A case of granulocyte colony-stimulating factor and interleukin 6 receptor-producing mediastinal mature cystic teratoma with somatic-type malignancy.

Mediastinal germ cell tumor with somatic-type malignancy is a rare neoplasm. We describe one such case in a 49-year-old Japanese man who had shown an elevated serum concentration of granulocyte colony-stimulating factor (GCSF) and leukocytosis without a shift to the left. Histologically, the tumor formed a teratomatous cyst whose wall contained benign epithelial components, well-differentiated tubular and mucinous adenocarcinoma, and poorly-differentiated pleomorphic carcinoma. Immunohistochemically, both the well differentiated adenocarcinoma and poorly differentiated pleomorphic carcinoma expressed GCSF. Immunohistochemistry and molecular analysis revealed that both components also produced interleukin 6 receptor (IL6R). We diagnosed this tumor as a GCSF- and IL6R-producing mediastinal mature cystic teratoma with somatic-type malignancy. The tumor showed immunohistochemical expression of activated signal transducer and activator of transcription 3. The patient died 6 months after developing systemic symptoms. For a GCSF-producing tumor, complete resection appears to offer the best outcome at present. For any patient presenting with leukocytosis without a shift to the left, a thorough analysis should be conducted, and the tumor diagnosed as early as possible.

Combination effect between bortezomib and tumor necrosis factor alpha on gefitinib-resistant non-small cell lung cancer cell lines.

Tumor cells that have acquired resistance to gefitinib may complicate the future treatment of patients with non-small cell lung cancer (NSCLC). To investigate the mechanisms of acquired resistance, an acquired gefitinib-resistant cell line, PC-9/ZD2001, has been established using a gefitinib-sensitive NSCLC cell line, PC-9. PC-9/ZD2001 showed collateral sensitivity to tumor necrosis factor (TNF)-alpha. Bortezomib is a proteasome inhibitor and enhances TNF-alpha-induced cell death. These observations suggest that the combination of bortezomib and TNF-alpha might have effects against gefitinib-resistant cells. To verify this hypothesis, a combination effect between these drugs was examined using MTT assay and immunoblotting. This combination showed synergistic cytotoxic effect in NSCLC cell lines with either acquired or intrinsic gefitinib resistance. However, this combination effect was not observed in gefitinib-sensitive cells. On the other hand, bortezomib inhibited TNF-alpha-induced IkappaB degradation in all cell lines. From these observations, it is concluded that the combination of bortezomib and TNF-alpha could be used to overcome gefitinib-resistance.

Combined small cell carcinoma with pulmonary blastoma and adenocarcinoma: case report and clonality analysis.

We describe a rare tumor occurring in the left pulmonary lobe of a 71-year-old Japanese man. The tumor, which was resected by left lower lobectomy, measured 65 x 50 x 50 mm. Histologic examination revealed papillary adenocarcinoma in small cell carcinoma, and chondrosarcoma. Also, the blastemal cells were located between the small cell carcinoma and the chondrosarcoma, and intermingled with both components. In blastemal cells, some glands resembled a well-differentiated fetal adenocarcinoma. The tumor was diagnosed as combined small cell carcinoma with pulmonary blastoma and papillary adenocarcinoma according to the 2004 WHO classification. Immunohistochemically, the small cell carcinoma expressed TTF-1, pancytokeratin, CD56, synaptophysin, and S100 protein, while blastemal cells expressed vimentin, desmin, smooth muscle actin, CD56, and S100 protein. To investigate whether the tumor was clonal or not, p53 gene mutation of each tumor component was analyzed by laser-captured microdissection, polymerase chain reaction-single-strand conformation polymorphism and direct sequencing. Despite the histologic complexity, all components showed the same mutation at exon5 of the p53 gene. These results indicate that the tumor was clonal and arose from a relatively primitive cell, and that p53 mutation occurred before histologic metamorphosis or differentiation.

Enhancement of sensitivity to tumor necrosis factor alpha in non-small cell lung cancer cells with acquired resistance to gefitinib.

Tumor cells that have acquired resistance to gefitinib through continuous drug administration may complicate future treatment. To investigate the mechanisms of acquired resistance, we established PC-9/ZD2001, a non-small-cell lung cancer cell line resistant to gefitinib, by continuous exposure of the parental cell line PC-9 to gefitinib. After 6 months of culture in gefitinib-free conditions, PC-9/ZD2001 cells reacquired sensitivity to gefitinib and were established as a revertant cell line, PC-9/ZD2001R. PC-9/ZD2001 cells showed collateral sensitivity to several anticancer drugs (vinorelbine, paclitaxel, camptothecin, and 5-fluorouracil) and to tumor necrosis factor alpha (TNF-alpha). Compared with PC-9 cells, PC-9/ZD2001 cells were 67-fold more sensitive to TNF-alpha and PC-9/ZD2001R cells were 1.3-fold more sensitive. Therefore, collateral sensitivity to TNF-alpha was correlated with gefitinib resistance. PC-9/ZD2001 cells expressed a lower level of epidermal growth factor receptor (EGFR) than did PC-9 cells; this down-regulation was partially reversed in PC-9/ZD2001R cells. TNF-alpha-induced autophosphorylation of EGFR (cross-talk signaling) was detected in all three cell lines. However, TNF-alpha-induced Akt phosphorylation and IkappaB degradation were observed much less often in PC-9/ZD2001 cells than in PC-9 cells or PC-9/ZD2001R cells. Expression of the inhibitor of apoptosis proteins c-IAP1 and c-IAP2 was induced by TNF-alpha in PC-9 and PC-9/ZD2001R cells but not in PC-9/ZD2001 cells. This weak effect of EGFR on Akt pathway might contribute to the TNF-alpha sensitivity of PC-9/ZD2001 cells. These results suggest that therapy with TNF-alpha would be effective in some cases of non-small-cell lung cancer that have acquired resistance to gefitinib.

Both BRAF and KRAS mutations are rare in colorectal carcinomas from patients with hereditary nonpolyposis colorectal cancer.

The BRAF mutations have been suggested to be linked with defective mismatch repair in colorectal carcinomas. To clarify the extent of BRAF mutations in HNPCC colorectal carcinomas, which are typical mismatch repair deficient carcinomas, we compared the frequency of BRAF mutations between HNPCC, familial adenomatous polyposis (FAP) and sporadic cases. The frequency of KRAS mutations was also compared between these three syndromes. No BRAF mutations were detected in 33 HNPCC colorectal carcinomas, while they were detected in 3 of 26 (12%) FAP carcinomas and 2 of 53 (4%) microsatellite stable sporadic carcinomas. KRAS mutations were detected in 2 of 33 (6%) HNPCC, 9 of 26 (35%) FAP and 18 of 53 (34%) sporadic carcinomas. Such extremely low frequencies of BRAF and KRAS mutations in HNPCC colorectal carcinomas suggest that the participation of RAS-RAF signaling is minor in HNPCC, and that the previously suggested high frequency of BRAF mutations in mismatch repair deficient colorectal carcinomas is not due to mutations of mismatch repair genes.