A functional identification platform reveals frequent, spontaneous neoantigen-specific T cell responses in patients with cancer.

The clinical impact of tumor-specific neoantigens as both immunotherapeutic targets and biomarkers has been impeded by the lack of efficient methods for their identification and validation from routine samples. We have developed a platform that combines bioinformatic analysis of tumor exomes and transcriptional data with functional testing of autologous peripheral blood mononuclear cells (PBMCs) to simultaneously identify and validate neoantigens recognized by naturally primed CD4+ and CD8+ T cell responses across a range of tumor types and mutational burdens. The method features a human leukocyte antigen (HLA)-agnostic bioinformatic algorithm that prioritizes mutations recognized by patient PBMCs at a greater than 40% positive predictive value followed by a short-term in vitro functional assay, which allows interrogation of 50 to 75 expressed mutations from a single 50-ml blood sample. Neoantigens validated by this method include both driver and passenger mutations, and this method identified neoantigens that would not have been otherwise detected using an in silico prediction approach. These findings reveal an efficient approach to systematically validate clinically actionable neoantigens and the T cell receptors that recognize them and demonstrate that patients across a variety of human cancers have a diverse repertoire of neoantigen-specific T cells.

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).

Comparative Treatment Outcomes for Idiopathic Subglottic Stenosis: 5-Year Update.

The North American Airway Collaborative (NoAAC) previously published a 3-year multi-institutional prospective cohort study showing variation in treatment effectiveness between 3 primary surgical techniques for idiopathic subglottic stenosis (iSGS). In this report, we update these findings to include 5 years of data evaluating treatment effectiveness. Patients in the NoAAC cohort were re-enrolled for 2 additional years and followed using the prespecified published protocol. Consistent with prior data, prospective observation of 487 iSGS patients for 5 years showed treatment effectiveness differed by modality. Cricotracheal resection maintained the lowest rate of recurrent operation (5%), followed by endoscopic resection with adjuvant medical therapy (30%) and endoscopic dilation (50%). These data support the initial observations and continue to provide value to providers and patients navigating longitudinal decision-making. Level of evidence: 2-prospective cohort study.

Association of Social Determinants of Health with Time to Diagnosis and Treatment Outcomes in Idiopathic Subglottic Stenosis.

OBJECTIVES: To examine whether social determinants of health (SDH) factors are associated with time to diagnosis, treatment selection, and time to recurrent surgical intervention in idiopathic subglottic stenosis (iSGS) patients. METHODS: Adult patients with diagnosed iSGS were recruited prospectively (2015-2017) via clinical providers as part of the North American Airway Collaborative (NoAAC) and via an online iSGS support community on Facebook. Patient-specific SDH factors included highest educational attainment (self-reported), median household income (matched from home zip code via U.S. Census data), and number of close friends (self-reported) as a measure of social support. Main outcomes of interest were time to disease diagnosis (years from symptom onset), treatment selection (endoscopic dilation [ED] vs cricotracheal resection [CTR] vs endoscopic resection with adjuvant medical therapy [ERMT]), and time to recurrent surgical intervention (number of days from initial surgical procedure) as a surrogate for disease recurrence. RESULTS: The total 810 participants were 98.5% female, 97.2% Caucasian, and had a median age of 50 years (IQR, 43-58). The cohort had a median household income of $62 307 (IQR, $50 345-$79 773), a median of 7 close friends (IQR, 4-10), and 64.7% of patients completed college or graduate school. Education, income, and number of friends were not associated with time to diagnosis via multivariable linear regression modeling. Univariable multinominal logistic regression demonstrated an association between education and income for selecting ED versus ERMT, but no associations were noted for CTR. No associations were noted for time to recurrent surgical procedure via Kaplan Meier modeling and Cox proportional hazards regression. CONCLUSIONS: Patient education, income, and social support were not associated with time to diagnosis or time to disease recurrence. This suggests additional patient, procedure, or disease-specific factors contribute to the observed variations in iSGS surgical outcomes.

Development of a National Academic Boot Camp to Improve Fellowship Readiness.

Background: Pulmonary and critical care medicine (PCCM) fellowship requires a high degree of medical knowledge and procedural competency. Gaps in fellowship readiness can result in significant trainee anxiety related to starting fellowship training.Objective: To improve fellowship readiness and alleviate anxiety for PCCM-bound trainees by improving confidence in procedural skills and cognitive domains.Methods: Medical educators within the American Thoracic Society developed a national resident boot camp (RBC) to provide an immersive, experiential training program for physicians entering PCCM fellowships. The RBC curriculum is a 2-day course designed to build procedural skills, medical knowledge, and clinical confidence through high-fidelity simulation and active learning methodology. Separate programs for adult and pediatric providers run concurrently to provide unique training objectives targeted to their learners' needs. Trainee assessments include multiple-choice pre- and post-RBC knowledge tests and confidence assessments, which are scored on a four-point Likert scale, for specific PCCM-related procedural and cognitive skills. Learners also evaluate course material and educator effectiveness, which guide modifications of future RBC programs and provide feedback for individual educators, respectively.Results: The American Thoracic Society RBC was implemented in 2014 and has grown annually to include 132 trainees and more than 100 faculty members. Mean knowledge test scores for participants in the 2019 RBC adult program increased from 55% (±14% SD) on the pretest to 72% (±11% SD; P < 0.001) after RBC completion. Similarly, mean pretest scores for pediatric course attendees increased from 54% (±13% SD) to 62% (±19% SD; P = 0.17). Specific content domains that improved by 10% or more between pre- and posttests included airway management, bronchoscopy, pulmonary function testing, and code management for adult course participants, and airway management, pulmonary function testing, and extracorporeal membrane oxygenation for pediatric course participants. Trainee confidence also significantly improved across all procedural and cognitive domains for adult trainees and in 10 of 11 domains for pediatric course attendees. Course content for the 2019 RBC was overwhelmingly rated as "on target" for the level of learner, with <4% of respondents indicating any specific session was "much too basic" or "much too advanced."Conclusion: RBC participation improved PCCM-bound trainee knowledge, procedural familiarity, and confidence. Refinement of the RBC curriculum over the past 7 years has been guided by educator and course evaluations, with the ongoing goal of meeting the evolving educational needs of rising PCCM trainees.

Comparative Treatment Outcomes for Patients With Idiopathic Subglottic Stenosis.

Importance: Surgical treatment comparisons in rare diseases are difficult secondary to the geographic distribution of patients. Fortunately, emerging technologies offer promise to reduce these barriers for research. Objective: To prospectively compare the outcomes of the 3 most common surgical approaches for idiopathic subglottic stenosis (iSGS), a rare airway disease. Design, Setting, and Participants: In this international, prospective, 3-year multicenter cohort study, 810 patients with untreated, newly diagnosed, or previously treated iSGS were enrolled after undergoing a surgical procedure (endoscopic dilation [ED], endoscopic resection with adjuvant medical therapy [ERMT], or cricotracheal resection [CTR]). Patients were recruited from clinician practices in the North American Airway Collaborative and an online iSGS community on Facebook. Main Outcomes and Measures: The primary end point was days from initial surgical procedure to recurrent surgical procedure. Secondary end points included quality of life using the Clinical COPD (chronic obstructive pulmonary disease) Questionnaire (CCQ), Voice Handicap Index-10 (VHI-10), Eating Assessment Test-10 (EAT-10), the 12-Item Short-Form Version 2 (SF-12v2), and postoperative complications. Results: Of 810 patients in this cohort, 798 (98.5%) were female and 787 (97.2%) were white, with a median age of 50 years (interquartile range, 43-58 years). Index surgical procedures were ED (n = 603; 74.4%), ERMT (n = 121; 14.9%), and CTR (n = 86; 10.6%). Overall, 185 patients (22.8%) had a recurrent surgical procedure during the 3-year study, but recurrence differed by modality (CTR, 1 patient [1.2%]; ERMT, 15 [12.4%]; and ED, 169 [28.0%]). Weighted, propensity score-matched, Cox proportional hazards regression models showed ED was inferior to ERMT (hazard ratio [HR], 3.16; 95% CI, 1.8-5.5). Among successfully treated patients without recurrence, those treated with CTR had the best CCQ (0.75 points) and SF-12v2 (54 points) scores and worst VHI-10 score (13 points) 360 days after enrollment as well as the greatest perioperative risk. Conclusions and Relevance: In this cohort study of 810 patients with iSGS, endoscopic dilation, the most popular surgical approach for iSGS, was associated with a higher recurrence rate compared with other procedures. Cricotracheal resection offered the most durable results but showed the greatest perioperative risk and the worst long-term voice outcomes. Endoscopic resection with medical therapy was associated with better disease control compared with ED and had minimal association with vocal function. These results may be used to inform individual patient treatment decision-making.

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).

Lung Cancer Screening, Version 3.2018, NCCN Clinical Practice Guidelines in Oncology.

Lung cancer is the leading cause of cancer-related mortality in the United States and worldwide. Early detection of lung cancer is an important opportunity for decreasing mortality. Data support using low-dose computed tomography (LDCT) of the chest to screen select patients who are at high risk for lung cancer. Lung screening is covered under the Affordable Care Act for individuals with high-risk factors. The Centers for Medicare & Medicaid Services (CMS) covers annual screening LDCT for appropriate Medicare beneficiaries at high risk for lung cancer if they also receive counseling and participate in shared decision-making before screening. The complete version of the NCCN Guidelines for Lung Cancer Screening provides recommendations for initial and subsequent LDCT screening and provides more detail about LDCT screening. This manuscript focuses on identifying patients at high risk for lung cancer who are candidates for LDCT of the chest and on evaluating initial screening findings.

Simulation for Skills-based Education in Pulmonary and Critical Care Medicine.

The clinical practice of pulmonary and critical care medicine requires procedural competence in many technical domains, including vascular access, airway management, basic and advanced bronchoscopy, pleural procedures, and critical care ultrasonography. Simulation provides opportunities for standardized training and assessment in procedures without placing patients at undue risk. A growing body of literature supports the use and effectiveness of low-fidelity and high-fidelity simulators for procedural training and assessment. In this manuscript by the Skills-based Working Group of the American Thoracic Society Education Committee, we describe the background, available technology, and current evidence related to simulation-based skills training within pulmonary and critical care medicine. We outline working group recommendations for key procedural domains.

Lung cancer screening, version 1.2015: featured updates to the NCCN guidelines.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Lung Cancer Screening provide recommendations for selecting individuals for lung cancer screening, and for evaluation and follow-up of nodules found during screening, and are intended to assist with clinical and shared decision-making. These NCCN Guidelines Insights focus on the major updates to the 2015 NCCN Guidelines for Lung Cancer Screening, which include a revision to the recommendation from category 2B to 2A for one of the high-risk groups eligible for lung cancer screening. For low-dose CT of the lung, the recommended slice width was revised in the table on "Low-Dose Computed Tomography Acquisition, Storage, Interpretation, and Nodule Reporting."

Pulmonary langerhans cell histiocytosis diagnosed in a cervical lymph node: a case report.

BACKGROUND: Pulmonary Langerhans cell histiocytosis (PLCH) is usually confined to the lungs and is therefore an unexpected finding in a cervical lymph node. CASE: A 52-year-old male with a 40-pack-year smoking history presented to our clinic with cough, fever and cervical lymphadenopathy. Chest computed tomography (CT) showed bilateral pulmonary nodules and enlarged mediastinal lymph nodes, worrisome for an infectious or malignant process. Bronchioloalveolar lavage was nondiagnostic. Fine needle aspiration cytology of the enlarged cervical lymph node revealed atypical histiocytoid cells, suspicious for malignancy. Immunohistochemistry revealed CD1a- and S-100-positive Langerhans cells. These findings, along with the patient's extensive smoking history and characteristic radiographic nodules, favored a diagnosis of PLCH with cervical lymph node involvement. The patient was advised to cease smoking, and no therapy was administered. Months later, follow-up chest CT showed spontaneous resolution of the lung nodules. CONCLUSION: The demonstration of Langerhans cells by immunohistochemical staining of CD1a and S-100 on a fine needle aspiration cell block is a useful diagnostic adjunct. In this case, definitive cytology for Langerhans cells in the appropriate clinical and radiologic setting allowed us to arrive at the correct diagnosis of PLCH in a minimally invasive manner.

T cell pathways involving CTLA4 contribute to a model of acute lung injury.

Acute lung injury (ALI) is a frequent pulmonary complication in critically ill patients. We characterized a murine model of LPS-induced ALI, focusing on Th cells. Following LPS administration, bronchoalveolar lavage lymphocytes, neutrophils, IL-6, TNF-alpha, and albumin were increased. Analysis of LPS-induced T cells revealed increased Th cell-associated cytokines (IL-17A, -17F, and -22), as well as increased expression of CD69 (a cell activation marker), Foxp3, and CTLA4 in CD4(+) T cells. Administration of anti-CTLA4 Ab decreased LPS-induced bronchoalveolar lavage albumin and IL-17A, while increasing CD4(+)Foxp3(+) cell number and Foxp3 expression in CD4(+)Foxp3(+) cells. These data suggest that pulmonary LPS administration promotes CD4(+) T cells and that T cell pathways involving CTLA4 contribute to ALI.

New costimulatory families: signaling lymphocytic activation molecule in adaptive allergic responses.

The generation of an allergic immune response requires at least two signals for complete activation of T cells. Costimulatory molecules are integral to the second signal. In this review, we analyze the costimulatory molecule signaling lymphocytic activation molecule (SLAM) and other recently described SLAM family members. We highlight recent findings that position SLAM as critical for allergic inflammation and its role in modulation of cytokine secretion. Furthermore, a possible role of SLAM as a link between the adaptive and innate immune response is also discussed. Understanding the role of costimulatory molecules, including SLAM and SLAM family members, may elucidate mechanisms involved in the allergic immune response, and suggest potential therapeutic opportunities.

CD45RB ligation inhibits allergic pulmonary inflammation by inducing CTLA4 transcription.

CD45, a type I transmembrane protein tyrosine phosphatase expressed on nucleated hemopoietic cells, is prominently involved in T cell activation. Ligation of CD45RB isoforms has been associated with transplant tolerance. A recent genotyping analysis of asthma indicates a correlation with CD45 splicing. In this study, we administered an anti-CD45RB mAb (aCD45) in a murine model of allergic asthma and found that CD45RB ligation decreases allergic responses. aCD45 decreases allergen-induced pulmonary eosinophilia, bronchoalveolar lavage IL-13, IgE, and airway responses. Also, aCD45 increases the expression of CTLA4, a negative regulator of T cell activation. Furthermore, CD45RB signals no longer decrease allergic inflammation when CTLA4 is inhibited. These data support a role for CTLA4 in CD45RB-mediated inhibition of allergic inflammation. T cells and splenocytes stimulated with aCD45 exhibited increased CTLA4 levels, and analysis of CTLA4 promoter gene constructs identified a CD45RB-inducible regulatory region localized from -335 to -62 bp relative to the transcription start site. Together, these findings suggest that CD45RB signals mediate a novel role in the modulation of allergic inflammation, orchestrated by T cells through induction of CTLA4 transcription.