Search

Background: The link between organizing pneumonia (OP) and gastroesophageal reflux disease (GERD) is not well known. There is little evidence in the literature to establish a causal link between GERD and OP. Objectives: The aim of the study was to assess the hypothesis that OP is more severe when it is associated with GERD and that it leads to more frequent relapses. Methods: In a retrospective study on 44 patients suffering from OP, we compared the clinical, radiological and histological characteristics of 2 groups, 1 composed of patients with GERD (n = 20) and the other of patients without GERD (n = 24). Results: The GERD group was distinguished by a higher number of patients with migratory alveolar opacities on chest radiography and thoracic computerized tomography (14/20 vs. 9/24; p = 0.03 and 18/20 vs. 13/24; p = 0.01), greater hypoxemia [60 (42-80) vs. 70 (51-112) mm Hg; p = 0.03], greater bronchoalveolar lavage cellularity [0.255 (0.1-1.8) vs. 0.150 (0.05-0.4) g/l; p = 0.035] and more frequent relapses (14/20 vs. 9/24; p = 0.03). Conclusions: OP associated with GERD is more severe and results in more frequent relapses. Microinhalation of gastric secretions might induce lung inflammation leading to OP and relapse. We suggest that typical symptoms of GERD such as pyrosis should be investigated in OP.

The aim of this study was to evaluate on 1 day the prevalence of malnutrition in different types of cancer and the use of nutrition support in patients with cancer.A 1-day prevalence survey was carried out in 154 French hospital wards. Malnutrition was defined as a body mass index (BMI)18.5 in patients75 years old or21 in patients ≥75 years old and/or body weight loss10% since disease onset. Oral food intake was measured using a visual analog scale.Nutrition status was collected for 1903 patients (1109 men and 794 women, 59.3 ± 13.2 years). Cancer was local in 25%, regional in 31%, and metastatic in 44% of patients. Performance status was 0 or 1 in 49.8%, 2 in 23.7%, 3 or 4 in 19.6% and not available in 6.5% of patients. Overall, 39% of patients were malnourished. The prevalence of malnutrition by disease site was as follows: head and neck, 48.9%; leukemia/lymphoma, 34.0%; lung, 45.3%; colon/rectum, 39.3%; esophagus and/or stomach, 60.2%; pancreas, 66.7%; breast, 20.5%; ovaries/uterus, 44.8%; and prostate, 13.9%. Regional cancer (odds ratio, 1.96; 95% confidence interval, 1.42-2.70), metastatic cancer (2.97; 2.14-4.12), previous chemotherapy (1.41; 1.05-1.89), and previous radiotherapy (1.53; 1.21-1.92) were associated with malnutrition. Only 28.4% of non-malnourished patients and 57.6% of malnourished patients received nutrition support. In all, 55% of patients stated that they were eating less than before the cancer, while 41.4% of patients stated that they had received nutrition counseling.The prevalence of malnutrition is high in patients with cancer, and systematic screening for and treatment of malnutrition is necessary.

Summary Background Bronchogenic carcinoma (BC) is a worldwide health public problem with a parallel but delayed development to smoking. The prognosis of BC in young patients is poorly known mainly because of few studies that have looked at this group of patients. The hypothesis of our study is that ‘young’ patients with BC have a better prognosis than others. Methods We conducted a retrospective epidemiologic study of all patients aged 45 and under (n = 73) followed for BC between 2002 and 2007 in two hospitals in the central region in France, compared with patients over 45 years random (n = 73). We evaluated the clinical characteristics (sex, smoking habits, WHO status, clinical presentation, histology, TNM stage), the management and prognosis of these patients. Results The median survival of patients aged 45 and under was 13.4 months against 8.9 months for patients over 45 years. In multivariate analysis, age is not an independent prognostic factor (P = 0.41) in contrast to the WHO status (P = 0.002) and initial TNM stage (P Conclusion In our study, the better prognosis of the “young” patient group is not directly related to age but in good condition and lower TNM stage of these patients.

Lung cancer is the leading cause of cancer-related deaths in industrialized countries and non small cell lung cancer (NSCLC) accounts for 85% of all lung cancers. Cisplatin doublet based chemotherapy, which is the recommended regimen in first line therapy in advanced or metastatic NSCLC, improves survival but in low proportion. Monoclonal antibodies (mAbs) are a novel promising therapeutic class used with great results in inflammatory diseases such as rheumatoid arthritis. Antibodies are natural proteins with modular structure, specific pharmacodynamics and pharmacokinetics and possibly produced against any antigens, thus giving them several advantages over small drug therapeutics. In solid tumors, therapeutic mAbs improved progression free survival (PFS) and overall survival (OS) of patients with breast and colon cancers and had considerably changed the treatment in clinical practice. In NSCLC, bevacizumab, an anti-VEGF mAb, and cetuximab, an anti-EGFR mAb, are the most studied antibodies. Bevacizumab acts on angiognenesis and improved PFS of non squamous NSCLC but in low proportion as shown in two large phase III trials. It was approved by European Medicines Agency (EMEA) and Food and Drug administration (FDA) as a first line therapy in combination with cisplatin doublet chemotherapy. Cetuximab slightly enhanced OS but did not improve PFS in two large phase III trials. These results added to high adverse effect lead to cetuximab refusal by EMEA and FDA in NSCLC. At first glance, the results of mAbs in NSCLC are somewhat disappointing, in contrast to the benefits obtained with mAb treatments in other solid tumors. However, many other mAbs directed against novel targets, such as IGF1-R or CTLA-4, and new mAbs targeting VEGFR and EGFR pathways with different pharmacodymamical and pharmacokinetic properties are under evaluation and may change our vision of taking care of patients with NSCLC. In conclusion, it seems that mAbs therapy in NSCLC clearly marks the start of a new era in NSCLC treatment, with promises in improving patient survival and quality of life.

We investigated the biodistribution, pharmacokinetics, safety profile, and feasibility of aerosolized gemcitabine (GCB) in patients with lung carcinoma.Eleven patients with carcinoma localized in the lungs were studied in a dose escalation study of aerosolized GCB administered 1 day/week for 9 consecutive weeks. Safety data, scintigraphic assessment of the delivered dose and pharmacokinetic monitoring were analyzed. Patients were treated with doses of between 1 mg/kg and 4 mg/kg (dose in the nebulizer), using a new inhaler device (Aeroneb Pro with an Idehaler Chamber).The total dose of GCB delivered to the patient's lung was 42±16% of the initial amount of dose in the nebulizer. Safety data showed no hematologic toxicity, nephrotoxicity or neurotoxicity. At 4 mg/kg, one patient experienced grade 4 pulmonary toxicity (bronchospasm), which was the dose-limiting toxicity. Grade 2 and 3 toxic effects included fatigue, vomiting, dyspnea, and cough. Overall response: minor response in one patient, stable disease in four patients, progressive disease in four patients. Pharmacokinetic data showed very low plasma GCB levels. Maximal plasma concentration was observed at the end of nebulization. Aerosolized gemcitabin was safe, with minimal toxicity, for patients with lung carcinoma.

Introduction Vinflunine (Javlor) has shown significant antitumour activity in advanced non-small cell lung cancer (NSCLC). We propose to define the recommended dose of vinflunine in combination with gemcitabine for treatment of advanced NSCLC in chemonaive patients. Methods A phase I and pharmacokinetic study was conducted to determine the maximum tolerated dose and to establish the recommended dose of vinflunine (VFL) administered on day 1 every 21 days combined with gemcitabine given on days 1 and 8 every 3 weeks. Results Nineteen patients were included in this study. Three patients experienced a dose limiting toxicity, with constipation in one patient, hypertension in one patient, and constipation and febrile neutropenia in one patient. The combination of VFL 320 mg/m 2 and gemcitabine 1250 mg/m 2 was defined as the maximum tolerated dose. The recommended dose was established at the dose of VFL 320 mg/m 2 combined with gemcitabine 1000 mg/m 2 . Neither VFL nor gemcitabine seemed to be influencing the pharmacokinetics of each other. All patients were evaluable for tumor response. Seven presented a partial response and eight experienced a stable disease. Conclusions The combination of VFL 320 mg/m 2 administered on day 1 combined with gemcitabine 1000 mg/m 2 given on days 1 and 8 every 3 weeks is established as the RD and was shown to be active in these chemonaive NSCLC patients.

Resume Etats des connaissances Les instances scientifiques preconisent une attitude minimaliste dans la surveillance des cancers bronchiques operes (examen clinique et radiographie thoracique). D’apres une enquete, 70 % des pneumologues francais ont opte pour l’usage du scanner et souvent de l’endoscopie. Les donnees de la litterature sont disparates, souvent issues d’etudes retrospectives. Methodes Le cancer bronchique est un bon modele pour realiser un essai de surveillance postoperatoire. Les recidives surviennent frequemment dans une aire facile a surveiller, peuvent etre decouvertes alors qu’elles sont encore asymptomatiques, sont parfois accessibles a un traitement curatif, ont un siege identique a celui des 2 e cancers observes. L’Intergroupe Francophone de Cancerologie Thoracique (IFCT) a debute un essai comparant une surveillance legere (examen clinique, radiographie thoracique) a une surveillance lourde (scanner, fibroscopie). La surveillance est realisee tous les 6 mois pendant 2 ans puis annuellement jusqu’a 5 ans. Resultats attendus L’objectif principal est de savoir si une surveillance lourde permet d’augmenter la survie des patients. Toute aussi importante est la question inverse. Si une surveillance couteuse et penible n’interfere pas sur les chances de guerison, il est fondamental d’en tirer les consequences sur les pratiques.

Resume Les tumeurs germinales du mediastin (teratomes, seminomes et tumeurs germinales malignes non seminomateuses) constituent un groupe heterogene de tumeurs malignes et benignes. Le traitement standard des tumeurs germinales malignes non seminomateuses localisees au mediastin repose sur quatre cycles de chimiotherapie suivis de la resection de la masse residuelle. Les seminomes mediastinaux localises et de petite taille sont traites par chirurgie suivie d’une radiotherapie. Dans les formes avancees, le traitement debute par une chimiotherapie suivie de la resection de la masse residuelle Les thymomes peuvent etre localement invasifs et associes a des manifestations auto-immunes. Une resection chirugicale complete est possible dans bon nombre de cas. La radiotherapie est recommandee pour les formes invasives ou incompletement resequees. Les thymomes invasifs sont chimiosensibles

A study was carried out to investigate the predictive value of 81-metastable-krypton (81mKr) distribution, high-size 99-metastable-technetium (99mTc) aerosol deposition and low-size 99mTc aerosol (Technegas) deposition on the pulmonary ventilation evaluated by 133-xenon (133Xe) lung scintigraphy, and to assess the correlation between the 81mKr distribution, the 99mTc aerosols deposition, and the respiratory parameters of patients with chronic obstructive pulmonary disease (COPD). Twenty COPD patients were included. The 81mKr, 133Xe, and 99mTc aerosol lung scintigraphies were successively carried out. The 81mKr distribution and 99mTc deposition were compared to the 133Xe distribution at equilibrium and to the 133Xe clearance. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 81mKr and Technegas lung scintigraphies to detect alterations in ventilation revealed by 133Xe were defined. The 81mKr distribution and 99mTc deposition according to respiratory parameters were described using a principal component analysis. Compared to 133Xe distribution, a significantly higher distribution of 81mKr in the upper parts of the lungs in the more severe patients (p = 0.05), a significantly higher deposition of Technegas in the lower parts of the lungs (p = 0.0008), and a significantly higher deposition in the central parts of the high-size 99mTc aerosol were observed (p = 0.0001). The PPV and the NPV were, respectively, 0.54 and 0.58 for 81mKr and 0.54 and 0.55 for Technegas. There was a significant negative correlation between 81mKr distribution and 133Xe clearance (p = 0.0001) between Technegas deposition and 133Xe clearance (p = 0.0007), and between 99mTc diethylene-triamino-penta-acetate (DTPA) deposition and 133Xe clearance (p = 0.001). Both the 81mKr peripheral distribution and Technegas peripheral deposition correlated negatively with increased obstruction, as measured by forced expiratory volume in 1 sec (FEV1). Peripheral deposition of the high-size 99mTc aerosol deposition correlated with the inspiration/expiration time ratio. In conclusion, 81mKr and 99mTc aerosols' lung scintigraphies do not reflect exactly the pulmonary ventilation as measured by 133Xe scintigraphy.

Aim: To characterize gemcitabine aerosol, its in vitro activity against lung cancer cells, its deposition, and tolerance in a non-human primate model. Methods: In vitro cytotoxicity of nebulized gemcitabine against NCI-H460 and A549 lung cancer cells was tested using a growth inhibition assay and compared with non-nebulized gemcitabine. The 99mTc-DTPA-radiolabeled gemcitabine aerosol was characterized by cascade impaction and the gemcitabine mass/99mTc activity relationship was established for further quantitative nuclear imaging. Nine weekly inhalations at a target dose of 1 mg/kg body weight of gemcitabine were performed in three baboons using dynamic scintigraphic acquisitions for continuous monitoring of gemcitabine delivery during inhalation. Gemcitabine plasma concentrations were measured during the first inhalation. Results: Growth inhibition assays for both NCI-H460 and A549 cells did not differ between nebulized and non-nebulized gemcitabine. Aerosol characterization showed a particle mass median aerodynamic diameter of 3.7±0.8 μm and a linear relationship between gemcitabine mass (y) and 99mTc activity (x) (y=0.82x − 10−5, R 2=0.88). No toxicity was observed after nine weekly inhalations of a mean dose of gemcitabine of 11.1 mg (88% of the target dose) as assessed from scintigraphic data. A dose-dependent peak plasma concentration of gemcitabine (20–74 ng/ml) was observed by the tenth minute of inhalation. Conclusions: We have characterized a gemcitabine aerosol suitable for intrathoracic airway deposition and demonstrated that jet nebulization does not alter the cytotoxic properties of the drug. In a primate model, we have developed a scintigraphic procedure for the monitoring of aerosol deposition, and we have demonstrated the safety of nine weekly aerosol administrations of gemcitabine.

Background This multicenter, randomized, phase III study compared the efficacy, including progression-free survival (PFS), and safety of gemcitabine–docetaxel (GD) combination versus cisplatin–vinorelbine (CV) in the treatment of advanced non-small-cell lung cancer (NSCLC). Patients and methods Chemonaive patients with stage IIIB or IV NSCLC were treated with GD (gemcitabine 1000 mg/m2 days 1 and 8 plus docetaxel 85 mg/m2 day 8, every 3 weeks for eight cycles) or CV (cisplatin 100 mg/m2 day 1 plus vinorelbine 30 mg/m2, days 1, 8, 15 and 22, every 4 weeks for six cycles). Results A total of 311 patients were enrolled (155 GD and 156 CV). Neither PFS nor overall survival differed significantly between the two arms (median PFS 4.2 and 4 months; median survival 11.1 and 9.6 months; 1-year survival 46% and 42%, for GD and CV, respectively). For the GD arm compared with the CV arm, the hazard ratio for PFS was 1.04 [95% confidence interval (CI) 0.83–1.32], and for overall survival, it was 0.90 (95% CI 0.70–1.16). Objective response rates did not differ significantly (31% for GD, 35.9% for CV). Myelosupression, emesis and frequency of febrile neutropenia were less pronounced on the GD arm, whereas fluid retention and pulmonary events were more pronounced. The CV arm experienced a higher number of serious adverse events and a lower compliance with the protocol. There was no quality of life (QoL) difference between arms. Median time to definite impairment of health-related QoL was 153 and 168 days in GD and CV arms, respectively. Conclusions There was no advantage in PFS with GD compared with CV; however, the CV regimen had higher rate of toxic events, mainly myelosuppression. The herein, non-platinum-containing regimen could be considered as a rational alternative to the cisplatin-based doublet.

Resume On designe sous le terme de tumeur mediastinale d'origine embryonnaire les tumeurs qui resultent d'un trouble du developpement embryonnaire ou qui derivent de cellules germinales et dont le siege primitif est le mediastin. Ces tumeurs sont constituees de tissus ressemblant a ceux qui se succedent au cours du developpement depuis le stade embryonnaire jusqu'au stade adulte. Ces lesions, benignes ou malignes, sont classees selon leur histogenese et les possibilites therapeutiques. Les tumeurs germinales sont constituees de tissus ressemblant a ceux qui se succedent au cours du developpement, par differenciation des feuillets primordiaux et des feuillets extraembryonnaires. Du point de vue therapeutique, on distingue les seminomes, les tumeurs germinales non seminomateuses (TGNS) et les teratomes. Les kystes mediastinaux sont des malformations constituees de tissus normalement contenus dans la cavite thoracique adulte. Ils sont classes en cinq types selon leur structure : les kystes bronchogeniques et paraœsophagiens, les kystes pleuropericardiques, les lymphangiomes kystiques, les hemangiomes benins et les kystes meninges.

Background The survival benefit associated with first-line chemotherapy in advanced lung cancer led to the need for second-line chemotherapy. Docetaxel (Taxotere®) has proven efficacy in both settings. This study evaluated the safety and efficacy of two doses of docetaxel in patients with non-small-cell lung cancer who had failed first-line platinum-based chemotherapy. Patients and methods In total, 182 patients from 24 French centres were randomised and treated with either docetaxel 75 mg/m2 (arm A) or 100 mg/m2 (arm B) every 3 weeks. Baseline characteristics were well balanced, except more patients in arm A had metastatic disease (91.4% versus 78.7%) and therefore the median number of sites involved for arm A was three compared with two for arm B. Results Median time to treatment failure was 1.34 months [95% confidence interval (CI) 1.28–1.64] for arm A and 1.64 months (95% CI 1.34–2.62) for arm B. Median overall survival was 4.7 months (95% CI 3.8–5.9) for arm A versus 6.7 months (95% CI 4.8–7.1) for arm B. According to a blinded expert panel, disease control was achieved in 35 (43.8%) patients in arm A and 39 (49.4%) patients in arm B. More patients in arm B experienced grade 3–4 neutropenia (B: 72.7% versus A: 44.0%), asthenia (B: 20.2% versus A: 10.8%) and infection (B: 6.7% versus A: 2.2%). Three treatment-related deaths were reported in each arm. Conclusions The optimal docetaxel dosage in this second-line setting is 75 mg/m2, as it has a more favourable safety profile and on balance a similar efficacy to the 100 mg/m2 dose.

Aims: A case–control study was carried out between 1998 and 2000 to investigate the relation between systemic sclerosis and occupational exposure. Methods: Eighty cases of systemic sclerosis admitted consecutively to the Department of Internal Medicine at the University Hospital of Tours from 1998 to 2000 were included. For each case, two age, gender, and smoking habits matched controls hospitalised during the same period in the same department were selected. A committee of experts was set up retrospectively to assess occupational exposure. Exposure to silica dust and organic solvents (such as trichlorethylene and other chlorinated solvents, and benzene and other aromatic solvents) was investigated using semiquantitative estimates of exposure. An exposure score was calculated for each subject based on probability, intensity, daily frequency, and duration of exposure for each period of employment. The final cumulative exposure score was obtained, taking into account all periods of employment. Results: Significant associations with SS were observed for crystalline silica, trichlorethylene, chlorinated solvents, toluene, aromatic solvents, ketones, white spirit, epoxy resins, and welding fumes. Risk of SS was significantly associated with a high final cumulative exposure score of occupational exposure to crystalline silica, trichlorethylene, chlorinated solvents, welding fumes, and any types of solvents. Conclusion: Results confirm the influence of occupational risk factors in the occurrence of SS in both men and women. The link is not only with silica but also with other compounds such as solvents.

To evaluate whether preoperative chemotherapy (PCT) could improve survival in resectable stage I (except T1N0), II, and IIIA non-small-cell lung cancer (NSCLC).A randomized trial compared PCT to primary surgery (PRS). PCT consisted of two cycles of mitomycin (6 mg/m(2), day 1), ifosfamide (1.5 g/m(2), days 1 to 3) and cisplatin (30 mg/m(2), days 1 to 3), and two additional postoperative cycles for responding patients. In both arms, patients with pT3 or pN2 disease received thoracic radiotherapy.Three hundred fifty-five eligible patients were randomized. Overall response to PCT was 64%. There were two preoperative toxic deaths. Postoperative mortality was 6.7% in the PCT arm and 4.5% in the PRS arm (P =.38). Median survival was 37 months (95% confidence interval [CI], 26.7 to 48.3) for PCT and 26.0 months (95% CI, 19.8 to 33.6) for PRS (P =.15). Survival differences between both arms increased from 3.8% (95% CI, 1.3% to 25.1%) at 1 year to 8.6% (95% CI, 2.64% to 24.4%) at 4 years. A quantitative interaction between N status and treatment was observed, with benefit confined to N0 to N1 disease (relative risk [RR], 0.68; 95% CI, 0.49 to 0.96; P =.027). After a nonsignificant excess of deaths during treatment, the effect of PCT was significantly favorable on survival (RR, 0.74; 95% CI, 0.56 to 0.99; P =.044). Disease-free survival time was significantly longer in the PCT arm (P =.033).Although impressive differences in median, 3-year, and 4-year survival were observed, they were not statistically significant, except for stage I and II disease.

A randomized phase II trial of oral vs. intravenous (i.v.) vinorelbine was designed to determine the efficacy and safety of oral vinorelbine with an intrapatient dose escalation in previously untreated patients with advanced non-small-cell lung cancer (NSCLC).Between December 1997 and April 1999, 115 patients with stage IIIB or IV NSCLC were randomized (2 to 1) to receive either oral vinorelbine at a dose of 60 mg/m2/week for the first three administrations and then increased to 80 mg/m2/week in the absence of severe neutropenia, or i.v. vinorelbine at 30 mg/m2/week.One hundred and fourteen patients (76 in the oral arm and 38 in the i.v. arm) were treated. Ninety-eight patients (86%) were eligible and assessable. The two treatment arms were well-balanced for demographic and prognostic features. After external panel review, the response rates in evaluable patients were 14%, in the oral arm and 12% in the i.v. arm. The median progression-free survival with oral and i.v. vinorelbine was 3.2 months and 2.1 months, respectively, and the median survival 9.3 and 7.9 months, respectively. The most common hematological toxicity was neutropenia, which was severe (grade 3-4) in 46% of patients and for 7% of administrations in the oral arm, and in 62% of patients and for 25% of administrations in the i.v. arm. Non-hematological toxicities including nausea, vomiting, anorexia, weight loss, diarrhea .and constipation were generally mild to moderate.The activity of oral and i.v. vinorelbine in advanced NSCLC appears to be comparable. The safety profiles of both formulations look qualitatively similar. Oral vinorelbine can therefore be considered a good alternative to i.v. administration.

Context The 'Standards, Options and Recommendations' (SOR) project, started in 1993, is a collaboration between the Federation of the French Cancer Centres (FNCLCC), the 20 French cancer centres and specialists from French public universities, general hospitals and private clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and outcome for cancer patients. The methodology is based on literature review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery. Objectives To develop clinical practice guidelines according to the definitions of the Standards, Options and Recommendations project for the management of stage I and II non small cell lung carcinoma treated by radiotherapy alone. Methods Data were identified by searching Medline and personal reference lists of members of the expert groups. Once the guidelines were defined, the document was submitted for review to independent reviewers, and to the medical committees of the 20 French cancer centres. Results The main recommendations for the management of stage I and II non small cell lung carcinoma treated by radiotherapy alone are: 1) The curative external irradiation with a continual course is an alternative to surgery only in the case of medically inoperable tumors or because the patient refuses surgery; 2) The external irradiation of the primary tumor only without the mediastinum could be proposed in peripheral stage IA. In proximal stage IA and IB, external irradiation should be carried out only as part of prospective randomised controlled trials comparing a localised irradiation of the primary tumor with a large irradiation of the mediastinum and the primary tumor. The treated volume must include the macroscopic tumoral volume with or without the microscopic tumoral volume and with a security margin from 1.5 to 2 cm; 3) There is a benefit to delivering a total dose in the primary tumor higher than 60 Gy in so far as the proposed irradiation, taking into account the respiratory function, does not increase the likelihood of severe adverse events due to radiation; and 4) The change in fractionation, the radiochemotherapy combination, the endobronchial brachytherapy with high dose rate alone or with external irradiation could be proposed only as part of prospective controlled trials for tumors classified as stage IB or II.

Using nebulization to deliver aminoglycosides may be of benefit in cystic fibrosis (CF) patients colonized byPseudomonas aeruginosa. However, one problem with this route is the absence of clinical parameters allowing estimation of the mass of drug deposited in the lungs (MDL). The aim of this study was to assess whether aminoglycoside excretion in the urine reflects the MDL.Fourteen studies were performed in seven CF patients. Amikacin was mixed with albumin labelled with99mTc and nebulized with an ultrasonic nebulizer. The MDL was determined by the mass-balance technique. Urine was collected during the 24 h following inhalation and was assayed for amikacin by fluorescence polorization immunoassay (FPIA).The mean±sem MDL was 14.0±2.2% of the nebulizer charge. The mean±sem amount of amikacin excreted in the urine was 20.9±4.5 mg and correlated with the MDL (r=0.93; p=0.0001). There was, however, wide intersubject variability in both deposition and excretion in the urine.Monitoring excretion of aminoglycosides in the urine allows noninvasive estimation of the mass of drug deposited in the lung in cystic fibrosis patients, which might be useful to assess the dose-response relationship in groups of patients, but intersubject variability prevents its use for individual follow-up.

Contexte. - La Federation nationale des centres de lutte contre le cancer (FNCLCC) et les Centres regionaux de lutte contre le cancer (CRLCC), en collaboration avec des partenaires des secteurs public (CHU, CHG), prive et certaines societes savantes ont entrepris depuis 1993 d'elaborer des recommandations pour la pratique clinique en cancerologie: les « Standards, Options et Recommandations » (SOR). L'objectif de l'operation SOR est d'ameliorer la qualite et l'efficience des soins aux patients atteints de cancer en fournissant aux praticiens une aide a la decision facilement utilisable. La methodologie d'elaboration des SOR repose sur une revue et une analyse critique des donnees de la litterature scientifique par un groupe d'experts pluridisciplinaire, permettant de definir, sur la base du niveau de preuve scientifique et du jugement argumente des experts, des « Standards », des « Options » et des « Recommandations ». Avant publication, les SOR sont revus par des experts independants. Objectifs. - Definir, sur la base d'une revue de la litterature et de l'accord d'experts, des Standards, Options et Recommandations pour la prise en charge des patients atteints de cancer broncho-pulmonaire primitif de stade I ou Il traites par irradiation exclusive. Methodes. - Un groupe de travail multidisciplinaire mis en place par la Federation nationale des centres de lutte contre le cancer (FNCLCC) a revu les donnees scientifiques disponibles concernant la prise en charge des patients atteints de cancer broncho-pulmonaire primitif non a petites cellules de stade I et Il traites par irradiation exclusive. Apres selection des articles, synthese des resultats et redaction des SOR, le document a ete soumis pour relecture et approbation a des relecteurs. Resultats.- Les principales recommandations sont: 1) l'irradiation externe exclusive continue a visee curative, avec un fractionnement conventionnel, n'est une alternative a la chirurgie d'exerese qu'en cas de contre-indications a un acte chirurgical liees au terrain medical ou de refus du malade de tout acte chirurgical; 2) l'irradiation externe du volume tumoral primitif seul, sans le mediastin, peut etre proposee dans les formes classees stade IA, de topographie peripherique. Dans les formes classees stade IA proximal et IB, elle ne peut se concevoir que dans le cadre d'un essai therapeutique prospectif randomise et controle comparant une irradiation localisee au volume tumoral et une irradiation large mediastino-tumorale. Le volume traite doit inclure le volume tumoral macroscopique avec ou sans le volume tumoral microscopique, avec une marge de securite de 1,5 a 2 cm; 3) il y a un benefice a delivrer une dose totale dans le volume tumoral superieure a 60 Gy dans la mesure ou la technique d'irradiation proposee tenant compte de la fonction respiratoire du malade, n'augmente pas la probabilite de risque de complications severes radio-induites; 4) les modifications du fractionnement, l'association radiochimiotherapie concomitante, la curietherapie endoluminale a haut debit de dose seule ou en association a une irradiation externe, ne peuvent etre proposees que dans le cadre d'essais prospectifs controles pour des formes classees de stade IB ou II.

Background: The combination of etoposide plus cisplatin (EP) is considered to be standard therapy for small-cell lung cancer (SCLC). To determine whether drug intensification improves survival of patients with extensive SCLC, we compared this treatment with a four-drug regimen containing EP plus cyclophosphamide and 4'-epidoxorubicin (PCDE). Methods: In a phase III clinical trial organized by the French Federation of Cancer Institutes, patients were randomly assigned to receive either EP (n = 109; etoposide at a dose of 100 mg/m 2 on days 1-3 plus cisplatin at 100 mg/m 2 on day 2) or PCDE (n = 117; etoposide and cisplatin given as in EP plus cyclophosphamide at 400 mg/m 2 on days 1-3 and 4'-epidoxorubicin at 40 mg/m 2 on day 1) every 4 weeks. Both groups received a total of six cycles. Survival differences were analyzed by Wilcoxon and log-rank tests. Associations of treatment group and putative prognostic variables with survival were tested in the Cox proportional hazards model. Quality of life was assessed from the responses to the European Organization for Research and Treatment of Cancer quality-of-life questionnaire (C30, health status and lung cancer module 13). All statistical tests were two-sided. Results: Patients in the PCDE arm had a statistically significant higher frequency of combined complete plus partial responses compared with those in the EP arm (21% plus 55% versus 13% plus 48%, respectively; P = .02 for difference in combined objective responses). Patients in the PCDE arm survived longer than those in the EP arm (1-year survival rate: 40% and 29%, respectively; median survival: 10.5 and 9.3 months, respectively; log-rank P = .0067). In the Cox model, the relative risk of death for patients in the PCDE arm compared with those in the EP arm was 0.70 (95% confidence interval = 0.51 to 0.95); the disease also progressed more slowly in patients in the PCDE arm. Hematologic toxicity was higher in the PCDE arm (22% with documented infections compared with 8% in the EP arm; P = .0038), and the toxicity-related death rate was 9% in the PCDE arm versus 5.5% in the EP arm (P = .22). The global health status showed similar improvement in both arms during treatment. Conclusion: Compared with the EP regimen, the PCDE regimen yielded higher response rates and better survival rates in patients with extensive SCLC without affecting the quality of life of the patients during chemotherapy.

Study objective To determine the value of the level of anti-topoisomerase I (anti-topo I) to evaluate lung involvement defined by abnormal high-resolution computed tomography (HRCT) score and pulmonary function tests (PFTs) in systemic sclerosis (SS). Patients Forty-eight patients with SS, 20 with lung involvement and 28 with no lung involvement. Design PFT measurement, HRCT scoring of lung involvement, and anti-topo I assay by enzyme-linked immunosorbent assay. Normal anti-topo I level was defined as Results There was a significant association between cutaneous extent and anti-topo I level (6.5% of patients with limited cutaneous scleroderma had abnormal anti-topo I levels vs 70.6% of patients with diffuse cutaneous scleroderma, p = 0.0001). In patients with diffuse cutaneous scleroderma, pulmonary involvement was associated with a higher percentage of abnormal anti-topo I level: 91.7% vs 20% (p = 0.010). In patients with diffuse cutaneous scleroderma, a significant association was found between the class of anti-topo I level and total lung capacity (median, 69 in patients with abnormal anti-topo I level vs 87 in patients with normal anti-topo I level, p = 0.010), between the class of anti-topo I level and HRCT score (median, 12 in patients with abnormal anti-topo I level vs 5 in patients with normal anti-topo I level, p = 0.05). Conclusion Anti-topo I can be considered as a marker of lung involvement in patients with diffuse cutaneous scleroderma.

To determine the predictive value of abnormalities on high-resolution CT (HRCT) on pulmonary disease in systemic sclerosis.Fifty-two patients suffering from systemic sclerosis.Pulmonary disease was defined by pulmonary function test abnormalities, ie, total lung capacity (TLC)80% of predicted value and/or diffusion of carbon monoxide (DLCO)75% of predicted value, without any pulmonary event other than systemic sclerosis in the medical history. Patients were divided in two groups, group A with pulmonary disease (29 patients) and group B without pulmonary disease (23 patients). HRCT abnormalities were scored on whole lungs. A decision matrix was constructed to determine sensitivity, specificity, positive and negative predictive values, and false-positive and false-negative rates. A receiver operating characteristic curve was constructed to determine the best compromise between sensitivity and specificity.HRCT total scores were higher in group A (9.0+/-4.3) than in group B (5.0+/-2.8) (p0.001) and they correlated with TLC (r =-0.39, p0.005) and DLCO (r = -0.50, p0.0002). An HRCT score of 7 corresponded to the best compromise between sensitivity (0.60) and specificity (0.83), with a positive predictive value of 0.82. Taking into account a value of 10 for the HRCT score increased specificity to 1 but decreased sensitivity to 0.41.A minimum score of 7 would be required to consider HRCT abnormalities in systemic sclerosis as predictive of pulmonary disease. An HRCT score of 10 makes it possible to establish the diagnosis of lung involvement severe enough to impair pulmonary function.

The purpose of this study was to determine the ability of technetium-99m J001X scintigraphy to image active pulmonary involvement in patients suffering from rheumatoid arthritis (RA). J001X is a fully characterized acylated poly(1,3)galactoside, isolated from Klebsiella membranes, which is able to bind recruited macrophages after aerosol administration. J001X scintigraphy was compared with high-resolution computed tomography (HRCT), pulmonary function tests (PFTs) and bronchoalveolar lavage (BAL) in 15 patients suffering from RA. Patients were considered to have pulmonary involvement when they had an interstitial syndrome on HRCT and a decrease of 20% in TCO/VE (transfer coefficient) on PFTs and/or an abnormal BAL (lymphocytosis higher than 20% and/or percentage of neutrophils higher than 10%). Pulmonary involvement was present in eight patients, and absent in seven. Of the eight patients with pulmonary involvement, all had abnormal BAL, two had an interstitial syndrome on HRCT, two had decreased TCO/VE and three had positive J001X scintigraphy. Of the seven patients without pulmonary involvement, six had normal BAL (not available in one), two had an interstitial syndrome on HRCT, one had decreased TCO/VE and two had positive J001X scintigraphy. According to our gold standard of pulmonary involvement, the sensitivity of J001X scintigraphy for the detection of pulmonary involvement in RA was 37.5%, the specificity was 71.4% and the positive predictive value was 60%. The ability of J001X scintigraphy to detect active pulmonary involvement during RA appears unclear in this study but it may detect processes unnoticed by the other modalities. These patients will be followed 12 and 24 months later and the changes in J001X scintigraphy, HRCT and PFTs will be compared to demonstrate whether J001X scintigraphy is able to assess an active process in the pulmonary involvement during RA and to specify its predictive value.

The aim of the present study was to characterize amphotericin B aerosols nebulized by ultrasonic and jet nebulizers and to study their deposition and pharmacokinetics in patients with pulmonary mycetoma. The aerodynamic behaviour and pulmonary deposition of amphotericin B particles were measured using a direct isotopic method based on stable labelling of the drug with 99mTc. Each nebulizer was bench tested for inhaled mass and particle size distribution. Three patients suffering from pulmonary aspergilloma were enrolled for a 4 week clinical study. They received 5 mg of amphotericin B daily delivered by either Fisoneb or DP100 (ultrasonic) or Respirgard II (jet) nebulizers. Deposition of radiolabelled amphotericin B was measured once with each nebulizer using a gamma-camera. In two patients, amphotericin B serum concentration was monitored over a 330 min period after the nebulization had been completed. Inhaled masses of the three nebulizers, assessed as % of labelled drug caught in inspiratory filter in duplicate experiments, were: 5.8 and 3.6% for Respirgard II; 26.5 and 28.3% with Fisoneb; 5.9 and 6.3% for DP100. Mass median aerodynamic diameter (mean +/- SD) results were: 0.28 +/- 0.04 micron with Respirgard II; 4.82 +/- 0.78 microns with Fisoneb; and 2.27 +/- 1.14 microns with DP100. Because of larger particles and significantly greater inhaled mass, Fisoneb delivered more amphotericin B to the central airways, the lung periphery and in the mycetoma lung regions. Amphotericin B serum concentrations correlated with pulmonary deposition and remained below 25 ng.mL-1. No untoward effects were reported by the patients during the 4 week trial.(ABSTRACT TRUNCATED AT 250 WORDS)

Background Despite advances in cancer therapy, mortality is still high except in early-stage tumors, and screening remains a challenge. The randomized National Lung Screening Trial (NLST), comparing annual low-dose computed tomography (LDCT) and chest X-rays, revealed a 20% decrease in lung-cancer-specific mortality. These results raised numerous questions. The French intergroup for thoracic oncology and the French-speaking oncology group convened an expert group to provide a coherent outlook on screening modalities in France. Methods A literature review was carried out and transmitted to the expert group, which was divided into three workshops to tackle specific questions, with responses presented in a plenary session. A writing committee drafted this article. Results The multidisciplinary group favored individual screening in France, when carried out as outlined in this article and after informing subjects of the benefits and risks. The target population involves subjects aged 55–74 years, who are smokers or have a 30 pack-year smoking history. Subjects should be informed about the benefits of quitting. Screening should involve LDCT scanning with specific modalities. Criteria for CT positivity and management algorithms for positive examinations are given. Conclusions Individual screening requires rigorous assessment and precise research in order to potentially develop a lung-cancer screening policy.

BACKGROUND--J001X is an acylated poly-galactoside isolated from the membrane of Klebsiella and able to interact with macrophages, mainly in their activated state. The aim of the present study was to determine the ability of 99m-labelled technetium (99mTc)-J001X scintigraphy to image pulmonary disease, defined by high resolution computed tomographic scanning and pulmonary function tests, in patients suffering from scleroderma. METHODS--Patients were considered to have pulmonary disease when they had at least two positive signs on high resolution computed tomography, or a decrease in lung volume and single breath carbon monoxide transfer, or both, with no disease process other than scleroderma in their medical history. Positive J001X scintigraphic imaging was defined by symmetrical bilateral pulmonary fixation three and five hours after inhalation of 99mTc-J001X. J001X scintigraphic results were compared with disease activity as indicated by bronchoalveolar lavage (BAL) fluid lymphocytosis. RESULTS--Seventeen patients were studied, in 12 of whom J001X scintigraphy was positive. There was no correlation between BAL lymphocytosis and J001X scintigraphic findings, nor between BAL and pulmonary scleroderma. This was not surprising because of the high specificity of macrophage targeting by J001X. CONCLUSIONS--Follow up of a larger population over a longer period is needed to establish whether there is a prognostic value for positive J001X scintigraphic findings in scleroderma.

Summary Purpose The purpose of the study was to assess the possible benefit of the combination vinorelbine (NVB)-cisplatin (DDP) in comparison with NVB alone in advanced non- small cell lung cancer (NSCLC), not treated previously. It also involved confirmation of the efficacy of vinorelbine as monotherapy. Patients and methods In this phase 111 trial, 231 eligible patients were stratified by centre and randomized to receive either NVB alone, 30 mg/m2/week or the combination of NVB 30 mg/m2/week and DDP 80 mg/m2/3 weeks. Patients were to be treated for a minimum of 6 weeks, with the first response assessment performed 9 weeks after the beginning of treatment. Results The two groups differed in terms of objective response rates (16% and 43%, respectively, p = 0.0001) and median time to progression (10 weeks and 20 weeks, p = 0.0001). However, the difference was not significant for median survival time (32 weeks, 33 weeks, p = 0.48). The addition of DDP resulted in an increase in toxicity, in particular renal, hematologic, neurologic and emetic. This toxicity led to treatment discontinuation in 8% and 21% of patients, respectively. Respectively 3% and 13% of patients stopped treatment early during objective response (toxicity or refusal). Conclusions The NVB-DDP combination increased objective response rates and time to progression in comparison with NVB alone, but did not influence the survival of patients. The activity of NVB in the treatment of advanced NSCLC was confirmed.

Scintigraphy with radiolabeled J001 as a ligand for macrophage targeting is a new approach for sarcoidosis imaging. J001 is a fully characterized acylated peptido-poly (1,3) galactoside isolated from Klebsiella membrane proteoglycans and able to bind electively recruited macrophages. Its physiochemical properties allow rapid absorption by the respiratory tract when this agent, labeled by 99m technetium, is administered as an aerosol. Images are obtained within 3 to 5 h after inhalation. In the present study, we determined the ability of J001 scintigraphy to localize areas of sarcoidosis involvement in 22 patients compared with gallium scanning in ten of them. Nineteen patients underwent bronchoalveolar lavage (BAL) and serum angiotensin-converting enzyme (ACE) assay. J001 scintigraphy was also performed on a control group of six patients with extrathoracic melanoma, in whom J001 scintigraphy was used to evaluate the cutaneous extent of the tumor and the lymph node involvement. In this control group, no fixation appeared in the thoracic area. In the sarcoidosis group, 18 positive results were observed. One stage 0 patient had a mediastinal fixation. Five of the six stage 1 patients had a fixation located in the mediastinum, the lungs, and the wrists. Five of the six stage 2 patients had positive foci located in the mediastinum or the lung areas and in the myocardium in one of them. Six of the nine stage 3 patients had positive J001 scintigraphy occurring in the lungs and/or the mediastinum. One patient had a fixation on the main bronchi. J001 scintigraphy and gallium scanning, performed in ten patients, were positive in seven of them. There were discrepancies between the BAL results and J001 scintigraphy, as well as between the ACE results and J001 scintigraphy. In conclusion, 99mTc-J001 scintigraphy appears to be a sensitive and rapid technique for the imaging of thoracic sarcoidosis at the three stages of the disease.

A glycolipid (J001X) isolated from the membrane proteoglycans of a non-pathogenic strain of Klebsiella pneumoniae was developed to bind selectively to macrophages. A scintigraphic technique could thus be developed and applied to an experimental model of lung berylliosis. Six baboons were injected intratracheally with a beryllium metal suspension. Three to 24 months later, they were submitted to both an anatomical and a functional respiratory evaluation. Two baboons were explored at the early stage of alveolitis and four baboons at a more advanced stage characterised by a granulomatous disorder. Scintigraphy was performed using J001X labelled with 99mtechnetium administered as an aerosol. In the six baboons, conventional imaging techniques (chest x ray film, computed tomography scan, gallium scintigraphy), failed to show either any lung abnormality or mediastinal lymph nodes consistent with beryllium disease. In the two recently contaminated baboons, J001X scintigraphy showed a well defined parenchymal fixation facing the contaminated lobe. In the four baboons who were at a more advanced stage of berylliosis, J001X fixation was always focused paratracheally without any significant involvement of the lung parenchyma. The subcarinal and laterotracheal lymph nodes seen at necropsy corresponded to J001X scintigraphic fixations. In conclusion, when compared with conventional techniques such as chest x ray film, computed tomography scan, magnetic resonance imaging, and gallium scintigraphy, J001X scintigraphy has proved its ability to detect occult lesions in experimental berylliosis in baboons. By comparison with gallium scintigraphy, scintigraphy with J001X appears to have superior sensitivity and can be performed in four hours.

Introduction: Although airways route is an attractive alternative route to systemic administration, increasing concentration of the drug in the lungs while reducing whole-body toxicity, it is not often exploited in lung cancer treatment. After checking that cetuximab, an anti-cancer antibody binding to EGFR, resists the physical constraints of nebulization, we established an animal model of lung tumour sensitive to the antibody. Then, we used the animal model to evaluate cetuximab antitumor efficiency, biodistribution and pharmacokinetic following delivery through airways. Methods: Cetuximab was nebulized with the IA-1C MicroSprayer™ (PennCentury Inc., USA) connected to a FMJ-250 high pressure syringe, a device used to administrate, directly inside the trachea, aerosol in mice. The effect of nebulization on cetuximab was assessed in terms of its affinity for membrane EGFR (using flow cytometry), inhibition of cell growth and inhibition of EGFR phosphorylation. To ensure that airways delivery of cetuximab did not lead to additional toxicity, we compared tolerance to cetuximab delivered through systemic and pulmonary routes in mice without tumors. An animal model of lung cancer sensitive to cetuximab was established and consists in the instillation of human epidermoid carcinoma cells endotracheally in nude mice. The model was exploited to study cetuximab biodistribution and pharmacokinetic following delivery through systemic and pulmonary routes. Therapeutic efficiency of nebulized cetuximab was determined in tumor- bearing animals. Results: Firstly, our results showed that MicroSprayer™ did not alter cetuximab integrity, immunological and pharmacological properties. Secondly, airways administration of cetuximab in mice seemed to be well-tolerated and did not induced additional toxicity in lungs, kidney, colon, skin, liver or spleen. Finally, higher, more rapid and prolonged lung uptake was observed in animals receiving cetuximab through the pulmonary route. Antitumor efficiency of nebulized cetuximab is currently under investigation. Conclusion: These results highlight the potential of the pulmonary route for delivery of anticancer antibody in lung cancer.

The aim of this study was to evaluate the effect on tumour growth of gemcitabine delivered by aerosol in an orthotopic model of lung carcinoma. Large cell carcinoma (NCI-H460) cells were implanted intrabronchially in 24 male BALB/c nude mice on day (d) 0. Aerosols were delivered once a week from d1 to d29 using an endotracheal sprayer. Altogether, 16 animals received gemcitabine at 8 (n = 8) and 12 mg·kg −1 (n = 8), and eight received a vehicle aerosol. Animals were sacrificed on d36 for histological examination. All animals in the vehicle group developed a large infiltrating carcinoma. Comparatively, four of 13 (31%) animals treated with gemcitabine had no visible tumour and nine of 13 (69%) had a smaller carcinoma with a mean±sem largest tumour diameter of 2.05±0.7 versus 5±0.3 mm in the vehicle group. Gemcitabine was well tolerated at 8 mg·kg −1 . At 12 mg·kg −1 , three cases of fatal pulmonary oedema were observed, prompting a dose reduction to 8 mg·kg −1 in the remaining animals. A dose effect was observed, with more marked tumour growth inhibition in the animals treated at 12 mg·kg −1 on d1 and d8. In conclusion, in this study, an animal model of aerosolised chemotherapy in lung cancer was developed and demonstrated inhibition of orthotopic tumour growth by aerosol delivery of gemcitabine.

The purpose of this research was to evaluate the safety of pulmonary administration of gemcitabine and to determine the maximum tolerated dose by weekly pulmonary administrations in an animal model. Five groups of eight Wistar rats received gemcitabine at doses of 2, 4, 6, or 8 mg/kg or the vehicle solution by endotracheal spray with scintigraphic imaging of lung deposition. In order to document the safety of digestive exposure, five groups of eight rats received gemcitabine at the same dosages or the vehicle solution by gavage. Nine weekly sessions were planned, and blood cell counts and histological examinations were performed in live animals at day 64. Scintigraphic imaging confirmed pulmonary deposition in 310 of 316 spray administrations (98%) with homogeneous pattern of deposition. The maximum tolerated dose of gemcitabine by pulmonary administration was 4 mg/kg. At this dosage, administered once a week for 9 consecutive weeks, there were no chemotherapy-related deaths and no clinical, histological, or hematological signs of toxicity except for a decrease in platelet and red blood cell counts, with no clinical significance. The toxicity of gemcitabine was higher via oral than lung delivery in terms of weight loss and white blood cell toxicity at dosages of 2, 4, and 6 mg/kg. Pulmonary administration of gemcitabine is safe in rats at a maximum tolerated dose of 4 mg/kg once a week for 9 weeks. At an equivalent dosage, the toxicity of gemcitabine is lower by lung than oral administration.

Summary Purpose: This randomized phase II multicenter trial aimed at evaluating the efficacy and safety of the 4-week versus 3-week schedules of gemcitabine monotherapy in previously untreated elderly patients with advanced non-small cell lung cancer (NSCLC). Patients and methods: Chemonaive patients with stage IIIB or IV NSCLC, and age between 70 and 90 years, were randomized to receive gemcitabine dose of either 1000 mg/m2 on days 1, 8, 15, every 28 days (arm Q4W), or 1125 mg/m2 on days 1 and 8, every 21 days (arm Q3W). Results: From June 1999 to January 2001, 81 patients (42 on arm Q4W; 39 on arm Q3W) were included. The median age was 75 on both arms; most patients (82.7%) were male, and had a Karnofsky performance status of 80 or 90 (76.5%). For arms Q4W and Q3W, respectively, the median time to treatment failure was 83 days (95% CI, 69–98 days) versus 92 days (95% CI, 63–113), and the median survival was 154 days (95% CI, 108–227) versus 205 days (95% CI, 125–344). The objective response rate was higher on arm Q3W (28.2%) than on arm Q4W (14.3%). Total number of cycles administered was 132 on arm Q4W (median 3, range 1–10 cycles) and 169 on arm Q3W (median 4, range 1–9 cycles). Patients on arm Q4W and Q3W, respectively, received 100.1 and 99.8% of the planned weekly mean dose. The most common grade, three to four toxicities, was neutropenia (17.1% on arm Q4W versus 18.9% on arm Q3W) and thrombocytopenia (12.2% on arm Q4W versus 2.6% on arm Q3W). Conclusion: Although both 3- and 4-week gemcitabine regimens were safely and effectively administered in chemonaive elderly patients with advanced NSCLC, the 3-week schedule appears to be the more convenient for this population. Moreover, even if this is only a phase II study this 3-week schedule appears to be at least as efficient as the 4-week regimen.

Summary Background: Patient preference as well as concerns and difficulties with intravenous access and pharmaco-economic issues have driven the development of oral vinorelbine. Patients and methods: Four phase II studies were conducted in chemotherapy- naive non-small-cell lung cancer (NSCLC) and as first-line chemotherapy of advanced breast cancer (ABC). As recommended in the phase I dose-finding study, the first step used a weekly dose of 80 mg/m2. This regimen was associated with an excessive rate of early deaths (10%) due to complicated neutropenia and led to discontinuati on of the first two studies. In a second step, the dose of 60 mg/m2/week was given for the first three courses and subsequently increased to 80 mg/m2/week, in the absence of severe neutropenia. Results: One hundred and thirty eight patients (76 with NSCLC and 62 with ABC) received this regimen, of whom only five were unable to undergo dose escalation. The incidence of febrile neutropenia and neutropenic sepsis were low (2.9 and 3.6%, respectively). Although severe events were uncommon, nausea/vomiting and diarrhoea were frequent and primary prophylaxis with antiemetics should be recommended. Conclusions: Overall, the safety profile of oral vinorelbine at 60 mg/m"/week for the first three courses with escalation to 80 mg/m2 is qualitatively comparable to that of i.v. vinorelbine at standard doses. Similarly to i.v. chemotherapy, close haematological monitoring is necessary. Background Vinorelbine is a semi-synthetic vinca-alkaloid which has demonstrated broad clinical antitumour activity in a weekly intravenous (i.v.) schedule. Intravenous vinorelbine has been established as one of the most active agents in the treatment of non-small-cell lung cancer (NSCLC) [1-3] and advanced breast cancer (ABC) [4]. The development of oral chemotherapy may allow improvement of patient comfort and reduction of the constraints and overall cost of the treatment [5, 6]. A soft gelatin capsule was formulated and shown to be stable for at least 24 months. In a phase I dose-finding study in patients with ABC, the maximum tolerated dose was 100 mg/m2 on a weekly schedule, and the recommended dose for further clinical investigations was 80 mg/m 2 [7], Dose-limiting toxicities included neutropenia, nausea/vomiting and constipation. Preliminary evidence of activity was obtained in first and second-line treatment for ABC. An absolute bioavailability study compared an i.v. infusion of vinorelbine 25 mg/m2 with an oral administration of 80 mg/m 2 [8]. The bioavailability of the oral form was 43% ± 14. Based on the linearity of vinorelbine pharmacokinetics whatever the route of administration [9-11], it was established that the oral dose of 80 mg/m2 corresponded to an i.v. dose of 30 mg/m2 and the oral dose of 60 mg/m2 to an i.v. dose of 25 mg/m2. Interestingly, the pharmacokinetic behaviour of capsules was compared in fed and fasting conditions and was found to be similar [10]. Phase II studies were conducted in NSCLC and ABC to assess the efficacy of oral vinorelbine as a single agent. As recommended in the phase I dose-finding study, we initially studied the toxicity profile of a weekly dose of 80 mg/m2. Due to safety concerns, the study regimen had to be modified, and the starting dose of oral vinorelbine was reduced to 60 mg/m2. We will hereby report the safety profiles of oral vinorelbine in these two consecutive steps of the clinical investigation.

Performance status (PS) is universally used in oncology to evaluate the clinical condition of the patients. The performance status has been shown to correlate with survival, as well as with acute toxicity following anticancer chemotherapy [1–5]. To test whether altered performance status is associated with malnutrition, we retrospectively examined data from a 1-day malnutrition prevalence survey, carried out in 154 oncology wards of private or public hospitals in 24 cities in France [6]. Height and present and usual body weights were assessed in outpatients and inpatients who were present that day. The European Society for Clinical Nutrition and Metabolism and the Cachexia Society recently considered pre-cachectic a patient who involuntarily lost 5% of body weight during the previous 12 months [7, 8]. Malnutrition was defined as a body mass index 10% from diagnosis in our study. The prevalence of malnutrition was studied in the overall population and stratified for the performance status. Amongst 2,068 patients (1,189 men and 879 women) aged 60±13 years, nutritional status was available in 1,903 patients. The performance status was 0 in 338 (19%), 1 in 560 (32%), 2 in 451 (25%), 3 in 249 (14%), and 4 in 129 (7%) patients. Overall, 723 (38%) of the patients were malnourished. The prevalences of malnutrition were 14.4%, 31.4%, 52.3%, 53.6%, and 65.3% in patients with a performance status ranging from 0 to 4, respectively (Fig. 1). In comparison to patients with performance status 0, the relative risk of malnutrition was 2.5 (p

Summary Background Although the average age of lung cancer patients is increasing, many elderly patients remain undertreated, mainly because of the fear of higher treatment toxicity in this category of patients. We conducted a study to evaluate the efficacy and tolerability of a combination therapy with carboplatin (C) and etoposide phosphate (EP) in elderly patients with Small-Cell Lung Cancer (SCLC). Patients and methods Previously untreated patients older than 70 years with stage IIIB/IV SCLC received a combination of EP (100 mg/m2 D1, D2, D3) and C (Dl, dose calculated according to the Calvert formula). Response rate, survival and toxicity were assessed. Results Thirty-eight patients (mean age 76 years, range 70–88 years) received a total of 162 cycles. Eighteen patients (47%) received the six scheduled cycles. Thirty patients were evaluable for efficacy (2 CR and 20 PR). The median survival was 237 days and the one-year probability of survival was 26%. The most common adverse effect was transient grade 3 or 4 neutropenia, observed during 57% of evaluable cycles, while five episodes of febrile neutropenia also occurred, with one fatal (bactaeriemia). It is noteworthy that no renal or liver toxicity was observed, and no mucitis was noted. Unfortunately, a relatively high proportion of patients died shortly after the start of the study. Although most deaths seemed unrelated to the treatment, the possibility of its exacerbatory effect on comorbidities, especially cardiovascular, cannot be excluded. Conclusion The two-drug regimen of carboplatin and etoposide phosphate is feasible in most elderly patients with an acceptable toxicity, and the overall results suggest that patients even older than 70 years may benefit from full treatment. Therefore, consideration should be given to offering active treatment to most patients with SCLC, regardless of age but with special attention paid to comorbidities.

We report three cases of benign mediastinal lymphadenopathy revealed by chest radiography in patients ranging in age from 61 to 75 years. All three patients had severe coronary heart disease and a history of several episodes of acute cardiac decompensation. Chest CT scanning contributed to the diagnosis by revealing the existence of multiple enlarged lymph nodes, mostly 10 to 17 mm in short-axis diameter. CT scanning also confirmed the disappearance of the mediastinal lymph nodes in one patient on follow-up after treatment with diuretics and digitalis. Histopathology investigations of biopsy samples obtained by mediastinoscopy consistently revealed noninflammatory, benign lesions that did not affect the node structure. Our report draws attention to the particular nosology of left heart disease represented by benign enlarged lymph nodes of the mediastinum and pulmonary edema. The diagnostic approach to such lymphadenopathy should be guided by the radiologic regression seen on follow-up CT scanning while the patient was undergoing appropriate therapy for congestive heart failure, which constitutes a decisive argument for the congestive heart failure origin.

A phase II study was conducted to determine the efficacy and the safety of docetaxel combined with vinorelbine as first-line chemotherapy in patients with metastatic or unresectable non-small cell lung cancer (NSCLC). 39 patients, median age 54 years (range: 35–69), with stage IIIB (5 patients; 13%) or IV (34 patients; 87%) NSCLC were treated with 75 mg/m2 docetaxel given intravenously (i.v.) over 1 h on day 1 and with 20 mg/m2 vinorelbine given i.v. over 15 to 30 min on days 1 and 5. Cycles were repeated every 3 weeks. 9 of the 39 patients had a partial response (overall response rate 23.1%, 95% confidence interval (CI): 11.1–39.3%) with a median duration of response of 20 weeks (95% CI; 17–30). The median survival was 40 weeks (95% CI: 21–49 weeks) with a 1-year survival rate of 31% in the intent-to-treat population. Neutropenia grade IV occurred in 33 patients (92%). 16 patients (41%) experienced febrile neutropenia with a concomitant stomatitis in 9 patients (23%). One patient died due to febrile neutropenia associated with a grade 4 stomatitis and 1 patient due to a septicaemia concomitant with a grade 4 neutropenia. Although the combination of docetaxel and vinorelbine is feasible, the efficacy does not seem to be improved compared with single-agent docetaxel or vinorelbine and the rate of febrile neutropenia is unacceptable in this population with incurable disease. Therefore, different doses and/or schedules are to be explored.

Adjuvant treatments of non-small cell lung cancer (radiotherapy and chemotherapy) before or after surgery, have been tested in numerous trials, more particularly as regards postoperative chemotherapy. For a long time the results were disappointing, and in randomized studies none of the therapeutic regimens prescribed could improve the patient’s survival. New hopes of advances in this matter were raised by Goldie and Coldman [1] whose mathematical concept recommended a systemic treatment applied as early as possible in cases with localized tumour. The advent of Platinum [2], the results obtained in metastatic tumours by some associations with Platinum and those obtained in localized tumours by chemotherapy-radiotherapy [3] have been promising. Many phase II studies have shown that surgery was feasible after 2 or 3 cycles of chemotherapy [4, 8] even thought 1 of them [9] had observed a high rate of progression after chemotherapy which prevented surgery.

Diffuse interstitial lung diseases (ILD) constitute a heterogenous group of processes which have in common reticular or nodular, reticulonodular or linear patterns on chest roentgenogram. They are characterized by a diffuse infiltration of alveolar walls by inflammatory or malignant cells, connective tissue or fluid. About 100 entities have been ascribed to diffuse interstitial lung disease. The aim of the clinician is to confirm the diagnosis of ILD, to elicit an entity from history, symptoms, physical examination, chest roentgenogram, pulmonary function and laboratory data in order to plan treatment. Therefore, the pattern may include malignant, infectious, and cardiac diseases with roentgenographic reticulonodular patterns, i.e lymphangitic carcinomatosis, alveolar cell carcinoma, miliary tuberculosis, infection in immunosuppressed patients, and congestion of the lungs secondary to congestive heart failure. In fact, the term ILD usually excludes this heterogenous group of diseases and is focused on inflammatory processes in which the common outcome is dominated by fibrotic lung disorder. They are also commonly called pulmonary fibrosis and will be developed in this chapter.

7003 Background: To evaluate survival beyond 10 years of patients included in the French randomized trialcomparing neoadjuvant chemotherapy (CT-S) versus surgery alone (S) (initial publication: Dep...

In a randomized, multicenter, open-label study, 490 ambulatory adult patients with lower respiratory tract infection (LRTI) were randomized to roxithromycin (ROX) 150 mg b.i.d. orally (n = 244) or amoxicillin plus clavulanic acid (AMX + CA) as 500 mg AMX + 125 mg CA t.i.d orally (n = 24). Clinical results were analyzed in 477 patients with acute bronchitis (79%), chronic bronchitis (CB) (14%), and pneumonia (7%). There were significantly more patients with underlying disease (cardiovascular diseases, p = 0.045; and alcoholism, (p less than 0.001), and more patients over the age of 65 years (p = 0.045) in the ROX group. Overall clinical efficacy was similar in both groups: 88% (206:235) in the ROX group and 85% (205:242) in the AMX + CA group. Side effects were reported in 67 cases (28%) in the AMX + CA group and in 21 cases (9%) in the ROX group (p less than 0.0001), causing withdrawal in 21 and three cases, respectively (p less than 0.001). Thus, despite being administered to a significantly older and more ill group of patients with LRTI, roxithromycin was as effective as amoxicillin plus clavulanic acid and better tolerated.

9126 Background: The evaluation of the performance status (PS) is universally used in oncology and a PS of 2 is known as associated with reduced survival and increased risk of toxicity following chemotherapy. The aim of the present study was to evaluate the prevalence of malnutrition in a non selected population of cancer patients (pts) and how malnutrition correlates with poor PS. Methods: A prospective one-day prevalence survey was carried out in 154 wards of private or public hospitals in 24 cities in France. Height, present and usual body weight were assessed in outpatients and inpatients who were present that day. Malnutrition was defined as a Body Mass Index 10% from the beginning of the disease. The prevalence of malnutrition was studied in the overall population and stratified for the type of cancer and the PS. Results: 2,068 pts (1,189 men and 879 women) aged 60±13 yrs were evaluated and nutritional status was available in 1,903 pts. The PS was 0 or 1 in 52.3% of pts, 2 in 25.3%, 3 or 4 in 22.4%. Overall, 38% of pts were malnourished. Prevalence of malnutrition according to the primary tumor was: pancreas (n=42): 67%, oesophagus (n=41): 61%, stomach (n=41): 59%, head and neck (n=366): 49%, lung (n=247): 45%, ovary/uterus (n=87): 45%, colon/rectum (n=191): 39%, leukemia/lymphoma (n=377): 34%, breast (n=229): 21%, prostate (n=72): 14%. The prevalence of malnutrition was 14.4%, 31.4%, 52.3%, 53.6%, and 65.3% in pts with a PS ranging from 0 to 4, respectively. In comparison to PS-0 pts, Relative risk (RR) of malnutrition was 2.5 (p < 0.0001) in PS-1 pts and 6.4 in PS-2 pts (p50% of PS-2 pts. Systematic screening and care of malnutrition is mandatory to improve the PS and subsequently treatment tolerability in these pts. No significant financial relationships to disclose.

Introduction Human tissue kallikreins (hKs) are secreted serine proteases with diverse expression patterns and physiological roles. Several members of the kallikrein gene (KLK) family, which now includes 15 genes, are differentially expressed in various cancers and some emerge as useful diagnostic/ prognostic markers for hormone dependent cancers. Although clinically effective non-invasive meth-ods for early detection and screening of lung cancer are lacking, analysis of kallikrein gene expression has never been performed in lung. The aim of this study was to investigate KLK5 and KLK7 gene expression in non small-cell lung cancers (NSCLC). Methods We used both RT-PCR and Western blotting to analyse KLK5 and KLK7 gene expression and their respective products (hK5 and hK7) in lung. Gene expression was then quantified by real-time PCR in matched malignant and nonmalignant lung tissue samples obtained from 56 patients with NSCLC and results were compared to clinico-pathological parameters. Results We detected for the first time the expression of both KLK5 and KLK7 genes and their protein products (hK5 and hK7) in tumoral and nontumoral lung tissues. A significant increase in KLK5 expression was observed in squamous cell carcinoma (P = 0.02) compared to matched nontumoral tissue, whereas KLK7 expression was decreased in adenocarcinoma (P = 0.003). In non-cancerous tissues, multivariate analysis revealed a negative correlation between KLK5 expression and the metastatic status of the paired tumors (P = 0.05) and, a positive correlation between KLK7 expression and tumor differentiation (P = 0.02). In cancerous tissues, KLK5 and KLK7 expressions were mainly associated with squamous cell carcinoma (P = 0.04 and P = 0.01, respectively). Fur-thermore, KLK7 expression correlated positively with differentiation (P = 0.03) and negatively with adenocarcinoma histotype (P = 0.003). Conclusions Our results demonstrate that KLK5 and KLK7 are differentially expressed in NSCLC subtypes and indicate that the variability in KLK5 and KLK7 expressions hâve to be taken into account not only to better understand the lung tumorogenesis but also for clinical purposes.