CADM1 inhibits squamous cell carcinoma progression by reducing STAT3 activity.

Although squamous cell carcinomas (SqCCs) of the lungs, head and neck, oesophagus, and cervix account for up to 30% of cancer deaths, the mechanisms that regulate disease progression remain incompletely understood. Here, we use gene transduction and human tumor xenograft assays to establish that the tumour suppressor Cell adhesion molecule 1 (CADM1) inhibits SqCC proliferation and invasion, processes fundamental to disease progression. We determine that the extracellular domain of CADM1 mediates these effects by forming a complex with HER2 and integrin α6ß4 at the cell surface that disrupts downstream STAT3 activity. We subsequently show that treating CADM1 null tumours with the JAK/STAT inhibitor ruxolitinib mimics CADM1 gene restoration in preventing SqCC growth and metastases. Overall, this study identifies a novel mechanism by which CADM1 prevents SqCC progression and suggests that screening tumours for loss of CADM1 expression will help identify those patients most likely to benefit from JAK/STAT targeted chemotherapies.

Management and prognosis of primary tracheal cancer: a national analysis.

OBJECTIVES/HYPOTHESIS: To perform a national review of the incidence and treatment of primary tracheal cancer and to identify gaps in service provision and factors associated with survival. STUDY DESIGN: Retrospective analysis of Hospital Episode Statistics data for England between 1996 and 2011. METHODS: Information about age, sex, morbidity, provider trust, diagnostic delay, nature of hospital admission and treatment, and palliation-free survival were recorded. The relationship between variables and survival was explored with Cox regression. RESULTS: There were 874 patients, giving an incidence of 0.9 per million. Mean age at diagnosis was 66 ± 13, and there were 456 (52%) males. Mean presentation to diagnosis latency was 2.5 ± 8 months, and 40% of patients presented as emergency admissions. There were 19 cases of oesophageal involvement and 241 cases of bronchopulmonary involvement; and 188 patients developed distant metastases. There were 60 curative resections (6.9%), which was the most significant predictor of palliation-free survival (hazard ratio: 0.23; 95% confidence interval 0.13-0.38). Other prognostic variables included age, sex, emergency admission, interventional bronchoscopy, chemotherapy, oesophageal involvement, and distant metastases. Ten-year palliation-free survival was 60.8% with curative resection and 19.5% overall. Eighty-six percent of patients were treated in units that treated fewer than one patient per year. CONCLUSION: Tracheal cancer is under-recognized and under-treated. Early diagnosis, access to interventional bronchoscopy, and surgical treatment in specialist units may improve the survival of patients with this condition.

Not always asthma: clinical and legal consequences of delayed diagnosis of laryngotracheal stenosis.

Laryngotracheal stenosis (LTS) is a rare condition that occurs most commonly as a result of instrumentation of the airway but may also occur as a result of inflammatory conditions or idiopathically. Here, we present the case of a patient who developed LTS as a complication of granulomatosis with polyangiitis (GPA), which was misdiagnosed as asthma for 6 years. After an admission with respiratory symptoms that worsened to the extent that she required intubation, a previously well 14-year-old girl was diagnosed with GPA. Following immunosuppressive therapy, she made a good recovery and was discharged after 22 days. Over subsequent years, she developed dyspnoea and "wheeze" and a diagnosis of asthma was made. When she became pregnant, she was admitted to hospital with worsening respiratory symptoms, whereupon her "wheeze" was correctly identified as "stridor," and subsequent investigations revealed a significant subglottic stenosis. The delay in diagnosis precluded the use of minimally invasive therapies, with the result that intermittent laser resection and open laryngotracheal reconstructive surgery were the only available treatment options. There were numerous points at which the correct diagnosis might have been made, either by proper interpretation of flow-volume loops or by calculation of the Empey or Expiratory Disproportion Indices from spirometry data.

Diagnosis of laryngotracheal stenosis from routine pulmonary physiology using the expiratory disproportion index.

OBJECTIVE/HYPOTHESIS: The study's objective was to determine the utility of expiratory disproportion index (EDI), the ratio of forced expiratory volume in 1 second (FEV1) to peak expiratory flow rate (PEFR) (EDI = FEV1[L] /PEFR[L/s] × 100), in differentiating between laryngotracheal stenosis (LTS) and other respiratory diagnoses. LTS is an uncommon complication of mechanical ventilation or vasculitis or a manifestation of airway compression or malignancy. It frequently masquerades as asthma and evades timely diagnosis, causing prolonged morbidity and airway-related mortality. STUDY DESIGN: Observational study. METHODS: We compared spirometry results of 9,357 healthy subjects and nonstenosis pulmonary patients with 217 cases of LTS. Bootstrap analysis, receiver-operating characteristic (ROC) statistics, and Pearson correlation were used to assess the diagnostic utility of the EDI and its correlation with stenosis severity. RESULTS: Mean EDI values were 36 ± 7 in nonstenosis cases, 76 ± 17 in benign stenoses, and 69 ± 23 in tracheal cancer (P < .0001). A significant correlation existed between anatomic stenosis severity and EDI (P < .0001; R = 0.61). Area under the ROC curve was 0.98, and at a threshold of >50, EDI had a sensitivity of 95.9% and a specificity of 94.2% in differentiating between stenosis and nonstenosis cases. CONCLUSIONS: EDI can reliably diagnose LTS using routine lung function data. Its simplicity and clinical utility, first recognized by Duncan Empey, are underpinned by a unique physiology whereby PEFR, being determined by total tracheobronchial tree resistance, falls disproportionately compared with FEV1 , which is determined within small intrathoracic airways. EDI provides valuable information about the presence and extent of LTS particularly in nonspecialist clinical settings and its routine inclusion within standard lung function reports could prevent the prolonged morbidity and mortality that currently result from missed and delayed diagnoses.

ß-Catenin determines upper airway progenitor cell fate and preinvasive squamous lung cancer progression by modulating epithelial-mesenchymal transition.

Human lung cancers, including squamous cell carcinoma (SCC) are a leading cause of death and, whilst evidence suggests that basal stem cells drive SCC initiation and progression, the mechanisms regulating these processes remain unknown. In this study we show that ß-catenin signalling regulates basal progenitor cell fate and subsequent SCC progression. In a cohort of preinvasive SCCs we established that elevated basal cell ß-catenin signalling is positively associated with increased disease severity, epithelial proliferation and reduced intercellular adhesiveness. We demonstrate that transgene-mediated ß-catenin inhibition within keratin 14-expressing basal cells delayed normal airway repair while basal cell-specific ß-catenin activation increased cell proliferation, directed differentiation and promoted elements of early epithelial-mesenchymal transition (EMT), including increased Snail transcription and reduced E-cadherin expression. These observations are recapitulated in normal human bronchial epithelial cells in vitro following both pharmacological ß-catenin activation and E-cadherin inhibition, and mirrored our findings in preinvasive SCCs. Overall, the data show that airway basal cell ß-catenin determines cell fate and its mis-expression is associated with the development of human lung cancer.

Outcome of treating airway compromise due to bronchial stenosis with intralesional corticosteroids and cutting-balloon bronchoplasty.

OBJECTIVES: To determine the feasibility, safety, and efficacy of treating benign bronchial stenosis with laryngoscopy, jet ventilation, intralesional corticosteroids, and cutting-balloon bronchoplasty. STUDY DESIGN: Case series with planned data collection. SETTING: National airway unit. SUBJECTS AND METHODS: Ten adult patients with bronchial stenosis caused by Wegener's granulomatosis (n = 6), tuberculosis (n = 2), intubation (n = 1), and photodynamic therapy (n = 1) who underwent bronchoplasty using cutting-balloon dilation via suspension laryngoscopy in 2009. Information about patient demography, etiology, lesion characteristics, and details of the interventions were recorded. Patients underwent spirometry before surgery and at last follow-up. Chest infection rate in the 6 months before bronchoplasty and from bronchoplasty to the last follow-up was ascertained. RESULTS: There were 3 men and 7 women. Mean age at bronchoplasty was 46 ± 20 years. Length of stay was 1 day in all cases, and no treatment-related complications occurred. One patient required a second bronchoplasty at 55 days. Mean follow-up was 7 ± 2.3 months. Forced expiratory volume in 1 second increased from a prebronchoplasty mean of 1.6 ± 0.6 to 2.2 ± 0.5 at last follow-up (P < .0001; paired Student t test). Forced vital capacity rose from 2.7 ± 0.6 to 3.1 ± 0.6 (P = .02), and peak expiratory flow rate increased from 3.7 ± 0.8 to 5.0 ± 0.8 (P < .0001). Chest infection rate fell from an average of 0.7 ± 0.3 infections per month to 0.2 ± 0.2 (P < .003; paired Student t test). CONCLUSION: Cutting-balloon bronchoplasty via suspension laryngoscopy is an effective treatment for benign bronchial stenosis. It is safer than airway stenting and is less invasive than thoracotomy. The authors propose its use as first-line treatment for this condition.

Genomic evidence of pre-invasive clonal expansion, dispersal and progression in bronchial dysplasia.

The term 'field cancerization' is used to describe an epithelial surface that has a propensity to develop cancerous lesions, and in the case of the aerodigestive tract this is often as a result of chronic exposure to carcinogens in cigarette smoke 1, 2. The clinical endpoint is the development of multiple tumours, either simultaneously or sequentially in the same epithelial surface. The mechanisms underlying this process remain unclear; one possible explanation is that the epithelium is colonized by a clonal population of cells that are at increased risk of progression to cancer. We now address this possibility in a short case series, using individual genomic events as molecular biomarkers of clonality. In squamous lung cancer the most common genomic aberration is 3q amplification. We use a digital PCR technique to assess the clonal relationships between multiple biopsies in a longitudinal bronchoscopic study, using amplicon boundaries as markers of clonality. We demonstrate that clonality can readily be defined by these analyses and confirm that field cancerization occurs at a pre-invasive stage and that pre-invasive lesions and subsequent cancers are clonally related. We show that while the amplicon boundaries can be shared between different biopsies, the degree of 3q amplification and the internal structure of the 3q amplicon varies from lesion to lesion. Finally, in this small cohort, the degree of 3q amplification corresponds to clinical progression.

Progressive 3q amplification consistently targets SOX2 in preinvasive squamous lung cancer.

RATIONALE: Amplification of distal 3q is the most common genomic aberration in squamous lung cancer (SQC). SQC develops in a multistage progression from normal bronchial epithelium through dysplasia to invasive disease. Identifying the key driver events in the early pathogenesis of SQC will facilitate the search for predictive molecular biomarkers and the identification of novel molecular targets for chemoprevention and therapeutic strategies. For technical reasons, previous attempts to analyze 3q amplification in preinvasive lesions have focused on small numbers of predetermined candidate loci rather than an unbiased survey of copy-number variation. OBJECTIVES: To perform a detailed analysis of the 3q amplicon in bronchial dysplasia of different histological grades. METHODS: We use molecular copy-number counting (MCC) to analyze the structure of chromosome 3 in 19 preinvasive bronchial biopsy specimens from 15 patients and sequential biopsy specimens from 3 individuals. MEASUREMENTS AND MAIN RESULTS: We demonstrate that no low-grade lesions, but all high-grade lesions, have 3q amplification. None of seven low-grade lesions progressed clinically, whereas 8 of 10 patients with high-grade disease progressed to cancer. We identify a minimum commonly amplified region on chromosome 3 consisting of 17 genes, including 2 known oncogenes, SOX2 and PIK3CA. We confirm that both genes are amplified in all high-grade dysplastic lesions tested. We further demonstrate, in three individuals, that the clinical progression of high-grade preinvasive disease is associated with incremental amplification of SOX2, suggesting this promotes malignant progression. CONCLUSIONS: These findings demonstrate progressive 3q amplification in the evolution of preinvasive SQC and implicate SOX2 as a key target of this dynamic process.