Context: Genetic aberration in phosphatidylinositol 3-kinase (PI3K)/AKT pathway has been detected in numerous and diverse human cancers. PIK3CA, which encodes for the catalytic subunit of p110␣ of PI3K, is amplified in some cases of papillary thyroid cancer (PTC). Mutations in the PIK3CA have also been identified in thyroid cancers and, although relatively common in anaplastic thyroid carcinoma, are uncommon in PTC.Objective: The objective of the study was to investigate genetic alterations like PIK3CA gene mutation, PIK3CA amplification, RAS, and RAF mutations and to further explore the relationship of these genetic alterations with various clinicopathological characteristics in Middle Eastern PTC. Design:We used the fluorescence in situ hybridization technique for analysis of PIK3CA amplification from 536 PTC cases, and selected amplified samples were further validated by real-time quantitative PCR. Mutation analysis was done by direct DNA sequencing of PIK3CA, N2-RAS, and BRAF genes.Results: PIK3CA amplification was seen in 265 of 499 PTC cases analyzed (53.1%); PIK3CA gene mutations in four of 207 PTC (1.9%); N2-RAS mutations in 16 of 265 PTC (6%); and BRAF mutations in 153 of 296 PTC (51.7%). N-RAS mutations were-associated with an early stage (P ϭ 0.0465) and lower incidence of extrathyroidal extension (P ϭ 0.027), whereas BRAF mutations were-associated with metastasis (P ϭ 0.0274) and poor disease-free survival (P ϭ 0.0121) in PTCs. P apillary thyroid carcinoma (PTC) is the most common malignant thyroid tumor, representing 80 -90% of all thyroid malignancies. PTC is usually well differentiated; however, the clinical behavior of PTC varies widely. For example, incidental microcarcinomas grow very slowly and are noninvasive or minimally invasive. On the other hand, invasive PTC with metastasis can be lethal. PTC often recurs many years after surgical removal. The prognosis for PTC is often favorable; however, approximately 20% of PTC tumors recur, and some reach advanced stages (1). Several clinicopathological variables including stage, cancer invasion, and distant metastasis are used for prognostication and treatment selection for PTC (2, 3). A better understanding of the factors and mechanisms determining the aggressive behavior of some papillary carcinomas is critical in developing new treatment. Conclusion

The putative role of leptin and its receptor (Ob-R) in the pathogenesis of various primary human malignancies has been reported; however, their role in papillary thyroid cancer (PTC) has not yet been evaluated. We investigated the role of Ob-R in a large tissue microarray cohort of PTC followed by in vitro studies using a panel of PTC cell lines. Ob-R overexpression was seen in 80% PTCs and was significantly associated with poor disease-free survival (PZ0.0235). PTCs that overexpressed Ob-R showed a aggressive phenotype characterized by older age, extrathyroid extension, larger tumor size, nodal metastasis, advanced stage, tall cell variant histological subtype, and a poor disease-free survival (PZ0.0005, PZ0.0006, PZ0.0398, PZ0.0004, PZ0.0111, PZ0.0003, and PZ0.0235 respectively). However, Ob-R expression was not an independent prognostic marker to predict disease-free survival in multivariate analysis. PTCs with overexpression of Ob-R showed a significant direct association with overexpression of XIAP (P!0.0001) and Bcl-XL (P!0.0001). In vitro analysis showed that leptin stimulated cell proliferation and inhibited apoptosis via activation of phosphatidylinisitol 3 0 kinase (PI3K)/protein kinase B (AKT) signaling pathway. Inhibition of PI3K activity by its inhibitor LY294002 abrogated leptin-mediated PI3K/AKT signaling. Gene silencing of Ob-R in PTC cells resulted in downregulation of phospho-AKT, Bcl-XL, and XIAP expression suggesting that leptin-mediated pathogenesis of PTC occurs via involvement of these downstream targets. Altogether, these data show that leptin plays an important role in PTC pathogenesis through PI3K/AKT pathway via Ob-R and is a potential prognostic marker associated with an aggressive phenotype and poor diseasefree survival.

Altogether, this is the first study showing that FoxM1 and its associated signaling pathway play a critical role in the pathogenesis of PTC and may be a potential target for therapeutic intervention for treatment of these cancers.

Nephrotoxicity can complicate HIPEC with cisplatin therapy and that permanent renal dysfunction may rarely occur. More attention to be directed toward monitoring magnesium levels after cisplatin use with HIPEC.

Both glargine insulin and RI-in-PN are effective basal insulin modalities for blood glucose control in noncritically ill surgical patients with diabetes who are receiving PN. Uncontrolled hyperglycemic events occurred more frequently with glargine insulin, and the rate of hypoglycemia was acceptable for both regimens.