Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have poor efficacy in head and neck squamous cell carcinoma (HNSCC). Because the insulin-like growth factor-1 receptor (IGF1R) generates potent prosurvival signals and has been implicated in therapeutic resistance, its ability to induce resistance to EGFR-TKIs was studied in vitro. Five HNSCC cell lines demonstrated reduced sensitivity to the EGFR-TKI gefitinib when the IGF1R was activated. In SCC-25 and Cal27 cells, gefitinib inhibited basal and EGF-stimulated EGFR, Erk and Akt phosphorylation and reduced cell number. This correlated with initiation of apoptosis based on a 4-fold increase poly-(ADP-ribose) polymerase (PARP) cleavage and a 2.5-fold increase in Annexin V positivity. The apoptotic response and reduction in cell number were blocked by IGF1R activation, which resulted in phosphorylation of both Erk and Akt. In both cell lines, IGF1R-induced Erk but not Akt activation was eliminated by gefitinib. IGF1R-induced gefitinib resistance was unaffected by MEK inhibition with U0126, but was partially impaired by inhibition of phosphatidylinositol 3′-kinase (PI3K) with LY294002. The IGF1R-TKI PQ401 inhibited growth of SCC-25 and Cal27 cells alone and also acted synergistically with gefitinib. Thus the IGF1R can make HNSCC cells resistant to EGFR-TKI treatment via a prosurvival mechanism. Of 8 studied, all HNSCC tumor samples expressed the IGF1R and 5 demonstrated detectable IGF1R phosphorylation, suggesting that this receptor may be relevant in vivo, and thus combined EGFR/IGF1R inhibition may be necessary in some patients for effective targeted molecular therapy.
This case report describes a novel presentation of littoral cell angioma (LCA) and lymphatic malformations involving the omentum and mesentery. To our knowledge, these 2 entities have not been reported in the same patient. A 1-month term infant male presented with chylous ascites. During his workup, imaging detected splenic nodules. Biopsies revealed that the nodules were LCA and the chylous ascites was secondary to microscopic mesenteric and omental lymphatic malformations. Evaluation for a secondary malignancy, an underlying immunologic defect, and genetic causes were unrevealing. The presence of LCA and lymphatic malformations in the same patient suggests a genetic link between these 2 rare vascular disorders and may help elucidate the etiopathogenesis of these 2 poorly understood anomalies.
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