Interleukin-7-based identification of liver lymphatic endothelial cells reveals their unique structural features.

Background & Aims: The lymphatic system plays crucial roles in maintaining fluid balance and immune regulation. Studying the liver lymphatics has been considered challenging, as common lymphatic endothelial cell (LyEC) markers are expressed by other liver cells. Additionally, isolation of sufficient numbers of LyECs has been challenging because of their extremely low abundance (<0.01% of entire liver cell population) in a normal liver. Methods: Potential LyEC markers was identified using our published single-cell RNA sequencing (scRNA-seq) dataset (GSE147581) in mouse livers. Interleukin-7 (IL7) promoter-driven green fluorescent protein knock-in heterozygous mice were used for the validation of IL7 expression in LyECs in the liver, for the development of liver LyEC isolation protocol, and generating liver ischemia/reperfusion (I/R) injury. Scanning electron microscopy was used for the structural analysis of LyECs. Changes in LyEC phenotypes in livers of mice with I/R were determined by RNA-seq analysis. Results: Through scRNA-seq analysis, we have identified IL7 as an exclusive marker for liver LyECs, with no overlap with other liver cell types. Based on IL7 expression in liver LyECs, we have established an LyEC isolation method and observed distinct cell surface structures of LyECs with fenestrae and cellular pores (ranging from 100 to 400 nm in diameter). Furthermore, we identified LyEC genes that undergo alterations during I/R liver injuries. Conclusions: This study not only identified IL7 as an exclusively expressed gene in liver LyECs, but also enhanced our understanding of LyEC structures and demonstrated transcriptomic changes in injured livers. Impact and implications: Understanding the lymphatic system in the liver is challenging because of the absence of specific markers for liver LyEC. This study has identified IL7 as a reliable marker for LyECs, enabling the development of an effective method for their isolation, elucidating their unique cell surface structure, and identifying LyEC genes that undergo changes during liver damage. The development of IL7 antibodies for detecting it in human liver specimens will further advance our understanding of the liver lymphatic system in the future.

Hypoxia derived exosomes promote the proliferation and metastasis of colorectal cancer through the regulation of HIF-1α/miR-4299/ZBTB4.

AIMS: The biological functions of colorectal cancer (CRC) cell derived exosomes responding to hypoxic microenvironment and its underlying mechanisms remain unclear. MAIN METHODS: Extracted exosomes were confirmed. CRC cells were incubated with hypoxic and normoxic exosomes and its biological behavior were analyzed. miRNA microarray were conducted. Cells were incubated with miRNAs mimics, inhibitors, or small interfering RNAs; expression of reporter constructs was measured in luciferase assays. Cells were transfected with Lentivirus vectors containing eGFP-miR-4299 overexpression (or ZBTB4 siRNA expression plasmid) and they were injected into BALB/C nude mice subcutaneously or by tail vein and the growth of xenograft tumors or lung metastasis were measured. The clinical significance of ZBTB4 was measured in tumor tissues and adjacent non-tumor tissues. KEY FINDINGS: Hypoxic exosomes could tranfer to the recipient normoxic cells and promote the cell proliferation and migration. We found several miRNAs were significantly up-regulated in hypoxic exosomes and the expression levels of miR-4299 increased in both hypoxic cells and hypoxic exosomes. We observed that miR-4299 was upregulated in a HIF-1α dependent way. In addition, ectopic expression of miR-4299 promoted the tumor growth and metastasis in vitro and in vivo. ZBTB4, an identified direct target of miR-4299, could abrogate the effect on tumor growth and distant metastasis. The expression of ZBTB4 were decreased in tumor tissues compared with non-tumor colon tissues from patients. SIGNIFICANCE: We demonstrated that in response to hypoxia, CRC cells had an increased production of exosomes. The hypoxia derived exosomes promote the proliferation and metastasis of colorectal cancer by exporting miR-4299 and modulating its target gene ZBTB4.

HOXC10 indicates poor survival outcome in gastric cancer and promotes G1/S cell cycle transition through transcriptional repression of p21.

Homeobox (HOX) genes encode proteins that function as transcription factors during embryogenesis and tumorigenesis. We have previously reported upregulation of HOXC10 in gastric cancer (GC) tissues using cDNA microarray analysis. Though the functional role of HOXC10 in GC has been briefly reported, its specific mechanism is not fully understood. We analyzed the expression of HOXC10 in GC tissues, as well as its correlation with the survival outcome. By in vitro and in vivo assays, we further investigated the role of HOXC10 on cell cycle control and proliferation. Finally, we screened potential downstream targets of HOXC10 by cDNA microarray and explored the role of HOXC10 in p21 transcriptional repression through a dual luciferase reporter and chromatin immunoprecipitation. We illustrated the upregulation of HOXC10 in GC tissues and high HOXC10 expression related to poor survival outcome. Multivariable COX regression analysis showed that HOXC10 was an independent predictor of survival (HR=1.863; 95% CI: 1.076-3.225). Functionally, HOXC10 could promote GC cell proliferation and tumor growth in nude mice. Overexpression of HOXC10 accelerated G1/S cell cycle transition, whereas knocking down HOXC10 induced cell cycle arrest at the G1 phase. Critical factors of G1/S cell cycle transition including p21, CDK2, and c-Myc, were regulated by HOXC10. Importantly, an inverse correlation between p21 and HOXC10 expression in GC cell lines and tissues was observed. HOXC10 could directly bind to the promoter region of p21 and repress its transcriptional activity. Collectively, we identified HOXC10 as a predictor of poor prognosis in GC patients, and a novel transcriptional regulator of p21 in the G1/S cell cycle transition.

Single-Cell Transcriptomics Reveals Zone-Specific Alterations of Liver Sinusoidal Endothelial Cells in Cirrhosis.

BACKGROUND: Dysfunction of liver sinusoidal endothelial cells (LSECs) is permissive for the progression of liver fibrosis and cirrhosis and responsible for its clinical complications. Here, we have mapped the spatial distribution of heterogeneous liver ECs in normal vs cirrhotic mouse livers and identified zone-specific transcriptomic changes of LSECs associated with liver cirrhosis using scRNA-seq technology. APPROACH & RESULTS: Cirrhosis was generated in endothelial specific green fluorescent protein (GFP) reporter mice through carbon tetrachloride inhalation for 12 weeks. GFP-positive liver EC populations were isolated from control and cirrhotic mice by FACS. We identified 6 clusters of liver EC populations including 3 clusters of LSECs, 2 clusters of vascular ECs and 1 cluster of lymphatic ECs. Based on previously reported LSEC-landmarks, we mapped the 3 clusters of LSECs in zones 1, 2, and 3, and determined phenotypic changes in each zone between control and cirrhotic mice. We found genes representing capillarization of LSECs (eg, CD34) as well as extracellular matrix genes were most upregulated in LSECs of zone 3 in cirrhotic mice, which may contribute to the development of basement membranes. LSECs in cirrhotic mice also demonstrated decreased expression of endocytic receptors, most remarkably in zone 3. Transcription factors (Klf2 [Kruppel-like factor-2], Klf4 [Kruppel-like factor-4], and AP-1) that induce nitric oxide production in response to shear stress were downregulated in LSECs of all zones in cirrhotic mice, implying increased intrahepatic vascular resistance. CONCLUSION: This study deepens our knowledge of the pathogenesis of liver cirrhosis at a spatial, cell-specific level, which is indispensable for the development of novel therapeutic strategies to target the most dysfunctional liver ECs.

Klotho-mediated targeting of CCL2 suppresses the induction of colorectal cancer progression by stromal cell senescent microenvironments.

Senescent microenvironments play an important role in tumor progression. Here, we report that doxorubicin (DOX)-pretreated or replicative senescent stromal cells (WI-38 and HUVEC) promote colorectal cancer (CRC) cell growth and invasion in vitro and in vivo. These pro-tumorigenic effects were attenuated by exogenous administration of Klotho, an anti-aging factor. We subsequently identified several senescence-associated secretory phenotype (SASP)-associated genes, including CCL2, which were significantly upregulated in both types of senescent stromal cells during replication and DNA damage-induced senescence. Importantly, we found that the secretion of CCL2 by senescent stromal cells was significantly higher than that seen in nonsenescent cells or in senescent cells pretreated with Klotho. Notably, CCL2 was found to accelerate CRC cell proliferation and invasion, while this effect could be blocked by administration of a specific CCR2 antagonist. We further show that Klotho can suppress NF-κB activation during DOX-induced senescence and thus block CCL2 transcription. Low expression of Klotho, or high expression of CCL2 in patient tumor tissues, correlated with poor overall survival of CRC patients. Collectively, our findings suggest that senescent stromal cells are linked to progression of CRC. Klotho can suppress the senescent stromal cell-associated triggering of CRC progression by inhibiting the expression of SASP factors including CCL2. The identification of key SASP factors such as CCL2 may provide potential therapeutic targets for improving CRC therapy.

The impact of Helicobacter pylori infection, eradication therapy and probiotic supplementation on gut microenvironment homeostasis: An open-label, randomized clinical trial.

BACKGROUND: Helicobacter pylori (H. pylori) infection is associated with remodeling of gastric microbiota. However, comprehensive analyses of the impact of H. pylori infection, eradication therapy and probiotic supplementation on gut microbiota are still lacking. We aimed to provide evidence for clinical decision making. METHODS: Seventy H. pylori-positive and 35 H. pylori-negative patients (group C) were enrolled. H. pylori-positive patients were randomly assigned to group A (14-day bismuth-containing quadruple therapy) and group B (quadruple therapy supplemented with Clostridium butyricum). Stool samples of group A and B were collected on day 0, 14 and 56 while stool samples of group C were collected on day 0. Gut microbiota was investigated by 16S rRNA sequencing. FINDINGS: The Sobs index (richness estimator) was significantly higher in H. pylori-positive samples than H. pylori-negative samples (p < .05). Several metabolic pathways were more abundant in H. pylori-positive communities while some disease-associated pathways had higher potential in H. pylori-negative community through KEGG pathway analysis. Abundances of most butyrate-producing bacteria significantly decreased, while several detrimental bacteria increased after eradication therapy. Probiotic supplementation was associated with improved gastrointestinal symptoms as well as increased Bacteroidetes:Firmicutes ratio. INTERPRETATION: While H. pylori infection may not be necessarily detrimental in all patients, eradication of H. pylori was associated with widespread changes in gut microbial ecology and structure. Probiotic supplementation could relieve more gastrointestinal symptoms by inducing alterations in gut microbiota and host immune responses. As such, the decision to eradicate H. pylori should be based on comprehensive analysis of individual patients.

The impact of a history of cancer on pancreatic ductal adenocarcinoma survival.

BACKGROUND AND OBJECTIVE: Previous studies indicated cancer survivors had a higher risk of developing subsequent pancreatic ductal adenocarcinoma. However, the influence of prior cancer on survival outcomes of current pancreatic cancer remains unclear. METHODS: Eligible populations were selected from the Surveillance, Epidemiology, and End Results programs from 2000 to 2012. We adopted Kaplan-Meier curves and Cox analysis to compare survival differences between patients with and without prior cancer. RESULTS: Overall, 67,555 pancreatic cancer patients, including 5582 (8.26%) with and 61,973 (91.74%) without prior cancer, were included. The most common types of prior cancers were prostate, breast, and colorectal cancers. The median time from diagnosis of an initial malignancy to subsequent pancreatic cancer was 59.8 months. Patients with a prior cancer had higher overall one-year and three-year survival rates compared with those without a prior cancer. Multivariable Cox analysis demonstrated that a history of prior malignancy could independently predict the better overall survival outcome of pancreatic cancer (HR = 0.92, 95% CI, 0.89-0.94, p < 0.001), especially for colorectal, breast, corpus uteri and prostate cancer survivors. CONCLUSIONS: A history of cancer did not contribute to a poor survival outcome for patients with pancreatic cancer. More prospective trials might be warranted to validate our findings.

Altered Intestinal Microbiota with Increased Abundance of Prevotella Is Associated with High Risk of Diarrhea-Predominant Irritable Bowel Syndrome.

Alterations in gut microbiota are postulated to be an etiologic factor in the pathogenesis of irritable bowel syndrome (IBS). To determine whether IBS patients in China exhibited differences in their gut microbial composition, fecal samples were collected from diarrhea-predominant IBS (IBS-D) and healthy controls and evaluated by 16S ribosomal RNA gene sequence and quantitative real-time PCR. A mouse model of postinfectious IBS (PI-IBS) was established to determine whether the altered gut microbiota was associated with increased visceral hypersensitivity. The results indicated that there were significant differences in the bacterial community profiles between IBS-D patients and healthy controls. Prevotella was more abundant in fecal samples from IBS-D patients compared with healthy controls (p < 0.05). Meanwhile, there were significant reductions in the quantity of Bacteroides, Bifidobacteria, and Lactobacillus in IBS-D patients compared with healthy controls (p < 0.05). Animal models similarly showed an increased abundance of Prevotella in fecal samples compared with control mice (p < 0.05). Finally, after the PI-IBS mice were cohoused with control mice, both the relative abundance of Prevotella and visceral hypersensitivity of PI-IBS mice were decreased. In conclusion, the altered intestinal microbiota is associated with increased visceral hypersensitivity and enterotype enriched with Prevotella may be positively associated with high risk of IBS-D.

Prognostic value of resected lymph nodes numbers for Siewert II gastroesophageal junction cancer.

We aim to evaluate whether resected lymph nodes (RLNs) numbers have prognostic value in patients with gastroesophageal junction cancers (GEJ, Siewert type II). Patients with gastroesophageal junction cancers were identified from the Surveillance Epidemiology and End Results (SEER) registry between 1988 to 2013. Multivariate Cox regression analyses and Kaplan-Meier method were performed to analyze risk factors for overall survival (OS) and cause-specific survival(CSS). A total of 8396 patients who underwent surgeries and had reginal lymph nodes examined were identified. Kaplan-Meier analysis indicated that more numbers of resected lymph nodes (RLNs) were associated with better survival. The five-year OS rates for 1-20 and 21-90 RLNs were 26.8% and 32.4%, with a median survival time of 62 and 72 months, respectively (P < 0.001). The five-year CSS rates were 32.2% and 37.2% in each group, with median survival time of 90 and 101 months, respectively (P < 0.001). Cox regression multivariate analysis showed that year of diagnosis, age, sex, marital status, grade, seer histology, tumor histology, lymph node ratio (LNR) and RLNs as a categorical variable were all significant prognostic factors for both OS and CSS. RLN count is an independent prognostic factor for Siewert type II GEJ cancer patients and patients can achieve better overall and cancer-specific survival with more than 20 RLNs dissected.

1-Day or 5-Day Fecal Samples, Which One is More Beneficial to be Used for DNA-Based Gut Microbiota Study.

Fecal sample collection is an important influential factor for DNA-based gut microbiota study. It is controversial whether the microbiome detected in fecal sample collected at one random day could fully represent the gut microbial community. The aim of the study is to figure out whether the use of fecal sample mixture collected at consecutive 5 days could more accurately represent gut microbial community. 1- and 5-day fecal samples were collected from 8 healthy adults and analyzed by 16S rRNA sequence. Our results indicated that both 1-day fecal samples and 5-day samples exhibited relatively high repeatability. The relative abundance of majority of bacterial taxa did not changed between 1-day fecal samples and 5-day fecal samples. However, the alpha diversity of 5-day fecal samples was higher than that of 1-day fecal samples. When the aims of studies are to analyze the relative abundance of specific OTUs among subjects, fecal samples collected at one day could be used. When microbial diversity is one of essential factors to be analyzed, the use of 5-day fecal samples may be more recommended.

Meta-analysis: proton pump inhibitors moderately increase the risk of small intestinal bacterial overgrowth.

The use of proton pump inhibitors (PPIs) may potentially predispose to the development of small intestinal bacterial overgrowth (SIBO), but this association is controversial due to conflicting results from studies conducted to date. The aim of this meta-analysis was to evaluate the association between the use of PPIs and the risk of SIBO. We systematically searched the online PubMed, Embase, and Cochrane Library databases and Web of Science for relevant articles published up to November 2016. Two researchers identified and extracted data independent of each other. The pooled analysis was performed using the generic inverse-variance random-effects model. Subgroup and sensitivity analysis were conducted to assess the stability and heterogeneity of the pooled results. The risk of publication bias was evaluated by assessing for funnel plot asymmetry and by Egger's test and Begg's test. A total of 19 articles met the eligibility criteria for the meta-analysis, reporting on 7055 subjects. The pooled odds ratio (OR) showed a statistically significant association between increased risk of SIBO and PPI use (OR 1.71, 95% confidence interval 1.20-2.43). Subgroup analyses demonstrated an association between SIBO and PPI use in studies that employed small bowel aspirates culture and glucose hydrogen breath tests (GHBT) as diagnostic tests for SIBO. Our meta-analysis suggests that the use of PPI moderately increases the risk of SIBO, thereby highlighting the need for appropriate prescribing of PPIs.

Decreased long non-coding RNA MTM contributes to gastric cancer cell migration and invasion via modulating MT1F.

The role of long non-coding RNAs (lncRNA) on gastric cancer (GC) are an emerging field. Here, we focused on a cancer-related lncRNA MTM and tried to explore its correlation with the development of GC. The expression of MTM was detected by qRT-PCR in GC cell lines and tissues. The relationship between MTM level and clinicopathological factors was then analyzed. Cell biological assays with overexpression or co-transfection approaches were examined to probe the functional relevance of this lncRNA and its potential targets. The results showed that MTM expression was significantly lower in GC cell lines and tissues, and closely correlated with lymphatic metastasis, invasive depth, tumor staging and overall survival. Overexpression of MTM significantly inhibited GC cell migration and invasion, suppressed cell proliferation and induced cell apoptosis. In addition, we found a positive correlation between the expression level of MTM and MT1F both in cell and tissue samples. MT1F overexpression decreased GC cell migration and invasion, while knockdown of MT1F restored cell migration and invasion in MTM-overexpressing GC cells, suggesting MT1F as a key target of MTM. Conclusively, abnormal decreased expression of MTM was observed in human GC, which might contribute to gastric carcinogenesis by modulating MT1F expression.

Combined Detection of Plasma ZIC1, HOXD10 and RUNX3 Methylation is a Promising Strategy for Early Detection of Gastric Cancer and Precancerous Lesions.

We try to explore the value of aberrant DNA methylation of several cancer-related genes in plasma as non-invasive biomarkers for gastric cancer (GC) and precancerous lesions. By using methylation-specific polymerase chain reaction assay we determined the methylation status of three selected genes ZIC1, HOXD10 and RUNX3 in blood samples from patients with GC and precancerous lesions. We discovered that the methylation rate of ZIC1, HOXD10 and RUNX3 increased significantly in the progression of gastric carcinogenesis. Methylation of ZIC1 was associated with positive serum CA19-9, while that of HOXD10 was related to H. pylori status, serum CA19-9 and CEA levels and tumor invasion depth. The Odds ratios (ORs) of ZIC1, HOXD10 and RUNX3 methylation for predicting GC were 4.285 (95%CI: 2.435-7.542), 3.133 (95%CI: 1.700-5.775) and 2.674 (95%CI: 1.441-4.960), while for predicting "gastric cancer and intraepithelial neoplasia" (GnI), the ORs were 12.011 (95%CI: 0.050-28.564), 9.174 (95%CI: 3.220-26.135) and 12.794 (95%CI: 4.115-39.778), respectively. In terms of combined detection of these three genes, the sensitivity was 91.6% for GC and 89.8% for GnI, with the highest Youden index in both GC and GnI determination. Conclusively, combined detection of ZIC1, HOXD10 and RUNX3 promoter hypermethylation might be a promising strategy for early detection of GC and precancerous lesions.

Survival benefits of gastrectomy in gastric cancer patients with stage IV: a population-based study.

OBJECTIVE: The aim of the current study is to investigate the role of gastrectomy for survival among metastatic gastric cancer patients. RESULTS: We finally identified 12,986 eligible patients with stage IV GC between 2004 and 2012, including 1,981 (15.3%) patients with gastrectomy and 11,005 (84.7%) without surgery. The median overall survival time for patients with and without surgery were 9.0 (95%, 8.3-9.7) and 4.0 (95%, 3.9-4.1) months respectively. Patients who received gastrectomy had a significantly better survival outcome compared with those without surgery (P < 0.05). In the multivariate Cox analysis, gastrectomy was associated with decreased overall mortality (HR, 0.47, 95% CI 0.44-0.49, P < 0.001) and cancer-specific mortality (HR, 0.46, 95% CI 0.44-0.50, P < 0.001). The survival benefits associated with surgery persisted even after performing the propensity score matching analysis (overall survival, HR, 0.47, 95% CI 0.43-0.50, cancer-specific survival, HR, 0.47, 95% CI 0.44-0.50). CONCLUSIONS: Based on population-based study, we demonstrated that there was a survival advantage of gastrectomy in stage IV GC patients. Further prospective trials need to verify our findings. MATERIALS AND METHODS: We included an eligible cohort of stage IV gastric cancer (GC) patients in the Surveillance, Epidemiology and End Results (SEER) database from 2004 to 2012. The survival difference of patients with and without gastrectomy were assessed by Kaplan-Meier analysis and log-rank test. Multivariate Cox analyses were performed to analyze the effect of gastrectomy on overall and cancer-specific mortality. Furthermore, we performed propensity score matching (PSM) to reduce the potential selection bias.

Survival outcomes and surgical intervention of small intestinal neuroendocrine tumors: a population based retrospective study.

BACKGROUND: Small intestinal neuroendocrine tumors (SiNETs) without distant metastasis typically behave in an indolent manner, but there can be heterogeneity. We aimed to define the survival outcomes and impacts of surgical intervention. METHODS: A retrospective cohort study was conducted by using data from the Surveillance, Epidemiology, and End Results (SEER) database. Clinicopathologic features were analyzed in 4407 patients between 2000 and 2012. The cancer specific survival (CSS) was calculated by the Kaplan-Meier method. Multivariable Cox regression models with hazard ratios (HRs) were constructed to analyze survival outcomes and risk factors. RESULTS: The adjusted incidence of early SiNETs is 1.3/100,000. Tumors are most commonly located in the ileum and are small (≤ 2 cm). The 5-year and 10-year CSS rates were 95.0% and 88.5%, respectively. Age > 50 years, large tumor size (> 2cm), poor differentiation, advanced T classification, and absence of surgical treatment were independent predictors of poor survival. Stratified analysis indicated that surgery significantly improved survival in patients that were white (HR, 0.45), > 50 years old (HR, 0.61), had duodenal tumors (HR, 0.43), large tumors (> 2cm) (HR, 0.32), advanced T classification (T3: HR, 0.29; T4: HR, 0.18) or well differentiation (HR, 0.55). There was no significant survival difference between local resection and radical resection (P =0.884). CONCLUSIONS: Early SiNETs have a favorable prognosis. Surgical resection may improve outcomes, particularly in older patients and those with large tumors. More aggressive resections couldn't improve outcomes.

A retrospective study of pyogenic liver abscess focusing on Klebsiella pneumoniae as a primary pathogen in China from 1994 to 2015.

Pyogenic liver abscess (PLA) is a common intra-abdominal infection in adults. In this study, we aim to explore demographic and clinical characteristics of PLA focusing on Klebsiella pneumoniae (K. pneumoniae) induced PLA (KP-PLA) in mainland China. A retrospective review of medical records from all patients with KP-PLA admitted to a tertiary teaching hospital over a 21-year period (1994-2015) was performed. Among 296 PLA cases with confirmed culture-positive data, K. pneumoniae was revealed as the predominant pathogen (n = 189, 63.9%), followed by Escherichia coli (n = 39, 13.2%). Strikingly, KP-PLA patients had a higher incidence of metabolic disorders, such as diabetes mellitus (49.7% vs. 36.4%, P = 0.027; odds ratio (OR): 1.725; 95% confidence interval (CI): 1.061-2.805), hypertension (38.1% vs. 19.6%, P = 0.001; OR: 2.520; 95% CI: 1.439-4.413), and fatty liver (32.3% vs. 14.0%, P = 0.001; OR: 2.923; 95% CI: 1.564-5.462) than those with non-K. pneumoniae induced PLA (non-KP-PLA). Moreover, patients with KP-PLA had higher susceptibility to septic metastatic infection at distant sites compared to those with non-KP-PLA (10.6% vs. 3.7%, p = 0.038). Our results indicate that K. pneumoniae is the predominant pathogen of PLA in mainland China. KP-PLA is frequently diagnosed in patients with metabolic diseases and has a higher risk for septic metastatic infection.

Klebsiella pneumoniae invasive liver abscess syndrome with purulent meningitis and septic shock: A case from mainland China.

We present a rare case of invasive liver abscess syndrome due to Klebsiella pneumoniae (K. pneumoniae) with metastatic meningitis and septic shock. A previously healthy, 55-year-old female patient developed fever, liver abscess, septic shock, purulent meningitis and metastatic hydrocephalus. Upon admission, the clinical manifestations, laboratory and imaging examinations were compatible with a diagnosis of K. pneumoniae primary liver abscess. Her distal metastasis infection involved meningitis and hydrocephalus, which could flare abruptly and be life threatening. Even with early adequate drainage and antibiotic therapy, the patient's condition deteriorated and she ultimately died. To the best of our knowledge, this is the first case of K. pneumoniae invasive liver abscess syndrome with septic meningitis reported in mainland China. Our findings reflect the need for a better understanding of the epidemiology, risk factors, complications, comorbid medical conditions and treatment of this disease.

How Commonly Is the Diagnosis of Gastric Low Grade Dysplasia Upgraded following Endoscopic Resection? A Meta-Analysis.

Gastric dysplasia is a well-known precancerous lesion. Though the diagnosis of gastric low grade dysplasia (LGD) is generally made from endoscopic forceps biopsy (EFB), the accuracy is doubtful after numerous EFB-proven gastric LGD were upgraded to gastric high grade dysplasia (HGD) or even carcinoma (CA) by further diagnostic test with the procedure of endoscopic resection (ER). We aimed to evaluate the upgraded diagnosis rate (UDR) and the risk factors by ER in EFB-proven gastric LGD lesions. Two investigators independently searched studies reporting the UDR by ER in EFB-proven gastric LGD lesions from databases and analyzed the overall UDR, HGD-UDR and CA-UDR. The pooled UDR by ER in EFB-proven gastric LGD lesions was 25.0% (95% CI, 20.2%-29.8%), made up of HGD-UDR and CA-UDR by rates of 16.7% (95% CI, 12.8%-20.6%) and 6.9% (95% CI, 4.2%-9.6%) respectively. Lesion size larger than 2 cm, surface with depression and nodularity under endoscopic examinations were the major risk factors associated with UDR. In conclusion, one quarter of EFB-proven gastric LGD lesions will be diagnosed as advanced lesions, including gastric HGD (16.7%) and gastric CA (6.9%) by ER. The diagnosis of those LGD lesions with an endoscopic diameter larger than 2cm, and depressed or nodular surface are more likely to be upgraded after ER.