Ellagic acid inhibits gastric cancer cells by modulating oxidative stress and inducing apoptosis

Objective:To evaluate the anticancer effect of ellagic acid on gastric cancer cells.Methods:MTT assay was used to evaluate the effect of ellagic acid at different concentrations(0.5-100μg/mL)on gastric cancer AGS cells.RT-qPCR and Western blot analyses were applied to assess apoptosis(BCL-2,CASP-3,and BAX)and autophagy(LC3,ATG5,and BECN1)in AGS cells treated with ellagic acid.The expression of invasion-related markers including TP53,CDKN2A,and PTEN was determined.In addition,cell cycle markers including cyclin A,B,D,and E were measured by ELISA.Oxidative stress markers were evaluated using spectrophotometry.Results:Ellagic acid inhibited the proliferation of AGS cells in a concentration-and time-dependent manner.The expression of BCL-2 was significantly decreased(P<0.05)and CASP-3 and BAX were markedly increased(P<0.01)in AGS cells treated with ellagic acid.However,this compound induced no significant changes in the expression levels of LC3,ATG5,and BECN1(P>0.05).Moreover,the oxidative stress markers including SOD,TAC,and MDA were increased by ellagic acid(P<0.01).Conclusions:Ellagic acid can inhibit cell proliferation,induce apoptosis,and modulate oxidative stress in AGS cells.However,further in vivo and molecular studies are needed to verify its anticancer efficacy.

Extrahepatic biliary cancer:New staging classification

Tumor staging defines the point in the natural history of the malignancy when the diagnosis is made. The most common staging system for cancer is the tumor, node, metastases classification. Staging of cancers provides useful parameters in the determination of the extent of disease and prognosis. Cholangiocarcinoma are rare and refers to cancers that arise from the biliary epithelium. These tumors can occur anywhere along the biliary tree. These tumors have been previously divided into extrahepatic and intrahepatic lesions. Until recently the extrahepatic bile duct tumors have been considered as a single entity per American Joint Com- mission on Cancer (AJCC) staging classification. The most recent changes to the AJCC classification of bile duct cancers divide the tumors into two major catego- ries: proximal and distal tumors. This practical classifi- cation is based on anatomy and surgical management. High quality cross-sectional computed tomography (CT) and/or magnetic resonance (MR) imaging of the abdomen are essential information to accurately stage this tumors. Imaging plays an important role in diag-nosis, localization, staging and optimal management of cholangiocarcinoma. For example, it helps to localize the tumor to either perihilar or distal bile duct, both of which have different management. Further, it helps to accurately stage the disease and identify the presence of significant nodal and distant metastasis, which may preclude surgery. Also, it helps to identify the extent of local invasion, which has a major impact on the management. For example, extensive involvement of hepatic duct reaching up to second-order biliary radi- cals or major vascular encasement of portal vein or hepatic arteries precludes curative surgery and patient may be managed by palliative therapy. Further, imag- ing helps to identify any anatomical variations in the hepatic arterial or venous circulation and biliary ductal system, which is vital information for surgical planning. This review presents relevant clinical presentation and imaging acquisition and presentation for the accurate staging classification of bile duct tumors based on the new AJCC criteria. This will be performed with the as- sistance of anatomical diagrams and representative CT and MR images. The image interpretation must include all relevant imaging information for optimum staging. Detailed recommendations on the items required on the radiology report will be presented.

Imaging of pancreatic ductal adenocarcinoma: State of the art

Significant advances in imaging technology have changed the management of pancreatic cancer. In computed tomography (CT), this has included development of multidetector row, rapid, thin-section imaging that has also facilitated the advent of advanced reconstructions, which in turn has offered new perspectives from which to evaluate this disease. In magnetic resonance imaging, advances including higher field strengths, thin-section volumetric acquisitions, diffusion weighted imaging, and liver specific contrast agents have also resulted in new tools for diagnosis and staging. Endoscopic ultrasound has resulted in the ability to provide high-resolution imaging rivaling intraoperative ultrasound, along with the ability to biopsy via real time imaging suspected pancreatic lesions. Positron emission tomography with CT, while still evolving in its role, provides whole body staging as well as the unique imaging characteristic of metabolic activity to aid disease management. This article will review these modalities in the diagnosis and staging of pancreatic cancer.

Can imaging patterns of neuroendocrine hepatic metastases predict response yttruim-90 radioembolotherapy?

AIM:To evaluate the response to treatment in patients with neuroendocrine tumor liver metastases following yttrium-90 ( 90 Y) radioembolotherapy, as a function of image patterns at presentation for 90 Y radioembolotherapy. METHODS: The study cohort consisted of patients with hepatic metastatic neuroendocrine tumors treated with 90 Y at our institution during a two-year time period. Hepatic metastases were evaluated on a pretherapy study assessing relative arterial enhancement compared to liver, lesion size, necrosis of the lesion, and associated tumor burden in the liver. We used six response criteria: Response Evaluation Criteria in Solid Tumors (RECIST) size, World Health Organization (WHO) size, European Association for the Study of the Liver (EASL) necrosis guidelines, Choi size, Choi necrosis and combination of Choi size and necrosis. RESULTS: About 65 lesions in 17 patients met study criteria and formed the cohort. Statistically significant response was found for lesions 【 5 cm vs those ≥5 cm with RECIST (P = 0.04), WHO (P = 0.002) and combined Choi criteria (P = 0.02). Hyperenhancing lesions demonstrated greater response only with the Choi size criteria (P = 0.04). Lesions with ≤ 50% necrosis on the pre-scan had statistically significant greater response with the Choi necrosis criteria (P = 0.01). There was no statistical significance for response comparing lesions 【 2 cm vs ≥ 2 cm or in comparing the degrees of tumor burden. CONCLUSION: Based on our findings in this study, it is suggested that initial imaging findings, as listed above, are not a good predictor of response to 90 Y radioembolization.

Liver atrophy after percutaneous transhepatic portal embolization occurs in two histological phases: Hepatocellular atrophy followed by apoptosis

AIM To clarify the histological changes associated with liver atrophy after percutaneous transhepatic portalembolization(PTPE) in pigs and humans. METHODS As a preliminary study, we performed pathological examinations of liver specimens from five pigs that had undergone PTPE in a time-dependent model of liver atrophy. In specimens from embolized lobes(EMB) and nonembolized lobes(controls), we measured the portal vein to central vein distance(PV-CV), the area and number of hepatocytes per lobule, and apoptotic activity using the terminal deoxynucleotidyl transferase dU TP nickend labeling assay. Immunohistochemical reactivities were evaluated for light chain 3(LC3) and lysosomal-associated membrane protein 2(LAMP2) as autophagy markers and for glutamine synthetase and cytochrome P450 2 E1(CYP2 E1) as metabolic zonation markers. Samples from ten human livers taken 20-36 d after PTPE were similarly examined. RESULTS PV-CVs and lobule areas did not differ between EMB and controls at day 0, but were lower in EMB than in controls at weeks 2, 4, and 6(P ≤ 0.001). Hepatocyte numbers were not significantly reduced in EMB at day 0 and week 2 but were reduced at weeks 4 and 6(P ≤ 0.05). Apoptotic activity was higher in EMB than in controls at day 0 and week 4. LC3 and LAMP2 staining peaked in EMB at week 2, with no significant difference between EMB and controls at weeks 4 and 6. Glutamine synthetase and CYP2 E1 zonation in EMB at weeks 2, 4, and 6 were narrower than those in controls. Human results were consistent with those of porcine specimens. CONCLUSION The mechanism of liver atrophy after PTPE has two histological phases: Hepatocellular atrophy is likely caused by autophagy in the first 2 wk and apoptosis thereafter.

Second premolar agenesis is associated with mandibular form： a geometric morphometric analysis of mandibular cross-sections

The aim of this study was to compare mandibular form （i.e., size and shape） between patients with agenesis of the lower second premolar （P2） and a control group with no agenesis. Three hypotheses were tested： （H1） agenesis causes a change in mandibular morphology because of inadequate alveolar ridge development in the area of the missing tooth （mandibular plasticity）; （H2） agenesis is caused by spatial limitations within the mandible （dental plasticity）; and （H3） common genetic/ epigenetic factors cause agenesis and affect mandibular form （pleiotropy）. A geometric morphometric analysis was applied to cross-sectional images of computed tomography （CT） scans of three matched groups （n= 50 each）： （1） regularly erupted P2; （2） agenesis of P2 and the primary second molar in situ; and （3） agenesis of P2 and the primary second molar missing for 〉3 months. Cross-sections of the three areas of interest （first premolar, P2, first molar） were digitized with 23 landmarks and superimposed by a generalized Procrustes analysis. On average, the mandibular cross-sections were narrower and shorter in patients with P2 agenesis compared with that in the control group. Both agenesis groups featured a pronounced submandibular fossa. These differences extended at least one tooth beyond the agenesis-affected region. Taken together with the large interindividual variation that resulted in massively overlapping group distributions, these findings support genetic and/or epigenetic pleiotropy （H3） as the most likely origin of the observed covariation between mandibular form and odontogenesis. Clinically, reduced dimensions and greater variability of mandibular form, as well as a pronounced submandibular fossa, should be expected during the treatment planning of patients with P2 agenesis.

A model System for Validation of PET Radiopharmaceuticals: Focusing on Tumor Microenvironment

Positron emission tomography (PET) imaging has emerged as an important clinical tool for cancer management, and specifically targeted radiopharmaceuticals play critical roles on PET molecular imaging. Solid cancers have highly complex and heterogeneous microenvironment, this review focused on those microenvironmental factors such as hypoxia, proliferation and perfusion and, accordingly, a novel test system for validation of current and novel targeted imaging radiopharmaceuticals. In this review, we have introduced the establishment of cancer and metastases models in nude mice, visualization of microenvironmental components of hypoxia, proliferation, perfusion, stroma and necrosis in cancers and metastases for establishing the microenvironment based model system, and validation of several radio- pharmaceuticals such as 18F-fluoro-2-deoxyglucose (18F-FDG) 18F-fluorothymidine (18F-FLT), 18F-misonidazole (18F- FMISO) using the system. We found that 18F-FLT accumulates in proliferating cancer cells, while 18F-FMISO and 18F-FDG mostly accumulate in hypoxic and non-proliferative cancer cells, 18F-FDG shares roughly similar intratumoral distribution pattern with 18F-FMISO and IAZGP, but mutually excludes 18F-FLT. This model system validated current tracers for imaging glucose metabolism, hypoxia and proliferation in cancer and metastases, therefore, can be used for novel targeted radiopharmaceuticals validation.

北美神经内分泌肿瘤学会和核医学与分子影像学会有关177Lu-DOTATATE肽受体放射性核素治疗患者选择和合理应用共识

随着177Lu-1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸-D-苯丙氨酸1-酪氨酸3-苏氨酸8-奥曲肽(DOTATATE)肽受体放射性核素治疗(PRRT)的日益普及,有关患者合理选择的问题日益增多。该文回顾了有关177Lu-DOTATATE在不同原发性神经内分泌肿瘤(NETs)中的应用文献,讨论了一些有争议的问题,并回顾了治疗的潜在禁忌证。此共识是由北美神经内分泌肿瘤学会(NANETS)和核医学与分子影像学会(SNMMI)共同制定的。NANETS是成立于2005年的北美多学科神经内分泌专家专业学会,目的在于通过增加研究和教育机会改善对NETs的管理。NANETS致力于多学科研究,由NETs涉及的不同专业的医师和科学家组成。SNMMI成立于1954年,旨在促进核医学科学、技术和实践应用的国际性科学专业组织,除了出版期刊、时事通讯和书籍外,还主办提高核医学从业人员能力和促进核医学科学新发展的国际会议及讲习班。