Inhibitory effects of polysaccharides isolated from Phellinus gilvus on benzo(a)pyrene-induced forestomach carcinogenesis in mice

AIM: Although polysaccharides from Phellinus mushrooms are a well-known material with anti-tumor properties, there is no information about the effect of polysaccharides from Phellinus gilvus (PG) on tumor. The modulating effect of polysaccharides isolated from PG on the benzo(a)pyrene (BaP)-induced forestomach carcinogenesis in ICR female mice was investigated in this study.METHODS: A forestomach carcinogenesis model was established in 40 ICR female mice receiving oral administration of BaP for 4 wk. The mice were randomly assigned to 4 groups (10 each). The mice in each group were treated with sterile water or PG for 4 and 8 wk (SW4,PGW4, SW8, and PGW8 groups). Eight or 12 wk after the first dose of BaP, forestomachs were removed for histopathological and RT-PCR analysis.RESULTS: In histopathological changes and RT-PCR analysis, sterile water-treated mice showed significant hyperplasia of the gastric mucosa with a significantly increased expression of mutant p53 mRNA compared to mice treated with PG for 8 wk.CONCLUSION: Polysaccharides isolated from PG may inhibit BaP-induced forestomach carcinogenesis in mice bydown-regulating mutant p53 expression.

Risk factors for immediate post-operative fatal recurrence after curative resection of hepatocellular carcinoma

AIM： To investigate the clinicopathological risk factors for immediate post-operative fatal recurrence of hepatocellular carcinoma （HCC）, which may have practical implication and contribute to establishing high risk patients for pre- or post-operative preventive measures against HCC recurrence. METHODS： From June 1994 to May 2004, 269 patients who received curative resection for HCC were reviewed. Of these patients, those who demonstrated diffuse intrahepatic or multiple systemic recurrent lesions within 6 mo after surgery were investigated （fatal recurrence group）. The remaining patients were designated as the control group, and the two groups were compared for clinicopathologic risk factors. RESULTS： Among the 269 patients reviewed, 30 patients were enrolled in the fatal recurrence group. Among the latter, 20 patients showed diffuse intrahepatic recurrence type and 10 showed multiple systemic recurrence type. Multivariate analysis between the fatal recurrence group and control group showed that preoperative serum alpha-fetoprotein （AFP） level was greater than 1 000 μg/L （P= 0.02; odds ratio = 2.98）, tumor size greater than 6.5 cm （P= 0.03; OR= 2.98）, and presence of microvascular invasion （P= 0.01; OR=4.89） were the risk factors in the fatal recurrence group. The 48.1% of the patients who had all the three risk factors and the 220 of those who had two risk factors experienced fatal recurrence within 6 mo after surgery. CONCLUSION： Three distinct risk factors for immediate post-operative fatal recurrence of HCC after curative resection are pre-operative serum AFP level 〉 1 000 μg/L,tumor size〉6.5 cm, and microvascular invasion. The high risk patients with two or more risk factors should be the candidates for various adjuvant clinical trials.

Long-term outcomes of endoscopic submucosal dissection and surgery for undifferentiated intramucosal gastric cancer regardless of size

BACKGROUND The clinical outcomes of endoscopic submucosal dissection(ESD)for undifferentiated(UD)intramucosal early gastric cancer(EGC)compared with those of surgery,regardless of lesion size,are not well known.Furthermore,there is a concern regarding the treatment plan before and after ESD in cases of UD intramucosal EGC within expanded indications.AIM To evaluate clinical outcomes of ESD compared with those of surgery in UD intramucosal EGC patients regardless of tumor size.METHODS We enrolled patients with UD intramucosal EGC after ESD with complete resection or surgery from January 2005 to August 2020 who met the within or beyond expanded indications with lesion size>2 cm(the only non-curative factor).Overall,123 and 562 patients underwent ESD and surgery,respectively.After propensity-score matching,clinical and long-term outcomes,i.e.,recurrencefree survival(RFS)and overall survival(OS),were analyzed.The multivariable Cox proportional hazard model with treatment modality and ESD indication was used to evaluate the recurrence risk.RESULTS After matching,119 patients each were finally enrolled in the ESD and surgery groups.The median length of hospital stay was shorter in the ESD group than surgery group(4.0 vs 9.0 days,P<0.001).Four cases of recurrence after ESD were local recurrences,all of which occurred within 1 year.Total recurrence was seven(5.9%)and two(1.7%)in the ESD and surgery groups,respectively.No difference was observed between the two groups with respect to OS(P=0.948).However,the ESD group had inferior RFS compared with the surgery group(P=0.031).ESD was associated with the risk of recurrence after initial treatment in all enrolled patients(hazard ratio,5.2;95%confidence interval:1.0-25.8,P=0.045).CONCLUSION Although OS was similar between the two groups,surveillance endoscopy was important for the ESD than for the surgery group because RFS was inferior and local recurrence was an issue.

Diagnosis of gastric epithelial neoplasia:Dilemma for Korean pathologists

The histopathological diagnosis of gastric mucosal biopsy and endoscopic mucosal resection/endoscopic submucosal dissection specimens is important,but the diagnostic criteria,terminology,and grading system are not the same in the East and West.A structurally invasive focus is necessary to diagnose carcinoma for most Western pathologists,but Japanese pathologists make a diagnosis of cancer based on severe dysplastic cytologic atypia irrespective of the presence of invasion.Although the Vienna classification was introduced to reduce diagnostic discrepancies,it has been difficult to adopt due to different concepts for gastric epithelial neoplastic lesions.Korean pathologists experience much difficulty making a diagnosis because we are influenced by Japanese pathologists as well as Western medicine.Japan is geographically close to Korea,and academic exchanges are active.Additionally,Korean doctors are familiar with Western style medical terminology.As a result,the terminology,definitions,and diagnostic criteria for gastric intraepithelial neoplasia are very heterogeneous in Korea.To solve this problem,the Gastrointestinal Pathology Study Group of the Korean Society of Pathologists has made an effort and has suggested guidelines for differential diagnosis:(1) a diagnosis of carcinoma is based on invasion;(2) the most important characteristic of low grade dysplasia is the architectural pattern such as regular distribution of crypts without severe branching,budding,or marked glandular crowding;(3) if nuclear pseudostratification occupies more than the basal half of the cryptal cells in three or more adjacent crypts,the lesion is considered high grade dysplasia;(4) if severe cytologic atypia is present,careful inspection for invasive foci is necessary,because the risk for invasion is very high;and(5) other structural or nuclear atypia should be evaluated to make a final decision such as cribriform pattern,papillae,ridges,vesicular nuclei,high nuclear/cytoplasmic ratio,loss of nuclear polarity,thick and irregular nuclear membrane,and nucleoli.

Cancer-associated fibroblast-derived secreted phosphoprotein 1 contributes to resistance of hepatocellular carcinoma to sorafenib and lenvatinib

Background:Cancer-associated fibroblasts(CAFs)play an important role in the induction of chemo-resistance.This study aimed to clarify the mechanism underlying CAF-mediated resistance to two tyrosine kinase inhibitors(TKIs),sorafenib and lenvatinib,and to identify a novel therapeutic target for overcoming TKI resistance in hepatocellular carcinoma(HCC).Methods:We performed a systematic integrative analysis of publicly available gene expression datasets and whole-transcriptome sequencing data from 9 pairs of CAFs and para-cancer fibroblasts isolated from human HCC and para-tumor tissues,respectively,to identify key molecules that might induce resistance to TKIs.We then performed in vitro and in vivo experiments to validate selected targets and related mechanisms.The associations of plasma secreted phosphoprotein 1(SPP1)expression levels before sorafenib/lenvatinib treatment with progression-free survival(PFS)and overall survival(OS)of 54 patients with advanced HCC were evaluated using Kaplan-Meier and Cox regression analysis.Results:Bioinformatic analysis identified CAF-derived SPP1 as a candidate molecule driving TKI resistance.SPP1 inhibitors reversed CAF-induced TKI resistance in vitro and in vivo.CAF-derived SPP1 activated rapidly accelerated fibrosarcoma(RAF)/mitogen-activated protein kinase(MAPK)and phosphatidylinositol 3-kinase(PI3K)/protein kinase B(AKT)/mammalian target of rapamycin(mTOR)through the integrin-protein kinase C-alpha(PKCα)signaling pathway and promoted epithelial-to-mesenchymal transition(EMT).A high plasma SPP1 level before TKI treatment was identified as an independent predictor of poor PFS(P=0.026)and OS(P=0.047)in patients with advanced HCC after TKI treatment.Conclusions:CAF-derived SPP1 enhances TKI resistance in HCC via bypass activation of oncogenic signals and EMT promotion.Its inhibition represents a promising therapeutic strategy against TKI resistance inHCC.Moreover,plasma SPP1 level before TKI treatment represents a potential biomarker for treatment response prediction.

Risk factor for ischemic-type biliary lesion after ABO-incompatible living donor liver transplantation

AIM: To evaluate the risk factors for ischemic-type biliary lesion(ITBL) after ABO-incompatible(ABO-I) adult living donor liver transplantation(ALDLT).METHODS: Among 141 ALDLTs performed in our hospital between 2008 and 2014, 27(19%) were ABO-I ALDLT and 114 were ABO-identical/compatible ALDLT. In this study, we extensively analyzed the clinico-pathological data of the 27 ABO-I recipients to determine the risk factors for ITBL after ABO-I ALDLT. All ABO-I ALDLT recipients underwent an identical B-cell depletion protocol with preoperative rituximab, plasma exchange(PE), and operative splenectomy. The median follow-up period after transplantation was 26 mo. The clinical outcomes of the 27 ABO-I ALDLT recipients were compared with those of 114 ABO-identical/compatible ALDLT recipients.RESULTS: ITBL occurred in four recipients(14.8%) between 45 and 112 d after ABO-I ALDLT. The overall survival rates were not different between ABO-I ALDLT and ABO-identical/compatible ALDLT(P = 0.303). Among the ABO-I ALDLT recipients, there was no difference between patients with ITBL and those without ITBL in terms of B-cell and T-cell count, serum isoagglutinin titers, number of PEs, operative time and transfusion, use of graft infusion therapy, or number of remnant B-cell follicles and plasma cells in the spleen. However, the perioperative NK cell counts in the blood of patients with ITBL were significantly higher than those in the patients without ITBL(P < 0.05). Preoperative NK cell count > 150/μL and postoperative NK cell count > 120/μL were associated with greater relative risks(RR) for development of ITBL(RR = 20 and 14.3, respectively, P < 0.05). CONCLUSION: High NK cell counts in a transplant recipient's blood are associated with ITBL after ABO-I ALDLT. Further research is needed to elucidate the molecular mechanism of NK cell involvement in the development of ITBL.