EGFR mutations are the strongest predictive biomarker for PFS and tumor response to first-line gefitinib versus carboplatin/paclitaxel. The predictive value of EGFR gene copy number was driven by coexisting EGFR mutation (post hoc analysis). Treatment-related differences observed for PFS in the EGFR mutation-positive subgroup were not apparent for OS. OS results were likely confounded by the high proportion of patients crossing over to the alternative treatment.

This report confirms the findings of the Intergroup 00-99 Trial and demonstrates its applicability to endemic NPC. This study also confirms that chemotherapy improves the distant metastasis control rate in NPC.

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Aneuploidy is a key process in tumorigenesis. Dysfunction of the mitotic spindle checkpoint proteins has been implicated as a cause of aneuploidy in cells. We have previously reported that FAT10, a member of the ubiquitin-like modifier family of proteins, is overexpressed in several gastrointestinal and gynecological cancers. Here we show that FAT10 interacts with MAD2, a spindle checkpoint protein, during mitosis. Notably, we show that localization of MAD2 at the kinetochore during the prometaphase stage of the cell cycle was greatly reduced in FAT10-overexpressing cells. Furthermore, compared with parental HCT116 cells, fewer mitotic cells were observed after double thymidine-synchronized FAT10-overexpressing cells were released into nocodazole for more than 4 h. Nonetheless, when these double thymidine-treated cells were released into media, a similar number of G 1 parental and FAT10-overexpressing HCT116 cells was observed throughout the 10-h time course. Additionally, more nocodazole-treated FAT10-overexpressing cells escape mitotic controls and are multinucleate compared with parental cells. Significantly, we observed a higher degree of variability in chromosome number in cells overexpressing FAT10. Hence, our data suggest that high levels of FAT10 protein in cells lead to increased mitotic nondisjunction and chromosome instability, and this effect is mediated by an abbreviated mitotic phase and the reduction in the kinetochore localization of MAD2 during the prometaphase stage of the cell cycle. Genetic instability is an important phenomenon that underlies tumorigenesis. Chromosome instability (CIN)2 involving gains and loss of chromosomes has been found to occur in most malignancies, whereas microsatellite instability, which occurs at the nucleotide level, is less commonly observed in cancers (1). Two forms of CIN, namely structural instability and numerical instability (aneuploidy), can be observed in various tumors. Genes responsible for CIN in human cancers include those involved in the condensation of chromosomes, cohesion of sister chromatids, formation of microtubules, and kinetochore structure and function as well as mitotic "checkpoint" genes that monitor the proper progression through the cell cycle (1, 2).MAD2 (mitotic arrest-deficient 2) is a key mitotic spindle checkpoint protein whose primary role is to ensure that all of the chromosomes are properly attached to the mitotic spindle before the onset of anaphase (3). It is activated by associating with unattached kinetochores. Activated MAD2 binds to Cdc20 and prevents the anaphase-promoting complex from ubiquitylating securin. As a result, anaphase is delayed until all of the kinetochores are attached by microtubules and the chromosomes are properly aligned along the metaphase plate (4 -6). MAD2 is an essential gene, and MAD2 Ϫ/Ϫ mice die in utero (7). Loss of one allele of MAD2 has been reported to result in premature anaphase and CIN in mammalian cells (8). Dysregulation of MAD2 has been implicated in various cancers. Reduced expression of ...

3-AP did not enhance clinical response to gemcitabine in this cohort of patients with prior exposure to gemcitabine for advanced NSCLC. Further development of 3-AP in lung cancer is challenged by its potential of causing methemoglobinemia and hypoxia, which could be problematic in patients with compromised pulmonary reserves.

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Gemcitabine has moderate activity in NPC with minimal toxicity, and is also an effective salvage agent for patients who have failed or progressed after treatment with other agents.