Hyvä näytteenotto keuhkosyövän diagnostiikassa ja levinneisyyden arviossa

Teema : keuhkosyövän diagnostiikka ja hoito. English summaryPeer reviewe

Haploinsufficiency of A20 impairs protein–protein interactome and leads into caspase-8-dependent enhancement of NLRP3 inflammasome activation

Objectives TNFAIP3 encodes A20 that negatively regulates nuclear factor kappa light chain enhancer of activated B cells (NF-κB), the major transcription factor coordinating inflammatory gene expression. TNFAIP3 polymorphisms have been linked with a spectrum of inflammatory and autoimmune diseases and, recently, loss-of-function mutations in A20 were found to cause a novel inflammatory disease ‘haploinsufficiency of A20’ (HA20). Here we describe a family with HA20 caused by a novel TNFAIP3 loss-of-function mutation and elucidate the upstream molecular mechanisms linking HA20 to dysregulation of NF-κB and the related inflammasome pathway.Methods NF-κB activation was studied in a mutation-expressing cell line using luciferase reporter assay. Physical and close-proximity protein–protein interactions of wild-type and TNFAIP3 p.(Lys91*) mutant A20 were analysed using mass spectrometry. NF-κB -dependent transcription, cytokine secretion and inflammasome activation were compared in immune cells of the HA20 patients and control subjects.Results The protein–protein interactome of p.(Lys91*) mutant A20 was severely impaired, including interactions with proteins regulating NF-κB activation, DNA repair responses and the NLR family pyrin domain containing 3 (NLRP3) inflammasome. The p.(Lys91*) mutant A20 failed to suppress NF-κB signalling, which led to increased NF-κB -dependent proinflammatory cytokine transcription. Functional experiments in the HA20 patients’ immune cells uncovered a novel caspase-8-dependent mechanism of NLRP3 inflammasome hyperresponsiveness that mediated the excessive secretion of interleukin-1β and interleukin-18.Conclusions The current findings significantly deepen our understanding of the molecular mechanisms underlying HA20 and other diseases associated with reduced A20 expression or function, paving the way for future therapeutic targeting of the pathway.Peer reviewe

Association of CT findings with invasive subtypes and the new grading system of lung adenocarcinoma

Aim: To predict the differentiation between invasive growth patterns and new grades of lung adenocarcinoma (LAC) using computed tomography (CT). Materials and methods: The CT features of 180 surgically treated LAC patients were compared retrospectively to pathological invasive subtypes and tumour grades as defined by the new grading system published in 2021 by the World Health Organization. Two radiologists reviewed the images semi-quantitatively and independently. Univariable and multivariable regression models were built from the statistical means of their assessments to predict invasive subtypes and grades. The area under the curve (AUC) calculation was used to select the best models. The Youden index was applied to determine the cut-off values for radiological parameters. Results: The acinar/papillary patterns were associated with ill-defined margins, lower consolidation/tumour ratio and air bronchogram. The solid growth pattern was associated with a well-defined margin and hypodensity, and the micropapillary (MP) subtype with spiculation. From Grades 1 to 3, the amount of air bronchogram decreased and the consolidation/tumour ratio increased. In the sub-analyses, the best model for differentiating Grade 2 from Grade 1 had the following CT features: solid/subsolid type, consolidation/tumour ratio, well-defined margin, and air bronchogram (AUC = 0.783) and Grade 3 from Grade 2: size of the consolidation part/whole tumour ratio, size of the consolidation part, and well-defined margin (AUC = 0.759). The interobserver agreements between the two radiologists varied between 0.67 and 0.98. Conclusions: Air bronchogram, consolidation/tumour ratio, and well-defined margin are among the best imaging findings to discriminate between both invasive subtypes and the new grades in LAC.AIM: To predict the differentiation between invasive growth patterns and new grades of lung adenocarcinoma (LAC) using computed tomography (CT). MATERIALS AND METHODS: The CT features of 180 surgically treated LAC patients were compared retrospectively to pathological invasive subtypes and tumour grades as defined by the new grading system published in 2021 by the World Health Organization. Two radiologists reviewed the images semi-quantitatively and independently. Univariable and multivariable regression models were built from the statistical means of their assessments to predict invasive subtypes and grades. The area under the curve (AUC) calculation was used to select the best models. The Youden index was applied to determine the cut-off values for radiological parameters. RESULTS: The acinar/papillary patterns were associated with ill-defined margins, lower consolidation/tumour ratio and air bronchogram. The solid growth pattern was associated with a well-defined margin and hypodensity, and the micropapillary (MP) subtype with spiculation. From Grades 1 to 3, the amount of air bronchogram decreased and the consolidation/tumour ratio increased. In the sub-analyses, the best model for differentiating Grade 2 from Grade 1 had the following CT features: solid/subsolid type, consolidation/tumour ratio, well-defined margin, and air bronchogram (AUC = 0.783) and Grade 3 from Grade 2: size of the consolidation part/whole tumour ratio, size of the consolidation part, and well-defined margin (AUC = 0.759). The interobserver agreements between the two radiologists varied between 0.67 and 0.98. CONCLUSIONS: Air bronchogram, consolidation/tumour ratio , well-defined margin are among the best imaging findings to discriminate between both invasive subtypes , the new grades in LAC. (c) 2023 The Authors. Published by Elsevier Ltd on behalf of The Royal College of Radiologists. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/ 4.0/).Peer reviewe

A prospective randomized controlled multicenter trial comparing antibiotic therapy with appendectomy in the treatment of uncomplicated acute appendicitis (APPAC trial)

Abstract Background Although the standard treatment of acute appendicitis (AA) consists of an early appendectomy, there has recently been both an interest and an increase in the use of antibiotic therapy as the primary treatment for uncomplicated AA. However, the use of antibiotic therapy in the treatment of uncomplicated AA is still controversial. Methods/design The APPAC trial is a randomized prospective controlled, open label, non-inferiority multicenter trial designed to compare antibiotic therapy (ertapenem) with emergency appendectomy in the treatment of uncomplicated AA. The primary endpoint of the study is the success of the randomized treatment. In the antibiotic treatment arm successful treatment is defined as being discharged from the hospital without the need for surgical intervention and no recurrent appendicitis during a minimum follow-up of one-year (treatment efficacy). Treatment efficacy in the operative treatment arm is defined as successful appendectomy evaluated to be 100%. Secondary endpoints are post-intervention complications, overall morbidity and mortality, the length of hospital stay and sick leave, treatment costs and pain scores (VAS, visual analoque scale). A maximum of 610 adult patients (aged 18–60 years) with a CT scan confirmed uncomplicated AA will be enrolled from six hospitals and randomized by a closed envelope method in a 1:1 ratio either to undergo emergency appendectomy or to receive ertapenem (1 g per day) for three days continued by oral levofloxacin (500 mg per day) plus metronidazole (1.5 g per day) for seven days. Follow-up by a telephone interview will be at 1 week, 2 months and 1, 3, 5 and 10 years; the primary and secondary endpoints of the trial will be evaluated at each time point. Discussion The APPAC trial aims to provide level I evidence to support the hypothesis that approximately 75–85% of patients with uncomplicated AA can be treated with effective antibiotic therapy avoiding unnecessary appendectomies and the related operative morbidity, also resulting in major cost savings. Trial registration Clinicaltrials.gov http://NCT01022567</p

A family with A20 haploinsufficiency presenting with novel clinical manifestations and challenges for treatment

Abstract Background: Tumor necrosis factor α–induced protein 3 gene (TNFAIP3, also called A20) haploinsufficiency (HA20) leads to autoinflammation and autoimmunity. We have recently shown that a p.(Lys91*) mutation in A20 disrupts nuclear factor κB signaling, impairs protein-protein interactions of A20, and leads to inflammasome activation. Methods: We now describe the clinical presentations and drug responses in a family with HA20 p.(Lys91*) mutation, consistent with our previously reported diverse immunological and functional findings. Results: We report for the first time that inflammasome-mediated autoinflammatory lung reaction caused by HA20 can be treated with interleukin 1 antagonist anakinra. We also describe severe anemia related to HA20 successfully treated with mycophenolate. In addition, HA20 p.(Lys91*) was found to associate with autoimmune thyroid disease, juvenile idiopathic arthritis, psoriasis, liver disease, and immunodeficiency presenting with specific antibody deficiency and genital papillomatosis. Conclusions: We conclude that HA20 may lead to combination of inflammation, immunodeficiency, and autoimmunity. The condition may present with variable and unpredictable symptoms with atypical treatment responses