Cavitary Hodgkin Lymphoma of the Lung.

It has been shown that some cases of Hodgkin lymphoma (HL) may present with pulmonary parenchymal involvement usually in the form of multiple irregularly marginated pulmonary nodules. Other radiographic patterns such as consolidation, interstitial infiltrates, and cavitary lesions are less common. We present a case of HL, nodular sclerosis type, with pulmonary involvement presenting as a large cavitary consolidation and axillary and mediastinal lymphadenopathy. Initial diagnostic work-up including sputum culture, bronchoscopy, and a fine needle aspiration of lymph node was not conclusive favoring a reactive process with a presumptive diagnosis of cavitary pneumonia. A follow-up chest imaging revealed worsening right upper lung mass, axillary adenopathy, and new nodular satellite lesions, and a repeat bronchoscopy with multiple biopsies remained non-diagnostic requiring an excisional biopsy of the axillary lymph node confirming HL. Further transthoracic core biopsies of the cavitary lung lesion were consistent with pulmonary lymphoma involvement.

Evaluation and management of pleural sepsis.

Pleural sepsis stems from an infection within the pleural space typically from an underlying bacterial pneumonia leading to development of a parapneumonic effusion. This effusion is traditionally divided into uncomplicated, complicated, and empyema. Poor clinical outcomes and increased mortality can be associated with the development of parapneumonic effusions, reinforcing the importance of early recognition and diagnosis. Management necessitates a multimodal therapeutic strategy consisting of antimicrobials, catheter/tube thoracostomy, and at times, video-assisted thoracoscopic surgery.

Introduction of an academic medical center's point-of-care ultrasound curriculum to internal medicine residents at a community-based teaching hospital.

BACKGROUND: Despite its proven utility, integration of point-of-care ultrasound (POCUS) into internal medicine (IM) residency training has been inconsistent. Due to their unique constraints, community-based teaching hospitals may face particular challenges in providing POCUS training to IM residents. OBJECTIVES: To evaluate short-term educational outcomes of an academic center's POCUS curriculum following its adaptation and delivery to IM residents at a community-based teaching hospital. METHODS: A needs assessment (NA) regarding POCUS training was distributed to PGY-2 and PGY-3 IM residents at a community-based teaching hospital in 2017. Based on the NA results, a POCUS curriculum from an academic center was modified and a revised course was offered to the same residents. Participants completed cognitive assessments before and after three of the four didactic sessions. Observed placement of an ultrasound-guided peripheral IV before and after the training program comprised the skills assessment. RESULTS: 17 of 28 (61%) residents completed the NA; eleven participated in the course. Of 33 possible quiz pairs, 15 (45%) were completed. Average quiz scores rose after the first and third sessions. Skills assessment scores increased after course completion. CONCLUSION: Adaptation of POCUS curricula from academic centers may be a feasible instructional strategy for community-based IM residency programs.

Optimizing B-lines on lung ultrasound: an in-vitro to in-vivo pilot study with clinical implications.

B-lines on lung ultrasound (US) are the hallmark of pulmonary edema. It is unknown if ultrasound machine settings or probe type matter. We created an in-vitro gelatin model. Using lung presets as baseline, five blinded investigators assessed the impact of 32 distinct settings on B-line visibility based on a Likert-Scale (LS) from 0 to10 (< 5 worse, > 5 better) separately for two probes. The experiment was then repeated in-vivo in a patient with known pulmonary edema. Based on a multivariable regression LS-ratings were similar when comparing the in-vitro versus in-vivo experiment (P = 0.16; partial R2 = 0.2%) and when using the curvilinear versus linear probe (P = 0.69; partial R2 = 0.02%) but significantly different across machine settings (P < 0.0001; partial R2 = 34.4%). Limited by its pilot character, our study suggests that (1) certain US-machine settings heavily impact B-line visibility, with no clear difference between probes; (2) in-vitro models are a valid and practical alternative to more challenging patient-based research; (3) there is significant potential to improve B-line visibility and thus diagnostic yield in the clinical setting by using lung presets, centering the focal zone at the pleural line and increasing the distal time gain compensation, most of which are (in our experience) rarely done.

A road map for point-of-care ultrasound training in internal medicine residency.

BACKGROUND: Ever-expanding uses have been developed for ultrasound, including its focused use at the bedside, often referred to as point-of-care ultrasound (POCUS). POCUS has been well developed and integrated into training in numerous fields, but remains relatively undefined in internal medicine training. This training has been shown to be desirable to both educators and trainees, but has proven difficult to implement. We sought to create a road map for internal medicine residency programs looking to create a POCUS program. RESULTS: Four internal medicine residency programs that have successfully integrated POCUS training describe their programs, as well as the principles and concepts underlying program development and execution. Review of educational teaching and assessment methods is outlined, as well as suggestions for integration into an already busy residency curriculum. Commonly reported barriers to POCUS implementation such as faculty development, equipment purchasing, resident supervision and quality assurance are addressed. Specific POCUS applications to target are touched upon, and a comparison of applications taught within these four programs suggest that there may be enough similarities to suggest a common curriculum. Finally, future needs are discussed. CONCLUSIONS: POCUS can be successfully taught to internal medicine residents as a part of internal medicine training. Many common elements and principles are evident on review of these four described successful programs. Future support, in the form of endorsed medical society guidelines, will be needed before POCUS is universally incorporated across internal medicine residency training programs.

Medical management of drug-sensitive active thoracic tuberculosis: the work-up, radiographic findings and treatment.

Tuberculosis (TB) infection and disease have plagued human civilization across time and led to immeasurable morbidity and mortality. This review article focuses on the most currently available information regarding the diagnostic workup, radiologic presentation and treatment of drug-sensitive active TB. As discussed, if adequate resources and methods are available to diagnose, evaluate, and treat patients, drug sensitive TB is an imminently curable disease.

MicroRNA 4423 is a primate-specific regulator of airway epithelial cell differentiation and lung carcinogenesis.

Smoking is a significant risk factor for lung cancer, the leading cause of cancer-related deaths worldwide. Although microRNAs are regulators of many airway gene-expression changes induced by smoking, their role in modulating changes associated with lung cancer in these cells remains unknown. Here, we use next-generation sequencing of small RNAs in the airway to identify microRNA 4423 (miR-4423) as a primate-specific microRNA associated with lung cancer and expressed primarily in mucociliary epithelium. The endogenous expression of miR-4423 increases as bronchial epithelial cells undergo differentiation into mucociliary epithelium in vitro, and its overexpression during this process causes an increase in the number of ciliated cells. Furthermore, expression of miR-4423 is reduced in most lung tumors and in cytologically normal epithelium of the mainstem bronchus of smokers with lung cancer. In addition, ectopic expression of miR-4423 in a subset of lung cancer cell lines reduces their anchorage-independent growth and significantly decreases the size of the tumors formed in a mouse xenograft model. Consistent with these phenotypes, overexpression of miR-4423 induces a differentiated-like pattern of airway epithelium gene expression and reverses the expression of many genes that are altered in lung cancer. Together, our results indicate that miR-4423 is a regulator of airway epithelium differentiation and that the abrogation of its function contributes to lung carcinogenesis.

Serotonin syndrome associated with clozapine withdrawal.

IMPORTANCE: We describe a case of serotonin syndrome secondary to clozapine withdrawal and concomitant use of citalopram hydrobromide, a phenomenon that has been rarely reported. OBSERVATIONS: This is a case report of a 47-year-old woman admitted to an academic medical center intensive care unit with coma, hypersalivation, hyperreflexia, and stimulus-induced clonus. The patient received a diagnosis of serotonin syndrome attributed to abrupt clozapine withdrawal with concomitant use of citalopram. She improved only minimally with supportive treatment (intravenous fluids, benzodiazapines, and withdrawal of selective serotonin-reuptake inhibitor) and received cyproheptadine hydrochloride on her third day of symptoms. Four hours after she received the loading dose of cyproheptadine, she was alert and oriented and at her baseline mental status, although some clonus remained. CONCLUSIONS AND RELEVANCE: Serotonin syndrome can result from the abrupt withdrawal of a 5-hydroxytryptamine receptor 2A antagonist from a treatment regimen that also includes a medication that increases serotonin availability.

Characterizing the impact of smoking and lung cancer on the airway transcriptome using RNA-Seq.

Cigarette smoke creates a molecular field of injury in epithelial cells that line the respiratory tract. We hypothesized that transcriptome sequencing (RNA-Seq) will enhance our understanding of the field of molecular injury in response to tobacco smoke exposure and lung cancer pathogenesis by identifying gene expression differences not interrogated or accurately measured by microarrays. We sequenced the high-molecular-weight fraction of total RNA (>200 nt) from pooled bronchial airway epithelial cell brushings (n = 3 patients per pool) obtained during bronchoscopy from healthy never smoker (NS) and current smoker (S) volunteers and smokers with (C) and without (NC) lung cancer undergoing lung nodule resection surgery. RNA-Seq libraries were prepared using 2 distinct approaches, one capable of capturing non-polyadenylated RNA (the prototype NuGEN Ovation RNA-Seq protocol) and the other designed to measure only polyadenylated RNA (the standard Illumina mRNA-Seq protocol) followed by sequencing generating approximately 29 million 36 nt reads per pool and approximately 22 million 75 nt paired-end reads per pool, respectively. The NuGEN protocol captured additional transcripts not detected by the Illumina protocol at the expense of reduced coverage of polyadenylated transcripts, while longer read lengths and a paired-end sequencing strategy significantly improved the number of reads that could be aligned to the genome. The aligned reads derived from the two complementary protocols were used to define the compendium of genes expressed in the airway epithelium (n = 20,573 genes). Pathways related to the metabolism of xenobiotics by cytochrome P450, retinol metabolism, and oxidoreductase activity were enriched among genes differentially expressed in smokers, whereas chemokine signaling pathways, cytokine-cytokine receptor interactions, and cell adhesion molecules were enriched among genes differentially expressed in smokers with lung cancer. There was a significant correlation between the RNA-Seq gene expression data and Affymetrix microarray data generated from the same samples (P < 0.001); however, the RNA-Seq data detected additional smoking- and cancer-related transcripts whose expression was were either not interrogated by or was not found to be significantly altered when using microarrays, including smoking-related changes in the inflammatory genes S100A8 and S100A9 and cancer-related changes in MUC5AC and secretoglobin (SCGB3A1). Quantitative real-time PCR confirmed differential expression of select genes and non-coding RNAs within individual samples. These results demonstrate that transcriptome sequencing has the potential to provide new insights into the biology of the airway field of injury associated with smoking and lung cancer. The measurement of both coding and non-coding transcripts by RNA-Seq has the potential to help elucidate mechanisms of response to tobacco smoke and to identify additional biomarkers of lung cancer risk and novel targets for chemoprevention.

MiRNAs as regulators of the response to inhaled environmental toxins and airway carcinogenesis.

miRNAs are a class of small, noncoding RNAs averaging 22 nucleotides in length that down-regulate gene expression by complimentary binding to the 3' UTR of target genes. A growing body of research suggests that these small RNA species play significant roles in modulating the cellular response to a variety of types of stress. In this review, we summarize the available literature regarding the general response of miRNA to cellular stress, and then specifically focus on the miRNA response to inhaled toxins. These miRNA responses to inhaled toxins appear to be recapitulated in lung carcinogenesis, opening the possibility that modulation of the miRNA response could be a novel strategy for chemoprevention.

Similarities and differences between smoking-related gene expression in nasal and bronchial epithelium.

Previous studies have shown that physiological responses to cigarette smoke can be detected via bronchial airway epithelium gene expression profiling and that heterogeneity in this gene expression response to smoking is associated with lung cancer. In this study, we sought to determine the similarity of the effects of tobacco smoke throughout the respiratory tract by determining patterns of smoking-related gene expression in paired nasal and bronchial epithelial brushings collected from 14 healthy nonsmokers and 13 healthy current smokers. Using whole genome expression arrays, we identified 119 genes whose expression was affected by smoking similarly in both bronchial and nasal epithelium, including genes related to detoxification, oxidative stress, and wound healing. While the vast majority of smoking-related gene expression changes occur in both bronchial and nasal epithelium, we also identified 27 genes whose expression was affected by smoking more dramatically in bronchial epithelium than nasal epithelium. Both common and site-specific smoking-related gene expression profiles were validated using independent microarray datasets. Differential expression of select genes was also confirmed by RT-PCR. That smoking induces largely similar gene expression changes in both nasal and bronchial epithelium suggests that the consequences of cigarette smoke exposure can be measured in tissues throughout the respiratory tract. Our findings suggest that nasal epithelial gene expression may serve as a relatively noninvasive surrogate to measure physiological responses to cigarette smoke and/or other inhaled exposures in large-scale epidemiological studies.

MicroRNAs as modulators of smoking-induced gene expression changes in human airway epithelium.

We have shown that smoking impacts bronchial airway gene expression and that heterogeneity in this response associates with smoking-related disease risk. In this study, we sought to determine whether microRNAs (miRNAs) play a role in regulating the airway gene expression response to smoking. We examined whole-genome miRNA and mRNA expression in bronchial airway epithelium from current and never smokers (n = 20) and found 28 miRNAs to be differentially expressed (P < 0.05) with the majority being down-regulated in smokers. We further identified a number of mRNAs whose expression level is highly inversely correlated with miRNA expression in vivo. Many of these mRNAs contain potential binding sites for the differentially expressed miRNAs in their 3'-untranslated region (UTR) and are themselves affected by smoking. We found that either increasing or decreasing the levels of mir-218 (a miRNA that is strongly affected by smoking) in both primary bronchial epithelial cells and H1299 cells was sufficient to cause a corresponding decrease or increase in the expression of predicted mir-218 mRNA targets, respectively. Further, mir-218 expression is reduced in primary bronchial epithelium exposed to cigarette smoke condensate (CSC), and alteration of mir-218 levels in these cells diminishes the induction of the predicted mir-218 target MAFG in response to CSC. These data indicate that mir-218 levels modulate the airway epithelial gene expression response to cigarette smoke and support a role for miRNAs in regulating host response to environmental toxins.

Smoking-induced gene expression changes in the bronchial airway are reflected in nasal and buccal epithelium.

BACKGROUND: Cigarette smoking is a leading cause of preventable death and a significant cause of lung cancer and chronic obstructive pulmonary disease. Prior studies have demonstrated that smoking creates a field of molecular injury throughout the airway epithelium exposed to cigarette smoke. We have previously characterized gene expression in the bronchial epithelium of never smokers and identified the gene expression changes that occur in the mainstem bronchus in response to smoking. In this study, we explored relationships in whole-genome gene expression between extrathorcic (buccal and nasal) and intrathoracic (bronchial) epithelium in healthy current and never smokers. RESULTS: Using genes that have been previously defined as being expressed in the bronchial airway of never smokers (the "normal airway transcriptome"), we found that bronchial and nasal epithelium from non-smokers were most similar in gene expression when compared to other epithelial and nonepithelial tissues, with several antioxidant, detoxification, and structural genes being highly expressed in both the bronchus and nose. Principle component analysis of previously defined smoking-induced genes from the bronchus suggested that smoking had a similar effect on gene expression in nasal epithelium. Gene set enrichment analysis demonstrated that this set of genes was also highly enriched among the genes most altered by smoking in both nasal and buccal epithelial samples. The expression of several detoxification genes was commonly altered by smoking in all three respiratory epithelial tissues, suggesting a common airway-wide response to tobacco exposure. CONCLUSION: Our findings support a relationship between gene expression in extra- and intrathoracic airway epithelial cells and extend the concept of a smoking-induced field of injury to epithelial cells that line the mouth and nose. This relationship could potentially be utilized to develop a non-invasive biomarker for tobacco exposure as well as a non-invasive screening or diagnostic tool providing information about individual susceptibility to smoking-induced lung diseases.

Airway epithelial gene expression in the diagnostic evaluation of smokers with suspect lung cancer.

Lung cancer is the leading cause of death from cancer in the US and the world. The high mortality rate (80-85% within 5 years) results, in part, from a lack of effective tools to diagnose the disease at an early stage. Given that cigarette smoke creates a field of injury throughout the airway, we sought to determine if gene expression in histologically normal large-airway epithelial cells obtained at bronchoscopy from smokers with suspicion of lung cancer could be used as a lung cancer biomarker. Using a training set (n = 77) and gene-expression profiles from Affymetrix HG-U133A microarrays, we identified an 80-gene biomarker that distinguishes smokers with and without lung cancer. We tested the biomarker on an independent test set (n = 52), with an accuracy of 83% (80% sensitive, 84% specific), and on an additional validation set independently obtained from five medical centers (n = 35). Our biomarker had approximately 90% sensitivity for stage 1 cancer across all subjects. Combining cytopathology of lower airway cells obtained at bronchoscopy with the biomarker yielded 95% sensitivity and a 95% negative predictive value. These findings indicate that gene expression in cytologically normal large-airway epithelial cells can serve as a lung cancer biomarker, potentially owing to a cancer-specific airway-wide response to cigarette smoke.

Effects of cigarette smoke on the human airway epithelial cell transcriptome.

Cigarette smoke is the major cause of lung cancer, the leading cause of cancer death, and of chronic obstructive pulmonary disease, the fourth leading cause of death in the United States. Using high-density gene expression arrays, we describe genes that are normally expressed in a subset of human airway epithelial cells obtained at bronchoscopy (the airway transcriptome), define how cigarette smoking alters the transcriptome, and detail the effects of variables, such as cumulative exposure, age, sex, and race, on cigarette smoke-induced changes in gene expression. We also determine which changes in gene expression are and are not reversible when smoking is discontinued. The persistent altered expression of a subset of genes in former smokers may explain the risk these individuals have for developing lung cancer long after they have discontinued smoking. The use of gene expression profiling to explore the normal biology of a specific subset of cells within a complex organ across a broad spectrum of healthy individuals and to define the reversible and irreversible genetic effects of cigarette smoke on human airway epithelial cells has not been previously reported.