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Supplementary Data from 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, κ 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.

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 FEV 1 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

Background and Study Aims: Screening programs for lung cancer may lead to a heightened awareness of the risks of smoking and enhance quitting. The aim of this study was to evaluate whether the participation on a chemoprevention study for premalignant lesions could influence smoking cessation. Methods: Two hundred one volunteers, current (n 188) and former smokers (n 13) with more than 20 pack years had been screened for the chemoprevention study. One hundred forty-six of the current smokers at time of chemoprevention study screening have been retrospectively interviewed about their smoking behavior 1 year after their first contact for the chemoprevention study. Structured questionnaires were used, and interviews were held by telephone. The quitters at the time of these first interviews were contacted again 4 years after the initial interview about their current smoking behavior. Results: Of the 146 smoking volunteers, 83 were diagnosed with premalignant lesions of the bronchial mucosa and participated in the chemoprevention study, and 63 had no premalignant lesions and were not included in that study. The majority of participants were men: 87 (60%). The mean age of the participants was 52 9 years, and the mean age at which volunteers started smoking was 15 3. Mean number of pack years was 47 27. Ten volunteers in the group without premalignant lesions and 19 in the group with premalignant lesions had quit smoking at time of the first interview. The smoking cessation rate of the total study group was 20%. Univariate logistic regression analysis demonstrated that smoking cessation was only significantly associated with male gender. No significant associations were found between smoking cessation and the finding of premalignant lesions, sex, age, level of addiction, educational level, marital condition, history of cancer/ pulmonary diseases, age at start smoking, previous attempts to quit smoking, and motivation to quit smoking. Within the group of subjects who had quit smoking at the time of the first interview, 15 of 29 persons who had stopped smoking at the time of the first interview have reported that participation in the bronchoscopy screening and/or the trial has been of major influence on their decision to stop smoking. Conclusions: A smoking cessation rate of 20% has been found among volunteers for a chemopreventive trial investigating smoking-related premalignant lesions after almost 2 years after initial contact has been found. Volunteers experienced screening and trial participation as having influenced their smoking cessation. Smoking cessation was significantly associated with male gender, whereas the finding of premalignant lesions by bronchoscopy was not.

Summary 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.

Background An evidence-based approach is necessary for the localization and management of intraepithelial and microinvasive non-small cell lung cancer in the central airways. Methods Material appropriate to this topic was obtained by literature search of a computerized database. Recommendations were developed by the writing committee and then reviewed by the entire guidelines panel. The final recommendations were made by the Chair and were voted on by the entire committee. Results White light bronchoscopy has diagnostic limitations in the detection of microinvasive lesions. Autofluorescence bronchoscopy (AFB) is a technique that has been shown to be a sensitive method for detecting these lesions. In patients with moderate dysplasia or worse on sputum cytology and normal chest radiographic findings, bronchoscopy should be performed. If moderate/severe dysplasia or carcinoma in situ (CIS) is detected in the central airways, then bronchoscopic surveillance is recommended. The use of AFB is preferred if available. In a patient being considered for curative endobronchial therapy to treat microinvasive lesions, AFB is useful. A number of endobronchial techniques as therapeutic options are available for the management of CIS and can be recommended to patients with inoperable disease. In patients with operable disease, surgery remains the mainstay of treatment, although patients may be counseled about these techniques. Conclusions AFB is a useful tool for the localization of microinvasive neoplasia. A number of endobronchial techniques available for the curative treatment can be considered first-line therapy in inoperable cases. For operable cases, the techniques may be considered and discussed with the patients.

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.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.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.

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.

Minimally invasive diagnostic and therapeutic approaches in medicine have been applied for a more selective and tailored approach to reduce patients' morbidity and mortality. The efficacy of interventional pulmonology for palliation of patients with central airways obstruction has been established and its curative potential for intralesional treatment of early cancer has raised great interest in current screening programmes. This is due to the fact that surgical resection and systemic nodal dissection as the gold standard is relatively morbid and risky, especially when dealing with individuals with limited functional reserves due to smoking-related comorbidities, such as chronic obstructive pulmonary disease. Furthermore, such comorbidities have been proven to harbour early stage lesions of several millimetres in size without involvement of nodal disease that may be amenable to local bronchoscopic treatment. Therefore, the success of minimally invasive strategies for palliation and treatment with curative intent strongly depends on the diligent identification of the various factors in lung cancer management, including full comprehension of the limits and potential of each particular technique. Maximal preservation of quality of life is a prerequisite in successfully dealing with individuals at risk of harbouring asymptomatic early lung cancer, to prevent aggressive surgical diagnostic and therapeutic strategies since overdiagnosis remains an issue that is heavily debated. In the palliative setting of alleviating central airway obstruction, laser resection, electrocautery, argon plasma coagulation and stenting are techniques that can provide immediate relief, in contrast to cryotherapy, brachytherapy and photodynamic therapy with delayed effects. With curative intent, intraluminal techniques that easily coagulate early stage cancer lesions will increase the implementation of interventional pulmonology for benign and relatively benign diseases, as well as early cancer lesions and its precursors at their earliest stage of disease.

Study objectives Microscopic residual disease in the bronchial resection margins after surgical resection of lung cancer is rare, and its clinical significance remains unsettled. We studied the natural history of patients with carcinoma in situ (CIS) at their bronchial resection margins to focus on the issue of stump recurrence. Methods Eleven individuals who had undergone radical surgery for N0M0 lung tumors were found to have CIS at the bronchial resection margins. All of the resection specimens were reviewed with respect to the pattern of CIS extension and reclassified as follows: superficial CIS, involving surface epithelium only (CIS-S), CIS extending into the submucosal gland ducts but not deeper (CIS-D), and CIS extending into submucosal gland acini (CIS-A). Patients were followed using autofluorescence bronchoscopy and high-resolution computer tomography. Clinical parameters and the local extent of CIS at histology review were correlated with outcome. Results Median follow-up was 35 months (range, 15 to 89). Histology review showed two CIS-S cases, six CIS-D cases, and three CIS-A cases. All of the patients with CIS-A developed stump recurrences in contrast with those with only CIS-S. Three patients with CIS-D have developed metachronous primaries in the contralateral lung, whereas the stump region remained free of tumor. Conclusions The presence of CIS in the bronchial resection margin after resection of lung cancers is associated with stump recurrences. Although absolute numbers are too small for firm conclusions, our data suggest that those with deep glandular extension of CIS bear the highest risk of early recurrence. However, the development of new primaries away from the stump region and the possible development of distant disease are equally relevant considerations with respect to the choice of additional therapy.

It is generally assumed that squamous cell carcinoma develops in a stepwise manner from normal bronchial epithelium towards cancer by the accumulation of (epi)genetic alterations. Several mechanisms including mutations and homozygous deletions or hypermethylation of the p16(INK4a) promoter region can cause loss of p16 expression. Recent studies suggest overexpression of the polycomb-group gene BMI-1 might also down-regulate p16 expression. In this study, we analyzed the p16 expression in relation to the methylation status of the p16 promoter region of the p16(INK4a) gene and the expression of BMI-1 in bronchial squamous cell carcinomas (SCC) and its premalignant lesions. Nine (69%) SCC showed loss of p16 expression and 10 (77%) showed expression of BMI-1. Of four p16 positive samples two (50%) were BMI-1 positive, whereas among nine p16 negative samples, eight (89%) revealed BMI-1 staining. Four (44%) p16 negative samples were hypermethylated at the p16(INK4a) promoter region; the other p16 negative tumors that showed no hypermethylation revealed BMI-1 staining. Only two premalignant lesions showed absence of p16 expression, of which one (carcinoma in situ) was hypermethylated at the p16(INK4a) promoter region and the other (severe dysplasia) showed BMI-1 expression. In total, 11 precursor lesions (48%) revealed BMI-1 expression. In conclusion, the results of this study suggest that loss of p16 expression by promoter hypermethylation is inconsistently and occurs late in the carcinogenic process at the level of severe dysplasia. To what extent overexpression of the polycomb-group protein BMI-1 attributes to down regulating of p16 expression remains unclear.

The dismal cure rate of patients with lung cancer and the stage shift hypothesis have propelled the interest to perform screening at large, despite that previous randomized clinical trials failed to show any mortality benefit and the controversial issue of overdiagnosis. Due to early detection programs, a larger number of individuals at risk will be found to harbor small and potentially malignant early stage lesions. The application of non- and minimal invasive techniques for early detection, staging and treatment will become increasingly important. This review deals with the available clinical, surgical and pathological data focusing on early lung cancer lesions ≤1 cm. Literature data from both centrally located and parenchymal lesions ≤3 cm. have been analyzed. For all sub-centimeter lesions, minimal invasive staging and treatment approaches must still be considered inappropriate. Less invasive and less extensive treatment methods may be considered in high risk individuals with ≤1 cm. peripheral lesion showing ≥50 ground glass opacity on high resolution CT scan and those with superficial lesion in their central airways without deeper tumor invasion in the bronchial wall. Caution is necessary, however, as clinical staging remains inferior to pathological staging which is based on tissue samples collected after complete tumor removal and mediastinal lymph nodes dissection have been performed.

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.

Objective To describe the population-based incidence and clinical characteristics of granular cell tumors of the tracheobronchial tree. Methods All newly registered tracheobronchial granular cell tumors in the Dutch Network and National Database for Pathology for 10 consecutive years (1990-1999) were identified. The histologic diagnosis was confirmed and patient demographics, management, and follow-up data were analyzed. Results Thirty-one tumors were registered in 30 patients (12 male patients and 18 female patients; mean age 51 years; range 11-84) in a population of approximately 15 million. Tracheal tumors were identified in 11 patients and bronchial tumors in 19 patients (1 patient had 2 tumors). About half of the patients were asymptomatic. In the majority of the patients (61%) the granular cell tumor was an incidental finding during workup for lung carcinoma. Tracheal granular cell tumors were more frequent in women, whereas bronchial granular cell tumors showed no sex predilection. In the lung these tumors occurred more often in the upper (10 tumors) than in the lower lobes (3 tumors). There was no preference for either side. Four patients with tracheal and 4 with bronchial granular cell tumors were treated with surgery and remain in complete remission. Four bronchial granular cell tumor patients were treated locally with neodymium/yttrium-aluminum-garnet laser or electrocautery and are in complete remission or have stable residual disease. In 3 patients no residual disease was found after biopsy. Of all granular cell tumor patients 17 received no treatment for a variety of reasons, but none of these patients died in the follow-up period because of the granular cell tumors. Conclusion Tracheobronchial granular cell tumor is a benign tumor with a good prognosis. In symptomatic patients surgical intervention is the first choice of treatment, but local treatment is a reasonable option and gives successful results.

Endobronchial carcinoma develops through a continuum of morphologically recognizable pre-neoplastic changes. At present, no marker has been identified that can reliably predict the biological behavior of these lesions. Endobronchial lesions (n=39) sampled from patients (n=20) without clinically overt lung cancer, were analyzed by immunohistochemistry (IHC) for abnormal expression regarding the p53 protein, i.e. suprabasal p53 expression. Clear suprabasal p53 immunostaining was found in two (12%) of the hyperplastic or squamous metaplastic lesions, in one (10%) of the mildly or moderately dysplastic lesions and in nine (75%) of the severely dysplastic or carcinoma in situ (CIS) lesions. Suprabasal p53 immunostaining was found significantly more frequent in severe dysplasia or CIS (P0.01). Of 17 patients follow-up data were available. After a median follow up of 7 months (range 2-37 months), six patients presented with bronchial carcinoma within the same lobe or bronchial spur where biopsies had been taken. Four of these patients revealed suprabasal p53 immunostaining in the biopsies obtained from the sites of future cancer. In three patients biopsies were obtained from future cancer sites as well as from distant sites in the ipsilateral lung. Suprabasal p53 immunostaining was found exclusively at future cancer sites of these patients (P=0.02). Suprabasal p53 immunostaining in addition to histology improved the specificity and the positive predictive value for bronchial carcinoma development in the same lobe or bronchial spur, compared with histology alone. These results suggest that suprabasal p53 immunostaining is associated with bronchial cancer and might have additive value to predict the biological behavior of pre-neoplastic endobronchial lesions in the population at risk of bronchial cancer.

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

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

Background Carcinoid of the lung is considered to be a low-grade malignancy. A subgroup presents as an endobronchial tumour. Surgical resection is considered the standard approach because of its metastatic potential and the possibility of an iceberg phenomenon for the endobronchial subgroup. Advances in non-invasive and minimally invasive technologies seem to justify a more lung parenchyma-sparing approach. Methods In patients presenting with bronchial carcinoids, initial bronchoscopic treatment (IBT) is first attempted for complete tumour eradication and sufficient tissue sampling for the proper differentiation of typical (TC) versus atypical (AC) histological type. Furthermore in cases with postobstruction problems the desobstruction is aimed at improving the patient9s condition and by that alleviate surgery if that is needed. High resolution CT is performed 6 weeks post IBT to determine local tumour growth. Surgical resection follows in case of extraluminal disease, residual carcinoid inaccessible for IBT, or late recurrences not salvaged by repeat IBT. Results Minimum follow-up was 5 years from start of treatment for 112 patients (65 women, 47 men), with a median age of 47 years (range 16–77 years). Eighty-three patients (74%) had TC, and 29 (26%) AC. IBT only was ultimately curative in 42% of the cases (47/112): 42 TC, 5 AC. Disease-specific mortality including surgical mortality has been 2.6% (3/112) in patients with extraluminal carcinoids (3 AC). Conclusions IBT, if with unsuccessful rescue surgery, is justifiable with excellent long-term outcome. IBT made surgery unnecessary in 42% of the cases. Iceberg phenomenon and metastatic potential in this group of patients with bronchial carcinoids are clinically insignificant.

Autofluorescence bronchoscopy (AFB) and computed tomography (CT) enable lung cancer (LC) detection at the early (pre-)invasive stage. However, LC risk in patients with preinvasive endobronchial lesions is unclear.To assess LC incidence and identify potential risk determinants in patients with preinvasive lesions.In our tertiary care referral center, 164 subjects with preinvasive lesions were monitored up to 12.5 years by repeated AFB and CT. Occurrence of LC was monitored. Clinical management depended on histological grade, with cancer patients receiving standard care. Potential risk determinants (smoking status, baseline histology, cancer history, and chronic obstructive pulmonary disease [COPD] status) were evaluated in relation to cancer occurrence, event-free survival (EFS), and overall survival (OS).During surveillance (median of 30 mo, range 4-152) of 164 subjects with preinvasive lesions (80 high grade and 84 low grade at inclusion), 61 LCs were detected in 55 subjects (median time to event 16.5 mo). Twenty-three LCs (38%) were detected by CT, and 38 (62%) were detected by AFB. More cancers (36 of 61; 59%) developed from separate, rather than initial lesional sites. Subjects with high-grade lesions were more likely to be diagnosed with LC at the same or another site in the lungs than those with low-grade lesions (P = 0.03). Independent risk determinants for OS were previous curatively treated cancer and COPD (P ≤ 0.05).Presence of preinvasive lesions, especially high-grade lesions, may serve as LC risk markers. LCs occur both at preinvasive lesion sites and elsewhere in the bronchial epithelium or lung parenchyma. Prospective validation of biomarkers and randomized intervention studies are needed to determine optimal management strategies.

⇓The purpose of this European Respiratory Society/American Thoracic Society (ERS/ATS) Task Force position paper is to define the field of interventional pulmonology as well as to describe the minimal requirements in methodology and logistics, the indications, contraindications, outcome and training requirements for each interventional procedure. This position paper has been prepared by a group of European and North American experts. Fig. 1.— Schematic illustration of the three main types (a–c) of malignant central airway obstruction shown at the tracheal level, with identical degrees of narrowing of the lumen. a) intraluminal; b) extraluminal; c) mixed obstruction. Fig. 2.— Algorithm for the management of malignant central airway obstructions. Terms in hexagonal boxes are conditions; terms in rectangular boxes are procedures. Two-way arrows indicate the tendency of endobronchial tumours to recur and the repetitive need of multimodality treatment. Interrupted arrows: 1: rare cases of primarily inoperable lung cancers which become secondarily operable after initial therapeutic bronchoscopy usually followed by neo-adjuvant treatment; 2: rare cases of operated lung cancers initially presenting with central airway obstruction and still being operable after careful restaging of an endobronchial recurrence. TNM: tumour staging, including histology; CPR: cardiopulmonary reserves of the patient. Reproduced with permission from 81. Fig. 3.— Interventional pulmonology can be defined as “the art and science of medicine as related to the performance of diagnostic and invasive therapeutic procedures that require additional training and expertize beyond that required in a standard pulmonary medicine training programme”. Disease processes encompassed within this discipline include complex airway management problems, benign and malignant central airway obstruction, pleural diseases, and pulmonary vascular procedures. Diagnostic and therapeutic procedures pertaining to these areas include, but are not limited to, rigid bronchoscopy, transbronchial needle aspiration, autofluorescence bronchoscopy, endobronchial ultrasound, transthoracic needle aspiration and biopsy, laser bronchoscopy, endobronchial electrosurgery, argon-plasma coagulation, cryotherapy, airway stent insertion, balloon bronchoplasty and dilatation …

The conventional method of bronchoscopy has only a 30% sensitivity to detect early stage cancer in the central airways. For patients with positive sputum cytology who clearly harbor early cancers, repeat and lengthy sessions of bronchoscopies are required for accurate localization of these lesions. This leads to a significant delay in obtaining the diagnosis, postponing an appropriate treatment and reduces the chance for cure. There are valid reasons for improving the detection rate of early stage lung cancers. The number of individuals at risk forms a large population, the outcome of patients treated with early stage cancer has been shown to be better and bronchoscopic treatments, e.g. photodynamic therapy and electrocautery, are currently alternatives for surgical resection. Finding more early stage cancers by screening the population at risk and accurate staging to enable treatment at the earliest stage feasible, may improve the dismal prognosis of many patients. This article deals with the clinical background and current problems in early detection of lung cancer and discusses our expectations regarding new developments in bronchoscopy for early detection, accurate staging and treatment of lung cancer.

To determine the influence of interobserver variability in histopathologic reporting of bronchial biopsy specimens on the results of autofluorescence bronchoscopy in detection of preinvasive bronchial neoplasia, we compared original histopathologic reports with reports of a review panel. Fo

Study objectives To study tissue effects of bronchoscopic electrocautery (BE). Design In six patients with non-small cell lung cancer, a BE procedure was performed immediately before surgery. After patients were placed on ventilation, normal mucosa on different carinae was treated with a cautery probe (2-mm 2 surface area) at a power setting of 30 W with a variable time of application of 1 to 5 s. Bronchoscopic appearance of the treated area was documented photographically, and histologic changes of the bronchial wall were examined. Setting Bronchoscopy unit of a university hospital. Measurements and results BE resulted bronchoscopically in whitening of the bronchial mucosa with crater-shaped lesions. After longer duration of BE application, deeper craters with more profound charring were seen. Histologic changes of the lesions showed craters containing a variable amount of necrotic tissue. In one case, thin subsegmental carinae were coagulated and measurements could not be performed. In the remaining five cases, microscopic findings revealed 0.2 ± 0.1-mm necrosis after 1 s; 0.4 ± 0.2-mm necrosis after 2 s; 0.9 ± 0.5-mm necrosis after 3 s; and 1.9 ± 0.8-mm necrosis after 5 s. A variable degree of tissue damage surrounding the necrotic tissue area was found. In one case, cartilage damage appeared after 3 s of coagulation, and extensive damage of the underlying cartilage was seen in four cases after 5 s of application. Conclusions Superficial damage was obtained by short duration of BE (≤ 2 s), and longer duration of coagulation (3 s or 5 s) caused damage to the underlying cartilage. Bronchoscopic appearance after endobronchial electrocautery corresponded with the histologic changes.

Lipomas are rare endobronchial tumors that may cause severe parenchymal damage due to bronchus obstruction and subsequent pneumonia. Therefore, accurate diagnosis and radical treatment are essential. We describe three cases of endobronchial lipoma. One patient presented with hemoptysis, two patients were initially diagnosed as COPD. They were all treated by electrocautery which achieved complete removal. We recommend electrocautery as an easy and cost-effective alternative for removal of intraluminal tumors including lipoma.

Study objective: To evaluate the cost effectiveness of the Nd-YAG laser and bronchoscopic electrocautery for palliation in patients with symptomatic tumor obstruction. Design: A retrospective study. Setting: Bronchoscopy unit of a university hospital. Patients and intervention: Thirty-one consecutive patients with inoperable non-small cell lung cancer and symptomatic intraluminal tumor underwent bronchoscopic treatment. Dyspnea relief was the primary goal of treatment. Fourteen patients were treated with the Nd-YAG laser and 17 patients with electrocautery. Measurements and results: Improvement of symptoms was achieved in 70% of patients treated by either Nd-YAG laser or electrocautery. Mean 6 SD survival was 8.0 6 2.5 months after Nd-YAG laser treatment and 11.5 6 3.5 months after electrocautery. The number of treatment sessions per patient was comparable: Nd-YAG laser, 1.1; electrocautery, 1.2. Duration of hospital stay was longer in patients treated with the Nd-YAG laser (8.4 vs 6.7 days). Average treatment costs, including admission charges, were $5,321 for the Nd-YAG laser and $4,290 for electrocautery. Higher costs in the group treated with the Nd-YAG laser were caused by a longer hospital stay before bronchoscopic treatment. Costs of equipment (electrocautery $6,701 and Nd-YAG laser $208,333), write-offs, maintenance, and repair were not included in this calculation. Conclusion: Bronchoscopic electrocautery is equally effective but is a less expensive and, in our hospital, a more accessible modality than the Nd-YAG laser for symptomatic palliation of patients with intraluminal airway obstruction. (CHEST 1999; 116:1108 ‐1112)

The aim of the study was to determine whether use of fluorescence bronchoscopy improves the detection of preinvasive neoplastic bronchial lesions. The data of all patients who underwent fluorescence bronchoscopy and in whom bronchial biopsies were taken, were analyzed. Most patients were at risk for preinvasive lesions. A total of 174 bronchoscopies were performed in 95 patients. Of the 681 representative biopsies, 31 were found to be moderate dysplastic, 39 were found to be severe dysplastic and 9 exhibited carcinoma in situ. These 79 preinvasive lesions were found in 34 patients. The respective results of fluorescence bronchoscopy in addition to conventional bronchoscopy and of conventional bronchoscopy alone for detection of preinvasive lesions were: sensitivity 85% (67/79) and 59% (47/79); specificity 60% (351/581) and 85% (493/581); positive predictive values of 23% (67/297) and 35% (47/135); negative predictive values of 97% (351/363) and 94% (493/525). A separate analysis of only the first bronchoscopy of each patient showed similar results. Results of fluoresence bronchoscopy were better in the second part of the patient group. We conclude that after a learning period fluorescence bronchoscopy can increase the yield of finding preinvasive neoplastic lesions when used in addition to conventional bronchoscopy.

Photodynamic therapy (PDT) has been introduced in the early eighties for treating patients with malignancies in the tracheobronchial tract. After intravenous injection of the photosensitizers, the tumor area in the tracheobronchial tree is illuminated bronchoscopically using a laser fiber to transmit light of a specific wavelength during the procedure. Secondary tissue necrosis ensues, because of the thrombosis of the tumor vasculature leading to late tissue hypoxia. Ample data have shown that PDT is effective to obtain full depth tissue necrosis with relative sparing of the normal tissue. Local tumor control can be achieved. Competitive endoscopic techniques such as lasers and electrocautery are applicable to debulk tumor in a less selective but more immediate manner. Skin photosensitivity is a potential morbidity of PDT, especially in using the first generation photosensitizers. This limits its palliative potential. More selective and more phototoxic sensitizers in combination with the use of portable diode laser, may improve the clinical usefulness of PDT in the management of lung cancer patients. However, cost-effectiveness studies comparing PDT and other local bronchoscopic treatment modalities such as thermal lasers, electrocautery, cryotherapy, brachytherapy, whether or not in addition to external radiotherapy and chemotherapy, should be conducted to define its definite role in the palliative treatment of advanced obstructive bronchial cancers.

Objective: The curative potential of various bronchoscopic treatments such as Nd:YAG laser, photodynamic therapy, and brachytherapy for the treatment of intraluminal tumor has been reported previously. Bronchoscopic treatment can be used to treat small intraluminal tumor with curative intent, such as in patients with roentgenologically occult squamous cell cancer. In a retrospective study, we showed that bronchoscopic treatment provided excellent local control with surgical proof of cure in 6 of 11 patients with intraluminal typical bronchial carcinoid. Methods: In a prospective study, 19 patients (8 women and 11 men) with resectable intraluminal typical bronchial carcinoid have undergone bronchoscopic treatment under general anesthesia. Median age was 44 years (range, 20-74 years). If tumor persisted after 2 bronchoscopic treatment sessions, surgery was performed within 4 months after the treatment. Results: Bronchoscopic treatment was able to completely eradicate tumor in 14 of the 19 patients (complete response rate 73%, 95% CI: 49%-91%). Median follow-up of these patients is 29 months (range, 8-62 months). One patient had severe cicatricial stenosis after bronchoscopic treatment, and sleeve lobectomy was necessary. No residual carcinoid was found in the resected specimen. In the remaining 5 patients, bronchoscopic treatment did not result in a complete response and radical surgical resection was performed afterward with confirmation of residual carcinoid in the resected specimen. Median follow-up of the surgical group is 34 months (range, 12-62 months). Conclusions: Current data suggest that bronchoscopic treatment may be an effective alternative to surgical resection in a subgroup of patients with resectable intraluminal typical bronchial carcinoid. It alleviated the necessity of surgical resection in 68% (95% CI: 43%-87%) of the patients. (J Thorac Cardiovasc Surg 1998;116:402-6)

The curative potential of bronchoscopic intervention, e.g. photodynamic therapy (PDT) and brachytherapy, for resectable radiographically occult lung cancer has been reported previously. Bronchoscopic electrocautery is currently feasible using an insulated flexible bronchoscope to coagulate and vaporize tumour tissue. Since the lesions are usually small, noninvasive bronchoscopic electrocautery may be able to eradicate radiographically occult lung cancer completely. In a prospective study, 13 patients with 15 radiographically occult lung cancer lesions were treated with bronchoscopic electrocautery. The duration of follow-up was > or = 16 months. The median age of the patients was 69 yrs (range 48-79 yrs). Fibreoptic bronchoscopy under local anaesthesia was used to coagulate the occult lung cancer. Approximately 30 W of energy was applied until visible necrosis of the tumour area became apparent. There were no immediate complications. In 10 patients with 12 lesions, a complete response (CR) was obtained (CR rate 80%; 95% confidence interval (95% CI) 52-96%). Median duration of follow-up was 21 months (range 16-43 months). Bronchoscopic electrocautery did not obtain a CR in the remaining three patients, but PDT also failed to achieve CR. Two patients underwent radical resection, and the tumours were histologically confirmed to be more invasive. One patient received external radiotherapy. Three patients with a CR died during follow-up, two as a result of myocardial infarction and apoplexy, and one because of metastasis from his previously resected T3N1 primary large cell cancer. Current data show bronchoscopic electrocautery to be equally effective and potentially as curative as photodynamic therapy for treating patients with radiographically occult lung cancer. Obvious advantages are that it is an inexpensive and simple procedure, which does not cause photosensitivity.

We recently identified a DNA copy number aberration (CNA)-based classifier, including changes at 3p26.3-p11.1, 3q26.2-29, and 6p25.3-24.3, as a risk predictor for cancer in individuals presenting with endobronchial squamous metaplasia. The current study was set out to validate the prediction accuracy of this classifier in an independent series of endobronchial squamous metaplastic and dysplastic lesions. The study included 36 high-risk subjects who had endobronchial lesions of various histological grades that were identified and biopsied by autofluorescence bronchoscopy and were subjected to arrayCGH in a nested case-control design. Of the 36 patients, 12 had a carcinoma in situ or invasive carcinoma at the same site at follow-up (median 11 months, range 4-24), while 24 controls remained cancer free (78 months, range 21-142). The previously defined CNA-based classifier demonstrated 92% (95% CI 77% to 98%) accuracy for cancer (in situ) prediction. All nine subjects with CNA-based classifier-positive endobronchial lesions at baseline experienced cancer outcome, whereas all 24 controls and 3 cases were classified as being low risk. In conclusion, CNAs prove to be a highly accurate biomarker for assessing the progression risk of endobronchial squamous metaplastic and dysplastic lesions. This classifier could assist in selecting subjects with endobronchial lesions who might benefit from more aggressive therapeutic intervention or surveillance.

The Nd:YAG laser is the most popular instrument to treat patients with intraluminal tumor in the major airways. It is usually performed under general anesthesia. Fiberoptic bronchoscopic electrocautery (FBE) under local anesthesia was shown to be effective in providing rapid palliation. We have studied prospectively the effectiveness of FBE for clearing intraluminal tumor. Patients with visible intraluminal tumor in the large airways were treated with FBE. ND:YAG laser equipment was kept ready for use during FBE sessions. A treatment session was terminated when significant tumor clearance had been achieved, or in cases with extraluminal tumor compression. Fifty-six patients, median age 64 years (range 20–90), were treated, and 82 FBE sessions were completed. Thirty-seven patients (66%) had intraluminal non-small-cell cancer, ten had typical carcinoid and the rest had miscellaneous tumors. Significant tumor clearance was documented in 39 patients (70%). The remaining patients proved to have extraluminal tumor. Ten sessions (12%) were completed under general anesthesia, in nine cases for the treatment of carcinoid. No conversion to Nd:YAG laser treatment was necessary, but additional Nd:YAG treatment was given to obtain more in-depth necrosis in one patient. A switch to rigid bronchoscopy was necessary to control bleeding in one patient. In this phase II prospective study, FBE achieved sufficient clearance of intraluminal tumor in the majority of patients who were considered to be Nd:YAG laser candidates. Our findings indicate that FBE may be competitive with Nd:YAG laser treatment for this category of patients. A randomized phase III study is underway.

Demonstration of small apical pneumothoraces is supposed to be facilitated by expiratory chest radiographs. This study aimed to analyse the assumed enhancement of visual contrast on expiratory chest radiographs in patients with small apical pneumothoraces. Optical densities (OD) were obtained with a densitometer (X-rite 3001) on 54 paired inspiratory and expiratory chest radiographs of 22 consecutive patients with small apical pneumothoraces. The ODs were measured: at the intervertebral space between the first and second thoracic vertebrae (Area 1); at the peripheral part of the affected lung parenchyma (Area 2); and at the adjacent intrapleural space (Area 3). Excellent correlations of OD of each area were obtained between paired inspiratory and expiratory chest radiographs. The ODs of all areas on expiratory chest radiographs were significantly higher than on inspiratory chest radiographs. Contrast between pulmonary parenchyma and intrapleural air in inspiratory and expiratory films did not differ significantly. Expiratory chest radiographs do not improve visibility of small apical pneumothoraces by enhanced contrast between pulmonary parenchyma and intrapleural air. Expiratory chest radiographs show equally increased OD in the area of lung tissue and intrapleural air, caused by increased extrapulmonary tissue density during expiration, resulting in increased radiation exposure monitored by the ionization chambers of standard radiological equipment. If expiratory chest radiographs are really improving the visibility of apical pneumothoraces, there must be other reasons than contrast enhancement to explain this.

The strategy regarding centrally located early squamous cell cancer (SCC) and its precursor lesions currently relies on sensitive diagnostic tools, such as autofluorescence bronchoscopy (AFB), high-resolution computed tomography (HRCT) and positron emission tomography with 18 fluorodeoxyglucose (FDG-PET) [1, 2].

Study objective Comparison of the videothoracoscopic appearance of first and recurrent pneumothorax, and assessment of a relation between endoscopic appearance and recurrence rate. Setting University hospital. Patients Eighty-two patients, 64 men (mean age, 32.7 years) and 18 women (mean age, 31.5 years), were included. Patients with known underlying pulmonary disease at the time of hospital admission were excluded. There were 61 patients (74%) with first pneumothorax, and 21 patients (26%) with recurrent pneumothorax. Interventions All patients underwent videothoracoscopy under general anesthesia, with double-lumen intubation. Results Blebs or bullae were found in 47 patients (77%) with first pneumothorax, and in 14 patients (67%) with recurrent pneumothorax. Bullae >2 cm were found in 34 patients (56%) with first pneumothorax and 10 patients (48%) with recurrent pneumothorax. Patients with blebs or bullae were significantly older than patients with normal videothoracoscopic appearance (mean age, 36.5±15.7 years vs 25.3±5.8 years, p Conclusions No significant differences in videothoracoscopic appearance were found between first and recurrent pneumothorax. These results suggest that recurrence after the first event of spontaneous pneumothorax cannot be predicted by thoracoscopic findings. Smoking and blebs or bullae are independent risk factors for development of spontaneous pneumothorax. (CHEST 1995; 108:330-34)

To analyse the efficacy of video-assisted thoracoscopy (VAT) in patients with spontaneous pneumothorax (SP) and to identify clinical factors associated with outcome after VAT, one hundred and one VATs were performed in 97 patients in this prospective study. Based on thoracoscopic appearance of the visceral pleura three groups were identified, group 1 (n = 23) showing no abnormalities treated with talcage, group 2 (n = 23) showing bullae less than 2 cm treated with talcage and coagulation, and group 3 (n = 51) showing bullae larger than 2 cm treated with bullectomy by staplers, coagulation and pleural scarification. Data were analyzed with regard to clinical factors such as age, smoking behavior, pulmonary function and recurrent pneumothorax at presentation. No perioperative deaths occurred. Overall relapse rate was 4.0% during a follow-up period of 3 to 38 months (median 27.2). Univariate analysis did not show any association of clinical factors with postoperative complications (n = 19). Patients with extensive pulmonary lesions had longer drainage and hospitalization time, probably due to insufficient sealing effects of stapler devices and/or pleural scarification. Using multivariate analysis, none of the clinical factors had any association with complication rate, drainage/hospitalization time or relapses after VAT. Only patients with bullae larger than 2 cm treated with bullectomy by stapler devices were associated with longer drainage and hospitalization time. This study suggests that VAT is effective in the treatment of spontaneous pneumothorax, although the use of stapler devices and/or pleural scarification was associated with longer drainage and hospitalization time, however, none of the clinical factors were associated with the outcome after VAT.

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. © 2012 Optical Society of America.

BACKGROUND--Obstruction of a major airway by tumour causes serious morbidity. There is still scope for a widely applicable, simple and effective treatment to provide rapid palliation. METHODS--A fibreoptic bronchoscope prototype with an insulated inner sheath was used under local anaesthesia in 17 patients with locally advanced tracheobronchial malignancies. An insulated flexible electro-surgery probe was used to coagulate intraluminal tumour mass using standard electrosurgery equipment. RESULTS--Immediate reopening of the airway was obtained in 15 of the 17 patients. Two appeared to have extraluminal disease. Eleven patients had an obvious bronchoscopic response in whom a > 75% reopening of the normal airway diameter was achieved. Eight patients had subjective improvement of their dyspnoea, but only in four cases was there an objective improvement in physiological parameters. Haemoptysis resolved in four. There were no deaths resulting from treatment. Minor bleeding occurred in one patient and an aspiration pneumonia occurred in one. Three patients received additional treatment. CONCLUSIONS--Fibreoptic bronchoscopic electrosurgery is a simple technique for rapid palliation and immediate tumour debulking in patients with central tracheobronchial tumours. Further work is needed to compare its efficacy with other techniques.

aCentre Hospitalier Universitaire Vaudois. CHUV, Lausanne, Switzerland bCancer Center, University of Rochester, Rochester NY, USA ‘University of Texas MD. Anderson Cancer Center, Houston. TX, USA ‘University of Ca&ornia Davis Cancer Center, Sacramento, CA, USA ‘C.M.C., Porte de Choisy. Paris, France ‘University of Michigan. Ann Arbor, MI, USA Wedical Academy, Gdansk. Poland hUniversity Hospital, Helsinki, Finland ‘Centre LPon B&ard, Lyon, France jlstituto Narionale Tumori, Milan. Italy ‘Hfipital Jean Minjoz. Besqn. France ‘Clinique Ste-Catherine. Avignon. France mh4ayo Clinic, Rochester, MN, USA n V. U. B., Brussels, Belgium ‘Christie Hospital, Manchester, UK PFree LJniversity Hospital, Amsterdam, The Netherlands W R. 0. Aviano and G. H.. Pordenone, Italy ‘University of Chicago, Chicago, IL, USA