or TBLC and methodological experts. Four PICO (Patient, Intervention, Comparator, Outcomes) questions and two narrative questions were formulated. Systematic literature searches were performed in MEDLINE and Embase (up to June 2021). GRADE (Grading, Recommendation, Assessment, Development and Evaluation) methodology was applied. RESULTS: In patients with undiagnosed ILD and an indication to obtain histopathological data: 1) TBLC is suggested as a replacement test in patients considered eligible to undergo SLB, 2) TBLC is suggested in patients not considered eligible to undergo SLB, 3) SLB is suggested as an add-on test in patients with a non-informative TBLC, 4) no recommendation is made for or against a second TBLC in patients with a non-informative TBLC and 5) TBLC operators should undergo training, but no recommendation is made for the type of training required. CONCLUSIONS: TBLC provides important diagnostic information in patients with undiagnosed ILD. Diagnostic yield is lower compared to SLB, at reduced serious adverse events and length of hospitalisation. Certainty of the evidence is mostly "very low".

Assessing Pathologic Response in Resected Lung Cancers: Current Standards, Proposal for a Novel Pathologic Response Calculator Tool, and Challenges in Practice.

The efficacy of neoadjuvant treatment for NSCLC can be pathologically assessed in resected tissue. Major pathologic response (MPR) and pathologic complete response (pCR), defined as less than or equal to 10% and 0% viable tumor cells, respectively, are increasingly being used in NSCLC clinical trials to establish them as surrogate end points for efficacy to shorten time to outcome. Nevertheless, sampling and MPR calculation methods vary between studies. The International Association for the Study of Lung Cancer recently published detailed recommendations for pathologic assessment of NSCLC after neoadjuvant treatment, with methodology being critical. To increase methodological rigor further, we developed a novel MPR calculator tool (MPRCT) for standardized, comprehensive collection of percentages of viable tumor, necrosis, and stroma in the tumor bed. In addition, tumor width and length in the tumor bed are measured and unweighted and weighted MPR averages are calculated, the latter to account for the varying proportions of tumor beds on slides. We propose sampling the entire visible tumor bed for tumors having pCR regardless of size, 100% of tumors less than or equal to 3 cm in diameter, and at least 50% of tumors more than 3 cm. We describe the uses of this tool, including potential formal analyses of MPRCT data to determine the optimum sampling strategy that balances sensitivity against excessive use of resources. Solutions to challenging scenarios in pathologic assessment are proposed. This MPRCT will facilitate standardized, systematic, comprehensive collection of pathologic response data with a standardized methodology to validate studies designed to establish MPR and pCR as surrogate end points of neoadjuvant treatment efficacy.

The Spectrum of Airway Involvement in Inflammatory Bowel Disease.

Inflammatory bowel disease is associated with a wide spectrum of central, large, and small airway abnormalities, including bronchiectasis. The bronchiectasis associated with inflammatory bowel disease has a distinct phenotype, with marked inflammation and at times severe sterile bronchorrhea that can be responsive to inhaled corticosteroids.

Impact of Lung Biopsy Information on Treatment Strategy of Patients with Interstitial Lung Diseases.

Rationale: Lung biopsy (LBx) has a relevant role in the prediction of prognosis of interstitial lung diseases (ILDs), but its impact on the clinical management of patients remains unexplored. Objectives: This study evaluates whether LBx may change the therapeutic strategy and assesses the effect of diagnostic reclassification after LBx on long-term prognosis. Methods: We evaluated the LBx of 426 consecutive patients with ILDs, without a definite usual interstitial pneumonia pattern on high-resolution computed tomographic imaging. A total of 266 patients underwent transbronchial lung cryobiopsy (TBLC), and 160 patients underwent surgical lung biopsy (SLB). The multidisciplinary team (MDT) determined a diagnosis with high or low confidence, and a management strategy, both before and after the LBx data. Results: Final MDT diagnoses were 189 idiopathic pulmonary fibrosis (IPF), 143 non-IPF fibrotic ILDs, and 94 nonfibrotic ILDs. LBx data changed the management strategy in 145 cases (34%), with similar results for TBLC and SLB (the treatment strategy changed in 31.5% of TBLC cases, 84/266, P < 0.001, and in 38% of SLB, 61/160, P < 0.001). After LBx, the MDT was less inclined to "wait and see" (from 15% to 4% of cases, P < 0.001) or to prescribe steroids only (from 54% to 37%, P < 0.001) and was more confident to treat with antifibrotics (from 23% to 44%, P < 0.001) or immunosuppressive drugs (from 7% to 14%, P < 0.001). The therapeutic strategy changed in 70% of reclassified cases (60/85) and in 59% of cases in which LBx increased the MDT confidence (84/142). Reclassification significantly impacted the outcome. The cases classified as non-IPF by clinician and radiologist and then reclassified to be IPF after LBx showed a significantly worse survival compared with non-IPF confirmed cases (adjusted hazard ratio [HR], 3.8; 95% confidence interval [CI], 1.75-8.3); P = 0.001. Cases initially classified as IPF and then reclassified as non-IPF after LBx showed a better prognosis compared with IPF confirmed cases (HR, 0.41; 95% CI, 0.18-0.94; P = 0.03). Conclusions: Reclassification of cases with LBx data increased diagnostic confidence and changed the therapeutic strategy in one-third of cases. Pathologic reclassification of cases refined prognosis prediction. Patients classified as non-IPF by clinician and radiologist and then reclassified IPF after LBx had worse prognosis compared with the non-IPF confirmed cases.

Comparison of Forceps, Cryoprobe, and Thoracoscopic Lung Biopsy for the Diagnosis of Interstitial Lung Disease - The CHILL Study.

RATIONALE: Transbronchial lung cryobiopsy (TBLC) has emerged as a less invasive method to obtain a tissue diagnosis in patients with interstitial lung disease (ILD). The diagnostic yield of TBLC compared to surgical lung biopsy (SLB) remains uncertain. OBJECTIVES: The aim of this study was to determine the diagnostic accuracy of forceps transbronchial lung biopsy (TBLB) and TBLC compared to SLB when making the final diagnosis based on multidisciplinary discussion (MDD). METHODS: Patients enrolled in the study underwent sequential TBLB and TBLC followed immediately by SLB. De-identified cases, with blinding of the biopsy method, were reviewed by a blinded pathologist and then discussed at a multidisciplinary conference. MAIN RESULTS: Between August 2013 and October 2017, we enrolled 16 patients. The raw agreement between TBLC and SLB for the MDD final diagnosis was 68.75% with a Cohen's kappa of 0.6 (95% CI 0.39, 0.81). Raw agreement and Cohen's kappa of TBLB versus TBLC and TBLB versus SLB for the MDD final diagnosis were much lower (50%, 0.21 [95% CI 0, 0.42] and 18.75%, 0.08 [95% CI -0.03, 0.19], respectively). TBLC was associated with mild bleeding (grade 1 bleeding requiring suction to clear) in 56.2% of patients. CONCLUSIONS: In patients with ILD who have an uncertain type based on clinical and radiographic data and require tissue sampling to obtain a specific diagnosis, TBLC showed moderate correlation with SLB when making the diagnosis with MDD guidance. TBLB showed poor concordance with both TBLC and SLB MDD diagnoses.

Diagnosis of Hypersensitivity Pneumonitis: Review and Summary of American College of Chest Physicians Statement.

Assessment of lung biopsies for the diagnosis of hypersensitivity pneumonitis (HP) is one of the most difficult diagnostic problems for surgical pathologists. It is a form of interstitial lung disease resulting from an immune reaction provoked by an inhaled antigen in susceptible individuals. Although this definition sounds simple, in practice, the diagnosis of HP can be challenging. To address these issues, the American College of Chest Physicians (CHEST) has recently published a guideline for the diagnosis of HP. In this review, we will explore the multidisciplinary diagnostic evaluation of HP with a focus on the pathologic features as outlined in the CHEST guidelines. The histologic criteria are divided into 4 diagnostic categories: (1) Typical nonfibrotic HP or fibrotic HP; (2) Compatible with nonfibrotic HP or fibrotic HP; (3) Indeterminate for nonfibrotic or fibrotic HP; and (4) Alternative Diagnosis. It is important to emphasize that patterns 1 to 3 do not represent discrete histologic entities or pathologic diagnoses. Rather, these categories are meant to serve as a practical guide for organizing a complex set of overlapping histologic patterns into an integrated diagnostic framework for facilitating multidisciplinary discussion. High-resolution computed tomography features are also summarized, emphasizing how the correlation of lung biopsies with computed tomography findings can help to favor the diagnosis, particularly in cases where biopsies are not typical for HP. This review highlights details of the histologic spectrum of HP as well as the utility of different types of biopsies and bronchoalveolar lavage. We also emphasize the importance of multidisciplinary discussion and the complex differential diagnosis.

Long-Term Outcomes of Phototherapeutic Keratectomy for Bullous Keratopathy.

PURPOSE: To report the long-term outcomes after phototherapeutic keratectomy (PTK) for the treatment of bullous keratopathy. METHODS: This is a retrospective medical record review of all patients with symptomatic bullous keratopathy who underwent PTK between June 2005 and March 2019 at the Royal Victorian Eye and Ear Hospital who were followed up for at least 12 months after the procedure. Medical records were used to extract demographic data, etiology of bullous keratopathy, complication rates, and subsequent procedures after PTK. The main outcomes recorded were pain and recurrence of bullae, which were assessed according to three time periods: 0 to 3 months, 4 to 12 months, and greater than 12 months after PTK. RESULTS: During the study period, 64 eyes of 64 patients underwent PTK for bullous keratopathy. The mean follow-up duration was 51 months (range 12-140). The most common indication was pseudophakic bullous keratopathy (44% of cases). Pain had resolved in 88% of eyes within 0 to 3 months, 77% of eyes between 3 and 12 months (P = 0.031, compared with 0-3 months), and 70% of eyes with greater than 12-month follow-up (P = 0.131, compared with 3-12 months). Bullae recurred in 17% of eyes within 0 to 3 months, 22% of eyes between 3 and 12 months (P < 0.001 compared with 0-3 months), and 33% of eyes after the 12-month follow-up (P < 0.001 compared with 3-12 months). Eighty-six percent of patients undergoing PTK had no postoperative complications, and 73% of cases did not require subsequent procedures. CONCLUSIONS: PTK is effective in providing long-term symptom relief from bullous keratopathy in most of the treated patients.

Bronchoalveolar lavage and lung biopsy in connective tissue diseases, to do or not to do?

Bronchoalveolar lavage and lung biopsy (LBx) are helpful in patients with connective tissue diseases (CTD) and interstitial lung diseases (ILD) regardless of cause, including infectious, noninfectious, immunologic, or malignant. The decision whether to perform only bronchoalveolar lavage (BAL), and eventually a subsequent LBx in case of a nondiagnostic lavage, or one single bronchoscopy combining both sampling methods depends on the clinical suspicion, on patient's characteristics (e.g. increased biopsy risk) and preferences, and on the resources and biopsy techniques available locally (e.g. regular forceps versus cryobiopsy). In CTD-ILD, BAL has major clinical utility in excluding infections and in the diagnosis of specific patterns of acute lung damage (e.g. alveolar hemorrhage, diffuse alveolar damage, and organizing pneumonia). LBx is indicated to exclude neoplasm or diagnose lymphoproliferative lung disorders that in CTD patients are more common than in the general population. Defining BAL cellularity and characterizing the CTD-ILD histopathologic pattern by LBx can be helpful in the differential diagnosis of cases without established CTD [e.g. ILD preceding full-blown CTD, interstitial pneumonia with autoimmune features (IPAF)], but the prognostic and theragnostic role of those findings remains unclear. Few studies in the pretranscriptomics era have investigated the diagnostic and prognostic role of BAL and LBx in CTD-ILD, and it is reasonable to hypothesize that future studies conducted applying innovative techniques on BAL and LBx might open new and unexpected avenues in pathogenesis, diagnosis, and treatment approach to CTD-ILD. This is particularly desirable now that a new drug treatment era is emerging, in which we have more than one therapeutic choice (immunosuppressive agents, antifibrotic drugs, and biological agents). We hope that future research will pave the path toward precision medicine providing data for a more accurate ILD-CTD endotyping that will guide the physicians through targeted therapeutic choices, rather than to the approximative approach 'one drug fits them all'.

Diagnostic Yield of Transbronchial Lung Cryobiopsy Compared to Transbronchial Forceps Biopsy in Patients with Sarcoidosis in a Prospective, Randomized, Multicentre Cross-Over Trial.

BACKGROUND: Transbronchial lung forceps biopsy (TBLF) is of limited value for the diagnosis of interstitial lung disease (ILD). However, in cases with predominantly peribronchial pathology, such as sarcoidosis, TBLF is considered to be diagnostic in most cases. The present study examines whether transbronchial lung cryobiopsy (TBLC) is superior to TBLF in terms of diagnostic yield in cases of sarcoidosis. METHODS: In this post hoc analysis of a prospective, randomized, controlled, multicentre study, 359 patients with ILD requiring diagnostic bronchoscopic tissue sampling were included. TBLF and TBLC were both used for each patient in a randomized order. Histological assessment was undertaken on each biopsy and determined whether sarcoid was a consideration. RESULTS: A histological diagnosis of sarcoidosis was established in 17 of 272 cases for which histopathology was available. In 6 out of 17 patients, compatible findings were seen with both TBLC and TBLF. In 10 patients, where the diagnosis of sarcoidosis was confirmed by TBLC, TBLF did not provide a diagnosis. In one patient, TBLF but not TBLC confirmed the diagnosis of sarcoidosis. CONCLUSIONS: In this post hoc analysis, the histological diagnosis of sarcoidosis was made significantly more often by TBLC than by TBLF. As in other idiopathic interstitial pneumonias (IIPs), the use of TBLC should be considered when sarcoidosis is suspected.

Structural basis for protein glutamylation by the Legionella pseudokinase SidJ.

Legionella pneumophila (LP) avoids phagocytosis by secreting nearly 300 effector proteins into the host cytosol. SidE family of effectors (SdeA, SdeB, SdeC and SidE) employ phosphoribosyl ubiquitination to target multiple host Rab GTPases and innate immune factors. To suppress the deleterious toxicity of SidE enzymes in a timely manner, LP employs a metaeffector named SidJ. Upon activation by host Calmodulin (CaM), SidJ executes an ATP-dependent glutamylation to modify the catalytic residue Glu860 in the mono-ADP-ribosyl transferase (mART) domain of SdeA. SidJ is a unique glutamylase that adopts a kinase-like fold but contains two nucleotide-binding pockets. There is a lack of consensus about the substrate recognition and catalytic mechanism of SidJ. Here, we determined the cryo-EM structure of SidJ in complex with its substrate SdeA in two different states of catalysis. Our structures reveal that both phosphodiesterase (PDE) and mART domains of SdeA make extensive contacts with SidJ. In the pre-glutamylation state structure of the SidJ-SdeA complex, adenylylated E860 of SdeA is inserted into the non-canonical (migrated) nucleotide-binding pocket of SidJ. Structure-based mutational analysis indicates that SidJ employs its migrated pocket for the glutamylation of SdeA. Finally, using mass spectrometry, we identified several transient autoAMPylation sites close to both the catalytic pockets of SidJ. Our data provide unique insights into the substrate recognition and the mechanism of protein glutamylation by the pseudokinase SidJ.

Small Airway Reduction and Fibrosis Is an Early Pathologic Feature of Idiopathic Pulmonary Fibrosis.

Rationale: To improve disease outcomes in idiopathic pulmonary fibrosis (IPF), it is essential to understand its early pathophysiology so that it can be targeted therapeutically. Objectives: Perform three-dimensional assessment of the IPF lung microstructure using stereology and multiresolution computed tomography (CT) imaging. Methods: Explanted lungs from patients with IPF (n = 8) and donor control subjects (n = 8) were inflated with air and frozen. CT scans were used to assess large airways. Unbiased, systematic uniform random samples (n = 8/lung) were scanned with microCT for stereological assessment of small airways (count number, and measure airway wall and lumen area) and parenchymal fibrosis (volume fraction of tissue, alveolar surface area, and septal wall thickness). Measurements and Main Results: The total number of airways on clinical CT was greater in IPF lungs than control lungs (P < 0.01), owing to an increase in the wall (P < 0.05) and lumen area (P < 0.05) resulting in more visible airways with a lumen larger than 2 mm. In IPF tissue samples without microscopic fibrosis, assessed by the volume fraction of tissue using microCT, there was a reduction in the number of the terminal (P < 0.01) and transitional (P < 0.001) bronchioles, and an increase in terminal bronchiole wall area (P < 0.001) compared with control lungs. In IPF tissue samples with microscopic parenchymal fibrosis, terminal bronchioles had increased airway wall thickness (P < 0.05) and dilated airway lumens (P < 0.001) leading to honeycomb cyst formations. Conclusions: This study has important implications for the current thinking on how the lung tissue is remodeled in IPF and highlights small airways as a potential target to modify IPF outcomes.

Diagnostic Accuracy of Endobronchial Optical Coherence Tomography for the Microscopic Diagnosis of Usual Interstitial Pneumonia.

Rationale: Early, accurate diagnosis of interstitial lung disease (ILD) informs prognosis and therapy, especially in idiopathic pulmonary fibrosis (IPF). Current diagnostic methods are imperfect. High-resolution computed tomography has limited resolution, and surgical lung biopsy (SLB) carries risks of morbidity and mortality. Endobronchial optical coherence tomography (EB-OCT) is a low-risk, bronchoscope-compatible modality that images large lung volumes in vivo with microscopic resolution, including subpleural lung, and has the potential to improve the diagnostic accuracy of bronchoscopy for ILD diagnosis. Objectives: We performed a prospective diagnostic accuracy study of EB-OCT in patients with ILD with a low-confidence diagnosis undergoing SLB. The primary endpoints were EB-OCT sensitivity/specificity for diagnosis of the histopathologic pattern of usual interstitial pneumonia (UIP) and clinical IPF. The secondary endpoint was agreement between EB-OCT and SLB for diagnosis of the ILD fibrosis pattern. Methods: EB-OCT was performed immediately before SLB. The resulting EB-OCT images and histopathology were interpreted by blinded, independent pathologists. Clinical diagnosis was obtained from the treating pulmonologists after SLB, blinded to EB-OCT. Measurements and Main Results: We enrolled 31 patients, and 4 were excluded because of inconclusive histopathology or lack of EB-OCT data. Twenty-seven patients were included in the analysis (16 men, average age: 65.0 yr): 12 were diagnosed with UIP and 15 with non-UIP ILD. Average FVC and DlCO were 75.3% (SD, 18.5) and 53.5% (SD, 16.4), respectively. Sensitivity and specificity of EB-OCT was 100% (95% confidence interval, 75.8-100.0%) and 100% (79.6-100%), respectively, for both histopathologic UIP and clinical diagnosis of IPF. There was high agreement between EB-OCT and histopathology for diagnosis of ILD fibrosis pattern (weighted κ: 0.87 [0.72-1.0]). Conclusions: EB-OCT is a safe, accurate method for microscopic ILD diagnosis, as a complement to high-resolution computed tomography and an alternative to SLB.

Serine-ubiquitination regulates Golgi morphology and the secretory pathway upon Legionella infection.

SidE family of Legionella effectors catalyze non-canonical phosphoribosyl-linked ubiquitination (PR-ubiquitination) of host proteins during bacterial infection. SdeA localizes predominantly to ER and partially to the Golgi apparatus, and mediates serine ubiquitination of multiple ER and Golgi proteins. Here we show that SdeA causes disruption of Golgi integrity due to its ubiquitin ligase activity. The Golgi linking proteins GRASP55 and GRASP65 are PR-ubiquitinated on multiple serine residues, thus preventing their ability to cluster and form oligomeric structures. In addition, we found that the functional consequence of Golgi disruption is not linked to the recruitment of Golgi membranes to the growing Legionella-containing vacuoles. Instead, it affects the host secretory pathway. Taken together, our study sheds light on the Golgi manipulation strategy by which Legionella hijacks the secretory pathway and promotes bacterial infection.