Po-Chin Liang

Adiponectin as a potential differential marker to distinguish pancreatic cancer and chronic pancreatitis.

Serum adiponectin (ADP) levels are reported inversely related to the risk in breast, endometrial cancer, and gastric cancer. Serum ADP as a potential marker compared with CA-19-9 in pancreatic carcinoma (PC) and chronic pancreatitis (CP) was studied. Adiponectin and CA-19-9 levels were examined at the time of diagnosis in patients with CP and PC. Methods: Serum ADP and CA-19-9 levels were measured by immunoassays in 72 patients with PC and 39 with CP and 290 control subjects. Results: The median levels of ADP for PC were significantly higher than those for CP and control subjects (P = 0.0035). Increasing the upper reference value of ADP allowed for better discrimination between CP and PC. The introduction of 28 ng/mL as a cutoff for ADP significantly improved its specificity. At an elevated cutoff level for ADP (28 ng/mL), a better discrimination between PC and CP was obtained. Conclusions: Adiponectin might be useful in the differential diagnosis of PC and CP with elevated CA-19-9. This gives rise to the possibility that ADP has a potential role in differentiating CP and PC.

Serum vascular endothelial growth factor/soluble vascular endothelial growth factor receptor 1 ratio is an independent prognostic marker in pancreatic cancer.

Objectives: Tumor angiogenesis is the consequence of an imbalance between positive and negative angiogenic regulatory factors. We sought to determine the role of pretreated serum angiogenic factors, including vascular endothelial growth factor (VEGF), placental growth factor (PlGF), and soluble vascular endothelial growth factor receptor 1 (sVEGFR-1), in predicting clinical outcome in patients with pancreatic cancer. Methods: We assessed pretreated serum VEGF, PlGF, and sVEGFR-1 levels in 92 patients with pancreatic adenocarcinoma and 60 healthy control subjects using an enzyme-linked immunosorbent assay. The correlation between these angiogenesis-related factors and clinicopathologic factors, including staging and overall survival, was analyzed. Results: Serum levels of VEGF, PlGF, and sVEGFR-1 were significantly higher in patients with pancreatic cancer compared with those in controls (583.8 ± 559.5 vs 187.63 ± 393.32, 17.65 ± 7.34 vs 10.93 ± 1.21, and 50.94 ± 51.17 vs 15.55 ± 1.98 pg/mL, respectively; P < 0.0001). A reverse correlation was observed between sVEGFR-1 level and the advance of tumor stage. Cox regression analysis showed that the VEGF/sVEGFR-1 ratio was an independent predictor for pancreatic cancer survival. Higher VEGF/sVEGFR-1 ratio was significantly correlated with poor outcome in patents with pancreatic cancer. Conclusions: Vascular endothelial growth factor/sVEGF-1 ratio is an independent prognostic factor for survival in pancreatic cancer. Its significance should be assessed when considering antiangiogenic therapy in treating pancreatic cancer patients.

Polymersomes conjugated with des-octanoyl ghrelin and folate as a BBB-penetrating cancer cell-targeting delivery system

Chemotherapy for brain cancer tumors remains a big challenge for clinical medicine due to the inability to transport sufficient drug across the blood-brain barrier (BBB) and the poor penetration of drug into the tumors. To effectively treat brain tumors and reduce side effects on normal tissues, both des-octanoyl ghrelin and folate conjugated with polymersomal doxorubicin (GFP-D) was developed in this study to help transport across the BBB and target the tumor as well. The size measurements revealed that this BBB-penetrating cancer cell-targeting GFP-D was about 85 nm. In-vitro experiments with a BBB model and C6 glioma cells demonstrated that GFP-D owned a robust penetrating-targeting function for drug delivery. In C6 cell viability tests, GFP-D exhibited an inhibitory effect significantly different from the unmodified polymersomal doxorubicin (P-D). In-vivo antitumor experiments showed that GFP-D performed a much better anti-glioma effect and presented a significant improvement in the overall survival of the tumor-bearing mice as compared to the treatments with free doxorubicin (Dox), liposomal doxorubicin (L-D), P-D, or single ligand conjugated P-D. In addition, Cy 5.5 was used as a probe to investigate the delivery property of this penetrating-targeting delivery system. The overall experimental results indicate that this BBB-penetrating cancer cell-targeting GFP is a highly potential nanocarrier for the treatment of brain tumors.

Spectrum of mutations and variants/haplotypes of CFTR and genotype–phenotype correlation in idiopathic chronic pancreatitis and controls in Chinese by complete analysis

Mutations in cystic fibrosis transmembrane conductance regulator (CFTR) gene have been reported in patients with chronic pancreatitis. The authors examine whether the mutations and haplotypes of CFTR will increase the risk of developing idiopathic chronic pancreatitis (ICP) in Chinese and their genotype and phenotype correlations. Seventy‐eight patients with ICP and 200 geographically and ethnically matched controls in Taiwan were analyzed. The entire 27 coding and intronic regions of the CFTR gene were identified using heteroduplex analytical techniques and confirmed by sequencing analysis. The presence of 125G/C, 1001+10C>T, IVSTn(TG)m, 1540A>G, c2694T>G, and c4521G>A were determined by directing sequencing. Abnormal CFTR allele was found to be thrice as frequent in ICP patients as in controls (22/156 vs 19/400, p < 0.0001). T5 allele was associated with early onset of ICP. In six‐loci haplotype analysis, 13 common haplotypes were assembled in the 278 individuals tested. The 125G/1001+11C/TG12/470M/2694T/4521G haplotype was associated with risk of ICP (odds ratio 11.3; 95% confidence interval 2.3–54.6, p = 0.008) in Chinese. The mutation spectrum is different from other ethnic groups. A population‐specific panel of CFTR changes should be recommended for targeted populations including ICP in Chinese. It is important to design suitable screening programs for different populations.

Association of Novel Chymotrypsin C Gene Variations and Haplotypes in Patients with Chronic Pancreatitis in Chinese in Taiwan

Background/Aims: Variations and haplotypes of the chymotrypsin C (CTRC) gene in Chinese patients with chronic pancreatitis (CP) and control subjects with genotype-phenotype correlation were investigated. Methods: One hundred and twenty-six patients with CP were analyzed. The entire sequence of coding regions of exons 2, 3 and 7 and their neighboring intronic regions in introns 1, 2 and 6 of the CTRC gene were analyzed using PCR sequence-specific primers and direct sequencing. The exonic region of exon 7 and the neighboring intronic region of intron 6 were also analyzed in 90 geographically matched healthy control subjects. Results: In total, 4 novel variations were identified in exons 2, 3 and 7 in 3 CP patients. A total of 2.3% (3/126) of our CP patients carried variations of the CTRC gene. We also first identified six new intronic variations in intron 6 which had not been reported before. The GAGGGG, GAGGAG and GAGTAG haplotypes assembled by six locus intronic variations c.640-41/c.640-40/c.640-39/c.640-37/c.640-36/c.640-35 in intron 6 were associated with a significantly higher susceptibility risk of CP (OR 66.75, 37.00, and 9.37, respectively). Conclusion: Novel CTRC gene variations and haplotypes are associated with CP in a Chinese population.

Simvastatin inhibits cytokine-stimulated Cyr61 expression in osteoblastic cells: A therapeutic benefit for arthritis

OBJECTIVE To examine the effects of proinflammatory cytokines on Cyr61 expression in osteoblastic cells and the modulatory action of simvastatin, to assess the role of CREB in Cyr61 induction, and to investigate the relationship of osteoblastic expression of Cyr61 to disease progression in experimental arthritis. METHODS Cyr61 expression and CREB phosphorylation at serine 133 were examined by Western blotting. Promoter activity of Cyr61 was assessed by luciferase assay with promoter deletion/mutagenesis and forced expression/gene silencing of CREB. Interaction between CREB and the Cyr61 promoter was evaluated by electrophoretic mobility shift assay and chromatin immunoprecipitation. CCL2 expression was examined by Northern blotting and enzyme-linked immunosorbent assay. In rats with collagen-induced arthritis (CIA), osteoblastic expression of Cyr61 was examined by immunohistochemistry, and disease progression was assessed by clinical, radiographic, and histologic examination. RESULTS In primary human osteoblasts and U2OS cells, Cyr61 expression stimulated by tumor necrosis factor α, interleukin-1β (IL-1β), oncostatin M (OSM), and other IL-6-family cytokines was suppressed by simvastatin. In U2OS cells, simvastatin inhibited OSM-induced CREB phosphorylation and CREB-DNA binding. Knockdown of CREB by short hairpin RNA reduced Cyr61 synthesis. OSM-induced Cyr61 promoter activation was dependent on CRE-CREB interaction and inhibited by simvastatin. Cyr61 enhanced CCL2 expression by U2OS cells. Intraarticular injection of simvastatin inhibited CIA progression and diminished the number of Cyr61+ osteoblasts and infiltrating macrophages. CONCLUSION Simvastatin inhibited cytokine-stimulated Cyr61 expression in osteoblastic cells and suppressed disease progression and osteoblastic expression of Cyr61 in inflammatory arthritis. This finding indicates that simvastatin may have potential as a therapeutic agent for inflammatory arthritis.

Quantification of hepatic steatosis: A comparison of the accuracy among multiple magnetic resonance techniques

Magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) are important diagnostic tools for the non‐invasive assessment of hepatic steatosis (HS). This study was conducted to compare different magnetic resonance (MR) techniques and correlate the MR findings with histological and intracellular lipid density findings.

Combining antiangiogenic therapy with immunotherapy exerts better therapeutical effects on large tumors in a woodchuck hepatoma model

Cytokine and antiangiogenic gene therapies have proved effective in implanted hepatocellular carcinoma (HCC) models in which small tumor burdens were established in small rodents. These models, however, may not reflect human HCCs, which are frequently detected at a stage when tumors are large and multifocal. In addition, HCC in patients is often associated with viral hepatitis. To investigate the effectiveness of a mixture type of gene therapy strategy on large tumor burdens, we used the woodchuck model in which woodchuck hepatitis virus-induced HCCs are large and multifocal, simulating the conditions in humans. Adenoviruses encoding antiangiogenic factors (pigment epithelium-derived factor and endostatin) or cytokines (GM-CSF and IL-12) were delivered via the hepatic artery separately or in combination into woodchuck livers bearing HCCs. Our results showed that the mixture type of strategy, which contained two cytokines and two antiangiogenic factors, had better antitumor effects on large tumors as compared with monotherapy either with antiangiogenic or cytokine genes. The immunotherapy recruited significant levels of CD3+ T cells that infiltrated the tumors, whereas the antiangiogenesis-based therapy significantly reduced tumor vasculature. The mixture type of gene therapy achieved both effects. In addition, it induced high levels of natural killer cells and apoptotic cells and reduced the levels of immunosuppressive effectors in the tumor regions. Hence, antiangiogenic therapy may provide the advantage of reducing immune tolerance in large tumors, making them more vulnerable to the immune reactions. Our study implies that in the future, the combination therapy may prove effective for the treatment of patients with advanced HCC.

Preoperative Diagnosis of Gastric Tumors by Three-dimensional Multidetector Row CT and Double Contrast Barium Meal Study: Correlation with Surgical and Histologic Results

BACKGROUND/PURPOSE Recent three-dimensional multidetector row computed tomography (3D MDCT) can provide detailed images of a gastric tumor, including its general contour, location and depth. We therefore evaluated the efficacy of MDCT in the differential diagnosis and staging of gastric tumors in patients prepared for surgery. METHODS Seventy-nine patients with gastric tumors identified by gastric optical endoscopy were admitted for preoperative evaluation. All patients received double-contrast barium meal (DCBM) study and abdominal MDCT with 3D reconstruction before surgery. We compared the accuracy of MDCT with DCBM study in detecting and differentiating gastric tumors. In addition, the MDCT findings were correlated with surgical and pathologic results in gastric cancers for Borrmann type, T and N stages. RESULTS Among the 79 patients with gastric tumors, there were 24 cases of early gastric cancer, 40 cases of advanced gastric cancer, 12 cases of gastrointestinal stromal tumor, and three cases of gastric lymphoma. Both MDCT and DCBM were very accurate in picking up the lesions (100%). The diagnostic accuracies of MDCT and DCBM were similar (94% vs. 96%) in differentiating mucosal and submucosal lesions as well as classification of Borrmann type in advanced gastric cancer (70% vs. 63%). In 64 patients with gastric cancers, there was good correlation between MDCT images and pathology in 73% of T staging and 69% of N staging. CONCLUSION MDCT has a similar high accuracy in the preoperative diagnosis of different gastric tumors compared with DCBM and provides additional information including tumor depth, lymph node and hepatic metastasis. Therefore, MDCT may be used as a primary tool for preoperative tumor diagnosis and staging.

Hepatic arterial infusion of chemotherapy for advanced hepatocellular carcinoma

Treatment of advanced hepatocellular carcinoma (HCC) remains a significant problem for clinicians. Sorafenib, the only approved agent, improves survival rate, but is associated with a low tumor response rate. Alternative approaches for the treatment of advanced HCC are urgently needed. Hepatic arterial infusion of chemotherapy (HAIC) is a promising modality for the treatment of advanced HCC. Since its introduction, there have been improvements in implantable pumps, in catheter implantation and in the convenience and safety of HAIC in general. Numerous clinical studies have shown that HAIC provides moderate therapeutic efficacy with substantially favorable toxicity profiles in selected patient groups with advanced HCC. However, the lack of large randomized studies means that HAIC is not yet a well‐established treatment for advanced HCC. We believe there is an urgent need for the further investigation of HAIC for the treatment of advanced HCC.