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The objectives of this study were to evaluate the delamination of convex-shaped metformin HCl (MF) and evogliptin tartrate (EG) multi-layer tablets depending on the pre-compression and main compression pressures and simultaneously correlate these results with those of a surface roughness analysis. Free-flowing MF and EG (median diameters of 38.3 and 44.7 μm, respectively) granules prepared using the wet granulation method were pre-compressed and subsequently compressed into bilayer and trilayer tablets using a universal testing machine. The compaction force required to break the tablets increased linearly as the main compression pressure increased (30–150 MPa). Conversely, the interfacial strength and compaction breaking force decreased as the pre-compression pressure increased (10–110 MPa). A surface roughness analysis employing a profilometer revealed that the first layer (MF) roughness drastically decreased from 5.89 to 0.51 μm (Ra, arithmetic average of profile height deviations from the mean line) as the pre-compression pressure increased from 10 to 150 MPa in the bilayer tablet. Accordingly, the decrease in the roughness of the first layer reduced the inter-penetration at the interface, as observed via energy dispersive spectrometer (EDS)-equipped scanning electron microscopy, decreasing the interfacial bonding strength and causing delamination of the MF/EG multi-layer tablets. These findings indicate the significance of roughness control in the actual preparation of multi-layer tablets and the usefulness of profilometer- and EDS-based surface analyses for interpreting the delamination of multi-layer tablets. [ABSTRACT FROM AUTHOR]

Initially, endoscopic ultrasound ( EUS) was developed to inspect the pancreas and other organs adjacent to the gastrointestinal tract. After introduction of curvilinear-array echoendoscopes, EUS has been used for a variety of interventions in gastroenterology, including fine needle aspiration, pancreatobiliary drainage and tumor ablation. EUS-guided ablation of pancreatic cystic tumors with ethanol and with or without cytotoxic agents has been studied, showing its potential to become an alternative to surgery. However, only few attempts at using ethanol ablation to treat solid pancreatic tumors have been reported. Recently, EUS-guided radiofrequency ablation was introduced and has been cautiously applied for pancreatic cancer. This article focuses on the clinical application of EUS for the ablation of solid pancreatic tumors. [ABSTRACT FROM AUTHOR]

Background and Aim Radiofrequency ablation (RFA) and ethanol ablation are accepted methods of tissue destruction for treating cystic tumors. The aim of the present study was to evaluate the feasibility, efficacy, and safety of endoscopic ultrasound (EUS)-guided ablation using normal porcine gallbladders as a substitute model for branch-duct intraductal papillary mucinous neoplasms (BD-IPMN). Methods Six adult mini pigs were included in this prospective study. EUS-guided RFA with or without ethanol ablation of the gallbladder was carried out using a prototype 18-gauge endoscopic RFA electrode, and RFA and ethanol ablation were done in a single session. Outcomes were assessed in terms of macroscopic and microscopic evaluations of the treated gallbladders. Results The prototype RFA electrode was used for ablation of the mucosa, aspiration of the internal contents of the gallbladder, and ethanol injection. RFA plus ethanol lavage resulted in a greater mean percentage of denuded gallbladder mucosa (97.5%) than RFA alone (55.8%). Effects of ablation extending to the cystic duct and partially denuded cystic duct mucosae were detected in five of the six pigs. There were no major procedure-related adverse events. Conclusions EUS-guided ablation of the gallbladder mucosa was feasible and effective in the porcine model. Additional studies will be required to fully assess the risk of procedure-related damage to the main pancreatic duct before using this technique in a clinical setting. [ABSTRACT FROM AUTHOR]

In this study, we report the anti-proliferative effect and molecular mechanism of Chrysanthemum indicum ( C. indicum) on A549 human alveolar basal epithelial cells. We also analyzed the changes in C. indicum component profiles due to modifications of predrying process, flower size, and extraction method. Among the varieties of modifications tested, high-temperature heat dry (HTD) of small flower biotype followed by the methanolic extraction resulted in the strongest anti-proliferative activity of C. indicum extract in A549 cells. High-performance liquid chromatography of C. indicum revealed that the levels of acacetin 7- O-rutinoside (linarin) are markedly increased by heat treatment, especially HTD. Finally, we showed that linarin-mediated inhibition of cell proliferation is associated with suppression of Akt activation and induction of cyclin-dependent kinase inhibitor p27Kip1 as evidenced by cell cycle analysis and treatment with LY294002, an inhibitor of phosphatidylinositol 3-kinase/Akt pathway. Taken together, these findings suggest the need for further development and evaluation of linarin from C. indicum for the treatment and prevention of lung cancer. [ABSTRACT FROM AUTHOR]

Conjugated cis/trans isomer-based polymer membranes were prepared with 15–25 mol% of bis(4-hydroxyphenyl)-1,2-diphenylethylene (BHDPE). BHDPE has a conjugated nonplanar conformation structure containing the peripheral four aromatic rings which facilitate the formation of π-π interactions. A series of sulfonated poly(ethersulfone)s (S-PBHDPE) was synthesized with concentrated sulfuric acid. The sulfonation took place selectively on the BHDPE unit, and simultaneously on the side-chain and main-chain phenyl groups. The S-PBHDPEs consisted of a 4:6 ratio of cis and trans form mixtures. The S-PBHDPE membrane structures and characteristics were evaluated by 1H NMR spectroscopy, and their thermal stabilities evaluated. The ion exchange capacity (IEC), water uptake (WU) and proton conductivity of the membranes were evaluated as a function of the molar percentage of the sulfonic acid group. The WU of the synthesized S-PBHDPE membranes ranged from 21 to 52%, compared with 28% for Nafion 211®. The S-PBHDPE membranes exhibited proton conductivities (80 °C, RH100) of 42.7–125.6 mS/cm, compared with 137.4 mS/cm for Nafion 211®. The surface morphologies of S-PES 40 and S-PBHDPE 20 membranes were studied by AFM images. [ABSTRACT FROM AUTHOR]

Abstract: Phosphoric acid-doped sulfonated poly(tetra phenyl phthalazine ether sulfone) (PA-SPTPPES) copolymers were successfully synthesized by the 4,4′-dihydroxydiphenylsulfone with 1,2-bis(4-fluorobenzoyl)-3,4,5,6-tetraphenylbenzene (BFBTPB) and 4,4′-difluorodiphenylsulfone in sulfolane. Poly(tetra phenyl phthalazine ether sulfone)s (PTPPESs) were prepared via an intramolecular ring-closure reaction of dibenzoylbenzene of precursor and hydrazine. The sulfonated poly(tetra phenyl phthalazine ether sulfone) (SPTPPES) membranes were obtained by sulfonation under concentrated sulfuric acid, and followed phosphoric acid-doped by immersion in phosphoric acid. Different contents of doped and sulfonated unit of PA-SPTPPES (10, 15, 20 mol% of BFBTPB) were studied by FT-IR, 1H NMR spectroscopy, and thermo gravimetric analysis (TGA). The ion exchange capacity (IEC) and proton conductivity of SPTPPESs and PA-SPTPPESs were evaluated with increase of degree of sulfonation and doping level. The PA-SPTPPESs membranes exhibit proton conductivities (80 °C, relative humidity 30%) of 41.3 ∼ 74.1 mS/cm and the maximum power densities of PA-SPTPPES 10, 15, and 20 were about 294, 350, and 403 mW/cm2. [Copyright &y& Elsevier]

Abstract: Phosphoric acid-doped sulfonated poly(tetra phenyl isoquinoline ether sulfone)s (PA-SPTPIESs) were successfully synthesized for high temperature proton exchange membrane. Poly(tetra phenyl ether ketone sulfone)s (PTPEKS) were prepared from 1,2-bis(4-fluorobenzoyl)-3,4,5,6-tetraphenyl benzene (BFBTPB) and bis(4-fluorohenyl) sulfone with bis(4-hydroxyphenyl) sulfone. The synthesis of the poly(tetra phenyl isoquinoline ether sulfone)s (PTPIESs), was carried out via an intramolecular ring-closure reaction of dibenzoylbenzene of PTPEKS with benzylamine. The sulfonated poly(tetra phenyl isoquinoline ether sulfone)s (SPTPIESs) were obtained by following sulfonation with concentrated sulfuric acid and doped by phosphoric acid. Different contents of sulfonated unit on PTPIESs (8, 12, 16 mol% of BFBTPB) and PA-SPTPIESs were studied by FT-IR, 1H NMR spectroscopy, and thermogravimetric analysis (TGA). Strong acid–base interaction effect between poly benzisoquinoline (PBI) and sulfonic acid groups formed ionic crosslinking network between polymer chains. The ion exchange capacity (IEC) and proton conductivity of PA-SPTPIESs were evaluated with degree of sulfonation and doping of phosphoric acid. [Copyright &y& Elsevier]

Abstract: Sulfonated multi-block copolymers (SMBPs) were successfully synthesized from precursors of hydrophilic and hydrophobic block oligomers. The hydrophilic block oligomer was synthesized using 1,2-bis(4-fluorobenzoyl)-3,4,5,6-tetraphenylbenzene (BFBTPB) and 4,4′-(2,2-diphenylethenylidene) diphenol (DHTPE). The hydrophobic block oligomer was prepared by bis(4-hydroxyphenyl) sulfone and bis(4-fluorophenyl) sulfone. The sulfonation was taken selectively on hydrophilic block segment as well as para position of the pendant phenyl groups with concentrated sulfuric acid. To control the IEC the stoichiometry mole ratios were changed with hydrophilic blocks of 10, 13 and 17 mol%. The structural properties of SMBPs were studied by FT-IR, 1H NMR spectroscopy, thermogravimetric analysis (TGA), and atomic force microscope (AFM). The water uptakes were 9.7–42.3% at 30 °C and 14.3%–70.4% at 80 °C with changing the ion exchange capacities. The resulted ion exchange capacities (IEC) were 1.09–1.63 meq./g. The highest power density of a fuel cell using SMBP 17 (IEC = 1.63 meq./g) and Nafion 211 was 0.41 and 0.45 W/cm2, respectively, at 0.6 V. [Copyright &y& Elsevier]

Abstract: The poly(tetraphenyl ether ketone sulfone)s (PTPEKSs) were synthesized from 1,2-bis(4-fluorobenzoyl)-3,4,5,6-tetraphenyl benzene (BFBTPB) and bis(4-fluorophenyl) sulfone with bis(4-hydroxydiphenyl) sulfone in sulfolane. The synthesis of poly(tetraphenyl phthalazine ether sulfone)s (PTPPESs) was carried out via an intramolecular ring-closure reaction of dibenzoylbenzene moiety with hydrazine monohydrate. The PTPPES-QAHs [poly(tetraphenyl phthalazine ether sulfone-quaternary ammonium hydroxide)]s were synthesized via chloromethylation of PTPPES, quaternization with trimethylamine, and followed by an anion exchange of tetra-quaternary ammonium chloride polymers with KOH. Different contents of quaternized unit in PTPPES-QAH (15, 20, 25 mol% of BFBTPB) were studied by FT-IR, 1H NMR spectroscopy, and thermogravimetric analysis (TGA). Sorption experiments were conducted to observe the interaction of quaternized polymers with water. The ion exchange capacity (IEC), ion conductivity and cell performance of PTPPES-QAH were evaluated with increasing the degree of quaternization. [Copyright &y& Elsevier]

Abstract: Multi-sulfonated block copolymers (MSBPs) with sulfonated units of 5, 9, 10, and 14mol% were successfully synthesized for proton exchange membrane. The hydrophobic block oligomer was prepared by 4,4′-dihydroxydiphenylsulfone and 4,4′-difluorodiphenylsulfone. And also hydrophilic block oligomer was prepared by multiphenyl structured monomers of 1,2-bis(4-fluorobenzoyl)-3,4,5,6-tetraphenylbenzene and 1,2-bis(4-hydroxyphenyl)-3,4,5,6-tetraphenylbenzene by varying the different mole ratio to control the degree of sulfonation. The two steps of sulfonation was carried out under chlorosulfonic acid, and then concentrated sulfuric acid separately. The sulfonation was performed selectively on hydrophilic block segment and para position of the side chain phenyl groups. MSBPs were studied by FT-IR, 1H NMR spectroscopy, and thermo gravimetric analysis (TGA). Sorption experiments were conducted to observe the interaction of MSBPs with water. The wateruptakes were 9.6–42.5% at 25°C and 14.7–90.8% at 80°C. The resulted ion exchange capacities (IEC) were 0.79–1.87(mmolg−1) and proton conductivities were evaluated as increasing IEC. [Copyright &y& Elsevier]

Abstract: A series of poly(arylene ether sulfone)s containing tetra-quaternary ammonium hydroxide on fluorenyl group (QAPAES-OH) were synthesized via polycondensation, chloromethylation, quaternization, and the subsequent ion exchange reactions. The tetra-quaternary ammonium hydroxide polymers rendered an elevated molecular weight and exhibited an outstanding solubility in aprotic polar solvents. Consequently, flexible and tough alkaline membranes with varying ionic contents were obtained by an anion exchange of tetra-quaternary ammonium chloride polymers with 1.0M KOH at room temperature. Quaternization and the following ion exchange reactions were quantitative so that the obtained ionomer membranes could have high ion exchange capacity (IEC) upto 1.73mmolg−1. High hydroxide ion conductivity was achieved up to 30.7mScm−1 at 80°C with the membrane of the highest IEC. The resulting polymers were characterized by 1H NMR, FT-IR, and TGA. [Copyright &y& Elsevier]

Abstract: Sulfonated poly(tetra phenyl ether ketone sulfone)s SPTPEKS were successfully synthesized for proton exchange membrane. Poly(tetra phenyl ether ketone sulfone)s PTPEKS were prepared by the 4,4′-dihydroxydiphenylsulfone with 1,2-bis(4-fluorobenzoyl)-3,4,5,6-tetraphenylbenzene (BFBTPB) and 4,4′-difluorodiphenylsulfone, respectively, at 210 °C using potassium carbonate in sulfolane. PTPEKS were followed by sulfonation using chlorosulfonic acid and concentrated sulfuric acid at two stage reactions. Different contents of sulfonated unit of SPTPEKS (17, 20, 23 mol% of BFBTPB) were studied by FT-IR, 1H NMR spectroscopy, and thermo gravimetric analysis (TGA). Sorption experiments were conducted to observe the interaction of sulfonated polymers with water. The ion exchange capacity (IEC) and proton conductivity of SPTPEKS were evaluated with increase of degree of sulfonation. The water uptake of synthesized SPTPEKS membranes exhibit 25–61% compared with 28% of Nafion 211®. The SPTPEKS membranes exhibit proton conductivities (25 °C) of 11.7–25.3 × 10−3 S/cm compared with 33.7 × 10−3 S/cm of Nafion 211®. [Copyright &y& Elsevier]

Abstract: Novel ionic liquids based on acetyl imidazolium iodide named as ACII-(NH2, Amide, and Urea) were synthesized and used as electrolytes in dye-sensitized solar cells (DSSCs). The synthesized ACII-NH2 and ACII-Amide are solid state, but ACII-Urea was viscous liquid. These electrolytes have characteristics of an intra- or inter molecular hydrogen bonding interaction through its amine, amide, and urea bonds. And thermogravimetric analysis showed good thermal stability. Among the three ACII based electrolytes, ACII-Urea showed a maximum photo-conversion efficiency of 7.17%. In addition, the performance of the DSSCs showed relatively reasonable compared with other conventional liquid type electrolytes. [Copyright &y& Elsevier]

Abstract: Tissue inhibitor of metalloproteinases-2 (TIMP-2) inhibits angiogenesis by several mechanisms involving either MMP inhibition or direct endothelial cell binding. The primary aim of this study was to identify the TIMP-2 region involved in binding to the previously identified receptor integrin α3β1, and to determine whether synthetic peptides derived from this region retained angio-inhibitory and tumor suppressor activity. We demonstrated that the N-terminal domain of TIMP-2 (N-TIMP-2) binds to α3β1 and inhibits vascular endothelial growth factor-stimulated endothelial cell growth in vitro, suggesting that both the α3β1-binding domain and the growth suppressor activity of TIMP-2 localize to the N-terminal domain. Using a peptide array approach we identify a 24 amino acid region of TIMP-2 primary sequence, consisting of residues Ile43–Ala66, which shows α3β1-binding activity. Subsequently we demonstrate that synthetic peptides from this region compete for TIMP-2 binding to α3β1 and suppress endothelial growth in vitro. We define a minimal peptide sequence (peptide 8-9) that possesses both angio-inhibitory and, using a murine xenograft model of Kaposi''s sarcoma, anti-tumorigenic activity in vivo. Thus, both the α3β1-binding and the angio-inhibitory activities co-localize to a solvent exposed, flexible region in the TIMP-2 primary sequence that is unique in amino acid sequence compared with other members of the TIMP family. Furthermore, comparison of the TIMP-2 and TIMP-1 protein 3-D structures in this region also identified unique structural differences. Our findings demonstrate that the integrin binding, tumor growth suppressor and in vivo angio-inhibitory activities of TIMP-2 are intimately associated within a unique sequence/structural loop (B–C loop). [Copyright &y& Elsevier]

Abstract: Sulfonated amine-poly(ether sulfone)s (S-APES)s were prepared by nitration, reduction and sulfonation of poly(ether sulfone) (ultrason®-S6010). Poly(ether sulfone) was reacted with ammonium nitrate and trifluoroacetic anhydride to produce the nitrated poly(ether sulfone), and was followed by reduction using tin(II)chloride and sodium iodide as reducing agents to give the amino-poly(ether sulfone). The S-APES was obtained by reaction of 1,3-propanesultone and the amino-poly(ether sulfone) (NH2-PES) with sodium methoxide. The different degrees of nitration and reduction of poly(ether sulfone) were successfully synthesized by an optimized process. The reduction of nitro group to amino was done quantitatively, and this controlled the contents of the sulfonic acid group. The films were converted from salt to acid forms with dilute hydrochloric acid. Different contents of sulfonated unit of the S-APES were studied by FT-IR, 1H NMR spectroscopy, differential scanning calorimetry (DSC), and thermo gravimetric analysis (TGA). Sorption experiments were conducted to observe the interaction of sulfonated polymers with water and methanol. The ion exchange capacity (IEC), a measure of proton conductivity, was evaluated. The S-APES membranes exhibit conductivities (25 °C) from 1.05 × 10−3 to 4.83 × 10−3 S/cm, water swell from 30.25 to 66.50%, IEC from 0.38 to 0.82 meq/g, and methanol diffusion coefficients from 3.10 × 10−7 to 4.82 × 10−7 cm2/S at 25 °C. [ABSTRACT FROM AUTHOR]

ABSTRACT Background and aim: Recently, endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) has been introduced in the diagnosis of pancreatic lesions, adjacent lymph nodes, and organs. To investigate the usefulness of liquid-based cytology (LBC) in EUS-FNA, we compare the efficacy of the conventional smear (CS) and LBC in EUS-FNA specimens. Methods: Forty-three paired LBC and CS slides were obtained using a split sample protocol. The specimen adequacy and diagnostic values were compared. Results: The adequate cases for diagnosis were 36 (83.7%) in CS and 22 (51.2%) in LBC. Inadequate samples were mostly obtained from lymph nodes: 6 cases in CS and 17 in LBC. The sensitivity, specificity, and accuracy of CS and LBC were as follows: 90.5%, 95.5%, and 93.0% in CS, respectively, and 57.1%, 100%, and 79.1% in LBC. The false-negative and false-positive rates were 4.7% and 2.3% in CS, respectively, and 20.9% and 0% in LBC. The overall agreement of CS and LBC for the diagnosis of malignancy was high (κ= 0.616). Conclusions: CS is a more effective and adequate preparation method for use in EUS-FNA-based diagnosis. Considering the split sample protocol of this study, LBC is a comparable diagnostic tool to CS in the evaluation of EUS-FNA specimens. [ABSTRACT FROM AUTHOR]

Abstract: A series of new imidazolium-based oligomers with different length of a poly(ethylene glycol) moiety as a linker were synthesized and studied as electrolytes for dye-sensitized solar cell (DSSC). These oligomeric molecules are expected to have an intra- or inter-molecular hydrogen bonding interaction through its urethane and urea bonds. They can be used to prepare the liquid-type electrolytes for DSSC by dissolving them into conventional solvent system or to develop solvent-free electrolytes by incorporating an extra redox mediator and other functional materials together as additives. It was found that these oligomers could replace the cationic component of the conventional electrolytes and became the source of redox species when iodine is added. The photocurrent–voltage characteristics of DSSCs with the electrolytes containing these oligomers demonstrated that they can successfully replace the conventional ionic liquid-type electrolytes such as 1-methyl-3-propyl imidazolium iodide (PMII) in 3-methoxypropionitrile (MPN) if the length of the linker is optimized. [Copyright &y& Elsevier]

Abstract: Novel polymer electrolyte membranes containing the sulfonic acid groups attached on polymer backbone and side group simultaneously were synthesized. The bromo-poly(2,6-dimethyl-1,4-phenylene oxide)-co-(2,6-diphenyl-1,4-phenylene oxide) copolymer (BrcoPPO) was prepared by oxidative coupling polymerization with 2,6-dimethyl phenol, 2,6-diphenyl phenol, CuCl(I) and pyridine, and followed by bromination with bromine. Copolymer was maintained in 2,6-diphenyl phenol 10mol% and 2,6-dimethyl phenol 90mol%. Sulfonation of BrcoPPO (S-BrcoPPO) was carried out in a chlorobenzene solvent using chlorosulfonic acid. The polymeric membranes were cast from dimethylsulfoxide solution. The membranes were studied by nuclear magnetic resonance (NMR), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). Sorption experiments were conducted to observe the interaction of sulfonated polymers with water and methanol. S-BrcoPPO membranes exhibited proton conductivities from 2.3×10−3 to 1.4×10−2 S/cm, water uptake from 7.00 to 49.43%, IEC from 0.58 to 1.38mequiv./g, methanol permeability from 1.9×10−7 to 3.5×10−7 cm2/S. [Copyright &y& Elsevier]

Objectives. Endoscopic ultrasonography (EUS)-guided intervention has recently been tried in the treatment of cystic tumors of the pancreas. Factors that can influence the treatment response include cyst wall thickness and the presence of septation and mural nodules. This study aimed to evaluate the effectiveness of EUS-guided ethanol lavage with paclitaxel injection (EUS-EP) in the treatment of septated cystic tumors of the pancreas. Methods. Ten patients with oligolocular septated cystic tumors underwent EUS-EP and the treatment response was analyzed by measuring cyst volume before and more than 6 months after treatment. Results. The 10 patients comprised 7 women and 3 men, of mean age 38.4 years (range 22-54 years). Median tumor diameter was 29.5 mm (range 20-68 mm), while median tumor volume was 5.07 ml (range 1.51-68.74 ml). Median carcinoembryonic antigen and amylase concentrations in the cyst fluid were 39.2 ng/ml (range 1-8,190 ng/ml) and 115.5 U/L (range 5-75,633 U/L), respectively. Three tumors were diagnosed as mucinous cystic neoplasms, four as serous cystadenomas, and three as indeterminate cysts. Median tumor volume had decreased to 0.54 ml (range 0.00-12.42 ml). Complete resolution was achieved in six patients and partial resolution in two, whereas two patients had persistent cysts. Two patients with persistent cysts underwent surgical resection, and focal remnant neoplastic epithelial lining was observed on the resected specimens. Conclusions. EUS-EP resulted in complete resolution in 6 of 10 patients with septated cystic tumors. Careful patient selection and tailored intervention are required to maximize the therapeutic efficacy of this procedure. [ABSTRACT FROM AUTHOR]

Abstract: We have previously reported that tissue inhibitor of metalloproteinases-2 (TIMP-2), an endogenous inhibitor of matrix metalloproteinase, modulates angiogenic responses through the MMP inhibition-independent activity. In this study, we investigate the molecular mechanisms of TIMP-2-mediated growth inhibition in response to fibroblast growth factor-2 (FGF-2). Pre-treatment with a protein tyrosine phosphatase inhibitor orthovanadate or expression of a dominant negative Shp-1 mutant fails to induce TIMP-2 inactivation of FGF-2 signaling pathways in human microvascular endothelial cells. We also show that TIMP-2 inhibition of FGF-2-induced p42/44MAPK activation and cell proliferation is associated with TIMP-2 binding to integrin α3β1 on endothelial cell surfaces, as demonstrated by use of anti-integrin α3 or β1 blocking antibodies, or disruption of integrin α3 expression by siRNA. Collectively, our results indicate that TIMP-2 inhibits FGF-2 signaling pathways through association with integrin α3β1 and Shp-1-dependent inhibition of p42/44MAPK signaling, which in turn, results in suppression of FGF-2-stimulated endothelial cell mitogenesis. [Copyright &y& Elsevier]

Abstract: Tissue inhibitor of metalloproteinase-1 (TIMP1) is a survival factor of germinal center (GC) B cells, and its over-expression is correlated with aggressive B cell lymphomas and classical Hodgkin lymphomas. We previously demonstrated that TIMP1 down-regulates B-cell receptor and BCL6, and activates interleukins-6,-10 (ILs)/signal transducer and activator of transcription-3 (STAT3) signaling in GC B cells. The activation of ILs/STAT3 signaling can amplify CD44 function, and vice versa, and induce protein-tyrosine phosphatase SHP1 activity by a negative feedback mechanism. Here, we show that TIMP1 up-regulates cell surface CD44 (standard and variants 3 and 7–10) and induces the activity and nuclear localization of SHP1 in an Epstein Barr virus (EBV)-negative Burkitt lymphoma cell line, the neoplastic counterpart of GC centroblasts. These results suggest that TIMP1 functions as a differentiating and survival factor of GC B cells by modulating CD44 and SHP1 in the late centrocyte/post-GC stage, regardless of EBV infection. [Copyright &y& Elsevier]

Abstract: Histone deacetylase (HDAC) inhibitors are appreciated as one of promising anticancer drugs, but they exert differential responses depending on the cell type. We recently reported the critical role of NF-κB as a modulator in determining cell fate for apoptosis in response to an HDAC inhibitor. In this study, we investigate a possible signaling pathway required for NF-κB activation in response to the HDAC inhibitor apicidin. Treatment of HeLa cells with apicidin leads to an increase in transcriptional activity of NF-κB and the expression of its target genes, IL-8 and TNF-α. TNF-α expression by apicidin is induced at earlier time points than NF-κB activation or IL-8 expression. In addition, our data show that the early expression of TNF-α does not lead to activation of NF-κB, because disruption of TNF-α activity by a neutralizing antibody does not affect nuclear translocation of NF-κB, IκBα degradation or reporter gene activation by apicidin. However, this activation of NF-κB requires the PI3K and PKC signaling pathways, but not ERK or JNK. Furthermore, apicidin activation of NF-κB seems to result from HDAC1 inhibition, as evidenced by the observation that overexpression of HDAC1, but not HDAC2, 3 or 4, dramatically inhibits NF-κB reporter gene activity. Collectively, our results suggest that activation of NF-κB signaling by apicidin requires both the PI3K/PKC signaling pathways and HDAC1, and functions as a critical modulator in determining the cellular effect of apicidin. [Copyright &y& Elsevier]

Abstract: Although many studies have been performed to elucidate the molecular consequences of ultraviolet irradiation, little is known about the effect of natural products. Ultraviolet irradiation is widely considered to be an environmental stress. Here we investigated the effect of erythrodiol-3-acetate on the expressions of MMP-1,2 in cultured human skin fibroblasts. Erythrodiol-3-acetate was isolated from the stems of Styrax japonica (Styracaceae). Erythrodiol-3-acetate reduced the expression of MMP-1 but not MMP-2, at the mRNA and protein levels in a dose-dependent manner by ultraviolet irradiation. Taken together, our results suggest that erythrodiol-3-acetate an important role in the reduction of MMP-1 induction by ultraviolet irradiation. [Copyright &y& Elsevier]

Remodeling of the extracellular matrix – regulated by the matrix metalloproteinases (MMPs) and their endogenous inhibitors – is an important component of disease progression in many chronic disease states. Unchecked MMP activity can result in significant tissue damage, facilitate disease progression and is associated with host responses to pathologic injury, such as angiogenesis. The tissue inhibitors of metalloproteinases (TIMPs) have been shown to regulate MMP activity. However, recent findings demonstrate that an MMP-independent effect of TIMP-2 inhibits the mitogenic response of human microvascular endothelial cells to growth factors. This is the first demonstration of a cell-surface signaling receptor for a member of the TIMP family and suggests that TIMP-2 functions to regulate cellular responses to growth factors. These new findings are integrated in a comprehensive model of TIMP-2 function in tissue homeostasis. [Copyright &y& Elsevier]

Tissue inhibitors of metalloproteinases (TIMPs) suppress matrix metalloproteinase (MMP) activity critical for extracellular matrix turnover associated with both physiologic and pathologic tissue remodeling. We demonstrate here that TIMP-2 abrogates angiogenic factor-induced endothelial cell proliferation in vitro and angiogenesis in vivo independent of MMP inhibition. These effects require α3β1 integrin-mediated binding of TIMP-2 to endothelial cells. Further, TIMP-2 induces a decrease in total protein tyrosine phosphatase (PTP) activity associated with β1 integrin subunits as well as dissociation of the phosphatase SHP-1 from β1. TIMP-2 treatment also results in a concomitant increase in PTP activity associated with tyrosine kinase receptors FGFR-1 and KDR. Our findings establish an unexpected, MMP-independent mechanism for TIMP-2 inhibition of endothelial cell proliferation in vitro and reveal an important component of the antiangiogenic effect of TIMP2 in vivo. [Copyright &y& Elsevier]

Background: This study analyzed the factors associated with the yield of percutaneous transhepatic cholangioscopic biopsies in patients with bile duct cancer. Methods: One-hundred-and-sixteen patients who had received percutaneous transhepatic cholangioscopy and who had been confirmed as having bile duct cancer were enrolled in this study. Multiple targeted biopsies were taken under direct cholangioscopic view. Results: When the location of the tumor was divided into intrahepatic duct (IHD), hilar duct and common bile duct (CBD), the biopsy yield was significantly higher in IHD cancer (93.7%) than in cases of hilar cancer (69.6%) (P < 0.05). After a bile duct cancer had been classified as a nodular type (n = 31), papillary type (n = 27) or infiltrative type (n = 58) cancer upon cholangioscopic findings, the biopsy yields from nodular (96.8%) or papillary types (96.3%) were significantly higher than from infiltrative types (58.6%; P < 0.01). The positive rate for malignant cells was not influenced by the presence of tumor vessels or the number of biopsy samples taken. However, the sensitivity of the combination of cholangioscopic biopsy and tumor vessel in overall bile duct cancer, especially in the infiltrative type, was significantly increased when it was compared with that of cholangioscopic biopsies (P < 0.01) or tumor vessels alone (P < 0.01). Conclusions: Cholangioscopic biopsy provides a high positive yield of malignant cells in those patients with IHD, nodular-type and papillary-type cancers. The cholangioscopic classification of bile duct tumors might thus provide important clues to predict biopsy yield. [ABSTRACT FROM AUTHOR]

Background and aims: Endoscopic multiple plastic stents are an established first-line treatment for anastomotic biliary stricture (ABS) management after liver transplantation (LT). Fully covered self-expandable metallic stents (FCSEMSs) have recently been used with favorable outcomes, but long-term treatment outcomes remain an issue for ABS. We evaluated the long-term outcomes of FCSEMS for the management of refractory ABS after LT. Methods: We reviewed the prospectively collected and maintained endoscopic retrograde cholangiography database at Asan Medical Center to retrieve consecutive post-LT ABS cases that underwent an endoscopic FCSEMS placement between August 2009 and August 2019 after MPS placement failure. Results: A total of 34 patients were enrolled in this study. Technical success had been achieved in all subjects (100%). The median stent placement duration was 3.1 months (IQR 2.7–6.1). Stricture resolution was achieved in 26 patients (clinical success 76.5%, 95% confidence interval 62–91). Early adverse events developed in 3 patients (8.8%), including distal stent migration. Late adverse events occurred in 9 patients (26.5%), including cholangitis (n = 7, 20.6%) and asymptomatic distal stent migration (n = 2, 5.9%). The median follow-up period was 57.9 months (IQR 51.9–64.3). Stricture recurrence occurred in 3 of 26 patients who achieved clinical success (11.5%). Conclusions: FCSEMS placement appears to be an effective and advisable intervention for refractory ABS as it can provide persistent stricture improvement over the long-term. [ABSTRACT FROM AUTHOR]

The article presents the case history of a 38-year-old woman who was referred to the hospital for a 7-cm sized pancreatic cyst. Most of the pancreatic cysts are asymptomatic, however, few may have malignant potential. The cyst of the women was detected on transabdominal ultrasonography. Booster endoscopic ultrasonography-guided ablation was used to remove the cyst from the body.

Objectives Methods Results Conclusion This consensus was developed by the Asian EUS Group (AEG), who aimed to formulate a set of practice guidelines addressing various aspects of endoscopic ultrasound‐guided tissue acquisition (EUS‐TA).The AEG initiated the development of consensus statements and formed an expert panel comprising surgeons, gastroenterologists, and pathologists. Three online consensus meetings were conducted to consolidate the statements and votes. The statements were presented and discussed in the first two consensus meetings and revised according to comments. Final voting was conducted at a third consensus meeting. The Grading of Recommendations, Assessment, Development, and Evaluation system was adopted to define the strength of the recommendations and quality of evidence.A total of 20 clinical questions and statements regarding EUS‐TA were formulated. The committee recommended that fine‐needle biopsy (FNB) needles be preferred over conventional fine‐needle aspiration (FNA) needles for EUS‐TA of subepithelial lesions. For solid pancreatic masses, rapid on‐site evaluation is not routinely recommended when FNB needles are used. For dedicated FNB needles, fork‐tip and Franseen‐tip needles have essentially equivalent performance.This consensus provides guidance for EUS‐TA, thereby enhancing the quality of EUS‐TA. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the ejection pressure and the correlation of the findings with the occurrence of internal cracks within bilayer tablets (BLTs) consisting of metformin HCl (MF) and evogliptin tartrate (EG). Then, the mechanism of tablet failure was provided by the finite element method (FEM). The ejection pressure and the difference in diameter depending on MAIN-P were evaluated to understand the correlation between ejection pressure and change in the BLT internal structure. The ejection pressure and the difference in diameter increased as the MAIN-P increased, then steeply decreased from 350 MPa to 375 MPa of MAIN-P, despite there being no pattern in compaction breaking force and porosity. The mechanical integrity at the BLT interface was weakened by internal cracks, reducing ejection pressure. The stress distribution analysis during the compression revealed that crack formation caused by entrapped air located at the center of the BLT interface may not propagate due to concentrated stress, which promotes a tight bond at the edge of the BLT. Furthermore, complete delamination can occur in the ejection process due to localized and intensive shear stresses at the BLT interface. These findings indicate that the mechanisms of internal cracking and delamination were successfully confirmed by FEM simulation. Moreover, measuring ejection pressure before BLT manufacturing can prevent invisible tablet cracks without damaging the tablets. [ABSTRACT FROM AUTHOR]

Background and Aim: Endoscopic ultrasound (EUS)‐guided biliary drainage is being increasingly performed as an alternative to percutaneous transhepatic biliary drainage (PTBD) to treat malignant hilar obstruction (MHO) after failed endoscopic retrograde cholangiopancreatography (ERCP). However, no study has compared EUS‐guided hepaticoduodenostomy (EUS‐HDS) with PTBD for right intrahepatic duct (IHD) obstruction after failed ERCP in patients with unresectable MHO. Methods: We retrospectively reviewed the data of consecutive patients with right IHD obstruction developed by unresectable MHO who underwent EUS‐HDS or PTBD after a previous placement of a stent in the left and/or right IHD between March 2018 and October 2021. Technical success, clinical success, stent or tube‐related adverse events, frequency of reintervention, and stent patency were evaluated. Results: A total of 42 patients (18 EUS‐HDS, 24 PTBD) were analyzed. Both groups did not show significant differences in technical success (EUS‐HDS, 94% vs PTBD, 100%; P = 0.429), clinical success (83% vs 83%; P = 0.999), early adverse events (24% vs 46%; P = 0.144), and stent or tube‐related late adverse events (29% vs 54%; P = 0.116). During follow‐up, the EUS‐HDS group had a longer median duration of patency (131 days vs 58.5 days; P = 0.041), and lower mean frequency of reinterventions per patient (0.35 vs 1.92; P = 0.030) than the PTBD group. Conclusions: EUS‐HDS showed comparable efficacy and safety to PTBD for drainage of the right biliary system and produced longer duration of patency and lower frequency of reinterventions in patients with unresectable MHO. [ABSTRACT FROM AUTHOR]

BACKGROUND : Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) has been increasingly used for the management of various solid pancreatic tumors. This study aimed to evaluate the feasibility and safety of EUS-RFA for serous cystic neoplasms (SCNs). METHODS : 13 patients with microcystic SCNs with honeycomb appearance underwent EUS-RFA using a 19-gauge RFA needle. Before ablation, cystic fluid was aspirated until a thin layer of fluid remained. RESULTS : EUS-RFA was successful in all patients. Seven patients underwent a single session and the remaining six patients underwent a second session of EUS-RFA. One patient (7.7 %) experienced self-limited abdominal pain after EUS-RFA. During a median follow-up period of 9.21 months (interquartile range [IQR] 5.93 - 15.38), the median volume of the SCNs decreased from 37.82 mL (IQR 15.03 - 59.53) at baseline to 10.95 mL (IQR 4.79 - 32.39) at the end of follow-up. A radiologic partial response was achieved in eight patients (61.5 %). CONCLUSIONS : EUS-RFA is technically feasible and showed an acceptable rate of adverse events for patients with SCNs. A long-term follow-up study is required to evaluate the efficacy of EUS-RFA. [ABSTRACT FROM AUTHOR]

Objectives: Many studies showed better outcomes of endoscopic ultrasound‐guided gallbladder drainage (EUS‐GBD) when compared with percutaneous transhepatic gallbladder drainage (P‐GBD) in which most tubes were left in situ. However, no studies have directly compared EUS‐GBD with P‐GBD after tube removal (ex situ). We compared the long‐term outcomes of EUS‐GBD and ex situ or in situ P‐GBD in high surgical risk patients with acute cholecystitis. Methods: We reviewed the records of 182 patients (EUS‐GBD, n = 75; P‐GBD, n = 107) who underwent gallbladder drainage. The procedural outcomes, long‐term outcomes, and adverse events were compared. Results: The EUS‐GBD group and the P‐GBD group had similar rates of technical and clinical success. Early adverse events were less common in the EUS‐GBD group (5.5% vs. 18.9%, P = 0.010). The long‐term outcomes were evaluated in 168 patients (EUS‐GBD, n = 67; P‐GBD ex situ, n = 84; P‐GBD in situ, n = 17). The rate of cholecystitis recurrence in the EUS‐GBD group (6.0%) was similar to that in the P‐GBD ex situ group (9.6%, P = 0.422), but significantly lower than that in the P‐GBD in situ group (23.5%, P = 0.049). P‐GBD in situ was a significant predictor of recurrent cholecystitis (hazard ratio 14.6; 95% confidence interval 2.9–72.8). Conclusion: The long‐term recurrence rate of acute cholecystitis in patients who underwent EUS‐GBD was comparable to that in patients whose P‐GBD could be removed. However, patients in whom P‐GBD could not be removed showed higher rates of recurrent cholecystitis than patients with EUS‐GBD. [ABSTRACT FROM AUTHOR]

Background and Aims: Immunoglobulin G4‐related sclerosing cholangitis (IgG4‐SC) is considered a biliary manifestation of IgG4‐related diseases. However, there has been a controversy on the clinical outcomes according to the location of the involved bile duct. We therefore compared the clinical outcomes and long‐term prognosis of IgG4‐SC with proximal bile duct involvement (proximal IgG4‐SC) and IgG4‐SC with distal bile duct involvement (distal IgG4‐SC). Methods: We reviewed the data of patients with IgG4‐SC that were prospectively collected at 10 tertiary centers between March 2002 and October 2020. Clinical manifestations, outcomes, association with autoimmune pancreatitis (AIP), steroid‐responsiveness, and relapse of IgG4‐SC were evaluated. Results: A total of 148 patients (proximal IgG4‐SC, n = 59; distal IgG4‐SC, n = 89) were analyzed. The median age was 65 years (IQR, 56.25–71), and 86% were male. The two groups were similar in terms of jaundice at initial presentation (51% vs 65%; P = 0.082) and presence of elevated serum IgG4 (66% vs 70%; P = 0.649). The two groups showed significant differences in terms of steroid‐responsiveness (91% vs 100%; P = 0.008), association with AIP (75% vs 99%; P = 0.001), and occurrence of liver cirrhosis (9% vs 1%; P = 0.034). During a median follow‐up of 64 months (IQR, 21.9–84.7), the cumulative relapse‐free survival was significantly different between the two groups (67% vs 79% at 5 years; P = 0.035). Conclusions: Relapse of IgG4‐SC frequently occurred during follow‐up. Proximal IgG4‐SC and distal IgG4‐SC had different long‐term outcomes in terms of steroid‐responsiveness, occurrence of liver cirrhosis, and recurrence. It may be advantageous to determine the therapeutic and follow‐up strategies according to the location of bile duct involvement. [ABSTRACT FROM AUTHOR]

Background and Aims: A fully covered self‐expandable metal stent (FCSEMS) has recently been applied in the management of chronic pancreatitis patients with pancreatic strictures. However, related long‐term effects remain unclear. This study aimed to evaluate the long‐term outcomes of FCSEMS placement in chronic pancreatitis patients with refractory strictures. Method: We retrospectively reviewed our database for patients undergoing FCSEMS placement for refractory pancreatic strictures between September 2008 and December 2010. The main outcomes were technical, radiological, and clinical success, as well as recurrence and adverse events. Results: A total of 35 patients were included. Technical success was achieved in all patients. The median FCSEMS indwelling time was 3.2 months (interquartile range [IQR], 3.0–4.9 months). Radiological success was achieved in all patients (complete, n = 2; partial, n = 33). Clinical success was achieved in 29 patients (82.9%; complete analgesic cessation, n = 19; analgesic reduction >50%, n = 11). During the median follow‐up of 136 months, (IQR, 85.8–145.5 months), eight patients (22.9%) experienced recurrence. The median interval from stent removal to recurrence was 24.9 months (IQR, 11.3–30.3 months). Biliary obstruction, an early adverse event, occurred in two patients (5.7%); the late adverse event stent‐induced de novo stricture was observed in 17 patients (48.6%). Conclusions: Our findings suggest that an FCSEMS is effective for relieving refractory strictures in chronic pancreatitis. However, FCSEMSs were associated with stent‐induced de novo strictures in nearly half of the patients. Prospective studies are required to further evaluate the long‐term efficacy and safety of FCSEMSs in chronic pancreatitis. [ABSTRACT FROM AUTHOR]

Objectives: Endoscopic retrograde cholangiopancreatography (ERCP) has revolutionized the treatment of many pancreaticobiliary conditions. However, little is known about the global practices, training programs, and credentialing of the procedure. The aim of the current study is to address the above questions. Methods: This was an international cross‐sectional survey conducted between October 2020 and May 2021. Participating countries were requested to complete an online survey on ERCP services and training. Results: Eighty‐nine countries responded to the survey. There were significant increases in the proportion of ERCP services provided by the government (P < 0.0001), number of endoscopists per million of population (P < 0.0001), and number of institutions per million of population (P < 0.0001) from low to high human development index (HDI). Eighteen percent of the countries offer the procedure as part of a standard training program, 68.5% do not follow a standardized training curriculum. Risk factors for higher incidence and mortality from pancreatic cancers include higher HDI category, smaller population, a larger number of endoscopists proficient in ERCP, and lower number of institutions providing ERCP training. Countries with very high HDI have four times higher incidence and mortality from pancreatic cancers as compared to those with low HDI. Conclusions: There is still an ongoing need for improving ERCP training in low to very high HDI countries. A structured training program is still lacking in many parts of the world. With increasing incidence and mortality of pancreatic cancers, particularly in high HDI countries, there is a need for further increasing facilities for ERCP training. [ABSTRACT FROM AUTHOR]

Background and Aim: EB‐RFA with self‐expandable metal stent (SEMS) may improve the stent patency and patient survival in malignant extrahepatic biliary obstruction. However, there are few studies on the role of EB‐RFA for malignant hilar obstruction (MHO). This study aimed to assess the feasibility, efficacy, and safety of EB‐RFA for MHO. Methods: We retrospectively compared the stent patency and survival among 79 consecutive patients with MHO who underwent bilateral uncovered SEMS placement without and with EB‐RFA between April 2016 and January 2020. Results: Fifty‐one patients (64.6%) underwent SEMS placement alone (stent alone group), whereas 28 (35.4%) underwent SEMS placement after EB‐RFA (RFA‐stent group). All procedures were successful (100%). During follow‐up, stent occlusion occurred in 59 patients (74.7%), of which 40 (78.4%) and 19 (67.9%) were in the stent alone and RFA‐stent groups, respectively. There was no difference in stent patency (192 ± 39.2 days vs 140 ± 53.7 days, P = 0.41) and survival (311 ± 24.7 days vs 311 ± 46.9 days, P = 0.73) between the stent alone and RFA‐stent groups. Multivariate cox analysis showed a hazard ratio (HR) of 2.892 (1.579–5.294, P = 0.001) for stent occlusion in patients who did not receive chemotherapy. EB‐RFA had no significant effect on stent occlusion (HR, 1.150, 0.644–2.053, P = 0.636). Conclusions: SEMS placement after EB‐RFA in MHO was not associated with improvement in the stent patency or patient survival. Further prospective randomized studies are necessary to establish the effectiveness of EB‐RFA with stents in MHO. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this study was to compare the different versions of the National Comprehensive Cancer Network (NCCN) guidelines for defining resectability of pancreatic ductal adenocarcinoma (PDAC) in predicting margin-negative (R0) resection, and to assess inter-reader agreement.This retrospective study included 283 patients (mean age, 65.1 years ± 9.4 [SD]; 155 men) who underwent upfront pancreatectomy for PDAC between 2017 and 2019. Two radiologists independently determined the resectability on preoperative CT according to the 2017, 2019, and 2020 NCCN guidelines. The sensitivity and specificity for R0 resection were analyzed using a multivariable logistic regression analysis with generalized estimating equations. Inter-reader agreement was assessed using kappa statistics.R0 resection was accomplished in 239 patients (84.5%). The sensitivity and specificity averaged across two readers were, respectively, 76.6% and 29.5% for the 2020 guidelines, 74.1% and 32.9% for the 2019 guidelines, and 72.6% and 34.1% for the 2017 guidelines. Compared with the 2020 guidelines, both 2019 and 2017 guidelines showed significantly lower sensitivity for R0 resection (p ≤ .009). Specificity was significantly higher with the 2017 guidelines (p = .043) than with the 2020 guidelines. Inter-reader agreements for determining the resectability of PDCA were strong (k ≥ 0.83) with all guidelines, being highest with the 2020 guidelines (k = 0.91).The 2020 NCCN guidelines showed significantly higher sensitivity for prediction of R0 resection than the 2017 and 2019 guidelines.Methods: The purpose of this study was to compare the different versions of the National Comprehensive Cancer Network (NCCN) guidelines for defining resectability of pancreatic ductal adenocarcinoma (PDAC) in predicting margin-negative (R0) resection, and to assess inter-reader agreement.This retrospective study included 283 patients (mean age, 65.1 years ± 9.4 [SD]; 155 men) who underwent upfront pancreatectomy for PDAC between 2017 and 2019. Two radiologists independently determined the resectability on preoperative CT according to the 2017, 2019, and 2020 NCCN guidelines. The sensitivity and specificity for R0 resection were analyzed using a multivariable logistic regression analysis with generalized estimating equations. Inter-reader agreement was assessed using kappa statistics.R0 resection was accomplished in 239 patients (84.5%). The sensitivity and specificity averaged across two readers were, respectively, 76.6% and 29.5% for the 2020 guidelines, 74.1% and 32.9% for the 2019 guidelines, and 72.6% and 34.1% for the 2017 guidelines. Compared with the 2020 guidelines, both 2019 and 2017 guidelines showed significantly lower sensitivity for R0 resection (p ≤ .009). Specificity was significantly higher with the 2017 guidelines (p = .043) than with the 2020 guidelines. Inter-reader agreements for determining the resectability of PDCA were strong (k ≥ 0.83) with all guidelines, being highest with the 2020 guidelines (k = 0.91).The 2020 NCCN guidelines showed significantly higher sensitivity for prediction of R0 resection than the 2017 and 2019 guidelines.Results: The purpose of this study was to compare the different versions of the National Comprehensive Cancer Network (NCCN) guidelines for defining resectability of pancreatic ductal adenocarcinoma (PDAC) in predicting margin-negative (R0) resection, and to assess inter-reader agreement.This retrospective study included 283 patients (mean age, 65.1 years ± 9.4 [SD]; 155 men) who underwent upfront pancreatectomy for PDAC between 2017 and 2019. Two radiologists independently determined the resectability on preoperative CT according to the 2017, 2019, and 2020 NCCN guidelines. The sensitivity and specificity for R0 resection were analyzed using a multivariable logistic regression analysis with generalized estimating equations. Inter-reader agreement was assessed using kappa statistics.R0 resection was accomplished in 239 patients (84.5%). The sensitivity and specificity averaged across two readers were, respectively, 76.6% and 29.5% for the 2020 guidelines, 74.1% and 32.9% for the 2019 guidelines, and 72.6% and 34.1% for the 2017 guidelines. Compared with the 2020 guidelines, both 2019 and 2017 guidelines showed significantly lower sensitivity for R0 resection (p ≤ .009). Specificity was significantly higher with the 2017 guidelines (p = .043) than with the 2020 guidelines. Inter-reader agreements for determining the resectability of PDCA were strong (k ≥ 0.83) with all guidelines, being highest with the 2020 guidelines (k = 0.91).The 2020 NCCN guidelines showed significantly higher sensitivity for prediction of R0 resection than the 2017 and 2019 guidelines.Conclusion: The purpose of this study was to compare the different versions of the National Comprehensive Cancer Network (NCCN) guidelines for defining resectability of pancreatic ductal adenocarcinoma (PDAC) in predicting margin-negative (R0) resection, and to assess inter-reader agreement.This retrospective study included 283 patients (mean age, 65.1 years ± 9.4 [SD]; 155 men) who underwent upfront pancreatectomy for PDAC between 2017 and 2019. Two radiologists independently determined the resectability on preoperative CT according to the 2017, 2019, and 2020 NCCN guidelines. The sensitivity and specificity for R0 resection were analyzed using a multivariable logistic regression analysis with generalized estimating equations. Inter-reader agreement was assessed using kappa statistics.R0 resection was accomplished in 239 patients (84.5%). The sensitivity and specificity averaged across two readers were, respectively, 76.6% and 29.5% for the 2020 guidelines, 74.1% and 32.9% for the 2019 guidelines, and 72.6% and 34.1% for the 2017 guidelines. Compared with the 2020 guidelines, both 2019 and 2017 guidelines showed significantly lower sensitivity for R0 resection (p ≤ .009). Specificity was significantly higher with the 2017 guidelines (p = .043) than with the 2020 guidelines. Inter-reader agreements for determining the resectability of PDCA were strong (k ≥ 0.83) with all guidelines, being highest with the 2020 guidelines (k = 0.91).The 2020 NCCN guidelines showed significantly higher sensitivity for prediction of R0 resection than the 2017 and 2019 guidelines. [ABSTRACT FROM AUTHOR]

Background and aims: Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is frequently used for the preoperative histologic diagnosis of pancreatic cancer. However, debate continues regarding the clinical merits of preoperative EUS-FNA for the management of resectable pancreatic cancer. We aimed to evaluate the benefits and safety of preoperative EUS-FNA for resectable distal pancreatic cancer. Methods: The medical records of 304 consecutive patients with suspected distal pancreatic cancer who underwent EUS-FNA were retrospectively reviewed to evaluate the clinical benefits of preoperative EUS-FNA. We also reviewed the medical records of 528 patients diagnosed with distal pancreatic cancer who underwent distal pancreatectomy with or without EUS-FNA. The recurrence rates and cancer-free survival periods of patients who did or did not undergo preoperative EUS-FNA were compared. Results: The diagnostic accuracy of preoperative EUS-FNA was high (sensitivity, 87.5%; specificity, 100%; positive predictive value 100%; accuracy, 90.7%; negative predictive value, 73.8%). Among patients, 26.7% (79/304) avoided surgery based on the preoperative EUS-FNA findings. Of the 528 patients who underwent distal pancreatectomy, 193 patients received EUS-FNA and 335 did not. During follow-up (median 21.7 months), the recurrence rate was similar in the two groups (EUS-FNA, 72.7%; non-EUS-FNA, 75%; P = 0.58). The median cancer-free survival was also similar (P = 0.58); however, gastric wall recurrence was only encountered in the patients with EUS-FNA (n = 2). Conclusion: Preoperative EUS-FNA is not associated with increased risks of cancer-specific or overall survival. However, clinicians must consider the potential risks of needle tract seeding, and care should be taken when selecting patients. [ABSTRACT FROM AUTHOR]

Abstract: In this study, we investigate the molecular mechanism by which protein arginine methyltransferase 6 (PRMT6) exerts anti-invasiveness effect against breast cancer cells and prostate cancer cells. PRMT6 has been known to be responsible for asymmetric dimethylation of histone H3 at R2 (H3R2me2a). To investigate the biological role of PRMT6, we first established stable cell lines expressing GFP-PRMT6 with MCF7 and PC3 cells. Growth rates and colony forming abilities of PRMT6-overexpressing cells were significantly retarded compared to control GFP expressing cells. This growth retardation seems to be associated with p21WAF1 induction. In addition, our data show that migration and invasion of prostate cancer cells was strongly suppressed by PRMT6 overexpression. In parallel, the levels of thrombospondin-1 (TSP-1), a potent natural inhibitor of angiogenesis, were highly up-regulated in both PRMT6-overexpressing cells. Furthermore, this suppression of migration and invasion by PRMT6 overexpression was significantly rescued by specific knock-down of TSP-1. Concomitantly, down-regulations of MMP-2 and -9 were observed in PRMT6-overexpressing cells. Taken together, our data demonstrate that PRMT6 overexpression is associated with regulation of motility and invasion through up-regulation of TSP-1 and down-regulation of MMPs in human cancer cells. [Copyright &y& Elsevier]

Abstract: Overexpression of P-glycoprotein (P-gp) is one of the major obstacles to successful cancer chemotherapy. In this study, we examined the ability of 4-chloro-N-(3-((E)-3-(4-hydroxy-3-methoxyphenyl)acryloyl)phenyl)benzamide (C-4) to reverse multidrug resistance (MDR) in P-gp expressing KBV20C cells. Treatment of KBV20C cells with C-4 led to a dramatic increase in paclitaxel- or vincristine-induced cytotoxicity without any cytotoxicity by itself. In parallel, C-4 treatment caused an increase in apoptotic cell death by paclitaxel or vincristine. Furthermore, C-4 treatment significantly increases in intracellular accumulation of fluorescent P-gp substrate rhodamine 123, indicating that C-4 treatment leads to reversal of the MDR phenotype resulting from an increased accumulation of anticancer drugs by inhibiting drug efflux function of P-gp. This notion is further supported by the observation that C-4 treatment potentiates paclitaxel-induced G2/M arrest of the cell cycle. In addition, the drug efflux function of P-gp was reversibly inhibited by C-4 treatment, while the expression level of P-gp was not affected. Collectively, our results describe the potential of C-4 to reverse the P-gp-mediated MDR phenotype through reversible inhibition of P-gp function, which may make it an attractive new agent for the chemosensitization of cancer cells. [Copyright &y& Elsevier]

Background and Aim: While recent evidences support endoscopic resection as curative in ampullary tumors with high‐grade intraepithelial neoplasia, only small case series have reported endoscopic management of early‐stage ampullary cancer; thus, radical surgery remains the only accepted treatment modality. We evaluated the long‐term outcomes of early ampullary adenocarcinoma administered endoscopic management. Methods: We retrospectively reviewed electronic medical records of 715 patients undergoing endoscopic papillectomy (EP) in a single tertiary medical center in Korea in 2004–2016. We included patients incidentally diagnosed with early‐stage adenocarcinoma (Tis and T1a, American Joint Committee on Cancer 8th edition) after EP and with >2 years of follow‐up data and analyzed their demographics, histopathologic data, and clinical outcomes. Results: Among 70 total patients in the EP‐alone (n = 42) and subsequent surgery (n = 28) groups, we observed no significant differences in demographics or tumor size (2.0 ± 0.6 vs 1.9 ± 0.5 cm, P = 0.532), histologic grade (P = 0.077), tumor extent (P = 1.000), lymphovascular invasion (2.4% vs 10.7%, P = 0.344), or complete resection rates (57.1% vs 57.1%, P = 1.000) between groups. Adenocarcinoma lesions were larger in the subsequent surgery group (0.7 ± 0.5 vs 1.1 ± 0.7 cm, P = 0.002). The EP‐alone group received more additional ablative treatment (42.9% vs 14.3%, P = 0.024). The 5‐year disease‐free and cancer‐free survival rates were 79.1% vs 87.4% (P = 0.111) and 93.5% versus 87.4% (P = 0.726), respectively, and did not differ significantly between groups. Conclusions: Endoscopic papillectomy followed by endoscopic surveillance showed long‐term outcomes comparable with surgical resection for early ampullary cancer and maybe curable alternative to surgery for incidentally found early‐stage ampullary cancer, especially in patients unfit for or refusing radical surgery. [ABSTRACT FROM AUTHOR]

Even if only a partial response was shown in 62 % of patients without complete response, their symptoms still improved after ablation. The authors declare that they have no conflict of interest. letter We thank Dr. Lorenzo and colleagues for their interest in our study, which involved the follow up of 379 patients with serous cystic neoplasms (SCNs) [1]. Among these 60 patients, those with an uncertain diagnosis underwent surgery, and only symptomatic patients with pathologically confirmed SCNs (5.3 %) underwent endoscopic treatment. [Extracted from the article]

The Asian Federation of Societies for Ultrasound in Medicine and Biology aimed to provide information on techniques and indications for contrast-enhanced harmonic endoscopic ultrasound (CH-EUS), and to create statements including the level of recommendation. These statements are based on current scientific evidence reviewed by a Consensus Panel of 15 internationally renowned experts. The reliability of clinical questions was measured by agreement rates after voting. Six statements were made on techniques, including suitable contrast agents for CH-EUS, differences between contrast agents, setting of mechanical index, dual imaging and duration and phases for observation. Thirteen statements were made on indications, including pancreatic solid masses, pancreatic cancer staging, pancreatic cystic lesions and mural nodules, detection of subtle pancreatic lesions, gallbladder sludge and polyps, hepatic lesions, lymph nodes, subepithelial lesions, visceral vascular diseases, guidance of fine needle aspiration and evaluation for local therapy. These international expert consensus guidelines will assist endosonographers in conducting CH-EUS according to evidence-based information. [ABSTRACT FROM AUTHOR]

Background: Although endoscopic ultrasound (EUS) features and criteria have been described in chronic pancreatitis, challenges remain with interoperator variability and ease of adoption. The aim of this study was to define and validate the EUS features of chronic pancreatitis in a multicenter prospective study in Asia.Method: The study was divided into two parts: the first part was conducted to derive the EUS features of chronic pancreatitis with adequate interoperator agreement; the second was to prospectively evaluate these features in a multicenter cross-sectional study and determine the optimal combination of features for the diagnosis of chronic pancreatitis. Prospectively enrolled cases had standard internationally validated radiologic or histologic features of chronic pancreatitis, and controls were patients without chronic pancreatitis who underwent EUS examination.Results: The top six EUS features that had good interobserver agreement (mean kappa 0.73, range 0.60 - 0.90) were selected to be further evaluated in part II of the study. These included: hyperechoic foci with shadowing, lobularity with honeycombing, cysts, dilated main pancreatic duct, dilated side branches, and calculi in the main pancreatic duct. A total of 284 subjects (132 cases, 152 controls) were enrolled from 12 centers in Asia. All six features had high accuracy ranging from 63.3 % to 89.1 %. Two or more of these six EUS features accurately defined chronic pancreatitis (sensitivity 94.7 %, specificity 98.0 %), with an area under the receiver operating curve of 0.986.Conclusion: This multicenter Asian study characterized and defined the EUS features of chronic pancreatitis. This provides a useful tool in clinical practice and further research in pancreatic cancer surveillance. [ABSTRACT FROM AUTHOR]

Introduction: For unresectable hilar obstruction, restoring and maintaining biliary ductal patency are crucial for improved survival and quality of life. The endoscopic placement of stents is now a mainstay of its treatment, and bilateral stenting is effective for biliary decompression. This study aimed to determine the clinical outcomes of bilateral metal stent placement using large cell-type stents and the clinical predictors of stent dysfunction in patients with malignant hilar obstruction. Methods: We performed a retrospective analysis of patients who underwent bilateral metal stent placement using two large cell-type stents at two academic teaching hospitals between September 2017 and February 2019. The primary outcome was stent dysfunction. Secondary outcomes included predictors related to stent dysfunction and overall survival. Results: The study included 87 patients who underwent bilateral metal stent placement for malignant hilar obstruction. Technical success and clinical success were achieved in 80 patients (92.0%) and 83 patients (95.4%), respectively. During the follow-up period (median: 201, range: 18–671 days), stent dysfunction occurred in 42 patients (48.3%), and the median stent patency was 199 days (95% confidence interval [CI]: 181–262). In univariate analysis, age, cholangitis before stent insertion, and subsequent chemotherapy were found to be associated with the cumulative risk of stent dysfunction. In multivariate analysis, cholangitis before stent insertion (hazards ratio [HR]: 2.26, 95% CI: 1.216–4.209, P = 0.010) and subsequent chemotherapy (HR: 0.250, 95% CI: 0.130–0.482, P<0.001) remained as statically significant factors associated with the cumulative risk of stent dysfunction. The median overall survival was 288 days (95% CI: 230–327). Conclusion: The bilateral placement of large cell-type stents for malignant hilar obstruction was effective with high technical and clinical success rates and acceptable patency. Cholangitis before stent insertion was associated with shorter patency, and subsequent chemotherapy was associated with longer stent patency. [ABSTRACT FROM AUTHOR]