Phase 2 trial of oxaliplatin and pemetrexed as an induction regimen in locally advanced head and neck cancer.

BACKGROUND: This phase 2 trial evaluated the tolerability and clinical efficacy of the combination of oxaliplatin and pemetrexed as an induction chemotherapy regimen in locally advanced head and neck squamous cell carcinoma (HNSCC). METHODS: Forty-two patients were enrolled in the study. Patients received pemetrexed 300 mg/m(2) intravenously (IV) and oxaliplatin 85 mg/m(2) IV every 14 days for a total of 4 cycles. A subset of patients consented to correlative studies including tumor tissue for human papillomavirus (HPV) detection and expression of DNA repair genes that may be predictive of response or resistance to oxaliplatin or pemetrexed. RESULTS: Response data were available for 40 patients. Eighteen had a partial response, and 1 had a complete response, for a response rate of 47.5%. Patients with HPV(+) disease demonstrated superior response rates, progression-free survival, and overall survival. The regimen was well tolerated, with predominantly grade 1 or 2 alanine aminotransferase/aspartate aminotransferase elevation. One patient had grade 5 toxicity with neutropenia and sepsis. The authors did not identify genes predictive of response or toxicity, although HPV(+) tumors demonstrated a unique gene expression signature. CONCLUSIONS: Although the response rate of oxaliplatin and pemetrexed proved less than anticipated, the combination remains an active induction regimen in HNSCC. This regimen should be evaluated further in combination with targeted agents, such as cetuximab, especially in the HPV(+) patient population.

Regulation of low-threshold afferent activity may contribute to short-term habituation in Aplysia californica.

The goal of this study was to characterize the contribution of a population of low-threshold mechanoreceptors to short-term habituation of siphon-elicited reflex responses in Aplysia californica. Since the location of their somata is unknown, we refer to them as the Unidentified Low-Threshold mechanoreceptors (ULTs). The ULTs operate in parallel to the higher-threshold and well-characterized LE sensory neurons, yet little is known regarding their contribution to behavioral plasticity. Using extracellular recordings from the siphon nerve, we found that habituation training that favors ULT activation resulted in a significant decrease in afferent activity at training intervals up to 1 min per stimulus (1 min ISI). To determine how this reduction impacts responses at other sites of the reflex network, we used intracellular recordings to measure training-induced changes in either L29 excitatory interneurons or LFS siphon motor neurons. With a 30s ISI, changes at both locations were training site-specific and matched the rate of change of afferent activity, implicating regulated sensory activity as a primary mechanism. With a shorter training interval (1s ISI), site-specificity of training was not observed in the L29s, but was still preserved in the motor neurons. For both, the rate of change during training was faster than the rate of change of afferent activity. Taken together, we conclude that regulation of low-threshold sensory neuron activity can play a significant role in short-term habituation, but other network processes may be recruited at more rapid training intervals.

Regulation of heparin-binding EGF-like growth factor by miR-212 and acquired cetuximab-resistance in head and neck squamous cell carcinoma.

BACKGROUND: We hypothesized that chronic inhibition of epidermal growth factor receptor (EGFR) by cetuximab, a monoclonal anti-EGFR antibody, induces up-regulation of its ligands resulting in resistance and that microRNAs (miRs) play an important role in the ligand regulation in head and neck squamous cell carcinoma (HNSCC). METHODOLOGY/PRINCIPAL FINDINGS: Genome-wide changes in gene and miR expression were determined in cetuximab-sensitive cell line, SCC1, and its resistant derivative 1Cc8 using DNA microarrays and RT-PCR. The effects of differentially expressed EGFR ligands and miRs were examined by MTS, colony formation, ELISA, and western blot assays. Heparin-binding EGF-like growth factor (HB-EGF) and its regulator, miR-212, were differentially expressed with statistical significance when SCC1 and 1Cc8 were compared for gene and miR expression. Stimulation with HB-EGF induced cetuximab resistance in sensitive cell lines. Inhibition of HB-EGF and the addition of miR-212 mimic induced cetuximab sensitivity in resistant cell lines. MicroRNA-212 and HB-EGF expression were inversely correlated in an additional 33 HNSCC and keratinocyte cell lines. Six tumors and 46 plasma samples from HNSCC patients were examined for HB-EGF levels. HB-EGF plasma levels were lower in newly diagnosed HNSCC patients when compared to patients with recurrent disease. CONCLUSIONS/SIGNIFICANCE: Increased expression of HB-EGF due to down-regulation of miR-212 is a possible mechanism of cetuximab resistance. The combination of EGFR ligand inhibitors or miR modulators with cetuximab may improve the clinical outcome of cetuximab therapy in HNSCC.