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Plasma circulating cell-free (cf)DNA is of interest in oncology because it has been shown to contain tumour DNA and may thus be used as liquid biopsy. In nonsmall cell lung cancer (NSCLC), cfDNA quantification has been proposed for the monitoring and follow-up of patients. However, available studies are limited and need to be confirmed by studies with larger sample sizes and including patients who receive more homogenous treatments. Our objective was to assess the predictive and prognostic value of plasma cfDNA concentration in a large series of patients with NSCLC and treated with a standard chemotherapy regimen. We included samples from lung cancer patients recruited into the Pharmacogenoscan study. The cfDNA of 218 patients was extracted and quantified by fluorometry before and after two or three cycles of platinum-based chemotherapy. The association between baseline and post-chemotherapy concentrations and treatment response, assessed by RECIST (response evaluation criteria in solid tumours) or patient survival was analysed. Patients with high cfDNA concentrations (highest tertile) at baseline had a significantly worse disease-free and overall survival than those with lower concentrations (lowest and middle tertiles) (median overall survival 10 months (95% CI 10.7–13.9) versus 14.2 months (95% CI 12.6–15.8), respectively; p=0.001). In multivariate analysis, increased baseline concentration of cfDNA was an independent prognostic factor. However, we did not find any association between cfDNA concentration and response to treatment. cfDNA may be a biomarker for the assessment of prognosis in NSCLC. However, total concentration of cfDNA does not appear to predict chemotherapy response. Total cell-free DNA is not associated with chemotherapy response in advanced nonsmall cell lung cancer

Purpose Antiangiogenic therapies targeting the vascular endothelial growth factor (VEGF) pathway have yielded more modest clinical benefit to patients with non–small-cell lung cancer (NSCLC) than initially expected. Clinical data suggest a distinct biologic role of the VEGF pathway in the different histologic subtypes of lung cancer. To clarify the influence of histologic differentiation in the prognostic relevance of VEGF-mediated signaling in NSCLC, we performed a concomitant analysis of the expression of three key elements of the VEGF pathway in the earliest stages of the following two principal histologic subtypes: squamous cell carcinoma (SCC) and adenocarcinoma (ADC). Patients and Methods We evaluated tumor cell expression of VEGF, VEGF receptor (VEGFR) 1, and VEGFR2 using automatic immunostaining in a series of 298 patients with early-stage NSCLC recruited as part of the multicenter European Early Lung Cancer Detection Group project. A score measuring the VEGF signaling pathway was calculated by adding the tumor cell expression value of VEGF and its two receptors. The results were validated in two additional independent cohorts of patients with NSCLC. Results The combination of high VEGF, VEGFR1, and VEGFR2 protein expression was associated with lower risk of disease progression in early SCC (univariate analysis, P = .008; multivariate analysis, hazard ratio, 0.62; 95% CI, 0.42 to 0.92; P = .02). The results were validated in two independent patient cohorts, confirming the favorable prognostic value of high VEGF signaling score in early lung SCC. Conclusion Our results clearly indicate that the combination of high expression of the three key elements in the VEGF pathway is associated with a good prognosis in patients with early SCC but not in patients with ADC.

The incidence of adenocarcinoma is increasing, particularly among females. We sought to assess the role of tobacco consumption in clinical presentation according to sex. In this retrospective study, 848 patients diagnosed between 1997 and 2006 at Grenoble University Hospital (Grenoble, France) were stratified into four groups according to smoking habits. Differences between sexes and two contrasting female profiles emerged. Female current smokers were younger than female never-smokers (median 51 versus 69 yrs; p < 0.001), more often had surgery (62.7% versus 39%; p = 0.01) and had a median (95% CI) estimated survival of 26.2 (18.1-49.2) versus 15.1 (12.8-22.2) months (p = 0.002). Both groups had similar survival when taking treatment into account. Among males, smoking did not influence presentation. Male current smokers were older than female current smokers (median 59 yrs; p < 0.001) and fewer had surgery (48.8%; p = 0.015), although the percentage of stage IIIb-IV disease was similar (53% and 46%; nonsignificant) and they had a poorer estimated survival of 14.3 (13.0-18.5) months (p = 0.0024). Males smoked more than females (median 41 versus 30 pack-yrs; p < 0.001). Quitting smoking delayed age at diagnosis by 11 yrs for females (p = 0.0035) and 8 yrs for males (p < 0.001). Our results support the hypothesis that carcinogenesis differs between males and females, and between female smokers and never-smokers.

BACKGROUND: Patients with a previous history of cancer of the upper respiratory and digestive tracts (URDT) frequently develop a bronchial carcinoma (synchronous or metachronous) that may affect their survival. OBJECTIVE: To determine the prevalence of bronchial carcinoma at an early stage in a population of patients treated for cancer of the URDT. MATERIALS AND METHODS: This was a single centre prospective study (2002-2006). Patients in remission following treatment of cancers of the buccal cavity, pharynx (stages I -II) and larynx (stages I - III), were examined by a spiral CT scan and fibreoptic bronchoscopy (white light and autofluorescence), with biopsies, and cytology of the bronchial aspirate. RESULTS: 60 patients (55 men) were included. Two peripheral bronchial carcinomas were detected by scanning and two more (proximal) by endoscopy. All 4 bronchial tumours were squamous carcinomas (stage IA). Three patients had surgery, the fourth declined intervention. CONCLUSION: Our study confirms the high prevalence (6.7%) of bronchial carcinoma in patients with a past history of cancer of the URDT. It emphasises the complimentary roles of spiral scanning and bronchoscopy in early diagnosis. It is still too early to evaluate the impact of these investigations on the survival of the patients.

Resume Introduction Les nodules pulmonaires partiellement ou totalement en verre depoli en tomodensitometrie sont d’identification recente. Etat des connaissances Ces nodules representent 2,9 % a 19 % des nodules detectes dans des populations a risque de cancer bronchique. Les correlations anatomo-radio-cliniques revelent une origine benigne (pneumonie chronique, fibrose localisee, hyperplasie adenomateuse atypique) ou maligne (cancer bronchiolo-alveolaire, adenocarcinome, plus rarement metastase). Le risque de cancer est superieur pour ces nodules que pour les nodules solides. Cependant, le temps de doublement des cancers a forme nodulaire en verre depoli est en moyenne superieur a celui des cancers a forme partiellement en verre depoli et largement superieur aux adenocarcinomes a forme solide. Le pronostic des patients est donc correle a la presence et a la proportion de verre depoli au sein du nodule. Perspectives La prise en charge de ces nodules impose une surveillance prolongee pour les nodules 10 mm persistant sur un scanner de controle entre 1 et 3 mois apres leur decouverte et traitement anti-inflammatoire et ou infectieux. Conclusion Les nodules totalement ou partiellement en verre depoli necessitent une prise en charge particuliere.

We report the case of a 48-year-old man with a recent history of cardiac tamponade, who presented 6 months later recurrent hemoptysis of small volume. The CT scan revealed a bilateral pulmonary infiltration associating areas of ground-glass opacification of lobular distribution and tiny pulmonary nodules. Maximum intensity projection reconstructions were useful to better characterize the pulmonary infiltrates highlighting the CT halo sign. Contrast enhanced CT depicted a mass involving the right atrium and pericardium, confirmed by cardiac MRI. The surgical biopsy allowed radiological–pathological correlation revealing epithelioid angiosarcoma of the right atrium with pulmonary metastases.

Pulmonary adenocarcinoma of the lung and its variants are well-defined entities, since the recent WHO classification of lung tumours. However, scant descriptions have been allocated to associated stromal changes, such as prominent inflammation and fibrosis, which can overshadow a tumoral proliferation and masquerade as a benign reactive process and this has not been recognised as a histopathological variant. The case of a 72-yr-old farmer who presented a multifocal well-differentiated adenocarcinoma that mimicked honeycomb lung with bronchiolectasis radiologically, on computed tomography scan and histologically at open lung biopsy, is reported. Histological pitfalls in the biopsy were represented by mild atypical cuboidal or columnar epithelial cells lining bronchiolar structures resembling florid bronchiolar metaplasia in a background of extensive fibrosis and inflammation, features that mimicked inflammatory honeycombing. However, histological analysis of the surgical resection of the main lesion, performed because of a clinical alteration of the patient, confirmed the diagnosis of multifocal adenocarcinoma of mixed subtype. A monomorphic proliferation of clear cells, lack of associated ciliated or squamous cells and presence of significant cytologic atypia gave a diagnosis of malignancy. This case illustrates how inflammatory and fibrotic changes may conceal a correct diagnosis of carcinoma and emphasises the importance of adequate sampling in such cases.

Study objectives Autofluorescence bronchoscopy (AFB), when used as an adjunct to standard white light bronchoscopy (WLB), enhances the bronchoscopist's ability to localize small neoplastic lesions, especially intraepithelial lesions. The current study was undertaken in order to define the population in which the rate of detection is higher using AFB. Design and patients Two hundred forty-four consecutive patients, who were symptomatic smokers or patients who previously had been treated for lung cancer or head and neck cancers, underwent WLB and AFB. All patients with endoscopic abnormalities underwent biopsies. Data concerning smoking history were prospectively registered. Results We report the prevalence of high-grade or invasive lesions at the time of examination. On a lesion-by-lesion analysis, 92 low-grade lesions, 42 high-grade lesions (ie, moderate dysplasia, severe dysplasia, and carcinoma in situ), and 39 invasive carcinomas were diagnosed. There was no effect of age, gender, and age at smoking initiation on the prevalence of preinvasive or invasive lesions. The 10 patients who previously had undergone surgery for lung cancer and exhibited high-grade preinvasive lesions had a history of carcinoma of the epidermoid histologic type (p = 0.01). These 10 patients displayed multiple lesions in the bronchial tree (mean No. of lesions, 1.8 per patient). In current smokers, the prevalence of high-grade or invasive lesions were both related to the number of pack-years smoking had occurred (p = 0.01) and to the duration of smoking (p = 0.01). In contrast, the prevalence of preinvasive lesions in former smokers was related to a history of epidermoid carcinoma. Conclusions AFB should be recommended in patients with a history of epidermoid carcinomas of the lung. Current smokers with a prolonged smoking history appear to comprise a population in which the rate of detection of preneoplastic lesions is high with AFB.

Resume L’histoire du depistage du cancer bronchique semble s’accelerer depuis quelques mois. En effet, 30 ans apres avoir montre par le biais de plusieurs etudes, que le depistage par radiographie thoracique et cytologie de l’expectoration n’ameliorait pas la survie dans les populations depistees, 15 ans apres l’introduction du scanner volumique comme technique de depistage dans des etudes observationnelles qui ont montre la sensibilite superieure (entre 2 et 3 fois) du scanner par rapport a la radiographie pour detecter des cancers pulmonaires, les premiers resultats d’une large etude randomisee de depistage du cancer bronchique utilisant le scanner volumique (National Lung Cancer Screening Trial) montrent que cette technique de depistage permet de reduire la mortalite par cancer bronchique de 20,3 % et la mortalite toutes causes confondues de 7 %, en comparaison aux donnees du bras controle ayant beneficie d’une simple radiographie thoracique de depistage. De nombreuses questions restent en suspens concernant le depistage de masse du cancer bronchique.

Copious bronchorrhea can be related to bronchioloalveolar carcinoma, but reports of bronchorrhea related to lung metastasis are rare. We report the case of a woman presenting lung metastases of a cervical adenocarcinoma revealed by bronchorrhea, eventually identified as ectopic cervical mucus. Treatment included anticancer drugs and erythromycin, the latter in order to reduce the bronchorrhea, with eventually poor efficacy. This observation illustrates the importance of respiratory signs in the post-therapeutic follow up of cancer, especially cough and bronchorrhea in adenocarcinoma.

Erdheim-Chester disease (ECD) is a rare non-Langerhans' cell histiocytosis that may present with pulmonary symptoms. The condition seems to be nonfamilial and typically affects middle-aged adults. Radiographic and pathologic changes in the long bones are diagnostic, but patients often present with extraskeletal manifestations. Advanced pulmonary lesions are associated with extensive fibrosis that may lead to cardiorespiratory failure. The clinical, radiologic, and pathologic features of six patients with ECD with lung involvement are presented. The patients were three men and three women (mean age, 57). Five presented with progressive dyspnea, and one presented with diabetes insipidus. Open-lung biopsies showed histiocytic infiltrates in a lymphangitic pattern with associated fibrosis and lymphoplasmacytic inflammatory infiltrates. The histiocytes did not stain with periodic acid-Schiff. Immunoperoxidase studies performed on specimens from five of six patients showed that the histiocytes were positive for CD68 and Factor XIIIa and negative for CD1a. Specimens from two patients exhibited immunoreactivity for S-100 protein. Electron microscopy studies performed on specimens from two patients showed phagocytic lysosomes but no Birbeck granules. Clinical follow-up of up to 16 years was available. At the end of that time, five patients were dead of complications related to their disease; one patient remains alive 4 years after diagnosis but with severe respiratory compromise. ECD is a rare non-Langerhans' cell histiocytosis that may present as interstitial lung disease and resemble other pulmonary conditions, particularly usual interstitial pneumonitis and pulmonary Langerhans' cell histiocytosis. Recognition of this entity will allow better assessment of its true incidence, therapeutic options, and prognosis.

The aim of this study was to report our experience on the management of superior vena cava obstruction (SVCO) secondary to malignant disease, using endovascular procedures. Twenty-six patients with SVCO due to primary or secondary tumors of the lung or the mediastinum, or catheter inserted for treatment of an extra-thoracic neoplasm, had an endovascular therapy which consisted of stenting, angioplasty, thrombo-aspiration or local fibrinolysis. Immediately after the procedure, rapid relief of symptoms occurred in 24 (90 %) of the patients. The mean Kishi's score decreased from 5.5 to 0.96. Immediate complications included one death related to pericarditis bleeding following fibrinolysis. Three patients relapsed after 20 days, 4 months and 6 months, and needed a second stenting. At 6 months the primary patency rate was 83 % and the secondary patency rate was 89 %. Endovascular treatment of SVCOs is a simple and safe procedure to restore the patency of the superior vena cava in malignant SVCO. It should be indicated in most cases as first-line treatment and performed as early as possible.

Purpose/Objective: To report on two consecutive Phase II cooperative trials in which we evaluated the combination of alternating hyperfractionated accelerated radiotherapy and cisplatin-based chemotherapy in inoperable Stage III non-small cell lung cancer (NSCLC). Patients & Methods: Between February 1986 and September 1989, 65 patients were entered in the first trial (GOTHA I), and between December 1989 and October 1992 67 were enrolled in the second trial (GOTHA II). In both protocols, radiotherapy (RT) was administered twice daily, at 6 h intervals, 5 days a week, to a total dose of 63 Gy in 42 fractions of 1.5 Gy. RT was given during weeks 2, 3, 6, and 7, over an elapsed time of 6 weeks. In GOTHA I, three cycles of cisplatin, 60 mg/m 2 day 1, mitomycin, 8 mg/m 2 day 1, and vindesin 3 mg/m 2 day 1 and the first day of the following week, were given during weeks 1, 5, and 9; in GOTHA II, cisplatin 70 mg/m 2 day 1 and vinblastin 5 mg/m 2 day 1 and the first day of the following week were given during weeks 1, 5, 9, 13, 17, and 21. Results: With a minimum follow-up of 3 years, the 1-, 2-, 5-, and 8-year overall survival probability was 56% (95% CI 47–64%), 27% (20–35%), 12% (7–18%) and 9% (3–16%), respectively, with a median survival of 13.6 months (11.4–16.8). Median follow-up for survivors was 6 years (3.3–9.9). There were no survival differences between Stages IIIA and IIIB ( p = 0.84), performance status 0, 1, 2 (p = 0.87), sex ( p = 0.45) or between the two treatment protocols. At this time, 14 patients are alive, and 118 have died: 102 from NSCLC, 4 from acute toxicity, 2 from secondary surgery, 4 from other medical causes, and 6 from unknown causes. Correlation between response and long-term survival was poor, since of the 24 patients who survived 3 years or more, only 6 (25%) were classified as having a complete response; the remainder having either a partial response (11, 46%), no change (6, 25%), or “progressive disease” (1, 4%). First site of relapse was local in 31% of these cases, distant in 43%, local and distant in 15%, and unknown in 11%. Main grade 3–4 acute toxicities were nausea-vomiting (17%), mucositis (15%), leukopenia (41%), and thrombocytopenia (11%). Eight patients presented with grade 3–4 symptomatic lung radiation pneumopathy. Conclusion: Based on this experience with 132 patients, this combination of alternated RT and chemotherapy (CT) for inoperable Stage III NSCLC is feasible with acceptable toxicity, and long-term results suggest a gain in survival when compared to those obtained with conventional RT alone. However, the still high local and distant failure rates indicate that both local and systemic therapies need to be improved.

Erdheim-Chester disease (ECD) is a rare focal or systemic infiltrative disorder resulting from xanthogranulomatous tissue deposition. Usually, bone marrow involvement affects long bone metaphyses symmetrically, but it spares the epiphyses. Retroperitoneal space, periaortic area, skin, and brain involvement have been described. Pulmonary involvement is frequent, occurring in 20% of cases. Reported histologic features in the lung include an infiltration of so-called lipid-laden macrophages and granulomatous lesions with fibrosis. Lung function outcome is unpredictable, but terminal respiratory failure is the most frequent cause of death. No effective treatment strategies have been described. We report a new case with lung and bone involvement occurring in a symptomatic woman. Histologic and electron microscopic analysis of the pulmonary infiltrate showed abnormal macrophages devoid of lipids forming nodular granulomas and rendering the previous hypothesis of this disease as a primary lipid storage disorder unlikely. These findings suggest that ECD histogenesis is instead based on a primary macrophage cell disease.

Objectives Platinum-based chemotherapy regimens are the standard treatment of non-small cell lung cancer (NSCLC). In this study, our objective was to identify tumor tissue protein biomarkers that might predict a benefit from these treatments. Materials and methods The Pharmacogenoscan study prospectively included consecutive chemotherapy-naive NSCLC patients at any stage between 2005 and 2010 at six hospitals in the Rhone-Alpes-Auvergne region of France. Of the 537 patients in the full analysis set, 460 had a complete histological diagnosis. We used the tumor tissue samples for an immunohistochemical evaluation of eight biomarkers: ERCC1, BRCA1, p53, p27kip1, class III β-tubulin (TUBB3), Bax, Fas, and FasL. We looked for associations between these biomarkers and the disease control rate (DCR) after 2/3 cycles of platinum-based chemotherapy, progression-free survival (PFS), and overall survival (OS). Results A tissue sample adequate for testing at least one biomarker was available for 289 patients. We found no significant association between biomarker expression levels and clinical or pathological variables; TUBB3 showed a trend toward higher expression in adenocarcinomas ( P =0.005). For none of the biomarkers were significant associations found between expression level and DCR, PFS, or OS. TUBB3-negative and FasL-negative tumors showed associations of borderline significance with higher DCR. Conclusion In a large cohort of patients with predominantly advanced or metastatic NSCLC, none of eight tested immunohistochemical biomarkers predicted the chemotherapy response or survival. Our data indicate limited usefulness of protein biomarkers in metastatic NSCLC and a need for further research based on molecular signatures of greater complexity.

Purpose Characterization of the genomic changes that drive an individual patient's disease is critical in management of many cancers. In patients with non–small-cell lung cancer (NSCLC), obtaining tumor samples of sufficient size for genomic profiling on recurrence is often challenging. We undertook this study to compare genomic alterations identified in archived primary tumors from patients with NSCLC with those identified in metachronous or synchronous metastases. Patients and Methods Primary and matched metastatic tumor pairs from 15 patients were analyzed by using a targeted next-generation sequencing assay in a Clinical Laboratory Improvement Amendments laboratory. Genomic libraries were captured for 3,230 exons in 182 cancer-related genes plus 37 introns from 14 genes often rearranged in cancer and sequenced to high coverage. Results Among 30 tumors, 311 genomic alterations were identified of which 63 were known recurrent (32 in primary tumor, 31 in metastasis) and 248 were nonrecurrent (likely passenger). TP53 mutations were the most frequently observed recurrent alterations (12 patients). Tumors harbored two or more (maximum four) recurrent alterations in 10 patients. Comparative analysis of recurrent alterations between primary tumor and matched metastasis revealed a concordance rate of 94% compared with 63% for likely passenger alterations. Conclusion This high concordance suggests that for the purposes of genomic profiling, use of archived primary tumor can identify the key recurrent somatic alterations present in matched NSCLC metastases and may provide much of the relevant genomic information required to guide treatment on recurrence.

Study objective Daily duration of oxygen administration is an important factor in the effectiveness of long-term oxygen therapy (LTOT) for hypoxic chronic pulmonary disease. We have assessed the daily use of oxygen therapy in 930 patients with COPD and examined factors associated with the effective use of this treatment. Methods Objective daily duration of oxygen use over a 3-month period was prospectively measured using the counter clock of the oxygen concentrators or by weighing the liquid oxygen container at each delivery. A questionnaire was filled in by an independent investigator asking about home situation, lifestyle, and whether oxygen therapy was used during all domestic and outside activities. In addition, prescribing physicians were asked about the duration and modalities of oxygen prescribed in each case. Results The patients had been receiving LTOT for 36±24 months and had hypoxemia (Pa02=56±9 mm Hg), hypercapnia (PaCO 2 =47±8 mm Hg), and severe airflow obstruction (FEV 1 /VC =42±14%). The mean duration of oxygen treatment prescribed was 16±3 h/d. The mean duration of oxygen therapy achieved was 14.5±5 h, but only 45% of the patients achieved oxygen therapy for 15 h or more per day. Patients with effective use of LTOT, ie receiving oxygen therapy for at least 15 h/d, were significantly more hypoxic (PaO 2 =54±9 vs 57±9 mm Hg; p 2 =48±8 vs 46±7 mm Hg; p 1 /VC=39.5±13 vs 45±14%; p Conclusions Attention by the prescribing physicians to such factors could optimize oxygen prescription and constitute goals for education of patients.

Study objective The cost and inconvenience of polysomnography make simplified techniques of screening desirable in the strategy of diagnosis of sleep apnea syndrome (SAS). We have evaluated, in a prospective study of 301 consecutive patients referred for suspected sleep disorders, an index (Δindex) that detects apneic events by quantifying arterial oxygen saturation (SaO 2 ) variability. Setting Regional sleep laboratory taking referrals from general practitioners and specialists. Design Classic polysomnography was the gold standard, with 15 apneas plus hypopneas per hour (RDI) being used as a threshold for definition of obstructive sleep apnea (OSA). Oximetry was recorded over the same night. Signal variability was quantified as a function of time, using digital processing of oximetric data. Sensitivity, specificity, and positive and negative predictive values of oximetry testing were calculated. A receiver operating characteristic (ROC) curve was constructed representing the comparative courses of sensitivity and 1-specificity at different thresholds of A index. Results Three hundred one patients were included (age, 56±12 years). Their RDI was 30±24. For a A threshold at 0.6, the sensitivity of oximetry for the diagnosis of OSA was 98% and the specificity was 46%. The positive and negative predictive values for diagnosing SAS were 77% and 94%, respectively. The three false-negative cases had a relatively high awake SaO 2 (97 vs 93.9±2.8%), a moderate RDI (23.3±1.6), and were less obese than the other patients (body mass index: 25±3 vs 33±8). The 58 false-positive cases had an RDI of 8±4, an awake SaO 2 of 93.1±3.6 vs 94.1±2.6 for the rest of the population (p=0.01). Finally, the false-positive cases had more airways obstruction (FEV 1 /VC=72±13 vs 77±15%; p=0.026). Using a A value of 0.8 leads to a sensitivity of 90% with 19 false-negative cases but with a higher specificity of 75%. Conclusions A nocturnal oximetry test with a A index below 0.6 is helpful in ruling out the diagnosis of SAS in patients being screened for this condition, as this yielded only three negative test results in 301 screening procedures.

Background. Mucinous cystadenoma is an unusual pulmonary tumor that must be distinguished from mucinous cystic carcinoma and mucinous cystic tumors of borderline malignancy. Methods. This study of two cases was performed to characterize mucinous cystadenoma clinically and immunohistochemically, using proliferation markers (proliferating cell nuclear antigen [PCNA], MIB1) and carcinoembryonic antigen expression. Results. Pathologic examination in each instance showed unilocular cysts containing abundant clear mucus. The cysts were lined by tall mucinous epithelium, with absence of cytologic atypia and invasive growth. Proliferation markers using immunohistochemical methods showed less than 10% and 5% of labeled nuclei, respectively. Carcinoembryonic antigen immunostaining in both cases was negative. Patients remained free from recurrence for at least 2 years after surgery. Conclusions. Mucinous cystadenoma of the lung appears to be a benign neoplasm because of its clinical course and immunohistochemical low expression of proliferation markers such as PCNA and MIB1. Cancer 1995; 76:1540–4.

CEA, SCC and CYFRA 21-1 were measured in samples of serum coming from 105 'Non small cell lung cancer' (NSCLC) patients. The present study has been carried out to compare these markers, to analyse their prognostic significance and to determine the best combination of tumor markers. The median value and interquartile range were: CYFRA 21-1: 2,3 ng/ml, CEA: 3,7 ng/ml, SCC: 1,2 ng/ml. CEA demonstrated higher values in adenocarcinomas (P = 0.04). SCC and CYFRA 21-1 were comparable in the different histologic groups. CYFRA 21-1 and CEA values were dependant on tumor stage. Advanced tumors (T3 and T4) demonstrated higher serum CYFRA 21-1 level (P = 0.0006). CYFRA 21-1 was higher than 3,3 ng/ml in 36% of patients. CEA was higher than 5 ng/ml in 38% of patients and SCC was higher than 2 ng/ml in 27% of patients. Patients with a high CEA and CYFRA21-1 serum level had a shorter survival than those with a normal serum level. In a Cox regression analysis four variables (TNM stage, age, CYFRA 21-1 and CEA level) were found to be significant in the prediction of survival; CYFRA 21-1 level had the lowest P value (P = 0.0002). The current study suggests the use of a combination of CEA and CYFRA 21-1 in the clinical care of NSCLC.

Standard treatment of small-cell lung cancer (SCLC) is a combination of etoposide and platinum for patients with extensive disease, associated with radiotherapy for patients with limited disease (LD). Therapeutic strategies for relapse, although well characterized, are disappointing. Between 1997 and 2009, 300 patients were treated for SCLC at Grenoble University Hospital. We analyzed patients' characteristics and outcomes at different treatment steps, to determine prognostic factors and propose subsequent treatment strategies according to "sensitive", "resistant" or "refractory" status established after first-line treatment (L1). The median patient age was 63.2 years, 46.3% had LD, and 23% were female. The objective response rate (ORR) to first-line chemotherapy was 73% [CI(95%): 67.6-77.9] and median survival was 13 months. After L1, comparison between "refractory" and "sensitive" groups showed more extensive disease (76.6% vs. 34.3%, p=0.003), poorer Performance Status (PS 0-1: 48.4% vs. 67.8%, p=0.008), more endocrine paraneoplastic syndrome (18.7% vs. 8.4%, p=0.03) and more composite histology (17.2% vs. 4.9%, p=0.004) in "refractory" patients. After second line (L2), ORR was 55.8% [CI(95%): 45.2-66.0] in "sensitive", 18.2% [CI(95%): 8.2-32.7] in "resistant", and 14.7% [CI(95%): 4.9-31.0] in "refractory" groups; with partial response only for the last two groups. After L3 and L4, ORR was 24.0% [CI(95%): 14.9-35.2] in "sensitive", 9.1% [CI(95%): 11.2-29.2] in "resistant" with partial response only. No response was observed for "refractory". After L1, the median survival was respectively 23, 10 and 6.4 months for "sensitive", "resistant" and "refractory" groups (p

Nonsmall cell lung cancer samples from the European Early Lung Cancer biobank were analysed to assess the prognostic significance of mutations in the TP53, KRAS and EGFR genes. The series included 11 never-smokers, 86 former smokers, 152 current smokers and one patient without informed smoking status. There were 110 squamous cell carcinomas (SCCs), 133 adenocarcinomas (ADCs) and seven large cell carcinomas or mixed histologies. Expression of p53 was analysed by immunohistochemistry. DNA was extracted from frozen tumour tissues. TP53 mutations were detected in 48.8% of cases and were more frequent among SCCs than ADCs (p

The efficacy of the modes of inhalation of 2 inhaled steroids (IS) were compared: beclomethasone dipropionate (BDP) delivered by pressurised metered dose inhaler (p MDI) and budesonide delivered by the inspiratory driven powder inhaler Turbuhaler®. 146 asthmatic patients (mean age ± SD: 49 ± 13 years) treated for at least 6 months with constant doses of BDP (1000 to 2000μg per day) entered into an open, parallel group trial. After a 4-week run-in period, they were randomised to receive either BDP or budesonide at supposedly equivalent doses (BDP 1 puff 250μg = budesonide 1 dose 200μg) for 12 weeks. Every 4 weeks the daily dose of IS was adjusted for control of disease as assessed by a 4-graded asthma score. Both treatment groups were comparable: puffs/doses (mean ± SD) of IS per day at randomisation were 5.6 ± 1.5 for the budesonide group versus 5.8 ± 1.4 for the BDP group (p = NS). 18 patients (10 in the budesonide group, 8 in the BDP group) did not complete the trial. At the end of the study, symptoms of asthma, morning and evening peak expiratory flow, puffs of β2-agonists per 24 hours, and short courses of oral steroids were comparable, but puffs/doses of IS per day (primary efficacy variable) were significantly lower in the budesonide than in the BDP group (4.5 ± 2.1 vs 5.4 ± 2.0; p = 0.009). The results of this trial show that budesonide administered via Turbuhaler® is more effective per μg than BDP delivered by p MDI.

BACKGROUND: Basal cell carcinomas (BCCs) have been described in various locations, such as skin, anal canal, tongue, larynx, and recently, the lungs. These tumors seem to have a poor prognosis. METHODS: A series of 115 surgically resected lung tumors, previously classified as poorly or undifferentiated carcinoma, were reviewed retrospectively. From these, 37 cases were reclassified as BCCs and were compared in terms of clinical features and survival, with 40 cases reclassified as poorly differentiated squamous cell (PDSC) carcinoma of the lung. RESULTS: There was no difference between the groups regarding age, clinical presentation, pattern of relapse, and cause of death. Median and overall survival were different between the two groups, especially for Stage I and II patients: 5-year actuarial survival in the BCC group was 15% and in the PDSC group 47% (P = 0.004). CONCLUSIONS: This subset of non-small cell lung cancer (NSCLC) has a worse prognosis than other NSCLC, and this should be considered in survival studies and new treatment trials.

28 patients with primitive lung cancers were imaged by immunoscintigraphy (IS) with 111 indium-labelled F(ab′) 2 anti-carcinoembryonic antigen (CEA), to assess this technique for mediastinal staging. IS revealed primitive tumours in 21 cases in whom mediastinal extension was assessed. There was concordance between clinical staging and IS confirmed by surgery in 17 cases, and discordance in 4. After surgery, discordance was in favour of IS in 2 cases (1 true positive and 1 true negative) and in favour of clinical staging in 2 (false positive of immunoscintigraphy). Anti-CEA IS could be useful for improving mediastinal staging of lung cancer.

We describe a case of extramedullary tracheal plasmacytoma that was incidentally discovered in a 73-year-old man on a PET scan performed for assessing the extent of colon cancer. CT scan showed the tumor; multiplanar reformation coupled with virtual bronchoscopy allowed proper treatment planning. The tracheal tumor was resected during rigid bronchoscopy. Relevant investigations excluded multiple myeloma. Follow-up CT showed persistent thickening of the tracheal wall, but there has been no recurrence after one-year followup.

We propose an innovative, integrated, cost-effective health system to combat major non-communicable diseases (NCDs), including cardiovascular, chronic respiratory, metabolic, rheumatologic and neurologic disorders and cancers, which together are the predominant health problem of the 21st century. This proposed holistic strategy involves comprehensive patient-centered integrated care and multi-scale, multi-modal and multi-level systems approaches to tackle NCDs as a common group of diseases. Rather than studying each disease individually, it will take into account their intertwined gene-environment, socio-economic interactions and co-morbidities that lead to individual-specific complex phenotypes. It will implement a road map for predictive, preventive, personalized and participatory (P4) medicine based on a robust and extensive knowledge management infrastructure that contains individual patient information. It will be supported by strategic partnerships involving all stakeholders, including general practitioners associated with patient-centered care. This systems medicine strategy, which will take a holistic approach to disease, is designed to allow the results to be used globally, taking into account the needs and specificities of local economies and health systems. Part of the conceptual work presented has received support from the European commission FP7 projects AIRProm (Grant Agreement FP7 270194), BioSHaRE-EU (Grant Agreement FP7 261433), MeDALL (Grant Agreement FP7 264357), SYNERGY-COPD (Grant Agreement) and U-BIOPRED (Grant Agreement IMI 115010). JB, JMA, AC-T, FK, MLK, SP, CP and CA were supported by MeDALL; PJS, IMA and KFC were supported by U-BIOPRED; JR and AA were supported by SYNERGY-COPD; CB was supported by AIRProm; AC-T was supported by BioSHaRE-EU

Introduction: Adenocarcinoma is the most common histologic type of lung cancer. To address advances in oncology, molecular biology, pathology, radiology, and surgery of lung adenocarcinoma, an international multidisciplinary classification was sponsored by the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society. This new adenocarcinoma classification is needed to provide uniform terminology and diagnostic criteria, especially for bronchioloalveolar carcinoma (BAC), the overall approach to small nonresection cancer specimens, and for multidisciplinary strategic management of tissue for molecular and immunohistochemical studies. Methods: An international core panel of experts representing all three societies was formed with oncologists/pulmonologists, pathologists, radiologists, molecular biologists, and thoracic surgeons. A systematic review was performed under the guidance of the American Thoracic Society Documents Development and Implementation Committee. The search strategy identified 11,368 citations of which 312 articles met specified eligibility criteria and were retrieved for full text review. A series of meetings were held to discuss the development of the new classification, to develop the recommendations, and to write the current document. Recommendations for key questions were graded by strength and quality of the evidence according to the Grades of Recommendation, Assessment, Development, and Evaluation approach. Results: The classification addresses both resection specimens, and small biopsies and cytology. The terms BAC and mixed subtype adenocarcinoma are no longer used. For resection specimens, new concepts are introduced such as adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) for small solitary adenocarcinomas with either pure lepidic growth (AIS) or predominant lepidic growth with ≤5 mm invasion (MIA) to define patients who, if they undergo complete resection, will have 100% or near 100% disease-specific survival, respectively. AIS and MIA are usually nonmucinous but rarely may be mucinous. Invasive adenocarcinomas are classified by predominant pattern after using comprehensive histologic subtyping with lepidic (formerly most mixed subtype tumors with nonmucinous BAC), acinar, papillary, and solid patterns; micropapillary is added as a new histologic subtype. Variants include invasive mucinous adenocarcinoma (formerly mucinous BAC), colloid, fetal, and enteric adenocarcinoma. This classification provides guidance for small biopsies and cytology specimens, as approximately 70% of lung cancers are diagnosed in such samples. Non-small cell lung carcinomas (NSCLCs), in patients with advanced-stage disease, are to be classified into more specific types such as adenocarcinoma or squamous cell carcinoma, whenever possible for several reasons: (1) adenocarcinoma or NSCLC not otherwise specified should be tested for epidermal growth factor receptor (EGFR) mutations as the presence of these mutations is predictive of responsiveness to EGFR tyrosine kinase inhibitors, (2) adenocarcinoma histology is a strong predictor for improved outcome with pemetrexed therapy compared with squamous cell carcinoma, and (3) potential life-threatening hemorrhage may occur in patients with squamous cell carcinoma who receive bevacizumab. If the tumor cannot be classified based on light microscopy alone, special studies such as immunohistochemistry and/or mucin stains should be applied to classify the tumor further. Use of the term NSCLC not otherwise specified should be minimized. Conclusions: This new classification strategy is based on a multidisciplinary approach to diagnosis of lung adenocarcinoma that incorporates clinical, molecular, radiologic, and surgical issues, but it is primarily based on histology. This classification is intended to support clinical practice, and research investigation and clinical trials. As EGFR mutation is a validated predictive marker for response and progression-free survival with EGFR tyrosine kinase inhibitors in advanced lung adenocarcinoma, we recommend that patients with advanced adenocarcinomas be tested for EGFR mutation. This has implications for strategic management of tissue, particularly for small biopsies and cytology samples, to maximize high-quality tissue available for molecular studies. Potential impact for tumor, node, and metastasis staging include adjustment of the size T factor according to only the invasive component (1) pathologically in invasive tumors with lepidic areas or (2) radiologically by measuring the solid component of part-solid nodules.

Lung adenocarcinoma (AD) represents a predominant type of lung cancer demonstrating significant morphologic and molecular heterogeneity. We sought to understand this heterogeneity by utilizing gene expression analyses of 432 AD samples and examining associations between 27 known cancer-related pathways and the AD subtype, clinical characteristics and patient survival. Unsupervised clustering of AD and gene expression enrichment analysis reveals that cell proliferation is the most important pathway separating tumors into subgroups. Further, AD with increased cell proliferation demonstrate significantly poorer outcome and an increased solid AD subtype component. Additionally, we find that tumors with any solid component have decreased survival as compared to tumors without a solid component. These results lead to the potential to use a relatively simple pathological examination of a tumor in order to determine its aggressiveness and the patient's prognosis. Additional results suggest the ability to use a similar approach to determine a patient's sensitivity to targeted treatment. We then demonstrated the consistency of these findings using two independent AD cohorts from Asia (N = 87) and Europe (N = 89) using the identical analytic procedures.

BACKGROUND: Assessments of the upper airways in patients with the obstructive sleep apnoea syndrome are usually carried out on awake patients who are upright. The dynamics of the airway in a patient who is asleep and lying down may be different. METHODS: Somnofluoroscopy, computed tomography of the upper airway, and cephalometry were carried out in 11 patients with the obstructive sleep apnoea syndrome (10 male; mean (SD) age 53 (10) years) to examine the airway while they were awake and asleep. RESULTS: At somnofluoroscopy 10 patients were in stage 2 sleep and only one in REM sleep. At least five obstructive events were visualised by lateral fluoroscopy in each patient. Imaging allowed observation of the dynamics of airway collapse, which began in the oropharynx in all cases, progressing to the hypopharynx in 10 cases and to the laryngopharynx in five. At fluoroscopy the soft palate was seen to hook up during airway occlusion in 10 patients, thereby increasing its cross sectional area. It was then sucked down into the hypopharynx. Somnofluoroscopic and cephalometric findings agreed, eight of the 10 patients with hypopharyngeal collapse shown by somnofluoroscopy having an inferiorly placed hyoid bone according to cephalometry (distance from the mandibular plane to the hyoid bone (MP-H distance) increased); the one patient with no hypopharyngeal collapse had a normal MP-H. By contrast, six of the 11 patients had a normal or supranormal hypopharyngeal cross sectional area of the airway on the computed tomogram. CONCLUSIONS: Somnofluoroscopy allows examination of the dynamics of airway closure in this disorder and shows the important role of the soft palate in acting as a plug in the oropharynx. Dynamic studies are required to determine the pattern of pharyngeal obstruction in obstructive sleep apnoea.

Rationale: Fragile histidine triad (FHIT) is a tumor suppressor gene involved in the pathogenesis of lung cancer. Objectives: The purpose of this study was to investigate the different molecular alterations leading to the inactivation of FHIT gene function and to validate their use as biomarkers of risk for progression of the disease in patients belonging to the multicentric European study for the Early detection of Lung Cancer (EUELC) who were resected for early-stage lung tumors. Methods: FHIT immunostaining was performed on 305 tumor samples. Themethylation status of FHIT promoterwas assessed by nested methylation-specific polymerase chain reaction (MSP-PCR) in 232 tumor and 225 normal lung samples ofwhich a subset of 187 patients had available normal/tumorDNA pairs. Loss of heterozygosity (LOH) at the FHIT locus was analyzed in 202 informative cases by D3S1300 and D3S1234 microsatellite markers. Measurements and Main Results: Lost or reduced FHIT expression was found in 36.7 and 75.7% of the tumor samples, respectively. Methylation of the FHIT promoter was found in 36.7%of tumor and 32.7% of normal lung samples, whereas LOH was detected in 61.9% of the tumors. A strong association with complete loss of FHIT expression was presentwhenmethylation and LOHwere analyzed together (P5 0.0064). Loss of FHIT protein expression was significantly more frequent in squamous cell carcinoma histotype (P , 0.0001) and in smokers (P5 0.008). FHIT methylation in normal lung was associated with an increased risk of progressive disease (OR, 2.27; P 5 0.0415). Conclusions:Our results indicate thatdifferentmolecularmechanisms interplay to inactivate FHIT expression and support the proposition that FHIT methylation in normal lung tissue could represent a prognostic marker for progressive disease.

Background Netrin-1 may promote colorectal and breast tumorigenesis, by inhibiting apoptosis induced by its dependence receptors, deleted in colorectal cancer (DCC) and uncoordinated-5-homolog (UNC5H). The status of netrin-1 and its receptors in non – small cell lung cancer (NSCLC) was unknown. Methods The levels of netrin-1 and its receptors were analyzed in a panel of 92 NSCLC and 25 human lung cancer cell lines by quantitative reverse transcription – polymerase chain reaction and immunohistochemistry. In lung cancer cell lines that express netrin-1, the expression of netrin-1 was inhibited by using small interfering RNA (siRNA), or interference with netrin-1 was performed by treatment with a decoy recombinant DCC ectodomain protein (DCC-5Fbn). Cell death was monitored with a trypan blue exclusion assay or by measuring caspase-3 activity. The effect of netrin-1 interference on tumor growth was analyzed by DCC5Fbn intratumoral or netrin-1 siRNA intraperitoneal injection in mice engrafted with lung cancer cell lines. All statistical tests were two-sided. Results High levels of netrin-1 were found in 43 of the 92 NSCLC tumor samples (47%). Interference with netrin-1 in human lung cancer cell lines was associated with UNC5H-mediated cell death in vitro (percentage of cell death in untreated and in DCC-5Fbn – treated cells = 8% and 26%, respectively, difference = 18%, 95% confidence interval [CI] = 10% to 26%; P = .049) and with lung tumor growth inhibition and/or regression in xenografted nude mice (12 mice in DCC-5Fbn – treated group and 13 mice in control group). Mean volume of control and DCC-5Fbn – treated tumors on day 46 was 489 and 84 mm 3 , respectively (difference = 404 mm 3 , 95% CI = 145 to 664 mm 3 ; P < .001). Conclusions Almost half of the NSCLC tissue samples examined expressed high levels of netrin-1. Extracellular targeting of the interaction between netrin-1 and UNC5H may be a promising therapeutic approach for NSCLCs that express netrin-1.

The purpose of this study was to assess the ability of continuous nocturnal oximetry to detect sleep apnea syndrome (SAS) and to recognize nonapneic oxyhemoglobin desaturations. Oxygen saturation oscillations, related to successive apneas in SAS or to apneic episodes in COPD or restrictive patients, were quantified using a new index: delta = 1/n sigma 1 n magnitude of delta(SaO2)/delta(t)(12-s intervals) Twenty-six patients (15 SAS, 8 COPD, and 3 restrictive patients) were included in a prospective study comparing nocturnal oximetry and polysomnography over 34 nights. In apneic patients, we found a strong correlation (r2 = 0.73, p less than 0.01) between time spent in apnea and the delta index. In COPD, the number of apneas was also correlated to the delta index (r2 = 0.92, p less than 0.01). A lower threshold for delta of 1.5 is accurate enough to detect apneas if initial SaO2 is greater than 93 percent. If initial SaO2 is greater than 93 percent, the delta threshold should be 0.8 (sensitivity 95 percent). Such a method could contribute to the accurate selection of patients for polysomnography.

Despite the high response rates resulting from chemotherapy, the majority of small-cell lung cancer (SCLC) patients relapse with chemoresistant tumors. To analyze the phenotypic changes that are precursors of chemoresistant status, and to investigate the role of chemotherapy in these changes, tumor samples from 20 patients, taken before chemotherapy (etoposide, doxorubicin, and cyclophosphamide) and again at the onset of chemoresistance (after at least three courses of chemotherapy), were compared. The histologic changes were minor in 10 of 20 patients, as shown by an increase in cell size; they were major in 10 of 20 patients, with the appearance of mixed composite tumors in which neuroendocrine (NE), epidermoid, and glandular components were mixed. Major changes correlated with a good response to chemotherapy (P = .001). Ultrastructural studies showed an increase in neurosecretory granules and desmosomes, and a high frequency of multidirectional differentiation (45%) when comparison was made with pretherapy samples (10%) (P less than .01). Immunohistochemical (IH) analysis showed an increase in cytokeratin (CK) expression in treated patients, with a different labeling pattern and the expression of higher molecular weight CK. The expression of NE lineage markers (Leu 19, Sy 38, SL 11-14) remained stable, while that of NE differentiation markers (Leu 7, chromogranin) increased in the treated patients. The neuron-specific enolase (NSE) activity remained stable in treated SCLC. Large cells with a more differentiated phenotype and proliferative capacity (as shown by Ki 67 labeling), appeared to be characteristic of treated and secondary chemoresistant SCLC. The acquisition of a more complex phenotype, which correlates with primary response to therapy, implies a drug-induced differentiation in SCLC.

International audience; OBJECTIVES: To evaluate the diagnostic accuracy of percutaneous computed tomography (CT)-guided coaxial core needle biopsy in patients with nonresolving pulmonary focal air space consolidations and negative fiberoptic bronchoscopy results. METHODS: From 1997 to 2005, 23 patients (11 woman, 12 men; age range, 45 to 81 y; mean age, 66 y) presenting with nonresolving pneumonia persisting more than 8 weeks (mean, 22 wk; range, 8 to 40 wk) with negative fiberscopic results, underwent coaxial percutaneous biopsy using an automated core needle (18-gauge) under CT guidance. Histologic and bacteriologic evaluations were obtained. The final diagnosis was confirmed by surgical pathology, culture results, or clinical follow-up. RESULTS: Specimens adequate for histopathologic evaluations were obtained in 20 (87%) cases. Final diagnoses were lung cancer (n=15) and benign diseases (infectious pneumonia, 3; lipoid pneumonia, 1; Erdheim Chester disease: 1; and nonspecific chronic pneumonia, 3). Diagnostic yield of core needle biopsy was 78% (18 of 23). The sensitivity and specificity for malignancy were 87% and 100%, respectively. Immediate pneumothorax was present in 11 patients of cases, but only 2 patients required pleural drainage. DISCUSSION: CT-guided lung biopsy using a core needle biopsy provides a high degree of diagnostic accuracy and allows specific characterization of nonresolving pulmonary focal air space consolidation.

International audience; Lung carcinoma with a basaloid pattern (BC) is classified as either a basaloid variant of squamous cell carcinoma (SCC) or as variant of large cell carcinoma (LCC) depending on the presence of a squamous component. In a previous study of 37 cases, the present authors showed that BC presented with a shorter median and overall survival. In order to confirm its clinical significance in a larger series, 90 BC, including 46 basaloid variants of LCC and 44 basaloid variants of SCC, were compared with 1,328 other nonsmall cell lung carcinoma (NSCLC) with regard to clinical features and survival. The survival of basaloid variants of LCC and SCC was comparable. Median and overall survival were significantly lower for BC than for NSCLC in stage I-II patients, with a median survival of 29 and 49 months, respectively, and 5-yr survival rates of 27 and 44% for BC and NSCLC. When disease-specific survival was considered, BC had a shorter survival than both NSCLC and SCC. Basaloid pattern confers a poor prognosis in nonsmall cell lung carcinoma, especially in stage I-II patients, suggesting that lung carcinoma with a basaloid pattern is not only a variant of squamous cell carcinoma or large cell carcinoma, but is a unique entity with a significantly poor prognosis.

The case reported herein consists of nodular pulmonary amyloidosis presenting with unusual cystic radiological features which reveal a pulmonary localisation of an extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). The present case is the first to report a radiological presentation of nodular pulmonary amyloidosis in the absence of Sjogren's syndrome. Although transthoracic fine-needle biopsy was helpful for the diagnostic of amyloidosis, final diagnosis of associated MALT-type lymphoma required an open lung biopsy. This emphasises the importance of performing surgical investigations in pulmonary nodular amyloidosis in order to depict the presence of underlying lung tumours or lymphoproliferative disorders.

International audience; This study aimed at evaluating the diagnostic benefits of maximum intensity projections (MIP) and a commercially available computed-assisted detection system (CAD) for the detection of pulmonary nodules on MDCT as compared with standard 1-mm images on lung cancer screening material. Thirty subjects were randomly selected from our database. Three radiologists independently reviewed three types of images: axial 1-mm images, axial MIP slabs, and CAD system detections. Two independent experienced chest radiologists decided which were true-positive nodules. Two hundred eighty-five nodules > or =1 mm were identified as true-positive by consensus of two independent chest radiologists. The detection rates of the three independent observers with 1-mm axial images were 22 +/- 4.8%, 30 +/- 5.3%, and 47 +/- 2.8%; with MIP: 33 +/- 5.4%, 39 +/- 5.7%, and 45 +/- 5.8%; and with CAD: 35 +/- 5.6%, 36 +/- 5.6%, and 36 +/- 5.6%. There was a reading technique effect on the observers' sensitivity for nodule detection: sensitivities with MIP were higher than with 1-mm images or CAD for all nodules (F-values = 0.046). For nodules > or =3 mm, readers' sensitivities were higher with 1-mm images or MIP than with CAD (p < 0.0001). CAD was the most and MIP the less time-consuming technique (p < 0.0001). MIP and CAD reduced the number of overlooked small nodules. As MIP is more sensitive and less time consuming than the CAD we used, we recommend viewing MIP and 1-mm images for the detection of pulmonary nodules.

Patients with nonsmall cell lung cancer (NSCLC) have been shown to have a higher prevalence of comorbidity associated with age and tobacco consumption. The objective of the present study was to determine the impact of comorbidity on survival after surgery of stage I NSCLC. In total, 588 consecutive patients operated on for a pathological stage I NSCLC between January 1, 1979 and December 31, 2003 were studied. Comorbidities were analysed individually. Overall comorbidity was assessed using the Charlson index of comorbidity (CCI). Survival data were collected for each patient from the date of operation, with a median duration of follow-up of 104 months. Survival analyses and Cox proportional hazards model analyses were used. The mean age of patients was 62.7 yrs, and 529 (89%) patients were male. The distribution of overall comorbidity severity was as follows. CCI grade 0: 47.1%; grade 1-2: 43.7%; grade 3-4: 8.3%; and grade > or =5: 0.8%. The 2, 3 and 5 yrs survival were 69, 62 and 50%, respectively. Multivariable analysis showed that T stage, age, a concomitant history of moderate-to-severe liver disease, a past history of cured cancer, cerebrovascular disease and CCI were independent predictors of survival (Hazard Ratio for CCI grade >2: 1.81; 95% confidence interval 1.25-2.63). In conclusion, comorbidity has a significant impact on survival after surgical resection of patients with stage I nonsmall cell lung cancer. The use of a validated index of comorbidity in prognostic analyses of resected nonsmall cell lung cancer is recommended.

A prospective screening program, including CT, autofluorescent bronchoscopy, biopsies and bronchial lavage (BL) collection, was initiated with the specific goal of identifying biomarkers for the early detection of non-small cell lung cancer. We report and discuss the results of p16, DAPK, MGMT, FHIT and APC methylation analysis in the 126 first patients: 77 at high risk of cancer and 49 followed up after primary cancer resection. Positive results were found in 49% of BLs, 53% in current smokers and 43% in former smokers. In presence of peripheral tumours, only 38% of BLs were abnormal versus 73% in presence of central tumours, 50% in presence of preneoplasic lesions and 47% in absence of lesions. FHIT methylation was an early event, observed in one-third of the BLs from patients with or without lesions as well as in tumours. APC methylation was a late event observed in 33% of tumours but rarely in BLs. p16 was methylated in 17% of BLs but in 48% of tumours; DAPK in 15% of BL and 22% of tumours. MGMT methylation was rare. Among patients followed up after cancer surgery, 14 were in remission with normalised BL, whereas three had positive BLs and relapsed with a central tumour. Thus, gene methylation in BL might help to detect central tumours but a CT is crucial for peripheral cancer detection.

Lung cancer arises from multistep genetic damage of bronchial epithelium, driving multifocal progressive dysplastic lesions. However, the risk of progression of high-grade pre-invasive bronchial lesions to cancer is poorly assessed. The purpose of this study was to better define the parameters that predict the outcome of these lesions. The current authors prospectively studied 27 patients with 31 histologically proven severe dysplasia (SD) and carcinoma in situ (CIS), with repeated bronchoscopy and endobronchial treatment. The influence of respiratory-cancer history, histopathological classification, tobacco consumption, and number of biopsies on the progression rate into cancer was studied. The actuarial progression rate to cancer was 17% at 1 yr and 63% at 3 yrs. A total of 11 cases of CIS progressed to invasive cancer, 17 were stable or regressed during the study, two with SD regressed and one progressed to invasive cancer. Progression of CIS appeared more frequent in lesions diagnosed as “questionable CIS”. Persistence of smoking did not influence high-grade lesion outcome. The existence of synchronous lung cancer did not seem to impact on progression. The number of biopsies did not influence the outcome. In conclusion, the current study suggests that the outcome of high-grade pre-invasive lesions is not modified by the number of biopsies performed on these lesions. Careful pathological examination of these lesions and pathological revision seem necessary, since questionable cases have the worse progression rate.

Although salmeterol and formoterol are both long-acting beta(2) adrenergic receptor agonist bronchodilators, there are distinct differences between them that could translate into differences in clinical response in some patients.The goal of this study was to examine the efficacy of formoterol in patients with moderate to severe persistent asthma that was suboptimally controlled with an inhaled corticosteroid (ICS) combined with on-demand salbutamol (albuterol in the United States) with or without salmeterol.This multicenter, 4-week, randomized, open-label, parallel-group study included adult patients (age/=18 years) with suboptimally controlled asthma (mean salbutamol use,/=2 puffs/d via pressurized metered-dose inhaler [100 microg/puff]). Patients were randomized in a 2:1 ratio to receive formoterol 12 microg BID via single-dose dry powder inhaler plus on-demand salbutamol or to continue their existing treatment with either on-demand salbutamol alone or salmeterol 50 microg BID via multidose dry powder inhaler plus on-demand salbutamol. ICS regimens were unchanged during the trial. The primary efficacy variable was evening predose peak expiratory flow (PEF). Secondary variables included further measures of asthma symptom control.A total of 6239 adult patients entered the study; data from 6155 patients were available for analysis. Patients who were switched from salmeterol to formoterol reported a significant increase in mean (SD) evening predose PEF compared with patients who continued their existing treatment (402.9 [112.1] vs 385.5 [107.5] Umin, respectively; P0.001). Similarly, patients who were switched from on-demand salbutamol alone to formoterol plus on-demand salbutamol reported a significant increase in mean evening predose PEF compared with those who continued treatment with on-demand salbutamol alone (409.3 [105.6] vs 385.0 [105.3] L/min, respectively; P0.001). The results for the secondary efficacy measures mirrored the significant improvements seen in patients switched to formoterol compared with those who continued to receive on-demand salbutamol alone or salmeterol plus on-demand salbutamol.In this study, formoterol significantly improved lung function and control of asthma symptoms and decreased use of rescue medication in patients whose asthma had been suboptimally controlled with an ICS in combination with on-demand salbutamol with or without salmeterol.

Background: Bronchiolitis obliterans syndrome (BOS) is a common complication of lung transplantation (LT), associated with a tremendous mortality and morbidity. Recent innovative research has focused on bronchoalveolar lavage (BAL) analysis, assuming that neutrophilia might be a marker of chronic rejection. Patients and methods: To address this issue, we retrospectively analyzed 258 sequential BAL from 44 lung transplant recipients, having survived for more than 3 months after surgery. Results: At the end of the follow-up, 22, 7, 7 and 8 patients had BOS stage 0, 1, 2 and 3, respectively. The total cell count and neutrophilia increased with BOS severity (P