Bronchoscopic Lung Volume Reduction: A Review.

Bronchoscopic lung volume reduction (BLVR) is an established treatment modality for the management of advanced chronic obstructive pulmonary disease complicated by severe emphysema and hyperinflation refractory to other therapies. BLVR aims to reduce hyperinflation and residual volume, thereby improving pulmonary function, symptom control, and quality of life. Multiple distinct devices and technologies, including endobronchial coils, thermal vapor ablation, bio-lung volume reduction, and airway bypass stenting, have been developed to achieve lung volume reduction with varying degrees of accessibility and evidence. The most promising BLVR treatment modality to date has been the placement of one-way endobronchial valves (EBVs), with more than 25,000 cases performed worldwide. Identifying symptomatic patients who would benefit from BLVR is challenging and can be time and resource intensive, and candidacy may be limited by physiologic parameters. Additional new technologies may be able to improve the identification and evaluation of candidates as well as increase the portion of evaluated patients who ultimately qualify for BLVR. In this review, we aim to provide historical context to BLVR, summarize the available evidence regarding its use, discuss potential complications, and provide readers with a clear guide to patient selection and referral for BLVR, with a focus on EBV placement. In addition, we will highlight potential future directions for the field.

Depletion of the chromatin remodeler CHD4 sensitizes AML blasts to genotoxic agents and reduces tumor formation.

Chromodomain helicase DNA-binding protein 4 (CHD4) is an ATPase that alters the phasing of nucleosomes on DNA and has recently been implicated in DNA double-stranded break (DSB) repair. Here, we show that depletion of CHD4 in acute myeloid leukemia (AML) blasts induces a global relaxation of chromatin that renders cells more susceptible to DSB formation, while concurrently impeding their repair. Furthermore, CHD4 depletion renders AML blasts more sensitive both in vitro and in vivo to genotoxic agents used in clinical therapy: daunorubicin (DNR) and cytarabine (ara-C). Sensitization to DNR and ara-C is mediated in part by activation of the ataxia-telangiectasia mutated pathway, which is preliminarily activated by a Tip60-dependent mechanism in response to chromatin relaxation and further activated by genotoxic agent-induced DSBs. This sensitization preferentially affects AML cells, as CHD4 depletion in normal CD34(+) hematopoietic progenitors does not increase their susceptibility to DNR or ara-C. Unexpectedly, we found that CHD4 is necessary for maintaining the tumor-forming behavior of AML cells, as CHD4 depletion severely restricted the ability of AML cells to form xenografts in mice and colonies in soft agar. Taken together, these results provide evidence for CHD4 as a novel therapeutic target whose inhibition has the potential to enhance the effectiveness of genotoxic agents used in AML therapy.

Monosomy 7/del (7q) in inherited bone marrow failure syndromes: A systematic review.

Inherited bone marrow failure syndromes (IBMFS) are rare cancer predisposition syndromes with an especially high risk of transformation to myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML). We performed a retrospective systematic review of reported MDS/AML arising in the eight most common IBMFS to determine the frequency and outcome of chromosome 7 abnormalities. We identified 738 MDS/AML cases of 4,293 individuals. Monosomy 7 or del (7q) occurred in ∼17%. Greater understanding of the roles played by sequential acquisition of genetic and cytogenetic changes will provide insights into myeloid leukemogenesis and improve the surveillance and hopefully outcomes for individuals with IBMFS.

Cystic fibrosis-related mortality in the United States from 1999 to 2020: an observational analysis of time trends and disparities.

Cystic fibrosis transmembrane conductance regulator modulators have revolutionized cystic fibrosis (CF) care in the past decade. This study explores the CF-related mortality trends in the US from 1999 to 2020. We extracted CF-related mortality data from the CDC WONDER database. CF age-standardized mortality rates (ASMRs) were identified by ICD-10 code E84 and were stratified by demographic and geographical variables. Temporal trends were analyzed using Joinpoint modeling. CF-related ASMRs decreased from 1.9 to 1.04 per million population (p = 0.013), with a greater reduction in recent years. This trend was replicated in both sexes. The median age of death increased from 24 to 37 years. CF mortality rates decreased across sex, white race, non-Hispanic ethnicity, census regions, and urbanization status. Incongruent trends were reported in non-white races and Hispanic ethnicity. A lower median age of death was observed in women, non-white races, and Hispanic ethnicity. SARS-CoV-2 infection was the primary cause of death in 1.7% of CF decedents in 2020. The national CF-related mortality rates declined and the median age of death among CF decedents increased significantly indicating better survival in the recent years. The changes were relatively slow during the earlier period of the study, followed by a greater decline lately. We observed patterns of sex, ethnic, racial, and geographical disparities associated with the worsening of the gap between ethnicities, narrowing of the gap between races and rural vs. urban counties, and closing of the gap between sexes over the study period.

Efficacy and Safety of Cone-Beam CT Augmented Electromagnetic Navigation Guided Bronchoscopic Biopsies of Indeterminate Pulmonary Nodules.

Bronchoscopic biopsy results for indeterminate pulmonary nodules remain suboptimal. Electromagnetic navigation bronchoscopy (ENB) coupled with cone beam computed tomography (CBCT) for confirmation has the potential to improve diagnostic yield. We present our experience using this multimodal approach to biopsy 17 indeterminate nodules in 14 consecutive patients from April to August 2021. Demographic information, nodule characteristics, and biopsy results were recorded. Procedures were performed in a hybrid operating room equipped with a Siemens Artis Q bi-plane CBCT (Siemens, Munich, Germany). After ENB using the superDimension version 7.1 (Medtronic, Plymouth, MN, USA) to target the lesion, radial endobronchial ultrasound was used as secondary confirmation. Next, transbronchial needle aspiration was performed prior to CBCT to evaluate placement of the biopsy tool in the lesion. The average nodule size was 21.7+/−15 mm with 59% (10/17) < 2 cm in all dimensions and 35% (6/17) showing a radiographic bronchus sign. The diagnostic yield of CBCT-guided ENB was 76% (13/17). No immediate periprocedural or postprocedural complications were identified. Our experience with CBCT-guided ENB further supports the comparable efficacy and safety of this procedure compared to other mature biopsy modalities. Studies designed to optimize the lung nodule biopsy process and to determine the contributions from different procedural aspects are warranted.

Spontaneous pneumothorax: An emerging complication of COVID-19 pneumonia.

Spontaneous Pneumothorax in the setting of coronavirus disease 19 (COVID-19) has been rarely described and is a potentially lethal complication. We report our institutional experience. Patients with confirmed COVID-19 who were admitted at 5 hospitals within the Inova health system between February 21 and May 2020 were included in the study. We identified 1619 patients, 22 patients (1.4%) developed spontaneous pneumothorax during their hospitalization without evidence of traumatic injury.

A case of extrapulmonary tuberculosis in a patient with end-stage renal disease with elevated parathyroid hormone-related protein.

The diagnosis of extrapulmonary tuberculosis in patients with end-stage renal disease can be challenging as the signs and symptoms are often non-specific. In this study, we present a case of extrapulmonary tuberculosis in an Ethiopian woman with end-stage renal disease who had subcarinal and right hilar lymphadenopathy, moderate sized right pleural effusion, hypercalcemia, and elevated parathyroid hormone-related protein in the setting of an elevated 1,25-dihydroxyvitamin D. After being started on appropriate tuberculosis treatment, patient's parathyroid hormone-related protein level decreased and calcium level normalized. Our literature review showed that the elevation of parathyroid hormone-related protein in extrapulmonary tuberculosis has not been well studied, and it is our aim to explore the role of parathyroid hormone-related protein in extrapulmonary tuberculosis.

The clinical spectrum of myocardial injury associated with COVID-19 infection.

Although respiratory symptoms are the dominant features of COVID-19 infection, myocardial injury has been described in these patients. Reported cardiac manifestations of COVID-19 infection include myocarditis, arrhythmia and acute coronary syndrome including ST elevation myocardial infarction (STEMI). STEMI is a medical emergency and timely intervention is of utmost importance to prevent mortality and long-term morbidities. In this report, we present a wide spectrum of clinical presentations, management, and outcomes for five patients with COVID-19 infection and ST elevation on ECG.

Coordination of Myeloid Differentiation with Reduced Cell Cycle Progression by PU.1 Induction of MicroRNAs Targeting Cell Cycle Regulators and Lipid Anabolism.

During macrophage development, myeloid progenitor cells undergo terminal differentiation coordinated with reduced cell cycle progression. Differentiation of macrophages from myeloid progenitors is accompanied by increased expression of the E26 transformation-specific transcription factor PU.1. Reduced PU.1 expression leads to increased proliferation and impaired differentiation of myeloid progenitor cells. It is not understood how PU.1 coordinates macrophage differentiation with reduced cell cycle progression. In this study, we utilized cultured PU.1-inducible myeloid cells to perform genome-wide chromatin immunoprecipitation sequencing (ChIP-seq) analysis coupled with gene expression analysis to determine targets of PU.1 that may be involved in regulating cell cycle progression. We found that genes encoding cell cycle regulators and enzymes involved in lipid anabolism were directly and inducibly bound by PU.1 although their steady-state mRNA transcript levels were reduced. Inhibition of lipid anabolism was sufficient to reduce cell cycle progression in these cells. Induction of PU.1 reduced expression of E2f1, an important activator of genes involved in cell cycle and lipid anabolism, indirectly through microRNA 223. Next-generation sequencing identified microRNAs validated as targeting cell cycle and lipid anabolism for downregulation. These results suggest that PU.1 coordinates cell cycle progression with differentiation through induction of microRNAs targeting cell cycle regulators and lipid anabolism.

PU.1 promotes cell cycle exit in the murine myeloid lineage associated with downregulation of E2F1.

Acute myeloid leukemia (AML) is characterized by increased proliferation and reduced differentiation of myeloid lineage cells. AML is frequently associated with mutations or chromosomal rearrangements involving transcription factors. PU.1 (encoded by Sfpi1) is an E26 transformation-specific family transcription factor that is required for myeloid differentiation. Reduced PU.1 levels, caused by either mutation or repression, are associated with human AML and are sufficient to cause AML in mice. The objective of this study was to determine whether reduced PU.1 expression induces deregulation of the cell cycle in the myeloid lineage. Our results showed that immature myeloid cells expressing reduced PU.1 levels (Sfpi1(BN/BN) myeloid cells) proliferated indefinitely in cell culture and expanded in vivo. Transplantation of Sfpi1(BN/BN) cells induced AML in recipient mice. Cultured Sfpi1(BN/BN) cells expressed elevated messenger RNA transcript and protein levels of E2F1, an important regulator of cell cycle entry. Restoration of PU.1 expression in Sfpi1(BN/BN) myeloid cells blocked proliferation, induced differentiation, and reduced E2F1 expression. Taken together, these data show that PU.1 controls cell cycle exit in the myeloid lineage associated with downregulation of E2F1 expression.