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Both type 1 and type 2 diabetes are associated with increased risk for cardiovascular disease (CVD) events. This risk seems to be reduced by achievement of euglycemia. However, after the withdrawal of rosiglitazone from the market, the question arose as to whether this risk concerns simply a matter of euglycemia or the distinct role played by each antidiabetic drug with respect to its effect on CVD risk. To address this issue, many studies have been published during the last decade involving old and new antidiabetic agents, which however yielded contradictory results. Briefly, metformin is still considered safe and confers a beneficial effect on CVD risk. Conflicting data exist as concerns sulfonylureas, although the second and third generation representatives are regarded as relatively safe. Pioglitazone use seems to be associated with a reduction in CVD risk, whereas the dipeptidyl-dipeptidase-4 inhibitors (DPP-4i), lixisenatide and exenatide-LAR [from the category of glucagon-like-peptide-1 receptor (GLP-1R) agonists], confer a neutral effect. Two other GLP-1R agonists, liraglutide and semaglutide, as well as the sodium-glucose transporter-2 (SGLT2)-inhibitors, empagliflozin and cangliflozin, have shown an additional effect on CVD risk reduction, although their safety is in doubt. Insulin analogues and newer long-acting compounds are also safe for the cadiovascular system. The aim of this narrative review is to present and critically analyse the current data for each antidiabetic drug category with regard to their effect on CVD risk.

Purpose: Cetuximab, an antibody directed against the EGF receptor, is an effective clinical therapy for patients with head and neck squamous cell cancer (HNSCC). Despite great clinical promise, intrinsic or acquired cetuximab resistance hinders successful treatment outcomes but little is known about the underlying mechanism. Experimental Design: To study the role of oncogenic HRAS in cetuximab resistance in HNSCC, the frequency of oncogenic HRAS mutations was determined in a cohort of 180 genomic DNAs from head and neck cancer specimens. We also used a combination of cetuximab-resistant cell lines and a transgenic mouse model of RAS-driven oral cancer to identify an oncogenic RAS-specific gene expression signature that promotes cetuximab resistance. Results: Here, we show that activation of RAS signaling leads to persistent extracellular signal–regulated kinase 1/2 signaling and consequently to cetuximab resistance. HRAS depletion in cells containing oncogenic HRAS or PIK3CA restored cetuximab sensitivity. In our study, the gene expression signature of c-MYC, BCL-2, BCL-XL, and cyclin D1 upon activation of MAPK signaling was not altered by cetuximab treatment, suggesting that this signature may have a pivotal role in cetuximab resistance of RAS-activated HNSCC. Finally, a subset of patients with head and neck cancer with oncogenic HRAS mutations was found to exhibit de novo resistance to cetuximab-based therapy. Conclusions: Collectively, these findings identify a distinct cetuximab resistance mechanism. Oncogenic HRAS in HNSCC promotes activation of ERK signaling, which in turn mediates cetuximab resistance through a specific gene expression signature. Clin Cancer Res; 20(11); 2933–46. ©2014 AACR.

Objectives The aim of this study was to investigate the clinical significance of cytology versus histology-based diagnosis among patients diagnosed with small cell lung cancer (SCLC). Materials and methods Retrospective analysis of medical records of 443 patients with histologically or cytologically confirmed small cell lung carcinoma (SCLC) was performed. All patients received platinum-based chemotherapy regimens. Survival data (overall survival) were compared between patients with histology or cytology-based diagnosis in the overall study population as well as after stratification of patients according to disease stage (limited or extensive) at the time of diagnosis. Results Distribution of demographics and clinicopathological characteristics among the two groups (“histology” and “cytology”) was similar. No statistically significant differences in the survival curves between the “histology” and “cytology” groups were found in the overall study population (log rank test, p = 0.237), as well as in the subgroup of patients with limited disease (log rank test, p = 0.474). In contrast, patients with histology-based diagnosis had a statistically significant longer survival as compared to those with cytology-based diagnosis in the extensive disease subgroup (log rank test, p = 0.031), but this association was not retained after adjusting the analysis for demographics and clinical characteristics via a Cox regression model (HR = 1.18, 95% CI: 0.96–1.44, p = 0.110). Conclusion The results of our study suggest that the type of diagnostic modality employed (histology or cytology-based) for the establishment of a diagnosis of SCLC may not have a significant effect on the overall survival of patients. Further studies are warranted to further investigate this important, yet rather unexplored, issue.

Purpose: Cetuximab, an antibody directed against the EGF receptor, is an effective clinical therapy for patients with head and neck squamous cell cancer (HNSCC). Despite great clinical promise, intrinsic or acquired cetuximab resistance hinders successful treatment outcomes but little is known about the underlying mechanism. Experimental Design: To study the role of oncogenic HRAS in cetuximab resistance in HNSCC, the frequency of oncogenic HRAS mutations was determined in a cohort of 180 genomic DNAs from head and neck cancer specimens. Wealso used a combination of cetuximab-resistant cell lines and a transgenic mouse model of RAS-driven oral cancer to identify an oncogenic RAS-specific gene expression signature that promotes cetuximab resistance. Results: Here, we show that activation of RAS signaling leads to persistent extracellular signal-regulated kinase 1/2 signaling and consequently to cetuximab resistance. HRAS depletion in cells containing oncogenic HRAS or PIK3CA restored cetuximab sensitivity. In our study, the gene expression signature of c-MYC, BCL-2, BCL-XL, and cyclin D1 upon activation of MAPK signaling was not altered by cetuximab treatment, suggesting that this signature may have a pivotal role in cetuximab resistance of RAS-activated HNSCC. Finally, a subset of patients with head and neck cancer with oncogenic HRAS mutations was found to exhibit de novo resistance to cetuximab-based therapy. Conclusions: Collectively, these findings identify a distinct cetuximab resistance mechanism. Oncogenic HRAS in HNSCC promotes activation of ERK signaling, which in turn mediates cetuximab resistance through a specific gene expression signature. ©2014 AACR.

Objectives: The aim of this study was to investigate the clinical significance of cytology versus histology-based diagnosis among patients diagnosed with small cell lung cancer (SCLC). Materials and methods: Retrospective analysis of medical records of 443 patients with histologically or cytologically confirmed small cell lung carcinoma (SCLC) was performed. All patients received platinum-based chemotherapy regimens. Survival data (overall survival) were compared between patients with histology or cytology-based diagnosis in the overall study population as well as after stratification of patients according to disease stage (limited or extensive) at the time of diagnosis. Results: Distribution of demographics and clinicopathological characteristics among the two groups (”histology” and “cytology”) was similar. No statistically significant differences in the survival curves between the “histology” and “cytology” groups were found in the overall study population (log rank test, p = 0.237), as well as in the subgroup of patients with limited disease (log rank test, p = 0.474). In contrast, patients with histology-based diagnosis had a statistically significant longer survival as compared to those with cytology-based diagnosis in the extensive disease subgroup (log rank test, p = 0.031), but this association was not retained after adjusting the analysis for demographics and clinical characteristics via a Cox regression model (HR = 1.18, 95% CI: 0.96-1.44, p = 0.110). Conclusion: The results of our study suggest that the type of diagnostic modality employed (histology or cytology-based) for the establishment of a diagnosis of SCLC may not have a significant effect on the overall survival of patients. Further studies are warranted to further investigate this important, yet rather unexplored, issue. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

Purpose: To report our experience with a sequential regimen of induction TPF-C followed by radioimmunotherapy with cetuximab in patients with locally advanced head and neck squamous cell carcinoma (HNSCC). Patients and Methods: Toxicity and outcome was retrospectively analyzed in 22 patients receiving sequential therapy with induction TPF-C followed by radioimmunotherapy between October 2008 and December 2011. Outcome was estimated using Kaplan-Meier analyses. In addition, we performed mutation analysis for PIK3CA genes and high-risk HPV-DNA detection using PCR. Results: Median follow-up was 16 months. Six patients were TNM Stage III, 15 patients IV (IVA or IVB) and 1 patient Stage II with bulky disease. During TPF-C, Grade 3 and 4 toxicities occurred in 8 patients (36.4%), dose modifications in 7 (31.8%), delays in 1 (4.5%), and unplanned admissions in 5 (22.7%). Clinical tumor response was documented in 18 of the 21 patients who completed at least 3 cycles of TPF-C (85.7%) with 3 patients developing complete response and 15 partial responses. Grade 3/4 mucositis was observed in 6 (31.6%) patients. At a median follow up of 19 months, 13 patients were alive and 9 (40.9%) had died including 7 patients as a result of disease persistence or recurrence and two as a result of unrelated causes. PIK3CA mutations were not identified and our 2 oropharynx cases were HPV negative. Conclusions: The combination of induction TPF-C with concurrent cetuximab radioimmunotherapy in patients with locally advanced HNSCC is tolerable, with encouraging efficacy. Keywords: HNSCC, TPF-C, cetuximab radiotherapy, toxicity and outcome, mutation analysis, PIK3CA, HPV-DNA.

6076 Background: Epithelial-mesenchymal transtition (EMT) of adherent epithelial cells to migratory mesenchymal state has been implicated in tumor metastasis in preclinical models. To investigate i...

5574 Background: Aberrant signaling through RAS/MAPK pathway is implicated in resistance to EGFR-targeted agents in cancer. Genetic alterations in Hras gene such as mutations and specific polymorphisms are associated with aggressive phenotype in several smoking-related malignancies. We sought to determine the impact of Hras genetic alterations on response to cetuximab and prognosis in HNSCC. Methods: Clinical outcome according to Hras status was investigated in a retrospective cohort of 140 HNSCC specimens. Primary endpoints were overall survival (OS) and disease-free survival (DFS) and secondary endpoint was treatment response. For statistical analysis, T-test was used for continuous data and x2 –test for categorical data. Cetuximab-resistant cell lines harboring mutant Hras (BB49, T24) were infected with lentivirus expressing shRNA targeting the Hras or a scrambled- shRNA. MTT assay was used to determine the effect of cetuximab on growth of lentivirus infected cells. Biochemical analysis involved immunoblotting for pERK1/2. Results: Mutationanalysis of tumor samples showed that 5.7% participants harbored Hras mutations and 16.42% harbored Hras polymorphisms (rs12628, rs41258054) that are associated with tumorigenesis. Patients bearing tumors with mutated Hras had inferior mean OS ( 22.13vs 35.20, p=0.02) and a non-significant trend for inferior mean DFS. Patients with tumors containing Hras genetic alterations (mutation or polymorphism) had significantly inferior mean OS (p=0.02) compared to those harboring wt Hras and trended towards inferior DFS (p=0.07). Patients had received various treatments such as surgery plus/minus RT and various chemotherapy regimens. A subgroup analysis of 38 patients treated with cetuximab-based regimens showed that wt Hras was associated with higher likelihood of attaining CR or PR to treatment of borderline significance (p=0.06) due to small sample size. Silencing of Hras in Hras-mutant cell lines restored sensitivity to cetuximab and caused a direct downregulation of pERK1/2 levels. Conclusions: Hras genetic alterations are associated with aggressive clinical course and may affect response to cetuximab in HNSCC.