Sequential screening for lung cancer in a high-risk group: randomised controlled trial: LungSEARCH: a randomised controlled trial of Surveillance using sputum and imaging for the EARly detection of lung Cancer in a High-risk group.

BACKGROUND: Low-dose computed tomography (LDCT) screening detects early-stage lung cancer and reduces mortality. We proposed a sequential approach targeted to a high-risk group as a potentially efficient screening strategy. METHODS: LungSEARCH was a national multicentre randomised trial. Current/ex-smokers with mild/moderate chronic obstructive pulmonary disease (COPD) were allocated (1:1) to have 5 years surveillance or not. Screened participants provided annual sputum samples for cytology and cytometry, and if abnormal were offered annual LDCT and autofluorescence bronchoscopy (AFB). Those with normal sputum provided annual samples. The primary end-point was the percentage of lung cancers diagnosed at stage I/II (nonsmall cell) or limited disease (small cell). RESULTS: 1568 participants were randomised during 2007-2011 from 10 UK centres. 85.2% of those screened provided an adequate baseline sputum sample. There were 42 lung cancers among 785 screened individuals and 36 lung cancers among 783 controls. 54.8% (23 out of 42) of screened individuals versus 45.2% (14 out of 31) of controls with known staging were diagnosed with early-stage disease (one-sided p=0.24). Relative risk was 1.21 (95% CI 0.75-1.95) or 0.82 (95% CI 0.52-1.31) for early-stage or advanced cancers, respectively. Overall sensitivity for sputum (in those randomised to surveillance) was low (40.5%) with a cumulative false-positive rate (FPR) of 32.8%. 55% of cancers had normal sputum results throughout. Among sputum-positive individuals who had AFB, sensitivity was 45.5% and cumulative FPR was 39.5%; the corresponding measures for those who had LDCT were 100% and 16.1%, respectively. CONCLUSIONS: Our sequential strategy, using sputum cytology/cytometry to select high-risk individuals for AFB and LDCT, did not lead to a clear stage shift and did not improve the efficiency of lung cancer screening.

Cell migration leads to spatially distinct but clonally related airway cancer precursors.

BACKGROUND: Squamous cell carcinoma of the lung is a common cancer with 95% mortality at 5 years. These cancers arise from preinvasive lesions, which have a natural history of development progressing through increasing severity of dysplasia to carcinoma in situ (CIS), and in some cases, ending in transformation to invasive carcinoma. Synchronous preinvasive lesions identified at autopsy have been previously shown to be clonally related. METHODS: Using autofluorescence bronchoscopy that allows visual observation of preinvasive lesions within the upper airways, together with molecular profiling of biopsies using gene sequencing and loss-of-heterozygosity analysis from both preinvasive lesions and from intervening normal tissue, we have monitored individual lesions longitudinally and documented their visual, histological and molecular relationship. RESULTS: We demonstrate that rather than forming a contiguous field of abnormal tissue, clonal CIS lesions can develop at multiple anatomically discrete sites over time. Further, we demonstrate that patients with CIS in the trachea have invariably had previous lesions that have migrated proximally, and in one case, into the other lung over a period of 12 years. CONCLUSIONS: Molecular information from these unique biopsies provides for the first time evidence that field cancerisation of the upper airways can occur through cell migration rather than via local contiguous cellular expansion as previously thought. Our findings urge a clinical strategy of ablating high-grade premalignant airway lesions with subsequent attentive surveillance for recurrence in the bronchial tree.

LRIG1 regulates cadherin-dependent contact inhibition directing epithelial homeostasis and pre-invasive squamous cell carcinoma development.

Epidermal growth factor receptor (EGFR) pathway activation is a frequent event in human carcinomas. Mutations in EGFR itself are, however, rare, and the mechanisms regulating EGFR activation remain elusive. Leucine-rich immunoglobulin repeats-1 (LRIG1), an inhibitor of EGFR activity, is one of four genes identified that predict patient survival across solid tumour types including breast, lung, melanoma, glioma, and bladder. We show that deletion of Lrig1 is sufficient to promote murine airway hyperplasia through loss of contact inhibition and that re-expression of LRIG1 in human lung cancer cells inhibits tumourigenesis. LRIG1 regulation of contact inhibition occurs via ternary complex formation with EGFR and E-cadherin with downstream modulation of EGFR activity. We find that LRIG1 LOH is frequent across cancers and its loss is an early event in the development of human squamous carcinomas. Our findings imply that the early stages of squamous carcinoma development are driven by a change in amplitude of EGFR signalling governed by the loss of contact inhibition.

Immune Surveillance in Clinical Regression of Preinvasive Squamous Cell Lung Cancer.

Before squamous cell lung cancer develops, precancerous lesions can be found in the airways. From longitudinal monitoring, we know that only half of such lesions become cancer, whereas a third spontaneously regress. Although recent studies have described the presence of an active immune response in high-grade lesions, the mechanisms underpinning clinical regression of precancerous lesions remain unknown. Here, we show that host immune surveillance is strongly implicated in lesion regression. Using bronchoscopic biopsies from human subjects, we find that regressive carcinoma in situ lesions harbor more infiltrating immune cells than those that progress to cancer. Moreover, molecular profiling of these lesions identifies potential immune escape mechanisms specifically in those that progress to cancer: antigen presentation is impaired by genomic and epigenetic changes, CCL27-CCR10 signaling is upregulated, and the immunomodulator TNFSF9 is downregulated. Changes appear intrinsic to the carcinoma in situ lesions, as the adjacent stroma of progressive and regressive lesions are transcriptomically similar. SIGNIFICANCE: Immune evasion is a hallmark of cancer. For the first time, this study identifies mechanisms by which precancerous lesions evade immune detection during the earliest stages of carcinogenesis and forms a basis for new therapeutic strategies that treat or prevent early-stage lung cancer.See related commentary by Krysan et al., p. 1442.This article is highlighted in the In This Issue feature, p. 1426.

The surgical management of non-malignant aerodigestive fistula.

BACKGROUND: Acquired aerodigestive fistula (ADF) are rare, but associated with significant morbidity. Surgery affords the best prospect of cure. We present our experience of the surgical management of ADFs at a specialist unit, highlighting operative techniques, challenges and assess clinical outcomes following intervention. We also illustrate findings of a Hospital Episodes Statistics search for ADFs. METHODS: A prospectively-maintained database was searched to identify all patients diagnosed with an ADF who were managed at our institution. Of 48 patients with an ADF, eight underwent surgical intervention. RESULTS: Four patients underwent an exploration of the ADF with primary repair of the defect. Two of these patients had proximal ADFs, amenable to repair through a neck incision, and two required a thoracotomy. Two patients suffered fistulae secondary to endoscopic therapy and underwent oesophageal exclusion surgery, with subsequent staged reconstruction. Two patients with previous Tuberculosis had a lung segmentectomy and lobectomy respectively, and a further patient in remission after treatment for lymphoma underwent oesophageal resection with synchronous reconstruction. Three patients suffered a complication, with one post-operative mortality. The remaining seven patients all achieved normal oral alimentation, with no evidence of ADF recurrence at a median follow-up of 32 months. CONCLUSIONS: Surgery to manage ADFs is effective in restoring normal alimentation and alleviates soiling of the airway, with a very low risk of recurrence. Several operative techniques can be utilised dependent on the features of the ADF. Early referral to specialist units is advocated, where the expertise to facilitate the complete management of patients is present, within a multi-disciplinary setting.

Acquired Adult Aerodigestive Fistula: Classification and Management.

BACKGROUND: Acquired aerodigestive fistulae (ADF) are rare, but associated with a high mortality rate. We present our experience of the diagnosis, management and outcomes of patients with ADFs treated at a tertiary centre. Utilising our findings, we propose an anatomical classification system, demonstrating how specific features of an ADF may determine management. METHODS: A clinical database was searched and 48 patients with an ADF were identified. A classification system was developed based on anatomical location of the ADF and differences in clinico-pathological features based on this categorisation were performed, with the chi-squared test used for inferential analyses and Kaplan-Meier curves with log-rank test to assess survival. RESULTS: Twenty (41.6%) patients developed an ADF secondary to malignancy, with previous radiotherapy (18.7%), post-operative anastomotic dehiscence and endotherapy (14.6% each) representing other causes. Thirty-one patients were managed with tracheal and/or oesophageal stents and eight underwent surgical repair. The classification system demonstrated benign causes of ADF were either proximally or distally sited, whilst a malignant cause resulted in mid-tracheal fistulae (p = 0.001), with the latter associated with poorer survival. ADFs over 20 mm in size were associated with poor survival (p = 0.011), as was the use of previous radiotherapy. Proximal and distal ADFs were associated with improved survival (p = 0.006), as were those patients managed surgically (p = 0.001). CONCLUSION: By classifying ADFs, we have demonstrated that anatomical location correlates with the size, history of malignancy, previous radiotherapy and aetiology of ADF, which can affect management. The proposed classification system will aid in formulating multi-modality individualised treatment plans.

Central airway obstruction caused by a peripheral hamartoma.

We report the first case of a hamartoma, arising from peripheral lung tissue, which extended proximally over several decades to occlude the large airways. The patient's symptoms were originally attributed to asthma and the correct diagnosis was only made when she developed life-threatening airway obstruction. The endobronchial component of the hamartoma was debulked with urgent laser therapy, while the peripheral base of the tumour was resected by elective right middle lobectomy.

Interventional bronchoscopy in the management of thoracic malignancy.

Interventional bronchoscopy is a rapidly expanding field in respiratory medicine offering minimally invasive therapeutic and palliative procedures for all types of lung neoplasms. This field has progressed over the last couple of decades with the application of new technology. The HERMES European curriculum recommendations include interventional bronchoscopy skills in the modules of thoracic tumours and bronchoscopy [1]. However, interventional bronchoscopy is not available in all training centres and consequently, not all trainees will obtain experience unless they rotate to centres specifically offering such training. In this review, we give an overview of interventional bronchoscopic procedures used for the treatment and palliation of thoracic malignancy. These can be applied either with flexible or rigid bronchoscopy or a combination of both depending on the anatomical location of the tumour, the complexity of the case, bleeding risk, the operator's expertise and preference as well as local availability. Specialised anaesthetic support and appropriately trained endoscopy staff are essential, allowing a multimodality approach to meet the high complexity of these cases.

Early lung cancer: screening and detection.

The most significant factor which determines the survival of a patient newly-diagnosed with lung cancer is the stage at which the disease has been diagnosed. Late diagnosis is common. This review focuses upon the possibility of earlier diagnosis using various cytological and radiological imaging techniques such as sputum cytology or cytometry, CT scanning, and fluorescence bronchoscopy.

Somatic genetic changes accompanying lung tumor development.

Carcinomas are believed to develop by incremental steps of increasingly abnormal morphology driven by accumulating somatic genetic changes. This process is often difficult to study, as the early stages are undetectable. We used fluorescence bronchoscopy, which enhances detection of preinvasive bronchial lesions, and have obtained sequential biopsies of carcinoma in situ (CIS) from a patient with no detectable tumor and from a squamous cell carcinoma that developed 19 months after presentation at the site of one of the previous CIS lesions. Biopsies of preinvasive CIS, which follow-up showed had different pathologic outcomes, and tumor were microdissected to obtain enriched cell populations and DNA prepared from them. Molecular characteristics of these biopsies were compared by loss of heterozygosity analysis, TP53 mutation analysis, and comparative genomic hybridization. Although all lesions examined had the same TP53 mutation and almost identical allelotypes, differences were observed. Loss in 5q21 and amplification of 3q25-26 were associated with the lesion that progressed and the subsequent carcinoma. Allele loss at 4p16 was detected in the tumor but not in any of the CIS lesions, suggesting it was a late event associated with tumor invasion. Amplification at 4q12 was specifically observed in the tumor and in the CIS at the site of eventual tumor formation. Although these findings may be unique to this one patient, the successful demonstration of sequential genetic changes raises the possibility that this approach, unencumbered by interpatient variability between lesions, will greatly facilitate the identification of molecular events driving the invasive process

Survival benefits of lung cancer patients undergoing laser and brachytherapy.

We aimed to compare the duration of survival among subjects receiving brachytherapy (BT) in combination with Nd:YAG laser therapy (LT), and those receiving LT or BT alone. The medical records of subjects who received endobronchial treatment for unresectable tracheobronchial malignancies between January 1997 and December 1999 in a single center were reviewed retrospectively. A total of 80 patients were evaluated. The overall symptomatic response rate after treatment was 86.5%. Median survival durations for the LT, BT, and combined therapy (CT) group were 111, 115, and 264 days, respectively. The survival duration was significantly longer in the CT group than in the BT group (p=0.0078), but the difference was not statistically significant between the CT and the LT group. The bronchoscopic finding of endobronchial polypoid lesion was associated with a longer survival time than extraluminal with compression type (p=0.0023) by univariate analysis. Other factors associated with the better prognosis included hemoglobin > or = 12.5 g/dL, serum albumin level > or = 37 g/L, and BT dose > or = 15 Gy at 1 cm distance. Of these factors, specific bronchoscopic findings, serum albumin level, CT modality, and dose of BT retained statistical significance in multivariate analysis. In conclusion, combined LT and BT is associated with increased patient survival compared with BT alone. Combined therapy may improve survival time in selected patients with endobronchial malignancies.