Clonal Hematopoiesis of Indeterminate Potential With Loss of Tet2 Enhances Risk for Atrial Fibrillation Through Nlrp3 Inflammasome Activation.

BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP), a common age-associated phenomenon, associates with increased risk of both hematological malignancy and cardiovascular disease. Although CHIP is known to increase the risk of myocardial infarction and heart failure, the influence of CHIP in cardiac arrhythmias, such as atrial fibrillation (AF), is less explored. METHODS: CHIP prevalence was determined in the UK Biobank, and incident AF analysis was stratified by CHIP status and clone size using Cox proportional hazard models. Lethally irradiated mice were transplanted with hematopoietic-specific loss of Tet2, hematopoietic-specific loss of Tet2 and Nlrp3, or wild-type control and fed a Western diet, compounded with or without NLRP3 (NLR [NACHT, LRR {leucine rich repeat}] family pyrin domain containing protein 3) inhibitor, NP3-361, for 6 to 9 weeks. Mice underwent in vivo invasive electrophysiology studies and ex vivo optical mapping. Cardiomyocytes from Ldlr-/- mice with hematopoietic-specific loss of Tet2 or wild-type control and fed a Western diet were isolated to evaluate calcium signaling dynamics and analysis. Cocultures of pluripotent stem cell-derived atrial cardiomyocytes were incubated with Tet2-deficient bone marrow-derived macrophages, wild-type control, or cytokines IL-1ß (interleukin 1ß) or IL-6 (interleukin 6). RESULTS: Analysis of the UK Biobank showed individuals with CHIP, in particular TET2 CHIP, have increased incident AF. Hematopoietic-specific inactivation of Tet2 increases AF propensity in atherogenic and nonatherogenic mouse models and is associated with increased Nlrp3 expression and CaMKII (Ca2+/calmodulin-dependent protein kinase II) activation, with AF susceptibility prevented by inactivation of Nlrp3. Cardiomyocytes isolated from Ldlr-/- mice with hematopoietic inactivation of Tet2 and fed a Western diet have impaired calcium release from the sarcoplasmic reticulum into the cytosol, contributing to atrial arrhythmogenesis. Abnormal sarcoplasmic reticulum calcium release was recapitulated in cocultures of cardiomyocytes with the addition of Tet2-deficient macrophages or cytokines IL-1ß or IL-6. CONCLUSIONS: We identified a modest association between CHIP, particularly TET2 CHIP, and incident AF in the UK Biobank population. In a mouse model of AF resulting from hematopoietic-specific inactivation of Tet2, we propose altered calcium handling as an arrhythmogenic mechanism, dependent on Nlrp3 inflammasome activation. Our data are in keeping with previous studies of CHIP in cardiovascular disease, and further studies into the therapeutic potential of NLRP3 inhibition for individuals with TET2 CHIP may be warranted.

Cutaneous Manifestations of Myeloid Neoplasms Exhibit Broad and Divergent Morphologic and Immunophenotypic Features but Share Ancestral Clonal Mutations With Bone Marrow.

In this study, we performed a comprehensive molecular analysis of paired skin and peripheral blood/bone marrow (BM) samples from 17 patients with cutaneous myeloid or cutaneous histiocytic-dendritic neoplasms. The cutaneous manifestations included 10 patients with cutaneous acute myeloid leukemia (c-AML), 2 patients with full or partial Langerhans cell differentiation, 2 patients with blastic plasmacytoid dendritic cell neoplasms (BPDCN), 1 patient with both Langerhans cell differentiation and BPDCN, and 2 patients with full or partial indeterminate dendritic cell differentiation. Seven of the 10 c-AML patients (70%) exhibited concurrent or subsequent marrow involvement by acute myeloid leukemia, with all 7 cases (100%) demonstrating shared clonal mutations in both the skin and BM. However, clonal relatedness was documented in one additional case that never had any BM involvement. Nevertheless, NPM1 mutations were identified in 7 of the 10 (70%) of these c-AML cases while one had KMT2A rearrangement and one showed inv(16). All 3 patients (100%) with Langerhans cell neoplasms, 2 patients with BPDCN (100%), and one of the 2 patients (50%) with other cutaneous dendritic cell neoplasms also demonstrated shared mutations between the skin and concurrent or subsequent myeloid neoplasms. Both BM and c-AML shared identical founding drivers, with a predominance of NPM1, DNMT3A, and translocations associated with monocytic differentiation, with common cutaneous-only mutations involving genes in the signal transduction and epigenetic pathways. Cutaneous histiocytic-dendritic neoplasms shared founding drivers in ASXL1, TET2, and/or SRSF2. However, in the Langerhans cell histiocytosis or histiocytic sarcoma cases, there exist recurrent secondary RAS pathway hits, whereas cutaneous BPDCN cases exhibit copy number or structural variants. These results enrich and broaden our understanding of clonally related cutaneous manifestations of myeloid neoplasms and further illuminate the highly diverse spectrum of morphologic and immunophenotypic features they exhibit.

An International Survey of Practices in the Investigation and Endoscopic Treatment of Peripheral Pulmonary Lesions amongst Interventional Bronchoscopists.

INTRODUCTION: The investigation of peripheral pulmonary lesions (PPLs) can be challenging. Several bronchoscopic modalities have been developed to reach and biopsy PPL but the level of adoption of these techniques by interventional pulmonologists (IPs) is unknown. This international survey was conducted to describe current practices in PPL investigation among IP. METHODS: This survey was sent to all members of the World Association for Bronchology and Interventional Pulmonology, Canadian Thoracic Society Procedures Assembly, AABIP, and the Groupe d'Endoscopie Thoracique et Interventionnel Francophone. The survey was composed of 48 questions and three clinical cases to establish a portrait of modalities used to investigate and treat PPL by IP around the world. RESULTS: Three hundred and twelve IP responded to the survey. Most of them practice in Europe (n = 122), North America (n = 97), and Asia (n = 49). Half of responders perform more than 100 endoscopic procedures for PPL annually. General anesthesia and conscious sedation are used in similar proportions (53% and 47%, respectively). Rapid on site evaluation (ROSE) is used when sampling PPL by 42%. Radial EBUS (69%), fluoroscopy (55%), and electromagnetic navigation (27%) are the most widely used techniques. Most IP combine techniques (89%). Robotic bronchoscopy (15%) and cone-beam CT (8%) are almost exclusively used in the USA where, respectively, 60% and 37% of respondents reported using these modalities. Ten percent of IP currently had access to endoscopic treatment modalities for PPL. However, half of the remaining IP plan to acquire an endoscopic treatment modality in the next 2 years. CONCLUSION: Available techniques and practices worldwide vary significantly regarding PPL investigation and treatment.

Molecular analysis of endobronchial ultrasound needle aspirates in patients with non-small cell lung cancer: Results from the SCOPE database.

OBJECTIVE: Molecular subtyping of non-small cell lung cancer (NSCLC) is critical in the diagnostic evaluation of patients with advanced disease. This study aimed to examine whether samples from endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) of intrathoracic lymph nodes and/or lung lesions are adequate for molecular analysis across various institutions. METHODS: We retrospectively reviewed all cases of linear EBUS-TBNA with a final bronchoscopic diagnosis of NSCLC entered in the Stather Canadian Outcomes registry for chest ProcEdures database. The primary outcome was specimen inadequacy rate for each molecular target, as defined by the local laboratory or pathologist. RESULTS: A total of 866 EBUS-TBNA procedures for NSCLC were identified. Specimen inadequacy rates were 3.8% for EGFR, 2.5% for ALK-1 and 3.5% for PD-L1. Largest target size was not different between adequate and inadequate specimens, and rapid onsite evaluation did not increase specimen adequacy rates. One centre using next-generation sequencing for EGFR had lower adequacy rates than 2 others using matrix-assisted laser desorption/ionization time-of-flight mass spectrophotometry. CONCLUSION: EBUS-TBNA specimens have a very low-specimen inadequacy rate for molecular subtyping of non-small cell lung cancer.

Mentorship in medicine is a Complex opportunity.

Mentorship is now recognized as essential to the personal and professional development of physicians. Over the past decade, it has become a common theme in medical education literature, and through this our understanding of mentorship has evolved. Despite this progress, we believe that the prevailing reductionist view of mentorship is oversimplified and may hinder further advances in this space. Instead, we propose that mentorship be viewed through the lens of complexity theory, positioning it as a prototypical complex adaptive system. This shift in perspective will inform our mentorship interventions and evaluations, and can avoid the disappointment that invariably follows when we apply a simple approach to a complex situation.

A Massive Case of Cutaneous Diffuse Large B-Cell Lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma, and extranodal involvement is seen in approximately 40% of cases. However, cases involving the skin and muscle are rare, and skin manifestations most commonly present as plaques, papules, small nodules, or ulcers. In this report, we discuss a case of a large exophytic mass involving skin, soft tissue, and muscle initially thought to be baso-squamous carcinoma subsequently identified as DLBCL and treated solely with chemotherapy. J Drugs Dermatol. 2023;22(12):1223-1224.     doi:10.36849/JDD.6936.

Canadian Internal Medicine Ultrasound (CIMUS) Expert Consensus Statement on the Use of Lung Ultrasound for the Assessment of Medical Inpatients With Known or Suspected Coronavirus Disease 2019.

OBJECTIVES: To develop a consensus statement on the use of lung ultrasound (LUS) in the assessment of symptomatic general medical inpatients with known or suspected coronavirus disease 2019 (COVID-19). METHODS: Our LUS expert panel consisted of 14 multidisciplinary international experts. Experts voted in 3 rounds on the strength of 26 recommendations as "strong," "weak," or "do not recommend." For recommendations that reached consensus for do not recommend, a fourth round was conducted to determine the strength of those recommendations, with 2 additional recommendations considered. RESULTS: Of the 26 recommendations, experts reached consensus on 6 in the first round, 13 in the second, and 7 in the third. Four recommendations were removed because of redundancy. In the fourth round, experts considered 4 recommendations that reached consensus for do not recommend and 2 additional scenarios; consensus was reached for 4 of these. Our final recommendations consist of 24 consensus statements; for 2 of these, the strength of the recommendations did not reach consensus. CONCLUSIONS: In symptomatic medical inpatients with known or suspected COVID-19, we recommend the use of LUS to: (1) support the diagnosis of pneumonitis but not diagnose COVID-19, (2) rule out concerning ultrasound features, (3) monitor patients with a change in the clinical status, and (4) avoid unnecessary additional imaging for patients whose pretest probability of an alternative or superimposed diagnosis is low. We do not recommend the use of LUS to guide admission and discharge decisions. We do not recommend routine serial LUS in patients without a change in their clinical condition.

Improving Lung Function in Severe Heterogenous Emphysema with the Spiration Valve System (EMPROVE). A Multicenter, Open-Label Randomized Controlled Clinical Trial.

Rationale: Less invasive, nonsurgical approaches are needed to treat severe emphysema.Objectives: To evaluate the effectiveness and safety of the Spiration Valve System (SVS) versus optimal medical management.Methods: In this multicenter, open-label, randomized, controlled trial, subjects aged 40 years or older with severe, heterogeneous emphysema were randomized 2:1 to SVS with medical management (treatment) or medical management alone (control).Measurements and Main Results: The primary efficacy outcome was the difference in mean FEV1 from baseline to 6 months. Secondary effectiveness outcomes included: difference in FEV1 responder rates, target lobe volume reduction, hyperinflation, health status, dyspnea, and exercise capacity. The primary safety outcome was the incidence of composite thoracic serious adverse events. All analyses were conducted by determining the 95% Bayesian credible intervals (BCIs) for the difference between treatment and control arms. Between October 2013 and May 2017, 172 participants (53.5% male; mean age, 67.4 yr) were randomized to treatment (n = 113) or control (n = 59). Mean FEV1 showed statistically significant improvements between the treatment and control groups-between-group difference at 6 and 12 months, respectively, of 0.101 L (95% BCI, 0.060-0.141) and 0.099 L (95% BCI, 0.048-0.151). At 6 months, the treatment group had statistically significant improvements in all secondary endpoints except 6-minute-walk distance. Composite thoracic serious adverse event incidence through 6 months was greater in the treatment group (31.0% vs. 11.9%), primarily due to a 12.4% incidence of serious pneumothorax.Conclusions: In patients with severe heterogeneous emphysema, the SVS shows significant improvement in multiple efficacy outcomes, with an acceptable safety profile.Clinical trial registered with www.clinicaltrials.gov (NCT01812447).

Peptidoglycan from the gut microbiota governs the lifespan of circulating phagocytes at homeostasis.

Maintenance of myeloid cell homeostasis requires continuous turnover of phagocytes from the bloodstream, yet whether environmental signals influence phagocyte longevity in the absence of inflammation remains unknown. Here, we show that the gut microbiota regulates the steady-state cellular lifespan of neutrophils and inflammatory monocytes, the 2 most abundant circulating myeloid cells and key contributors to inflammatory responses. Treatment of mice with broad-spectrum antibiotics, or with the gut-restricted aminoglycoside neomycin alone, accelerated phagocyte turnover and increased the rates of their spontaneous apoptosis. Metagenomic analyses revealed that neomycin altered the abundance of intestinal bacteria bearing γ-d-glutamyl-meso-diaminopimelic acid, a ligand for the intracellular peptidoglycan sensor Nod1. Accordingly, signaling through Nod1 was both necessary and sufficient to mediate the stimulatory influence of the flora on myeloid cell longevity. Stimulation of Nod1 signaling increased the frequency of lymphocytes in the murine intestine producing the proinflammatory cytokine interleukin 17A (IL-17A), and liberation of IL-17A was required for transmission of Nod1-dependent signals to circulating phagocytes. Together, these results define a mechanism through which intestinal microbes govern a central component of myeloid homeostasis and suggest perturbations of commensal communities can influence steady-state regulation of cell fate.

Lesion heterogeneity and risk of infectious complications following peripheral endobronchial ultrasound.

BACKGROUND AND OBJECTIVE: The reported incidence of peripheral endobronchial ultrasound (pEBUS)-related infectious complications is below 1%, although studies have never focused solely on them or reported their risk factors. The goal of this study is to describe our local pEBUS infectious complication rate and characterize patient, lesion and procedural factors associated with infectious complications. METHODS: All charts, computed tomography scans and electronic records of patients who underwent a pEBUS at the Foothills Medical Center and South Health Campus Hospital in Calgary between 1 May 2014 and 1 October 2015 were reviewed. RESULTS: One hundred and ninety-nine pEBUS procedures were included in our study. The local infectious complication rate was 4.0% (8/199). Two lesion characteristics were more frequent in patients who suffered infectious complications: larger lesion diameter (P = 0.016) and lesion heterogeneity on imaging suggestive of areas of necrosis (P < 0.001). In a multivariate analysis, only the presence of lesion heterogeneity was significantly associated with infectious complications (OR = 16.74 (2.95-95.08)). The rate of infectious complications in lesions with a heterogeneous appearance was 20.7% (6/29). CONCLUSION: The rate of infectious complications after pEBUS is elevated when biopsying heterogeneous appearing lesions. This may not have previously been reported as studies of pEBUS focused on smaller and probably rarely necrotic lesions. Future studies of methods to prevent infections complications in pEBUS-guided biopsies of heterogeneous appearing lesions are warranted.

Flexible 19-Gauge Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration Needle: First Experience.

BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a well-established first-line invasive modality for mediastinal lymph node staging in lung cancer patients and in the diagnostic workup of patients with mediastinal adenopathy. With the current 21- and 22-gauge (G) EBUS-TBNA needles, the procedure can be limited by the degree of flexibility in the needle and the size of the lumen in tissue acquisition. OBJECTIVE: We report our initial experience with a first-generation flexible 19-G EBUS-TBNA (Flex 19G; Olympus Respiratory America, Redmond, WA, USA) needle with regards to efficacy and safety. METHODS: The Flex 19G EBUS-TBNA needle was used in 47 selected patients with enlarged hilar and/or mediastinal lymphadenopathy at 3 centers. The standard Olympus EBUS scope with a 2.2-mm working channel was used in all cases. RESULTS: The diagnostic yield of the Flex 19G needle according to clinical cytopathology reports was 89% (42/47). The diagnosis and their respective diagnostic yield with the Flex 19G EBUS-TBNA needle were malignancy 24/27 (89%), sarcoidosis 13/14 (93%), and reactive lymph node hyperplasia 5/6 (83%). The mean short axis of the sampled lymph nodes was 19 ± 9 mm. No complications occurred except for 1 instance of moderate bleeding, which did not require intervention beyond suctioning and subsequently resolved. All 13 patients diagnosed with adenocarcinoma by the 19-G needle had sufficient tissue for genetic testing. CONCLUSION: EBUS-TBNA using the first-generation Flex 19G needle is feasible and safe with promising diagnostic yield while providing a greater degree of flexion with the Olympus EBUS scope. Additional clinical evaluations are warranted.

Macrophage migration inhibitory factor promotes clearance of pneumococcal colonization.

Human genetic polymorphisms associated with decreased expression of macrophage migration inhibitory factor (MIF) have been linked to the risk of community-acquired pneumonia. Because Streptococcus pneumoniae is the leading cause of community-acquired pneumonia and nasal carriage is a precursor to invasive disease, we explored the role of MIF in the clearance of pneumococcal colonization in a mouse model. MIF-deficient mice (Mif(-/-)) showed prolonged colonization with both avirulent (23F) and virulent (6A) pneumococcal serotypes compared with wild-type animals. Pneumococcal carriage led to both local upregulation of MIF expression and systemic increase of the cytokine. Delayed clearance in the Mif(-/-) mice was correlated with reduced numbers of macrophages in upper respiratory tract lavages as well as impaired upregulation of MCP-1/CCL2. We found that primary human monocyte-derived macrophages as well as THP-1 macrophages produced MIF upon pneumococcal infection in a pneumolysin-dependent manner. Pneumolysin-induced MIF production required its pore-forming activity and phosphorylation of p38-MAPK in macrophages, with sustained p38-MAPK phosphorylation abrogated in the setting of MIF deficiency. Challenge with pneumolysin-deficient bacteria demonstrated reduced MIF upregulation, decreased numbers of macrophages in the nasopharynx, and less effective clearance. Mif(-/-) mice also showed reduced Ab response to pneumococcal colonization and impaired ability to clear secondary carriage. Finally, local administration of MIF was able to restore bacterial clearance and macrophage accumulation in Mif(-/-) mice. Our work suggests that MIF is important for innate and adaptive immunity to pneumococcal colonization and could be a contributing factor in genetic differences in pneumococcal disease susceptibility.

Macrophage Migration Inhibitory Factor Is Detrimental in Pneumococcal Pneumonia and a Target for Therapeutic Immunomodulation.

Mortality from pneumococcal pneumonia remains high despite antibiotic therapy, highlighting the pathogenic potential for host inflammation. We demonstrate that macrophage migration inhibitory factor (MIF), an innate immune mediator, is detrimental for survival and associated with lung pathology, inflammatory cellular infiltration, and bacterial replication in a mouse model of pneumococcal pneumonia, despite being necessary for clearance from the nasopharynx. Treatment of animals with a small-molecule inhibitor of MIF improves survival by reducing inflammation and improving bacterial control. Our work demonstrates that MIF modulates beneficial versus detrimental inflammatory responses in the host-pneumococcal interaction and is a potential target for therapeutic modulation.

Endobronchial ultrasound learning curve in interventional pulmonary fellows.

BACKGROUND AND OBJECTIVE: Little published data exist regarding the learning curve for endobronchial ultrasound-transbronchial needle aspiration (EBUS-TBNA). We sought to assess the improvement in skill as trainees learned EBUS-TBNA in a clinical setting. METHODS: This is a multicentre cohort study of EBUS-TBNA technical skill of interventional pulmonology (IP) fellows as assessed with EBUS-TBNA computer simulator testing every 25 clinical cases throughout IP fellowship training. RESULTS: Nine fellows from three academic centres in the United States and Canada were enrolled in the study. Ongoing improvements were seen for EBUS-TBNA efficiency score and percentage of lymph nodes correctly identified on ultrasound exam, even after 200 clinical cases. Expert-level technical skill was obtained for EBUS efficiency score and for percentage of lymph nodes correctly identified on ultrasound exam at a median of 212 and 164 procedures, respectively; however, 33% of fellows did not achieve expert-level technical skill for either metric during their fellowship training. Significant variation in learning curves of the fellows was observed. CONCLUSIONS: Significant variation is seen in the EBUS-TBNA learning curves of individual IP fellows and for individual procedure components, with ongoing improvement in EBUS-TBNA skill even after 200 clinical cases. These results highlight the need for validated, objective measures of individual competence, and can assist training programmes in ensuring adequate procedure volumes required for a majority of trainees to successfully complete these assessments.

Subunit-specific analysis of cohesin-mutant myeloid malignancies reveals distinct ontogeny and outcomes.

Mutations in the cohesin complex components (STAG2, RAD21, SMC1A, SMC3, and PDS5B) are recurrent genetic drivers in myelodysplastic neoplasm (MDS) and acute myeloid leukemia (AML). Whether the different cohesin subunit mutations share clinical characteristics and prognostic significance is not known. We analyzed 790 cohesin-mutant patients from the Dana-Farber Cancer Institute (DFCI) and the Munich Leukemia Laboratory (MLL), 390 of which had available outcome data, and identified subunit-specific clinical, prognostic, and genetic characteristics suggestive of distinct ontogenies. We found that STAG2 mutations are acquired at MDS stage and are associated with secondary AML, adverse prognosis, and co-occurrence of secondary AML-type mutations. In contrast, mutations in RAD21, SMC1A and SMC3 share features with de novo AML with better prognosis, and co-occurrence with de novo AML-type lesions. The findings show the heterogeneous nature of cohesin complex mutations, and inform clinical and prognostic classification, as well as distinct biology of the cohesin complex.

Sustained Clinical Benefits of Spiration Valve System in Patients with Severe Emphysema: 24-Month Follow-Up of EMPROVE.

Rationale: Follow-up of patients with emphysema treated with endobronchial valves is limited to 3-12 months after treatment in prior reports. To date, no comparative data exist between treatment and control subjects with a longer follow-up. Objectives: To assess the durability of the Spiration Valve System (SVS) in patients with severe heterogeneous emphysema over a 24-month period. Methods: EMPROVE, a multicenter randomized controlled trial, presents a rigorous comparison between treatment and control groups for up to 24 months. Lung function, respiratory symptoms, and quality-of-life (QOL) measures were assessed. Results: A significant improvement in forced expiratory volume in 1 second was maintained at 24 months in the SVS treatment group versus the control group. Similarly, significant improvements were maintained in several QOL measures, including the St. George's Respiratory Questionnaire and the COPD Assessment Test. Patients in the SVS treatment group experienced significantly less dyspnea than those in the control group, as indicated by the modified Medical Research Council dyspnea scale score. Adverse events at 24 months did not significantly differ between the SVS treatment and control groups. Acute chronic obstructive pulmonary disease exacerbation rates in the SVS treatment and control groups were 13.7% (14 of 102) and 15.6% (7 of 45), respectively. Pneumothorax rates in the SVS treatment and control groups were 1.0% (1 of 102) and 0.0% (0 of 45), respectively. Conclusions: SVS treatment resulted in statistically significant and clinically meaningful durable improvements in lung function, respiratory symptoms, and QOL, as well as a statistically significant reduction in dyspnea, for at least 24 months while maintaining an acceptable safety profile. Clinical trial registered with www.clinicaltrials.gov (NCT01812447).