Abstract We reviewed case reports of idiopathic CD4 lymphocytopenia (ICL) associated with opportunistic infections and added 2 cases seen and treated by one of us (R.E.N). Cryptococcal infections were most common, occurring in 61% of the reported cases. Pneumocystis carinii pneumonia (PCP) and other opportunistic infections occurred much less frequently. The lower incidence of PCP in ICL patients, relative to the incidence of cryptococcal infections in this patient population, stands in sharp contrast to the relative frequencies of these infections in persons infected with HIV, in whom PCP is the most common presenting opportunistic infection. This unexpected discrepancy may be explainable by person-to-person spread of pneumocystis among individuals with HIV infection who may congregate socially or in medical settings and the relative absence of a "clustering effect" in persons with ICL. Further study of the prevalence of ICL in apparently healthy adults, its natural history, and the optimal management of opportunistic infections, particularly cryptococcosis, in this population is needed.

1875 c-MET is believed to be an attractive target for molecular therapeutic inhibition in cancers associated with overexpression or activating mutations of c-MET. Since non-small cell lung cancer (NSCLC) is a difficult disease to treat, we have examined the expression of c-MET in 15 NSCLC cell lines using standard immunoblotting with anti-human c-MET antibody. There was overexpression of c-MET in most of the cell lines, including A549, H1838, H2170, SW-900, H358, H1993, Calu-3, Calu-1 and H596; while SK-NES-1, SW-1573, SK-LU-1, and Calu-6 had a lower c-MET expression. H661 did not express c-MET, and H520 expressed c-MET only minimally. Utilizing standard immunoperoxidase staining technique with anti-c-MET antibody and also phosphospecific c-MET antibodies (pY1230/1234/1235 auto-phosphorylation sites; and pY1003 juxtamembrane c-Cbl binding site), we show that expression of both total c-MET and also phosphorylated activated-MET are present in various subtypes of NSCLC tumor tissues. Specifically, strong activated-MET immunoperoxidase staining was seen in the invasion fronts of the tumor tissues. Also, up to 80% or more of the various NSCLC tumor tissue subtypes, including adenocarcinoma, squamous cell, large cell, examined expressed pY1003-Met and pY1230/1234/1235-Met. Since we have recently identified novel somatic missense mutations and alternatively spliced transcripts of c-MET in SCLC, we have begun to screen for mutations of c-MET in NSCLC cell lines (n=8) and also adenocarcinoma tumor tissues (n=127). Most interestingly, preliminary analysis of the sequencing results show clustering of mutations within the Sema (semaphorin) and JM (juxtamembrane) domains; however no mutations of the tyrosine kinase domain have been identified. We have now identified two novel sema domain missense mutations, S323G and N375S, in 3 different tumor tissue samples. In addition, we found several interesting JM mutations in the various cDNA samples. These include the R988C JM mutation, simultaneous JM mutations of R988C and T1010I, and also an alternative splice form with 47 amino acid deletion of the entire exon 14 (JM domain) of c-MET. Utilizing the adenocarcinoma A549 cell line that overexpresses c-MET to study signal transduction, we further show that HGF/c-MET pathway is functional and responsive to HGF (40 ng/ml) stimulation in a time-dependent fashion, with significant HGF-induced phosphorylation of c-MET, AKT, and p70-S6K. Also, there was HGF-induced tyrosine phosphorylation of the pY1230/1234/1235 sites demonstrated with the immunofluorescent staining using the phosphospecific antibodies. c-MET appears to be an important therapeutic target in NSCLC, and inhibitory strategies developed to target the receptor tyrosine kinase would be important to improve the therapeutic outcome.

Lung cancer is a deadly disease with high mortality and morbidity. Most cases of lung cancer are due to non-small cell carcinoma, with 16% of cases being small cell carcinoma. The biology at a cellular level is of interest at many levels. Knowing cellular pathways helps to further enhance our knowledge of how lung cancer cells survive, proliferate, and metastasize. The receptor tyrosine kinases (RTKs) located at the cellular membrane are becoming of great interest as sites for targeted therapies for lung cancers. This review will discuss the RTKs that are involved in lung cancers and the newer therapies that are being tested. We will specifically discuss receptors such as epidermal growth factor receptor, c-Kit receptor, VEGF receptor, c-Met receptor, insulin growth factor receptor, and Eph receptor. The inhibitors against the specific RTKs are in various preclinical and clinical trials, and this will be detailed.

Small cell lung cancer (SCLC) is an aggressive tumor which metastasizes early. Patients with this disease have a poor prognosis even with immediate treatment. Because of the aggressive nature of this disease, all aspects of this tumor are studied extensively. This review will provide an update of the biology of SCLC at both the molecular and cellular levels. Cellular pathways and their relationship to cellular function will also be discussed. Treatment of both primary limited- and extensive-stage diseases as well as recurrent disease will be discussed including chemotherapy, thoracic radiotherapy, and surgery. The role of novel therapeutics being investigated will also be addressed.