Low Prevalence of High-Grade Lesions Detected With Autofluorescence Bronchoscopy in the Setting of Lung Cancer Screening in the Pan-Canadian Lung Cancer Screening Study.

BACKGROUND: Lung cancer screening with low-dose CT (LDCT) scan has been demonstrated to reduce lung cancer mortality. Preliminary reports suggested that up to 20% of lung cancers may be CT scan occult but detectable by autofluorescence bronchoscopy (AFB). We evaluated the prevalence of CT scan occult, invasive, and high-grade preinvasive lesions in high-risk participants undergoing screening for lung cancer. METHODS: The first 1,300 participants from seven centers in the Pan-Canadian Early Detection of Lung Cancer Study who had ≥ 2% lung cancer risk over 5 years were invited to have an AFB in addition to a LDCT scan. We determined the prevalence of CT scan and AFB abnormalities and analyzed the association between selected predictor variables and preinvasive lesions plus invasive cancer. RESULTS: A total of 776 endobronchial biopsies were performed in 333 of 1,300 (25.6%) participants. Dysplastic or higher-grade lesions were detected in 5.3% of the participants (n = 68; mild dysplasia: n = 36, moderate dysplasia: n = 25, severe dysplasia: n = 3, carcinoma in situ [CIS]: n = 1, and carcinoma: n = 4). Only one typical carcinoid tumor and one CIS lesion were detected by AFB alone, for a rate of CT scan occult cancer of 0.15% (95% CI, 0.0%-0.6%). Fifty-six prevalence lung cancers were detected by LDCT scan (4.3%). The only independent risk factors for finding of dysplasia or CIS on AFB were smoking duration (OR, 1.05; 95% CI, 1.02-1.07) and FEV1 percent predicted (OR, 0.99; 95% CI, 0.98-0.99). CONCLUSIONS: The addition of AFB to LDCT scan in a high lung cancer risk cohort detected too few CT occult cancers (0.15%) to justify its incorporation into a lung cancer screening program. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00751660; URL: www.clinicaltrials.gov.

Exhaled breath analysis for lung cancer.

Early diagnosis of lung cancer results in improved survival compared to diagnosis with more advanced disease. Early disease is not reliably indicated by symptoms. Because investigations such as bronchoscopy and needle biopsy have associated risks and substantial costs, they are not suitable for population screening. Hence new easily applicable tests, which can be used to screen individuals at risk, are required. Biomarker testing in exhaled breath samples is a simple, relatively inexpensive, non-invasive approach. Exhaled breath contains volatile and non-volatile organic compounds produced as end-products of metabolic processes and the composition of such compounds varies between healthy subjects and subjects with lung cancer. Many studies have analysed the patterns of these compounds in exhaled breath. In addition studies have also reported that the exhaled breath condensate (EBC) can reveal gene mutations or DNA abnormalities in patients with lung cancer. This review has summarised the scientific evidence demonstrating that lung cancer has distinct chemical profiles in exhaled breath and characteristic genetic changes in EBC. It is not yet possible to accurately identify individuals with lung cancer in at risk populations by any of these techniques. However, analysis of both volatile organic compounds in exhaled breath and of EBC have great potential to become clinically useful diagnostic and screening tools for early stage lung cancer detection.

High speed miniature motorized endoscopic probe for optical frequency domain imaging.

We present a miniature motorized endoscopic probe for Optical Coherence Tomography with an outer diameter of 1.65 mm and a rotation speed of 3,000-12,500 rpm. This is the smallest motorized high speed OCT probe to our knowledge. The probe has a motorized distal end which provides a significant advantage over proximally driven probes since it does not require a drive shaft to transfer the rotational torque to the distal end of the probe and functions without a fiber rotary junction. The probe has a focal Full Width at Half Maximum of 9.6 µm and a working distance of 0.47 mm. We analyzed the non uniform rotation distortion and found a location fluctuation of only 1.87° in repeated measurements of the same object. The probe was integrated in a high-speed Optical Frequency Domain Imaging setup at 1310 nm to acquire images from ex vivo pig lung tissue through the working channel of a human bronchoscope.

Color fluorescence ratio for detection of bronchial dysplasia and carcinoma in situ.

BACKGROUND: Autofluorescence bronchoscopy is more sensitive than conventional bronchoscopy for detecting early airway mucosal lesions. Decreased specificity can lead to excessive biopsy and increased procedural time. Onco-LIFE, a device that combines fluorescence and reflectance imaging, allows numeric representation by expressing red-to-green ratio (R/G ratio) within the region of interest. The aim of the study was to determine if color fluorescence ratio (R/G ratio) added to autofluorescence bronchoscopy could provide an objective means to guide biopsy. METHODS: Subjects at risk for lung cancer were recruited at two centers: VU University Medical Centre (Amsterdam) and BC Cancer Agency (Canada). R/G ratio for each site appearing normal or abnormal was measured before biopsy. R/G ratios were correlated with pathology, and a receiver operating characteristic curve of R/G ratio for high-grade and moderate dysplasia was done. Following analysis of the training data set obtained from two centers, a prospective validation study was done. RESULTS: Three thousand three hundred sixty-two adequate biopsies from 738 subjects with their corresponding R/G ratios were analyzed. R/G ratio 0.54 conferred 85% sensitivity and 80% specificity for the detection of high-grade and moderate dysplasia, area under the curve was 0.90, and 95% confidence interval was 0.88 to 0.92. In another 70 different sites that were assessed, kappa measurements of agreement of R/G ratios with visual scores and pathology were 0.66 (P < 0.0001) and 0.61 (P < 0.0001), respectively. R/G ratio combined with visual score improved specificity to 88% (95% confidence interval, 0.73-0.96) for high-grade and moderate dysplasia. CONCLUSION: Color fluorescence ratio can objectively guide the bronchoscopist in selecting sites for biopsy with good pathologic correlation.

Primary lung cancer after treatment of head and neck cancer without lymph node metastasis: is there a role for autofluorescence bronchoscopy?

BACKGROUND: Head and neck cancer (HNC) is the 5th most common cancer worldwide. As good locoregional tumor control can be achieved with current treatment strategies, patients who develop second primary tumors from field cancerization have poorer prognosis. OBJECTIVES: To determine if autofluorescence bronchoscopy (AF) played a role in the detection of second primary lung cancer (SPLC), and impact of SPLC on survival of patients with HNC and no cervical lymph node metastasis (N0). METHODS: Patients with HNC(N0) referred for symptoms and/or radiology suspicious for lung cancer were assessed with AF. Data on patient demographics, smoking, cancer characteristics, and outcome were prospectively collected. RESULTS: Fifty-one patients (44 males) with curatively treated HNC(N0) were evaluated. Median age was 70 years, all were current or former smokers of 35 pack years, and 25 had chronic obstructive lung disease. Over a median follow up of 60 months, 8 patients were diagnosed with synchronous and 26 with metachronous SPLC. Forty-two SPLC were found; 12 (29%) affected the tracheobronchial tree and 30 (71%) involved the lung parenchyma. Median time to metachronous SPLC was 22 months. Most of SPLC were surgically resectable. Five radiographically occult lung cancers detected by AF were successfully treated with endobronchial therapy. Lung cancer mortality was 24%. HNC patients who developed synchronous and metachronous SPLCs had significantly shorter survival (51 and 144 months) compared to those without (240 months) (p=0.0005). CONCLUSION: SPLC impacted negatively on the survival of patients with HNC. Close surveillance with AF and CT for SPLC combined with aggressive treatment of early stage lung cancer might be a strategy to improve outcome.

Lung cancer screening: has there been any progress? Computed tomography and autofluorescence bronchoscopy.

PURPOSE OF REVIEW: Advances in imaging technologies are currently being explored in the attempt to reduce lung cancer morbidity and mortality by achieving stage shift. We reviewed recent important publications on lung cancer screening. RECENT FINDINGS: Autofluorescence bronchoscopy has established its important role in the intervention of early central airway lesions. Multidetector computed tomography (CT) and CT-positron emission tomography may facilitate diagnosis of early parenchymal lung lesions. Practical implications of screening are reaching far beyond early diagnostic efforts per se as lead-time, length-time, overdiagnosis biases combined with low specificity of screening tests undermine its cost-effectiveness in the era of healthcare budget constraints. SUMMARY: Advanced imaging technologies may allow early detection and prudent intervention in some individuals that harbour asymptomatic early lung cancer, but disproportional expenses may be required to sieve out many more individuals at risk to attain stage shift. Confounding co-morbidities and practical hurdles may reduce screening's efficacy as it is plausible that for the majority of smokers, lung cancer may not be the ultimate cause of suffering since 90% of them will not develop lung cancer. This fact remains true despite increased use of noninvasive and minimally invasive technologies for the maximum preservation of quality of life irrespective of whether early intervention is a success or failure.

Dual digital video-autofluorescence imaging for detection of pre-neoplastic lesions.

AIM: The incorporation of autofluorescence (AF) to white light bronchoscopy has led to improved sensitivity for the detection of pre-neoplastic lesions in the airways. However, AF has difficulty distinguishing benign epithelial changes such as bronchitis, previous biopsy, and airway fibrosis from pre-invasive lesions, which necessitates extensive biopsy. This frequently results in longer procedural time and need for additional sedation that may compromise patient safety, increase the risk of bronchospasm, and bleeding from multiple endobronchial biopsies. We postulate that dual imaging with simultaneous video and AF bronchoscopy of the tracheobronchial tree could improve the low specificity observed with AF in the detection of pre-invasive lesions, leading to targeted biopsy, good correlation with pathological diagnosis and shorter procedural time. METHODS: Forty-eight patients with known or suspected of lung cancer underwent video and AF bronchoscopy, which were provided as real-time dual images with SAFE 3000 (Pentax, Tokyo) between March and August 2006. Biopsy specimens were taken from all suspicious areas with two random specimens from normal areas. Values were expressed as median and range, and p<0.05 was considered statistically significant. RESULTS: Twenty-five suspicious sites were detected by dual imaging bronchoscopy, and 126 endobronchial biopsies were evaluated, of which 22 (17.5%) were graded as moderate dysplasia and worse. Sensitivity and specificity of dual imaging for the detection of high-grade dysplasia were 86% and 94%, respectively, with good correlation between bronchoscopic assessment and pathology (r=0.77, p<0.0001). However, there were three random biopsy specimens obtained from normal or abnormal sites that showed severe dysplasia in two and moderate dysplasia in one. Median time taken for airway examination was 4 min (range, 4-4.8), and 5 min (range, 4-5) for biopsy, giving a total procedural time of 9 min (range, 8-10). There were no procedure-related complications noted. CONCLUSION: Dual imaging that allows simultaneous real-time assessment of the lesion with video and AF bronchoscopy not only achieves satisfactory sensitivity for the detection of pre-neoplastic lesions, importantly it improves specificity by allowing targeted biopsy, which has led to a marked decrease in procedural time and better patient safety.

Initial bronchoscopic treatment for patients with intraluminal bronchial carcinoids.

OBJECTIVE: Carcinoid of the lung is considered low-grade malignancy, and less invasive treatment may therefore be considered. We analyzed the long-term outcome of initial bronchoscopic treatment in patients with intraluminal bronchial carcinoids. METHODS: Initial bronchoscopic treatment was applied to improve presurgical condition, to obtain tissue samples for proper histologic classification, and to enable less extensive parenchymal resection. For intraluminal bronchial carcinoid, complete tumor eradication with initial bronchoscopic treatment was attempted. High-resolution computed tomography in addition to bronchoscopy was used to determine intraluminal versus extraluminal tumor growth. Surgery followed in cases of atypical carcinoid, residue, or recurrence. RESULTS: Seventy-two patients, 43 of them female, have been treated (median age 47 years, range 16-80 years). Median follow-up has been 65 months (range 2-180 months). Fifty-seven (79%) had typical carcinoids and 15 (21%) had atypical carcinoids. Initial bronchoscopic treatment resulted in complete tumor eradication in 33 of 72 cases (46%), 30 typical and 3 atypical. Thirty-seven of 72 cases (51%), 11 atypical, required surgery (2 for late detected recurrences). Two patients had metastatic atypical carcinoid, 1 already at referral. Of the 6 deaths, 1 was tumor related. CONCLUSIONS: Initial bronchoscopic treatment is a potentially more tissue-sparing alternative than immediate surgical resection in patients with intraluminal bronchial carcinoids. For successful tumor eradication with initial bronchoscopic treatment in central carcinoids, assessment of intraluminal versus extraluminal growth may be of much more importance than histologic division between typical and atypical carcinoid. Disease-specific mortality is low, and long-term outcome has been excellent. Implementation of initial bronchoscopic treatment had no negative impact on surgical treatment outcome.

Detection and staging of preinvasive lesions and occult lung cancer in the central airways with 18F-fluorodeoxyglucose positron emission tomography: a pilot study.

PURPOSE: To evaluate the role of (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) in radiologically occult preinvasive lesions and lung cancer in the central airways. EXPERIMENTAL DESIGN: Twenty-two patients with 24 preinvasive lesions and early squamous cell cancer (SCC) being occult on high-resolution computed tomography were studied. All lesions were diagnosed based on histology sampled using autofluorescence bronchoscopy. FDG-PET findings were correlated with WHO histologic classification. FDG-PET was considered true-positive when the final diagnosis was SCC and true-negative when the lesions were classified as severe dysplasia or less. RESULTS: FDG-PET was true-positive in 8 of 11 and true-negative in 11 of 13 cases corresponding with a sensitivity of 73% [95% confidence interval (CI), 0.43-0.91] and specificity of 85% (95% CI, 0.57-0.97). Positive and negative predictive values were 80% (95% CI, 0.48-0.96) and 79% (95% CI, 0.52-0.93), respectively. CONCLUSIONS: Our very preliminary data suggest that FDG-PET might be useful for the evaluation of early central airway lesions, being positive in most SCC and negative in cases of severe dysplasia. Validation in a larger multicenter study is needed.

Cost-effectiveness of early intervention: comparison between intraluminal bronchoscopic treatment and surgical resection for T1N0 lung cancer patients.

BACKGROUND: For patients with early-stage lung cancer (ESLC) and severe comorbidities, the cost-effectiveness of early intervention may be reduced by screening and treatment-related morbidity and mortality in addition to the risk for non-cancer-related deaths. OBJECTIVES: The use of bronchoscopic treatment (BT) for centrally located ESLC as minimally invasive technique has raised questions whether this approach will be more cost-effective than standard surgical resection in the above-mentioned cohort of patients. METHODS: The cost-effectiveness of BT of 32 medically inoperable patients with intraluminal tumor has been compared to a matched control group of surgically treated stage IA cancer patients. RESULTS: Median follow-up after BT for ESLC has been 5 years (range 2-10) versus 6.7 years (range 2-10) for the surgical group. Five patients (16%) developed subsequent primaries/local recurrences after BT versus 4 (12.5%) in the surgical group. The respective percentages of actual survival during follow-up have been 50 and 41%, non-lung-cancer-related death 22 and 31% and lung-cancer-related death 28% in both groups, respectively. So far, the average costs per individual for early management by BT have been Euro 22,638 by surgery, and total expenses have been Euro 209,492 and Euro 724,403, respectively. CONCLUSIONS: Despite the worse initial health status of patients treated with BT, actual survival rates and costs for early intervention underscore the superior cost-effectiveness of BT as early intervention in properly selected individuals with ESLC in the central airways.

Multiple suspicious lesions detected by autofluorescence bronchoscopy predict malignant development in the bronchial mucosa in high risk patients.

Autofluorescence bronchoscopy (AFB) has been shown to be sensitive to detect preneoplastic lesions in central airways. Apart from bronchial mucosa thickness, tissue autofluorescence is also related to the biochemical properties of the target cells. Genetic studies have shown molecular abnormalities to be present in histologically normal mucosal specimens. Forty-six high-risk individuals, free of micro-invasive cancer at the initiation of the study, were included in this analysis and have been subjected to repeat bronchoscopic examinations every 4-6 months. They had previous curatively treated lung cancer (n=18), ENT tumor (n=11) or were at risk to acquire lung cancer primaries (n=17). Baseline AFB is scored for each suspicious lesion, thus the total score represents the number of AFB suspicious lesions present in each individual at risk. Baseline AFB score was correlated to outcome, i.e. the development of squamous-cell cancer (SCC) in each individual. So far, 11/46 (24%) of the individuals acquired SCC. Follow up has been 12-80 months. All five individuals with >/=3 lesions (100%, 12-36 months), five of the ten (50%, 12-48 months) individuals who had two lesions and one among the 12 (8%, 36 months) individuals with one suspicious AFB lesion, developed SCC. Up till now (12-80 months), the remaining 19 individuals without any suspicious AFB lesion have not acquired SCC. The average AFB score for the group of individuals which developed SCC was significantly different (P<0.001) from the remaining individuals who did not acquire SCC (2.64+/-1.1 vs. 0.6+/-0.7 S.D.). The number of suspicious lesions at baseline AFB is a good predictor for the development of SCC in the individuals at risk in our study population. This finding is compatible with field carcinogenesis and warrants a more upfront use of AFB in a lung cancer screening to sift the different risk-cohorts in a population mainly at risk for developing metachronous lung cancer.

Bronchoscopic treatment of patients with intraluminal microinvasive radiographically occult lung cancer not eligible for surgical resection: a follow-up study.

Bronchoscopic treatment (BT) has a curative potential for patients with intraluminal microinvasive radiographically occult lung cancer (ROLC). We report the long-term follow-up in a group of 32 patients, ineligible for surgery, in whom ROLC was diagnosed and treated with BT. Tumors were strictly