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For EUS-guided fine-needle biopsy (EUS-FNB) of solid pancreatic lesions (SPLs), the role of sampling strategy between a targeted biopsy and wide sampling has not been reported. This study aimed to investigate the benefits of the two sampling techniques on EUS-FNB with rapid on-site evaluation.Patients with SPLs were prospectively enrolled and randomly assigned (1:1) to undergo EUS-FNB using either contrast guidance or the fanning technique. The primary outcome was the total number of passes required to establish a diagnosis, and the secondary outcomes were overall diagnostic accuracy and complication rates.A total of 118 patients were enrolled from February 2019 to January 2021, with 59 patients assigned to each group. There was no significant difference in the total number of passes required to establish a diagnosis between the contrast and fanning groups (median 1 [interquartile range 1-1] vs. 1 [1-2]; P = .629). The sensitivity, specificity, and diagnostic accuracy in the contrast and fanning groups were 100%, 66.7%, and 98.3%, versus 100%, 100%, and 100%, respectively (P = 1). An SPL size4 cm (odds ratio [OR], 2.47; 95% confidence interval [CI], 1.05-5.81; P = .037) and macroscopic visible core length1 cm (OR, 2.89; 95% CI, 1.07-7.84; P = .037) were independently associated with increased cytologic and histologic accuracy.The diagnostic accuracy of EUS-FNB with the fanning technique for SPLs was comparable with the contrast guidance technique. Without additional cost, EUS-FNB with the fanning technique may be preferred for SPLs.

Supplementary Figure legends (Figures 1-8)

Supplementary Figures 1-8. Supplementary Figure 1: Stably expressing Keap1 by CL1-5 cells is accompanied by decreasing migratory and invasive abilities. Supplementary Figure 2: Manipulation of Keap1 expression (overexpression or knockdown) had no significant effect on the cell growth rate. Supplementary Figure 3: Keap1 suppresses the mobility of cancer cells. Supplementary Figure 4: Functional confirmation of Keap1 and Nrf2 expressions in CL1-0 and CL1-5 cells. Supplementary Figure 5: Cell proliferation was not affected by Nrf2 or S100P expression. Supplementary Figure 6: Representative IHC images of Nrf2 in lung cancer tissues from surgically resected specimens. Supplementary Figure 7: Keap1 regulates intra-pulmonary metastasis in a CL1-0 xenograft model. Supplementary Figure 8: Keap1 mediates the degradation of RhoA in CL1-5 cells.

Purpose: Kelch-like ECH-associated protein 1 (Keap1) is an E3 ligase participated in the cellular defense response against oxidative stress through nuclear factor erythroid-2–related factor 2 (Nrf2). However, the role of Keap1 in regulating cancer motility is still controversial. We investigated the contribution of the Keap1–Nrf2 axis in the progression of non–small cell lung cancer (NSCLC).Experimental Design: The expression of Keap1 and Nrf2 was examined via immunohistochemistry, real-time PCR, and Western blot analysis in a cohort of NSCLC tissues and cells. A series of in vivo and in vitro assays was performed to elucidate the contribution of the Keap1–Nrf2 axis in lung cancer mobility and progression.Results: Keap1 expression was decreased in specimens from NSCLC patients with lymph node metastasis compared with patients without metastasis. Higher Keap1 expression levels were correlated with the survival of NSCLC patients. Moreover, manipulation of Keap1 expression affected cell migration/invasion abilities. Depletion of Nrf2 relieved the migration promotion imposed by Keap1 suppression. Mechanistic investigations found that S100P was downregulated in both Keap1-overexpressing and Nrf2-knockdown NSCLC cells. Overexpression of Keap1 and knockdown of Nrf2 both suppressed S100P expression in NSCLC cells. Knockdown of S100P inhibited cell migration in highly invasive NSCLC cells and also relieved the migration promotion imposed by Keap1 suppression in weakly invasive NSCLC cells.Conclusions: Our findings suggest that Keap1 functions as a suppressor of tumor metastasis by targeting the Nrf2/S100P pathway in NSCLC cells. In addition, overexpression of Keap1 may be a novel NSCLC treatment strategy and/or useful biomarker for predicting NSCLC progression. Clin Cancer Res; 21(20); 4719–32. ©2015 AACR.

Supplementary Tables 1-3. Supplementary Table 1: Clinicopathologic characteristics of patients with associated expression of Keap1 protein in NSCLC. Supplementary Table 2: Correlation between levels of Keap1 and Nrf2 expression in lung cancer. Supplementary Table 3: Clinicopathologic characteristics of lung tumors with high and low expression of Nrf2 protein.

Supplementary Methods, Figure Legends 1-12, Tables 1-5 from H3K9 Histone Methyltransferase G9a Promotes Lung Cancer Invasion and Metastasis by Silencing the Cell Adhesion Molecule Ep-CAM

Supplementary Figures 1-12 from H3K9 Histone Methyltransferase G9a Promotes Lung Cancer Invasion and Metastasis by Silencing the Cell Adhesion Molecule Ep-CAM

The small endoscopic ultrasound (EUS)-suspected gastric gastrointestinal stromal tumors (GISTs), gastric subepithelial tumors at the muscularis propria layer on EUS, are detected frequently. Bite-on-bite forceps biopsy and EUS-guided tissue sampling yield variable results. This study aimed to analyze clinicopathologic features of the small EUS-suspected gastric GISTs 2 cm or less in size and to evaluate the efficacy and safety of the endoscopic incisional biopsy (EIB) for these small tumors.This prospective study investigated 70 patients with small EUS-suspected gastric GISTs 2 cm or less in size in two stages. Firstly, 30 patients were recruited for the efficacy and safety evaluation of the EIB. Secondly, 40 patients were randomly assigned to receive either EIB or the bite-on-bite biopsy for comparison of the diagnostic yield, procedure time, and adverse event rate.Combining two study stages, leiomyoma (74%) was diagnosed histologically to outnumber GIST (26%) with a diagnostic rate of 94% for patients receiving EIB. KIT exon 11 mutations (50%) and PDGFRA exon 12 mutations (16%) were detected in the small gastric GISTs. In the direct comparison, the diagnostic yield of EIB and the bite-on-bite biopsy was 85% and 50%, respectively (P = 0.018). There was no statistically significant difference of the mean procedure time or adverse event rate between these two groups.Leiomyoma is more common than expected among these small tumors. Tissue diagnosis with an effective and safe sampling technique, such as EIB, is necessary for making further clinical decisions.

Background The use of macroscopic on-site evaluation (MOSE) to estimate the adequacy of a specimen for histological diagnosis during endoscopic ultrasound (EUS)-guided fine-needle tissue acquisition (FNTA) has recently been advocated. This study aimed to evaluate the diagnostic yield of MOSE compared with conventional EUS-FNTA without rapid on-site evaluation (ROSE).Methods This was an international, multicenter, prospective, randomized controlled study. After providing informed consent, consecutive adult patients referred for EUS-FNTA for solid lesions larger than 2 cm were randomized to a MOSE arm or to a conventional arm without ROSE. A designated cytopathologist from each center performed all cytopathological examinations for that center and was blinded to the randomization results. The primary outcome measure was the diagnostic yield, and the secondary outcomes included sensitivity, specificity, positive predictive value, negative predictive value, diagnostic accuracy, and the rate of procedure-related complications.Results 244 patients (122 conventional, 122 MOSE) were enrolled during the study period. No significant differences between the two arms were found in procedure time or rate of procedure-related adverse events. The diagnostic yield for the MOSE technique (92.6 %) was similar to that for the conventional technique (89.3 %; P = 0.37), with significantly fewer passes made (median: conventional 3, MOSE 2; P Conclusions EUS-FNTA with the MOSE technique provided a similar diagnostic yield to conventional EUS-FNTA technique in the absence of ROSE but with fewer passes. This technique can be used when ROSE is not available.

Summary: Background/Objective: The atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) category is one of six diagnostic categories of The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC). In this study, we report the diagnostic distribution of thyroid fine needle aspiration (FNA) cytology and analyze the outcome of AUS/FLUS cases. Methods: A total of 29,937 thyroid FNA results, reported between April 2012 and December 2016, were retrieved from the database of a medical center. We reviewed the electronic medical records and analyzed the management of these patients. Results: Overall frequency of AUS/FLUS is 3.1% in our laboratory, which is at the lower limit of the recommended range. Of these, 891 reports of AUS/FLUS from 770 patients were identified. Out of the 770 patients, 367 had surgical intervention. In these 367 patients, final surgical pathology yielded 204 (55.6%) malignancies, 12 indeterminateness (3.3%), and 151 (41.1%) benignity. Among these surgical patients, 113 (30.8%) had received a repeat FNA of the thyroid before thyroid resection. The difference between the malignancy rates among patients who directly received surgery after the first AUS/FLUS diagnosis (132 of 254, 52.0%) and patients having a repeat FNA before surgery (72 of 113, 63.7%) was not statistically significant. Conclusion: Our results are in agreement with AUS/FLUS diagnoses in less than 7% of specimens, and confirm that it is appropriate to perform either a repeat thyroid FNA or thyroid lobectomy, with the clinical decision being subject to the standardized management protocols of the second edition of TBSRTC in the AUS/FLUS category. Keywords: Atypia, The Bethesda System, Thyroid FNA cytology

Background & Aims We aimed to compare the efficacy of genotypic resistance–guided therapy vs empirical therapy for eradication of refractory Helicobacter pylori infection in randomized controlled trials. Methods We performed 2 multicenter, open-label trials of patients with H pylori infection (20 years or older) failed by 2 or more previous treatment regimens, from October 2012 through September 2017 in Taiwan. The patients were randomly assigned to groups given genotypic resistance–guided therapy for 14 days (n = 21 in trial 1, n = 205 in trial 2) or empirical therapy according to medication history for 14 days (n = 20 in trial 1, n = 205 in trial 2). Patients received sequential therapy containing esomeprazole and amoxicillin for the first 7 days, followed by esomeprazole and metronidazole, with levofloxacin, clarithromycin, or tetracycline (doxycycline in trial 1, tetracycline in trial 2) for another 7 days (all given twice daily) based on genotype markers of resistance determined from gastric biopsy specimens (group A) or empirical therapy according to medication history. Resistance-associated mutations in 23S ribosomal RNA or gyrase A were identified by polymerase chain reaction with direct sequencing. Eradication status was determined by 13C-urea breath test. The primary outcome was eradication rate. Results H pylori infection was eradicated in 17 of 21 (81%) patients receiving genotype resistance–guided therapy and 12 of 20 (60%) patients receiving empirical therapy (P = .181) in trial 1. This trial was terminated ahead of schedule due to the low rate of eradication in patients given doxycycline sequential therapy (15 of 26 [57.7%]). In trial 2, H pylori infection was eradicated in 160 of 205 (78%) patients receiving genotype resistance–guided therapy and 148 of 205 (72.2%) patients receiving empirical therapy (P = .170), according to intent to treat analysis. The frequencies of adverse effects and compliance did not differ significantly between groups. Conclusions Properly designed empirical therapy, based on medication history, is an acceptable alternative to genotypic resistance–guided therapy for eradication of refractory H pylori infection after consideration of accessibility, cost, and patient preference. ClinicalTrials.gov ID: NCT01725906.

Solid pancreatic or peripancreatic lesions comprise a heterogeneous group of diseases that rely on a multimodality imaging approach for subsequent tissue procurement. Endoscopic ultrasound (EUS)-guided fine needle aspiration (FNA)/biopsy is an effective and safe method for tissue diagnosis in this region. The failure to obtain adequate tissue for diagnosis under EUS guidance is still a rare but important issue. Percutaneous core needle biopsy (CNB) provides an alternative pathway for adequate specimen acquisition. Because of the deep retroperitoneal location, the percutaneous biopsy of pancreatic or peripancreatic lesions may inevitably pass through visceral organs. The procedure is relatively risky and difficult for general radiologists, particularly beginners, and an adequate knowledge of the abdominal anatomy and biopsy technique is indispensable. In this review, various aspects of percutaneous CNB for solid pancreatic or peripancreatic lesions using different trans-organ approaches are reviewed to increase the chance of successful biopsy.

Cancer cells encounter metabolic stresses such as hypoxia and nutrient limitations because they grow and divide more quickly than their normal counterparts. In response to glucose restriction, we found that nuclear translocation of the glycolic enzyme, pyruvate kinase M2 (PKM2), helped cancer cells survive under the metabolic stress. Restriction of glucose stimulated AMPK activation and resulted in co-translocation of AMPK and PKM2 through Ran-mediated nuclear transport. Nuclear PKM2 subsequently bound to Oct4 and promoted the expression of cancer stemness-related genes, which might enrich the cancer stem cell population under the metabolic stress. Nuclear PKM2 was also capable of promoting cancer metastasis in an orthotopic xenograft model. In summary, we found that cytosolic AMPK helped PKM2 carry out its nonmetabolic functions in the nucleus under glucose restriction and that nuclear PKM2 promoted cancer stemness and metastasis. These findings suggested a potential new targeting pathway for cancer therapy in the future.

The aim of the present study was to evaluate the clinical utility of plasma chromogranin A (CgA) in patients diagnosed with early-stage pancreatic neuroendocrine tumors (PNETs) in terms of diagnostic value and treatment response. A total of 35 patients with PNETs were prospectively enrolled from August 2010 to April 2014. Demographic and clinicopathological data were collected, and serial plasma CgA levels were measured. Tumor responses were defined by the Response Evaluation Criteria In Solid Tumors criteria. Pearson's χ2 test was used for the analysis of the association between the plasma CgA level and various factors. Plasma CgA level was significantly associated with the size (P=0.03), metastasis (P=0.02) and tumor stage (P=0.03) of the PNETs. Using 126 U/l as the optimal cutoff value, the sensitivity and specificity were 87.5 and 81.5%, respectively. For localized tumors, the sensitivity of CgA for diagnosing PNETs was relatively low, even following a lowering of the cutoff values (29.6-51.9%). Plasma CgA level was correlated with therapeutic response in those patients with high baseline CgA levels (P=0.025), but not in the patients with low baseline CgA levels (P=0.587). In conclusion, plasma CgA level was associated with tumor size, metastasis and tumor stage in patients with PNET. For early-stage PNETs, CgA exhibited a limited role in diagnosis and treatment response evaluation in the population of the present study.

KH-type splicing regulatory protein (KSRP) is a single-strand RNA binding protein which regulates mRNA stability either by binding to AU-rich elements (AREs) of mRNA 3'UTR or by facilitating miRNA biogenesis to target mRNA. Unlike its well-characterized function at the molecular level in maintaining RNA homeostasis, the role of KSRP in cancer progression remains largely unknown. Here we investigate the role of KSRP in non-small cell lung cancer (NSCLC). We first examined KSRP expression by immunohistochemistry in a cohort containing 196 NSCLC patients and observed a strong positive correlation between KSRP expression and survival of NSCLC patients. Multivariate analysis further identified KSRP as an independent prognostic factor. Manipulating KSRP expression significantly affected in vitro cell mobility and in vivo metastatic ability of NSCLC cells. Microarray analysis identified an ARE-containing gene, EGR3, as a downstream effector of KSRP in NSCLC. Interestingly, we found that KSRP decreased EGR3 mRNA stability in an ARE-independent manner. By screening KSRP-regulated miRNAs in NSCLC cells, we further found that miR-23a directly binds to EGR3 3'UTR, reducing EGR3 expression and thereby inhibiting NSCLC cell mobility. Our findings implicate a targetable KSRP/miR-23a/EGR3 signaling axis in advanced tumor phenotypes.

Carbonic anhydrase IX (CA9) expression level has been considered as a poor prognostic factor in hepatocellular carcinoma (HCC) patients. However, the judging criteria of CA9 level is hard to define for potential clinical applications. Unlike CA9 expression level, CA9 polymorphism is poorly documented in HCC. Here, we found that people carry A allele at CA9 rs1048638, a 3′UTR SNP, has higher risk of HCC. rs1048638-CA correlates with advanced stages, larger tumor sizes, more vascular invasion, and shorter survival of HCC patients. A allele at CA9 rs1048638 impairs miR-34a, a tumor suppressor miRNA in HCC, binding to CA9 3′UTR and desensitizes CA9 mRNA to miR-34a-dependent RNA degradation. CA9 expression levels were also correlated with miR-34a levels and rs1048638 genotypes in HCC patients. rs1048638 influences HCC risk and progression through effects on miR-34a-targeted CA9 expression in HCC. In conclusion, genetic variations of the CA9 3′UTR play important roles in regulating CA9 expression and cancer progression, which is a novel determinant and target for HCC metastasis and prognosis.

Supplemental Digital Content is available in the text, Gastric neuroendocrine tumors (GNETs) are a heterogeneous group of neoplasm with varying biological characteristics. This study aimed to investigate the clinical features and outcomes of GNET patients after endoscopic diagnosis and treatment in a multicenter registry. Patients with GNETs confirmed histologically were recruited from 17 hospitals between January 2010 and April 2016 in Taiwan. Clinical, laboratory, radiological, endoscopic, pathological data, treatment strategies, follow-up periods, and survivals were collected retrospectively. Totally 187 (107 female, 80 male) patients were recruited. Mean ( ± standard deviation [SD]) age and size of tumors were 63.2-year-old ( ± 14.6) and 2.3-cm ( ± 3.0). World Health Organization (WHO) grading were 93 (49.7%) G1, 26 (13.9%) G2, 40 (21.4%) G3, and 28 (15.0%) unknown. G3 patients were older (mean ± SD, 71.6 ± 12.4 vs. 60.9 ± 14.3/56.7 ± 15.4 years), larger (6.1 ± 4.0 vs.1.2 ± 1.3/2.4 ± 2.5 cm), more distally located (35.0% vs. 7.6%/15.4%), lower proportion of superficial lesions (17.5% vs. 61.9%/53.8%) and higher rates of lymphovascular invasion (32.5% vs. 3.2%/7.7%) than G1/G2. There was no nodal or distant organ metastases despite different grading of lesions≦10 mm and those 20 mm (log-rank test P = .02). Male gender (P = .01), deeper invasion (P = .0001), nodal (P

Endoscopic ultrasound (EUS) along with fine-needle aspiration (FNA) has become a popular method and safe bridge to accurate tissue diagnosis for biliopancreatic tissue acquisition. EUS-FNA can alter patient management after a definite cytopathologic diagnosis or tumor staging, and it also has an impact on facilitating medical decision-making of both patients and physicians. EUS-FNA procedure involves the aspiration of cell samples by passing an aspiration needle through the working channel of a curvilinear echoendoscope under real-time guidance into an EUS visualized lesion. Various techniques such as peripheral sampling and fanning aspiration have been developed and can improve the diagnostic accuracy and efficiency of the EUS-FNA tissue acquisition. EUS-FNA can be performed from either the trans-duodenal or the trans-gastric approach for pancreatic tumors at the head or body and tail, respectively. Besides, EUS can evaluate the biliary tract and associated tumors from the ampulla to the bifurcation. Being superior to ERCP tissue sampling in pancreatic tumors, EUS-FNA has comparable sensitivity to ERCP-related methods for biliary tumors in evaluating suspected malignant biliary obstruction.

Secondary mutation of epidermal growth factor receptor (EGFR) resulting in drug resistance is one of the most critical issues in lung cancer therapy. Several drugs are being developed to overcome EGFR tyrosine kinase inhibitor (TKI) resistance. Here, we report that pyruvate kinase M2 (PKM2) stabilized mutant EGFR protein by direct interaction and sustained cell survival signaling in lung cancer cells. PKM2 silencing resulted in markedly reduced mutant EGFR expression in TKI-sensitive or -resistant human lung cancer cells, and in inhibition of tumor growth in their xenografts, concomitant with downregulation of EGFR-related signaling. Mechanistically, PKM2 directly interacted with mutant EGFR and heat-shock protein 90 (HSP90), and thus stabilized EGFR by maintaining its binding with HSP90 and co-chaperones. Stabilization of EGFR relied on dimeric PKM2, and the protein half-life of mutant EGFR decreased when PKM2 was forced into its tetramer form. Clinical levels of PKM2 positively correlated with mutant EGFR expression and with patient outcome. These results reveal a previously undescribed non-glycolysis function of PKM2 in the cytoplasm, which contribute to EGFR-dependent tumorigenesis and provide a novel strategy to overcome drug resistance to EGFR TKIs.

Purpose: Kelch-like ECH-associated protein 1 (Keap1) is an E3 ligase participated in the cellular defense response against oxidative stress through nuclear factor erythroid-2–related factor 2 (Nrf2). However, the role of Keap1 in regulating cancer motility is still controversial. We investigated the contribution of the Keap1–Nrf2 axis in the progression of non–small cell lung cancer (NSCLC). Experimental Design: The expression of Keap1 and Nrf2 was examined via immunohistochemistry, real-time PCR, and Western blot analysis in a cohort of NSCLC tissues and cells. A series of in vivo and in vitro assays was performed to elucidate the contribution of the Keap1–Nrf2 axis in lung cancer mobility and progression. Results: Keap1 expression was decreased in specimens from NSCLC patients with lymph node metastasis compared with patients without metastasis. Higher Keap1 expression levels were correlated with the survival of NSCLC patients. Moreover, manipulation of Keap1 expression affected cell migration/invasion abilities. Depletion of Nrf2 relieved the migration promotion imposed by Keap1 suppression. Mechanistic investigations found that S100P was downregulated in both Keap1-overexpressing and Nrf2-knockdown NSCLC cells. Overexpression of Keap1 and knockdown of Nrf2 both suppressed S100P expression in NSCLC cells. Knockdown of S100P inhibited cell migration in highly invasive NSCLC cells and also relieved the migration promotion imposed by Keap1 suppression in weakly invasive NSCLC cells. Conclusions: Our findings suggest that Keap1 functions as a suppressor of tumor metastasis by targeting the Nrf2/S100P pathway in NSCLC cells. In addition, overexpression of Keap1 may be a novel NSCLC treatment strategy and/or useful biomarker for predicting NSCLC progression. Clin Cancer Res; 21(20); 4719–32. ©2015 AACR.

Background and study aims: Two 22G needles with similar designs, apart from the absence (A) or presence of a side port (B), are available for endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA). The side port was designed to increase diagnostic yield but this advantage was unproven. This study evaluated the difference in diagnostic yield between both needles in pancreatic masses. Patients and methods: This was a prospective multicenter randomized cross-over study. Patients with pancreatic masses were randomized to one needle for the first two passes, followed by the other for the next two passes. A pathologist blinded to the needle assessed each puncture for cellularity and morphology. The diagnostic yield between both needles was compared. Results: In total, 30 patients were recruited (mean lesion size: 3.5 cm, range: 1.2 – 6.3). Comparison of cellularity adequacy: first pass: A vs. B: 26/30 vs. 24/30 (P = 0.488): 2nd pass: A vs. B: 25/30 vs. 26/30 (P = 0.718). Comparison of diagnostic accuracy: first pass: A vs. B: 22/30 vs. 23/30 (P = 0.766); after two passes: A vs. B: 26/30 vs. 26/30 (P = 1.0). When all four passes were assessed, adequate cellularity was obtained in 29/30 and the correct diagnosis was obtained in 28/30 patients. There were no procedural complications. Conclusions: There was no significant difference in diagnostic yield between EUSFNA needles with or without a side port for pancreatic masses. Study registration: NCT02092519.

Pyruvate kinase muscle isozymes (PKMs) have crucial roles in regulating metabolic changes during carcinogenesis. A switch from PKM1 to PKM2 isoform was thought to lead to aerobic glycolysis promoting carcinogenesis, and was considered as one of the cancer signatures. However, recent evidence has argued against the existence of PKM isoform switch and related metabolic effects during cancer progression. We compared the effects of PKM1 and PKM2 in cell invasiveness and metastasis of pancreatic ductal adenocarcinoma (PDAC). Both PKM1 and PKM2 expression affected cell migration and invasion abilities of PDAC cells, but only knockdown of PKM2 suppressed metastasis in a xenograft model. By comparing the established PKM2 mutants in the regulation of cell invasion, we found that PKM2 may control cell mobility through its protein kinase and phopho-peptide binding abilities. Further survey for PKM2-associated proteins identified PAK2 as a possible phosphorylation target in PDAC. In vitro binding and kinase assays revealed that PKM2 directly phosphorylated PAK2 at Ser20, Ser141, and Ser192/197. Knockdown of PKM2 decreased PAK2 protein half-life by increasing ubiquitin-dependent proteasomal degradation. Moreover, we identified PAK2 as an HSP90 client protein and the mutation at Ser192/197 of PAK2 reduced PAK2-HSP90 association. Knockdown of PAK2 diminished in vitro cell mobility and in vivo metastatic ability of PKM2 overexpressed PDAC cells. PKM2 and PAK2 protein expression also positively correlated with each other in PDAC tissues. Our findings indicate that PKM2-PAK2 regulation is critical for developing metastasis in PDAC, and suggest that targeting the PKM2/HSP90/PAK2 complex has a potential therapeutic value in this deadly disease.

Hepatocellular carcinoma (HCC) relies on angiogenesis for growth and metastasis. Leukocyte cell-derived chemotaxin 2 (LECT2) is a cytokine and preferentially expressed in the liver. Previous studies have found that LECT2 targets to both immune and tumor cells to suppress HCC development and vascular invasion. Although LECT2 did not affect HCC cells growth in vitro, it still suppressed HCC xenografts growth in immune-deficient mice, suggesting other cells such as stroma cells may also be targeted by LECT2. Here, we sought to determine the role of LECT2 in tumor angiogenesis in HCC patients. We found that LECT2 expression inhibited tumor growth via angiogenesis in the HCC xenograft model. Specifically, we demonstrated that recombinant human LECT2 protein selectively suppressed vascular endothelial growth factor (VEGF)165-induced endothelial cell proliferation, migration, and tube formation in vitro and in vivo. Mechanistically, LECT2 reduced VEGF receptor 2 tyrosine phosphorylation and its downstream extracellular signal-regulated kinase and AKT phosphorylation. Furthermore, LECT2 gene expression correlated negatively with angiogenesis in HCC patients. Taken together, our findings demonstrate that LECT2 inhibits VEGF165-induced HCC angiogenesis through directly binding to VEGFR2 and has broad applications in treating VEGF-mediated solid tumors.

BACKGROUND: Annexin A1 (AnxA1) has been well-known as a glucocorticoid-regulated anti-inflammatory protein, and it is implicated in tumorigenesis in a tumor type–specific pattern. However, the role of AnxA1 in gastric cancer (GC) is indeterminate, and the underlying mechanism is not clear. The purpose of this study was to evaluate the prognostic significance and associated mechanism of AnxA1 in GC. METHODS: Immunohistochemical staining was employed to analyze 118 GC patients. Both AnxA1 gain-of-function and loss-of-function approaches were performed in GC cells. Western blotting and reverse-transcription polymerase chain reaction were used for assessment of the AnxA1 regulation mechanism in GC cells. An intraperitoneal inoculation model in severe combined immunodeficient mice was used for an in vivo assay. RESULTS: High AnxA1 expression was significantly associated with peritoneal metastasis (P = .009) and serosal invasion (P = .044). Cox multivariate analysis showed that high AnxA1 expression was an independent risk factor for poor overall survival in GC patients (P = .037). AnxA1 expression positively correlated with invasiveness of human GC cells both in vitro and in vivo. AnxA1 could regulate the GC cell invasion through the formyl peptide receptor (FPR)/extracellular signal-regulated kinase/integrin beta-1-binding protein pathway, and all 3 FPRs (FPR1 through FPR3) were involved in the regulation process. CONCLUSIONS: High AnxA1 expression was associated with more serosal invasion, more peritoneal metastasis, and poorer overall survival in GC patients. The current study demonstrated a novel mechanism involving FPRs, extracellular signal-regulated kinases 1 and 2, and integrin beta-1-binding protein 1 by which AnxA1 regulated GC cell invasion. Cancer 2012. © 2012 American Cancer Society.

Background/Purpose Although the incidence of asymptomatic small gastric submucosal tumors increased gradually with routine medical health examination, there was little clinical evidence for management consensus in these small gastric submucosal tumors including endoscopic ultrasound (EUS)-suspected gastric gastrointestinal stromal tumors (GISTs). We investigated the clinical course of small EUS-suspected gastric GISTs and propose a cutoff value of tumor size for treatment policy. Methods In this retrospective study, 50 patients with EUS-suspected gastric GISTs of sizes less than 3 cm were enrolled and were followed up by EUS at least twice over a period of more than 24 months (range 24–101 months). An at least 20% increase of the maximal diameter of the tumors was set as a significant change. Results Significant changes in tumor size were found during the follow-up in 14 patients (28.0%). The one-dimensional 20% change corresponded well to 50% change in two-dimensional area measurement (correlation coefficient = 0.929). The receiver operating characteristic curve analysis showed that the best cutoff size, associated with tumor progression, was 1.4 cm having an 85.7% sensitivity, 86.1% specificity, and 86.0% accuracy. A larger tumor size (35.7% vs. 2.8%, p = 0.005) and irregular tumor margin on the EUS (71.4% vs. 0, p = 0.004) were two significant factors associated with the progression of tumor growth of small suspected gastric GISTs. Conclusion Small EUS-suspected GISTs, larger than 1.4 cm, with irregular margin were associated with significant progression. This subgroup is suggested to be monitored by more intensive follow-up.

Gastric neuroendocrine tumors (GNETs) are a heterogeneous group of neoplasm with varying biological characteristics. This study aimed to investigate the clinical features and outcomes of GNET patients after endoscopic diagnosis and treatment in a multicenter registry. Patients with GNETs confirmed histologically were recruited from 17 hospitals between January 2010 and April 2016 in Taiwan. Clinical, laboratory, radiological, endoscopic, pathological data, treatment strategies, follow-up periods, and survivals were collected retrospectively. Totally 187 (107 female, 80 male) patients were recruited. Mean ( ± standard deviation [SD]) age and size of tumors were 63.2-year-old ( ± 14.6) and 2.3-cm ( ± 3.0). World Health Organization (WHO) grading were 93 (49.7%) G1, 26 (13.9%) G2, 40 (21.4%) G3, and 28 (15.0%) unknown. G3 patients were older (mean ± SD, 71.6 ± 12.4 vs. 60.9 ± 14.3/56.7 ± 15.4 years), larger (6.1 ± 4.0 vs.1.2 ± 1.3/2.4 ± 2.5 cm), more distally located (35.0% vs. 7.6%/15.4%), lower proportion of superficial lesions (17.5% vs. 61.9%/53.8%) and higher rates of lymphovascular invasion (32.5% vs. 3.2%/7.7%) than G1/G2. There was no nodal or distant organ metastases despite different grading of lesions≦10 mm and those 20 mm (log-rank test P = .02). Male gender (P = .01), deeper invasion (P = .0001), nodal (P < .0001), and distant organ metastases (P = .0001) were associated with worse outcome. In conclusion, treatment strategies for GNET should be decided by grading, size, invasiveness, and LN metastasis risk. Curative endoscopic resection is feasible for G1/2 lesions less than 20 mm and limited to mucosa/submucosa layers without lymphovascular invasion.

Background/Purpose Fine needle aspiration (FNA) cytology has been widely accepted as a safe method for diagnosis of salivary gland lesions. This study investigated the accuracy of FNA cytology of salivary gland lesions by correlation between histology and cytology. Methods One hundred and thirty-one archived salivary gland FNA specimens collected between January 1994 and December 2002 from 131 patients were correlated with histopathology findings. The major reasons for false-negative and false-positive results in cytologic diagnosis were determined. Results Considering the results of histopathology as the diagnostic standard, the sensitivity of FNA cytology in diagnosing malignancy was 74% (17/23) after excluding two cases which had a cytodiagnosis of suspicion of malignancy. Excluding eight cases that had a cytodiagnosis of suspicion of malignancy, the diagnostic specificity was 99% (97/98). There were six false-negative and one false-positive cases. Conclusion This study demonstrated that FNA cytology of the salivary gland is a useful technique for diagnosis of salivary gland lesions. Inadequate labeling of the aspiration sites and insufficient cellularity were the most important factors that resulted in incorrect cytologic interpretation.

Background Because myocardial infarction (MI) after emergency endoscopy for upper gastrointestinal bleeding carries high mortality, we investigated factors associated with procedure-related MI in high-risk patients. Methods Consecutive patients with coronary artery disease or age-based risk for coronary artery disease (men, age >45 years; women, >55 years) who underwent emergency endoscopy were enrolled at a single ED. Demographic, laboratory, and outcome data were recorded. Patients fit 1 of 3 groups: MI before endoscopy (pre-panendoscopy [PES] MI), MI after endoscopy (post-PES MI), or non-MI. Results We enrolled 108 high-risk patients, including 5 (4.6%) with MI diagnosed preendoscopy. Five patients (4.6%) had MIs postendoscopy. Compared with non-MI patients, significantly more post-PES MI patients had heart disease (60.0% vs 12.2%; P = .021), lower systolic pressure on arrival (86.2 ± 16.6 vs 128.0 ± 27.2 mm Hg; P = .002), lower diastolic pressure on arrival (50.0 ± 6.3 vs 69.5 ± 15.8 mm Hg; P = .003), lower hemoglobin on arrival (6.7 ± 1.1 vs 9.1 ± 2.4 g/dL; P = .021), and more persistent shock status preendoscopy (80.0% vs 13.3%; P = .002). There was no significant difference in factors including duration of procedure and rates of recurrent bleeding, postprocedure complication, and mortality. Conclusions Heart disease, lower blood pressure or hemoglobin level on arrival, and persistent shock before endoscopy are associated with increased risk for procedure-related MI.

Question: A 25-year-old woman presented to the outpatient clinic because she had multiple pancreatic tumors incidentally found on evaluating 1 episode of pelvic inflammatory disease. She had no fever, epigastralgia, nausea, diarrhea, jaundice, or weight loss. She was referred for further management. The physical examination and routine blood tests were unremarkable. The serum carcinoembryonic antigen and carbohydrate antigen 19-9 levels were 1.18 ng/mL (normal

Clinical Infectious Diseases 2006;43:498-9 ? 2006 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2006/4304-0017$15.00 pain could not be relieved by rest and was not related to meals. He had a medical history of diabetes mellitus, which had been controlled by oral hypoglycemic agents. Physical examination revealed stable vital signs without fever. The tumor mass was not palpable. The laboratory analysis demonstrated a WBC count of 5.91 X 106 cells/mL (eosinophil percentage, 8.5%), a creatinine level of 0.9 mg/dL, a total bilirubin level of 7.31 mg/dL, a direct bilirubin level of 7.20 mg/dL, an aspartate aminotransferase level of 96 IU/L (normal level

Background and Aim: For reduction in cost, time and risk of complications, the number of endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) passes should be minimized. Previous studies have shown that tumor differentiation and site of aspiration will affect the number of passes in patients with pancreatic cancer. There have been no reports that EUS features of pancreatic malignancies per se will influence the number of passes. Our aim was to prospectively assess various factors that would affect the number of passes in patients with pancreatic cancer. Methods: Between May 2003 and December 2004, 41 patients with presumed pancreatic cancer were studied. EUS-guided FNA was performed with an Olympus GF-UC2000P echoendoscope and a 22-gauge needle. On-site assessment of the specimen by a cytopathologist was available during the procedure. Results: Adenocarcinomas were confirmed in 25 patients. Pancreatic adenocarcinomas with intratumoral anechoic foci required a higher number of diagnostic passes than those without anechoic change (3.40 vs 2.27, P

Interindividual differences in degrees and extent of gastritis are responsible for the divergent outcomes after H. pylori infection. Cellular responses in gastric inflammation are mediated by lipopolysaccharide of H. pylori, which activate monocytes to express cytokine expression and growth factors via CD14 and toll-like receptor 4 (TLR4). Whether functional polymorphisms of TLR 4 and CD14 account for H. pylori-related gastric malignancies remains unknown. This study aimed to investigate the contribution of CD14 and TLR4 genotypes to the risk of H. pylori-related gastric malignancies in a Chinese population.Genotyping for CD14 (-159C/T) and TLR4 (Asp 299Gly and Thr 399Ile) was performed in 70 patients with gastric mucosa-associated lymphoid tissue lymphoma (MALToma), 204 patients with non-cardia gastric adenocarcinoma (GAC), and 210 unrelated healthy controls. Distribution of genotype and allele frequencies among three groups was compared.The seropositive rate of H. pylori was significantly higher for non-cardia GAC (164/204, 80.4%) and MALToma (66/70, 94.3%) than controls (120/210, 57.5%, p0.001). A complete absence of Gly or Ile variants was noted for all the studied subjects. The genotype frequencies of CD14 in controls were C/C, 25.7%, C/T, 48.6%, and T/T, 25.7%, and did not deviate from the Hardy-Weinberg equilibrium. The distribution of CD14 genotype did not differ significantly among GAC, MALToma patients, and controls.These data suggest no apparent association of CD14 polymorphisms with H. pylori-related gastric malignancy and provide evidence for race-specific distribution of TLR4 alleles in Chinese population.

Purpose Helicobacter pylori infection and host susceptibility interact to develop gastric mucosa-associated lymphoid tissue (MALT) lymphoma, and activation of specific T cells might play a crucial role in this process. Recent investigations show that the CTLA4, CD28, and ICOS genes are located on chromosome 2q33 and their polymorphisms confer susceptibility to infectious and immune diseases through deregulation of T-cell stimulation. We aimed to determine the role of CTLA4, CD28, and ICOS polymorphisms in gastric MALT lymphoma. Patients and Methods Genotyping for CTLA4 (49 A/G, −318 C/T, and CT60 A/G), CD28 (IVS3+ 17T/C), and ICOS (c.602 A/C and c.1624C/T) was performed for 62 patients with gastric MALT lymphoma and compared with 250 unrelated healthy controls. Results H pylori infection was significantly higher in patients with gastric MALT lymphoma (90.3%) compared with controls (66.4%; P < .001). The CTLA4 −318 C/T genotype was associated with a lower risk of developing gastric MALT lymphoma (odds ratio [OR] = 0.3; P = .022), whereas CTLA4 49 G/G genotype was linked to a higher risk (OR = 4.1; P = .044). In patients with H pylori infection, CTLA4 49 G/G genotype was associated with an even higher risk (OR = 6.4; P = .047). Carriage of the tightly linked −318C –49G haplotype conferred a four-fold higher susceptibility to MALT lymphoma (OR = 4.2; P = .042). Complete remission after H pylori eradication was related to tumor stage but not to genotypes or haplotypes. Conclusion These results indicate a genetic link of CTLA4 gene polymorphisms to development of gastric MALT lymphoma and indirectly support the crucial role of host activated T cells in the MALT lymphomagenesis.

Gastric cancer (GC) is the second leading cause of cancer-related death. The poor survival rate may reflect the relatively aggressive tumor biology of GC. Recently, the importance of the tumor microenvironment in carcinogenesis has emerged. In the tumor microenvironment, tumor cells and the surrounding stromal cells aberrantly secrete matricellular proteins capable of modulating carcinogenesis and regulating metastasis. The Cyr61/CTGF/Nov (CCN) proteins are a family of matricellular proteins with variable roles in many physiological and pathological processes. The evidence suggests that CCN family proteins contribute to GC carcinogenic processes. Here, we briefly review recent research on the effects of CCN family proteins in GC carcinogenesis and the development of new targeted agents in this field.