Search

Introduction: Stage classification is an important underpinning of management in patients with cancer and rests on a combination of three components-T for tumor extent, N for nodal involvement, and M for distant metastases. This article details the revision of the N and the M components of thymic epithelial tumors for the ninth edition of the TNM classification of malignant tumors proposed by the Thymic Domain of the International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee., Methods: The N and M components of the eighth edition staging system were verified by a large international collaborative data source through a data-driven analysis. A total of 9147 cases were included for analysis, including 7662 thymomas, 1345 thymic carcinomas, and 140 neuroendocrine thymic tumors., Results: Lymph node involvement rates were 1.5% in thymomas and 17.6% and 27.7% in thymic carcinomas and neuroendocrine thymic tumors, respectively. Rates of lymph node metastasis were increasingly higher in tumors with higher T stage and higher-grade histologic type. Survival analysis validated the differences in the N and M categories proposed in the eighth edition staging system. Good discrimination in overall survival was detected among pathologic (p)N and pM categories in patients with thymoma and thymic carcinoma., Conclusions: No changes are proposed from the eighth edition for the N and M components. The proposed stage classification will provide a useful tool for management of the disease among the global thymic community., (Copyright © 2023 International Association for the Study of Lung Cancer. All rights reserved.)

Introduction: A lymph node map is the pillar on which accurate assignment and documentation of nodal classification stands. The International Thymic Malignancy Interest Group created the first map for thymic epithelial malignancies in conjunction with the eighth edition of the TNM classification, representing the first official TNM classification of thymic epithelial malignancies. The map was based on clinical experience and published studies, but it was largely empirical because of limited available data. Dissemination of the map and implementation of a standard thymic stage classification across the world in 2017 have provided more consistent and granular data., Methods: More than twice as many cases of node involvement are available for analysis in the current database compared with that of the eighth edition database, allowing validation of many aspects of the eighth edition map. This article details the process and considerations for refinement of the thymic map for the ninth TNM used by the Thymic Domain of the Staging and Prognostic Factors Committee of the International Association for the Study of Lung Cancer. The committee evaluated a large international collaborative data set, published anatomical and clinical studies pertaining to lymph node spread from thymic epithelial tumors, in conjunction with the analysis underlying refinements of the TNM components for the ninth edition TNM classification., Results: The node map boundaries of the N1 and N2 categories remain unchanged. Visual clarifications have been added to the nomenclature of nodal stations within these regions., Conclusions: On the basis of the recommendation to keep the N component unchanged for the ninth edition TNM classification, the lymph node map remains unchanged as well; however, clarifications have been added to facilitate clinical use., (Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: A TNM-based stage classification system of thymic epithelial tumors was adopted for the eighth edition of the stage classification of malignant tumors. The Thymic Domain of the Staging and Prognostics Factor Committee of the International Association for the Study of Lung Cancer developed a new database with the purpose to make proposals for the ninth edition stage classification system. This article outlines the proposed definitions for the T categories for the ninth edition TNM stage classification of thymic malignancies., Methods: A worldwide collective database of 11,347 patients with thymic epithelial tumors was assembled. Analysis was performed on 9147 patients with available survival data. Overall survival, freedom-from-recurrence, and cumulative incidence of recurrence were used as outcome measures. Analysis was performed separately for thymomas, thymic carcinomas, and neuroendocrine thymic tumors., Results: Proposals for the T categories include the following: T1 category is divided into T1a (≤5 cm) and T1b (>5 cm), irrespective of mediastinal pleura invasion; T2 includes direct invasion of the pericardium, lung, or phrenic nerve; T3 denotes direct invasion of the brachiocephalic vein, superior vena cava, chest wall, or extrapericardial pulmonary arteries and veins; and T4 category remains the same as in the eighth edition classification, involving direct invasion of the aorta and arch vessels, intrapericardial pulmonary arteries and veins, myocardium, trachea, or esophagus., Conclusions: The proposed T categories for the ninth edition of the TNM classification provide good discrimination in outcome for the T component of the TNM-based stage system of thymic epithelial tumors., (Copyright © 2023. Published by Elsevier Inc.)

Introduction: A TNM-based system for all types of thymic epithelial tumors was introduced in the eighth edition of the TNM classification of thoracic malignancies. The Thymic Domain of the Staging and Prognostic Factors Committee of the International Association for the Study of Lung Cancer, composed of multispecialty international experts, was charged to develop proposals for the ninth edition. This article outlines the proposed definitions for the T, the N, and the M components and their combination into stage groups., Methods: A large central database of 11,347 patients with thymic epithelial tumors was assembled thanks to the contribution of the major thymic organizations worldwide and analyses were carried out for the T, the N, and the M components and the stage groups. Overall survival was the outcome measure for patients with completely and incompletely resected tumors, and recurrence for those with complete resection. When the number of patients was sufficient, analyses were performed separately for thymomas, thymic carcinomas, and neuroendocrine thymic tumors., Results: Tumor size is included in the T1 category as T1a (≤5cm) and T1b (>5 cm); the mediastinal pleura is dropped as a T descriptor; invasion of the lung or phrenic nerve is reclassified as T2 (instead of T3). No changes are proposed for the N and the M components from the eighth edition. The stage groups remain the same., Conclusions: The proposed changes for the ninth edition of the TNM classification set the stage for further progress in the future for these rare tumors., (Copyright © 2023 International Association for the Study of Lung Cancer. All rights reserved.)

Introduction: In 2014, a TNM-based system for thymic epithelial tumors was proposed. The TNM stage classification system was published as a result of a joint project from the International Association for the Study of Lung Cancer and the International Thymic Malignancy Interest Group for the eighth edition of the American Joint Commission on Cancer and the Union for International Cancer Control stage classification system. The Thymic Domain of the Staging and Prognostic Factors Committee of the International Association for the Study of Lung Cancer received the mandate to make proposals for the ninth edition of the TNM stage classification., Methods: A central thymic database was collected by the Cancer Research And Biostatistics with the contribution of the major thymic associations in the world., Results: A total of 11,347 patients were collected. Submitting organizations were the following: Japanese Association for Research in the Thymus, European Society of Thoracic Surgeons, Chinese Alliance for Research in Thymoma, Korean Association for Research in the Thymus, International Thymic Malignancy Interest Group, and Réseau tumeurs THYMiques et Cancer. Additional contributions came from centers in the United States, United Kingdom, Turkey, Australia, Spain, and Italy. A total of 9147 cases were eligible for analysis. Eligible cases for analysis came from Asia and Australia (5628 cases, 61.5%), Europe (3113 cases, 34.0%), and North America (406 cases, 4.4%)., Conclusions: This report provides an overview of the database that has informed the proposals for the updated T, N, and M components and the stage groups for the ninth TNM of malignant tumors., (Copyright © 2023. Published by Elsevier Inc.)

Thymic epithelial tumors are presently staged using a consistent TNM classification developed by the International Association for the Study of Lung Cancer (IASLC) and approved by the Union for International Cancer Control and the American Joint Committee on Cancer. The stage classification is incorporated in the eight edition of the TNM classification of thoracic malignancies. The IASLC Staging and Prognostic Factors Committee (SPFC)-Thymic Domain (TD) is in charge for the next (ninth) edition expected in 2024. The present article represents the midterm report of the SPFC-TD: in particular, it describes the unresolved issues identified by the group in the current stage classification which are worth being addressed and discussed for the ninth edition of the TNM classification on the basis of the available data collected in the central thymic database which will be managed and analyzed by Cancer Research And Biostatistics. These issues are grouped into issues of general importance and those specifically related to T, N, and M categories. Each issue is described in reference to the most recent reports on the subject, and the priority assigned by the IASLC SPFC-TD for the discussion of the ninth edition is provided., (Copyright © 2022 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Vagus nerve stimulation (VNS) using non-invasive approaches have attracted great attention due to their anti-epileptic, anti-depressive and pro-cognitive effects. It has been proposed that auricular transcutaneous VNS (atVNS) could benefit intellectual disability disorders, but preclinical data supporting this idea is limited., Objective: To develop an atVNS device for mice and to test its efficacy on memory performance in naïve mice and in a mouse model for intellectual disability., Methods: Naïve outbreed CD-1 mice and a model for fragile X syndrome, the Fmr1 knockout (Fmr1KO), were used to assess the effect of atVNS in the novel object-recognition memory performance., Results: We found that atVNS significantly improves memory persistence in naïve mice. Notably, atVNS was efficacious in normalizing the object-recognition memory deficit in the Fmr1KO model., Conclusion: Our data show that atVNS improves memory persistence in naïve mice and in a model of intellectual disability and support further studies taking advantage of preclinical mouse models of cognitive disorders., Competing Interests: Declaration of competing interest Authors declare no conflict of interest., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

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.

Algae are primary producers in a wide variety of natural ecosystems, and these microorganisms have been used in bioremediation studies. Nevertheless, very little is known about the in vivo effect of heavy metals on individual living cells. In this paper, we have applied a method based on confocal laser scanning microscopy and lambda scan function (CLSM-λscan) to determine the effect of lead (Pb), at different concentrations, on the DE2009 microalga. At the same time, we have optimized a method based on CLSM and image-analysis software (CLSM-IA) to determine in vivo biomass of this microorganism. The results obtained by lambda scan function indicated that the pigment peak decreases while the concentration of metal increases at pH 7. On the other hand at pH 4 there is no good correlation between the concentration of metal and the intensity of the emission of fluorescence of the pigment. Also, in some cases a displacement of the Chl a peak towards 680 nm is produced. Total and individual biomass determined by CLSM-IA shows statistically significant differences between unpolluted and 10 mM polluted cultures. Complementary studies using electron microscopy techniques coupled to energy dispersive X-ray microanalysis (EDX) demonstrate that the microalga can sequestrate Pb extra- and intracellularly., (Crown Copyright © 2010. Published by Elsevier B.V. All rights reserved.)

Background: Tuberculosis prevention has been based on generalized BCG vaccination in France since 1949. The aim of this cross-sectional survey was to assess the impact of the change in BCG administration (in January 2006) and the end of compulsory vaccination (in July 2007)., Method: A self-administered postal questionnaire was sent to a random sample of 2248 physicians practicing in 6 departments in the Rhône-Alpes region in 2008., Results: Overall, 923 questionnaires were analyzed. The median age of the respondents was 52 years, 67 % were male, 93 % were general practitioners, and 91 % practiced in private practice offices. The median number of BCG vaccines administered on a quarterly basis was 5 (interquartile range [IQR], 3-10) before January 2006, one (IQR, 0-3) between January 2006 and July 2007, and zero (IQR, 0-1) after July 2007 (P<0.001). The rate of BCG vaccination was significantly lower for male physicians, physicians older than 50 years, general practitioners, practitioners working in private offices, and for some departments. Thirty-nine percent of the physicians were informed of the national program against tuberculosis 2007-2009, and 41 % wished to be trained in the practice of intradermal vaccination., Conclusion: This survey suggests that the withdrawal of Monovax and the lifting of generalized vaccination requirements were followed by a substantial decrease in the number of BCG vaccinations. The intradermal route constitutes an obstacle for BCG vaccination that might be overcome by specific training., (Copyright 2009 Elsevier Masson SAS. All rights reserved.)

Objective: Evidence is growing that some patients are not responsive to the antithrombotic action of aspirin. We prospectively evaluated the ability of aspirin resistance status, determined by PFA-100, to predict new thrombotic events in patients with stable ischemic cerebrovascular disease., Methods: We studied 129 consecutive patients with stroke, transient ischemic attack (TIA) or vascular cognitive impairment. We assessed relationships between aspirin resistance, risk factors for ischemic cerebrovascular disease, and occurrence of new thrombotic events (composite of stroke, TIA, myocardial infarction, and cardiovascular death)., Results: Aspirin resistance, found in 26 (20.1%) cases, was unrelated to any of the examined vascular risk factors. During mean follow-up of 56 months, new thrombotic events occurred in 19 patients (14.7%), four with aspirin resistance (15.4%) and 15 (14.6%) without aspirin resistance (p=1.00)., Conclusion: Aspirin resistance determined by PFA-100 does not predict new thrombotic events in patients with stable ischemic cerebrovascular disease.

Aims: Despite laparoscopic surgery for gastric cancer has gained worldwide acceptance, long term results and survival are seldom reported. This study was designed to assess long term outcomes after laparoscopic gastrectomy with D2 dissection. The short term results of conventional and robot-assisted minimally invasive procedures were also examined., Patients and Methods: The charts of 65 patients who underwent laparoscopic surgery for non-metastatic adenocarcinoma were reviewed retrospectively. This series included 35 patients with early gastric cancer (EGC) and 30 with advanced gastric cancer (AGC). A 4/5 laparoscopic subtotal gastrectomy (LSG) with D2 nodal clearance was the procedure of choice for distal cancers. Laparoscopic total gastrectomy (LTG) with modified D1 lymphadenectomy was performed for mid-proximal EGC., Results: Sixty gastrectomies were carried out laparoscopically, 56 LSG and 4 LTG. Conversion to laparotomy was required in 5 patients with distal cancer. No intraoperative complication was registered. Morbidity included 2 duodenal leaks that healed conservatively. Two postoperative deaths were registered. An average number 31.3+/-8.8 lymph nodes were collected. The mean hospital stay was 10 days (range 7-24). The mean follow up was 30 months (range 2-86) and the cumulative overall 5 year survival rate was 78%. Survival at 5 years for EGC was 94% and survival at 4 years for AGC was 53% (57% for non-converted patients)., Conclusions: Laparoscopic gastrectomy for cancer represents a valid alternative to open surgery with minimal morbidity and acceptable long term survival. Considering the risk of preoperative under diagnoses a D2 lymphadenectomy is suggested also for EGC. This study validated the effectiveness of minimally invasive technique in the management of gastric cancer.

It has been recently suggested that in Alzheimer disease (AD), the current available therapy with cholinesterase inhibitors (ChEIs) influences platelets amyloid precursor protein (APP) metabolism towards the nonamyloidogenic pathway. In order to investigate whether ChEIs may exert a protective role on vascular damage due to abeta deposition, several parameters of coagulation and fibrinolysis were assessed. Twenty patients with mild AD and 30 age-matched controls entered the study. All subjects performed a multidimensional neuropsychological assessment and a laboratory protocol. Individuals with vascular risk factors and systemic diseases were excluded. In mild AD patients, increased levels of markers of endothelial dysfunction, such as thrombomodulin (TM) and sE-selectin (sE-sel), were seen. After 1-month ChEIs treatment, a significant reduction of TM (p<0.05) and sE-sel (p<0.05) values towards the normal range was observed. These findings suggest that endothelial-related ChEIs action might contribute to the clinical efficacy in AD, slowing down pathology progression.

Increasing biological and clinical findings argue for a link between brain cholesterol turnover and Alzheimer Disease (AD), high cerebral levels of the former increasing Abeta load. Cerebral cholesterol elimination involves two mechanisms dependent on Apolipoprotein E (ApoE) and cholesterol 24-hydroxylase (CYP46). The aim of this study was to evaluate an intronic variation in CYP46 (intron 2, T --> C ) along with ApoE genotype as risk factors for AD and to establish the correlation between CYP46/ApoE polymorphism and disease progression. One-hundred and fifty-seven AD patients, who had been followed periodically through 1-year follow-up after enrollment, and 134 age- and gender-matched controls entered the study. The distribution of CYP46 genotypes was significantly different in AD compared to controls (P<0.004), being CYP*C allele higher in AD patients ( P<0.002). ApoE 4 genotype was more frequent in AD (41.4%) than in controls (15.9%, P<0.0001). The odds ratio (OR) for AD risk in CYP46*C carriers was 2.8, and in ApoE epsilon4 carriers was 4.05; the OR for having both CYP46*C and ApoE epsilon4 was 17.75, demonstrating the their synergic effect on AD risk. In AD patients, CYP46*C along with ApoE epsilon4 genotype were associated with a higher cognitive decline at 1-year follow-up (P<0.02). These findings provide direct evidence that CYP46 and ApoE polymorphisms synergically increase the risk for AD development, and influence on the rate of cognitive decline.

This study compared the occlusal success rate of Class II orthodontic treatment results with either 2- or 4-premolar extraction protocols. Group 1 comprised dental study models of 81 patients treated with 2 premolar extractions, and group 2 comprised dental study models of 50 patients treated with 4 premolar extractions. The initial mean ages of the groups were 13.9 and 12.9 years, respectively. Grainger's treatment priority index (TPI) was used to assess the initial and final occlusal status of each patient. Individual variables, such as maxillary canine anteroposterior positioning, overjet, and overbite improvements were also evaluated. Independent t tests were used to compare the variables at the pretreatment and posttreatment stages and their improvement between the groups. The results showed a statistically significant difference in most of the variables and in their improvement at the end of treatment between the groups. The variables showed a better dental relationship in group 1, and the improvements in group 1 were larger than in group 2. Treatment of Class II malocclusion with 2 premolar extractions gives a better occlusal success rate than treatment with 4 premolar extractions.

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.

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 < 0.01). BOS occuring before and after the 12th month of LT were associated with early and more delayed increases of BAL neutrophils, respectively. Finally, the various kinetic profiles of neutrophil progression were identified, allowing for an earlier identification of BOS stages 2 and 3, by 3 and 6 months, respectively. Conversely, neutrophilia associated to BOS stage 1 remained low, and could not be distinguished from that of stage 0., Conclusions: These results support the possible role of neutrophils in BOS pathogenesis, and may be of interest for an earlier detection and management of chronic rejection.

Background: Chronic obstructive pulmonary disease (COPD) is a common, progressive respiratory disease that causes great morbidity and mortality despite treatment. There is evidence for airway inflammation in COPD. Cilomilast is an orally active, potent, selective phosphodiesterase type 4 inhibitor, which in vitro can affect cells thought to be of clinical importance in COPD. Our aim was to assess the safety, efficacy, and dose response of cilomilast in the treatment of patients with this disease., Methods: We did a 6-week, randomised, dose-ranging study in 424 patients with COPD (forced expiratory volume in 1 s [FEV(1)] 46.8% of predicted, FEV(1)/forced vital capacity [FVC] 54.6%, and postsalbutamol reversibility 5.4%). We randomly assigned individuals at 60 European centres to receive cilomilast 5 (n=109), 10 (n=102), or 15 (n=107) mg twice daily, or placebo (n=106). The main outcome measure was trough FEV(1) before and after use of a bronchodilator. Analyses were by intention to treat., Findings: Cilomilast 15 mg twice daily significantly improved FEV(1) compared with placebo (mean 130 mL vs -30 mL [95% CI 90-240] at week 6, p<0.0001). FVC and peak expiratory flow were also improved (p=0.001 and p<0.0001, respectively). Quality of life measures did not differ significantly between the groups. There were no significant differences in serious adverse events between the groups., Interpretation: Cilomilast 15 mg twice daily might be an effective maintenance treatment for COPD. Further clinical studies are underway.

Obliterative bronchiolitis remains the main cause of graft dysfunction and death after 1 year. Defined by an irreversible airway obstruction, bronchiolitis obliterans syndrome is usually recognized in the advanced stage of the disease, with histological evidence of fibrotic damage. Fibrosis represents the end-stage of an inflammatory process, leading to the postulate that chronic lung graft dysfunction is preceded by cellular and molecular events. This study was performed during the first year following lung transplantation, in the absence of histological or functional criteria of chronic rejection. Transbronchial biopsies from eight lung allografts were examined. Four developed a bronchiolitis obliterans syndrome (Group I), and 4 had good outcomes (Group II) at 2 years. Using immunohistochemistry, the aim of the study was to correlate early immunological events with graft outcomes at 2 years. An up-regulation of HLA class I antigen (P = 0.0001), an overexpression of Ki-67 (P = 0.006) on bronchial epithelium, and graft infiltration by CD45+, CD25+ cells (P = 0.003) were significantly associated with the development of chronic rejection. An overexpression of numerous adhesion molecules was observed. However, only very late antigen-4 had a discriminative value (P = 0.04), preceding chronic graft dysfunction. Our results suggest that graft dysfunction is associated with early molecular and cellular events, and raises the possibility that a fibroproliferative disorder is initiated shortly after transplantation. The recognition of such early immunological markers might facilitate improved graft management and prognosis.

Point mutations at the tumour suppressor gene p53 are one of the most frequent genetic alterations in squamous cell carcinoma of the head and neck (SCCHN), which lead to the nuclear accumulation and overexpression of inactive p53 protein. The overexpression of mutant p53 protein can induce a specific humoral response in cancer patients. p53 protein was studied in 112 SCCHN. Biopsies and sera samples were collected before initiation of treatment. 74 patients received neoadjuvant chemotherapy (5-fluorouracil-cisplatin-folinic acid). p53 protein expression was evaluated by immunohistochemistry (IHC) on paraffin-embedded sections. The analysis of mutations was assessed by PCR-SSCP of exons 5-10 on DNA from 28 representative cases. Antibodies specific for p53 protein were analysed in sera of 74 patients by an ELISA procedure. Overexpression (> 20% positive cells) of p53 protein was frequent (56%: 63/112) and was correlated with localisation of the primary tumour and tumour stage. p53 mutations were detected in 57% (16/28) of studied cases. The prevalence of p53 antibodies in sera was high (44% 32/74) and among this population, 68% (20/29) had a positive immunophenotype and 67% (6/9) a p53 mutation in the tumour. In addition, the presence of anti-p53 antibodies was slightly associated with complete response to neoadjuvant chemotherapy. If the humoral response seems to be an indicator of the p53 protein status, the detection of anti-p53 antibodies could be a good approach in the early detection of the presence of p53 alterations in SCCHN and recurrent tumours or the appearance of second primary cancer.

The malignant transformation of pulmonary epithelial cells is the result of multistep accumulation of genetic and molecular alterations highly related to tobacco carcinogens, involving key mechanisms of proliferation and apoptosis. Clonal expansion is the net result of acceleration of cell division and inhibition of active cell death (apoptosis). Oncogene activation in lung cancer (ras, myc, autocrine growth factor loops) results in acceleration of cell division. More importantly, tumor suppressor genes inactivation (p53, Rb, cyclin-dependent-kinase-Inhibitor p16) at genetic, epigenetic, or post-translational level removes important constraints on cell division at G1-check-point increasing cell proliferation. p 53 inactivation, through loss of transcription function may abrogate both G1-arrest control and apoptosis, thus accelerating clonal expansion. It is the most frequent alteration in lung cancer (70% of genetic alterations) with some differentiation dependent differences. p53 missense mutation is highly concordant with p53 stabilization and immunoreactivity. However, 20% of mutations with null phenotype (no p53 protein) provides 20% of false negative using immunohistochemistry for evaluation of p53 mutations in lung cancer. Rare situations are described with wild type p53 stabilization. p53 mutational spectrum in lung cancer reveals some specificities: 3 hot spot codons (codon 157, 248, 273) are the main target of selective adduct formation from a defined chemical carcinogen of cigarette smoke (BP). p53 stabilized mutants proteins are the targets for immune recognition in patients, leading to secretion of p53 auto-antibodies, and can also elicit T-cell specific cytotoxicity in vitro. p53 was not proven to be of prognostical importance once the tumor has developed. However, p53 stabilization is one of the best predictor of progression and irreversitiblity of preneoplastic bronchial lesion overwhelming morphological changes such as severe dysplasia. Restoration of wild type p53 function through p53 gene therapy, immunotherapy or modification of carboxy terminal end enable new therapeutic intervention. Finally, target genes and proteins situated on the downstream pathway of p53 transcription appears to be the most important factors of growth acceleration or even cell dissemination in lung cancer (Rb and its phosphorylation pathway, Bax-Bc12 balance and matrix degrading enzymes UPA and inhibitor PAI). Their constitutive deregulation could by-pass wild type p53 functions. p53 pathway offers several targets for future gene therapy or modulation in the future in lung cancer.

We have previously shown that the extracellular-matrix-degrading enzymes, urokinase-type plasminogen activator (u-PA), stromelysin 1, stromelysin 3, and matrilysin, may play an important role in the transition from lung preneoplasia to invasive carcinoma. Using in situ hybridization and immunohistochemistry, we analyzed serial frozen sections for the expression of these enzymes in 89 lung carcinomas including 25 neuroendocrine (NE) carcinomas (10 small-cell lung carcinomas, 7 large-cell NE carcinomas, 1 atypical, and 7 typical carcinoids) and 64 non-small-cell, non-NE carcinomas (29 squamous and 7 basaloid carcinomas, 23 adenocarcinomas, and 5 large-cell carcinomas). Proteases, except matrilysin, were more often expressed in stromal than cancer cells. In non-small-cell, non-NE carcinomas, stromal co-expression of u-PA and stromelysin 3 was seen in 80 to 90% of the tumors and was highly correlated (P < 0.0001). Stromal u-PA and stromelysin 3 expression was linked to tumor size (P = 0.01 and 0.03, respectively) and lymph node involvement (P = 0.001 and 0.02, respectively). Epithelial expression of u-PA was correlated to tumor size (P = 0.04). Epithelial expression of stromelysin 3 predominated in squamous and basaloid carcinomas (P = 0.0005) and was inversely correlated to squamous differentiation (P = 0.018). Epithelial expression of matrilysin predominated in adenocarcinomas and large-cell carcinomas (P = 0.07). In NE carcinomas including small-cell lung carcinomas, stromal expression of u-PA was correlated to lymph node metastasis (P = 0.017). Epithelial expression of all enzymes were significantly less frequent in NE than in non-NE tumors. We conclude that 1) epithelial expression of matrix proteases in lung cancer is linked to cell phenotype (NE versus non-NE, squamous versus glandular) and 2) their stromal, rather than epithelial, expression influences local metastasis.

Two thousand lung cancer patients were registered as Grenoble's university hospital joint oncology clinic from 1/1/1982 to 12/31/1991. These cases consisted of 449 small cell lung cancers (SCLC) and 1,551 non-small cell lung cancers (NSCLC). SCLC patients had a 4.6% and 2.9% survival rate at 5 and 10 years and only 7.2% of patients had a survival longer than 30 months. The main prognostic factors for survival were age, sex, TNM stage and WHO performance status. There was no increase in survival during the 2 periods of the study. NSCLC patients had a 14% and 7% survival rate at 5 and 10 years. Among 727 stage III or IV patients not treated with surgery, 2% were alive at 30 months. The main prognostic factors for survival were age, histology, TNM stage and WHO performance status. There was no increase in survival during the 2 periods of the study.

Neuroendocrine (NE) lung tumors comprise four classes of progressive aggressiveness for which proliferation and apoptosis rates could both contribute to their distinctive behavior. As p53 mutations may favor escape from apoptosis through changes in Bcl2-Bax expression balance, which are survival and apoptotic genes, respectively, we studied 121 NE lung tumors (16 typical carcinoids (TC), 5 atypical carcinoids (AC), 29 large-cell NE carcinomas (LCNECs), and 71 small-cell lung carcinomas (SCLCs) using immunohistochemistry. We quantified apoptosis by terminal-deoxynucleotidyl-transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) in 31 of these cases. There was a significant increase of p53 mutant immunophenotype (defined as immunoreactivity with at least two antibodies for at least 20% of tumor cells) between atypical/typical carcinoids group and the LCNEC/SCLC group (P = 0.0003). There was an inverse correlation (P < 0.0001) between the scores of Bax and Bcl2 expression in individual tumors and a significant inversion of the Bcl2. Bax ratio between low-grade (typical and atypical carcinoids) and high-grade (LCNECs and SCLCs) tumors with a predominant Bax expression in the first group and predominant Bcl2 expression in the second. Whereas carcinoids had variable apoptotic indexes, LCNECs had high indexes (1.3 to 6.8%), Bcl2 overexpression, Bax down-regulation, and Bcl2.Bax ratio > 1 correlated with lower apoptotic index in both LCNEC and the pool of LCNECs and SCLCs (P < 0.05) and a lower survival rate in the group of atypical and typical carcinoids and LCNECs (P < 0.002). The highest levels of Bcl2 expression and Bcl2.Bax ratios were associated with p53 mutant immunophenotype (P = 0.02). Our results suggest that aggressiveness in NE lung tumors could be linked, in addition to proliferation, to apoptosis-related factors.

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 (PaO2 = 56 +/- 9 mm Hg), hypercapnia (PaCO2 = 47 +/- 8 mm Hg), and severe airflow obstruction (FEV1/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 (PaO2 = 54 +/- 9 vs 57 +/- 9 mm Hg; p < 0.001), more hypercapnic (PaCO2 = 48 +/- 8 vs 46 +/- 7 mm Hg; p < 0.005), and also more obstructed (FEV1/VC = 39.5 +/- 13 vs 45 +/- 14%; p < 0.001) than the rest of the patients under treatment. Other factors associated with effective use of oxygen were (1) initial prescription for 15 h or more per day, (2) supplementary education on oxygen therapy by a nurse or physiotherapist, (3) cessation of smoking, (4) use of oxygen in all domestic situations (toilet, meals, leisure, etc.), and (5) absence of side effects from oxygen treatment., 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 (delta index) that detects apneic events by quantifying arterial oxygen saturation (SaO2) 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 delta index., Results: Three hundred one patients were included (age, 56 +/- 12 years). Their RDI was 30 +/- 24. For a delta 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 SaO2 (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 SaO2 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 (FEV1/VC = 72 +/- 13 vs 77 +/- 15%; p = 0.026). Using a delta 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 delta 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.

In order to compare the clinical efficacy and safety of cefatrizine (Cefaperos) and cefpodoxime proxetil (Orelox) in the treatment of secondarily infected chronic obstructive pulmonary disease (COPD) in adults, a multicentre, randomized, open study was conducted by 60 general practitioners in two parallel groups of patient suffering from COPD complicated by an acute episode of superinfection (Anthoniesen stages 2 and 3). After verification of the eligibility criteria, written consent and randomization, the patients received, for 10 days, either cefatrizine at the dose of 1 g/day or cefpodoxime proxetil at the dose of 400 mg/day. A self-assessment form was given to the patient. A telephone visit was planned for D3. The final visit on D11 +/- 1 evaluated clinical efficacy (success or failure) and safety. The study population was composed of 250 patients with a mean age of 59.9 +/- 15.9 years (sex ratio M/F = 1.5). The principal etiology of COPD was chronic bronchitis in 67.5% of patients, longstanding asthma in 24.5% and emphysema in 6.8%. The mean history of the disease was 13.0 +/- 10.8 years. The Anthoniesen score was equal to 2 in 73.6% of patients, 3 in 8.8% of patients and 1 in 17.6% of patients. No significant difference concerning these criteria was observed between the two study groups. The clinical success rate was equivalent in the two groups. The time to regression of clinical signs tended to be shorter, up until the sixth day (mainly between D4 and D6) for patients treated with cefatrizine (p = 0.09; NS). The clinical safety was considered to be good and was comparable in the two study groups. This study concluded on the equivalent clinical efficacy of cefatrizine and cefpodoxime proxetil in the treatment of superinfections of COPD in general practice (97.5% and 99%, respectively), with a satisfactory and comparable safety, but with a much lower cost of treatment for cefatrizine. This conclusion is particularly important in the context of opposable medical references, as, although the treatment of superinfections of COPD by second and third generation cephalosporins is frequently proposed, the prescription of a less expensive cephalosporin appears to be more relevant.

The c-ets-1 transcription factor has been involved in the in vitro transactivation of matrix-degrading protease genes that might play an important role in tumor invasion. Using in situ hybridization, we analyzed serial frozen sections for c-ets-1, collagenase 1, and urokinase-type plasminogen activator gene expression in 54 lung carcinomas including 34 non-neuroendocrine carcinomas (18 squamous carcinomas, 10 adenocarcinomas, 3 large cell carcinomas, and 3 basaloids) and 20 neuroendocrine carcinomas (7 small cell lung carcinomas, 4 large cell neuroendocrine carcinomas, 4 well differentiated neuroendocrine carcinomas, and 5 carcinoids). c-ets-1 gene was expressed in stromal cells in 44/54 lung carcinomas including one metastasizing carcinoid. c-ets-1 transcripts were also detected in cancer cells more frequently in neuroendocrine than in non-neuroendocrine carcinomas (P = 0.0059) and in stages III and IV and metastasis more frequently than in stages I and II ( P = 0.0065). Collagenase 1 gene was expressed in 16/34 non-neuroendocrine tumors and in 1/20 neuroendocrine tumors, either in stromal (12/17) or in cancer cells (6/17). Urokinase-type plasminogen activator mRNAs were expressed in 45/54 lung carcinomas in stromal and/or cancer cells. In non-neuroendocrine tumors, c-ets-1 and collagenase 1 gene expressions in stromal cells were correlated. These results demonstrate that the transcription factor c-ets-1, collagenase 1, and urokinase-type plasminogen activator are involved in lung cancer invasion and suggest that c-ets-1 protein might transactivate collagenase 1 gene during tumor invasion.

Expression of mdr1 and p53 was assessed on 119 cases of bronchial carcinomas, and compared with clinical chemoresistance. mdr1 expression was evaluated by immunohistochemistry (IHC), using the monoclonal antibody JSB1. The study of p53 expression was performed by both IHC, using six different antibodies, and Northern blotting. We observed a correlation between the expression of mdr1 and the presence of a mutation of p53 in neuro endocrine (NE) carcinomas (P = 0.02). Correlation was not observed when non NE carcinomas were evaluated, nor was found any correlation between mdr1 expression and clinical chemoresistance in patients with small cell lung carcinoma (SCLC). The frequency of complete response however was significantly higher in patients whose tumor did no express mdr1 (P = 0.02). Chemoresistance correlated well with the phenotype of p53 mutant in SCC (P = 0.015). We conclude that p53 mutation is a better predictive factor of clinical chemoresistance in SCLC than mdr1 IHC detection.

Thirty six SLC patients have been treated with a combination therapy of ifosfamide 2 g/m2, D1 and D2, carboplatin 300 mg/m2 D1 and teniposide 100 mg/m2 D1 to D3. All patients were younger than 70 years, 31 males, five females, ten limited diseases, 26 extended diseases (without brain metastasis) Performance status 0, 1 or 2, mean weight loss 3.7 kg. Thirty six patients were evaluable for response. We have noted three complete response and 28 partial response (objective response rate 86%). The main toxicity of this combination therapy was myelo-suppression (86% of grade 3 and 4). Twenty seven patients have relapsed, the median relapse free survival time is 310 days. The median survival of the 36 patients is 340 days, one patient is alive more than 30 months after the diagnosis. The ifosfamide-carboplatin-teniposide combination is an effective treatment in small cell lung cancer, its toxicity remains tolerable.

Immunohistochemical analysis of p53 protein was carried out on 95 lung carcinomas from all histological types, including 60 primary tumors, 35 lymph node metastases, and 36 corresponding nude mice xenografts, using four antibodies: PAb240 specific for some mutant conformations; PAb421, PAb1801, and CM1 reactive with most of the forms of p53. Nuclear staining with at least two of those four antibodies revealed the presence of an accumulated protein, considered as indicative of a missense mutation in the p53 gene, in 50% of primary tumors of all histological types, except carcinoids. Some defect of messenger RNA expression was detected by Northern blot analysis in an additional 26% of tumors. p53 immunophenotype of the original tumor was fairly maintained on nude mice. p53 accumulation was not correlated with survival, but with disease extension (P = 0.01). Finally, immunohistochemical analysis allowed the recognition of p53 mutant immunophenotype in 41% of tumors where p53 DNA and messenger RNA were apparently normal, using standard molecular biology. Thus, this method provides a rapid and efficient approach for studying p53 mutations leading to an accumulated protein in lung tumors cells.

Carboplatin, a platinum analog with single-agent activity in previously untreated breast cancer, is characterized by comparatively less renal toxicity and emesis than cisplatin. We combined carboplatin at different dose levels [from 200 to 350 mg/m2 by intravenous (IV) infusion on day 1] with 5-fluorouracil (500 mg/m2 IV on days 1 and 8) and cyclophosphamide (500 mg/m2 IV on day 1), with all three drugs recycled every 28 days, to evaluate anti-tumor activity and toxicity of this novel combination [5-fluorouracil/carboplatin/cyclophosphamide (FCC)] in untreated locally advanced (LABC) or metastatic breast cancer (M+). Of 37 patients treated between March 1990 and August 1991 [LABC 25, M+ 8; World Health Organization (WHO) performance status, 0-1; median number of treatment cycles, 5; median follow-up, 20 months], 33 are evaluable for response and toxicity. The overall complete plus partial remission rate was 57% (LABC 68%, M+ 25%). The median duration of response was 19+ months. The cumulative carboplatin dose ranged from 800 to 2350 mg/m2 (median, 1450 mg/m2). In this series, no correlation was observed between the carboplatin dose level and response rate or toxicity. Leukopenia and thrombocytopenia represented the most frequent toxicities. WHO grades 3 and 4 neutropenia were documented in 34% and 8% of patients, respectively. Thrombocytopenia below 50 x 10(9)/l was observed in 8%. No renal toxicity was observed, and moderate emesis occurred in 67% of patients. These results indicate that FCC is an active and relatively safe combination for the treatment of advanced breast cancer in patients not previously treated with chemotherapy.

Based on our previous Phase I study indicating good tolerability of the drug, we have evaluated therapeutic activity and acute and subacute toxicities associated with repeated courses of the new anthracycline 4'-iodo-4'-deoxydoxorubicin (I-Dox) at the maximum tolerated dose (80 mg/m2) every three weeks. Thirty-three patients (31 evaluated for activity and 32 for toxicity) with relapsed (11 cases) or advanced breast cancer at presentation (22 cases) were treated with 108 cycles (median 3, range 1-7) for a median cumulative dose of 240 mg/m2. We observed no complete and 11 (35%) partial responses. Minor response was documented in 5 additional patients. The most frequent and severe toxicity was hematological. In 47% of the cycles and 34% of the patients I-Dox administration was associated with WHO grade 4 neutropenia. Severe neutropenia was more frequent after repeated cycles. Similar cumulative toxicity was observed for thrombocytopenia and anemia. In three patients (7 cycles) fever and possible infection occurred during neutropenia and required oral antibiotics. Extra-hematological side-effects were limited to mild/moderate nausea lasting for a few hours and mild fatigue lasting 1-7 days. Alopecia or oral mucositis were minimal or absent in the majority of patients. One case of potential reversible cardiac toxicity was observed after 240 mg/m2 I-Dox in a patient with preexistent cardiac risk factors. In view of the reported activity, good general tolerability, and selective hematological toxicity, I-Dox should be evaluated at higher than the conventionally defined maximum tolerated dose in combination with recombinant human hemopoietic growth factors.

The psychometric characteristics of two indexes used to evaluate the subjective morbidity of chemotherapy regimens were analyzed. Both indexes assessed the duration of discomfort as perceived by the patient throughout therapy. The first index asked patients to state the number of days spent with 'discomfort', and the second index asked them which days they would like to eliminate altogether because of the unbearable symptoms experienced on those days. While the first index gives some idea of the duration of suffering, without defining it, the second highlights a specific time when the quality of her life was unacceptable to the patient. We studied these indexes in the form of a questionnaire completed by 168 women who had entered a cancer clinical trial. This trial evaluated the efficacy of primary chemotherapy in rendering conservative surgery feasible in women with operable breast cancer, but whose tumor size was greater than 3 cm. Four different treatment regimens were used: CMF, FAC, FEC, FNC (C = cyclophosphamide, M = methotrexate, F = fluorouracil, A = adriamycin, E = epirubicin, N = mitoxantrone). Seventy-nine patients were interviewed during chemotherapy and 89 during follow-up visits. Initial assessment of the reliability, discriminant and concurrent validity of the two indexes produced satisfactory results. Finally, we analyzed the responses given by 168 patients for a total of 600 treatment cycles. The average value of 'discomfort' was 3 days, whereas the average value of days 'to be eliminated' was 1. The range of subjective morbidity (for every cycle of treatment: 'discomfort = 0-30 days; 'to be eliminated' = 0-20 days) was very broad.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

A simple pneumoconiosis with lamellar birefringent crystals was observed in animals dying in the San Diego Zoo. We studied 100 autopsies from 11 mammalian and eight avian species. In mammals, mild pulmonary lesions comprised crystal-laden macrophages in alveoli and lymphatics. Interstitial fibrosis was present in 20% of cases. There were no nodules. In birds, dust retention produced large granulomas around tertiary bronchi without fibrosis. Mineralogic analysis using scanning and transmission electron microscopy showed most of the crystals to be silicates. Ninety percent were complex silicates, with aluminum-potassium silicates comprising 70% of the analyzed particles. Electron and x-ray diffraction showed the silicates to be muscovite mica and its hydrothermal degradation product, ie, illite clay. This mica was also present on filtration membranes of atmospheric air samples obtained from the San Diego Zoo. The amount of dust retention was related to the animal's age, anatomic or ecologic variances, and length of stay in the San Diego Zoo. Its semidesert atmosphere is rich in silicates, which are inhaled and deposited in the lungs. Similar mica-induced lesions are found in humans living in this region or the Southwest of the USA. This simple pneumoconiosis is likely to be widespread in human populations living in desert or semidesert climates.

Malignant cells can be distinguished from their normal counterpart at the DNA level: they carry molecular changes which are characteristic of the tumor type or which might have some prognostic value. Amplifications and mutations of oncogenes and loss of alleles have been reported to occur in lung cancers, but their prognostic value has not yet been estimated, mainly for technical reasons: primary fresh biopsies are usually too small for molecular investigation. From 79 biopsies (50 of which were obtained by fiberoptic bronchoscopy), DNA hybridization was performed using the Southern blot technique, with myc family genes probes and a polymorphic probe located on the short arm of chromosome 3. Our study indicates that: 1) in 88% cases, enough DNA can be obtained by 3 or 4 fiberoptic bronchoscopy biopsies: from 5 to 80 micrograms DNA with an average of 25; 2) the quality of DNA is good for analysis by the Southern blot technique; 3) the loss of allele on chromosome 3 (3p 14-23) can be detected both in the small cell and in the non small cell type, but contamination of the specimens by non-tumoral tissue (based on the cytological and histological analysis of each biopsy) remains a problem for this type of study; 4) gene amplifications and rearrangements can be easily evaluated for the genes of the myc family. This pilot study shows that DNA analysis is feasible on perendoscopic biopsies. Collection and analysis of a large series of such biopsies at diagnosis is essential to define the value of DNA markers as prognostic factors in lung cancers.