TMPRSS4 Drives Angiogenesis in Hepatocellular Carcinoma by Promoting HB-EGF Expression and Proteolytic Cleavage.

BACKGROUND AND AIMS: Heparin-binding epidermal growth factor (HB-EGF), a member of the epidermal growth factor family, plays a pivotal role in the progression of several malignancies, but its role and regulatory mechanisms in hepatocellular carcinoma (HCC) remain obscure. Here, we report that transmembrane protease serine 4 (TMPRSS4) significantly enhanced the expression and proteolytic cleavage of HB-EGF to promote angiogenesis and HCC progression. APPROACH AND RESULTS: A mechanistic analysis revealed that TMPRSS4 not only increased the transcriptional and translational levels of HB-EGF precursor, but also promoted its proteolytic cleavage by enhancing matrix metallopeptidase 9 expression through the EGF receptor/Akt/mammalian target of rapamycin/ hypoxia-inducible factor 1 α signaling pathway. In addition, HB-EGF promoted HCC proliferation and invasion by the EGF receptor/phosphoinositide 3-kinase/Akt signaling pathway. The level of HB-EGF in clinical samples of serum or HCC tissues from patients with HCC was positively correlated with the expression of TMPRSS4 and the microvessel density, and was identified as a prognostic factor for overall survival and recurrence-free survival, which suggests that HB-EGF can serve as a potential therapeutic target for HCC. More importantly, we provide a demonstration that treatment with the HB-EGF inhibitor cross-reacting material 197 alone or in combination with sorafenib can significantly suppress angiogenesis and HCC progression. CONCLUSIONS: HB-EGF can be regulated by TMPRSS4 to promote HCC proliferation, invasion, and angiogenesis, and the combination of the HB-EGF inhibitor cross-reacting material 197 with sorafenib might be used for individualized treatment of HCC.

Effect of p18 on endothelial barrier function by mediating vascular endothelial Rab11a-VE-cadherin recycling.

Endothelial barrier integrity requires recycling of VE-cadherin to adherens junctions. Both p18 and Rab11a play significant roles in VE-cadherin recycling. However, the underlying mechanism and the role of p18 in activating Rab11a have yet to be elucidated. Performing in vitro and in vivo experiments, we showed that p18 protein bound to VE-cadherin before Rab11a through its VE-cadherin-binding domain (aa 1-39). Transendothelial resistance showed that overexpression of p18 promoted the circulation of VE-cadherin to adherens junctions and the recovery of the endothelial barrier. Silencing of p18 caused endothelial barrier dysfunction and prevented Rab11a-positive recycling endosome accumulation in the perinuclear recycling compartments. Furthermore, p18 knockdown in pulmonary microvessels markedly increased vascular leakage in mice challenged with lipopolysaccharide and cecal ligation puncture. This study showed that p18 regulated the pulmonary endothelial barrier function in vitro and in vivo by regulating the binding of Rab11a to VE-cadherin and the activation of Rab11a.

Mannose-mediated inhibitory effects of PA-MSHA on invasion and metastasis of hepatocellular carcinoma via EGFR/Akt/IκBß/NF-κB pathway.

BACKGROUND & AIMS: Elevation of high-mannose glycans is a common feature of malignant cells and has been suggested to be the basis for alternative cancer therapy for several years. Here we want to investigate the antitumour effect of pseudomonas aeruginosa-mannosesensitive haemagglutinin (PA-MSHA), a genetically engineered heat-inactivated PA strain with mannose-sensitive binding activity, on hepatocellular carcinoma (HCC). METHODS: Tumourigenicity and metastatic potentials of HCC were studied after PA-MSHA treatment by utilizing the in vitro/in vivo model of HCC. Expression of apoptosis-associated proteins and epithelial-mesenchymal transition (EMT) related genes were evaluated, and possible signalling pathways involved were investigated. RESULTS: PA-MSHA induced significant cell proliferation inhibition and cell cycle arrest of HCC through decreasing the levels of cyclins D1, cyclins E, CDK2, CDK4, proliferating cell nuclear antigen (PCNA), and increasing the level of p21 and p27. Moreover, PA-MSHA suppressed the invasion, migration and adhesion of HCC through inhibiting epithelial-mesenchymal transition (EMT). PA-MSHA also inhibited EGFR/Akt/IκBß/NF-κB pathway and overexpression of NF-κB significantly abrogated PA-MSHA induced EMT inhibition. In addition, competitive inhibition of the mannose binding activity of PA-MSHA by D-mannose significantly blocked its effect on cell cycle arrest and EMT. PA-MSHA also abrogated lung metastasis of HCC and significantly inhibited tumour growth in the in vivo study. CONCLUSIONS: Our study demonstrated the essential role of EGFR/Akt/IκBß/NF-κB pathway in the inhibitory effect of PA-MSHA on invasion and metastasis of HCC through suppressing EMT, and revealed an attractive prospect of PA-MSHA as a novel candidate agent in the treatment of HCC.

Preoperative prediction of conversion from laparoscopic rectal resection to open surgery: a clinical study of conversion scoring of laparoscopic rectal resection to open surgery.

OBJECTIVE: The objectives of this paper were to establish a model for the conversion of laparoscopic rectal resection to open surgery and to predict possible conversion before surgery. METHODS: The clinical data of 602 cases of laparoscopic rectal resection were retrospectively assessed. Risk factors associated with conversion of laparoscopic rectal resection to open rectal surgery were identified by logistic regression analysis. Also, a scoring system was created to calculate a score for the conversion of laparoscopic rectal resection to predict possible conversion for patients who underwent laparoscopic rectal resection before surgery. RESULTS: A total of 90 patients required conversion (total conversion rate = 14.95%). The established model included six variables: male gender, surgical experience (≤25 cases), history of abdominal surgery, body mass index ≥ 28, tumor diameter ≥ 6 cm, and tumor invasion or metastasis, for which 6, 4, 5, 10, 15, and 21 points were assigned, respectively. A patient with a total score >14.5 points was considered to have a high probability of conversion, whereas a patient with a total score <14.5 points was considered at a low risk. CONCLUSION: Preoperative determination of conversion score may predict possible conversion of laparoscopic rectal resection and thus reduce unnecessary open rectal surgery.

Clinical Benefit of Antiviral Agents for Hepatocellular Carcinoma Patients With Low Preoperative HBV-DNA Loads Undergoing Curative Resection: A Meta-Analysis.

BACKGROUND AND AIMS: The clinical benefit of adjuvant antiviral therapy after curative therapy for HCC in patients with high preoperative HBV-DNA loads has been studied widely but that in patients with low preoperative HBV-DNA loads remains controversial. The purpose of this study was to determine the effect of antiviral treatment prophylaxis on HBV reactivation, overall survival (OS), and postoperative liver function in patients with low preoperative HBV-DNA levels undergoing curative resection. METHODS: A meta-analysis was conducted by searching Web of Science, PubMed, Embase, and Cochrane Library until May 2020. We used REVMAN for data analysis and completed the study under the PRISMA guidelines. RESULTS: Three randomized trials and seven cohort studies, comprising of 1,131 individuals, were included in the meta-analysis. Antiviral treatment significantly reduced the rate of HBV reactivation after curative treatment of HCC, with a pooled risk ratio of 0.12 (95% c.i. 0.07 to 0.21; P < 0.00001). The trials were consistently favorable for the antiviral group, with a pooled hazard ratio of 0.52 (95% c.i. 0.37 to 0.74; P = 0.0002) in respect of OS rate. However, by pooling the data from studies that reported ALT on the 30th day postoperatively, the result didn't reach statistical significance (mean difference -4.38, 95% c.i. -13.83 to 5.07; P = 0.36). The I² values of the heterogeneity test for the above three comparisons are zero. CONCLUSION: Antiviral therapy during curative resection is effective in reducing HBV reactivation and improving OS rate in HCC patients with low viral load.

RECK expression is associated with angiogenesis and immunogenic Tumor Microenvironment in Hepatocellular Carcinoma, and is a prognostic factor for better survival.

Angiogenesis and immunosuppression have been described as closely related processes that can occur in parallel. As an inhibitor of matrix metalloproteinase, whether the level of reversion-inducing cysteine-rich protein with Kazal motifs (RECK) in hepatocellular carcinoma (HCC) reflects a link between angiogenesis and immunosuppression is still unknown. We analyzed RNA expression, immune infiltration and survival of HCC from The Cancer Genome Atlas databases. Immune scores and stromal scores were calculated based on the ESTIMATE algorithm to quantify the immune and stromal components in HCC. The association between RECK and clinicopathological features was further investigated by immunohistochemistry on tissue microarray. We found that the prognosis of patients with high RECK expression was significantly better than that of patients with low RECK expression. High RECK expression was associated with high ESTIMATE Score, recruitment of more tumor-infiltrating lymphocytes, low tumor purity, and high PD-L1 expression. In addition, positive RECK expression was associated with a lower incidence of vascular invasion and recurrence, a lower level of alpha fetoprotein (AFP) and microvessel density and a better tumor differentiation. Multivariate analyses revealed that reduced RECK expression was an independent prognostic factor for recurrence and poor prognosis. In conclusion, high RECK expression reflects an immunogenic and hypovascularity status in HCC. RECK is a promising prognostic marker for survival of HCC and may act as a complementary indicator for patients to receive anti-angiogenic therapy or immunotherapy.

[A clinicopathologic study of biliary intraductal papillary neoplasm].

OBJECTIVE: To investigate the clinicopathologic features, diagnosis and treatment of biliary intraductal papillary neoplasm (IPN-B). METHODS: The clinical, histopathological, treatment and prognosis data of 23 patients with IPN-B treated from January 1998 to December 2007 were retrospectively analyzed. RESULTS: There were 13 male and 10 female, aged from 30 to 80 years [mean age was (61 +/- 12) years]. The clinical manifestation included 10 cases with asymptomatic, 7 cases with abdominal pain, 4 cases with jaundice, 1 case with emaciation, and 1 case with acute cholangitis, respectively. Nine patients were also associated with hepatolithiasis. The average diameter of the tumors was (6 +/- 4) cm, 4 lesions were located in the right lobe, 15 in the left lobe, and 4 in the extrahepatic bile duct. Histopathologically, there were 4 adenomas, 1 borderline neoplasm, 6 carcinomas in situ, and 12 carcinomas. All patients received operation;the mean duration of follow-up was (33 +/- 28) months. Overall 3-year and 5-year survival rates of IPN-B were 85.3% and 68.2% respectively. CONCLUSIONS: IPN-B represents a distinct clinicopathologic entity. Favorable prognosis for IPN-B is offered by curative resection.

An Incidentally Discovered Hepatic Mass with Rim Calcification.

A wide array of pathologic abnormalities can cause hepatic calcifications, which are relatively uncommon and may result from both benign and malignant tumors, as well as inflammatory and infectious conditions. A pattern recognition approach is important to follow when faced with characterization of a calcified hepatic lesion. Radiologists should be aware of morphologic imaging features of calcified liver lesions to help differentiate benign from malignant lesions. Liver biopsy should be offered when the diagnosis is doubtful.

Role of the E3 Ubiquitin Ligase TRIM4 in Predicting the Prognosis of Hepatocellular Carcinoma.

The E3 ubiquitin ligase TRIM4 has been reported to regulate the assembly of the antiviral signalling complex, induce mitochondrial aggregation and sensitize cells to H2O2-induced death. However, the relationship between TRIM4 and human malignancies, including hepatocellular carcinoma (HCC), is unclear. In this study, we detected the expression of TRIM4 in 134 pairs of HCC tissues and peritumoural tissues and investigated the association of TRIM4 expression with the prognosis of HCC. We found that the TRIM4 expression was much lower in HCC tissues than in peritumoural tissues and was significantly associated with vascular invasion, tumour capsule and Hong Kong Liver Cancer (HKLC) stage. Univariate and multivariate analyses revealed that the TRIM4 expression was an independent prognostic factor for overall survival (OS) and recurrence-free survival (RFS) in our HCC cohort. Patients with higher TRIM4 expression had a lower incidence of intrahepatic recurrence and a higher OS rate (p<0.001 and p<0.01, respectively). These results were further validated in another independent cohort of 200 HCC patients. In conclusion, the TRIM4 level in HCC tissues is an independent prognostic factor for HCC patients. Close clinical monitoring is recommended for patients with low TRIM4 expression.

A comparison of hepatic mucinous cystic neoplasms with biliary intraductal papillary neoplasms.

BACKGROUND & AIMS: There is controversy regarding the term biliary intraductal papillary neoplasms (IPN-B) and their pathology, which frequently are confused with hepatic mucinous cystic neoplasms (MCN). We aimed to summarize the clinicopathologic features of IPN-B and differentiate them from MCN. METHODS: From January 1998 to December 2007, there were 19 patients with intrahepatic IPN-B and 13 patients with MCN who underwent surgical treatment at Zhongshan Hospital. Multiple demographic and clinicopathologic parameters were reviewed retrospectively and compared between the groups. RESULTS: The mean ages of patients with IPN-B and MCN were 59.5 +/- 11.1 and 44.4 +/- 9.7 years, respectively (P = .0004); the male:female ratios also differed (11:8 vs 2:11; P = .028). Tumors were significantly smaller (6.0 vs 11.2 cm; P = .006) in patients with IPN-B than in those with MCN. More patients with IPN-B also had hepatolithiasis (47.4% vs 0%, P = .004); cholangiectasis and communication between the cyst and main bile duct were more frequent in patients with IPN-B than in those with MCN (P < .001). The IPN-B consisted of 4 subtypes--the gastric subtype was the least invasive. Malignant lesions were more common in patients with IPN-B than in those with MCN (78.9% vs 38.5%; P = .03). The overall 5-year survival rates of patients with IPN-B and MCN were 82% and 100%, respectively. CONCLUSIONS: Intrahepatic IPN-B represents a distinct clinicopathologic entity that differs clinically, histologically, and radiologically from MCN. Curative resection has a favorable prognosis for patients with IPN-B, but further studies of its subtype are required.

COX-2/PGE2 Axis Regulates HIF2α Activity to Promote Hepatocellular Carcinoma Hypoxic Response and Reduce the Sensitivity of Sorafenib Treatment.

Purpose: Hypoxia-inducible factor-2α (HIF2α) is regarded as a preferential target for individualized hepatocellular carcinoma (HCC) treatment and sorafenib resistance. Our study aimed to identify the regulatory mechanisms of HIF2α activity under hypoxic conditions. We sought to determine whether the COX-2/PGE2 axis is involved in the regulatory mechanisms of HIF2α activity and of sorafenib resistance in hypoxic HCC cells.Experimental Design: The cell viability, migration, and invasion abilities were measured to analyze the effects of HIF2α on hypoxic HCC cells. Both in vitro and in vivo HCC models were used to determine whether the COX-2/PGE2 axis is a driver of HIF2α level and activity, which then reduces the sensitivity of sorafenib treatment in hypoxic HCC cells.Results: Under hypoxic conditions, the COX-2/PGE2 axis effectively stabilized HIF2α and increased its level and activity via decreasing von Hippel-Lindau protein (p-VHL) level, and also enhanced HIF2α activity by promoting HIF2α nuclear translocation via MAPK pathway. The activation of HIF2α then led to the enhanced activation of VEGF, cyclin D1, and TGFα/EGFR pathway to mediate HCC development and reduce the sensitivity of sorafenib. More importantly, COX-2-specific inhibitors synergistically enhanced the antitumor activity of sorafenib treatment.Conclusions: Our data obtained demonstrate that the COX/PGE2 axis acts as a regulator of HIF2α expression and activity to promote HCC development and reduce sorafenib sensitivity by constitutively activating the TGFα/EGFR pathway. This study highlights the potential of COX-2-specific inhibitors for HCC treatment and particularly for enhancing the response to sorafenib treatment. Clin Cancer Res; 24(13); 3204-16. ©2018 AACR.

Von Hippel-Lindau disease involving pancreas and biliary system: A rare case report.

RATIONALE: Von Hippel-Lindau (VHL) disease is a rare inherited, autosomal-dominant syndrome caused by heterozygous germline mutations in the VHL gene. VHL patients are prone to develop benign and malignant tumors and cysts in multiple organ systems involving kidneys, pancreas and central nervous system (CNS). The varied and complex clinical manifestations and radiological findings of VHL are of interest. PATIENT CONCERNS: We report a 38-year-old woman with a ten-year history of VHL disease involving both pancreas and biliary system. To the best of our knowledge, direct involvement of the biliary system in VHL disease has never been reported. DIAGNOSES: The diagnosis was established via computed tomography scan and was confirmed by genetic testing. INTERVENTIONS: The patient chose to receive conservative treatment and was followed up by magnetic resonance cholangiopancreatography and magnetic resonance imaging examination. OUTCOMES: Renal angiomas and cysts were found during follow-up and there were no evidence of malignant change of the pancreas and biliary system. LESSONS: We described the first case of VHL-associated choledochal cysts and may present new visceral manifestations of VHL disease. Gastroenterologists should be aware of the clinical presentations of this rare disease for early detection of its life-threatening manifestations.

Preoperative Albumin-Bilirubin Score for Postoperative Solitary Hepatocellular Carcinoma within the Milan Criteria and Child-Pugh A Cirrhosis.

Surgical resection remains the initial treatment of choice for the majority of early stage hepatocellular carcinoma (HCC) patients. Although the factors that influence the prognosis of postoperative HCC patients have been well elucidated, there are a limited number of simple, objective, and distinct methods for estimating survival for postoperative patients with solitary HCC within the Milan criteria and Child-Pugh (C-P) A cirrhosis. The Albumin-Bilirubin (ALBI) score is a new evidence-based approach to assess liver function. The ALBI score eliminates subjective variables, such as ascites and encephalopathy which are the requirements for the conventional C-P grading system. This study enrolled 654 patients to determine whether the ALBI score can predict the outcomes of postoperative solitary HCC patients within the Milan criteria and C-P A cirrhosis. Our results showed the ALBI score significantly influenced the overall survival and cumulative recurrence rates. Furthermore, the ALBI score was significantly related to the degree of liver cirrhosis and serum γ-glutamyl transpeptidase (GGT) concentration in solitary HCC cases within the Milan criteria and C-P A cirrhosis. Additionally, the combination of the ALBI score and serum GGT concentration contributed to the prognosis prediction in this cohort. In conclusion, we externally validated the ALBI grade as a novel biomarker to predict prognosis for solitary HCC within the Milan Criteria and C-P A cirrhosis.

Calcified Cystic Lesion of the Pancreas.

Pancreatic cystic lesion is a relatively uncommon condition with an estimated prevalence of 2 % in the general population. In the past two decades, there has been a dramatic increase in the prevalence of pancreatic cystic lesions because of the widespread use of high-resolution imaging, as well as the aging of the population. Pancreatic cystic lesions cover a wide spectrum of pathology and can range from obviously benign to borderline malignant potential lesions to overt malignancy. Though the presence of mural nodules, septa-like structures, or calcification on imaging examination contributes to the differential diagnosis, preoperatively determining the biological nature of these cystic lesions is sometimes challenging. In this paper, we report a rare case of pancreatic cystic lesion with an egg-shell like calcification. Complete resection was performed and histological examination confirmed the diagnosis of calcified pancreatic pseudocyst.

Cholecystectomy is associated with higher risk of early recurrence and poorer survival after curative resection for early stage hepatocellular carcinoma.

Although cholecystectomy has been reported to be associated with increased risk of developing hepatocellular carcinoma (HCC), the association between cholecystectomy and prognosis of HCC patients underwent curative resection has never been examined. Through retrospective analysis of the data of 3933 patients underwent curative resection for HCC, we found that cholecystectomy was an independent prognostic factor for recurrence-free survival (RFS) of patients at early stage (BCLC stage 0/A) (p = 0.020, HR: 1.29, 95% CI: 1.04-1.59), and the 1-, 3-, 5-year RFS rates for patients at early stage were significantly worse in cholecystectomy group than in non-cholecystectomy group (80.5%, 61.8%, 52.0% vs 88.2%, 68.8%, 56.8%, p = 0.033). The early recurrence rate of cholecystectomy group was significantly higher than that of non-cholecystectomy group for patients at early stage (59/47 vs 236/333, p = 0.007), but not for patients at advanced stage (BCLC stage C) (p = 0.194). Multivariate analyses showed that cholecystectomy was an independent risk factor for early recurrence (p = 0.005, HR: 1.52, 95% CI: 1.13-2.03) of early stage HCC, but not for late recurrence (p = 0.959). In conclusion, cholecystectomy is an independent predictor for early recurrence and is associated with poorer RFS of early stage HCC. Removal of normal gallbladder during HCC resection may be avoided for early stage patients.

Management of gastroesophageal reflux disease: medications, surgery, or endoscopic therapy? (Current status and trends).

Gastroesophageal reflux disease (GERD) is a common chronic disorder in the Western world. The basic cause of GERD has been well characterized--the fundamental defect is a loss of integrity of the gastroesophageal barrier. What is less clear is the most appropriate means of addressing this reflux. GERD has a variety of symptoms, ranging from typical presentations of heartburn and regurgitation (without esophagitis) to atypical presentations, such as severe erosive esophagitis and its associated complications. Because of its symptomatic diversity, physicians may select from a variety of therapeutic approaches. Medical therapy aims at decreasing acidity by suppressing proton secretion and has been well established. Available medications include antacids and alginates, H2-receptor antagonists, motility agents, and proton pump inhibitors (PPIs). Antireflux surgery, commonly performed laparoscopically, aims at reinforcing and repairing the defective barrier through plication of the gastric fundus. The earliest performed successful procedures were the Nissen and Toupet fundoplications, to which several modifications have since been made. It has been demonstrated in preliminary studies and long-term outcomes of such open surgery and preliminary studies of such laparoscopic surgery that antireflux surgery is an effective approach, with overall outcomes superior to those achieved with medications. The precise indications for the surgical treatment of patients with GERD, however, remain controversial. In recent years, endoscopic intraluminal antireflux approaches have attracted the attention of physicians, surgeons, and commercial companies, especially after the approval of two endoscopic intraluminal methods by the United States FDA in 2000. The common element is prevention of acid reflux by construction of a functional or controlled barrier in the lower esophageal sphincter zone. Three main methods are currently employed: endoscopic intraluminal valvuloplasty, endoscopic radiofrequency therapy, and endoscopic injection or implantation of foreign material. The endoluminal suturing method is highly demanding technically, and its short-term results are encouraging, although largely dependent on the experience of the endoscopist. Several prospective cohort studies have shown that the radiofrequency procedure (Stretta) significantly improves GERD symptoms and quality of life while reducing esophageal acid exposure and eliminating the need for antisecretory medications in the majority of patients within 6-12 months. Most recently, some researchers have studied the endoluminal implantation of polymers, such as Plexiglas (polymethyl-methylacrylate), Gatekeeper hydrogel, and Enteryx (ethylene vinyl alcohol copolymer). The preliminary results of these studies showed that the implantation method was feasible and safe; however, the only multicenter trial related to outcome that has been published has included just 1 year of follow-up. Here, we review the treatment of GERD: medical, surgical, and endoscopic. In addition, we provide an algorithm based on symptoms and response to treatment for management of these patients.

Doxorubicin-loaded mesoporous magnetic nanoparticles to induce apoptosis in breast cancer cells.

Selective targeting of chemotherapeutic drugs toward the cancer cells overcomes the limitations involved in chemotherapy. Ideally, targeted delivery system holds great potential in cancer therapy due to specific release of drug in the cancer tissues. In this regard, DOX-loaded chitosan coated mesoporous magnetic nanoparticles (DOX-CMMN) were prepared and evaluated for its physicochemical and biological characteristics. Nanosized magnetic nanoparticles were observed with a high loading capacity for DOX. The drug-loaded nanoparticles exhibited a controlled and sustained release of drug without any burst release phenomenon. The DOX-DMMN showed a concentration-dependent cell proliferation inhibitory action against breast cancer cells. The blank nanoparticles showed excellent biocompatibility with cell viability >85% at the maximum tested concentration. Our results showed that chitosan coated magnetic system has high potential for breast cancer targeting under an alternating current magnetic field (ACMF). The present study showed that magnetic nanoparticles can be targeted to tumor cells under the presence of oscillating magnetic field. The combined effect of chemotherapy and thermotherapy can have a promising clinical potential for the treatment of breast cancer.