Long term follow-up of neoadjuvant chemotherapy for non-small cell lung cancer (NSCLC) investigating early positron emission tomography (PET) scan as a predictor of outcome.

BACKGROUND: Neoadjuvant chemotherapy is effective in improving survival of resectable NSCLC. Based on findings in the adjuvant and metastatic setting, FDG positron emission tomography (PET) scans may offer early prognostic or predictive value after one cycle of induction chemotherapy. METHODS: In this phase II non-randomized trial, patients with AJCC version 6 stage IB to IIIB operable NSCLC were treated with 3 cycles of cisplatin and pemetrexed neoadjuvant chemotherapy. Patients underwent FDG-PET scanning prior to and 18 to 21 days after the first cycle of chemotherapy. Investigators caring for patients were blinded to results, unless the scans showed evidence of disease progression. FDG-PET response was defined prospectively as a ≥ 20% decrease in the SUV of the primary lesion. RESULTS: Between October 2005 and February 2010, 25 patients enrolled. Fifty two percent were female, 88% white, and median age was 62 years. Histology was divided into adenocarcinoma 66%, not otherwise specified (NOS) 16%, squamous cell 12%, and large cell 4%. Stage distribution was: 16% IB, 4% IIB, and 79% IIIA. Treatment was well tolerated and only one patient had a grade 4 toxicity. The median follow up was 95 months. The 5 year progression free survival (PFS) and overall survival (OS) for the entire population were 54 and 67%, respectively. Eighteen patients had a baseline FDG-PET scan and a repeat scan at day 18-21 available for comparison. Ten patients (56%) were considered metabolic responders on the day 18-21 FDG-PET scan. Responders had a 5 year PFS and OS of 60 and 70%, respectively, while the percentage for non-responders was 63 and 75% (p = 0.96 and 0.85). CONCLUSIONS: This phase II trial did not demonstrate that a PET scan after one cycle of chemotherapy can predict survival outcomes of patients with NSCLC treated with neoadjuvant chemotherapy. TRIAL REGISTRATION: NCT00227539 registered September 28th, 2005.

Electromagnetic navigational bronchoscopic airway recanalization in patients with vanishing bronchus.

BACKGROUND: Stenosis is the most frequent airway complication after lung transplantation. When complete obstruction is diagnosed without possibility of recanalization, options are generally limited to either resection or retransplantation, both associated with increased morbidity and mortality. We describe our experience with a novel technique using electromagnetic navigational bronchoscopy (ENB) to recanalize the occluded airway after lung transplantation. METHODS: Patients who underwent lung transplantation between 2010 and 2016 with subsequent development of complete airway obstruction and failed conventional recanalization attempts were included in this study. All patients underwent attempted recanalization using ENB. Primary outcomes included success of the technique and long-term patency. Secondary outcomes included procedure-related complications. RESULTS: Four patients met inclusion criteria and underwent attempted recanalization using the ENB platform. Location of the obstruction was the bronchus intermedius in two patients, the lingular bronchus in one patient, and the left basilar bronchus in one patient. Mean length of stenosis was 8.8 mm. Three patients (75%) were successfully recanalized and all airways remain patent at 1, 48, and 66 mo. There were no procedure-related complications. The one patient who was unable to be recanalized successfully underwent bilobectomy and died 7 mo later. CONCLUSIONS: ENB is a feasible method of airway recanalization in select patients with bronchial occlusion after lung transplantation. ENB recanalization spares lung parenchyma and avoids risks associated with surgical resection and retransplantation. This novel technique can be added to the armamentarium for thoracic surgeons who diagnose and treat this complicated problem.

Assessing the Benefits of Preoperative Thoracic Epidural Placement for Lung Transplantation.

OBJECTIVE: The authors investigated the effect of preoperative thoracic epidural (PreTE) catheter placement versus not placing a preoperative thoracic epidural catheter (NoPreTE) on the duration of postoperative ventilation time, time to become coherent (measured as time to become Confusion Assessment Method-intensive care unit [ICU] negative), opioid consumption, ICU length of stay (LOS), and hospital LOS. DESIGN: Retrospective cohort design. SETTING: Single institution, university hospital. PARTICIPANTS: Patients undergoing lung transplantation. COMPARISON GROUPS: PreTE group was defined as patients who received a thoracic epidural preoperatively. NoPreTE group was defined as patients who either received a thoracic epidural postoperatively or who did not receive a thoracic epidural postoperatively. MEASUREMENTS AND MAIN RESULTS: Fifty-six patients for the PreTE and 99 for NoPreTE groups were included in the study. After a excluding patients with postoperative ventilation times greater than 96 hours, preoperative thoracic epidural was associated with shorter time on the ventilator (19.1 hours v 30.6 hours; p < 0.001), time to become coherent (26.4 hours v 37.6 hours; p = 0.008), ICU LOS (6.4 days v 12.4 days; p = 0.018), and hospital LOS (15.9 days v 23.5 days; p = 0.04) compared to patients who did not receive a preoperative epidural. After controlling for single versus double lung transplantation and duration of cardiopulmonary bypass (CPB), differences in time to become coherent, ICU LOS, and hospital LOS became nonsignificant. Opioid consumption was significantly higher in those patients who did not receive a preoperative epidural. Despite a high rate of anticoagulation for CPB (89.5%), no neurologic complications or epidural hematomas were observed. CONCLUSION: For those lung transplant patients ventilated for less than 96 hours postoperatively, preoperative thoracic epidural placement is associated with shorter postoperative ventilator time and reduced opioid consumption. Time to become coherent postoperatively, ICU LOS, and hospital LOS also improved in this cohort, though the significance decreased after adjusting for possible confounders. A larger prospective study is necessary to confirm if timing of thoracic epidural placement alters time to become coherent postoperatively and ICU LOS.

Multispectral Optical Tweezers for Biochemical Fingerprinting of CD9-Positive Exosome Subpopulations.

Extracellular vesicles (EVs), including exosomes, are circulating nanoscale particles heavily implicated in cell signaling and can be isolated in vast numbers from human biofluids. Study of their molecular profiling and materials properties is currently underway for purposes of describing a variety of biological functions and diseases. However, the large, and as yet largely unquantified, variety of EV subpopulations differing in composition, size, and likely function necessitates characterization schemes capable of measuring single vesicles. Here we describe the first application of multispectral optical tweezers (MS-OTs) to single vesicles for molecular fingerprinting of EV subpopulations. This versatile imaging platform allows for sensitive measurement of Raman chemical composition (e.g., variation in protein, lipid, cholesterol, nucleic acids), coupled with discrimination by fluorescence markers. For exosomes isolated by ultracentrifugation, we use MS-OTs to interrogate the CD9-positive subpopulations via antibody fluorescence labeling and Raman spectra measurement. We report that the CD9-positive exosome subset exhibits reduced component concentration per vesicle and reduced chemical heterogeneity compared to the total purified EV population. We observed that specific vesicle subpopulations are present across exosomes isolated from cell culture supernatant of several clonal varieties of mesenchymal stromal cells and also from plasma and ascites isolated from human ovarian cancer patients.

Comprehensive Proteomic Analysis of Mesenchymal Stem Cell Exosomes Reveals Modulation of Angiogenesis via Nuclear Factor-KappaB Signaling.

Mesenchymal stem cells (MSC) are known to facilitate healing of ischemic tissue related diseases through proangiogenic secretory proteins. Recent studies further show that MSC derived exosomes function as paracrine effectors of angiogenesis, however, the identity of which components of the exosome proteome responsible for this effect remains elusive. To address this we used high-resolution isoelectric focusing coupled liquid chromatography tandem mass spectrometry, an unbiased high throughput proteomics approach to comprehensively characterize the proteinaceous contents of MSCs and MSC derived exosomes. We probed the proteome of MSCs and MSC derived exosomes from cells cultured under expansion conditions and under ischemic tissue simulated conditions to elucidate key angiogenic paracrine effectors present and potentially differentially expressed in these conditions. In total, 6,342 proteins were identified in MSCs and 1,927 proteins in MSC derived exosomes, representing to our knowledge the first time these proteomes have been probed comprehensively. Multilayered analyses identified several putative paracrine effectors of angiogenesis present in MSC exosomes and increased in expression in MSCs exposed to ischemic tissue-simulated conditions; these include platelet derived growth factor, epidermal growth factor, fibroblast growth factor, and most notably nuclear factor-kappaB (NFkB) signaling pathway proteins. NFkB signaling was identified as a key mediator of MSC exosome induced angiogenesis in endothelial cells by functional in vitro validation using a specific inhibitor. Collectively, the results of our proteomic analysis show that MSC derived exosomes contain a robust profile of angiogenic paracrine effectors, which have potential for the treatment of ischemic tissue-related diseases.

Successful Repair of Acute Type A Aortic Dissection 15 Years Following Bilateral Lung Transplantation.

This report describes a patient treated for acute type A aortic dissection 15 years after undergoing bilateral lung transplantation by a clamshell thoracotomy.

Impact of Difficult Lung Transplantation on Short-Term and Long-Term Survival.

BACKGROUND: Lung transplantation (LTx) is a complex operation; however, certain factors can make LTx even more challenging. A difficult LTx could adversely affect immediate and long-term outcomes. We investigate the potential use of Modifier-22 to identify difficult LTx to evaluate postoperative outcomes. METHODS: A retrospective analysis was performed on patients who had undergone LTx between January 1, 2010, and October 1, 2018, at the University of Washington. Patients undergoing repeat LTx, other solid organ transplantation, and/or with prior major cardiothoracic surgery were excluded. Patients were classified into 2 categories: standard LTx and difficult LTx groups. We examined hospital length of stay (LOS), intensive care unit (ICU) LOS, duration on the ventilator, and 1-, 3-, and 5-year survival. RESULTS: A total of 370 patients were identified, with 268 patients in the standard LTx group and 102 patients in the difficult LTx group. The median LOS, ICU LOS, and duration on the ventilator in the difficult LTx group was 18.0 ± 1.6 days, 6.0 ± 1.2 days, and 2.0 ± 0.9 days compared with 15.0 ± 0.8 days, 4.0 ± 0.7 days, and 1.0 ± 0.3 days in the standard LTx group, respectively (all P < .01). Kaplan-Meier analysis revealed that both groups had similar survival. CONCLUSION: Modifier-2 can be used to identify challenging LTx. Difficult LTx negatively impacts early postoperative outcomes with longer LOS, ICU LOS, and duration on the ventilator. However, long-term survival was not affected. Clinicians should not view pleural space and anatomical complexities, which are a consequence of the underlying disease, as a risk factor for impaired survival.

Porous Precision-Templated 40 µm Pore Scaffolds Promote Healing through Synergy in Macrophage Receptor with Collagenous Structure and Toll-Like Receptor Signaling.

Porous precision-templated scaffolds (PTS) with uniform, interconnected, 40 µm pores have shown favorable healing outcomes and a reduced foreign body reaction (FBR). Macrophage receptor with collagenous structure (MARCO) and toll-like receptors (TLRs) have been identified as key surface receptors in the initial inflammatory phase of wound healing. However, the role of MARCO and TLRs in modulating monocyte and macrophage phenotypes within PTS remains uncharacterized. In this study, we demonstrate a synergetic relationship between MARCO and TLR signaling in cells inhabiting PTS, where induction with TLR3 or TLR4 agonists to 40 µm scaffold-resident cells upregulates the transcription of MARCO. Upon deletion of MARCO, the prohealing phenotype within 40 µm PTS polarizes to a proinflammatory and profibrotic phenotype. Analysis of downstream TLR signaling shows that MARCO is required to attenuate nuclear factor kappa B (NF-κB) inflammation in 40 µm PTS by regulating the transcription of inhibitory NFKB inhibitor alpha (NFKBIA) and interleukin-1 receptor-associated kinase 3 (IRAK-M), primarily through a MyD88-dependent signaling pathway. Investigation of implant outcome in the absence of MARCO demonstrates an increase in collagen deposition within the scaffold and the development of tissue fibrosis. Overall, these results further our understanding of the molecular mechanisms underlying MARCO and TLR signaling within PTS. Impact statement Monocyte and macrophage phenotypes in the foreign body reaction (FBR) are essential for the development of a proinflammatory, prohealing, or profibrotic response to implanted biomaterials. Identification of key surface receptors and signaling mechanisms that give rise to these phenotypes remain to be elucidated. In this study, we report a synergistic relationship between macrophage receptor with collagenous structure (MARCO) and toll-like receptor (TLR) signaling in scaffold-resident cells inhabiting porous precision-templated 40 µm pore scaffolds through a MyD88-dependent pathway that promotes healing. These findings advance our understanding of the FBR and provide further evidence that suggests MARCO, TLRs, and fibrosis may be interconnected.

Consensus Statement: Technical Standards for Thoracoabdominal Normothermic Regional Perfusion.

BACKGROUND: Thoracoabdominal normothermic regional perfusion (TA-NRP) has emerged as a powerful technique for optimizing organ procurement from donation after circulatory death donors. Despite its rapid adoption, standardized guidelines for TA-NRP implementation are lacking, prompting the need for consensus recommendations to ensure safe and effective utilization of this technique. METHODS: A working group composed of members from The American Society of Transplant Surgeons, The International Society of Heart and Lung Transplantation, The Society of Thoracic Surgeons, and The American Association for Thoracic Surgery was convened to develop technical guidelines for TA-NRP. The group systematically reviewed existing literature, consensus statements, and expert opinions to identify key areas requiring standardization, including predonation evaluation, intraoperative management, postdonation procedures, and future research directions. RESULTS: The working group formulated recommendations encompassing donor evaluation and selection criteria, premortem testing and therapeutic interventions, communication protocols, and procedural guidelines for TA-NRP implementation. These recommendations aim to facilitate coordination among transplant teams, minimize variability in practice, and promote transparency and accountability throughout the TA-NRP process. CONCLUSIONS: The consensus guidelines presented herein serve as a comprehensive framework for the successful and ethical implementation of TA-NRP programs in organ procurement from donation after circulatory death donors. By providing standardized recommendations and addressing areas of uncertainty, these guidelines aim to enhance the quality, safety, and efficiency of TA-NRP procedures, ultimately contributing to improved outcomes for transplant recipients.

Consensus Statement: Technical Standards for Thoracoabdominal Normothermic Regional Perfusion.

BACKGROUND: Thoracoabdominal normothermic regional perfusion (TA-NRP) has emerged as a powerful technique for optimizing organ procurement from donation after circulatory death donors. Despite its rapid adoption, standardized guidelines for TA-NRP implementation are lacking, prompting the need for consensus recommendations to ensure safe and effective utilization of this technique. METHODS: A working group composed of members from The American Society of Transplant Surgeons, The International Society of Heart and Lung Transplantation, The Society of Thoracic Surgeons, and The American Association for Thoracic Surgery was convened to develop technical guidelines for TA-NRP. The group systematically reviewed existing literature, consensus statements, and expert opinions to identify key areas requiring standardization, including predonation evaluation, intraoperative management, postdonation procedures, and future research directions. RESULTS: The working group formulated recommendations encompassing donor evaluation and selection criteria, premortem testing and therapeutic interventions, communication protocols, and procedural guidelines for TA-NRP implementation. These recommendations aim to facilitate coordination among transplant teams, minimize variability in practice, and promote transparency and accountability throughout the TA-NRP process. CONCLUSIONS: The consensus guidelines presented herein serve as a comprehensive framework for the successful and ethical implementation of TA-NRP programs in organ procurement from donation after circulatory death donors. By providing standardized recommendations and addressing areas of uncertainty, these guidelines aim to enhance the quality, safety, and efficiency of TA-NRP procedures, ultimately contributing to improved outcomes for transplant recipients.

Ex vivo lung perfusion in donation after circulatory death: A post hoc analysis of the Normothermic Ex Vivo Lung Perfusion as an Assessment of Extended/Marginal Donors Lungs trial.

OBJECTIVE: Donation after circulatory death (DCD) donors offer the ability to expand the lung donor pool and ex vivo lung perfusion (EVLP) further contributes to this ability by allowing for additional evaluation and resuscitation of these extended criteria donors. We sought to determine the outcomes of recipients receiving organs from DCD EVLP donors in a multicenter setting. METHODS: This was an unplanned post hoc analysis of a multicenter, prospective, nonrandomized trial that took place during 2011 to 2017 with 3 years of follow-up. Patients were placed into 3 groups based off procurement strategy: brain-dead donor (control), brain-dead donor evaluated by EVLP, and DCD donors evaluated by EVLP. The primary outcomes were severe primary graft dysfunction at 72 hours and survival. Secondary outcomes included select perioperative outcomes, and 1-year and 3-years allograft function and quality of life measures. RESULTS: The DCD EVLP group had significantly higher incidence of severe primary graft dysfunction at 72 hours (P = .03), longer days on mechanical ventilation (P < .001) and in-hospital length of stay (P = .045). Survival at 3 years was 76.5% (95% CI, 69.2%-84.7%) for the control group, 68.3% (95% CI, 58.9%-79.1%) for the brain-dead donor group, and 60.7% (95% CI, 45.1%-81.8%) for the DCD group (P = .36). At 3-year follow-up, presence observed bronchiolitis obliterans syndrome or quality of life metrics did not differ among the groups. CONCLUSIONS: Although DCD EVLP allografts might not be appropriate to transplant in every candidate recipient, the expansion of their use might afford recipients stagnant on the waitlist a viable therapy.

Potential role of exosome-based allorecognition pathways involved in lung transplant rejection.

Innate and adaptive immunity both contribute to allorecognition mechanisms that drive rejection after lung transplantation. Classic allorecognition pathways have been extensively described, but there continues to be several unanswered questions. Exosome research appears to be a novel and potentially significant area of allorecognition research and could be the missing link that answers some existing questions. This article reviews literature that is associated with allorecognition pathways and the role of exosomes in alloreactivity.

Balloon Pulmonary Angioplasty in Chronic Totally Occluded Pulmonary Arteries: Applying Lessons Learned From the Treatment of Coronary Artery Chronic Total Occlusions.

OBJECTIVES: This study aims to describe the safety and efficacy of revascularizing chronic total occlusions (CTOs) of the pulmonary arteries with balloon pulmonary angioplasty (BPA) in patients with chronic thromboembolic pulmonary hypertension (CTEPH). BACKGROUND: BPA has emerged as an effective treatment for CTEPH patients when surgical treatment is not possible. Experience to date has suggested treating CTOs may be associated with excess risk and less procedural success relative to other lesion types. METHODS: This study is a retrospective case series of all BPAs on CTOs for individuals with CTEPH at a single institution. Procedural approach, complications, and success rate over a 6-month period are described. RESULTS: During the study period, 6 individuals with 15 CTOs were identified and intervened upon during 21 interventions. Success rate for revascularization was 62% per attempt and 87% per lesion. Techniques used for successful intervention include true to true lumen wiring (n = 7) and subintimal dissection re-entry with subintimal tracking and re-entry (n = 3), Stingray balloon (Boston Scientific) assisted re-entry (n = 2), and direct wire re-entry (n = 1). Wire perforations were relatively common and occurred in 62% of interventions, but rarely resulted in a change in clinical status. CONCLUSIONS: Although important barriers to routine intervention on CTOs in CTEPH remain, the current series suggests a higher success rate than previously reported experiences using CTO revascularization techniques including subintimal tracking and re-entry and Stingray balloon-assisted re-entry. Although the frequency of wire perforation was relatively high, the clinical ramifications of these complications were mild.

Safety and Costs of Endobronchial Ultrasound-Guided Nodal Aspiration and Mediastinoscopy.

BACKGROUND: There remains debate over the best invasive diagnostic modality for mediastinal nodal evaluation. Prior studies have limited generalizability and insufficient power to detect differences in rare adverse events. We compared the risks and costs of endobronchial ultrasound (EBUS)-guided nodal aspiration and mediastinoscopy performed for any indication in a large national cohort. METHODS: We conducted a retrospective study (2007-2015) with MarketScan, a claims database of individuals with employer-provided insurance in the United States. Patients who underwent multimodality mediastinal evaluation (n = 1,396) or same-day pulmonary resection (n = 2,130) were excluded. Regression models were used to evaluate associations between diagnostic modalities and risks and costs while adjusting for patient characteristics, year, concomitant bronchoscopic procedures, and lung cancer diagnosis. RESULTS: Among 30,570 patients, 49% underwent EBUS. Severe adverse events-pneumothorax, hemothorax, airway/vascular injuries, or death-were rare and invariant between EBUS and mediastinoscopy (0.3% vs 0.4%; P = .189). The rate of vocal cord paralysis was lower for EBUS (1.4% vs 2.2%; P < .001). EBUS was associated with a lower adjusted risk of severe adverse events (OR, 0.42; 95% CI, 0.32-0.55) and vocal cord paralysis (OR, 0.57; 95% CI, 0.54-0.60). The mean cost of EBUS was $2,211 less than mediastinoscopy ($6,816 vs $9,023; P < .001). After adjustment this difference decreased to $1,650 (95% CI, $1,525-$1,776). CONCLUSIONS: When performed as isolated procedures, EBUS is associated with lower risks and costs compared with mediastinoscopy. Future studies comparing the effectiveness of EBUS vs mediastinoscopy in the community at large will help determine which procedure is superior or if trade-offs exist.

Underweight Patients With Cystic Fibrosis Have Acceptable Survival Following Lung Transplantation: A United Network for Organ Sharing Registry Study.

BACKGROUND: Reduced BMI is an absolute contraindication for lung transplantation (LTx) at most centers in the United States. The objective of this study was to quantify post-LTx survival of moderate to severely underweight patients with cystic fibrosis (CF) (BMI < 17 kg/m2) in the United States relative to normal-weight recipients with CF and other frequently transplanted patient cohorts. METHODS: Using United Network for Organ Sharing Registry data (undergoing transplant from June 2005-November 2015), Kaplan-Meier estimates of median posttransplant survival were calculated for all patients with CF, COPD, and idiopathic pulmonary fibrosis (IPF), as well as low and normal weight CF subgroups. Cox regression modeling stratified according to transplant center assessed risk of posttransplant mortality in recipients with CF and a BMI < 17 kg/m2 compared with recipients with COPD (reference). RESULTS: Median posttransplant survival (95% CI) for CF, COPD, and IPF was 7.9 (7.2-8.6), 5.9 (5.6-6.2), and 5.5 (5.2-5.8) years, respectively. Although an absolute decrease was noted in posttransplant survival for recipients with CF and a BMI < 17 kg/m2, compared with those with CF and a BMI ≥ 17 kg/m2 (7.0 years [4.5-7.9] vs 8.2 years [7.3-9.0]), Cox modeling found no increased mortality risk (adjusted hazard ratio, 1.09; 95% CI, 0.90-1.32; P = .38). There was no difference in posttransplant mortality between patients with CF and a BMI < 17 kg/m2 and recipients with COPD and all BMIs (adjusted hazard ratio, 1.04; 95% CI, 0.86-1.25; P = .71). CONCLUSIONS: Transplant recipients with CF and a BMI < 17 kg/m2 had posttransplant survival rates comparable to those of other groups frequently undergoing transplantation. BMI < 17 kg/m2 as a single risk factor in the CF population should not be treated as an absolute contraindication to LTx.

Video-Assisted Thoracoscopic Lobectomy for Lung Cancer.

The use of video-assisted thoracoscopic surgery (VATS) lobectomy has become a mainstay of modern-day thoracic oncology practice and the technique of choice for resection of early-stage lung cancers at many institutions. The feasibility of VATS lobectomy has long been well established, and there is considerable belief that it leads to better patient outcomes. In the following review we seek to summarize the current experience with VATS lobectomy, identify the strengths and weaknesses of the available literature, and address future areas of research for our field.

Prediction Model for Nodal Disease Among Patients With Non-Small Cell Lung Cancer.

BACKGROUND: We characterized the performance characteristics of guideline-recommended invasive mediastinal staging (IMS) for lung cancer and developed a prediction model for nodal disease as a potential alternative approach to staging. METHODS: We conducted a prospective cohort study of adults with suspected/confirmed non-small cell lung cancer without evidence of distant metastatic disease (by computed tomography/positron emission tomography) who underwent nodal evaluation by IMS and/or at the time of resection. The true-positive rate was the proportion of patients with true nodal disease selected to undergo IMS based on guideline recommendations, and the false-positive rate was the proportion of patients without true nodal disease selected to undergo IMS. Logistic regression was used to predict nodal disease using radiographic predictors. RESULTS: Among 123 eligible subjects, 31 (25%) had pathologically confirmed nodal disease. A guideline-recommended invasive staging strategy had a true-positive rate and false-positive rate of 100% and 65%, respectively. The prediction model fit the data well (goodness-of-fit test, p = 0.55) and had excellent discrimination (optimism corrected c-statistic, 0.78; 95% confidence interval, 0.72 to 0.89). Exploratory analysis revealed that use of the prediction model could achieve a false-positive rate of 44% and a true-positive rate of 97%. CONCLUSIONS: A guideline-recommended strategy for IMS selects all patients with true nodal disease and most patients without nodal disease for IMS. Our prediction model appears to maintain (within a margin of error) the sensitivity of a guideline-recommended invasive staging strategy and has the potential to reduce the use of invasive procedures.

Airway epithelium-shifted mast cell infiltration regulates asthmatic inflammation via IL-33 signaling.

Asthma is a heterogeneous syndrome that has been subdivided into physiologic phenotypes and molecular endotypes. The most specific phenotypic manifestation of asthma is indirect airway hyperresponsiveness (AHR), and a prominent molecular endotype is the presence of type 2 inflammation. The underlying basis for type 2 inflammation and its relationship to AHR are incompletely understood. We assessed the expression of type 2 cytokines in the airways of subjects with and without asthma who were extensively characterized for AHR. Using quantitative morphometry of the airway wall, we identified a shift in mast cells from the submucosa to the airway epithelium specifically associated with both type 2 inflammation and indirect AHR. Using ex vivo modeling of primary airway epithelial cells in organotypic coculture with mast cells, we show that epithelial-derived IL-33 uniquely induced type 2 cytokines in mast cells, which regulated the expression of epithelial IL33 in a feed-forward loop. This feed-forward loop was accentuated in epithelial cells derived from subjects with asthma. These results demonstrate that type 2 inflammation and indirect AHR in asthma are related to a shift in mast cell infiltration to the airway epithelium, and that mast cells cooperate with epithelial cells through IL-33 signaling to regulate type 2 inflammation.

Treatment of locally advanced adenoid cystic carcinoma of the trachea with neutron radiotherapy.

PURPOSE: To examine the efficacy of fast neutron radiotherapy in the treatment of locally advanced adenoid cystic carcinoma (ACC) of the trachea and to compare outcomes with and without high-dose-rate (HDR) endobronchial brachytherapy boost. METHODS AND MATERIALS: Between 1989 and 2005, a total of 20 patients with ACC of the trachea were treated with fast neutron radiotherapy at the University of Washington. Of these 20 patients, 19 were treated with curative intent. Neutron doses ranged from 10.7 to 19.95 Gy (median, 19.2 Gy). Six of these patients received an endobronchial brachytherapy boost using an HDR (192)Ir source (3.5 Gy x 2 fractions). Median duration of follow-up was 46 months (range, 10-121 months). RESULTS: The 5-year actuarial overall survival rate and median overall survival for the entire cohort were 89.4%, and 97 months, respectively. Overall survival was not statistically different among those patients receiving an endobronchial boost compared with those receiving neutron radiotherapy alone (100% vs. 68%, p = 0.36). The 5-year actuarial locoregional control rate for the entire cohort was 54.1%. The locoregional control rate was not statistically different among patients who received an endobronchial boost compared with those who received neutron radiotherapy alone (40% vs. 58%, p = 0.94). There were no cases of Grade > or =3 acute toxicity. There were 2 cases of Grade 3/4 chronic toxicity. CONCLUSIONS: Fast neutron radiotherapy is an effective treatment for locally advanced adenoid cystic carcinoma of the trachea, with acceptable treatment-related toxicity.