Psoralen: a narrative review of current and future therapeutic uses.

Psoralen is a family of naturally occurring photoactive compounds found in plants that acquire potential cytotoxicity when activated by specific frequencies of electromagnetic waves. Psoralens penetrate the phospholipid cellular membranes and insert themselves between the pyrimidines of deoxyribonucleic acid (DNA). Psoralens are initially biologically inert and acquire photoreactivity when exposed to certain classes of electromagnetic radiation, such as ultraviolet light. Once activated, psoralens form mono- and di-adducts with DNA, leading to marked cell apoptosis. This apoptotic effect is more pronounced in tumor cells due to their high rate of cell division. Moreover, photoactivated psoralen can inhibit tyrosine kinase signaling and influence the immunogenic properties of cells. Thus, the cytotoxicity of photoactivated psoralen holds promising clinical applications from its immunogenic properties to potential anti-cancer treatments. This narrative review aims to provide an overview of the current understanding and research on psoralen and to explore its potential future pharmacotherapeutic benefits in specific diseases.

Pretreatment Lung Function and Checkpoint Inhibitor Pneumonitis in NSCLC.

INTRODUCTION: Checkpoint inhibitor pneumonitis (CIP) is a serious toxicity of anti-programmed death-(ligand) 1 immunotherapy. Whether pretreatment differences in pulmonary function exist in patients who develop CIP is unknown. We analyzed the pulmonary function tests (PFTs) of patients with NSCLC treated with immune checkpoint inhibitors (ICIs) to evaluate whether pretreatment lung function was associated with CIP development. METHODS: Patients were included if they completed greater than or equal to 1 PFT within 2 years preceding ICI initiation. CIP status (CIP+: developed CIP, CIP-: did not develop CIP) was determined clinically. Generalized estimating equation-based linear regression was used to evaluate the effects of time and CIP on lung function. Primary outcomes included the following: percent-predicted forced expiratory volume in 1 second (FEV1pp), percent-predicted forced vital capacity (FVCpp), and FEV1/FVC. RESULTS: A total of 43 patients (34 CIP-, 9 CIP+) with 79 PFTs (59 CIP-, 20 CIP+) were included. CIP+ patients had a 21.7% lower pretreatment FEV1pp compared with the CIP- group (95% confidence interval: -38.6 to -4.7). No statistically significant differences in FVCpp or FEV1/FVC were observed. The prevalence of obstructive lung disease was similar in both groups at 67% and 62% for the CIP+ and CIP- cohorts, as was the prevalence of current/former smoking at 100% and 93%, respectively. CONCLUSIONS: Pretherapy differences in lung function were evident between patients who did and did not develop CIP, though the prevalence of obstructive lung disease was similar. Prospective studies are needed to validate these findings, inform potential risk factors for CIP, and investigate the effects of ICI treatment and CIP on pulmonary function in patients with NSCLC.

Sex differences in M2 polarization, chemokine and IL-4 receptors in monocytes and macrophages from asthmatics.

Allergic asthma affects more women than men. It is mediated partially by IL-4/IL-13-driven polarization of monocyte-derived macrophages in the lung. We tested whether sex differences in asthma are due to differential IL-4 responsiveness and/or chemokine receptor expression in monocytes and monocyte-derived macrophages from healthy and allergic asthmatic men and women. We found female cells expressed M2 genes more robustly following IL-4 stimulation than male cells, as did cells from asthmatics than those from healthy controls. This likely resulted from increased expression ofγC, part of the type I IL-4 receptor, and reduced IL-4-induced SOCS1, a negative regulator of IL-4 signaling, in asthmatic compared to healthy macrophages. Monocytes from asthmatic women expressed more CX3CR1, which enhances macrophage survival. Our findings highlight how sex differences in IL-4 responsiveness and chemokine receptor expression may affect monocyte recruitment and macrophage polarization in asthma, potentially leading to new sex-specific therapies to manage the disease.

Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration for PD-L1 Testing in Non-small Cell Lung Cancer.

BACKGROUND: Programmed death-ligand 1 (PD-L1) expression on cancer cells is a clinically important biomarker to select patients with non-small cell lung cancer (NSCLC) for treatment with programmed death-1/PD-L1 inhibitors. Clinical trials of immunotherapy in patients with NSCLC have required histologic evidence for PD-L1 testing; in clinical practice, cytologic samples commonly are acquired in patients with advanced disease. RESEARCH QUESTION: This study aims to investigate whether endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) samples are adequate for PD-L1 testing in NSCLC. STUDY DESIGN AND METHODS: This study investigates the sampling adequacy of EBUS-TBNA for PD-L1 testing when compared with other methods. Furthermore, the relationship between clinicopathologic characteristics and PD-L1 expression in the study population have been examined. Five hundred seventy-seven NSCLC specimens were analyzed from consecutive patients with NSCLC across six centers in the United Kingdom and one center in the United States between January 2015 and December 2016. RESULTS: In the EBUS-TBNA group (189 specimens), the overall percentage of patients with successful PD-L1 testing was 94.7%. There was no significant difference in sampling adequacy with other methods of tissue acquisition. Older patients had higher failure rates of PD-L1 testing (OR, 1.06; P = .008). In multivariate analysis, advanced N-stage (P = .048) and presence of brain metastasis (P < .001) were associated with high PD-L1 expression. INTERPRETATION: This large multicenter study shows that EBUS-TBNA provides samples adequate for PD-L1 testing and that advanced N stage and the presence of brain metastasis are associated with high PD-L1 expression.

Assessment of Ergonomic Strain and Positioning During Bronchoscopic Procedures: A Feasibility Study.

BACKGROUND: Poor ergonomics place health care workers at risk for work-related overuse injuries. Repetitive and prolonged hand maneuvers, such as those performed during endoscopic procedures, may lead to musculoskeletal complaints and work-related injuries. However, the prevalence of health care-related work injuries among physicians is thought to be underreported and there is a paucity of literature investigating the impact of ergonomic strain on bronchoscopy. We designed a feasibility study to explore the differences in ergonomic strain and muscle activity of bronchoscopists. MATERIALS AND METHODS: A prospective study of bronchoscopic procedures was performed in a simulated environment. Preselected target areas were identified and airway sampling was performed with real-time ergonomic assessment utilizing electromyogram (EMG), grip strength, and musculoskeletal use and motion analysis. RESULTS: Procedural data was obtained for all procedures (78 bronchoscopies by 13 subjects) for both ergonomic and EMG scores. Experienced bronchoscopists demonstrated less EMG burden (P=0.007) and improved ergonomic positioning (P=0.007) during bronchoscopy when compared with less experienced bronchoscopists. Procedures performed with rotational-head bronchoscopes trended toward improved ergonomics (P=0.15) and lower EMG scores (P=0.88). A significant improvement in ergonomic scores was seen with the rotational-head bronchoscope when targeting the left upper lobe (P=0.036). CONCLUSION: Poor ergonomic positioning and excessive muscle strain appear present within bronchoscopy procedures but may be improved in those with more bronchoscopy experience. Technological advances in bronchoscope design may also have the potential to improve procedural ergonomics. Additional prospective studies are warranted to define the long-term impact on bronchoscopic ergonomics.

First-in-Human Use of a Hybrid Real-Time Ultrasound-Guided Fine-Needle Acquisition System for Peripheral Pulmonary Lesions: A Multicenter Pilot Study.

BACKGROUND: The ability to successfully perform a biopsy on pulmonary lesions by means of bronchoscopy varies widely due to anatomic and technological limitations. One major limitation is the lack of the ability to utilize real-time guidance during tissue sampling in the periphery. A novel system has been developed that enables real-time visualization and sampling of peripheral lesions by displaying an ultrasound image of the lesion and needle simultaneously. METHODS: We performed a multicenter, prospective pilot in patients with peripheral pulmonary lesions undergoing a clinically indicated bronchoscopy. The purpose of this study was to demonstrate the feasibility of visualizing, accessing, and obtaining specimens adequate for the cytology of lung lesions when using a novel hybrid real-time ultrasound-guided fine-needle aspiration system for peripheral pulmonary lesions. RESULTS: Twenty-three patients underwent bronchoscopic sampling of a peripheral pulmonary lesion with the study device. Mean lesion size was 3.6 (range 1.7-5.7) cm. Targeted lesions were located in all lobes of the lung. All lesions were successfully visualized and sampled under real-time visualization with specimens adequate for cytological evaluation. The needle was visualized in all lesions throughout targeting and sampling. There were no incidents of pneumothorax or moderate-to-severe bleeding. CONCLUSION: In this feasibility study, we report the first-in-human use of a continuous real-time endobronchial ultrasound guidance system to sample peripheral pulmonary lesions. Future generations of this device may improve usability and further studies are needed to determine the true diagnostic capabilities of this novel technique.

Surgery for ulcerative colitis in geriatric patients is safe with similar risk to younger patients.

OBJECTIVE: A prior study indicated that postoperative mortality and complications were higher in geriatrics with inflammatory bowel disease (IBD). We sought to assess the rates of surgical complications and mortality in patients aged ≥65 years after colectomy for ulcerative colitis (UC). METHODS: This is a single center retrospective study at a tertiary care center. We reviewed all hospital discharges with ICD-9 code 556.X between January 2002 and January 2014. Patients were included if they underwent a colectomy for UC. All records were manually reviewed for demographics, complications and mortality within 90 days postoperatively. RESULTS: A total of 259 patients underwent surgery for UC during the study period and 34 patients were ≥65 years old (range 65-82) at the time of their surgery. There was no difference in overall length of stay (10.5 days vs. 9.6 days; P = 0.645) or complication rates (44% vs. 47%; P = 0.854) in the ≥65 cohort compared with the under 65 cohort. Mortality was higher in the geriatric cohort but this included only two deaths within 90 days, one of which was unrelated to the surgery, compared with one death related to surgery within 90 days in the younger cohort. Readmissions occurred in 24% of both cohorts within 90 days. CONCLUSION: Geriatric patients undergoing surgery for UC are not at increased risk of surgery-related morbidity or mortality compared with a younger cohort.

The alveolar immune cell landscape is dysregulated in checkpoint inhibitor pneumonitis.

BACKGROUND: Checkpoint inhibitor pneumonitis (CIP) is a highly morbid complication of immune checkpoint immunotherapy (ICI), one which precludes the continuation of ICI. Yet, the mechanistic underpinnings of CIP are unknown. METHODS: To better understand the mechanism of lung injury in CIP, we prospectively collected bronchoalveolar lavage (BAL) samples in ICI-treated patients with (n=12) and without CIP (n=6), prior to initiation of first-line therapy for CIP (high dose corticosteroids. We analyzed BAL immune cell populations using a combination of traditional multicolor flow cytometry gating, unsupervised clustering analysis and BAL supernatant cytokine measurements. RESULTS: We found increased BAL lymphocytosis, predominantly CD4+ T cells, in CIP. Specifically, we observed increased numbers of BAL central memory T-cells (Tcm), evidence of Type I polarization, and decreased expression of CTLA-4 and PD-1 in BAL Tregs, suggesting both activation of pro-inflammatory subsets and an attenuated suppressive phenotype. CIP BAL myeloid immune populations displayed enhanced expression of IL-1ß and decreased expression of counter-regulatory IL-1RA. We observed increased levels of T cell chemoattractants in the BAL supernatant, consistent with our pro-inflammatory, lymphocytic cellular landscape. CONCLUSION: We observe several immune cell subpopulations that are dysregulated in CIP, which may represent possible targets that could lead to therapeutics for this morbid immune related adverse event.

Routine monitoring with pleural manometry during therapeutic large-volume thoracentesis to prevent pleural-pressure-related complications: a multicentre, single-blind randomised controlled trial.

BACKGROUND: In patients with non-expandable lung, removal of pleural fluid can result in excessively negative pleural pressure, which is associated with chest discomfort, pneumothorax, and re-expansion pulmonary oedema. Pleural manometry is widely used to safeguard against pressure-related complications during thoracentesis despite little evidence to support the approach. We investigated whether monitoring of pleural pressure with manometry during thoracentesis could protect against complications compared with assessment of symptoms alone. METHODS: We did a prospective randomised single-blind trial involving patients with large pleural effusions at two academic medical centres in, Nashville, TN, and Baltimore, MD, USA. Eligible patients were adults with free-flowing effusions estimated to be at least 0·5 L who could remain seated throughout the procedure. Patients were randomly assigned 1:1 to receive thoracentesis guided by symptoms only (control) or by symptoms plus manometry at timepoints based on volume drained. The randomisation schedule was computer generated, used permuted blocks of four and six, and was stratified by participating institution. Patients, who were masked to study-group assignment, were asked to rate chest discomfort on 100 mm visual analogue scales before, during, and after drainage. In both groups drainage was discontinued before complete evacuation of pleural fluid if patients developed persistent chest discomfort, intractable cough, or other complications. In the manometry group, an additional criterion for stopping was if end-expiratory pleural pressure was lower than -20 cm H2O or declined by more than 10 cm H2O between two measurements to a value less than or equal to -10 cm H2O. The primary outcome was overall chest discomfort from before the start to after the procedure measured by patients 5 min after the end of drainage. Analysis was by modified intention to treat (ie, included all patients with any procedure or outcome data). This trial is registered with ClinicalTrials.gov, number NCT02677883. FINDINGS: Between March 4, 2016, and Sept 8, 2017, 191 patients were screened, of whom 128 were randomly assigned treatment and 124 were included in the final analysis (62 in each group). Four patients were excluded because of manometer malfunction (n=2), inability to access effusion due to pleural tumour burden (n=1), and inability to remain seated (n=1). Groups did not differ for the primary outcome (mean difference in chest discomfort score 2·4 mm, 95% CI -5·7 to 10·5, p=0·56). Six (10%) of 62 patients in the control group had asymptomatic pneumothorax ex vacuo compared with none in the manometry group (p=0·01). No serious complications occurred in either group. INTERPRETATION: Measurement of pleural pressure by manometry during large-volume thoracentesis does not alter procedure-related chest discomfort. Our findings do not support the routine use of this approach. FUNDING: Centurion Medical Products.

Learning Electromagnetic Navigational Bronchoscopy and Percutaneous Transthoracic Needle Biopsy (LEAP): A Pilot Study.

BACKGROUND: Prior studies in pulmonology have examined the validity of procedural training tools, however, translation of simulation skill acquisition into real world competency remains understudied. We examine an assessment process with a simulation training course for electromagnetic navigational (EMN) bronchoscopy and percutaneous transthoracic needle aspiration (PTTNA). METHODS: A cohort study was conducted by subjects using EMN bronchoscopy and PTTNA. A procedural assessment tool was developed to measure basic competency for EMN bronchoscopy and PTTNA at 3 different time points: first simulation case, final simulation case upon reaching a competent score, and at their first live case. The assessment tool was divided into 4 domains (total score, 4 to 16; competency ≥12) with each domain requiring a passing score (1 to 4; competency ≥3.0). Complication and procedural time were collected during their first live case. RESULTS: Twenty-two serial procedures (12 EMN bronchoscopies, 10 EMN PTTNA) were observed by 14 subjects. The mean first simulation score for EMN bronchoscopy (4.66±0.89) improved after cadaver simulation (12.67±0.89, median 3 simulations attempts). The subjects' mean score for their first live case was 13.0±0.85 (self-reported score 12.5±1.07). For EMN PTTNA, the mean first simulation score (4.3±2.40) improved after cadaver simulation (12.6±1.51, median 3 simulation attempts). The subjects' mean score for their first live PTTNA case was 12.5±2.87 (self-reported score 12.1±1.05). There was only 1 minor complication. CONCLUSION: Learning EMN bronchoscopy/PTTNA is feasible using a structured simulation course with an assessment tool.

Impact of Checkpoint Inhibitor Pneumonitis on Survival in NSCLC Patients Receiving Immune Checkpoint Immunotherapy.

With increasing use of immune checkpoint inhibitors (ICIs) for advanced NSCLC, there is increasing recognition of immune-related adverse events associated with ICI use. We recently reported increased incidence of checkpoint inhibitor pneumonitis (CIP) in ICI-treated NSCLC patients. Since development of immune-related adverse events in other organ systems has been associated with either no change or even improvement in tumor response/cancer outcomes, we sought to better understand the impact of CIP development on overall survival in ICI-treated NSCLC patients. Using baseline and follow-up data collected on a cohort of 205 ICI-treated NSCLC patients, we used a multi-state modeling approach to understand the effect of developing CIP on the risk of death. We observed time-dependent changes in risk of developing and recovery from CIP, with an increased risk of both developing and recovering from CIP in the first year after initiating ICI. We found that developing CIP independently increased the risk of transitioning to death in both adjusted and unadjusted models. In the multivariate model, we found that the increase in mortality associated with CIP was only seen in patients with adenocarcinoma tumor histology. Collectively, these findings suggest that in NSCLC, development of CIP worsens survival in patients receiving immunotherapy.

Pneumonitis in Non-Small Cell Lung Cancer Patients Receiving Immune Checkpoint Immunotherapy: Incidence and Risk Factors.

Checkpoint inhibitor pneumonitis (CIP) is an immune-related adverse event that can occur after initiation of anti-programmed death 1/programmed death ligand 1 immune checkpoint inhibitor (ICI) therapy for the treatment of multiple malignancies, including NSCLC. However, the incidence of CIP has not been previously examined in a population that included both trial-enrolled and non-trial-enrolled patients with advanced NSCLC. Furthermore, risk factors and other clinical characteristics associated with CIP severity are not known. In this study, we retrospectively examined clinical characteristics, incidence, and risk factors for CIP in a cohort of 205 patients with NSCLC, all of whom received anti-programmed death 1/programmed death ligand 1 ICIs. Our results demonstrate a higher incidence of CIP (19%) than previously reported in clinical trials (3%-5%). Our data also suggest that tumor histologic type may be a risk factor for CIP development. We observed a wide range of time to onset of CIP (median 82 days), with high morbidity and mortality associated with higher-grade CIP regardless of degree of immunosuppression. Our data provide new insight into the epidemiology and clinical characteristics of CIP. Further studies are needed to increase CIP pharmacovigilance, improve risk stratification, and refine diagnostic algorithms for the diagnosis and management of this potential life-threatening complication of ICI therapy.

Bronchoscopic Techniques Used in the Diagnosis and Staging of Lung Cancer.

With the greater use of chest CT, the incidental detection of lung nodules is expected to increase. However, because most lung nodules are benign, there is a high demand for minimally invasive procedures that provide valuable diagnostic information while minimizing complications. Recent advances in bronchoscopic technology meet this demand. These advanced technologies include navigational bronchoscopy and radial endobronchial ultrasound (EBUS) for the diagnosis of peripheral lung nodules, and linear EBUS, which has revolutionized the nonoperative nodal staging of lung cancer and provides a complementary option to surgical staging approaches. This article reviews these new bronchoscopic technologies.

Comparing approaches to the management of malignant pleural effusions.

INTRODUCTION: Management of symptomatic malignant pleural effusions is becoming more complex due to the range of treatment options, which include therapeutic thoracenteses, thoracoscopic talc pleurodesis, bedside pleurodesis with talc or other sclerosing agents via small-bore chest catheters, indwelling pleural catheters, surgery, or a combination of some of these procedures. Areas covered: Recent advances for the expanding range of treatment options in malignant pleural effusions are summarized, according to the best available evidence. Expert commentary: Selection of a treatment approach in malignant pleural effusions should take into account patient preferences and performance status, tumor type, predicted prognosis, presence of a non-expandable lung, and local experience or availability. The role of pleurodesis has decreased with the advent of indwelling pleural catheters, which provide a high degree of symptomatic relief on an outpatient basis and, therefore, are being positioned as a first choice therapy in many centers. Talc poudrage pleurodesis should probably be reserved for those situations in which pleural tumor invasion is discovered during diagnostic thoracoscopy. Ongoing randomized controlled trials will offer solid evidence on which of the available palliative approaches should be selected for each particular patient.

A Comparison of Different Training Methods in the Successful Learning of Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration.

BACKGROUND: Standardized training of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS- TBNA) is available only in highly developed countries. OBJECTIVE: To compare the skill differences in the performance of EBUS-TBNA by pulmonologists trained under different learning methods. METHODS: We performed a retrospective study of 145 EBUS-TBNA cases. We set up 3 comparative training groups: a standardized training group, a teaching group, and a self-study group. The main clinical outcomes were sensitivity, specificity and accuracy of EBUS-TBNA. Cumulative sum analysis was used to track EBUS-TBNA proficiency of the 3 groups. RESULTS: The sensitivities of EBUS-TBNA in the different groups were 90, 88, and 67%, respectively. The accuracies of the different groups were 91, 90, and 71%, respectively. With respect to the sensitivity and accuracy, there was no significant difference between the standardized training group and teaching group. However, the self-study group was inferior to the other 2 groups. By comparing the learning curve among the groups, we found that the minimum number of operations needed to reach a 90% accuracy for the standardized training group, the teaching group and the self-study group was 17, 32 and 40 cases, respectively. CONCLUSION: Compared with the teaching and self-study groups, the standardized training group resulted in practitioners achieving high skill levels following the performance of a lower number of cases. Pulmonologists trained in the teaching group achieved a similar level of skills, but required more experience to reach this level. Practitioners in the self-study group did not achieve a satisfactory level of skills, despite performing a high number of cases.

Procedural Learning Perspectives of Pulmonary Fellows and Practitioners.

BACKGROUND: Procedural learning requires both didactic knowledge and motor skills. Optimal teaching styles and techniques remain to be defined for pulmonary procedural learning. We investigated the preferences of learners at 2 different points in a pulmonary career; as pulmonary fellows and as clinical practitioners. METHODS: A perception survey was conducted among pulmonary fellows and practitioners from multiple institutions throughout the United States. Fellows and practitioners were immediately surveyed on procedural learning factors after completing a procedural learning course using low/high-fidelity and/or cadaver simulators. Survey questions consisting of biographical information and multiple choice, Likert style, and qualitative questions regarding learning preferences were collected. RESULTS: Seventy-five physicians (44 pulmonary fellows, 31 practitioners) from 35 centers completed the survey. Pulmonary practitioners preferred an academic expert, whereas fellows preferred familiar faculty as lecturers for procedural learning (P=0.03). There were no statistical differences between fellows/practitioners value of the use of simulators, didactics, or handouts. Both groups preferred animal/cadaver and high-fidelity simulators to low-fidelity simulators. Both groups also preferred a traditional course structure to problem-based learning/flipped classroom. The most common answer to barriers for learning a new procedure was "time" for training followed by "opportunities" to learn. CONCLUSIONS: Pulmonary fellows and practitioners we surveyed preferred a traditional course structure with cadaver/animal models and high-fidelity simulation training as compared with a flipped classroom model and low-fidelity simulators, but whether this holds true for the wider population is unknown. Larger studies are needed to validate learning perception with outcomes.

Same-Day Computed Tomographic Chest Imaging for Pulmonary Nodule Targeting with Electromagnetic Navigation Bronchoscopy May Decrease Unnecessary Procedures.

RATIONALE: Bronchoscopy is commonly used for the diagnosis of suspicious pulmonary nodules discovered on computed tomographic (CT) imaging of the chest. Procedural CT imaging for bronchoscopy planning is often completed weeks to months before the date of a scheduled bronchoscopy, which may not allow discovery of a decrease in nodule size or resolution before the bronchoscopic procedure. OBJECTIVES: To determine whether same-day CT imaging of the chest discovers partial or total resolution of some lung nodules and thereby reduces unnecessary bronchoscopic procedures. METHODS: We performed a prospective case series study of patients undergoing navigational bronchoscopy using a new technology requiring same-day preprocedural CT imaging at one university teaching hospital. Patients scheduled to undergo bronchoscopy who were found to have partial or complete resolution of their lesion on the same-day CT exam leading to the cancellation of their procedure were identified and further characterized. MEASUREMENTS AND MAIN RESULTS: From January 2015 to June 2016, 116 patients were scheduled for navigational bronchoscopy for the diagnosis of a pulmonary lesion. Of the 116 patients scheduled, 8 (6.9%) had a decrease in size or resolution of their lesion, leading to the cancellation of their procedure. The number needed to screen to prevent one unnecessary procedure was 15. For cancelled cases, the average time from initial CT prompting referral for bronchoscopy to the day of procedure scan was 53 days. CONCLUSIONS: Time from initial imaging to day of procedure is variable, occasionally allowing enough time for lesions to resolve, thereby obviating the need for biopsy. Same-day imaging may decrease unnecessary procedural risk.