Puttisak Puttawibul

Epidermal growth factor receptor and cyclin D1 are independently amplified and overexpressed in esophageal squamous cell carcinoma

PurposeTo assess the status of EGFR, HER-2, and CCND1 at the gene and protein levels in esophageal squamous cell carcinoma.MethodsDual-color FISH assays were performed using DNA probes for EGFR/CEP 7, HER-2/CEP 17, and CCND1/CEP 11. The respective proteins, furthermore, was assessed in IHC assays and correlated with patient and tumor characteristics.ResultsFrom 55 ESCCs, 8 (15%) tumors showed gene amplification and 20 (36%) had gene overrepresentation (balanced gene and chromosome 7 polysomy) for EGFR. High-level protein expression was frequent (49%), positively correlated with gene copy numbers (kappa=0.4), and associated with well-differentiated histology (p=0.02). For HER-2, gene amplification was detected in a single tumor (2%) and protein overexpression was rare (9%). CCND1 gene was amplified in 23 (42%) tumors; likewise, CCND1 protein overexpression was common (58%) and prevailed in gene overrepresentation or amplification. Only 1 patient showed gene amplification for both EGFR and CCND1. Survival was not associated with EGFR or CCND1 gene/protein status, whereas negative patients for HER-2 protein had a better survival than positive patients (p=0.04).ConclusionsFrequent overexpression and gene amplification of EGFR and CCND1 make these molecules and their pathways potential therapeutic targets for ESCC. In addition, EGFR and CCND1 appeared to be independently altered suggesting alternative mechanisms for pathway activation. Therapeutic agents targeting these molecules are urged to be tested in clinical trials and comprehensive biological analyses should be included to properly interpret the outcome.

Incidence and time course of everolimus-related adverse events in postmenopausal women with hormone receptor-positive advanced breast cancer: insights from BOLERO-2

BACKGROUND In the BOLERO-2 trial, everolimus (EVE), an inhibitor of mammalian target of rapamycin, demonstrated significant clinical benefit with an acceptable safety profile when administered with exemestane (EXE) in postmenopausal women with hormone receptor-positive (HR+) advanced breast cancer. We report on the incidence, time course, severity, and resolution of treatment-emergent adverse events (AEs) as well as incidence of dose modifications during the extended follow-up of this study. PATIENTS AND METHODS Patients were randomized (2:1) to receive EVE 10 mg/day or placebo (PBO), with open-label EXE 25 mg/day (n = 724). The primary end point was progression-free survival. Secondary end points included overall survival, objective response rate, and safety. Safety evaluations included recording of AEs, laboratory values, dose interruptions/adjustments, and study drug discontinuations. RESULTS The safety population comprised 720 patients (EVE + EXE, 482; PBO + EXE, 238). The median follow-up was 18 months. Class-effect toxicities, including stomatitis, pneumonitis, and hyperglycemia, were generally of mild or moderate severity and occurred relatively early after treatment initiation (except pneumonitis); incidence tapered off thereafter. EVE dose reduction and interruption (360 and 705 events, respectively) required for AE management were independent of patient age. The median duration of dose interruption was 7 days. Discontinuation of both study drugs because of AEs was higher with EVE + EXE (9%) versus PBO + EXE (3%). CONCLUSIONS Most EVE-associated AEs occur soon after initiation of therapy, are typically of mild or moderate severity, and are generally manageable with dose reduction and interruption. Discontinuation due to toxicity was uncommon. Understanding the time course of class-effect AEs will help inform preventive and monitoring strategies as well as patient education. TRIAL REGISTRATION NUMBER NCT00863655.The BOLERO-2 trial demonstrated that adding everolimus to exemestane substantially improved clinical benefit with acceptable safety in postmenopausal women with HR+ breast cancer relapsing/progressing on a nonsteroidal aromatase inhibitor. Incidences and severities of everolimus-related toxicity were consistent with other oncology settings, and were manageable using established strategies.

Lifestyle habits and genetic susceptibility and the risk of esophageal cancer in the Thai population

The association of lifestyle habits and polymorphism of ADH2 and ALDH2 genes with the risk of esophageal cancer in Thai population was investigated in a hospital-based case-control study: 202 cases and 261 controls. The results of multivariate logistic analysis showed that alcohol consumption >60g/day, smoking >10 cigarettes/day and chewing betel >or=10 quids/day significantly increased risk (odds ratio (OR) 5.84, 95% confidence interval (CI) 3.15-10.83; 4.65, 95% CI 1.99-10.84; and 4.68, 95% CI 2.05-10.72, respectively). ADH2*1/*1 also increased the risk significantly (OR 1.56, 95% CI 1.01-2.39) while ALDH2 did not (OR of ALDH2*1/*2 1.57, 95% CI 0.89-2.76). However, the combined at risk genotypes, ADH2*1/*1 and ALDH2*1/*2 increased risk to four-fold. In addition, significant gene-environment interaction was found. Heavy drinkers >60g/d harboring ADH2*1/*1 or ALDH2*1/*2 had about an 11-fold increased risk.

TP53 mutations and MDM2 gene amplification in squamous-cell carcinomas of the esophagus in South Thailand

Squamous‐cell carcinoma of the esophagus (SCCE) shows geographic variations in incidence that are thought to reflect the etiological involvement of environmental or dietary risk factors. Mutations of TP53 are frequent in SCCE, and there is evidence that both the frequency and type of these mutations may differ from one geographic area to the other. Although SCCE is relatively rare in most parts of Thailand, the province of Songkhla (south Thailand) has been described as a high‐risk area for SCCE. We have analyzed 56 SCCE cases from this area for TP53 mutations by denaturing gradient gel electrophoresis (DGGE, exons 5–8) and direct DNA sequencing. The same tumors were also analyzed for MDM2 gene amplification by differential PCR. TP53 mutations were detected in 23 cases (41%). In contrast, clear amplification of MDM2 was detected in only 2 cases (4%), both of which contained wild‐type TP53. Comparison with published results from other geographic areas of high SCCE incidence revealed that the spectrum of TP53 mutations in south Thailand is similar to that observed in central China (Henan Province) but clearly differs from that of SCCE from western Europe (Normandy, France; northern Italy), with more G:T transversions and fewer mutations affecting A and T base pairs. These results suggest that SCCE from south Thailand and from central China may involve similar risk factors. Int. J. Cancer 88:223–227, 2000.

Scaffold Library for Tissue Engineering: A Geometric Evaluation

Tissue engineering scaffold is a biological substitute that aims to restore, to maintain, or to improve tissue functions. Currently available manufacturing technology, that is, additive manufacturing is essentially applied to fabricate the scaffold according to the predefined computer aided design (CAD) model. To develop scaffold CAD libraries, the polyhedrons could be used in the scaffold libraries development. In this present study, one hundred and nineteen polyhedron models were evaluated according to the established criteria. The proposed criteria included considerations on geometry, manufacturing feasibility, and mechanical strength of these polyhedrons. CAD and finite element (FE) method were employed as tools in evaluation. The result of evaluation revealed that the close-cellular scaffold included truncated octahedron, rhombicuboctahedron, and rhombitruncated cuboctahedron. In addition, the suitable polyhedrons for using as open-cellular scaffold libraries included hexahedron, truncated octahedron, truncated hexahedron, cuboctahedron, rhombicuboctahedron, and rhombitruncated cuboctahedron. However, not all pore size to beam thickness ratios (PO : BT) were good for making the open-cellular scaffold. The PO : BT ratio of each library, generating the enclosed pore inside the scaffold, was excluded to avoid the impossibility of material removal after the fabrication. The close-cellular libraries presented the constant porosity which is irrespective to the different pore sizes. The relationship between PO : BT ratio and porosity of open-cellular scaffold libraries was displayed in the form of Logistic Power function. The possibility of merging two different types of libraries to produce the composite structure was geometrically evaluated in terms of the intersection index and was mechanically evaluated by means of FE analysis to observe the stress level. The couples of polyhedrons presenting low intersection index and high stress level were excluded. Good couples for producing the reinforced scaffold were hexahedron-truncated hexahedron and cuboctahedron-rhombitruncated cuboctahedron.

Results of gastric pull-up reconstruction for pharyngolaryngo-oesophagectomy in advanced head and neck cancer and cervical oesophageal squamous cell carcinoma.

OBJECTIVE To study long-term clinical swallowing function and survival outcome in head and neck and cervical oesophageal cancer patients who underwent pharyngolaryngo-oesophagectomy (PLE). METHODS The clinical data of 48 patients who were treated with PLE were analysed. All patients had advanced disease, so the construction required a transposed stomach. Body weight and clinical swallowing function were evaluated postoperatively. The swallowing function was assessed at an interview concerning food ingestion and regurgitation. The survival group was studied using a Kaplan-Meier survival curve. RESULTS Forty-one cases of hypopharyngeal cancer and four cases of cervical oesophageal cancer were studied. In three cases (6%), hypopharyngeal and thoracic oesophageal squamous cell carcinoma occurred together. Most cases had good-to-fair results. The average body weight gain was increased after surgery. There was one hospital death. The most common complications were pulmonary (4%). Median survival was 27 months. CONCLUSION A pharyngogastric anastomosis after PLE can be performed with low morbidity and good swallowing function.

Randomized study of antiinflammatory and immune-modulatory effects of enteral immunonutrition during concurrent chemoradiotherapy for esophageal cancer.

Concurrent chemoradiotherapy (CCRT) induces toxicities from inflammation and immunological suppression. Omega-3 fatty acids, glutamine, and arginine are therapeutic factors that can attenuate such inflammation and promote cellular immunity. The question is whether immunonutrition (IN) during CCRT reduces inflammation and improves the immune function in patients with esophageal squamous cell carcinoma (ESCC). Seventy-one locally advanced ESCC patients being treated with CCRT (5-FU and cisplatin) were randomized into 2 groups. The IN group received a combination of omega-3 fatty acids, glutamine, and arginine, whereas the control group received standard formula. The levels of C-reactive protein (CRP), tumor necrosis factor (TNF), interferon-gamma (IFN), interleukin (IL-6, IL-10), CD3, CD4, CD8, white blood cells, neutrophils, and total lymphocytes were measured before and during treatment. The levels of CRP (P = 0.001) and TNF (P = 0.014) increased more during treatment in the control group than the treatment group, whereas IFN, IL-6, and IL-10 were similar but not significantly. CD3, CD4, CD8, white blood cells, neutrophils, and total lymphocytes decreased more in the control group than in the treatment group, but not significantly. Enteral IN during CCRT reduced the increase of inflammatory cytokine levels.

Mimicked cartilage scaffolds of silk fibroin/hyaluronic acid with stem cells for osteoarthritis surgery: Morphological, mechanical, and physical clues

Osteoarthritis is a critical disease that comes from degeneration of cartilage tissue. In severe cases surgery is generally required. Tissue engineering using scaffolds with stem cell transplantation is an attractive approach and a challenge for orthopedic surgery. For sample preparation, silk fibroin (SF)/hyaluronic acid (HA) scaffolds in different ratios of SF/HA (w/w) (i.e., 100:0, 90:10, 80:20, and 70:30) were formed by freeze-drying. The morphological, mechanical, and physical clues were considered in this research. The morphological structure of the scaffolds was observed by scanning electron microscope. The mechanical and physical properties of the scaffolds were analyzed by compressive and swelling ratio testing, respectively. For the cell experiments, scaffolds were seeded and cultured with human umbilical cord-derived mesenchymal stem cells (HUMSCs). The cultured scaffolds were tested for cell viability, histochemistry, immunohistochemistry, and gene expression. The SF with HA scaffolds showed regular porous structures. Those scaffolds had a soft and elastic characteristic with a high swelling ratio and water uptake. The SF/HA scaffolds showed a spheroid structure of the cells in the porous structure particularly in the SF80 and SF70 scaffolds. Cells could express Col2a, Agg, and Sox9 which are markers for chondrogenesis. It could be deduced that SF/HA scaffolds showed significant clues for suitability in cartilage tissue engineering and in surgery for osteoarthritis.

Fabrication of three-dimensional honeycomb structure for aeronautical applications using selective laser melting: a preliminary investigation

Purpose – The purpose of this paper was to investigate the feasibility on design and production of a three-dimensional honeycomb based on selective laser melting (SLM) technique for use in aeronautical application. Design/methodology/approach – Various polyhedrons were investigated using their mechanical property, i.e. strain energy density (SED), by means of finite element (FE) analysis for the suitability of use in aerospace application; the highest SED polyhedron was selected as a candidate polyhedron. From the FE analysis, the truncated octahedron (three-dimensional honeycomb) structure was considered to be the potential candidate. Polyhedron size and beam thickness of the open-cellular three-dimensional honeycomb structure were modelled and analysed to observe how the geometric properties influence the stiffness of the structure. One selected model of open-cellular honeycomb (unit cell size: 2.5 mm and beam thickness: 0.15 mm) was fabricated using SLM. The SLM prototypes were assessed by their mechan...

Single Nucleotide Polymorphisms in the Gc Gene for Vitamin D Binding Protein in Common Cancers in Thailand

BACKGROUND This case-control study aimed to determine if there were any associations between the two single nucleotide polymorphisms (SNPs) in Gc, rs7041 (Asp416Glu) and rs4588 (Thr420Lys) and 3 common cancers (breast, lung and colorectal) in Thai patients. MATERIALS AND METHODS Two hundred and eighty two colorectal, 101 breast and 113 lung cancer patients were recruited from one institute during 2011-2013. The controls were age-matched volunteers who had a negative history of index cancers. In addition, vitamin D levels were compared among different genotypes in the 2 SNPs. RESULTS The minor allele frequencies of rs7041 (G) and rs4588 (A) were 0.32 and 0.24, respectively. Under the dominant model, the study found significant associations between minor-allele genotypes of the SNP rs7041 (TG/GG) and lung cancer (odds ratio [OR] 1.78, 95% CI 1.05-3.03). When subgroup analysis was performed according to sex and age at diagnosis, the study found that the minor- allele genotypes of rs7041 (TG/GG) were significantly associated with colorectal cancer in patients whose age at diagnosis was more than 60 years (OR 1.67, 95%CI 1.06-2.61) and the minor-allele genotypes of rs4588 (CA/AA) were significantly associated with colorectal cancer in males aged 60 years or less (OR 2.34, 95%CI 1.25-4.37). When SNP combinations (rs7041-rs4588) were examined, the TT-CA combination had a significant protective association with lung cancer (OR 0.44, 95% CI 0.22-0.85). On evaluation of serum 25(OH)D levels in 205 individuals without cancer (males 144, females 61), the proportion of subjects with low serum vitamin D (< 20 ng/ml) in those harboring CA or AA genotypes of rs4588 (41.7%) was significantly higher than the CC genotype (15.5%, p-value < 0.01). CONCLUSIONS Genetic polymorphisms in Gc were associated with lung and colorectal cancers in Thai patients. Lower serum 25(OH)D in minor variants of rs4588 may explain this association.