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Forceps, brushes or needles are currently the standard tools used during flexible bronchoscopy when diagnosing endobronchial malignancies. The new biopsy technique of cryobiopsy appears to provide better diagnostic samples. The aim of this study was to evaluate cryobiopsy over conventional endobronchial sampling. A total of 600 patients in eight centres with suspected endobronchial tumours were included in a prospective, randomised, single-blinded multicentre study. Patients were randomised to either sampling using forceps or the cryoprobe. After obtaining biopsy samples, a blinded histological evaluation was performed. According to the definitive clinical diagnosis, the diagnostic yield for malignancy was evaluated by a Chi-squared test. A total of 593 patients were randomised, of whom 563 had a final diagnosis of cancer. 281 patients were randomised to receive endobronchial biopsies using forceps and 282 had biopsies performed using a flexible cryoprobe. A definitive diagnosis was achieved in 85.1% of patients randomised to conventional forceps biopsy and 95.0% of patients who underwent cryobiopsy (p<0.001). Importantly, there was no difference in the incidence of significant bleeding. Endobronchial cryobiopsy is a safe technique with superior diagnostic yield in comparison with conventional forceps biopsy.

Purpose: This study aimed to determine whether three preoperative cycles of gemcitabine plus cisplatin followed by radical surgery provides a reduction in the risk of progression compared with surgery alone in patients with stages IB to IIIA non-small-cell lung cancer (NSCLC)., Patients and Methods: Patients with chemotherapy-naive NSCLC (stages IB, II, or IIIA) were randomly assigned to receive either three cycles of gemcitabine 1,250 mg/m(2) days 1 and 8 every 3 weeks plus cisplatin 75 mg/m(2) day 1 every 3 weeks followed by surgery, or surgery alone. Randomization was stratified by center and disease stage (IB/IIA v IIB/IIIA). The primary end point was progression-free survival (PFS). Results The study was prematurely closed after the random assignment of 270 patients: 129 to chemotherapy plus surgery and 141 to surgery alone. Median age was 61.8 years and 83.3% were male. Slightly more patients in the surgery alone arm had disease stage IB/IIA (55.3% v 48.8%). The chemotherapy response rate was 35.4%. The hazard ratios for PFS and overall survival were 0.70 (95% CI, 0.50 to 0.97; P = .003) and 0.63 (95% CI, 0.43 to 0.92; P = .02), respectively, both in favor of chemotherapy plus surgery. A statistically significant impact of preoperative chemotherapy on outcomes was observed in the stage IIB/IIIA subgroup (3-year PFS rate: 36.1% v 55.4%; P = .002). The most common grade 3 or 4 chemotherapy-related adverse events were neutropenia and thrombocytopenia. No treatment-by-histology interaction effect was apparent., Conclusion: Although the study was terminated early, preoperative gemcitabine plus cisplatin followed by radical surgery improved survival in patients with clinical stage IIB/IIIA NSCLC.

Background: Endobronchial forceps biopsies are often small and are associated with a relevant extent of artifacts. To overcome these limitations is an important task. Especially when considering predictive factors for pharmacological therapies of lung cancer (ERCC1, RRM1) a development of biopsy techniques seems to be essential. This is the first report on a new endobronchial biopsy technique called cryobiopsy., Objectives: In this study the feasibility and the potential advantages of applying cryoprobes for harvesting samples for histological examination in flexible bronchoscopies will be focused on., Methods: In 12 patients suffering from exophytic endobronchial malignancies, a modified flexible cryoprobe was used for immediate recanalization. The extracted tissue was examined histologically regarding sample quality and sample size., Results: Tissue samples obtained using the cryoprobe showed an extraordinary good quality in terms of size (median diameter of 6.7 mm, range 4.2-13 mm) and artifact-free sample area (75% of the samples showed an artifact-free sample area of more than 75%). Additionally molecular markers were shown to be well preserved., Conclusions: The new technique termed cryobiopsy might widen the chest physician's range of tools for diagnostic bronchoscopies., (Copyright 2008 S. Karger AG, Basel.)

Single-agent therapy with Docetaxel or Pemetrexed is the current therapy of choice for second-line treatment in advanced non-small-cell lung cancer (NSCLC). The role of older agents was underattended over the last years. This study presents the combination of Mitomycin C and Vinorelbine in pretreated patients. Forty-two patients (stage IIIB and IV, pretreated with platinum-based chemotherapy) received 8 mg m(-2) Mitomycin C on day 1 and 25 mg m(-2) Vinorelbine on days 1 and 8 of a 28-day cycle. End points were objective tumour response, survival, and toxicity. Additionally, quality of life (QoL) was assessed. Five patients (11.9 %) achieved partial responses and 13 patients (31.9%) stable disease. Progression-free survival was 16 weeks. The median overall survival was 8.5 month. Eleven patients (26.2 %) suffered from grade 3 or 4 neutropenia and four patients (9.52%) from grade 3 or 4 anaemia. Evaluation of QoL showed that some items ameliorated during therapy. The therapeutic concept including Mitomycin C and Vinorelbine offers an efficacious and well-tolerated regimen, with relatively low toxicity. Objective response and survival data correlate with other second-line studies using different medication. As costs of Mitomycin C and Vinorelbine are lower compared with current drugs of choice, this regimen is likely to be cost-saving.

The leading European and American professional societies recommend that bone scans (BS) should be performed in the staging of lung cancer only in those patients with bone pain. This prospective study investigated the sensitivity of conventional skeletal scintigraphy in detecting osseous metastases in patients with lung cancer and addressed the potential consequences of failure to use this method in the work-up of asymptomatic patients. Subsequent to initial diagnosis of non-small cell lung cancer, 100 patients were examined and questioned regarding skeletal complaints. Two specialists in internal medicine decided whether they would recommend a bone scan on the basis of the clinical evaluation. Skeletal scintigraphy was then performed blinded to the findings of history and physical examination. The combined results of magnetic resonance imaging (MRI) of the vertebral column, positron emission tomography (PET) of skeletal bone and the subsequent clinical course served as the gold standard for the identification of osseous metastases. Bone scintigraphy showed an 87% sensitivity in the detection of bone metastases. Failure to perform skeletal scintigraphy in asymptomatic patients reduced the sensitivity of the method, depending on the interpretation of the symptoms, to 19-39%. Without the findings of skeletal scintigraphy and the gold standard methods, 14-22% of patients would have undergone unnecessary surgery or neoadjuvant therapy. On this basis it is concluded that bone scans should not be omitted in asymptomatic patients.

Background: 2-[(18)F]-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography has been established as a standard diagnostic imaging method in the preoperative workup of suspicious pulmonary focal lesions, showing a sensitivity of more than 90% and a specificity of about 80%. Determination of malignant pulmonary lesions with FDG positron emission tomography depends on the assessment of glucose metabolism. However, false-positive findings can occur in inflammatory processes, such as sarcoidosis or pneumonia. The thymidine analogue 3-deoxy-3[(18)F]-fluorothymidine (FLT) is a new positron emission tomography tracer that more specifically targets proliferative activity of malignant lesions. The objective of this study was to determine whether FLT positron emission tomography, in comparison with FDG positron emission tomography, provides additional information in the preoperative workup of central pulmonary focal lesions., Methods: In this prospective study FLT and FDG positron emission tomography examinations were performed as a part of the preoperative workup in 20 patients with histologically confirmed bronchial carcinoma, 7 patients with benign lesions, and 1 patient with an atypical carcinoid. Results were compared with final pathologic findings., Results: For staging of the primary tumor, FLT positron emission tomography revealed a sensitivity of 86% and a specificity of 100% compared with a sensitivity of 95% and a specificity of 73% for FDG positron emission tomography. For N staging, the sensitivity of FLT positron emission tomography was 57% and the specificity was 100%, and for FDG positron emission tomography, the sensitivity was 86% and the specificity was 100%, respectively., Conclusions: Our preliminary findings indicate specific FLT uptake in malignant lesions. The number of false-positive findings in FDG positron emission tomography might be reduced with FLT positron emission tomography. Therefore positron emission tomography imaging with FLT represents a useful supplement to FDG in assessing the malignancy of central pulmonary focal lesions.

Background: Mediastinal lymph node staging is essential to determine treatment options in patients with NSCLC. Positron emission tomography (PET) detects increased glucose uptake in malignant tissue using the glucose analogue 2-[(18)F]fluoro-2-deoxy-D-glucose (FDG)., Patients and Methods: In the present study were evaluated 155 patients with focal pulmonary tumors who underwent both preoperative computed tomography (CT) and FDG-PET scanning (116 malignant and 39 benign lesions)., Results: Findings in 155 patients included 116 malignant and 39 benign lesions. For N-staging, FDG-PET showed a sensitivity of 88%, a specificity of 91%, and an accuracy of 89%. Corresponding figures for CT were 77%, 76%, and 77%, respectively., Conclusions: FDG-PET is an effective, noninvasive method for staging thoracic lymph nodes in patients with lung cancer and is superior to CT scanning in the assessment of hilar and mediastinal nodal metastases. With regard to operability, FDG-PET could differentiate reliable between patients with N1/N2 disease and those with unresectable N3 disease.

Unlabelled: As bone metastases might be present in lung cancer despite a normal bone scan, we examined various alternatives prospectively. Positron emission tomography using F-18 sodium fluoride (PET) and single photon emission tomography (SPECT) were more sensitive than a planar bone scan. PET was more accurate with a shorter examination time than SPECT but had higher incremental costs., Introduction: Previous studies have shown that vertebral bone metastases not seen on planar bone scans may be present on F-18 fluoride positron emission tomography (PET) scan or single photon emission computed tomography (SPECT). The purpose of this study was to measure the accuracy, clinical value and cost-effectiveness of tomographic bone imaging., Materials and Methods: A total of 103 patients with initial diagnosis of lung cancer was prospectively examined with planar bone scintigraphy (BS), SPECT of the vertebral column and PET using F-18 sodium fluoride (F-18 PET). Receiver operating characteristic (ROC) curve analysis was used for determination of the diagnostic accuracy. A decision-analysis model and the national charge schedule of the German Hospital Association were used for determination of the cost-effectiveness., Results: Thirteen of 33 patients with bone metastases were false negative on BS, 4 on SPECT, and 2 on F-18 PET. The area under the ROC curve was 0.771 for BS, 0.875 for SPECT, and 0.989 for F-18 PET (p < 0.05). As a result of SPECT and F-18 PET imaging, clinical management was changed in 8 (7.8%) and 10 (9.7%) patients. Compared with BS, the costs per additional correctly diagnosed patient were 1272 Euro with SPECT and 2861 Euro with F-18 PET. The threshold for the costs of F-18 PET being more cost-effective than SPECT was 345 EUR., Conclusion: Routine performance of tomographic bone imaging improves the therapeutic strategy because of detection of otherwise missed metastases. F-18 PET is more effective than SPECT but is associated with higher incremental costs.

We investigated whether uptake of the thymidine analogue 3-deoxy-3-[(18)F]fluorothymidine ([(18)F]FLT) reflects proliferation in solitary pulmonary nodules (SPNs). Thirty patients with SPNs were prospectively examined with positron emission tomography. Standardized uptake values were calculated for quantification of FLT uptake. Histopathology revealed 22 malignant and 8 benign lesions. Proliferation was evaluated by Ki-67 immunostaining and showed a mean proliferation fraction of 30.9% (range, 1-65%) in malignant SPNs and <5% in benign lesions. Linear regression analysis indicated a significant correlation between FLT-standardized uptake values and proliferative activity (P < 0.0001; r = 0.87). FLT uptake was specific for malignant lesions and may be used for differential diagnosis of SPNs, assessment of proliferation, and estimation of prognosis.

Unlabelled: Previous studies have shown that vertebral bone metastases (BM) not seen on planar bone scintigraphy (BS) might be present on (18)F-fluoride PET scans or at MRI. Therefore, we evaluated the effect of SPECT or (18)F-labeled NaF PET ((18)F PET) imaging on the management of patients with newly diagnosed lung cancer., Methods: Fifty-three patients with small cell lung cancer or locally advanced non-small cell lung cancer were prospectively examined with planar BS, SPECT of the vertebral column, and (18)F PET. MRI and all available imaging methods, as well as the clinical course, were used as reference methods. BS with and without SPECT and (18)F PET were compared using a 5-point scale for receiver operating characteristic (ROC) curve analysis., Results: Twelve patients had BM. BS produced 6 false-negatives, SPECT produced 1 false-negative, and (18)F PET produced no false-negatives. The area under the ROC curve was 0.779 for BS, 0.944 for SPECT, and 0.993 for (18)F PET. The areas under the ROC curve of (18)F PET and BS complemented by SPECT were not significantly different, and both tomographic methods were significantly more accurate than planar BS. As a result of SPECT or (18)F PET imaging, clinical management was changed in 5 patients (9%) or 6 patients (11%), respectively., Conclusion: As indicated by the area under the ROC curve analysis, (18)F PET is the most accurate whole-body imaging modality for screening for BM. Routinely performed SPECT imaging is practicable, is cost-effective, and improves the accuracy of BS.

Endobronchial therapy is commonly used in the palliative management of malignant disease, but the optimal combinations of treatment modalities (laser, brachytherapy, external beam radiotherapy) have not been defined. We have undertaken a prospective analysis of symptom response, duration of response, and prognostic factors for 117 patients treated with brachytherapy at a single centre, to identify hypotheses suitable for prospective randomised studies. All but one patient had received previous treatment. The percentage of patients with scores of 0 or 1 (none or mild) for each symptom pre-treatment and at 3 months were as follows: cough 62% to 77% (43% improving by at least one grade, N.S.); dyspnoea 32% to 56% (50% improvement by at least one grade, P = 0.0063); haemoptysis 78% to 97%; performance status 65% to 84% (54% by at least one grade, P = 0.0417). An actuarial risk of fatal haemoptysis at 2 years of 20% was associated with prior laser resection (P = 0.048). Death before 2 months was associated with dyspnoea scores of 3 or 4. Suggestions for randomised studies are made to address some of the uncertainties revealed by the analysis.

The risk of lung cancer in smokers was examined based on the debrisoquine metabolic phenotype and on exposure to occupational lung carcinogens, specifically asbestos and polycyclic aromatic hydrocarbons. Extensive metabolizers of debrisoquine are at a 4-fold increased risk for lung cancer compared to poor metabolizers, after adjustment for age, sex, and smoking (pack-years), when only occupationally unexposed subjects are considered. Increased risk related to the debrisoquine metabolic phenotype was greatest for squamous and small cell histologies, and least for the adenocarcinoma subtype. Men with a history of exposure to occupational carcinogens had significantly increased risk of lung cancer (relative risk = 2.8), after adjustment for age and smoking. Considering the combined effect of the high risk extensive metabolizers debrisoquine metabolic phenotype and likely occupational exposure to asbestos, the relative excess risk for lung cancer was 18-fold. This finding is consistent with a synergism in risk between the ability to extensively metabolize debrisoquine and occupational exposure to lung carcinogens in male smokers. Debrisoquine phenotyping has potential for identifying carcinogen-exposed workers at high risk of lung cancer.

Debrisoquine hydroxylation exhibits wide inter-individual variation in Caucasian populations. After similar doses of the drug, extensive metabolizers excrete up to several hundred times more of the urinary metabolite 4-hydroxy-debrisoquine than do poor metabolizers. The phenotypes have traditionally been defined by the metabolic ratio (MR), or the molar ratio of debrisoquine to its chief metabolite recovered in an aliquot of an eight hour urine sample, after a test dose of the drug. Deficient metabolism is inherited as an autosomal recessive condition. We have reanalyzed previously published data from a study of lung cancer patients and controls using a computerized optimization method to more accurately estimate the parameters describing the three phenotypic distributions. Using these new distributions to categorize controls, we show that Hardy-Weinberg conditions are now fulfilled. When the newly defined phenotype parameters are employed to assign the phenotypes of cases and controls, a highly significant difference in phenotype distribution between cases and controls is still observed. This result supports the hypothesis that the debrisoquine metabolic phenotype may be associated with lung cancer susceptibility.