Minimally invasive autopsies for the investigation of pulmonary pathology of COVID-19-experiences of a longitudinal series of 92 patients.

Minimally invasive autopsies (MIAs) allow the collection of tissue samples for diagnostic and research purposes in special situations, e.g., when there is a high risk of infection which is the case in the context of COVID-19 or restrictions due to legal or personal reasons. We performed MIA to analyze lung tissue from 92 COVID-19 patients (mean age 78 years; range 48-98; 35 women, 57 men), representing 44% of all patients who died from the disease between October 2020 and April 2021. An intercostal approach was used with removal of a 5-cm rib section followed by manual collection of four lung tissue samples (5-8 cm in size). Diffuse alveolar damage (DAD) was found in 89 (97%) patients at various stages. Exudative DAD (eDAD) predominated in 18 (20%) patients, proliferative DAD (pDAD) in 43 (47%) patients, and mixed DAD (mDAD) in 31 (34%) patients. There were no significant differences in the predominant DAD pattern between tissue samples from the same patient. Additional purulent components were present in 46 (50%) cases. Fungi were detected in 11 (12%) patients. The pDAD pattern was associated with longer hospital stay including intensive care unit (p=0.026 and p<0.001) and younger age (p=0.019). Positive bronchoalveolar lavage and blood cultures were observed more frequently in pDAD patterns (p<0.001; p=0.018). In contrast, there was no significant association between intravital positive microbiological results and superimposed bronchopneumonia or fungal infection at autopsy. Having demonstrated the characteristic lung changes in a large longitudinal autopsy series, we conclude that the presented MIA approach can be considered a reliable and safe method for performing post mortem lung diagnostics in COVID-19 and other high-risk situations. The lack of correlation between histological changes indicative of bacterial or fungal superinfection and microbiology could have clinical implications for disease and treatment surveillance.

Analysis of cardiopulmonary findings in COVID-19 fatalities: High incidence of pulmonary artery thrombi and acute suppurative bronchopneumonia.

Since its recognition in December 2019, coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has rapidly spread globally causing a pandemic that represents the greatest medical challenge in decades. The aim of the study was to evaluate the spectrum of cardiopulmonary pathology of COVID-19 based on (non-minimal invasive) autopsies performed on 14 COVID-19 decedents. Bilateral diffuse alveolar damage (DAD) was found in all patients. Superimposed acute bronchopneumonia was present in 11 of 14 (78.6%) patients and was considered the major cause of death in 2 patients. A key finding was the presence of thrombotic/thromboembolic vascular occlusions. We classified 5 types of pulmonary thrombi: 1. capillary microthrombi (11/14, 78.6%); 2. partially organized thrombi in mid-sized pulmonary arteries with complete vessel occlusion; 3. non-organized thrombi in mid-sized pulmonary arteries that did not completely fill out the vessel lumen and probably represented thromboemboli rather than thrombosis; 4. bone marrow emboli (1/14, 7.1%); and 5. septic pulmonary thromboemboli (1/14, 7.1%). Pulmonary thrombi in mid-sized arteries were noted in 5 of 14 (35.7%) patients, causing pulmonary infarction and/or pulmonary hemorrhage. All patients had evidence of chronic cardiac disease, including myocardial hypertrophy (13/14, 92.9%), mild to marked coronary artery atherosclerosis (14/14, 100%) and focal myocardial fibrosis (3/14, 21.4%). Acute myocardial infarction was found as concurrent cause of death in 3 (21.4%) patients, and significant cardiac hypertrophy (heart weight 750 g) was present in 1 (7.1%) patient with ATTR-positive cardiac amyloidosis. The autopsy findings confirm that COVID-19 is a systemic disease, with major involvement of the lungs, that increases the risk of cardiac and vascular complications including acute myocardial injury and thrombotic/thromboembolic events. Secondary acute bronchopneumonia is a common complication in patients with COVID-19 and may be the major cause of death.

Oncogenic driver mutations in Swiss never smoker patients with lung adenocarcinoma and correlation with clinicopathologic characteristics and outcome.

PURPOSE: Lung cancer in never smokers is recognized as a distinct molecular, clinicopathologic and epidemiologic entity. The aim of the study was to investigate the molecular profile in Swiss never smokers with lung adenocarcinoma and to correlate the mutation status with clinicopathologic and demographic patient characteristics and outcome. METHODS: One hundred thirty-eight never smokers diagnosed with lung adenocarcinoma at the University Hospital Zurich between 2011-2018 were included in the study. Data from the electronic medical records were reviewed to characterize clinicopathologic and demographic features, molecular profile, treatment and outcome. RESULTS: The majority of patients were female (58.7%) with a median age at diagnosis of 64.5 years (range, 27.1-94.2 years). The most common mutations were EGFR (58.7%) followed by ALK (12.3%), TP53 (5.8%), MET (5.8%), KRAS (4.3%), ERBB2 (4.3%), PIK3CA (2.9%), BRAF (2.2%), ROS1 (1.4%), RET (1.4%), CTNNB1 (0.7%), PARP1 (0.7%), TET1 (0.7%) and PIK3CG (0.7%). Median overall survival (mOS) was 51.0 months (mo). Early clinical stage (p = 0.002) and treatment with targeted therapy (HR 2.53, 95% CI 1.35-4.74, p = 0.004) were independently associated with longer mOS. Patients with oncogenic driver mutations had significantly longer mOS (52.2 mo) compared to patients without mutations (16.9 mo) (HR 3.38, 95% CI 1.52-7.55, p = 0.003). Besides, patients with EGFR mutated (57.8 mo) or ALK rearranged (59.9 mo) tumors had significantly longer mOS compared to the EGFR wildtype (35.0 mo), ALK wildtype (46.5 mo) and pan-negative (16.9 mo) cohorts (HR 2.35, 95% CI 1.37-4.04, p = 0.002; HR 7.80, 95% CI 3.28-18.55, p < 0.001; HR 3.96, 95% CI 1.21-12.95, p = 0.023 and HR 34.78, 95% CI 3.48-34.65, p = 0.003). CONCLUSION: Never smokers with lung adenocarcinoma display distinct clinicopathologic and molecular features and are characterized by a high incidence of targetable mutations. Never smokers with targetable mutations have significantly longer survival compared to patients without mutations.

Analysis of the frequency of oncogenic driver mutations and correlation with clinicopathological characteristics in patients with lung adenocarcinoma from Northeastern Switzerland.

BACKGROUND: Molecular testing of lung adenocarcinoma for oncogenic driver mutations has become standard in pathology practice. The aim of the study was to analyze the EGFR, KRAS, ALK, RET, ROS1, BRAF, ERBB2, MET and PIK3CA mutational status in a representative cohort of Swiss patients with lung adenocarcinoma and to correlate the mutational status with clinicopathological patient characteristics. METHODS: All patients who underwent molecular testing of newly diagnosed lung adenocarcinoma during a 4-year period (2014-2018) were included. Molecular analyses were performed with Sanger sequencing (n = 158) and next generation sequencing (n = 311). ALK, ROS1 and RET fusion gene analyses were also performed with fluorescence in situ hybridization and immunohistochemistry/immunocytochemistry. Demographic and clinical data were obtained from the medical records. RESULTS: Of 469 patients with informative EGFR mutation analyses, 90 (19.2%) had EGFR mutations. KRAS mutations were present in 33.9% of the patients, while 6.0% of patients showed ALK rearrangement. BRAF, ERBB2, MET and PIK3CA mutations and ROS1 and RET rearrangements were found in 2.6%, 1.9%, 1.9%, 1.5%, 1.7% and 0.8% of the patients, respectively. EGFR mutation was significantly associated with female gender and never smoking status. ALK translocations were more frequent in never smokers, while KRAS mutations were more commonly found in ever smokers. The association between KRAS mutational status and female gender was statistically significant only on multivariate analysis after adjusting for smoking. CONCLUSION: The EGFR mutation rate in the current study is among the higher previously reported mutation rates, while the frequencies of KRAS, BRAF, ERBB2 and PIK3CA mutations and ALK, ROS1 and RET rearrangements are similar to the results of previous reports. EGFR and KRAS mutations were significantly associated with gender and smoking. ALK rearrangements showed a significant association with smoking status alone.

Accuracy of grading pancreatic neuroendocrine neoplasms with Ki-67 index in fine-needle aspiration cellblock material.

OBJECTIVE: The aim of this study was to assess the preoperative tumour grade of pancreatic neuroendocrine neoplasms (panNENs) by determining the Ki-67 index in endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) material and to correlate the preoperative tumour grade with the postoperative tumour grade in surgical specimens. METHODS: We performed a retrospective review of the institutional pathology database over a 10-year period (2007-2017) to identify all cases of panNENs with corresponding preoperative EUS-FNA cytological material and surgical specimens. Fifteen cases with adequate EUS-FNA material (more than 400 tumour cells on cellblock) were identified. The cytological and histological samples were graded based on the mitotic rate and the Ki-67 index in accordance with the 2017 World Health Organisation grading system for panNENs. The tumour grades determined on EUS-FNA cellblock material were compared with the histological tumour grades. RESULTS: Mean age at diagnosis was 64.8 ± 12.7 years (range, 38-85 years). The grading scores assigned to the cytological and histological samples were concordant in all 15 (100%) cases. Of those, two (13%) cases were scored as grade 1, nine (60%) cases as grade 2 and four (27%) cases as grade 3 tumours. CONCLUSION: Our study shows that tumour grade in patients with PanNENs can be reliably determined by assessing the Ki-67 index in EUS-FNA specimens based on the 2017 World Health Organisation classification and grading system.

Evaluation of the CT imaging findings in patients newly diagnosed with chronic thromboembolic pulmonary hypertension.

PURPOSE: The aim of this study was to evaluate the vascular and parenchymal CT imaging findings, including vessel and cardiac chamber diameter measurements, in patients newly diagnosed with chronic thromboembolic pulmonary hypertension (CTEPH). The CT imaging findings were correlated with hemodynamic measurements and patient outcome. METHODS: Vascular and parenchymal CT findings were assessed on retrospectively ECG-gated MDCT angiography scans in 76 patients newly diagnosed with CTEPH. The diameters of the right and left ventricle (dRV, dLV), the right and left atrium (dRA, dLA), the ascending aorta (dAA), the right and left pulmonary arteries (drPA, dlPA), and the main pulmonary artery (dPA) were measured on axial CT scans. The CT imaging findings were correlated with demographic and hemodynamic data and adverse patient outcome due to right heart failure (RHF). RESULTS: The majority of patients showed chronic PE, mosaic perfusion, disparity in segmental vessel size, parenchymal densities, bronchial dilatation, and bronchial collaterals in CT. Mean pulmonary artery pressure (mPAP) was not significantly different in patients with and those without chronic PE, mosaic perfusion, disparity in segmental vessel size, parenchymal densities, bronchial dilatation, and bronchial collaterals. Mean PAP showed significant correlations with the CT metrics of dRV/dLV ratio, dRA, dRV, dPA and dPA/dAA ratio, but no correlation with the central thrombi score. By backward linear regression, the dPA/dAA ratio independently correlated with mPAP. Patients who died of RHF tended to have a higher frequency of exclusively chronic peripheral PE and greater dRV/dLV ratios on presenting CT scans compared with survivors. CONCLUSION: The majority of patients newly diagnosed with CTEPH show vascular signs of chronic PE, mosaic perfusion, parenchymal densities, disparity in segmental vessel size, bronchial dilatation, and bronchial collaterals on presenting CT scans. Particularly CTEPH patients with exclusively chronic peripheral PE and increased dRV/dLV ratios seem to be at risk of adverse outcome due to RHF.

Distinguishing Chronic Thromboembolic Pulmonary Hypertension From Other Causes of Pulmonary Hypertension Using CT.

OBJECTIVE: The purpose of this study was to discern imaging findings that separate chronic thromboembolic pulmonary hypertension (CTEPH) from other causes of pulmonary hypertension (PH). MATERIALS AND METHODS: A total of 143 patients with proven PH (group 1, pulmonary arterial hypertension; group 2, PH due to left heart disease; group 3, PH due to lung disease; group 4, CTEPH; and group 5, PH due to unclear or multifactorial mechanisms) underwent MDCT angiography. The CT images were assessed for the presence of chronic pulmonary embolism (PE), disparity in segmental vessel size, mosaic perfusion, parenchymal densities, bronchial dilatation, and collateral arteries. RESULTS: The frequencies of vascular signs of chronic PE, disparity in segmental vessel size, mosaic perfusion, parenchymal densities, bronchial collateral arteries, and bronchial dilatation were statistically significantly higher in patients with CTEPH than in patients with nonthromboembolic PH. Vascular signs of chronic PE, mosaic perfusion, parenchymal densities, and bronchial dilatation without bronchial wall thickening were significantly more frequent in patients with CTEPH than in patients in groups 1, 2, 3, and 5. There was no significant difference in the frequencies of bronchial collateral arteries between patients with CTEPH and patients in groups 3 and 5. CONCLUSION: Most patients with CTEPH have direct vascular signs of chronic PE. Secondary signs include disparity in segmental vessel size, mosaic perfusion pattern, parenchymal densities, collateral bronchial arteries, and bronchial dilatation, which help distinguish CTEPH from other causes of PH.

Activation of the Mitochondrial Apoptotic Signaling Platform during Rubella Virus Infection.

Mitochondria- as well as p53-based signaling pathways are central for the execution of the intrinsic apoptotic cascade. Their contribution to rubella virus (RV)-induced apoptosis was addressed through time-specific evaluation of characteristic parameters such as permeabilization of the mitochondrial membrane and subsequent release of the pro-apoptotic proteins apoptosis-inducing factor (AIF) and cytochrome c from mitochondria. Additionally, expression and localization pattern of p53 and selected members of the multifunctional and stress-inducible cyclophilin family were examined. The application of pifithrin µ as an inhibitor of p53 shuttling to mitochondria reduced RV-induced cell death to an extent similar to that of the broad spectrum caspase inhibitor z-VAD-fmk (benzyloxycarbonyl-V-A-D-(OMe)-fmk). However, RV progeny generation was not altered. This indicates that, despite an increased survival rate of its cellular host, induction of apoptosis neither supports nor restricts RV replication. Moreover, some of the examined apoptotic markers were affected in a strain-specific manner and differed between the cell culture-adapted strains: Therien and the HPV77 vaccine on the one hand, and a clinical isolate on the other. In summary, the results presented indicate that the transcription-independent mitochondrial p53 program contributes to RV-induced apoptosis.

Assisted suicide: Models of legal regulation in selected European countries and the case law of the European Court of Human Rights.

This paper presents three different models of the legal regulation of assisted suicide in European countries. First, the current legal regime governing assisted suicide in the Netherlands is described where both euthanasia and assisted suicide have been legalised. This section also includes some empirical data on euthanasia and assisted-suicide practices in the Netherlands, as well as a comparison with the current legal legislation in Belgium and Luxembourg. Next, Switzerland is presented as a country where euthanasia is punishable by law but assisted suicide is legally allowed, provided it is not carried out with selfish motives. This section also focuses on the assisted-suicide-related case law of the Swiss Federal Supreme Court and the European Court of Human Rights. Last, the current legal situation regarding assisted suicide in Austria and Germany is described. While the Austrian Penal Code explicitly prohibits assisted suicide, assistance with suicide is not specifically regulated by the German Penal Code. However, medical doctors are not allowed to assist suicides according to the professional codes of conduct drawn up by the German medical associations under the supervision of the health authorities.

CT findings in diseases associated with pulmonary hypertension: a current review.

Pulmonary hypertension may primarily affect either the arterial (precapillary) or the venous (postcapillary) pulmonary circulation. Pulmonary arterial hypertension may be idiopathic or arise in association with chronic pulmonary thromboembolism; pulmonary embolism caused by tumor cells, parasitic material, or foreign material; parenchymal lung disease; liver disease; vasculitis; human immunodeficiency virus infection; or a left-to-right cardiac shunt. Its histologic characteristics include vascular changes-medial hypertrophy, intimal cellular proliferation, intraluminal thrombosis, and the development of plexiform lesions-that manifest primarily in the muscular pulmonary arteries. Features of pulmonary arterial hypertension that may be seen at computed tomography (CT) are central pulmonary artery dilatation, abrupt narrowing or tapering of peripheral pulmonary vessels, right ventricular hypertrophy, right ventricular and atrial enlargement, dilated bronchial arteries, and a mosaic pattern of attenuation due to variable lung perfusion. Pulmonary venous hypertension may result from pulmonary veno-occlusive disease, pulmonary venous compression by extrinsic lesions (eg, mediastinal fibrosis), left-sided cardiac disease, or pulmonary vein stenosis. Its histologic hallmarks include venous intimal cellular proliferation, medial hypertrophy, and thickening of the internal elastic lamina; capillary congestion and proliferation; interlobular septal thickening; lymphatic dilatation; and, sometimes, venous infarction and vascular changes characteristic of pulmonary arterial hypertension. CT scans in patients with pulmonary venous hypertension show pulmonary interstitial and alveolar edema with signs of pulmonary arterial hypertension. High-resolution CT with standard axial and angiographic acquisitions is useful for identifying underlying disorders and differentiating among the various causes of secondary pulmonary hypertension.

What every radiologist should know about idiopathic interstitial pneumonias.

The American Thoracic Society-European Respiratory Society classification of idiopathic interstitial pneumonias (IIPs), published in 2002, defines the morphologic patterns on which clinical-radiologic-pathologic diagnosis of IIPs is based. IIPs include seven entities: idiopathic pulmonary fibrosis, which is characterized by the morphologic pattern of usual interstitial pneumonia (UIP); nonspecific interstitial pneumonia (NSIP); cryptogenic organizing pneumonia (COP); respiratory bronchiolitis-associated interstitial lung disease (RB-ILD); desquamative interstitial pneumonia (DIP); lymphoid interstitial pneumonia (LIP); and acute interstitial pneumonia (AIP). The characteristic computed tomographic findings in UIP are predominantly basal and peripheral reticular opacities with honeycombing and traction bronchiectasis. In NSIP, basal ground-glass opacities tend to predominate over reticular opacities, with traction bronchiectasis only in advanced disease. COP is characterized by patchy peripheral or peribronchovascular consolidation. RB-ILD and DIP are smoking-related diseases characterized by centrilobular nodules and ground-glass opacities. LIP is characterized by ground-glass opacities, often in combination with cystic lesions. AIP manifests as diffuse lung consolidation with ground-glass opacities, which usually progress to fibrosis in patients who survive the acute phase of the disease. Correct diagnosis of IIPs can be achieved only by means of interdisciplinary consensus and stringent correlation of clinical, imaging, and pathologic findings. (c) RSNA, 2007.