Brugge et al. reported that cyst fluid CEA with a cut-off of 192 ng/mL accurately differentiated mucinous from non-mucinous cystic lesions. The accuracy of cyst fluid CEA was significantly greater than the accuracy of EUS morphology or cytology for the differentiation of mucinous from non-mucinous cystic lesions.43 Another study using pooled analysis showed that when CEA were > 800 ng/mL, the specificity for mucinous cysts was 98%.53 Guidelines state that cytodiagnosis and examination

of tumor markers are useful to distinguish mucinous cysts from other cystic lesions.54,55 Genetic analysis of cystic fluid by EUS-FNA might also be performed. Similar to pancreatic cancer, the development of malignancy in pancreatic cysts occurs through progressive accumulation of molecular alterations, including K-ras mutations.56 Positive K-ras mutation of cystic check details fluid enabled mucinous cysts to be distinguished from other cystic lesions (sensitivity 45%, specificity 62%), and when combined with CEA, the sensitivity could be increased to 84%.57 In summary, although cytological confirmation of pancreatic cyst could avoid misdiagnosis of mucinous versus non-mucinous cysts, and benign versus malignant

cysts, the low diagnostic yield of cyst fluid cytology and the potential risk for mucinous material leakage into the peritoneum leading to pseudomyxoma peritonei16 detract against the widespread use of EUS-FNA for

the diagnosis of pancreatic cystic lesions in some Asian countries, such as Japan. In light of this, further studies on the precise Palbociclib purchase medchemexpress role of EUS-FNA in the diagnosis and management of some or all pancreatic cysts in Asia need to be undertaken. EUS-FNA of pancreatic cysts is safer than previously thought as shown in several recent large series. Earlier studies, which included both solid and cystic lesions, consistently showed higher complication rates of 14% for cystic lesions, mainly pancreatic cysts.58 The image quality was poor with old processors. Subsequent change from radial scanners to linear scanners, which provide real-time imaging of the needle track during procedure, has led to improvement.59 Recent studies have shown significantly lower complication rates. However, the lack of consensus in the definition, classification, and grading of complications is the main limitation in comparing study outcomes. Hemorrhage and infectious complications are the most common and can result in serious adverse outcomes, as reported in the earlier studies. Hemorrhage can be intracystic or retroperitoneal. Intracystic hemorrhage occurs with variable frequency.60 Factors that might account for variable frequency include operator experience, differences among patients, use of color Doppler, and possible use of medication, such as non-steroidal anti-inflammatory drugs, before procedure.

Conclusions: The DSS-induced mouse colitis may promote hepatic inflammation and fibrosis in mice treated by CCl4. Disclosures: The following people have nothing to disclose: Xiaolan Zhang, Yufeng Liu, Libo Zheng, Guochao Niu, Hong Zhang, Jinbo Guo, Guozun Zhang, Huicong Sun “
“Clinical trials and animal models suggest that infusion of IBET762 bone marrow cells (BMCs) is effective therapy for liver fibrosis,

but the underlying mechanisms are obscure, especially those associated with early effects of BMCs. Here, we analyzed the early impact of BMC infusion and identified the subsets of BMCs showing antifibrotic effects in mice with carbon tetrachloride–induced liver Epigenetics Compound Library fibrosis. An interaction between BMCs and activated hepatic stellate cells (HSCs) was investigated using an in vitro coculturing system. Within 24 hours, infused BMCs were in close contact with activated HSCs, which was associated with reduced liver fibrosis, enhanced hepatic expression of interleukin (IL)-10, and expanded regulatory T cells

but decreased macrophage infiltration in the liver at 24 hours after BMC infusion. In contrast, IL-10–deficient (IL-10−/−) BMCs failed to reproduce these effects in fibrotic livers. Intriguingly, in isolated cells, CD11b+Gr1highF4/80− and CD11b+Gr1+F4/80+ BMCs expressed more IL-10 after coculturing with activated HSCs, leading to suppressed expression of collagen and α-smooth 上海皓元医药股份有限公司 muscle actin in HSCs. Moreover, these effects were either enhanced or abrogated, respectively, when BMCs were cocultured with IL-6−/− and retinaldehyde dehydrogenase 1−/− HSCs. Similar to murine data, human BMCs expressed

more IL-10 after coculturing with human HSC lines (LX-2 or hTERT), and serum IL-10 levels were significantly elevated in patients with liver cirrhosis after autologous BMC infusion. Conclusion: Activated HSCs increase IL-10 expression in BMCs (CD11b+Gr1highF4/80− and CD11b+Gr1+F4/80+ cells), which in turn ameliorates liver fibrosis. Our findings could enhance the design of BMC therapy for liver fibrosis. (HEPATOLOGY 2012;56:1902–1912) For the past decade, clinical trials and experimental studies have suggested that infusion therapy of whole bone marrow cells (BMCs) has beneficial effects toward liver regeneration, injury, and fibrosis/cirrhosis by stimulating the proliferation of hepatocytes, increasing progenitor cells, and enhancing matrix degradation.1-3 However, the underlying mechanisms are unknown, in part because whole BMCs contain a wide range of cell types, including several types of stem and precursor cells of monocytic and granulocytic lineages.4 Events associated with hepatic fibrosis are well characterized, notably the excessive production of extracellular matrix (ECM) by activated hepatic stellate cells (HSCs).

Conclusions: The DSS-induced mouse colitis may promote hepatic inflammation and fibrosis in mice treated by CCl4. Disclosures: The following people have nothing to disclose: Xiaolan Zhang, Yufeng Liu, Libo Zheng, Guochao Niu, Hong Zhang, Jinbo Guo, Guozun Zhang, Huicong Sun “
“Clinical trials and animal models suggest that infusion of PKC412 bone marrow cells (BMCs) is effective therapy for liver fibrosis,

but the underlying mechanisms are obscure, especially those associated with early effects of BMCs. Here, we analyzed the early impact of BMC infusion and identified the subsets of BMCs showing antifibrotic effects in mice with carbon tetrachloride–induced liver this website fibrosis. An interaction between BMCs and activated hepatic stellate cells (HSCs) was investigated using an in vitro coculturing system. Within 24 hours, infused BMCs were in close contact with activated HSCs, which was associated with reduced liver fibrosis, enhanced hepatic expression of interleukin (IL)-10, and expanded regulatory T cells

but decreased macrophage infiltration in the liver at 24 hours after BMC infusion. In contrast, IL-10–deficient (IL-10−/−) BMCs failed to reproduce these effects in fibrotic livers. Intriguingly, in isolated cells, CD11b+Gr1highF4/80− and CD11b+Gr1+F4/80+ BMCs expressed more IL-10 after coculturing with activated HSCs, leading to suppressed expression of collagen and α-smooth MCE公司 muscle actin in HSCs. Moreover, these effects were either enhanced or abrogated, respectively, when BMCs were cocultured with IL-6−/− and retinaldehyde dehydrogenase 1−/− HSCs. Similar to murine data, human BMCs expressed

more IL-10 after coculturing with human HSC lines (LX-2 or hTERT), and serum IL-10 levels were significantly elevated in patients with liver cirrhosis after autologous BMC infusion. Conclusion: Activated HSCs increase IL-10 expression in BMCs (CD11b+Gr1highF4/80− and CD11b+Gr1+F4/80+ cells), which in turn ameliorates liver fibrosis. Our findings could enhance the design of BMC therapy for liver fibrosis. (HEPATOLOGY 2012;56:1902–1912) For the past decade, clinical trials and experimental studies have suggested that infusion therapy of whole bone marrow cells (BMCs) has beneficial effects toward liver regeneration, injury, and fibrosis/cirrhosis by stimulating the proliferation of hepatocytes, increasing progenitor cells, and enhancing matrix degradation.1-3 However, the underlying mechanisms are unknown, in part because whole BMCs contain a wide range of cell types, including several types of stem and precursor cells of monocytic and granulocytic lineages.4 Events associated with hepatic fibrosis are well characterized, notably the excessive production of extracellular matrix (ECM) by activated hepatic stellate cells (HSCs).

2A). Hepatocytes underwent drastic morphological changes, including significant cell death, in the first few days of culture.

The remaining live cells either became flattened, forming cell clusters with many nuclei (e.g., polykaryons via possible endomitosis), or smaller as if they were undergoing apoptosis (i.e., cell shrinkage or condensation). Between days 5 and 7 of culture, LDPCs began to appear by either shrinkage of hepatocytes or by budding off from multinucleated cell clusters, a mechanism reminiscent of budding yeast (Fig. 2B). By day 14, LDPCs were the only cells left in culture, with the exception of few scattered fibroblast-like cells. Fluorescence images showed that virtually all LDPCs exhibited KU-60019 clinical trial green fluorescence (i.e., PHK2 positive), which decreased over time. Results were consistent with the hypothesis that they were Idelalisib price derived directly from PKH2-labeled hepatocytes and then underwent further cell divisions. Morphological changes in LDPC cultures suggested the transformation of hepatocytes (i.e., epithelial) into fibroblast-like cells (i.e., mesenchymal) before the appearance of LDPCs. Thus, we examined the expression of the mesenchymal markers, CD44 and vimentin, in a time-dependent manner by the cells in culture. IF studies

revealed that, whereas hepatocytes were negative for these mesenchymal markers on day 0, the cells in the culture began to express both CD44 and vimentin around day 4 and LDPCs were strongly positive for these 上海皓元 markers on day 12. This finding suggested that hepatocytes may be undergoing an epithelial mesenchymal transition (EMT) before giving rise to LDPCs, which appear to have a nonepithelial, mesenchymal phenotype. To confirm our morphological findings and provide quantitative data, we examined the kinetics of LDPC cultures by performing a cell count at certain time points during the culture period. This confirmed our previous observations

showing that more than 80% of the plated hepatocytes died by day 6, followed by rapid repopulation of the culture by LDPCs by day 14 nearly restoring the original cell number (Supporting Fig. 1A). Additionally, we performed a quantitative assessment of the total fluorescence of cultured cells by flow cytometry as further evidence for the origin of LDPCs. On days 1 and 14 of LDPC cultures, we collected all the cells cultured within indentical flasks and measured their total fluorescence (Supporting Fig. 1B). We found that nonhepatocyte cells constituted <1% of all cells with a fluorescence intensity of 0.01 units (arbitrary units; total intensity of all cells on day 1 was assigned a value of 1.0). Total fluorescence of LDPCs on day 14 averaged approximately 0.5 (average of three separate experiments), which was at least 50 times greater than the total fluorescence of nonhepatocyte cells on day 1.

To overcome these problems, a new modified method (NX-PVKA ratio) has been developed and reported.[63, 64] This method uses two antibodies (P-11 and P-16) that are reactive mainly to DCP produced by vitamin K deficiency and less reactive to DCP produce by HCC.[41] Several systematic reviews have

been previously performed to evaluate diagnostic accuracy of DCP and/or AFP for HCC. Tateishi et al. included 17 articles to evaluate the diagnostic accuracy of AFP, DCP and Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3) for HCC, and the result showed that DCP and AFP-L3 were superior to AFP for detecting HCC.[65] Gupta et al. conducted a systematic review and critical analysis about a summary estimate of the test characteristics of AFP for detecting HCC,[66] they demonstrated that sensitivity of AFP ranged from 41% to 65%, and specificity ranged from 80% to Crenolanib solubility dmso 94%. A recent review indicated that the summary sensitivity and specificity of DCP were 67% and 92%, respectively.[67] This finding is similar with our selleck chemicals llc results. However, there are several significant differences in our review from other studies. First, to our knowledge, this meta-analysis is the first to compare the diagnostic accuracy of DCP, AFP and combination of both markers as surveillance markers for HCC. Second, the present

review compares the diagnostic accuracy of these markers for detecting early stage HCC, which is essential for improving prognosis during surveillance. Third, the revised tool QUADAS-2 is used for the quality assessment. Significant heterogeneity within sensitivity and specificity presents in the current study by the forest plots and SROC plots, which can be explained by differences in diagnostic test

cut-off value, type 上海皓元 of study and reference standard. An ideal design study should enroll a consecutive or random sample of eligible patients with suspected disease to prevent the potential for selection of bias.[42] Study of Marrero[19] and sterling[33] are important outliers for DCP, with the Marrero study using a cut-off value of 125 mAU/mL, which is higher than those Asia studies (40–100 mAU/mL).[10, 11, 13-18, 20, 22-24, 28, 31, 34, 35, 38, 40, 41, 44-46, 49-56] Study of Sassa[14] and Morroto[32] were the primary heterogeneity for AFP detection, because the study of Sassa is a retrospective study and did not avoid the case-control study, which may lead to overestimation or underestimation of diagnostic accuracy. The cut-off value of AFP was one of the main reasons of heterogeneity, when AFP levels above 200 ng/mL may increase the specificity, but this value sacrifices sensitivity.[61] Therefore, the sensitivity of small HCC was low (8%) in Sassa’s study.

Results selleck compound rs16943333, rs3809724 and rs3809723 of PPM1E were not significant differences between the HCC group and the control group. In the further analysis, we divided HCC patients into two groups according to tumor size, serum AFP level, UICC stage, radiologic morphology and portal vein thrombosis. We found that rs16943333 and rs3809724 in PPM1E were significantly associated with the tumor size. The genotype frequency of rs16943333 was associated with tumor size in the codominant 2 (G/G vs. A/A, p=0. 038, Fisher’s exact p=0. 06, 〇R=6. 27, 95% CI = 1. 11-35. 41), dominant (G/G / G/A vs. A/A, p=0. 014, 〇R=2. 27, 95% CI=1.

174. 41) and log-additive models (p=0. 0058, 〇R-2. 16, 95% CI=1. 23-3. 79). In the allele frequency analysis, rs16943333 was associated with tumor size (p=0. 010, 〇R=2. 07, 95% CI=1. 19-3. 59). The genotype frequency of rs3809724 was associated with tumor size in the codominant 2 (C/C vs. T/T, p=0. 030, Fisher’s exact p=0. 09, 〇R=5. 31, 95% CI=1. 1724. 05), dominant (C/C / C/T vs. T/T, p=0. 030, 〇R=2. 04, 95% と1=1. 07-3. 89) and log-additive models (p=0. 011,

OR-1.97, 95% CI=1. 16-3. 37). In the allele frequency analysis, rs3809724 was associated with tumor size (p=0. 023, 〇R=1. 84, 95% CI=1. 09-3. 12). Conclusion In conclusion, we found that PPM1E polymorphisms were significantly associated with tumor size of HCC patients. In particular, the click here frequency of A alleles (rs16943333) and T allele (rs3809724) increased in HCC patients with large tumor size. Disclosures: The following people have nothing to disclose: Min Su Park MicroRNAs (miRNAs) are expressed in a tissue-specific manner, and play important roles in development, cell proliferation, apoptosis, and oncogenesis. Some tumor-suppressive miRNAs

are known to be epigenetically silenced by promoter DNA methylation MCE公司 in cancer. In the present study, we aimed to identify miRNA genes that are silenced by DNA hypermethylation in hepatocellular carcinoma (HCC). We screened for miRNA genes with promoter DNA hypermethylation using a genomewide methylation microarray analysis called Microarray-based Integrated Analysis of Methylation by Isoschizomers (MIAMI) in HCC cells. We compared DNA methylation profiles between three HCC cell lines (SNU449, Li-7, and PLC/PRF/5) and one normal liver tissue using the MIAMI method. The hypermethylated genes included eight miRNA genes (miR-let-7b, miR-101- miR-122a, miR-146b, miR-149, miR-200b, miR-335, and miR-497). Expression levels of six miRNAs (miR-let-7b, miR-101- miR-122a, miR-146b, miR-335, and miR-497) were lower in more than half of the 21 HCC cells than normal liver. Expression of four miRNAs (miR-101-2, miR-146b, miR-335, and miR497) were restored with 5-aza-dCyd treatment in all three HCC cells.

Results selleck chemicals llc rs16943333, rs3809724 and rs3809723 of PPM1E were not significant differences between the HCC group and the control group. In the further analysis, we divided HCC patients into two groups according to tumor size, serum AFP level, UICC stage, radiologic morphology and portal vein thrombosis. We found that rs16943333 and rs3809724 in PPM1E were significantly associated with the tumor size. The genotype frequency of rs16943333 was associated with tumor size in the codominant 2 (G/G vs. A/A, p=0. 038, Fisher’s exact p=0. 06, 〇R=6. 27, 95% CI = 1. 11-35. 41), dominant (G/G / G/A vs. A/A, p=0. 014, 〇R=2. 27, 95% CI=1.

174. 41) and log-additive models (p=0. 0058, 〇R-2. 16, 95% CI=1. 23-3. 79). In the allele frequency analysis, rs16943333 was associated with tumor size (p=0. 010, 〇R=2. 07, 95% CI=1. 19-3. 59). The genotype frequency of rs3809724 was associated with tumor size in the codominant 2 (C/C vs. T/T, p=0. 030, Fisher’s exact p=0. 09, 〇R=5. 31, 95% CI=1. 1724. 05), dominant (C/C / C/T vs. T/T, p=0. 030, 〇R=2. 04, 95% と1=1. 07-3. 89) and log-additive models (p=0. 011,

OR-1.97, 95% CI=1. 16-3. 37). In the allele frequency analysis, rs3809724 was associated with tumor size (p=0. 023, 〇R=1. 84, 95% CI=1. 09-3. 12). Conclusion In conclusion, we found that PPM1E polymorphisms were significantly associated with tumor size of HCC patients. In particular, the Talazoparib frequency of A alleles (rs16943333) and T allele (rs3809724) increased in HCC patients with large tumor size. Disclosures: The following people have nothing to disclose: Min Su Park MicroRNAs (miRNAs) are expressed in a tissue-specific manner, and play important roles in development, cell proliferation, apoptosis, and oncogenesis. Some tumor-suppressive miRNAs

are known to be epigenetically silenced by promoter DNA methylation medchemexpress in cancer. In the present study, we aimed to identify miRNA genes that are silenced by DNA hypermethylation in hepatocellular carcinoma (HCC). We screened for miRNA genes with promoter DNA hypermethylation using a genomewide methylation microarray analysis called Microarray-based Integrated Analysis of Methylation by Isoschizomers (MIAMI) in HCC cells. We compared DNA methylation profiles between three HCC cell lines (SNU449, Li-7, and PLC/PRF/5) and one normal liver tissue using the MIAMI method. The hypermethylated genes included eight miRNA genes (miR-let-7b, miR-101- miR-122a, miR-146b, miR-149, miR-200b, miR-335, and miR-497). Expression levels of six miRNAs (miR-let-7b, miR-101- miR-122a, miR-146b, miR-335, and miR-497) were lower in more than half of the 21 HCC cells than normal liver. Expression of four miRNAs (miR-101-2, miR-146b, miR-335, and miR497) were restored with 5-aza-dCyd treatment in all three HCC cells.

Several studies tested neutralizing antibodies against mature VEGF proteins, blockade of VEGF receptors by VEGF receptor antibodies, soluble VEGF receptor mutants or fusion-proteins, and intra-cellular interference with VEGF mRNA or kinase signaling pathways in the target cell. Inhibiting the process of angiogenesis by knocking out the activity of VEGF has a significant impact CB-839 clinical trial on tumor growth and patient survival. However, it does not seem to be enough for a complete cure. So it is still necessary to explore as many regulatory steps as possible in the complex sequence of tumor-induced angiogenesis. Besides the VEGF, FGF and its family of receptors (FGFR) are potent

inducers of angiogenesis in HCC.4,5 Elevated serum FGF levels are an important prognostic factor in HCC,6 and the aberrant activation of FGFR has been shown to drive hepatocarcinogenesis.7 FGF might also modulate the resistance to VEGF/VEGFR inhibition. For example, FGF2 has been shown to synergistically augment the VEGF-mediated HCC development and angiogenesis8 and might play a central role in the “escape mechanisms” implicated in VEGF/VEGFR targeting. Clinical and translational studies suggest that FGF blockade might circumvent resistance to

the VEGFR modulating agents.9 In a study of patients undergoing surgery for HCC, the high serum levels of FGF2 was shown to be a predictor for invasiveness and recurrence.10 Although the VEGF inhibitors can reduce the growth of the primary tumors, there are data AZD6244 in vitro showing that they might also MCE promote the invasiveness and metastasis of the tumor.11 Accordingly, novel anti-angiogenic therapies targeting FGF to synergize with VEGF-mediated anti-angiogenesis might provide a mechanism to overcome resistance to VEGF-targeted agents in HCC. So we should use the knowledge to inhibit the process of angiogenesis at a more sensitive point of angiogenesis, or at several

points simultaneously. To achieve this goal, the newly developed in vitro models of tumor growth and of blood vessel formation could be helpful. Actually, several agents that target the VEGF pathway have been tested in patients with advanced HCC, such as the oral multikinase inhibitors, sorafenib and sunitinib, whose antitumor effects are partly as a result of the inhibition of VEGF receptors. Although the SHARP trial showed only a 2.8-month improvement in median overall survival rate (P = 0.0006), along with very limited increased time to disease progression and disease control rate, and a 2.3% response rate, sorafenib became the first targeted agent approved to use in advanced HCC by the USA Food and Drug Administration.12 The monoclonal antibody against VEGF, bevacizumab, either used alone or in combination with erlotinib, has shown improved survival in advanced HCC patients. In this issue of the Journal, Jie et al.

The two main metabolites of AZA/MP are measurable – 6-thioguanine nucleotides (6TGN) and 6-methyl-mercaptopurine (6MMP). Cross sectional observational data suggest higher remission rates with 6TGN > 235 pmol/8 × 108 RBC, and higher toxicity with either 6TGN > 450 or 6MMP > 5700 pmol/8 × 108 RBC, leading to a Abiraterone proposed “therapeutic range”. Short term data have shown the potential for therapeutic drug monitoring (TDM) to optimize AZA/MP

therapy, guiding dose adjustment and identifying “shunters” whom preferentially produce 6MMP. However, there is no data evaluating TDM-led dosing’s effect in the longer-term. We therefore evaluated patient outcomes at least 12 months after TDM-led dosing of AZA/MP in a large adult IBD population. Methods: A multi-center, cross-sectional study was performed in four Australian IBD Services. Retrospective data were collected from clinical records of all adults with an established IBD diagnosis, on AZA/MP for >4 weeks at time of index TDM. Baseline patient demographics, disease characteristics, clinical status based on physician global assessment, IBD therapy

at index AZA/MP TDM, and these data ≥12 months after TDM-led management were collected. Indications for TDM were categorized. Therapeutic 6TGN range was defined as 235–450 pmol/8 × 108 RBC. Shunters were defined as a 6MMP:6TGN ratio ≥11. It is anticipated that 350–400 patients MLN8237 will be included in this study at completion. Results: To date, there are data for 192 patients, 124 (65%) with Crohn’s disease (CD), 106 (55%) male, mean age 42 years (median 42, range 19–84), 140 (73%) with active disease at baseline and mean disease duration of 17.4 years (median 10.4, range 1.68–54). TDM was most commonly performed for proactive dose

assessment (43%), persistently active disease (26%) and flare (21.4%). Prior to TDM, AZA/MP would have been ceased, or blind dosing increase performed in 56%. Overall, TDM led to continuation of thiopurines (± dose adjustment ± allopurinol) in 157 (82%), anti-TNFα therapy in 15 (7.6%), another medical agent in 12 and surgery in 3. At 12 months, 128 (66.7%) were in clinical remission, 14 (7%) had improved disease activity, 45 (23%) uncontrolled disease, and MCE公司 5 unknown activity status. Focusing on the 128 with clinical remission at 12 months, 74 (58%) achieved this with AZA/MP (± allopurinol), 27 (21%) with the addition of anti-TNFα therapy, 15 (15%) with another medical agent and 12 (12%) had surgery. Interestingly, 66 shunters (34.5% of the cohort) were identified – 27 at baseline, 20 with TDM-led dosing over the subsequent 12 months and 19 only identified on chart review (unrecognized by treating physician). 68% of shunters were in clinical remission at 12 months with >50% achieving this with AZA/MP-allopurinol co-therapy. Conclusion: AZA/MP TDM-led dosing allows many patients apparently “failing” therapy to continue the agent.

29 HCCs were defined by topography code C22.0 (primary liver cancer) and morphology codes 8170-1875. ICCs were identified by topography code C22.0 (primary liver cancer) and morphology codes 8160 and 8161, or by topography code C22.1 (intrahepatic bile duct cancer) and morphology codes 8010, 8020, 8140, 8160, and 8161. Only persons enrolled in Medicare parts A and B for at least 3 years before diagnosis of HCC or ICC were eligible for inclusion

to insure adequate time for prior diagnoses to be recorded. This criterion resulted in a minimum age of 68 years for the study participants. The following groups were excluded: persons younger than age 65 years at diagnosis, persons enrolled in Medicare because of disabilities or end-stage renal disease, buy Cobimetinib persons with unspecified diagnostic confirmation of HCC or ICC, persons with HCC or ICC identified solely by autopsy or death certificate, and persons enrolled in a health maintenance organization

during the study period, because Medicare health maintenance organization plans are not required to submit individual claims to Medicare. To minimize the possibility of erroneously including cancer metastatic to the liver, persons with prior diagnoses of stomach, colon, lung, pancreatic, breast, prostate, or rectal cancers were excluded. Individuals with no prior cancer diagnoses were selected as controls from a 5% random sample of Medicare beneficiaries residing in the geographic regions of R788 manufacturer the SEER-13 registries. 上海皓元 Controls had to have at least 3 years of enrollment in Medicare parts A and B. Control selection was based on the same inclusion and/or exclusion criteria as used for case selection. Controls

were assigned a pseudo-diagnosis date using a random number generator. Cases and controls were matched on the year of search for risk factors to minimize possible diagnostic trends. Metabolic syndrome was defined, as suggested by the U.S. National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III), as the presence of at least three of the following conditions: elevated waist circumference/central obesity, dyslipidemia (elevated triglycerides, lowered high-density lipoprotein), hypertension, and impaired fasting glucose.30 The corresponding medical conditions were selected using the following ICD-9-CM codes: Overweight, obesity: 278.0, 278.1, 278.01, 278.00, V77. Dyslipoproteinemia: 272.0, 272.1, 272.2, 272.4, 272.5, 272.9; Hypertension: 401, 401.0, 401.1, 401.9, 402.0, 402.1, 402.9, 403.0, 403.1, 403.9, 404, 404.0, 404.1, 404.9, 278.0, 278.00, 278.01, 278.02, 278.1, V77.8, 783.1, 278.02; Impaired fasting glucose/diabetes mellitus: 250, 790.2, 790.21, 790.22, 790.29.31 Because there is no specific ICD-9-CM code for elevated waist circumference, obesity served as the proxy variable.