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Biomedical subjects

M Wislez

Publications and source records attributed to M Wislez.

At least 19 recordsLinked to original sources
PubMed2006

c-Jun N-terminal kinase is activated in non-small-cell lung cancer and promotes neoplastic transformation in human bronchial epithelial cells.

c-Jun N-terminal kinase (JNK) has been reported to either potentiate or inhibit oncogenesis, depending upon the cellular context, but its role in lung neoplasia is unclear. Here we sought to define the role of JNK in lung neoplasia by examining evidence of JNK phosphorylation in non-small-cell lung cancer (NSCLC) biopsy samples and by using genetic and pharmacologic approaches to modulate JNK expression and activity in cultured cells. Immunohistochemical staining for JNK phosphorylation was detected in 114 (45%) of 252 NSCLC biopsy samples and was predominantly nuclear, providing evidence of JNK activation in a subset of NSCLC cases. Introduction of a doxycycline-inducible, constitutively active, mutant mitogen-activated protein kinase kinase 4 (MKK4) into the human bronchial epithelial cell lines BEAS-2B and HB56B increased the cells' proliferation, migration, invasion and clonogenicity. Depletion of JNK in MKK4 mutant-transformed BEAS-2B cells by introduction of JNK1/2 short hairpin RNA reversed the transformed phenotype, indicating that JNK activation is oncogenic and MKK4 confers neoplastic properties in these cells. The proliferation of NSCLC cell lines HCC827 and H2009, in which JNK and its substrate c-Jun are constitutively phosphorylated, was inhibited by SP600125, a JNK kinase inhibitor. We conclude that JNK is activated in a subset of NSCLC biopsy samples and promotes oncogenesis in the bronchial epithelium, suggesting that strategies to inhibit the JNK pathway should be considered for the prevention and treatment of NSCLC.

Bronchi↗
PubMed2006

Lung cancer in HIV infected patients: facts, questions and challenges.

AIDS related mortality has fallen sharply in industrialised countries since 1996 following the introduction of highly active antiretroviral therapy. This has been accompanied by an increase in the proportion of deaths attributable to non-AIDS defining solid tumours, especially lung cancer. The risk of developing lung cancer seems to be higher in HIV infected subjects than in the general population of the same age, partly because the former tend more frequently to be smokers and, especially, intravenous drug users. The carcinogenic role of the antiretroviral nucleoside drugs and their interaction with smoking needs to be examined. Interestingly, there is no clear relationship between the degree of immunosuppression and the risk of lung cancer, so the reason for the increased risk is unknown. The mean age of HIV infected patients at the time of lung cancer diagnosis is 45 years and most are symptomatic. Lung cancer is diagnosed when locally advanced or metastatic (stage III-IV) in 75-90% of cases, similar to patients with unknown HIV status. Adenocarcinoma is the most frequent histological type. The prognosis is worse in HIV infected patients than in the general lung cancer population. Efficacy and toxicity data for chemotherapy and radiation therapy are few and imprecise. Surgery remains the treatment of choice for localised disease in patients with adequate pulmonary function and general good health, regardless of immune status. Prospective clinical trials are needed to define the optimal detection and treatment strategies for lung cancer in HIV infected patients.

Adult↗
PubMed2005

[Bronchioloalveolar carcinoma].

Bronchioloalveolar carcinoma is one of the four histological subtypes of adenocarcinoma and its incidence is increasing. It grows in a lepidic fashion along the alveolar septa without invading alveolar walls. The strict histological definition requires complete surgical resection to exclude any evidence of invasion. This definition is thus only applicable in practice to isolated operable pulmonary nodules. For other types high-resolution lung CT-scan is necessary to evaluate pulmonary involvement because of the high frequency of multifocal disease at initial presentation and because of the presence of ground glass opacities, which can be one of the first manifestations of CBA on CT. Therapeutic management does not differ from non-small cell lung cancer. Solitary nodules are treated by surgical resection with a good prognosis whereas multifocal disease is rarely respectable. Diffuse and/or pneumonic forms are treated with systemic chemotherapy with a generally poor prognosis. However, the recent discovery of the particular sensitivity of this form of adenocarcinoma to EGFR (Epidermal Growth Factor Receptor) tyrosine kinase inhibitors offers new possibilities for management.

Adenocarcinoma↗
PubMed2004

Upregulation of bronchioloalveolar carcinoma-derived C-X-C chemokines by tumor infiltrating inflammatory cells.

OBJECTIVE AND DESIGN: The presence of increased numbers of tumor-infiltrating neutrophils is associated with poorer outcome in patients with adenocarcinoma of the bronchioloalveolar (BAC) subtype. We evaluated the role of inflammatory environment on C-X-C chemokine tumor production. MATERIALS: Bronchoalveolar lavage from 31 consecutive patients with adenocarcinoma of the BAC subtype as well as tumor and normal pulmonary tissue samples. A549 BAC cell line. Peripheral blood mononuclear cells (PBMC), polymorphonuclear neutrophils (PMN) and alveolar macrophages (AM). METHODS: Elisa measurements and immunohistochemical studies of ENA-78, IL-8, IL-1beta and TNF-alpha. RNA isolation, reverse transcription, and PCR amplification of ENA-78 and IL-8. RESULTS: C-X-C peptides were expressed by tumor cells of all the tumor specimens tested. ENA-78 and IL-8 were also expressed by AM. To better understand the regulation of the C-X-C production, BAC cell line was cultured alone or with inflammatory cells. PBMC upregulated both tumor ENA-78 and IL-8 mRNA expression and protein release whereas AM only upregulated ENA-78 mRNA expression and protein release; PMN had no effect. Anti-human IL-1beta antibodies (ab) inhibited the A549 ENA-78 and IL-8 production stimulated by PBMC-CM. Anti-human TNF-alpha ab inhibited A549 ENA-78 production stimulated by AM-CM. IL-1beta and TNF-alpha were expressed in vivo by inflammatory cells, although TNF-alpha was also expressed by tumor cells. CONCLUSIONS: This work emphasizes the role of the host inflammatory response in promoting tumor growth in vivo.

Adenocarcinoma, Bronchiolo-Alveolar↗
PubMed2003

[Respiratory manifestations of common variable immunodeficiency in adults].

INTRODUCTION: Sporadic common variable immunodeficiency (CVID) is the most frequent cause of primary humoral immunodeficiency observed in adults. Respiratory complications occur frequently. STATE OF ART: Recurrent bacterial pneumonia and bronchial suppuration are the most frequent complications whilst reactive interstitial pneumonitis (lymphoid interstitial pneumonia and sarcoid-like granulomatosis) and pulmonary lymphoma involvement are rarer. Treatment is based on replacement infusions of gamma globulin (Ig-IV). Although treatment has been shown to reduce the frequency of pulmonary infections, respiratory complications are still responsible for one third of late mortality in CVID. PERSPECTIVES: Type and frequency of respiratory survey has to be defined, as well as the indication for other treatments than Ig-IV. CONCLUSIONS: Protein electrophoresis must be done in a young adult with recurrent low respiratory tract infections and/or diffuse bronchectasis. Hypogammaglobulinemia should result in immunological and hematological investigations which may help to the diagnosis of CVID and to the beginning of the adequate treatment.

Adolescent↗
PubMed2002

Primary pulmonary lymphoma.

Three distinct entities are now covered by the definition of primary pulmonary clonal lymphoid proliferation. The aim of this review is to describe the pathophysiological, diagnostic, prognostic and therapeutic aspects of these three entities. Low-grade pulmonary B-cell lymphoma is the most frequent form of primary pulmonary clonal lymphoid proliferation. It arises from mucosa-associated lymphoid tissue. It is usually indolent and appears in the form of a chronic alveolar opacity. The prognosis is excellent, but treatment is controversial (simple monitoring, surgery or single-agent chemotherapy). High-grade pulmonary B-cell lymphoma is far rarer and usually occurs in individuals with an underlying disorder (e.g. immunodeficiency). The prognosis is poor and therapeutic options depend on the underlying disorder. The inclusion of lymphomatoid granulomatosis in the definition of primary pulmonary lymphomas is controversial. The clonal nature of the proliferation is very rarely demonstrated and extrapulmonary involvement is frequent (upper airways, skin, kidneys, central nervous system, etc.). The prognosis is extremely variable, with some authors reporting complete remission with steroids and cyclophosphamide and others reporting failure of combination chemotherapy.

Humans↗
PubMed2001

Spectrum of CD4 to CD8 T-cell ratios in lymphocytic alveolitis associated with methotrexate-induced pneumonitis.

The present study was conducted to confirm the presence of severe lymphocytic alveolitis and to determine the factors responsible for the very different alveolar CD4 to CD8 T-cell ratios (CD4/ CD8) described in methotrexate-induced pneumonitis (MTX-pneumonitis). Clinical and radiologic findings, as well as bronchoalveolar lavage (BAL) data, including CD4 and CD8 subset analysis, were retrospectively reviewed for patients hospitalized between 1985 and 2000 for MTX-pneumonitis. BAL cell counts from patients with MTX-pneumonitis (cases) were compared with those from patients receiving MTX but who did not have evidence of MTX toxicity (MTX-exposed patients) and those from healthy subjects (control subjects). Nineteen BAL were performed in 14 consecutive cases of MTX-pneumonitis. MTX was given for various underlying diseases. All cases presented a subacute diffuse interstitial pneumonitis that recovered, with MTX discontinuation and/or initiation of adjunctive steroid therapy. At the time of diagnosis, BAL cell counts in MTX-pneumonitis indicated severe lymphocytic alveolitis when compared with MTX-exposed patients and control subjects and moderate neutrophil alveolitis compared with control subjects. The lymphocytic alveolitis resulted from an increase in both CD4 and CD8 lymphocyte cell counts. Nevertheless, alveolar CD4/ CD8 T-cell ratios ranged from 0.4 to 9.6. CD4/CD8 values correlated positively with lymphocyte counts but negatively with time elapsed between last MTX administration and BAL and with steroid cumulative dose received by the patients. Severe lymphocytic alveolitis was confirmed in our series of MTX-pneumonitis. The between-patient variation in CD4/CD8 T-cell ratios may reflect the large range of time intervals between last MTX administration and BAL evaluation and the use of adjunctive steroid therapy.

Adolescent↗
PubMed2001

Acute respiratory failure following HAART introduction in patients treated for Pneumocystis carinii pneumonia.

Cases of paradoxical worsening of opportunistic infections shortly after the beginning of highly active antiretroviral therapy (HAART) prompted questions on the optimal timing of introduction of HAART in patients with inaugural AIDS-related opportunistic infections. We describe three cases of acute respiratory failure after early introduction of HAART in patients treated for Pneumocystis carinii pneumonia (PCP). The three patients had severe PCP that initially improved with anti-PCP and adjunctive steroid therapy. HAART was introduced 1 to 16 d after diagnosis of PCP, and steroids were stopped on Day 15. Seven to 17 d after HAART introduction, the three patients developed a second episode of severe acute respiratory failure with high-grade fever and patchy alveolar opacities on the chest roentgenogram. PCP resistant to cotrimoxazole, pulmonary superinfection, and drug-related pneumonitis were suspected but subsequently ruled out. Bronchoalveolar lavage and lung pathologic findings showed severe nonspecific pulmonary inflammatory foci surrounding a few persistent P. carinii cysts. All three patients recovered after HAART interruption or steroid reintroduction. We conclude that acute respiratory failure can recur after initiation of antiretroviral therapy in patients being treated for severe PCP. This phenomenon could result from rapid pulmonary recruitment of fully competent immune and inflammatory cells responding to a few persistent P. carinii cysts. A short course of steroid therapy may suppress this reaction.

AIDS-Related Opportunistic Infections↗
PubMed2001

Tumor-derived granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor prolong the survival of neutrophils infiltrating bronchoalveolar subtype pulmonary adenocarcinoma.

We evaluated the role of the tumor environment in the regulation of apoptosis of tumor-infiltrating neutrophils, the number of which correlates negatively with outcome, in patients with adenocarcinoma of the bronchioloalveolar (BAC) subtype. We examined three different parameters of apoptosis, namely morphological aspect, annexin-V expression, and DNA fragmentation. Bronchoalveolar lavage fluid (BALF) supernatants from patients with BAC significantly inhibited the 24-hour spontaneous apoptosis of normal peripheral blood neutrophils in vitro compared to BALF supernatants from control patients (64 +/- 4% versus 90 +/- 2% measured by annexin-V flow cytometry, P = 0.04). The alveolar neutrophil count correlated positively with the granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) concentrations in the patient's BALF. Furthermore, neutralizing antibodies (Abs) against GM-CSF and G-CSF significantly inhibited BALF anti-apoptotic activity (15 to 40% and 34 to 63% inhibition, respectively), whereas neutralizing Abs against interleukin (IL)-8, IL-6, IL-1beta and tumor necrosis factor-alpha had no significant effect. In an attempt to identify the cell origin of anti-apoptotic cytokines, we tested in vitro the effect of BAC cells (A549 cell line and primary culture derived from a patient's BAC tumor) on the apoptosis of peripheral blood neutrophils. Cell-free supernatants from tumor cells did not inhibit neutrophil apoptosis. In contrast, cell-free supernatants from tumor cells previously exposed to conditioned media from peripheral blood mononuclear cells and alveolar macrophages significantly inhibited spontaneous neutrophil apoptosis. This inhibition was partially lifted when conditioned media from mononuclear cells were previously treated with Abs against IL-1beta and tumor necrosis factor-alpha. As in vivo, neutralizing Abs against GM-CSF significantly inhibited the anti-apoptotic activity of cell culture supernatants, and combination with Abs against G-CSF had an additive effect. In vivo, GM-CSF and G-CSF were strongly expressed by tumor cells and moderately or not expressed by the normal epithelium, as assessed by immunohistochemical studies. These findings demonstrate that the tumor environment generates local conditions that prolong alveolar neutrophil survival through the production of soluble factors, thereby contributing to the persistence of the neutrophil alveolitis observed in BAC.

Adenocarcinoma, Bronchiolo-Alveolar↗
PubMed2001

AIDS-related alveolar hemorrhage: a prospective study of 273 BAL procedures.

STUDY OBJECTIVES: To evaluate the frequency and diagnostic significance of alveolar hemorrhage (AH) in HIV-infected patients. DESIGN: A 3-year prospective cohort study. SETTING: A university hospital in Paris, France. PATIENTS: Two hundred forty-three HIV-infected patients undergoing 273 BAL procedures during the study period. METHODS: AH was assessed by using the Golde score. Data on the patients treated and observed in our institution were collected, as well as on their survival rate 12 months after undergoing BAL. Risk factors for AH were sought by comparing patients with AH (cases) and those without AH (control subjects). RESULTS: AH frequently occurred but usually was subclinical and cytologically mild. AH did not alter the 12-month survival rate. AH always was associated with at least one specific AIDS-related pulmonary disorder, and the following four independent risk factors were identified in a stepwise forward logistic regression model: pulmonary Kaposi's sarcoma (KS; odds ratio [OR], 5.3; 95% confidence interval [CI], 1.8 to 16.7; p = 0.003), cytomegalovirus (CMV) pneumonia (OR, 9.8; 95% CI, 1 to 100; p = 0.05), hydrostatic pulmonary edema (OR, 16.4; 95% CI, 1.8 to 142; p = 0.01), and platelet count < 60,000 cells/microL (OR, 5.6; 95% CI, 1.5 to 20; p = 0.009). CONCLUSIONS: AH is frequently diagnosed during BAL in HIV-infected patients. Its presence may point to an underlying cause, such as pulmonary KS, CMV pneumonia, or hydrostatic pulmonary edema, or to triggering factors such as thrombocytopenia.

AIDS-Related Opportunistic Infections↗
PubMed2000

[Diffuse infiltrative lung diseases of infectious and neoplastic origin].

Among the causes of chronic diffuse infiltrative lung diseases, infection and neoplasia have to be suspected in priority because of their frequency and their therapeutic specificities. Diffuse infiltrative lung diseases related to infection, often acute and feverish, are due to Pneumocystis carinii pneumonia, miliary tuberculosis, or virus and atypical pneumonia. Strategy for microbiological diagnosis depends on the pathogen suspected and the pulmonary disease severity. By contrast, diffuse infiltrative lung diseases due to neoplasia, mostly chronic diseases, include lymphangitic carcinomatosis and more rarely diffuse bronchoalveolar carcinoma and lymphoproliferative diseases.

Adenocarcinoma, Bronchiolo-Alveolar↗
PubMed2000

Organizing pneumonia related to common variable immunodeficiency. case report and literature review.

A 68-year-old woman suffering from common variable immunodeficiency (CVI) developed a typical picture of organizing pneumonia. Causative factors other than CVI were eliminated. Several antibiotic regimens failed to improve the patient's condition, while the clinical manifestations rapidly disappeared under steroid therapy, with complete radiological recovery, but relapsed after steroid withdrawal. Finally, organizing pneumonia was definitely demonstrated by pathological findings obtained by open lung biopsy. Interestingly, pathological examination exhibited two other well-known CVI-associated lesions, i.e. benign lymphoid hyperplasia and noncaseating granuloma. In view of reports in the literature, we speculate that these different histological patterns could have resulted in a spectrum of symptomatic CVI-associated pulmonary disorders that improved under steroid therapy.

Aged↗
PubMed2000

[A mediastinal opacity in a patient with cirrhosis].

Radiological mediastinal shadows have numerous causes. Paraesophageal varices might be revealed by such radiological findings. We described herein the case of a patient with radiological mediastinal opacity occurring after sclerotherapy that was finally related to esophageal varices.

Esophageal and Gastric Varices↗
PubMed1999

Lymphoma of pulmonary mucosa-associated lymphoid tissue: CT scan findings and pathological correlations.

The aim of this study was to describe the lesions of pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma observed by means of computed tomography (CT) and to determine the value of CT in the management of this disease. Sixty six CT scans were performed in 13 consecutive cases of histologically proven pulmonary MALT lymphoma at the time of diagnosis (n=13) or periodically (n=53). They were reviewed separately with chest radiographs by consensus between two observers. Pulmonary abnormalities were described and compared to histopathological findings on surgical specimens from seven patients. At the time of diagnosis, elementary lesions observed by means of CT consisted of nodular areas of attenuation (12 of 13), linear areas of attenuation (eight of 13) and consolidations (six of 13). All these lesions were centred on airways that appeared dilated in seven cases and were more often bilateral and multiple on CT than on the chest radiographs. CT abnormalities correlated with gross pathological appearance and were related to a lymphomatous infiltration with a peribronchovascular distribution. Pathological examination also confirmed the presence of dilated airways within lymphomatous lesions and showed that the bronchial wall was respected. During follow-up, in patients on chemotherapy, response, relapse or progression were easily identified by means of plain radiography. In the initial evaluation, computed tomography contributed to the choice of therapeutic strategy, avoiding unnecessary surgical resection in one-third of patients. By contrast, it is unclear whether computed tomography is useful for post-treatment follow-up of mucosa-associated lymphoid tissue.

Adult↗
PubMed1999

Pulmonary malignancies in the immunocompromised patient.

Clinicians should be familiar with immunodeficiency-related malignancies, as their incidence is expected to increase further with the rise in the number and survival of immunocompromised patients. The most common malignancies affecting the lungs in those patients are Kaposi's sarcoma, non-Hodgkin's lymphoma and, to a far less extent, Hodgkin's disease and bronchogenic carcinoma. However, their relative frequency depends on the types of immune deficiency, including those due to congenital disorders, AIDS and drug treatments. This review will summarize epidemiological data on the frequency of immmunodeficiency-related malignancies, recent advances on their pathogenesis and current approaches to their diagnosis and treatment in the various immunosuppressed groups.

Acquired Immunodeficiency Syndrome↗