MLH1 Inhibits Metastatic Potential of Pancreatic Ductal Adenocarcinoma via Downregulation of GPRC5C.

DNA mismatch repair gene MutL homolog-1 (MLH1) has divergent effects in many cancers; however, its impact on the metastasis of pancreatic ductal adenocarcinoma (PDAC) remains unclear. In this study, MLH1 stably overexpressed (OE) and knockdowned (KD) sublines were established. Wound healing and transwell assays were used to evaluate cell migration/invasion. In vivo metastasis was investigated in orthotopic implantation models (severe combined immunodeficiency mice). RT-qPCR and western blotting were adopted to show gene/protein expression. MLH1 downstream genes were screened by transcriptome sequencing. Tissue microarray-based immunohistochemistry was applied to determine protein expression in human specimens. In successfully generated sublines, OE cells presented weaker migration/invasion abilities, compared with controls, whereas in KD cells, these abilities were significantly stronger. The metastasis-inhibitory effect of MLH1 was also observed in mice. Mechanistically, G protein-coupled receptor, family C, group 5, member C (GPRC5C) was a key downstream gene of MLH1 in PDAC cells. Subsequently, transient GPRC5C silencing effectively inhibited cell migration/invasion and remarkably reversed the proinvasive effect of MLH1 knockdown in KD cells. In animal models and human PDAC tissues, tumoral GPRC5C expression, negatively associated with MLH1 expressions, was positively correlated with histologic grade, vessel invasion, and poor cancer-specific survival. In conclusion, MLH1 inhibits the metastatic potential of PDAC via downregulation of GPRC5C.

Clinical manifestations, diagnosis and long-term prognosis of adult autoimmune enteropathy: Experience from Peking Union Medical College Hospital.

BACKGROUND: Autoimmune enteropathy (AIE) is a rare disease whose diagnosis and long-term prognosis remain challenging, especially for adult AIE patients. AIM: To improve overall understanding of this disease's diagnosis and prognosis. METHODS: We retrospectively analyzed the clinical, endoscopic and histopathological characteristics and prognoses of 16 adult AIE patients in our tertiary medical center between 2011 and 2023, whose diagnosis was based on the 2007 diagnostic criteria. RESULTS: Diarrhea in AIE patients was characterized by secretory diarrhea. The common endoscopic manifestations were edema, villous blunting and mucosal hyperemia in the duodenum and ileum. Villous blunting (100%), deep crypt lymphocytic infiltration (67%), apoptotic bodies (50%), and mild intraepithelial lymphocytosis (69%) were observed in the duodenal biopsies. Moreover, there were other remarkable abnormalities, including reduced or absent goblet cells (duodenum 94%, ileum 62%), reduced or absent Paneth cells (duodenum 94%, ileum 69%) and neutrophil infiltration (duodenum 100%, ileum 69%). Our patients also fulfilled the 2018 diagnostic criteria but did not match the 2022 diagnostic criteria due to undetectable anti-enterocyte antibodies. All patients received glucocorticoid therapy as the initial medication, of which 14/16 patients achieved a clinical response in 5 (IQR: 3-20) days. Immunosuppressants were administered to 9 patients with indications of steroid dependence (6/9), steroid refractory status (2/9), or intensified maintenance medication (1/9). During the median of 20.5 months of follow-up, 2 patients died from multiple organ failure, and 1 was diagnosed with non-Hodgkin's lymphoma. The cumulative relapse-free survival rates were 62.5%, 55.6% and 37.0% at 6 months, 12 months and 48 months, respectively. CONCLUSION: Certain histopathological findings, including a decrease or disappearance of goblet and Paneth cells in intestinal biopsies, might be potential diagnostic criteria for adult AIE. The long-term prognosis is still unsatisfactory despite corticosteroid and immunosuppressant medications, which highlights the need for early diagnosis and novel medications.

Long-term prognosis and its associated predictive factors in patients with eosinophilic gastroenteritis.

BACKGROUND: Eosinophilic gastroenteritis (EGE) is a chronic recurrent disease with abnormal eosinophilic infiltration in the gastrointestinal tract. Glucocorticoids remain the most common treatment method. However, disease relapse and glucocorticoid dependence remain notable problems. To date, few studies have illuminated the prognosis of EGE and risk factors for disease relapse. AIM: To describe the clinical characteristics of EGE and possible predictive factors for disease relapse based on long-term follow-up. METHODS: This was a retrospective cohort study of 55 patients diagnosed with EGE admitted to one medical center between 2013 and 2022. Clinical records were collected and analyzed. Kaplan-Meier curves and log-rank tests were conducted to reveal the risk factors for long-term relapse-free survival (RFS). RESULTS: EGE showed a median onset age of 38 years and a slight female predominance (56.4%). The main clinical symptoms were abdominal pain (89.1%), diarrhea (61.8%), nausea (52.7%), distension (49.1%) and vomiting (47.3%). Forty-three (78.2%) patients received glucocorticoid treatment, and compared with patients without glucocorticoid treatments, they were more likely to have elevated serum immunoglobin E (IgE) (86.8% vs 50.0%, P = 0.022) and descending duodenal involvement (62.8% vs 27.3%, P = 0.046) at diagnosis. With a median follow-up of 67 mo, all patients survived, and 56.4% had at least one relapse. Six variables at baseline might have been associated with the overall RFS rate, including age at diagnosis < 40 years [hazard ratio (HR) 2.0408, 95% confidence interval (CI): 1.0082-4.1312, P = 0.044], body mass index (BMI) > 24 kg/m2 (HR 0.3922, 95%CI: 0.1916-0.8027, P = 0.014), disease duration from symptom onset to diagnosis > 3.5 mo (HR 2.4725, 95%CI: 1.220-5.0110, P = 0.011), vomiting (HR 3.1259, 95%CI: 1.5246-6.4093, P = 0.001), total serum IgE > 300 KU/L at diagnosis (HR 0.2773, 95%CI: 0.1204-0.6384, P = 0.022) and glucocorticoid treatment (HR 6.1434, 95%CI: 2.8446-13.2676, P = 0.003). CONCLUSION: In patients with EGE, younger onset age, longer disease course, vomiting and glucocorticoid treatment were risk factors for disease relapse, whereas higher BMI and total IgE level at baseline were protective.

Positive correlation between latent Epstein-Barr virus infection and severity of illness in inflammatory bowel disease patients.

BACKGROUND: Emerging studies indicate the critical involvement of microorganisms, such as Epstein-Barr virus (EBV), in the pathogenesis of inflammatory bowel disease (IBD). Immunosuppressive therapies for IBD can reactivate latent EBV, complicating the clinical course of IBD. Moreover, the clinical significance of EBV expression in B lymphocytes derived from IBD patients' intestinal tissues has not been explored in detail. AIM: To explore the clinical significance of latent EBV infection in IBD patients. METHODS: Latent EBV infection was determined by double staining for EBV encoded RNA and CD20 in colon specimens of 43 IBD patients who underwent bowel resection. Based on the staining results, the patients were divided into two groups, according to their latent EBV infection states - negative (n = 33) and positive (n = 10). Illness severity of IBD were assigned according to Crohn's disease activity index (ulcerative colitis) and Mayo staging system (Crohn's disease). The clinic-pathological data were analyzed between the two different latent EBV groups and also between the mild-to-moderate and severe disease groups. RESULTS: Systolic pressure (P = 0.005), variety of disease (P = 0.005), the severity of illness (P = 0.002), and pre-op corticosteroids (P = 0.025) were significantly different between the EBV-negative and EBV-positive groups. Systolic pressure (P = 0.001), variety of disease (P = 0.000), pre-op corticosteroids (P = 0.011) and EBV infection (P = 0.003) were significantly different between the mild-to-moderate and severe disease groups. CONCLUSION: IBD patients with latent EBV infection may manifest more severe illnesses. It is suggested that the role of EBV in IBD development should be further investigated, latent EBV infection in patients with serious IBD should be closely monitored, and therapeutic course should be optimized.

Expert Consensus on Pathological Diagnosis of Intrahepatic Cholangiocarcinoma (2022 version).

Intrahepatic cholangiocarcinoma (iCCA) can originate from the large bile duct group (segment bile ducts and area bile ducts), small bile duct group (septal bile ducts and interlobular bile ducts), and terminal bile duct group (bile ductules and canals of Hering) of the intrahepatic biliary tree, which can be histopathological corresponding to large duct type iCCA, small duct type iCCA and iCCA with ductal plate malformation pattern, and cholangiolocarcinoma, respectively. The challenge in pathological diagnosis of above subtypes of iCCA falls in the distinction of cellular morphologies, tissue structures, growth patterns, invasive behaviors, immunophenotypes, molecular mutations, and surgical prognoses. For these reasons, this expert consensus provides nine recommendations as a reference for standardizing and refining the diagnosis of pathological subtypes of iCCA, mainly based on the 5th edition of the World Health Organization Classification of Tumours of the Digestive System.

External validation of the Paddington International Virtual Electronic ChromoendoScopy ScOre as a good endoscopic score to define mucosal healing and predict long-term clinical outcomes in ulcerative colitis.

OBJECTIVES: To define endoscopic and histological remission in ulcerative colitis (UC) accurately, several scoring systems have been established. A novel virtual electronic chromoendoscopy score, the Paddington International Virtual ChromoendoScopy ScOre (PICaSSO), was developed, validated, and reproduced to assess inflammation grade and predict patient prognosis. We externally verified and validated the clinical value of PICaSSO in UC patients. METHODS: This prospective study enrolled 63 UC patients. The Mayo endoscopic score (MES), UC Endoscopic Index of Severity (UCEIS), and PICaSSO were adopted for endoscopic evaluation. All biopsy samples were scored using the Robarts histological index (RHI), Nancy histological index (NHI), and "Extent, Chronicity, Activity, Plus additional findings" (ECAP) score. Patients with an endoscopic MES of 0-1 at baseline were followed up during a median time of 23.5 months. RESULTS: PICaSSO was strongly correlated with other endoscopic and histological scoring systems. PICaSSO ≤3 had advantages in assessing histological remission (HR), with the highest accuracy of 88.9% for ECAP-HR. Relapse-free survival rates were significantly different between patients with MES 0 and MES 1 and patients with PICaSSO ≤3 and >3 (P = 0.010 and 0.018, respectively). CONCLUSIONS: PICaSSO was externally validated with strong correlations with other endoscopic and histological scoring systems in UC, and PICaSSO-ER might potentially predict a better long-term clinical outcome in UC patients.

FGFR3 Nuclear Translocation Contributes to Proliferative Potential and Poor Prognosis in Pancreatic Ductal Adenocarcinoma.

OBJECTIVES: Fibroblast growth factor receptor 3 (FGFR3) was revealed to have divergent, even opposite roles in different neoplasms. In pancreatic ductal adenocarcinoma (PDAC), its impact on biological behavior and prognosis was not well elucidated. METHODS: Fibroblast growth factor receptor 3 was downregulated by RNA interference to explore its impact on cell proliferative proclivity in PDAC cells. Furthermore, tissue microarray-based immunohistochemistry for FGFR3 was performed in 326 patients with PDAC who underwent radical resection, and its clinicopathologic and prognostic implications were then evaluated. RESULTS: First, successful FGFR3 knockdown remarkably decreased its expression, cell proliferation, and S-phase ratio in the cell cycle in 2 PDAC cell lines, BxPC-3 and AsPC-1. Meanwhile, alterations in p-Akt, cyclin D1, cyclin B1, and p21 were also observed. Subsequently, high nuclear FGFR3 expression, but not cytoplasmic, was significantly common in tumor tissues and positively associated with N stage and dismal overall survival in the entire cohort. In addition, nuclear FGFR3 expression was also prognostic in 10 of 14 subsets. Univariate and multivariate Cox regression analyses identified nuclear expression of FGFR3 as an independent prognosticator in the entire cohort. CONCLUSIONS: Our data showed that FGFR3 nuclear translocation contributes to cell proliferative potential and predicts poor long-term prognosis in PDAC after surgical resection.

An MMP-based risk score strongly distinguishes prognosis in hepatocellular carcinoma after resection.

Aim: To first explore the prognostic value of MMP11 and MMP15 in hepatocellular carcinoma. Methods: MMP11/MMP15 expression was immunohistochemically detected and correlated with clinicopathologic variables and survival and confirmed in publicly available databases. An MMP-based risk score (MMPRS) was established. Results: Tumoral MMP11/MMP15 expression was higher and univariately associated with crucial clinicopathologic parameters, overall survival and disease-free survival in all patients and/or many subsets. Multivariately, MMP11/MMP15 expression remained significant. Their overexpression and prognostic value were confirmed in the Ualcan and Kaplan-Meier plotter databases. Critically, the novel MMPRS integrating MMP11, MMP15 and tumor-node-metastasis stage identified subgroups with the best and worst prognoses, with much higher predictive power. Conclusion: MMP11 and MMP15 served as prognosticators in hepatocellular carcinoma. MMPRS might work more accurately.

MMP11 and MMP15, involved in cancer dissemination, were found to have important biological functions in several cancers. However, their prognostic value in hepatocellular carcinoma (HCC) remains unknown. In the present study, it was found that MMP11 and MMP15 were overexpressed and predictive of the outcome of HCC. Moreover, the novel MMP-based risk score integrating MMP11, MMP15 and tumor­node­metastasis stage had much higher prognostic power. MMP11, MMP15 and especially the MMP-based risk score were identified as promising indicators of prognosis in HCC.

The genomic landscape of Cronkhite-Canada syndrome: Possible clues for pathogenesis.

OBJECTIVES: Cronkhite-Canada syndrome (CCS) is a rare hamartomatous polyposis syndrome with a proposed association with chronic autoimmune inflammation. To date, genetic background of patients with CCS remains less investigated. In this study we aimed to explore the genomic landscape of CCS. METHODS: Whole exome sequencing was performed on peripheral blood samples extracted from 18 patients with CCS. Potential function-impacting germline variants were filtered by R software. Through systematic data analysis, a number of genetic variants were identified. Enrichment analysis was performed using the R package ClusterProfiler. RESULTS: Overall, 3960 low-frequency (<0.05 or not reported in the Exome Aggregation Consortium East Asian, 1000 Genomes, or ESP6500 database) potentially function-impacting germline variants were identified, with 18 genes (FDFT1, LOC400863, MUC3A, MUC4, ZNF806, GXYLT1, MUC6, PABPC3, PSPH, ZFPM1, CIC, LOC283710, ARSD, GOLGA6L2, LOC388282, SLC25A5, TMEM247, WDR89) involved over half the patients. Functional enrichment of these genes revealed several biological processes in relation to innate immune responses and glycosylation. Only one likely pathogenic germline variant of an hamartomatous polyposis syndrome-associated gene, PTCH1, was detected in one patient. CONCLUSIONS: CCS has genomic alteration patterns completely distinct from those of traditional hamartomatous polyposis syndrome. The germline mutation landscape indicates potential roles of innate immune responses and glycosylation in the pathogenesis of CCS.

Expression and Prognostic Value of Small Mothers Against Decapentaplegic 7, Matrix Metalloproteinase 2, and Matrix Metalloproteinase 9 in Resectable Pancreatic Ductal Adenocarcinoma.

OBJECTIVE: Thus far, expression, clinicopathologic, and prognostic implication of small mothers against decapentaplegic 7 (Smad7), matrix metalloproteinase 2 (MMP2), and matrix metalloproteinase 9 (MMP9) in pancreatic ductal adenocarcinoma (PDAC) were rarely investigated or controversial. METHODS: Expression of Smad7, MMP2, and MMP9 was detected using immunohistochemistry in tissue microarrays based on 322 patients with curatively resected PDAC. Their expression pattern, clinicopathologic, and prognostic relevance were further evaluated. RESULTS: Smad7 expression was found to be lower in tumor than in adjacent nontumor tissues, whereas tumoral MMP2 and MMP9 staining scores were much higher than in adjacent nontumor ones. Furthermore, Smad7 was negatively associated with serum carbohydrate antigen 19-9 level. Univariate survival analyses showed that patients with high Smad7 tumors had significantly better disease-specific survival (P = 0.0007), whereas MMP2 and MMP9 predicted poor disease-specific survival (P = 0.0211 and 0.0404). In multivariate Cox regression test, Smad7 was an independent prognostic indicator (P = 0.021). In addition, these 3 proteins were also prognostic in many subgroups. CONCLUSIONS: Smad7 and MMP2/9 significantly predict good or poor prognosis in resectable PDAC, respectively. Therefore, the genes might serve as a tool or targets for molecular therapy in PDAC.

Feasibility of standardized procedures of white light gastroscopy for clinical practice: A multicenter study in China.

OBJECTIVE: We aimed to establish a standardized procedure for white light gastroscopy (WLG) to screen gastric lesions including early gastric cancer (EGC) in China and to verify its efficacy and feasibility in clinical practice. METHODS: A standardized WLG procedure for outpatients at nine tertiary hospitals in Beijing was established. Clinical information of the participants and details of the endoscopic procedures were recorded. RESULTS: A total of 1051 participants were enrolled in a baseline conventional endoscopic survey between March 2014 and December 2015, while 2156 patients were enrolled in the standardized WLG operation from January 2016 to June 2017. The procedure time of the standardized procedure was significantly longer than that of the baseline conventional procedure (P = 0.003). More images were obtained during the standardized procedure compared with the baseline conventional procedure (P < 0.001). The overall detection rate of gastric lesions in the standardized procedure group was significantly higher than that in the baseline procedure group (52.5% vs 38.4%, P < 0.01). The satisfaction scores of both participants and endoscopists in the standardized procedure group were significantly higher than in the baseline procedure group. CONCLUSIONS: Compared with the conventional procedure, standardized WLG procedure significantly improves the detection rate of gastric lesions as well as the satisfaction score of participants and endoscopists despite its longer procedure time. It is effective and feasible in clinical practice in China for the use of currently available endoscopic equipment.

Autoimmune enteropathy and primary biliary cholangitis after proctocolectomy for ulcerative colitis: A case report and review of the literature.

BACKGROUND: Autoimmune enteropathy (AIE) and primary biliary cholangitis (PBC) are both immune-mediated diseases. AIE or PBC complicated with ulcerative colitis (UC) are rare. There are no cases of AIE and PBC diagnosed after proctocolectomy for UC reported before, and the pathogenesis of these comorbidities has not been revealed. CASE SUMMARY: A middle-aged woman diagnosed with UC underwent subtotal colectomy and ileostomy due to the steroid-resistant refractory disease, and a restorative proctectomy with ileal pouch-anal anastomosis and proximal neoileostomy was postponed due to active residual rectal inflammation in January 2016. A few months after the neoileostomy, she began to suffer from recurrent episodes of watery diarrhea. She was diagnosed with postcolectomy enteritis and stoma closure acquired a good therapeutic effect. However, her symptoms of diarrhea relapsed in 2019, with different histological features of endoscopic biopsies compared with 2016, which showed apoptotic bodies, a lack of goblet and Paneth cells, and villous blunting. A diagnosis of AIE was established, and the patient's stool volume decreased dramatically with the treatment of methylprednisolone 60 mg/d for 1 wk and tacrolimus 3 mg/d for 4 d. Meanwhile, her constantly evaluated cholestatic enzymes and high titers of antimitochondrial antibodies indicated the diagnosis of PBC, and treatment with ursodeoxycholic acid (16 mg/kg per day) achieved satisfactory results. CONCLUSION: Some immune-mediated diseases may be promoted by operation due to microbial alterations in UC patients. Continuous follow-up is essential for UC patients with postoperative complications.

Predicting Mucosal Proliferation in Ulcerative Colitis by Assessing Mucosal Vascular Pattern Under Narrow Band Imaging Colonoscopy.

BACKGROUND: Proliferative abnormalities are believed to represent an early phase of colorectal carcinogenesis. Narrow band imaging (NBI) colonoscopy allows visual assessment of the mucosal vascular pattern (MVP) without dyeing. The aim of this study was to investigate the predictive value of MVP for mucosal proliferation in ulcerative colitis (UC). METHODS: A total of 119 colorectal lesions were analyzed from 42 patients with UC who underwent NBI colonoscopy. Both the MVP and the Mayo endoscopic score (MES) were assessed. The mucosal inflammation was histologically graded using a colitis score. The proliferation marker Ki-67 was assessed by immunohistochemical staining. RESULTS: The results showed that MVP correlated well with the MES (r = 0.796, P < .001). There was moderate correlation between the distribution of Ki-67 staining and MVP (r = 0.492, P < .001), and the Ki-67 labeling index increased with the orderly patterns of MVP (P < .001). An expansion of Ki-67 staining upward from the crypt base may be caused by active inflammation. CONCLUSION: MVP based on NBI colonoscopy can predict mucosal proliferation which is associated with inflammation in patients with UC.

High MMP14 expression is predictive of poor prognosis in resectable hepatocellular carcinoma.

Matrix metalloproteinase 14 (MMP14) has been found to play multiple biological roles in cancers, including hepatocellular carcinoma (HCC). Up to now, its expression, clinicopathological and prognostic implications in HCC have not been comprehensively investigated. In the present study, MMP14 expression was detected, using tissue microarray-based immunohistochemical staining, in paired HCC and adjacent liver (AL) samples from 260 patients who underwent radical hepatectomy. The associations of MMP14 staining H-scores with clinicopathological parameters, overall and disease-free survival were then evaluated. Finally, its expression and prognostic value were confirmed in some online publicly available databases. It was shown that MMP14 expression was significantly higher in HCC than in AL tissues (p=0.035). Furthermore, MMP14 expression correlated positively with tumour size, Edmondson-Steiner grade and α-fetoprotein level (p<0.05). For survival, MMP14 expression was negatively associated with both overall and disease-free survival in univariate analyses (p<0.05), while it remained statistically significant for disease-free survival by multivariate Cox regression test. In the Ualcan and Kaplan-Meier Plotter databases, MMP14 was also revealed to be overexpressed and prognostic. Taken together, our study indicated that high MMP14 expression was predictive for unfavourable biological behaviours and long-term prognosis in resectable HCC.

Expression, clinicopathologic and prognostic significance of plasminogen activator inhibitor 1 in hepatocellular carcinoma.

OBJECTIVES: Thus far, biological roles of plasminogen activator inhibitor 1 (PAI1) in hepatocellular carcinoma (HCC) remain controversial. Moreover, its expression, clinicopathologic and prognostic significance in HCC have not been comprehensively investigated, therefore needing further evidence. METHODS: PAI1 expression was measured, using tissue microarray-based immunohistochemical staining, in matched HCC and adjacent liver samples from 178 patients with HCC after curative resection. The correlations of PAI1 H-scores with clinicopathologic variables and survival were further evaluated. Its prognostic value was finally confirmed in some public databases. RESULTS: It was found that PAI1 expression was significantly higher in HCC than in adjacent liver tissues. Moreover, high PAI1 expression was more frequent in those with multiple lesions. Univariate analyses showed that PAI1 expression was negatively associated with both overall and relapse-free survival. Although PAI1 expression was not statistically significant in multivariate Cox regression test, combination of it with TNM stage effectively distinguished survival and relapse, and served as an independent prognostic factor. In the online available datasets of HCC and liver cancer used, SERPINE1, the gene encoding PAI1, was also revealed to be prognostic. CONCLUSIONS: Our data suggested that high PAI1 expression was predictive for unfavorable biological behavior and long-term prognosis in HCC.

Primary hypertrophic osteoarthropathy related gastrointestinal complication has distinctive clinical and pathological characteristics: two cases report and review of the literature.

BACKGROUND: Primary hypertrophic osteoarthropathy (PHO) is a rare disease related to HPGD and SLCO2A1 gene mutation. Gastrointestinal involvement of PHO is even rarer with unknown pathogenesis. Clinical features of GI complication in PHO mimics other auto-immune based bowel entities, such as inflammatory bowel diseases and cryptogenic multifocal ulcerous stenosing enteritis (CMUSE). We aimed to analyze the clinical, genetic, radiological and pathological features of Chinese patients with PHO and determine the difference between PHO patients presenting with and without GI involvement. METHODS: We reported two PHO cases with gastrointestinal involvement and reviewed all the studies of PHO in Chinese population published from January 1, 2000, to April 30, 2018. Clinical and genetic presentations of PHO in Chinese patients were analyzed. We compared the characteristics of those patients with gastrointestinal involvement against those without. RESULTS: The two patients were both males with complete-form PHO for more than 10 years. GI related symptoms included diarrhea, chronic gastrointestinal hemorrhage, incomplete intestinal obstruction, anemia, and edema, which were unresponsive to etoricoxib treatment. Radiological examinations revealed segmental intestinal stenosis and thickened intestinal wall. Endoscopic findings included multiple ulcers and mucosal inflammation. Both patients had mutations of SLCO2A1 according to sequence analysis. The surgical pathology revealed chronic inflammation involving the intestinal mucosa and submucosa, similar to histological changes in CMUSE. According to the systemic review of 158 Chinese patients with PHO, 17.2% had gastrointestinal involvement, including peptic ulcer, gastric polyps, hypertrophic gastritis, and segmental intestinal stenosis. Patients with gastrointestinal involvement were more likely to have anemia (40.0% vs. 4.5%, P < 0.001), hypoalbuminemia (16.7% vs. 0.9%, P = 0.003), and myelofibrosis (19.0% vs. 0.9%, P = 0.002) than those without. Most patients with gastrointestinal complication had SLCO2A1 mutation (86.7%, 13 /15). CONCLUSIONS: Digestive tract involvement is uncommon in patients with PHO and often presents with anemia, and hypoalbuminemia resulted from intestinal inflammation. The intestinal pathologic characteristics are distinct from Crohn's disease but similar to CMUSE. Mutations in SLCO2A1 might be the pathogenic cause of GI involvement of PHO. NSAIDs may not be effective for PHO patients with gastrointestinal complications.

Similarities and differences in clinical and pathologic features of inflammatory bowel disease-associated colorectal cancer in China and Canada.

BACKGROUND: Colorectal cancer (CRC) has become one of the major life-threatening complications in patients with inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn's disease (CD). This study aimed to explore the clinical-pathologic similarities and differences in the IBD-associated CRC (IBD-CRC) between patients in China and Canada. METHODS: Data of 78 patients with IBD-CRC retrospectively retrieved from two representative medical institutions in Beijing (China) and Calgary (Canada) over the same past 13 years, including 25 (22 UC-associated and three CD-associated) from Beijing group and 53 (32 UC-associated and 21 CD-associated) from Calgary group, were compared with regards to their clinical and pathologic characteristics. RESULTS: Several known features of IBD-CRC were seen in both groups, including long duration and large extent of colitis, active inflammation background, multifocal lesions, and advanced tumor-node-metastasis stage. Beijing group showed a significantly higher percentage of UC (88.0% vs. 60.4%, P = 0.018), younger age at diagnosis of CRC (48.6 ±â€Š12.8 years vs. 61.6 ±â€Š14.7 years, P < 0.001), lower ratio of mucinous adenocarcinoma (7.1% vs. 42.4%, P = 0.001) compared with Calgary group. None of the Beijing group had concurrent primary sclerosing cholangitis, while 5.7% of Calgary group did. Surveillance colonoscopy favored the detection rate of precancerous lesions (41.4% vs.17.0%, P = 0.002). CONCLUSIONS: As compared with patients from the Calgary group, the IBD-CRC patients in Beijing group were younger, less CD-associated and had less mucinous features, otherwise they were similar in many common features.

Narrow-Band Imaging Colonoscopy to Assess Mucosal Angiogenesis in Ulcerative Colitis.

BACKGROUND AND AIM: It has been documented that angiogenesis is a largely unstudied component of the pathogenesis of ulcerative colitis (UC). Under narrow-band imaging (NBI) colonoscopy, the mucosal vascular pattern (MVP) can be visualized without the use of dyes. The aim of this study was to assess the grade of mucosal angiogenesis based on the MVP in UC. METHODS: A total of 119 colorectal segments taken from 42 patients with UC were observed using NBI colonoscopy. The MVP was classified as follows: clear, obscure, or absent. Quantification of the degree of inflammation was performed using histological colitis scoring. Potent angiogenic activity was assessed by immunohistochemical staining for vascular endothelial growth factor (VEGF). Microvascular density was assessed using vessel counts as revealed by CD31 staining. The correlation between the MVP and histological grades of inflammation and angiogenesis was evaluated. RESULTS: The MVP correlated well with the histological severity of inflammation. We also demonstrated an increasing level of microvascular density and VEGF staining along with the ordered types of MVPs. In addition, a statistically strong association existed between microvascular density and VEGF staining. CONCLUSIONS: NBI colonoscopy might be a useful tool for the in vivo assessment of the grade of mucosal angiogenesis in UC.

Plasminogen activator inhibitor 2 (PAI2) inhibits invasive potential of hepatocellular carcinoma cells in vitro via uPA- and RB/E2F1-related mechanisms.

BACKGROUND: Plasminogen activator inhibitor 2 (PAI2) has been shown to be associated with invasive phenotypes and prognosis in hepatocellular carcinoma (HCC). However, its biological roles and underlying mechanisms in invasion of HCC have not been explored. The present study aimed to address the issues. METHODS: First, sub-lines in that PAI2 was stably overexpressed and silenced were established based on MHCC97H and BEL7402 cell lines, respectively. Wound-healing and transwell assays were applied to evaluate cell migration and invasion. Urokinase-type plasminogen activator (uPA) activity was measured using an ELISA kit. Real-time RT-PCR and western blotting were used to show gene expression at mRNA and protein levels. E2F1 expression in human specimens was determined by tissue microarray-based immunohistochemical staining. RESULTS: The sub-lines, MHCC97H-PAI2 and BEL7402-siPAI2, were successfully established. The two sub-lines carried much lower and higher migration and invasion powers, respectively, in contrast to the controls. In MHCC97H-PAI2 sub-line, intra-medium uPA activity was significantly decreased, while RB expression was obviously elevated, compared with the controls. The BEL7402-siPAI2 sub-line presented the opposite trend. To identify the role of RB/E2F1 pathway, we transiently overexpressed E2F1 in MHCC97H-PAI2 sub-line, and largely reversed the inhibitory effects of PAI2 on cell migration and invasion, through regulating multiple matrix metalloproteinases and epithelial-mesenchymal transition. In HCC specimens, E2F1 expression was much higher in tumor than in non-tumor tissues, and was significantly related to Edmondson-Steiner grade, overall as well as tumor-free survival. CONCLUSIONS: Our data suggest that PAI2 inhibits invasive potential of HCC cells via uPA- and RB/E2F1-related mechanisms.

Clinicopathological and prognostic significance of MKK4 and MKK7 in resectable pancreatic ductal adenocarcinoma.

Mitogen-activated protein kinase kinase 4 (MKK4) and mitogen-activated protein kinase kinase 7 (MKK7) were shown to regulate biological behavior in many malignancies. In pancreatic ductal adenocarcinoma (PDAC), it remains controversial whether MKK4 and MKK7 have pro-oncogenic or tumor-suppressive activities. Furthermore, their clinicopathological and prognostic implications are unknown. In the present study, we detected MKK4 and MKK7 expressions in the nucleus and cytoplasm of resected PDAC tissues from 321 patients by tissue microarray-based immunohistochemistry. Cytoplasmic MKK4 and MKK7 expressions were significantly downregulated, whereas nuclear MKK4 expression was significantly upregulated in tumor tissues compared with nontumor tissues. Tumor cytoplasmic MKK4 and MKK7 expressions were significantly negatively associated with histologic grade. Cytoplasmic MKK4 expression was also negatively correlated with CA19-9 level. By univariate analysis, high cytoplasmic MKK4 expression was significantly associated with longer cancer-specific survival (hazard ratio [HR], 0.705; 95% confidence interval, 0.510-0.974), with a similar trend observed for MKK7 expression. High MKK4 and MKK7 messenger RNA expressions were significantly associated with longer overall survival in The Cancer Genome Atlas database. Although MKK4 expression was not significant in a multivariate Cox regression analysis, combination of MKK4/MKK7 and pN stage was identified as an independent prognostic indicator and had the lowest HR (HR, 0.308; 95% confidence interval, 0.126-0.752). Furthermore, combined analysis of MKK4 and MKK7 greatly increased the prognostic predictive power. In addition, downregulation of MKK4 or MKK7 increased proliferation of pancreatic cancer cells in vitro. In conclusion, high MKK4 expression and its combination with high MKK7 expression both predicted favorable prognosis in resectable PDAC.