Somatic profile in lung cancers is associated to reproductive factors in never-smokers women: Results from the IFCT-1002 BioCAST study.

BACKGROUND: Lung cancer in women is on the rise, with a higher proportion occurring in lifelong never-smokers. Lung cancer in never-smokers (LCINS) exhibits a high frequency of driver oncogene alterations. In this study, we aimed to investigate whether exposure to reproductive factors in women with LCINS may modulate the molecular pattern. METHODS: All newly diagnosed LCINSs were included in a prospective, observational study (IFCT-1002 BioCAST). Each patient responded to a questionnaire including reproductive factors. Biomarker test results were also collected. RESULTS: Two hundred and sixty women were included in this analysis, and 166 alterations were characterized. EGFR mutation frequency proved greater among patients with late menarche (74% in age>14 vs. 40% and 41% for 12-14 and ≤12 years, respectively; P=0.020) and tended to decrease with increasingly late age at menopause. In multivariate analysis, EGFR mutation frequency increased by 23% per increment of 1 year of age at menarche (P=0.048), and by 9% for each year at age at first birth (P=0.035). ALK alteration frequency was greater in women with high parity (50% in≥5 vs. 12% and 7% for 1-4 and nulliparity, respectively; P=0.021). CONCLUSION: In a cohort of women LCINSs, female hormonal factors appear to impact molecular pattern.

Outcomes of concurrent radiotherapy with weekly docetaxel and platinum-based chemotherapy in stage III non-small-cell lung cancer.

PURPOSE: The present study evaluated the outcomes of concurrent weekly docetaxel and platinum-based drug doublet in association with concurrent thoracic radiotherapy (TR) in the curative treatment of stage III locally advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with stage IIIA/B NSCLC were retrospectively included. Patients received weekly docetaxel and either cisplatin or carboplatin intravenous injections during concurrent TR (60 to 66Gy). Patients who received induction chemotherapy with the same drug doublet were also included. The endpoints were: disease control rate (DCR), overall recurrence rate, survival rates [disease-free survival (DFS) and overall survival (OS)] and toxicity. RESULTS: Eighty-nine consecutive patients treated with this association were included. Median follow-up time was 57.8 months. DCR was 76.5% at the first follow-up CT scan (6 to 12 weeks after the end of concurrent treatment). Median DFS and OS was 14.3 and 29.9 months respectively. Three-year survival was 43%. The overall recurrence rate was 65.9%. During overall treatment, grade 3 to 4 adverse events occurred in 29.2% of patients, the most common being esophagitis (12.4% of patients). Only 13.5% of patients presented with a grade 3 or higher adverse event after the end of concurrent treatment. CONCLUSIONS: Weekly docetaxel and platinum-based drug doublet combined with TR yielded promising results in stage III NSCLC, with high survival rates. The toxicity of this association is acceptable, with mainly manageable esophagitis. These findings warrant validation in a prospective study before considering this association for standard of care.

Liver fibrosis staging with contrast-enhanced ultrasonography: prospective multicenter study compared with METAVIR scoring.

We prospectively assessed contrast-enhanced sonography for evaluating the degree of liver fibrosis as diagnosed via biopsy in 99 patients. The transit time of microbubbles between the portal and hepatic veins was calculated from the difference between the arrival time of the microbubbles in each vein. Liver biopsy was obtained for each patient within 6 months of the contrast-enhanced sonography. Histological fibrosis was categorized into two classes: (1) no or moderate fibrosis (F0, F1, and F2 according to the METAVIR staging) or (2) severe fibrosis (F3 and F4). At a cutoff of 13 s for the transit time, the diagnosis of severe fibrosis was made with a specificity of 78.57%, a sensitivity of 78.95%, a positive predictive value of 78.33%, a negative predictive value of 83.33%, and a performance accuracy of 78.79%. Therefore, contrast-enhanced ultrasound can help with differentiation between moderate and severe fibrosis.

[Pulmonary embolism by cyanoacrylate following embolisation of an arteriovenous malformation]. / Embolie pulmonaire de cyanoacrylate après embolisation d'une malformation artérioveineuse.

INTRODUCTION: Symptomatic complications can occur after intravascular injection of cyanoacrylate glue. We report a case of pulmonary embolism following embolisation of an arteriovenous malformation (AVM). CASE REPORT: A 46-year-old woman was found to have an internal iliac AVM which was obliterated using N-butyl-2 cyanoacrylate (NBCA) mixed with lipiodol. The early clinical course was uneventful. On the third post-operative day she complained of sudden, transient chest tightness. On admission one hour later the chest pain had disappeared. Physical examination was normal. A chest roentgenogram showed multiple, dense, branched opacities scattered throughout both lung fields which were confirmed on HRCT, suggesting diffuse scattered embolism of iodine- labelled NBCA. The radiological signs persisted 6 months later. CONCLUSION: Endovascular treatment of arteriovenous malformations with NBCA can be responsible for symptomatic pulmonary embolism. This is not detectable radiologically in the absence of contrast medium. Radiologists should be aware of these often asymptomatic, but sometimes fatal, embolic complications.

Increase of CD4+ CD25+ regulatory T cells in the peripheral blood of patients with metastatic carcinoma: a Phase I clinical trial using cyclophosphamide and immunotherapy to eliminate CD4+ CD25+ T lymphocytes.

We determined the number and functional status of CD4+ CD25(high) regulatory T cells (Treg) in blood samples from patients with metastatic carcinoma, and evaluated their sensitivity to a single intravenous infusion of cyclophosphamide. Treg numbers were significantly higher in 49 patients with metastatic cancer (9.2% of CD4+ T cells) compared to 24 healthy donors (7.1%). These cells expressed the transcription factor forkhead box P3 (FoxP3), glucocorticoid-induced tumour necrosis factor receptor family-related protein (GITR) and intracellular CD152, and demonstrated a suppressive activity in vitro against CD4+ CD25- autologous proliferation. At a single intravenous infusion, cyclophosphamide failed, in association with a non-specific immunotherapy by intratumoral bacille Calmette-Guérin (BCG), to modulate significantly Treg numbers or function. Metastatic cancer is associated with an expansion of peripheral blood CD4+ CD25(high) FoxP3+ GITR+ CD152+ Treg cells whose immunosuppressive properties do not differ from those of healthy subjects. Moreover, cyclophosphamide administration may not represent an optimal therapy to eliminate Treg, which further underlines the need to identify specific agents that would selectively deplete these cells.

Drug-induced infiltrative lung disease.

An increasing number of drugs are recognized to induce distinctive patterns of infiltrative lung disease (ILD), ranging from benign infiltrates to life-threatening adult respiratory distress syndromes. In addition to drugs, biomolecules such as proteins and cytokines, and medicinal plants are also capable of inducing respiratory disease, some being severe and/or irreversible. For several reasons it is difficult to estimate the exact frequency of drug-induced infiltrative lung disease (DI-ILD). The risk for DI-ILD and the clinical patterns vary depending on a variety of host and drug factors. Although establishing the diagnosis is often difficult, systematic evaluation of the possible role of almost any kind of drugs in ILD is warranted, as stopping a drug may favourably influence prognosis. However, prognosis depends on the drug and the type of DI-ILD. Corticosteroids may suppress the inflammatory reaction, but for many drugs, proof of the effect of corticosteroids is lacking. Advances in prevention and prediction are needed. A user-friendly database of respiratory adverse drug reactions was made available on the web, to provide quick information in this area.

Antimyeloperoxidase-associated lung disease. An experimental model.

The lung is a common target in systemic vasculitides associated with antineutrophil cytoplasmic antibodies (ANCA). In the present study, we tested the hypothesis that the presence of antibodies directed against myeloperoxidase (MPO) induces pulmonary (vasculitic) lesions when neutrophils release lysosomal enzymes. Brown Norway (BN) rats were immunized with human MPO in complete Freund's adjuvant (CFA) or with CFA alone. Two weeks after immunization, rats had developed antibodies to human and rat MPO. Next, isolated single left lung perfusion was performed with human neutrophil lysosomal extract containing MPO and proteolytic enzymes. Rats were killed at 15 min, 4 h, and 10 d after perfusion. Tissue samples from the left and right lung were examined for vasculitic lesions and inflammatory cell infiltrates. At 15 min and 4 h, left lungs from control and MPO-immunized rats showed a mild influx of polymorphonuclear cells. At 10 d, patchy inflammatory cell infiltrates, consisting predominantly of polymorphonuclear leukocytes (PMNs) and monocytes, were observed throughout the parenchyma of the left lung in MPO-immunized rats. Occasionally, granuloma-like lesions, giant cells, and foci of alveolar hemorrhage were observed as well. Far less severe lesions were seen in control immunized rats. Strikingly, at 10 d after perfusion, severe pulmonary tissue injury was observed also in right lungs from MPO-immunized rats whereas right lungs from control immunized rats appeared normal. The lesions were characterized by influx of PMNs and monocytes and, in some rats, foci of alveolar hemorrhage. These studies suggest that the presence of an anti-MPO directed autoimmune response contributes to generalized pulmonary tissue injury after local release of products of activated neutrophils, which supports a pathogenic role of MPO-ANCA.

Transient pulmonary infiltrates during treatment with anti-thymocyte globulin.

We report the case of a 54-year-old woman with aplastic anemia, who developed transient pulmonary infiltrates following intravenous infusion of rabbit antithymocyte globulin (ATG) for 3 days. There was no other explanation than the infusion of ATG for the infiltrates. Rechallenge with ATG induced the recurrence of opacities on the chest radiograph. Although rarely involved with only 4 previous reports, ATG should be included in the list of drugs capable of inducing pulmonary infiltrates.

[Management of obesity and respiratory insufficiency. The value of dual-level pressure nasal ventilation]. / Prise en charge de l'obèse en décompensation respiratoire. Intérêt de la ventilation nasale à double niveau de pression.

Obstructive Sleep Apnea (OSA), Obesity-Linked Hypoventilation (OLH)--a hypoventilation which is independent of apneas and increased by sleep--, and COPD are mechanisms for respiratory failure in obese patients. We thought nasal bi-level positive airway pressure to be a suitable treatment: EPAP is useful to maintain upper airway patency and IPAP-EPAP difference to correct OLH and COPD hypoventilation. Our purpose is to report the results of such a therapeutic approach. We included 41 patients that we first treated by nasal bi-level positive airway pressure for a respiratory failure with an uncompensated respiratory acidosis. The initial setting was about 4 cm H2O for EPAP and 16 for IPAP. Under supervision of a real-time printed oximetry tracing, we furthermore increased EPAP until disappearance of repetitive dips in oxygen saturation (that we assimilated to obstructive events) and IPAP until obtaining an acceptable level of steady saturation (we assimilated a low level to a steady hypoventilation). Age (mean +/- SD) was 63 +/- 11 years, BMI 42 +/- 9 kg/m2, pH 7.32 +/- 0.04, PaCO2 71 +/- 13 mmHg, PaO2 45 +/- 7 mmHg. Thirty-nine out of 41 patients returned home without need for tracheal intubation. At 7 days of treatment, PaCO2 was 50 +/- 6 mmHg. Thus, nasal bi-level position airway pressure appears to be an efficient treatment in these patients.

Relative survival analysis of 252 patients with COPD receiving long-term oxygen therapy.

OBJECTIVES: A survival analysis was conducted on patients with COPD receiving long-term oxygen therapy (LTOT) to compare two different statistical methods. METHODS: We used a multivariate crude (observed) survival model (Cox) and a multivariate relative survival model (Hakulinen). Only the latter is able to correct the survival by adjusting it to the normal life expectancy of the studied patients. PATIENTS: Two hundred fifty-two hypoxemic COPD patients (207 male) requiring LTOT were included. Mean PaO2 was <50 mm Hg before oxygen therapy. Mean age was >69 years (SE: 9.9). They had severe bronchial obstruction: mean FEV1 was <33% (10.6) of predicted values, with some CO2 retention: mean PaCO2 was 45.6 (7.1) mm Hg. By December 31, 1995, 189 patients had died (75%) and 13 (5%) were unavailable for follow-up. RESULTS: The overall crude survival was poor: 80.9% after 1 year, 67.1% after 2 years, 34.7% after 5 years, and 7.1% after 10 years. In the crude multivariate analysis (Cox), the negative prognostic factors were age and hypercapnia. The overall relative survival (Hakulinen), corrected for life expectancy, was 82.8% after 1 year, 70.8% after 2 years, 41.5% after 5 years, and 10.25% after 10 years. In the final multivariate relative model, age was no longer significant and the only bad prognostic factor was hypercapnia with a relative risk of 1.97 (1.16 to 3.34). CONCLUSION: This work shows the inadequacy of the Cox observed survival model when it comes to appreciating the real prognostic impact of age, because of the confusing factor associated with a normal life expectancy.

Central sleep apnoea in Arnold-Chiari malformation: evidence of pathophysiological heterogeneity.

We report on the case of two young patients with type I Arnold-Chiari malformation (ACM), as revealed by a central sleep apnoea (CSA) syndrome without any other neurological defect. Case 1 was a 14-yr-old male patient, who developed severe alveolar hypoventilation and needed long-term mechanical ventilation via a tracheostomy. Case 2 was a 39-yr-old male patient, who developed features suggestive of sleep apnoea and responded to nasal continuous positive airway pressure ventilation despite the central type of apnoeas. These two cases illustrate the different pathophysiological mechanisms involved in CSA, namely a blunted chemical drive (in hypercapnic patients) and an increased chemical drive, which destabilizes the breathing pattern during sleep (in normo/hypocapnic patients). Central sleep apnoea can be the initial manifestation of Arnold-Chiari malformation and can lead to a life-threatening condition.

Hepatoid adenocarcinoma of the lung: report of a case of an unusual alpha-fetoprotein-producing lung tumor.

We report on a rare tumor of the lung characterized by its morphologic hepatoid features and alpha-fetoprotein production. This unusual neoplasm arose in the left lung of a 36-year-old man in whom clinical and radiologic examinations did not reveal any other tumor. The serum level of alpha-fetoprotein was measured at 6,090 ng/mL and was parallel to the evolution of the tumor. Despite treatment, the patient died 7 months after the diagnosis. The microscopic appearance of the tumor was the same as observed in hepatocarcinoma and hepatoid adenocarcinoma of the ovary or the stomach, with a tubular, papillary, or trabecular pattern. Periodic acid-Schiff-positive hyaline globules were numerous, and tumor cells showed immunohistologic positivity for alpha-fetoprotein and carcinoembryonic antigen. This lung adenocarcinoma was first described by Ishikura et al. in 1990 and was named hepatoid lung adenocarcinoma. Like the rare hepatoid carcinoma of the gallbladder, the pancreas, the ampulla of Vater, the renal pelvis, and the bladder, the exact histogenesis and the prognosis of this type of lung tumor are not yet known.

Systemic injection of products of activated neutrophils and H2O2 in myeloperoxidase-immunized rats leads to necrotizing vasculitis in the lungs and gut.

The strong association of anti-neutrophil cytoplasmic antibodies with various forms of systemic vasculitis suggests a role for these autoantibodies in the pathophysiology of systemic vasculitis. In the present study, we tested the hypothesis that release of neutrophil lysosomal enzymes in the presence of an anti-myeloperoxidase (anti-MPO) immune response may underlie the development of systemic vasculitis. Brown Norway rats were immunized with MPO in complete Freund's adjuvant or complete Freund's adjuvant alone. Two weeks after immunization, rats bad developed antibodies to human and rat MPO as measured by enzyme-linked immunosorbent assay. Next, rats were intravenously infused with 400 micrograms of a human neutrophil lysosomal extract containing 200 micrograms of MPO followed by 0.5 ml of a 1 mmol/L solution of H2O2 through a cannula inserted into the right jugular vein. Rats were sacrificed at 4 hours, 24 hours, 7 days, or 14 days, and several organs (lungs, heart, liver, spleen, gut, and kidneys) were examined for vasculitic lesions and inflammatory cell infiltrates. Macroscopically, patchy hemorrhagic spots were observed in the lungs and gut of MPO-immunized rats at days 7 and 14 after systemic infection of the neutrophil lysosomal extract and H2O2. Such changes were not observed at earlier time points or in control immunized rats. Histologically, the lungs of MPO-immunized rats sacrificed at days 7 and 14 showed patchy inflammatory cell infiltrates associated with vasculitis, granuloma formation, giant cells, and foci of hemorrhage. At 14 days, early signs of fibrosis were found with deposition of collagen and proliferation of fibroblasts. Furthermore, a prominent leukocytoclastic vasculitis was found in the small intestine of these rats characterized by fibrinoid necrosis and an extensive neutrophilic infiltrate. No inflammatory changes were found in the other organs studied (heart, liver, spleen, and kidneys). Control immunized rats, sacrificed at days 7 and 14 showed only some small foci of inflammatory infiltrates in the lungs whereas no inflammatory changes were found in the gastrointestinal tract. These studies show that release of products from activated neutrophils in the presence of anti-MPO autoantibodies may be relevant to the pathogenesis of anti-MPO-associated vasculitides.

[Modelling of length of stay and costs in 2 homogeneous groups of hematological and pneumological patients: clinical characterization of patients with long-stay and high costs]. / Modélisation de la distribution des durées de séjour et des coûts dans deux groupes homogènes de malades d'hématologie et de pneumologie: caractérisation clinique des patients de longue durée et de coût élevé.

After the implementation of the Medicare Prospective Payment System (PPS) in the USA, many European countries like France have introduced DRGs to curb hospital overspending. However, there has been some reluctance from hospital actors, especially because of the heterogeneous nature of DRG's. To analyse this situation, we propose a method based on distribution modelization of length of stays and costs within DRGs. For each DRG, the model is based on a mixture of Poisson and Weibull distributions identified as subgroups. The subgroups are characterized by their means and their proportions which are estimated by maximization of data likelihood. For a particular DRG, the proportion of long stay or high-cost patients can be explained by the introduction of clinical variables in the model. First the model was applied to the DRG "leukemia and lymphoma" (HCFA V.3), using 133 discharge abstract files from the Dijon public teaching hospital which were classified into this DRG in 1993. Among the studies parameters only acute leukemia, neutropenia < 500 PNN/mm3, high dose aplastic chemotherapy, central venous catheterization, parenteral nutrition, use of protected or laminar air flow room, septicemia, large spectrum intravenous antibiotherapy, and blood transfusion had a significant influence on the distribution of the patients in the long stay or costly subgroup. Second, for DRG "chronic bronchopneumopathies" (n = 220) the significant parameters were mechanical ventilation, antibiotherapy, post hospitalization medicalized care.