Untuned antiviral immunity in COVID-19 revealed by temporal type I/III interferon patterns and flu comparison.

A central paradigm of immunity is that interferon (IFN)-mediated antiviral responses precede pro-inflammatory ones, optimizing host protection and minimizing collateral damage1,2. Here, we report that for coronavirus disease 2019 (COVID-19) this paradigm does not apply. By investigating temporal IFN and inflammatory cytokine patterns in 32 moderate-to-severe patients with COVID-19 hospitalized for pneumonia and longitudinally followed for the development of respiratory failure and death, we reveal that IFN-λ and type I IFN production were both diminished and delayed, induced only in a fraction of patients as they became critically ill. On the contrary, pro-inflammatory cytokines such as tumor necrosis factor (TNF), interleukin (IL)-6 and IL-8 were produced before IFNs in all patients and persisted for a prolonged time. This condition was reflected in blood transcriptomes wherein prominent IFN signatures were only seen in critically ill patients who also exhibited augmented inflammation. By comparison, in 16 patients with influenza (flu) hospitalized for pneumonia with similar clinicopathological characteristics to those of COVID-19 and 24 nonhospitalized patients with flu with milder symptoms, IFN-λ and type I IFN were robustly induced earlier, at higher levels and independently of disease severity, whereas pro-inflammatory cytokines were only acutely produced. Notably, higher IFN-λ concentrations in patients with COVID-19 correlated with lower viral load in bronchial aspirates and faster viral clearance and a higher IFN-λ to type I IFN ratio correlated with improved outcome for critically ill patients. Moreover, altered cytokine patterns in patients with COVID-19 correlated with longer hospitalization and higher incidence of critical disease and mortality compared to flu. These data point to an untuned antiviral response in COVID-19, contributing to persistent viral presence, hyperinflammation and respiratory failure.

Endobronchial Ultrasound for the Screening of Pulmonary Embolism in Patients with Suspected Lung Cancer: A Prospective Cohort Study.

BACKGROUND: Patients with lung cancer exhibit increased risk of pulmonary embolism (PE). While the contrast phase of computed tomography of the chest in the diagnostic work-up of suspected chest malignancy does not allow reliable detection of PE, it may be feasible to screen for present PE during endobronchial ultrasound (EBUS) examination. OBJECTIVES: The aim of this study was to establish if screening during EBUS for PE in patients with suspected lung cancer is feasible and if positive findings are predictive of PE. METHODS: Patients undergoing EBUS due to suspicion of malignancy of the chest were prospectively enrolled. The pulmonary arteries were assessed during EBUS using a standardized protocol. Patients in whom PE suspicion was raised were referred to confirmatory imaging. RESULTS: From December 2020 to August 2021, 100 patients were included. Median time for vascular assessment during EBUS was 2 min (Q1-Q3: 1-3 min). EBUS identified two suspected PEs (2%), and the number needed to scan was 50. The positive predictive value of EBUS for PE was 100%. CONCLUSION: EBUS for PE screening seems feasible and with limited time use. The PPV of positive findings for the diagnosis of PE is high, but the utility is somewhat limited by a high number needed to scan even in a high-risk population. Based on our findings, we believe that EBUS assessment of the pulmonary vasculature may have a role as a routine screening tool for PE. The assessment for PE should be implemented in EBUS training programmes, as operators should be able to recognize incidental PEs.

Inherited predisposition to malignant mesothelioma and overall survival following platinum chemotherapy.

Survival from malignant mesothelioma, particularly pleural mesothelioma, is very poor. For patients with breast, ovarian, or prostate cancers, overall survival is associated with increased sensitivity to platinum chemotherapy due to loss-of-function mutations in DNA repair genes. The goal of this project was to evaluate, in patients with malignant mesothelioma, the relationship between inherited loss-of-function mutations in DNA repair and other tumor suppressor genes and overall survival following platinum chemotherapy. Patients with histologically confirmed malignant mesothelioma were evaluated for inherited mutations in tumor suppressor genes. Survival was evaluated with respect to genotype and site of mesothelioma. Among 385 patients treated with platinum chemotherapy, median overall survival was significantly longer for patients with loss-of-function mutations in any of the targeted genes compared with patients with no such mutation (P = 0.0006). The effect of genotype was highly significant for patients with pleural mesothelioma (median survival 7.9 y versus 2.4 y, P = 0.0012), but not for patients with peritoneal mesothelioma (median survival 8.2 y versus 5.4 y, P = 0.47). Effect of patient genotype on overall survival, measured at 3 y, remained independently significant after adjusting for gender and age at diagnosis, two other known prognostic factors. Patients with pleural mesothelioma with inherited mutations in DNA repair and other tumor suppressor genes appear to particularly benefit from platinum chemotherapy compared with patients without inherited mutations. These patients may also benefit from other DNA repair targeted therapies such as poly-ADP ribose polymerase (PARP) inhibitors.

Clinical prognostic factors in pleural mesothelioma: best supportive care and anti-tumor treatments in a real-life setting.

BACKGROUND: This study aims to investigate patient- and disease characteristics associated with survival in malignant pleural mesothelioma (MPM) patients with anti-tumor treatment or with best supportive care (BSC). MATERIALS AND METHODS: Consecutive MPM cases diagnosed in North Denmark Region from 1972 to 2015 were reevaluated and verified by two pathologists using modern immunohistochemical techniques. Danish registries and hospital records were used to gather patient-, asbestos exposure-, and disease information. RESULTS: Of the 279 patients, anti-tumor treatment was administered to 184 patients (66.0%). All of those received chemotherapy alone or as part of a multimodal treatment, where pemetrexed was given to 126 (68.5%) patients. Asbestos exposure was documented in 92.5% of all patients. In the treated group, mean age was lower (66 years versus 74 years, p < 0.01), rate of occupational asbestos exposure was higher (74.5 versus 54.7%, p < 0.01), more patients had better performance score (98.4 versus 60%, p < 0.01) and stage was lower (81 versus 63.2%, p < 0.01) compared to the BSC group. Multivariate analysis showed that epithelioid subtype was the only common prognostic factor for OS in both groups. In BSC patients, good PS and female gender was associated with improved OS. Median overall survival (OS) was 17 versus 4 months (p < 0.01), and independently of the histopathological subtype, the median and 2-year survival was higher in the treated versus the BSC group (p < 0.02). CONCLUSIONS: This retrospective study showed that epithelioid subtype is the only independent positive prognostic factor of survival in treated patients with MPM. For BSC patients, the epithelioid subtype, good PS, and female gender were positive prognostic factors, while age and comorbidities were not significant. This study with long-term follow-up of treated and BSC MPM patients can contribute to the clinical stratification of patients. Further validation is appropriate to verify these findings.

Inherited Genetic Mutations and Polymorphisms in Malignant Mesothelioma: A Comprehensive Review.

Malignant mesothelioma (MM) is mainly caused by air-born asbestos but genetic susceptibility is also suspected to be a risk factor. Recent studies suggest an increasing number of candidate genes that may predispose to MM besides the well-characterized BRCA1-associated protein-1 gene. The aim of this review is to summarize the most important studies on germline mutations for MM. A total of 860 publications were retrieved from Scopus, PubMed and Web of Science, of which 81 met the inclusion criteria and were consider for this review. More than 50% of the genes that are reported to predispose to MM are involved in DNA repair mechanisms, and the majority of them have a role in the homologous recombination pathway. Genetic alterations in tumor suppressor genes involved in chromatin, transcription and hypoxia regulation have also been described. Furthermore, we identified several single nucleotide polymorphisms (SNPs) that may promote MM tumorigenesis as a result of an asbestos-gene interaction, including SNPs in DNA repair, carcinogen detoxification and other genes previously associated with other malignancies. The identification of inherited mutations for MM and an understanding of the underlying pathways may allow early detection and prevention of malignancies in high-risk individuals and pave the way for targeted therapies.

Endoscopic ultrasound-guided fine-needle aspiration using the bronchial ultrasound scope (EUS-B-FNA) for diagnosing pancreatic metastasis in a lung cancer patient case report.

Endoscopic ultrasound-guided fine needle aspiration biopsy (EUS-FNA) of the pancreas is performed routinely in many endoscopic centers as part of the diagnostic set-up for suspected pancreatic cancer. The use of transesophageal bronchoscopic ultrasound-guided fine needle aspiration (EUS-B-FNA) by pulmonologists has expanded significantly, since it enables effective diagnosis of lesions in the mediastinum and upper abdomen. The following case demonstrates the safety and feasibility of EUS-B-FNA in a patient with non-small cell lung cancer (NSCLC) cancer and a pancreatic mass of unknown origin. A patient who was previously diagnosed with NSCLC was referred to the Department of Respiratory Medicine, Odense University Hospital due to suspected recurrence of NSCLC. The patient underwent endobronchial ultrasound guided (EBUS)-FNA from several suspected mediastinal lymph nodes and combined EUS-B-FNA from a pancreatic mass during the same procedure. Pathology results from the pancreatic mass and from the mediastinal lymph nodes showed squamous-cell carcinoma, metastasis from the previous NSCLC. We here by demonstrated that EUS-B-FNA is a feasible and safe technique to obtain tissue samples from pancreatic lesions in patients under investigation for lung cancer.

Advances in the diagnosis and follow-up of pleural lesions: a scoping review.

INTRODUCTION: Pleural lesions may have heterogeneous presentation and causes. In recent years, there have been significant advances in pleural lesions diagnostics. The aim of this review is to provide an overview of the state-of-the-art, and recent updates for diagnostic modalities and monitoring regimes for pleural lesions. AREAS COVERED: A literature search was conducted through PubMed and Web of Science for relevant articles published from 1 January 2000, to 1 March 2023. The article critically appraises the radiological modalities and biopsy techniques that are employed in pleural lesions diagnostics, including chest radiography, thoracic ultrasound, computed tomography, F-fluorodeoxyglycose positron emission tomography, magnetic resonance imaging, percutaneous and thoracoscopic pleural biopsies with reference to their strengths, limitations and clinical use. The review asserts also the available literature regarding monitoring algorithms. EXPERT OPINION: Despite the recent advances in the field, there are several key areas for improvement, including the development and validation of minimal invasive methods and tools for risk stratification, the integration of multi-omics technologies, the implementation of standardized, evidence-based diagnostic and monitoring guidelines and increased focus on research and patient-centric approaches. The broad establishment of dedicated pleural clinics may significantly assist toward this direction.

BAP1, Wilms' tumor 1, and calretinin in predicting survival and response to first-line chemotherapy in patients with pleural mesothelioma.

PURPOSE: There are currently no methods to predict response to chemotherapy in pleural mesothelioma (PM). The aim of this study is to investigate the predictive and prognostic role of BAP1, WT1 and calretinin expression and their combinations in pre-treatment tumor samples by immunohistochemical (IHC) staining. METHODS: The study included consecutive PM patients treated with chemotherapy alone at a University hospital between 2009 and 2020. BAP1 analyses were performed on formalin-fixed, paraffin-embedded tumor tissue samples of the patients, while WT1 and calretinin information were obtained from the histopathological diagnosis records. RESULTS: Of the total 107 patients included, 64% had loss of BAP1 expression, whereas 77% had WT1 and 86% had calretinin expression. Patients with the presence of BAP1 expression, one or both of the other two markers, or loss of expression of all three markers (unfavorable status) were more likely to not respond to chemotherapy than those with the presence of all three markers or loss of BAP1 expression and expression of one or two other markers (favorable status) (p = 0.001). Median survival time of patients with favorable and unfavorable status was 15 ± 1.7 and 8.0 ± 2.4 months, respectively (p = 0.027). After adjustment for histopathology and stage, loss of BAP1 (HR = 0.54, 95%CI 0.35-0.83), WT1 (1.75, 1.06-2.90), calretinin (2.09, 1.14-3.84) expression and favourable panel (0.50, 0.27-0.92) was associated with prognosis. CONCLUSIONS: The IHC biomarkers BAP1, WT1, and calretinin, used in the routine diagnosis of PM and their combinations, are the first biomarkers associated with response to chemotherapy and may be a useful tool to select patients for first-line platinum pemetrexed treatment in PM patients. Validation in a large cohort is ongoing.

Leveraging the pleural space for anticancer therapies in pleural mesothelioma.

Most patients with pleural mesothelioma (PM) present with symptomatic pleural effusion. In some patients, PM is only detectable on the pleural surfaces, providing a strong rationale for intrapleural anticancer therapy. In modern prospective studies involving expert radiological staging and specialist multidisciplinary teams, the population incidence of stage I PM (an approximate surrogate of pleura-only PM) is higher than in historical retrospective series. In this Viewpoint, we advocate for the expansion of intrapleural trials to serve these patients, given the paucity of data supporting licensed systemic therapies in this setting and the uncertainties involved in surgical therapy. We begin by reviewing the unique anatomical and physiological features of the PM-bearing pleural space, before critically appraising the evidence for systemic therapies in stage I PM and previous intrapleural PM trials. We conclude with a summary of key challenges and potential solutions, including optimal trial designs, repurposing of indwelling pleural catheters, and new technologies.

Network of doctors for multimorbidity and diabetes - the NOMAD intervention: protocol for feasibility trial of multidisciplinary team conferences for people with diabetes and multimorbidity.

BACKGROUND: The prevalence of diabetes and coexisting multimorbidity rises worldwide. Treatment of this patient group can be complex. Providing an evidence-based, coherent, and patient-centred treatment of patients with multimorbidity poses a challenge in healthcare systems, which are typically designed to deliver disease-specific care. We propose an intervention comprising multidisciplinary team conferences (MDTs) to address this issue. The MDT consists of medical specialists in five different specialities meeting to discuss multimorbid diabetes patients. This protocol describes a feasibility test of MDTs designed to coordinate care and improve quality of life for people with diabetes and multimorbidity. METHODS: A mixed-methods one-arm feasibility test of the MDT. Feasibility will be assessed through prospectively collected data. We will explore patient perspectives through patient-reported outcomes (PROs) and assess the feasibility of electronic questionnaires. Feasibility outcomes are recruitment, PRO completion, technical difficulties, impact of MDT, and doctor preparation time. During 17 months, up to 112 participants will be recruited. We will report results narratively and by the use of descriptive statistics. The collected data will form the basis for a future large-scale randomised trial. DISCUSSION: A multidisciplinary approach focusing on better management of diabetic patients suffering from multimorbidity may improve functional status, quality of life, and health outcomes. Multimorbidity and diabetes are highly prevalent in our healthcare system, but we lack a solid evidence-based approach to patient-centred care for these patients. This study represents the initial steps towards building such evidence. The concept can be efficiency tested in a randomised setting, if found feasible to intervention providers and receivers. If not, we will have gained experience on how to manage diabetes and multimorbidity as well as organisational aspects, which together may generate hypotheses for research on how to handle multimorbidity in the future. ADMINISTRATIVE INFORMATION: Protocol version: 01 TRIAL REGISTRATION: NCT05913726 - registration date: 21 June 2023.

Diagnostic capacity of BAP1 and MTAP in cytology from effusions and biopsy in mesothelioma.

INTRODUCTION: Serous effusion is often the first sign of mesothelioma. Diagnosis based on cytologic material from the effusions remains controversial and complementary biopsy is usually required. However, obtaining representative tissue sample may be challenging, while obtaining cytologic material is a minimally invasive procedure, providing potential for an earlier diagnosis. Loss of BRCA1-associated protein (BAP1), combined with loss of methylthionadenosine phosphorylase (MTAP) detected by immunohistochemistry, have shown to be reliable markers in the diagnosis of mesothelioma on histologic sections. Here we evaluate the value of these biomarkers in cytologic specimens. MATERIALS AND METHODS: The BAP1 and MTAP expression in specimens of 162 mesothelioma patients (156 pleural, 6 peritoneal)-71 cytologic, 91 histologic (44 epithelioid, 31 biphasic, 16 sarcomatoid)-and 20 patients with reactive mesothelial proliferations were investigated. RESULTS: The loss of BAP1 and/or MTAP was highly sensitive and specific in differentiating mesothelioma from reactive mesothelial proliferations, with no significant difference between pleural effusions and biopsies, specificity of 100% in both and a sensitivity of 78.9% and 80.2%, respectively (P = 0.3). There was a 100% concordance of the expression of BAP1 and MTAP in cytologic and corresponding histopathologic samples. Loss of BAP1 and/or MTAP in histologic sections discriminated sarcomatoid, biphasic, and epithelioid mesothelioma from reactive mesothelial proliferations with a sensitivity of 81.2%, 83.9%, and 77.3% respectively. CONCLUSION: Loss of expression of BAP1 and/or MTAP differentiated mesothelioma from reactive mesothelial proliferations with excellent specificity and high sensitivity in cytologic samples, comparable to histopathologic sections.

BAP1 Loss by Immunohistochemistry Predicts Improved Survival to First-Line Platinum and Pemetrexed Chemotherapy for Patients With Pleural Mesothelioma: A Validation Study.

INTRODUCTION: Pleural mesothelioma (PM) is an aggressive malignancy with no identified predictive biomarkers. We assessed whether tumor BAP1 status is a predictive biomarker for survival in patients receiving first-line combination platinum and pemetrexed therapy. METHODS: PM cases (n = 114) from Aalborg, Denmark, were stained for BAP1 on tissue microarrays. Demographic, clinical, and survival data were extracted from registries and medical records. Surgical cases were excluded. BAP1 status was associated with overall survival (OS) by Cox regression and Kaplan-Meier methods. Results were validated in an independent cohort from Perth, Australia (n = 234). RESULTS: BAP1 loss was found in 62% and 60.3% of all Danish and Australian samples, respectively. BAP1 loss was an independent predictor of OS in multivariate analyses corrected for histological subtype, performance status, age, sex, and treatment (hazard ratio = 2.49, p < 0.001, and 1.48, p = 0.01, respectively). First-line platinum and pemetrexed-treated patients with BAP1 loss had significantly longer median survival than those with retained BAP1 in both the Danish (20.1 versus 7.3 mo, p < 0.001) and Australian cohorts (19.6 versus 11.1 mo, p < 0.01). Survival in patients with BAP1 retained and treated with platinum and pemetrexed was similar as in those with best supportive care. There was a higher OS in patients with best supportive care with BAP1 loss, but it was significant only in the Australian cohort (16.8 versus 8.3 mo, p < 0.01). CONCLUSIONS: BAP1 is a predictive biomarker for survival after first-line combination platinum and pemetrexed chemotherapy and a potential prognostic marker in PM. BAP1 in tumor is a promising clinical tool for treatment stratification.

Physician-led in-hospital multidisciplinary team conferences with multiple medical specialities present - A scoping review.

Introduction: Multidisciplinary Team Conferences (MDTs) are complex interventions in the modern healthcare system and they promote a model of coordinated patient care and management. However, MDTs within chronic diseases are poorly defined. Therefore, the aim of this scoping review was to summarise the current literature on physician-led in-hospital MDTs in chronic non-malignant diseases. Method: Following the PRISMA-ScR guideline for scoping reviews, a search on MDT interventions in adult patients, with three or more medical specialties represented, was performed. Results: We identified 2790 studies, from which 8 studies were included. The majority of studies were non-randomised and focused on a single disease entity such as infective endocarditis, atrial fibrillation, IgG4-related disease, or arterial and venous thrombosis. The main reason for referral was confirmation or establishment of a diagnosis, and the MDT members were primarily from medical specialties gathered especially for the MDT. Outcomes of the included studies were grouped into process indicators and outcome indicators. Process indicators included changes in diagnostic confirmation as well as therapeutic strategy and management. All studies reporting process indicators demonstrated significant changes before and after the MDT. Conclusion: MDTs within chronic diseases appeared highly heterogeneous with respect to structure, reasons for referral, and choice of outcomes. While process indicators, such as change in diagnosis, and treatment management/plan seem improved, such have not been demonstrated through outcome indicators.

Non-occupational exposure to asbestos is the main cause of malignant mesothelioma in women in North Jutland, Denmark.

Objectives Diffuse malignant mesothelioma (MM) is mainly caused by asbestos inhalation. The malignancy is rare among women and studies of the prevalence and causative role of non-occupational asbestos exposure among women with MM are scarce. This observational study aimed to elucidate the asbestos exposure patterns among women with MM. Methods All histological and cytological specimens from women diagnosed with MM between 1974-2015 at the Institute of Pathology, Aalborg University Hospital in Denmark, were re-evaluated. Occupational and habitation information were obtained from Danish registries and medical journals based on record linkage via the unique person ID. The number of MM cases in each parish in the region of North Jutland was determined and the incidence density in parishes was used to calculate the spatial relative risk (RR) of MM among women. Results Diagnosis of MM was confirmed in 91 women. Exposure types were classified as occupational (9%), domestic (10%), environmental (22%), combination of domestic and environmental (34%) and unknown (25%). Twenty continuous parishes formed a MM "hotspot" around the asbestos-consuming industries in the city of Aalborg. Of these, the maximum RR was found in a parish housing an asbestos factory [RR 10.5, 95% confidence interval (CI) 5.5-19.4, environmental exposure in particular RR 2.9, 95% CI 0.7-6.1]. Conclusion Non-occupational asbestos exposure is the main cause of MM and may account for up to 66% of MM cases among women in North Jutland, Denmark.

Frequency of Germline Mutations in Cancer Susceptibility Genes in Malignant Mesothelioma.

PURPOSE: The aim of the current study was to determine the prevalence and clinical predictors of germline cancer susceptibility mutations in patients with malignant mesothelioma (MM). METHODS: We performed targeted capture and next-generation sequencing of 85 cancer susceptibility genes on germline DNA from 198 patients with pleural, peritoneal, and tunica vaginalis MM. RESULTS: Twenty-four germline mutations were identified in 13 genes in 23 (12%) of 198 patients. BAP1 mutations were the most common (n = 6; 25%). The remaining were in genes involved in DNA damage sensing and repair (n = 14), oxygen sensing (n = 2), endosome trafficking (n = 1), and cell growth (n = 1). Pleural site (odds ratio [OR], 0.23; 95% CI, 0.10 to 0.58; P < .01), asbestos exposure (OR, 0.28; 95% CI, 0.11 to 0.72; P < .01), and older age (OR, 0.95; 95% CI, 0.92 to 0.99; P = .01) were associated with decreased odds of carrying a germline mutation, whereas having a second cancer diagnosis (OR, 3.33; 95% CI, 1.22 to 9.07; P = .02) significantly increased the odds. The odds of carrying a mutation in BAP1 (OR, 1,658; 95% CI, 199 to 76,224; P < .001), BRCA2 (OR, 5; 95% CI, 1.0 to 14.7; P = .03), CDKN2A (OR, 53; 95% CI, 6 to 249; P < .001), TMEM127 (OR, 88; 95% CI, 1.7 to 1,105; P = .01), VHL (OR, 51; 95% CI, 1.1 to 453; P = .02), and WT1 (OR, 20; 95% CI, 0.5 to 135; P = .049) were significantly higher in MM cases than in a noncancer control population. Tumor sequencing identified mutations in a homologous recombination pathway gene in 52% (n = 29 of 54). CONCLUSION: A significant proportion of patients with MM carry germline mutations in cancer susceptibility genes, especially those with peritoneal MM, minimal asbestos exposure, young age, and a second cancer diagnosis. These data support clinical germline genetic testing for patients with MM and provide a rationale for additional investigation of the homologous recombination pathway in MM.

Hemoglobin variant (hemoglobin Aalborg) mimicking interstitial pulmonary disease.

Hemoglobin Aalborg is a moderately unstable hemoglobin variant with no affiliation to serious hematological abnormality or major clinical symptoms under normal circumstances. Our index person was a healthy woman of 58, not previously diagnosed with hemoglobinopathy Aalborg, who developed acute respiratory failure after a routine cholecystectomy. Initially she was suspected of idiopathic interstitial lung disease, yet a series of tests uncovered various abnormal physiological parameters and set the diagnosis of hemoglobinopathy Aalborg. This led us to examine a group of the index person's relatives known with hemoglobinopathy Aalborg in order to study whether the same physiological abnormalities would be reencountered. They were all subjected to spirometry and body plethysmography, six-minute walking test, pulse oximetry, and arterial blood gas samples before and after the walking test. The entire study population presented the same physiological anomalies: reduction in diffusion capacity, and abnormalities in P(a)O2 and p50 values; the latter could not be presented by the arterial blood gas analyzer; furthermore there was concordance between pulse oximetry and arterial blood gas samples regarding saturation. These data suggest that, based upon the above mentioned anomalies in physiological parameters, the diagnosis of hemoglobinopathy Aalborg should be considered.