Colleen L. Channick

Implementing multiplexed genotyping of non-small-cell lung cancers into routine clinical practice

BACKGROUND Personalizing non-small-cell lung cancer (NSCLC) therapy toward oncogene addicted pathway inhibition is effective. Hence, the ability to determine a more comprehensive genotype for each case is becoming essential to optimal cancer care. METHODS We developed a multiplexed PCR-based assay (SNaPshot) to simultaneously identify >50 mutations in several key NSCLC genes. SNaPshot and FISH for ALK translocations were integrated into routine practice as Clinical Laboratory Improvement Amendments-certified tests. Here, we present analyses of the first 589 patients referred for genotyping. RESULTS Pathologic prescreening identified 552 (95%) tumors with sufficient tissue for SNaPshot; 51% had ≥1 mutation identified, most commonly in KRAS (24%), EGFR (13%), PIK3CA (4%) and translocations involving ALK (5%). Unanticipated mutations were observed at lower frequencies in IDH and β-catenin. We observed several associations between genotypes and clinical characteristics, including increased PIK3CA mutations in squamous cell cancers. Genotyping distinguished multiple primary cancers from metastatic disease and steered 78 (22%) of the 353 patients with advanced disease toward a genotype-directed targeted therapy. CONCLUSIONS Broad genotyping can be efficiently incorporated into an NSCLC clinic and has great utility in influencing treatment decisions and directing patients toward relevant clinical trials. As more targeted therapies are developed, such multiplexed molecular testing will become a standard part of practice.

Molecular Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in ALK-Rearranged Lung Cancer

Advanced, anaplastic lymphoma kinase (ALK)-positive lung cancer is currently treated with the first-generation ALK inhibitor crizotinib followed by more potent, second-generation ALK inhibitors (e.g., ceritinib, alectinib) upon progression. Second-generation inhibitors are generally effective even in the absence of crizotinib-resistant ALK mutations, likely reflecting incomplete inhibition of ALK by crizotinib in many cases. Herein, we analyzed 103 repeat biopsies from ALK-positive patients progressing on various ALK inhibitors. We find that each ALK inhibitor is associated with a distinct spectrum of ALK resistance mutations and that the frequency of one mutation - ALK G1202R - increases significantly after treatment with second-generation agents. To investigate strategies to overcome resistance to second-generation ALK inhibitors, we examine the activity of the third-generation ALK inhibitor lorlatinib in a series of ceritinib-resistant, patient-derived cell lines, and observe that the presence of ALK resistance mutations is highly predictive for sensitivity to lorlatinib, whereas those cell lines without ALK mutations are resistant.

Airway stenoses after lung transplantation: Incidence, management, and outcome

OBJECTIVE Airway stenoses have been a significant cause of morbidity and mortality after lung transplantation. We reviewed our 11-year experience with dilatation and silicone stent treatment of airway strictures after lung transplantation. We adopted this approach after managing the complications of nitinol/wire mesh stents, including stent fracture, granulation tissue overgrowth, and difficulty with removal. METHODS Between January of 1996 and December of 2007, 240 patients underwent lung transplantation (132 single lung, 108 double lung; 121 male, 119 female; mean age 49.4 +/- 12.9 years). Twenty patients (8.3%) developed >50% stenosis in 22 airways over 35 to 135 days following surgery. Short and long-segment strictures were managed with rigid bronchoscopy, mechanical/laser debridement, balloon dilatation, and silicone stent placement. Mean follow-up was 4.9 +/- 3.5 years after stent removal. RESULTS The mean time to diagnosis of airway stenosis was 81.5 +/- 26.9 days. Pulmonary aspergillosis and pseudomonal infection, age less than 45 years, and early rejection correlated with airway stenosis; however, ischemic time, side of transplant, and preoperative disease did not. Airway patency and symptom improvement were achieved in 18 of 20 patients. Sixteen patients were able to have their stents removed at a mean of 362.3 +/- 126.4 days with permanent resolution of airway stenosis. Overall survival was similar for patients with and without airway stenosis. CONCLUSION Airway stenosis after lung transplantation can be successfully managed with bronchoscopic dilatation and temporary silicone stent placement. With time, most short and long airway stenoses resolve with atraumatic stenting of the affected areas. Removal of stents with permanent airway patency is achievable in most lung transplant recipients with airway stenosis.

Toward the Guidance of Transbronchial Biopsy: Identifying Pulmonary Nodules With Optical Coherence Tomography

BACKGROUND Solitary pulmonary nodules (SPNs) frequently require transbronchial needle aspiration (TBNA) or biopsy to determine malignant potential, but have variable diagnostic yields. Confirming needle placement within SPNs during TBNA could significantly increase diagnostic yield. Optical coherence tomography (OCT) provides nondestructive, high-resolution, microstructural imaging with potential to distinguish SPN from parenchyma. We have developed needle-based OCT probes compatible with TBNA. Before OCT can play any significant role in guiding clinical TBNA, OCT interpretation criteria for differentiating SPN from lung parenchyma must be developed and validated. METHODS OCT of SPN and parenchyma was performed on 111 ex vivo resection specimens. OCT criteria for parenchyma and SPN were developed and validated in a blinded assessment. Six blinded readers (two pulmonologists, two pathologists, and two OCT experts) were trained on imaging criteria in a 15-min training session prior to interpreting the validation data set. RESULTS OCT of lung parenchyma displayed evenly spaced signal-void alveolar spaces, signal-intense backreflections at tissue-air interfaces, or both. SPNs lacked both of these imaging features. Independent validation of OCT criteria by the six blinded readers demonstrated sensitivity and specificity of 95.4% and 98.2%, respectively. CONCLUSIONS We have developed and validated OCT criteria for lung parenchyma and SPN with sensitivity and specificity > 95% in this ex vivo study. We anticipate that OCT could be a useful complementary imaging modality to confirm needle placement during TBNA to potentially increase diagnostic yield.

Fully Biodegradable Airway Stents Using Amino Alcohol-Based Poly(ester amide) Elastomers

Airway stents are often used to maintain patency of the tracheal and bronchial passages in patients suffering from central airway obstruction caused by malignant tumors, scarring, and injury. Like most conventional medical implants, they are designed to perform their functions for a limited period of time, after which surgical removal is often required. Two primary types of airway stents are in general use, metal mesh devices and elastomeric tubes; both are constructed using permanent materials, and must be removed when no longer needed, leading to potential complications. This paper describes the development of process technologies for bioresorbable prototype elastomeric airway stents that would dissolve completely after a predetermined period of time or by an enzymatic triggering mechanism. These airway stents are constructed from biodegradable elastomers with high mechanical strength, flexibility and optical transparency. This work combines microfabrication technology with bioresorbable polymers, with the ultimate goal of a fully biodegradable airway stent ultimately capable of improving patient safety and treatment outcomes.

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.

The Diagnosis and Management of Airway Complications Following Lung Transplantation

&NA; Airway complications following lung transplantation result in considerable morbidity and are associated with a mortality of 2% to 4%. The incidence of lethal and nonlethal airway complications has decreased since the early experiences with double‐ and single‐lung transplantation. The most common risk factor associated with post‐lung transplantation airway complications is anastomotic ischemia. Airway complications include the development of exophytic granulation tissue, bronchial stenosis, bronchomalacia, airway fistula, endobronchial infection, and anastomotic dehiscence. The broadening array of bronchoscopic therapies has enhanced treatment options for lung transplant recipients with airway complications. This article reviews the risk factors, clinical manifestations, and treatments of airway complications following lung transplantation and provides our expert opinion when evidence is lacking.

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 patients 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.

Safety of topical tetracaine in patients undergoing flexible bronchoscopy.

Lidocaine is currently the most commonly used topical anesthetic during flexible bronchoscopy (FFB) in North America. Tetracaine, a longer-acting agent, might produce better airway analgesia; however, previous literature has suggested that tetracaine is more risky and can even result in cardiac arrest. The maximum recommended tetracaine dose for topical anesthesia is 20 mg. Over the past 30 years, our Pulmonary Special Procedures Unit has used topical tetracaine in considerably higher doses. In this study, we sought to review the safety of this approach. We completed a retrospective review of all FFBs performed on nonintubated patients by a single bronchoscopist from January 2005 to February 2007. The primary outcome variables included adverse reactions and tetracaine dose administered. Five hundred thirty-seven FFBs were performed on 431 patients. Patient age ranged from 20 to 94 years, with a mean age of 55 years. Eighty-one percent (n=434) of these FFBs were performed using only topical anesthesia. Tetracaine solution 0.45% was used in 99.6% of these procedures. Mean tetracaine dose was 120 mg (range: 18 to 158 mg). No adverse reactions attributable to tetracaine were noted. Specifically, no cardiac or neurologic events occurred. Bronchospasm was noted in 1.5% of patients and 1 patient required intubation after the procedure owing to severe hypoxemia. This retrospective study suggests that topical tetracaine at doses up to 8 times the “recommended” dose is safe for the use during FFB.

Postradiofrequency ablation inflammatory pseudotumor associated with pulmonary venoocclusive disease: case report and review of the literature.

Radiofrequency ablation of pulmonary veins is a common therapeutic intervention for atrial fibrillation. Pulmonary vein stenosis and venoocclusive disease are recognized complications, but the spectrum of pathologies postablation have not been previously reviewed. A recent case at our hospital showed a left hilar soft tissue mass in association with superior pulmonary vein stenosis in a patient 4 years postablation. On resection, this proved to be an inflammatory pseudotumor composed of myofibroblasts in an organizing pneumonia-type pattern with adjacent dendriform ossifications. Pulmonary venoocclusive change was a prominent feature. Literature on the histopathology of postradiofrequency ablation complications is limited. The severity of vascular pathology appears to increase with the postablation interval. Although pulmonary vascular changes are the most common late finding, fibroinflammatory changes including pulmonary pseudotumor formation, attributable to thermal injury, should be considered in the differential diagnosis of these cases.