Hye Won Chung

The clinical usefulness of 18-fluorodeoxyglucose positron emission tomography in the differential diagnosis, staging, and response evaluation after concurrent chemoradiotherapy for pancreatic cancer

Goals The aims of this study were to determine the clinical use of 18-fluorodeoxyglucose positron emission tomography (18FDG-PET) in the differential diagnosis of patients with suspected pancreatic cancer and in the determination of tumor response after concurrent chemoradiotherapy for pancreatic cancer. Background Despite advances in diagnostic tools for pancreatic cancer, it is difficult to differentiate pancreatic cancer from mass-forming pancreatitis. Even with current imaging modalities, it is also difficult to assess tumor response to therapeutic intervention. Study One hundred two patients with suspected pancreatic cancer were selected for this study. Dynamic computerized tomography (CT) scan and 18FDG-PET were used sequentially to diagnose pancreatic cancer. After diagnostic confirmation their diagnostic yields were compared. We also evaluated the treatment response in 15 patients who underwent chemoradiation therapy with dynamic CT scan and 18FDG-PET and compared their results. Results In 93 out of 102 patients, pancreatic cancer was confirmed. 18FDG-PET showed higher diagnostic accuracy than CT scan (95.1% vs. 76.5%). 18FDG-PET was also superior to CT in the detection of liver metastasis. 18FDG-PET detected treatment response in 5 out of 15 cases after chemoradiation therapy, whereas CT could not detect any treatment response. Comparing responder and nonresponder, 18FDG-PET was able to predict significantly different prognosis (399 vs. 233u2009d, P<0.05). Conclusions 18FDG-PET is a very useful tool in diagnosing pancreatic cancer. 18FDG-PET may be also used as an adjunct for determining the treatment modality of pancreatic cancer and evaluating tumor response to chemoradiation therapy.

Oct4 and Nanog expression is associated with early stages of pancreatic carcinogenesis.

Objective: To characterize the role of Oct4 and Nanog, two important homeobox transcription factors of embryonic development, in pancreatic carcinogenesis. Methods: Using a tissue microarray of human pancreatic carcinoma and adjacent noncancerous tissues as well as the N-nitrosobis(2-oxopropyl)amine-induced Syrian golden hamster pancreatic cancer model, we characterized the expression of Oct4 and Nanog. The presence of K-ras mutation with the time course of carcinogenesis in hamster model was also evaluated. Results: Oct4 expression in metaplastic ducts was significantly stronger than in normal acini and pancreatic carcinoma (P < 0.05). Of 24 cases, 19 (79.2%) showed a strong Oct4 expression in metaplastic ducts. In contrast, only 6 (19.4%) of 31 cancer tissues and 3 (16.7%) of 18 noncancer tissues showed a strong Oct4 expression. Nanog also showed similar patterns as Oct4. Restriction fragment length polymorphism-polymerase chain reaction showed the overt K-ras mutation after the expression of Oct4 in the hamster model. Conclusions: The strong expression of Oct4 and Nanog in metaplastic ducts and Oct4 expression preceding Ras mutation suggests that these homeobox transcription factors are associated with the early stage of pancreatic cancer carcinogenesis and may play an important role in that process.

Serum high mobility group box-1 (HMGB1) is closely associated with the clinical and pathologic features of gastric cancer

BackgroundHigh mobility group box-1 (HMGB1) is a newly recognized factor regulating cancer cell tumorigenesis, expansion and invasion. We investigated the correlation between the serum HMGB1 levels and the clinical and pathologic features of gastric cancer and evaluated the validity of HMGB1 as a potential biomarker for the early diagnosis of gastric cancer.MethodsA total of 227 subjects were classified into 5 disease groups according to the gastritis-dysplasia-carcinoma sequence of gastric carcinogenesis and their serum levels of HMGB1 were analyzed by an enzyme-linked immunosorbent assay (ELISA) method. Clinical parameters, International Union Against Cancer (UICC) TNM stage, cancer size, differentiation or lymphatic invasion, vascular or perineural invasion and prognosis were used as analysis variables.ResultsThe serum HMGB1 levels were significantly different among disease groups (ANOVA, p < 0.05) and HMGB1 levels tended to increase according to the progression of gastric carcinogenesis. Serum HMGB1 levels were significantly associated with depth of invasion, lymph node metastasis, tumor size, and poor prognosis (p < 0.05). However, HMGB1 levels were not associated with patient gender or age, differentiation of tumor cells, or lymphatic, vascular and perineural invasion, or the existence of distant metastasis in advanced cancer (p > 0.05). The sensitivity and specificity of serum HMGB1 was 71% and 67% (cut-off value of 5 ng/ml) for the diagnosis of early gastric cancer, and 70% and 64% (cut-off value of 4 ng/ml) for the diagnosis of high-risk lesions, respectively. These values were greater than those for carcinoembryonic antigen (CEA) (30–40% of sensitivity).ConclusionHMGB1 appears to be a useful serological biomarker for early diagnosis as well as evaluating the tumorigenesis, stage, and prognosis of gastric cancer.

CRM1 and BRAF Inhibition Synergize and Induce Tumor Regression in BRAF-Mutant Melanoma

Resistance to BRAF inhibitor therapy places priority on developing BRAF inhibitor-based combinations that will overcome de novo resistance and prevent the emergence of acquired mechanisms of resistance. The CRM1 receptor mediates the nuclear export of critical proteins required for melanoma proliferation, survival, and drug resistance. We hypothesize that by inhibiting CRM1-mediated nuclear export, we will alter the function of these proteins resulting in decreased melanoma viability and enhanced BRAF inhibitor antitumoral effects. To test our hypothesis, selective inhibitors of nuclear export (SINE) analogs KPT-185, KPT-251, KPT-276, and KPT-330 were used to induce CRM1 inhibition. Analogs PLX-4720 and PLX-4032 were used as BRAF inhibitors. Compounds were tested in xenograft and in vitro melanoma models. In vitro, we found CRM1 inhibition decreases melanoma cell proliferation independent of BRAF mutation status and synergistically enhances the effects of BRAF inhibition on BRAF-mutant melanoma by promoting cell-cycle arrest and apoptosis. In melanoma xenograft models, CRM1 inhibition reduces tumor growth independent of BRAF or NRAS status and induces complete regression of BRAF V600E tumors when combined with BRAF inhibition. Mechanistic studies show that CRM1 inhibition was associated with p53 stabilization and retinoblastoma protein (pRb) and survivin modulation. Furthermore, we found that BRAF inhibition abrogates extracellular signal–regulated kinase phosphorylation associated with CRM1 inhibition, which may contribute to the synergy of the combination. In conclusion, CRM1 inhibition impairs melanoma survival in both BRAF-mutant and wild-type melanoma. The combination of CRM1 and BRAF inhibition synergizes and induces melanoma regression in BRAF-mutant melanoma. Mol Cancer Ther; 12(7); 1171–9. ©2013 AACR.

Role of the tumor microenvironment in the pathogenesis of gastric carcinoma

Gastric carcinoma (GC) is the 4(th) most prevalent cancer and has the 2(nd) highest cancer-related mortality rate worldwide. Despite the incidence of GC has decreased over the past few decades, it is still a serious health problem. Chronic inflammatory status of the stomach, caused by the infection of Helicobacter pylori (H. pylori) and through the production of inflammatory mediators within the parenchyma is suspected to play an important role in the initiation and progression of GC. In this review, the correlation between chronic inflammation and H. pylori infection as an important factor for the development of GC will be discussed. Major components, including tumor-associated macrophages, lymphocytes, cancer-associated fibroblasts, angiogenic factors, cytokines, and chemokines of GC microenvironment and their mechanism of action on signaling pathways will also be discussed. Increasing our understanding of how the components of the tumor microenvironment interact with GC cells and the signaling pathways involved could help identify new therapeutic and chemopreventive targets.

Serum high mobility group box‐1 is a powerful diagnostic and prognostic biomarker for pancreatic ductal adenocarcinoma

Extracellular high mobility group box‐1 (HMGB1) contributes to tumor growth and invasiveness. We evaluated the diagnostic and prognostic ability of serum HMGB1 for pancreatic ductal adenocarcinoma (PDAC). Serum HMGB1 measured by enzyme‐linked immunosorbent assay (ELISA) were compared among normal, chronic pancreatitis, PDAC group in both training (n = 25, each group) and independent validation set (n = 45, each group). To determine the usability of serum HMGB1 as a diagnostic predictor of PDAC, receiver operating characteristic (ROC) curves with sensitivity/specificity and logistic regression were evaluated. To assess the HMGB1‐associated prognosis of PDAC, Kaplan–Meier survival and Cox proportional‐hazards regression were applied. Serum HMGB1 was correlated with presence and advanced‐stage of PDAC. Logistic regression exhibited serum HMGB1 was a remarkable biomarker to predict PDAC as a single or multiple‐markers; sensitivity/specificity of serum HMGB1 were superior to carbohydrate antigen (CA) 19‐9 or carcinoembryonic antigen (CEA) in both training and independent datasets. Kaplan–Meier survival analysis showed PDAC patients with high serum HMGB1 levels (>30 ng/mL; median survival, 192 days) had a worse prognosis than patients with low HMGB1 levels (≤30 ng/mL; 514 days) by log‐rank (P = 0.017). Cox proportional‐hazards model showed the relative hazard ratios in high‐serum HMGB1 group was 3.077 compared with the low‐serum HMGB1 group. In conclusion, serum HMGB1 is a desirable diagnostic and prognostic biomarker for PDAC compared with pre‐existing PDAC biomarkers, CA19‐9 and CEA.

Radiosensitization effect of STI-571 on pancreatic cancer cells in vitro.

PURPOSEnTo examine STI-571-induced radiosensitivity in human pancreatic cancer cells in vitro.nnnMETHODS AND MATERIALSnThree human pancreatic cancer cell lines (Bxpc-3, Capan-1, and MiaPaCa-2) exhibiting different expression levels of c-Kit and platelet-derived growth factor receptor beta (PDGFRbeta) and showing different K-ras mutation types were used. For evaluation of the antitumor activity of STI-571 in combination with radiation, clonogenic survival assays, Western blot analysis, and the annexin V/propidium iodide assay with microscopic evaluation by 4,6-diamidino-2-phenylindole were conducted.nnnRESULTSnDramatic phosphorylated (p)-c-Kit and p-PDGFRbeta attenuation, a modest dose- and time-dependent growth inhibition, and significant radiosensitization were observed after STI-571 treatment in view of apoptosis, although the levels of growth inhibition and increased radiosensitization were different according to cell lines. The grades of radiosensitivity corresponded to the attenuation levels of p-c-Kit and p-PDGFRbeta by STI-571, particularly to those of p-c-Kit, and the radiosensitivity was partially affected by K-ras mutation in pancreatic cancer cells. Among downstream pathways associated with c-Kit or PDGFRbeta, p-PLCgamma was more closely related to radiosensitivity compared with p-Akt1 or p-extracellular signal-regulated kinase 1.nnnCONCLUSIONnSTI-571 enhances radiation response in pancreatic cancer cells. This effect is affected by the attenuation levels of p-c-Kit or p-PDGFRbeta, and K-ras mutation status. Among them, p-c-Kit plays more important roles in the radiosensitivity in pancreatic cancer compared with p-PDGFRbeta or K-ras mutation status.

Comparison of the validity of three biomarkers for gastric cancer screening: carcinoembryonic antigen, pepsinogens, and high sensitive C-reactive protein.

Purpose To identify a desirable serum marker for screening tools for gastric cancer, we evaluated the validity of 3 biomarkers, namely, carcinoembryonic antigen (CEA), pepsinogens (PGs), and high sensitive C-reactive protein (hsCRP). Methods We estimated the mean serum levels of CEA, PGs, and hsCRP and compared the sensitivity and specificity of these 3 biomarkers in 378 subjects who were classified into 7 groups: normal, chronic atrophic gastritis, intestinal metaplasia, adenoma, early gastric cancer (EGC), advanced gastric cancer (AGC) without metastasis, and AGC with metastasis (M1). Results There were no significant differences among the normal, high-risk (chronic atrophic gastritis, intestinal metaplasia, and adenoma), and EGC groups for CEA and hsCRP. However, the levels of CEA were relatively higher in the AGC group with intestinal-type cancer (P<0.01). Likewise, hsCRP was relatively higher in the AGC group with diffuse-type cancer (P<0.01). For the PG I/II ratio, there was no significant difference among the normal, high-risk, and cancer groups, including EGC (P<0.01). In addition, there was a negative correlation with grades (γs=−0.480, P<0.01). However, the PG I/II ratio was relatively less effective in diffuse-type cancer compared with intestinal-type cancer. The combination of serum hsCRP and the PG I/II ratio had a higher sensitivity (77%) than did the PG I/II ratio alone (61%) in diffuse-type cancers. Conclusions The combination of serum hsCRP and PG I/II ratio would be helpful as a screening tool for gastric cancer in high incidence populations and may help to select high-risk subjects in need of further specific invasive screening tools such as endoscopy.

Combined targeting of high‐mobility group box‐1 and interleukin‐8 to control micrometastasis potential in gastric cancer

Micrometastasis is the major cause of treatment failure in gastric cancer (GC). Because epithelial‐to‐mesenchymal transition (EMT) is considered to develop prior to macroscopic metastasis, EMT‐promoting factors may affect micrometastasis. This study aimed to evaluate the role of extracellular high‐mobility group box‐1 (HMGB1) in EMT and the treatment effect of combined targeting of HMGB1 and interleukin‐8 (IL‐8) at early‐stage GC progression through interrupting EMT promotion. Extracellular HMGB1 was induced by human recombinant HMGB1 and pCMV‐SPORT6‐HMGB1 plasmid transfection. EMT activation was evaluated by immunoblotting, immunofluorescence and immunohistochemistry. Increased migration/invasion activities were evaluated by in vitro transwell migration/invasion assay using all histological types of human GC cell lines (N87, MKN28 SNU‐1 and KATOIII), N87‐xenograft BALB/c nude mice and human paired serum‐tissue GC samples. HMGB1‐induced soluble factors were measured by chemiluminescent immunoassay. Inhibition effects of tumor growth and EMT activation by combined targeting of HMGB1 and IL‐8 were evaluated in N87‐xenograft nude mice. Serum HMGB1 increases along the GC carcinogenesis and reaches maximum before macroscopic metastasis. Overexpressed extracellular HMGB1 promoted EMT activation and increased cell motility/invasiveness through ligation to receptor for advanced glycation end products. HMGB1‐induced IL‐8 overexpression contributed the HMGB1‐induced EMT in GC in vitro and in vivo. Blocking HMGB1 caused significant reduction of tumor growth, and addition of human recombinant IL‐8 rescues this antitumor effects. Our results imply the role of HMGB1 in EMT through IL‐8 mediation, and a potential mechanism of GC micrometastasis. Our observations suggest combination strategy of HMGB1 and IL‐8 as a promising diagnostic and therapeutic target to control GC micrometastasis.

Serum ENA78/CXCL5, SDF-1/CXCL12, and their combinations as potential biomarkers for prediction of the presence and distant metastasis of primary gastric cancer.

BACKGROUNDnChemokines play important roles in cancer development and progression. Epithelial-derived neutrophil-activating peptide-78 (ENA78/CXCL5) and stromal cell-derived factor (SDF-1/CXCL12) supposedly contribute to gastric cancer (GC) development and progression. This study aims to evaluate serum levels of ENA78/CXCL5 and SDF-1/CXCL12 along the GC carcinogenesis, and analyze their clinical significance, and diagnostic potentials through human serum samples.nnnMETHODSnA total of 300 subjects were enrolled in this study. Serum levels of ENA78/CXCL5 and SDF-1/CXCL12, measured by chemiluminescent immunoassay, were compared among 4 disease groups; normal, high-risk (intestinal metaplasia and adenoma), early GC (EGC), and advanced GC (AGC) groups in both training (n=25 per group) and validation dataset (n=70, 30, 50, 50, respectively) by ANOVA test (post hoc Bonferroni). Correlations between serum ENA78/CXCL5 or SDF-1/CXCL12 levels and clinicopathological parameters of GC patients were evaluated (Spearmans correlation; γs). To validate the diagnostic accuracy, receiver operating characteristic (ROC) curve and logistic regression analysis was performed.nnnRESULTSnSerum ENA78/CXCL5 and SDF-1/CXCL12 levels were significantly higher in AGC groups than EGC, high-risk and normal groups in both training and validation dataset (Bonferroni, from p<0.01 to p<0.001). Clinicopathologically, serum ENA78/CXCL5 was correlated with T-stage (γs=0.231, p=0.021) and distant metastasis (γs=0.357, p<0.001), while serum SDF-1/CXCL12 was correlated with lymph node (γs=0.220, p=0.029) and distant (γs=0.425, p<0.001) metastasis. ROC curve and logistic regression demonstrated that serum ENA78/CXCL5 and SDF-1/CXCL12 showed higher diagnostic accuracy compared with carcinoembryonic antigen (CEA) in predicting GC. Serum ENA78/CXCL5 could predict both the presence of GC and distant metastasis, while serum SDF-1/CXCL12 could mainly predict its distant metastasis. All combination of serum ENA78/CXCL5, SDF-1/CXCL12, and CEA achieved 92.8% specificity at 75.0% sensitivity to predict distant metastasis of GC.nnnCONCLUSIONSnCombinations of initial serum ENA78/CXCL5, SDF-1/CXCL12, and CEA before any treatment for GC can produce valuable serum biomarker panels to predict the presence and distant metastasis of GC.