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Introduction: The presence of the transforming fusion gene echinoderm microtubule-associated protein–like 4 (EML4)–anaplastic lymphoma kinase (ALK) in non–small-cell lung cancer (NSCLC) is a predictive marker for the efficacy of anaplastic lymphoma kinase inhibitors. However, the currently available assays for the detection of the different variants of EML4-ALK have limitations. Methods: We developed an assay system for the detection of EML4-ALK variants 1, 2, 3a, 3b, 4, 5a, 5b, 6, or 7 transcripts in total RNA obtained from formalin-fixed, paraffin-embedded (FFPE) specimens of NSCLC tissue. The assay is based on region-specific polymerase chain reaction amplification of EML4-ALK complementary DNA followed by specific single-base primer extension and analysis of the extension products by matrix-assisted laser desorption/ionization–time of flight mass spectrometry. The assay was validated by fluorescence in situ hybridization and the results confirmed by subcloning and sequencing of polymerase chain reaction products. Results: Evaluation of the analytic sensitivity of the assay with serial dilutions of plasmids containing EML4-ALK complementary DNA sequences revealed it to be capable of the reliable detection of one copy of each plasmid per reaction. The assay also detected EML4-ALK variants 1 or 3 in three FFPE samples of surgically resected NSCLC shown to be positive for anaplastic lymphoma kinase rearrangement by fluorescence in situ hybridization. Furthermore, the assay identified variant 1 of EML4-ALK in 3 of 20 FFPE biopsy samples from patients with advanced NSCLC. All positive samples were confirmed by subcloning and sequencing. Conclusions: Our novel assay is highly sensitive and effective for the detection of EML4-ALK in FFPE specimens.

Cancer chemotherapy is not well established for patients on hemodialysis (HD). A 77-year-old man on HD presented with small cell lung cancer. He was treated with the combination of carboplatin and etoposide while the pharmacokinetics of the drugs were monitored. The patient showed a response with manageable toxicity and remained progression free for at least 8 months. The area under the concentration-time curve for each antitumor agent in the patient was within the therapeutic range achieved in individuals with normal renal function. Carboplatin and etoposide chemotherapy combined with HD thus allowed the drugs to achieve an appropriate area under the concentration-time curve and sufficient efficacy in a small cell lung cancer patient with chronic renal failure.

Introduction Tyrosine kinase inhibitors (TKIs) targeted to MET are undergoing clinical trials in patients with solid tumors, but the precise mechanism of the antitumor activity of these drugs remains unclear. We examined the antitumor action of the MET-TKI crizotinib (PF-02341066) in lung cancer cells that are positive or negative for MET amplification or mutation. Methods The antitumor action of crizotinib was evaluated on the basis of signal transduction, cell proliferation, apoptosis, and progression of tumor xenografts. Results Inhibition of MET signaling by crizotinib or by RNA interference-mediated MET depletion resulted in the induction of apoptosis accompanied by inhibition of AKT and extracellular signal-regulated kinase phosphorylation in lung cancer cells with MET amplification but not in cells with a MET mutation or in those without amplification or mutation of MET. These results suggest that MET signaling is essential for the survival of cells with MET amplification but not for that of cells without this genetic change, including those with a MET mutation. Crizotinib up-regulated the expression of BIM, a proapoptotic member of the Bcl-2 family, and down-regulated that of survivin, a member of the inhibitor of apoptosis protein family, in cells with MET amplification. Forced depletion of BIM and expression of survivin each inhibited crizotinib-induced apoptosis, suggesting that both up-regulation of BIM and down-regulation of survivin contribute to the proapoptotic effect of crizotinib. Conclusions Crizotinib shows a marked antitumor action in MET amplification-positive lung cancer cells but not in cells without MET amplification, including those with a MET mutation.

Large cell neuroendocrine carcinoma (LCNEC) is a relatively new category of pulmonary neuroendocrine tumor. Although it was first detected in the lung, LCNEC has since been found in a variety of extrapulmonary sites. We now describe a patient who was diagnosed with LCNEC originating from the mediastinum, an extremely rare disorder. An increased serum concentration of alpha-fetoprotein (AFP) in the patient was reduced by chemotherapy in association with tumor shrinkage. Furthermore, the tumor was confirmed immunohistochemically to produce AFP. To our knowledge, this is the first report of a LCNEC that produces AFP.