Intrahepatic cholangiocarcinomas (ICCs) are made up of heterogenous carcinomas arising from different anatomical sites of the liver. Two types of candidate stem/progenitor cells of the biliary tree ...are postulated to exist at the peribiliary glands for large bile ducts and at the canals of Hering for small ducts and hepatocytes. According to the recent observations, ICCs can be subclassified into two types: tumors involving the large bile ducts comparable in size to the intrahepatic second branches and composed of a tubular or papillary component with tall columnar epithelium, and tumors involving the smaller duct than segmental branches and composed of small tubules with cuboidal epithelium. Perihilar large duct type ICCs can be interpreted as arising from large bile duct type ICCs, and peripheral small duct type ICCs may arise from small bile duct type or ductular type ICCs. Chronic biliary inflammation induces neoplastic change of the large bile ducts and thereby progression to the perihilar large duct type ICC, which can be grossly classified into periductal filtrating type ICC and intraductal growth type ICC, while chronic hepatitis or cirrhosis induces mass‐forming peripheral small duct type ICC. The different morphological and molecular features, including stromal components and tumor vasculature, support the hypothesis that perihilar large duct type ICCs and peripheral small duct type ICCs arise from different backgrounds, have different carcinogenetic pathways, and exhibit different biologic behaviors.
Background
Few studies have evaluated both liver fibrosis and steatosis in patients with nonalcoholic fatty liver disease (NAFLD) using both FibroScan
®
M and XL probes. This study was performed to ...investigate the accuracy of both FibroScan
®
probes to diagnose liver fibrosis and steatosis in patients with NAFLD.
Methods
We prospectively enrolled 137 consecutive patients with clinically suspected NAFLD in our joint-research facilities. Liver biopsies, liver stiffness measurements (LSMs), and controlled attenuation parameter (CAP) measurements were performed, and 122 patients with NAFLD diagnosed pathologically by central pathologists were included in the final analysis.
Results
Reliable LSM results were obtained in 85.2% (M) and 89.3% (XL) of patients, and CAP was reliable in 90.2% (M) and 90.2% (XL). The median LSM was significantly lower with the XL than M probe, and CAP was significantly higher with the XL than M probe. The optimal cut-off values for diagnosing the fibrosis stage were lower for LSM with the XL than M probe (stage ≥ 2, 6.7 vs. 7.0; stage ≥ 3, 8.2 vs. 10.8; stage 4, 14.3 vs. 16.8, respectively), whereas those of CAP were higher for the XL than M probe (score of ≥ 2, 273 vs. 267; score of 3, 302 vs. 286, respectively). There were no significant differences in accuracy of the LSM and CAP between the probes.
Conclusions
Liver fibrosis and steatosis could be equally evaluated with FibroScan
®
M and XL probes in patients with NAFLD. There was no significant difference in diagnostic accuracy between the two probes using probe-specific cut-off values.
Background The prognosis of advanced laryngeal cancer is unfavorable despite advances in multidisciplinary therapy. Dendritic cells (DCs) play a central role in antitumor immunity. Tumor-infiltrating ...CD1a.sup.+ DCs have been reported to be associated with clinical outcomes in carcinomas of various organs, but the clinical impact of CD1a.sup.+ DCs in laryngeal cancer remains to be unequivocally established. Methods We retrospectively analyzed the cases of 57 patients with Stage III or IV laryngeal cancer who underwent a total laryngectomy. Immunohistochemistry detection of CD1a, S100 and CD8 was performed on representative resected specimens. CD1a.sup.+ DCs, S100.sup.+ DCs and CD8.sup.+ cytotoxic T-lymphocytes (CTLs) were evaluated, and the cases divided into high and low groups according to the cut-off of the median values for each of these 3 parameters. Results Compared to the CD1a-low group, the CD1a-high group had more advanced cases and showed significantly worse disease-specific survival (DSS) (P = 0.008) and overall survival (OS) (P = 0.032). The analyses of S100 DCs and CD8.sup.+ CTLs revealed no significant impact on clinical outcomes. However, multivariate analysis revealed that infiltration of CD1a.sup.+ DCs was an independent unfavorable prognostic factor for both DSS (P = 0.009) and OS (P = 0.013). Conclusions Our results demonstrated that the infiltration of CD1a.sup.+ DCs was associated with unfavorable clinical outcomes in patients with advanced laryngeal cancer who underwent a total laryngectomy as the initial treatment. Keywords: Laryngeal cancer, CD1a, Dendritic cell, Prognosis, Immunohistochemistry
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Display omitted
•Heparin functionalized PCL/gelatin co-spun nanofibrous dressings were synthesized.•Fabricated dressings showed improved mechanical and degradation properties.•Fabricated dressings ...showed exogenous and endogenous GFs sequestration ability.•In-vivo, synergistic effect of exogenous and endogenous GFs promoted tissue regeneration.
Growth factors (GFs) are signaling molecules that are principle mediators in tissue regeneration. Biomaterial scaffolds employed as wound dressings are often hampered by their limitations to deliver GFs exogenously due to their instability and low half-life. The key to overcome this challenge lies in the better organization and use of endogenous pro-regenerative GFs released at regenerative site, with an aim to minimize the sole dependency on exogenous factors. Considering such challenges, this research utilizes the exogenous and endogenous GFs sequestering capability of heparin functionalized PCL/gelatin co-spun nanofabrics to mediate synergistically driven tissue regeneration by utilizing combined therapeutic effect of exogenous and endogenous GFs, and thereby minimizing the sole dependency on exogenous GFs for tissue regeneration. Basic fibroblast growth factor (bFGF) was chosen as GF for exogenous loading whereas vascular endothelial growth factor (VEGF) was chosen as a representative example to demonstrate the endogenous pro-regenerative GF sequestration capability of fabricated nanofabrics. From our results, the fabricated nanofabrics showed loading efficiency of 80% for exogenous bFGF and can sequester 15-fold more amount of endogenous VEGF compared to non-heparin functionalized nanofibrous dressings. When applied as wound dressings, heparin functionalized nanofibers showed better therapeutic capability compared to control groups that were treated using patches without heparin functionalization, indicating endogenously driven tissue regeneration. This was indicated by significant higher number of newly formed skin appendages, lesser scarring and lower inflammatory levels in newly formed granulation. Additionally, further improvements in therapeutic effect was observed when exogenous bFGF was employed indicating effectiveness of synergistically mediated tissue regeneration.
Mps One Binder Kinase Activator (MOB)1A/1B are core components of the Hippo pathway that coactivate large tumor suppressor homolog (LATS) kinases. Mob1a/1b double deficiency in mouse liver (LMob1DKO) ...results in hyperplasia of oval cells and immature cholangiocytes accompanied by inflammatory cell infiltration and fibrosis. More than half of mutant mice die within 3 wk of birth. All survivors eventually develop liver cancers, particularly combined hepatocellular and cholangiocarcinomas (cHC-CCs) and intrahepatic cholangiocellular carcinomas (ICCs), and die by age 60 wk. Because this phenotype is the most severe among mutant mice lacking a Hippo signaling component, MOB1A/1B constitute the critical hub of Hippo signaling in mammalian liver. LMob1DKO liver cells show hyperproliferation, increased cell saturation density, hepatocyte dedifferentiation, enhanced epithelial–mesenchymal transition and cell migration, and elevated transforming growth factor beta(TGF-β)2/3 production. These changes are strongly dependent on Yes-Associated Protein-1 (Yap1) and partially dependent on PDZ-binding motif (Taz) and Tgfbr2, but independent of connective tissue growth factor (Ctgf). In human liver cancers, YAP1 activation is frequent in cHC-CCs and ICCs and correlates with SMAD family member 2 activation. Drug screening revealed that antiparasitic macrocyclic lactones inhibit YAP1 activation in vitro and in vivo. Targeting YAP1/TAZ with these drugs in combination with inhibition of the TGF-β pathway may be effective treatment for cHC-CCs and ICCs.
Background
Hepatocellular carcinoma (HCC) is one of the most common solid tumors worldwide. Surgery is potentially curative, but high recurrence rates worsen patient prognosis. The interaction ...between the proteins programmed cell death 1 (PD-1) and programmed cell death 1 ligand 1 (PD-L1) is an important immune checkpoint. The significance of PD-L1 expression and human leukocyte antigen class I (HLA class I), recognized by CD8 T cells, in the prognosis of patients with HCC remains to be determined.
Methods
We assessed the levels of PD-L1 and HLA class I expression on HCC samples from 80 patients who had undergone hepatectomy at our institution, and evaluated the correlations between PD-L1 and HLA class I expression and patient prognosis.
Results
High HLA class I expression was correlated with significantly better recurrence-free survival (RFS), but not overall survival (OS). Multivariate analysis showed that high HLA class I expression was an independent predictor of improved RFS. Low expression of PD-L1 on HCC tended to predict better OS, but the difference was not statistically significant. PD-L1 expression on HCC correlated with the number of CD163-positive macrophages and HLA class I expression with CD3-positive cell infiltration. Univariable and multivariable analyses showed that combined PD-L1 low/HLA class I high expression on HCCs was prognostic for improved OS and RFS.
Conclusions
PD-L1 status may be a good predictor of prognosis in HCC patients with high HLA class I expression. Novel therapies targeting the PD-L1/PD-1 pathway may improve the prognosis of patients with HCC.
Background
Recently, a novel marker, hyperglycosylated
Wisteria floribunda
agglutinin-positive Mac-2 binding protein (WFA
+
-M2BP), was developed for liver fibrosis using the glycan “sugar ...chain”-based immunoassay; however, the feasibility of WFA
+
-M2BP for assessing liver fibrosis has not been proven with clinical samples of hepatitis.
Methods
Serum WFA
+
-M2BP values were evaluated in 200 patients with chronic liver disease who underwent histological examination of liver fibrosis. The diagnostic accuracy of WFA
+
-M2BP values was compared with various fibrosis markers, such as ultrasound based-virtual touch tissue quantification (VTTQ), magnetic resonance imaging based-liver-to-major psoas muscle intensity ratio (LMR), and serum markers, including hyaluronic acid, type 4 collagen, and aspartate transaminase to platelet ratio index (APRI).
Results
Serum WFA
+
-M2BP levels in patients with fibrosis grades F0, F1, F2, F3, and F4 had cutoff indices 1.62, 1.82, 3.02, 3.32, and 3.67, respectively, and there were significant differences between fibrosis stages F1 and F2, and between F2 and F3 (
P
< 0.01). The area under the receiver operating characteristic curves for the diagnosis of fibrosis (
F
≥ 3) using serum WFA
+
-M2BP values (0.812) was almost comparable to that using VTTQ examination (0.814), but was superior to the other surrogate markers, including LMR index (0.766), APRI (0.694), hyaluronic acid (0.683), and type 4 collagen (0.625) (
P
< 0.01 each).
Conclusions
Serum WFA
+
-M2BP values based on a glycan-based immunoassay is an accurate, reliable, and reproducible method for the assessment of liver fibrosis. This approach could be clinically feasible for evaluation of beneficial therapy through the quantification of liver fibrosis in hepatitis patients if this measurement application is commercially realized.
There are no detailed reports of clinical outcomes in Asian patients with nonalcoholic fatty liver disease (NAFLD) who undergo liver biopsy. We aimed to investigate the clinical outcomes of a large ...cohort of Asian patients with biopsy-proven NAFLD and evaluate the specific effects of nonalcoholic steatohepatitis and fibrosis stage.
This multicenter registry-based retrospective cohort study, called the CLIONE (Clinical Outcome Nonalcoholic Fatty Liver Disease) in Asia, included 1398 patients.
The median follow-up period was 4.6 years (range, 0.3-21.6 years), representing a total of 8874 person-years of follow-up. During that time, 47 patients died, and 1 patient underwent orthotopic liver transplantation. The leading cause of death was nonhepatic cancer (n = 10). The leading causes of liver-related death were liver failure (n = 9), hepatocellular carcinoma (HCC) (n = 8), and cholangiocellular carcinoma (n = 4). During follow-up, 37 patients developed HCC, 31 developed cardiovascular disease, and 68 developed nonhepatic cancer (mainly breast, stomach, and colon/rectum). Among our cohort of patients with NAFLD, liver-specific mortality was 2.34/1000 person-years (95% confidence interval CI, 1.52-3.58), overall mortality was 5.34/1000 person-years (95% CI, 4.02-7.08), and HCC incidence was 4.17/1000 person-years (95% CI, 3.02-5.75). Liver fibrosis was independently associated with liver-related events but not overall mortality.
Liver-related mortality was the leading cause of mortality in Asian patients with biopsy-confirmed NAFLD. Although fibrosis stage was independently associated with liver-related events, it was not associated with overall mortality after adjusting for confounders, such as histologic features of steatohepatitis.
Background
Because of the rarity and variety of pancreatic neuroendocrine tumors (PNETs), there have been few reports regarding the indication for lymph node dissection in patients with these tumors. ...This study aimed to evaluate the risk of lymph node metastasis of PNETs based on the tumor size and hormonal production.
Methods
Data for a total of 66 patients who had PNETs resected at our department between 1987 and 2010 were retrospectively studied. The clinicopathological features, including the disease-specific survival rate, were assessed based on the status of lymph node metastasis at the time of initial surgical resection. Then the cut-off point of tumor size to predict lymph node metastasis was estimated.
Results
There were 12 patients (18%) with lymph node metastasis. The frequency of lymph node metastasis tended to be higher in gastrinomas than that in other tumors (43 vs. 15%;
P
= 0.08). The size of PNETs with lymph node metastasis was significantly larger than that of the PNETs without metastasis (
P
= 0.04). The postoperative survival rate in the PNET patients with lymph node metastasis was significantly lower than that in the patients without metastasis (
P
< 0.0001). Only 2 (8%) of 26 PNETs with a tumor size of <15 mm had lymph node metastasis, and both of these were gastrinomas. On the other hand, 10 (25%) of the remaining 40 PNETs with a tumor size of ≥15 mm had lymph node metastasis. Notably, there were no PNETs with lymph node metastasis in 22 non-gastrinomas with a tumor size of <15 mm.
Conclusions
Non-gastrinomas with a tumor size of ≥15 mm and all gastrinomas would be an indication for pancreatectomy with lymph node dissection.
PDF
