Joel Greif

ErbB4 increases the proliferation potential of human lung cancer cells and its blockage can be used as a target for anti-cancer therapy.

Clinical and experimental data suggest that ErbB‐4, a member of the epidermal growth factor receptor family, may have a role in cancer progression and response to treatment. We found recently, using a retrospective clinical analysis, that expression of ErbB‐4 receptor is correlated with metastatic potential and patient survival in non‐small‐cell lung cancer (NSCLC). The purpose of this work was to correlate the expression of the ErbB‐4 and lung cancer cells growth in vitro and in vivo and to determine the therapeutic potential of a monoclonal antibody to ErbB‐4 against lung cancer. For this aim, we ectopically expressed ErbB‐4 in a human NSCLC cell line that did not express the ErbB‐4 protein. Overexpression of ErbB‐4 produced a constitutively activated ErbB‐4 receptor. The transfected ErbB‐4 positive clones showed an increased cell proliferation in vitro and in vivo in comparison with parental ErbB‐4 negative cells and with the cells transfected by neomycin‐resistant gene. A monoclonal antibody to ErbB‐4 showed both an inhibitory effect on growth rate and an increasing apoptotic rate in the cells expressing ErbB‐4. The results of the current study provide evidence that ErbB‐4 plays a significant role in human lung cancer and may serve as a molecular target for anticancer therapy.

Induced sputum compared to bronchoalveolar lavage for evaluating patients with sarcoidosis and non-granulomatous interstitial lung disease

Bronchoalveolar lavage (BAL), an important tool for evaluating interstitial lung diseases (ILDs), has limited utility due to its invasiveness and the difficulty of performing it in clinically contraindicated patients. We compared BAL with the induced sputum (IS) technique to analyse cells and T lymphocytes in patients with sarcoidosis (SA) and non-granulomatous ILD (NG-ILD). Pulmonary function tests and BAL were performed by conventional methods. IS induction was done 20 sec after inhalation of 3.5% saline with an ultrasonic nebulizer. Giemsa-stained cytopreps were differentially counted. T lymphocyte subsets were analysed by flow activated cell sorter (FACS). Patients with NG-ILD had impaired total lung capacity (TLC). Transbronchial biopsy demonstrated lung fibrosis in NG-ILD and non-caseating granuloma in SA. The differential cell count in both groups demonstrated a significantly lower percentage of neutrophils and a significantly higher percentage of macrophages in BAL than in IS. The IS samples of patients with SA were significantly richer in metachromatic cells and eosinophils, but had a lower percentage of lymphocytes, compared to the BAL samples. The profiles of T cell subsets showed the same pattern, in both samples, in both groups. A CD4/CD8 ratio of 2.5 or greater had a sensitivity of 100% and a specificity of 81.2%, with a positive predictive value of 81.2% to distinguish SA from NG-ILD. IS is an effective non-invasive technique to identify CD4+ inflammation which distinguishes sarcoidosis from other NG-ILDs.

The effect of food and exercise on the skin response to compound 48/80 in patients with food-associated exercise-induced urticaria-angioedema.

Food-associated, exercise-induced urticaria-angioedema is increasingly being recognized. We studied five atopic individuals in whom ingestion of food was followed by exercise-induced urticaria-angioedema. The combined effect of food and exercise on skin wheal response to compound 48/80 and histamine was studied. Symptoms could be reproduced in only four of the patients who performed strenuous exercise after ingestion of food to which they were skin sensitive. When symptoms appeared, that is, after a combination of food and exercise challenge, there was a marked increase in the wheal response to compound 48/80 (greater than 200%) and not to histamine. Food or exercise challenge alone did not induce any significant change in the skin reactivity to compound 48/80 or to histamine. It was concluded that mast cell releasability could be increased when the patient was subjected to combined factors.

Percutaneous core needle biopsy in the diagnosis of mediastinal tumors

OBJECTIVEnto determine the contribution of percutaneous core cutting needle biopsy (PCNB) in the diagnosis of mediastinal tumors.nnnDESIGNnretrospective review of 70 patients with mediastinal lesions who underwent CT-guided PCNB between 1988 and 1996.nnnRESULTSnPCNB provided adequate material in 62/70 cases, giving a total sample rate of 88.6%. Of these 62 patients, 57 were diagnosed correctly by PCNB whereas 5/62 were misdiagnosed as nonspecific inflammation, providing an overall sensitivity of 91.9%. PCNB established a specific histologic diagnosis in 90.3% of the patients, mainly in cases of lymphoma, bronchogenic carcinoma, and thymoma. Pneumothorax was the most commonly encountered complication (11%). Hemoptysis (30-50 ml) occurred in only one (1.6%) of the patients.nnnCONCLUSIONnCT guided PCNB is an easy and safe procedure which can provide a precise diagnosis in the majority of mediastinal tumors and can obviate the need for exploratory thoracic surgery in cases which are medically treatable or non-resectable.

Evaluation of Workers Exposed to Dust Containing Hard Metals and Aluminum Oxide

BACKGROUNDnFourteen worker exposed to hard metals and aluminum oxide were evaluated.nnnMETHODSnSix heavily exposed workers underwent bronchoscopy and bronchoalveolar lavage, and five workers underwent transbronchial biopsy.nnnRESULTSnMicrochemical analysis of transbronchial biopsies showed a high lung burden of exogenous particles, especially metal related to their hard metals exposure. Lung tissue and cellular changes, which were associated with exposure to hard metal and aluminum oxide, corresponded well with the microanalytic test results.nnnCONCLUSIONSnThree workers had at biopsy diffuse interstitial inflammatory changes: two of them were asymptomatic with normal chest X-ray films, and one had clinically evident disease with severe giant cell inflammation. Two other workers showed focal inflammation. The worker showing clinical disease and one asymptomatic worker with interstitial inflammatory changes had evaluated bronchoalveolar lavage fluid-eosinophilia counts. These two were father (with clinical disease) and son (asymptomatic).

Correlation between c-erbB-4 receptor expression and response to gemcitabine—cisplatin chemotherapy in non-small-cell lung cancer

BACKGROUNDnWhile the overexpression of c-erbB gene family in several malignancies is associated with poorer prognosis, the association between the expression of the cellular markers and the response to chemotherapy is not yet clear. In this study we investigated the expression of c-erbB-4 receptor in NSCLC and correlated it with the response to gemcitabine-cisplatin combination chemotherapy.nnnPATIENTS AND METHODSnForty-three NSCLC patients with histologically or cytologically proven disease were treated with gemcitabine-cisplatin combination chemotherapy. Immunohistochemical stains for c-erbB-4 receptor were performed in 20 cases on paraffin sections using the avidin-biotin-peroxidase method.nnnRESULTSnTwo patients achieved complete response (5%), and 16 achieved partial response (37%) yielding an overall objective response rate of 42%. Minimal response was observed in seven patients (16%) and disease stabilization in 7%. Immunohistochemical stain was positive for the presence of c-erbB-4 receptor in 25% of patients, and negative in 75%. No response was documented in c-erbB-4 positive patients (0 of 5) while an objective response (complete, partial or minimal) was seen in 11 of 15 (73%) c-erbB-4 negative patients. Negative stain for c-erbB-4 significantly favored response to gemcitabine-cisplatin combination (P < 0.01).nnnCONCLUSIONnC-erbB-4 expression status showed no correlation with survival and cannot be accepted at this time as a guiding factor for therapeutic management. These interesting results deserve further evaluation in a large-scale prospective trial before treatment recommendations on the basis of c-erbB-4 presence can be finally made.

Effect of Montelukast, a Cysteinyl Receptor Antagonist, on Myofibroblasts in Interstitial Lung Disease

Montelukast, a potent cysteinyl receptor antagonist, may be an antifibrotic therapeutic agent for lung fibrosis. Seven sarcoidosis patients and 10 with unusual interstitial pneumonia underwent conventional bronchoalveolar lavage, from which myofibroblasts were recovered. Myofibroblast proliferation was assayed, alpha smooth muscle actin levels were measured, TGFβ mRNA RT-PCR transcripts were semiquantitated, and secretion was evaluated in myofibroblast supernatants. Montelukast at 10−8 M concentration had a suppressive effect on cell proliferation (31 ± 18%), which was significantly enhanced by LTD4 10−8 M. No differences were found between sarcoidosis (31.28 ± 15.9%) and unusual interstitial pneumonia (30.56 ± 24.3%) lines. Fetal calf serum (20%) produced an enhancing effect (29.8 ± 21.6%) in all lines. Myofibroblasts recovered from sarcoidosis patients showed lower α-smooth muscle actin contents than unusual interstitial pneumonia lines (0.09 ± 0.02 vs. 0.34 ± 0.16, p=0.039, respectively). Montelukast suppressed α-actin in short-term cultures in sarcoidosis myofibroblasts and in long-term unusual interstitial pneumonia myofibroblasts. Montelukast at 10−6 M concentratin decreased the TGFβ-induced α-actin expression in all lines tested. Montelukast decreased mRNA expression of TGFβ. Montelukast may be a therapeutic agent in pathological conditions involving fibrotic and remodeling processes.

Pleuropulmonary metastasis from an intracranial glioblastoma

We present an unusual case of glioblastoma with intrathoracic and liver metastasis. The clinical diagnosis was confirmed by a percutaneous core needle biopsy from a metastatic lung lesion. The pathogenetic and diagnostic aspects of the case are discussed.

Computerized analysis of cytology and fluorescence in situ hybridization (FISH) in induced sputum for lung cancer detection

Lung cancer results from a multistep process, whereby genetic and epigenetic alterations lead to a malignant phenotype. Somatic mutations, deletions, and amplifications can be detected in the tumor itself, but they can also be found in histologically normal bronchial epithelium as a result of field cancerization. The present feasibility study describes a computer‐assisted analysis of induced sputum employing morphology and fluorescence in situ hybridization (target–FISH), using 2 biomarkers located at chromosomes 3p22.1 and 10q22.3.

Cell-free supernatants of sarcoid alveolar macrophages suppress proliferation of sarcoid alveolar fibroblasts

We have reported that alveolar macrophages (AM) isolated from sarcoidosis (SA) patients, as well as cell-free supernatants of these macrophages, markedly suppressed mitogenic stimulation of peripheral blood lymphocyte (PBL). We now show that cell-free supernatants of AM originating from sarcoidosis patients also suppress [3H]thymidine incorporation by fibroblast (Fb) cultures resulting from bronchoalveolar lavages (BAL) of SA: 40.6% inhibition compared with only 8.2% by supernatants of AM obtained from nonsarcoid controls. The clones of proliferating Fb appeared in cultures of BAL cells after most of the macrophages were detached from the tissue culture surface and actively synthesized collagen, as demonstrated by ultrastructural studies. In confirmation with previously reported results, the same supernatants from AM of SA patients also suppressed mitogenic stimulation of PBL (35.7% inhibition of [3H]thymidine incorporation compared with only 16.3% inhibition by control supernatants). They also contained high amounts of IL-1 (178 compared to 9.2 U/ml of control supernatants), whereas the PGE2 content was within normal levels (0.28 compared to 0.19 ng/ml/10(5) cells in control supernatants). It is concluded that AM from SA patients release a factor(s) which suppresses the proliferation of alveolar fibroblasts.