BRAF-rearranged spindle cell mesenchymal neoplasm with a predominant lipofibromatosis-like neural tumor pattern and co-expression of CD34, S100 protein, and markers associated with perineurial differentiation: A rare case with potential diagnostic pitfall.

Recently, a distinctive group of S100 protein/CD34-positive spindle cell mesenchymal neoplasms characterized by a predominant lipofibromatosis-like neural pattern harboring recurrent gene rearrangements involving NTRK1-3, RAF1, RET, ROS1, ALK, and MET has been identified. BRAF rearrangements have been rarely documented in this group of neoplasms. Herein, we report a 54-year-old man with a 1.3-cm painless mass located in the subcutis of left back. The tumor was composed of mildly atypical, short-spindle shaped to ovoid cells with fascicles and whorls intervening between and admixed with the subcutaneous adipose tissues and nerve bundles. Focally abundant thick, band-like stromal hyalinization was also noted. The neoplastic cells showed diffuse reactivity for S100 protein and CD34 and multifocal immunopositivity for markers associated with perineurial differentiation including epithelial membrane antigen, GLUT1, and claudin-1. Fluorescence in situ hybridization analyses showed positive for BRAF rearrangement and negative for rearrangements involving NTRK1, RET, and ROS1. The tumor was narrowly excised and recurred after 24 months of follow-up. To our knowledge, we report the second case of BRAF-rearranged spindle cell mesenchymal tumor with predominant lipofibromatosis-like neural tumor pattern. Expression of markers associated with perineurial differentiation is exceptional and represents a potential diagnostic pitfall, which may cause significant diagnostic confusion with a peripheral nerve sheath tumor.

A PHF1-TFE3 fusion atypical ossifying fibromyxoid tumor with prominent collagenous rosettes: Case report with a brief review.

Ossifying fibromyxoid tumor (OFMT) is a rare mesenchymal neoplasm of uncertain line of differentiation that can be subdivided into typical, atypical, and malignant tumors. Cytogenetically, OFMT is characterized by recurrent gene rearrangement involving PHF1 in up to 85% of cases. The most common PHF1 fusion partner is EP400, present in approximately half of cases. Most recently, a novel fusion of PHF1-TFE3 was identified in about 10% of PHF1-rearranged OFMTs. Herein, we report a unique case of PHF1-TFE3 fusion atypical OFMT with prominent collagenous rosettes. A 50-year-old male patient presented with a slowly growing, painless mass in the right foot for 4 years. Gross examination showed a 3.5-cm, subcutaneous well-circumscribed, lobulated mass. Microscopic examination revealed a well-demarcated but un-encapsulated tumor without a peripheral bony shell. The neoplasm was composed of mildly atypical spindle to ovoid cells with increased mitosis (2 mitoses per 10 high-power fields) arranged in a multinodular manner within a fibromyxoid stroma, which contained numerous small, irregular collagenous rosettes surrounded by radiating growth of tumor cells. The neoplastic cells were diffusely positive for TFE3 and CD10. RNA sequencing revealed an in-frame fusion between PHF1 exon 12 and TFE3 exon 7. Subsequent Fluorescence in-situ hybridization analyses demonstrated positive for rearrangements of both the PHF1 and TFE3 loci. The patient was free of disease at 63 months' follow-up. Our case exhibits atypical features and prominent collagenous rosettes, expanding the morphological spectrum of OFMT with PHF1-TFE3 fusion.

Fatigue in chronic hepatitis B patients is significant and associates with autonomic dysfunction.

BACKGROUND: Fatigue is an important clinical finding in patients with chronic hepatitis virus infection. However, studies assessing fatigue in patients with chronic hepatitis B (CHB) are very limited. This study aimed to quantify the severity of fatigue in patients with CHB, to determine whether perceived fatigue reflects impairment of functional ability, and to explore potential causes. METHODS: A total of 133 patients with histologically proven CHB and 59 community controls were assessed using the fatigue impact scale (FIS). RESULTS: The degree of fatigue was significantly higher in patients with CHB than in controls (mean (range) FIS 24.9 (0-91) vs. 15.7 (0-31), p < 0.001). Fatigue experienced by patients with CHB was similar to that in primary biliary cirrhosis (PBC) (n = 20) (FIS 22.2 vs. 20.9, p = 0.28). No association was found between FIS and biochemistry and histological parameters of liver disease severity. Significant associations were found between fatigue severity and cognitive impairment (r = 0.39, p < 0.001), daytime somnolence (r = 0.32, p < 0.001), scores of the Chronic Liver Disease Questionnaire (r = - 0.31, p < 0.001), and autonomic symptoms (r = 0.43, p < 0.001). The level of autonomic symptom was the only factor independently associated with the degree of fatigue. CONCLUSION: Fatigue is a significant problem of functional ability impairment in CHB and similar in degree to that in PBC patients. Fatigue in patients with CHB appears to be unrelated to the severity of liver disease but is associated with significant autonomic symptoms.

An Inexpensive Digital Image Analysis Technique for Liver Fibrosis Quantification in Chronic Hepatitis B Patients.

BACKGROUND AND AIM: Quantitative digital imaging analysis to evaluate liver fibrosis is accurate, but its clinical use is limited by its high cost and lack of standardization. We aimed to validate an inexpensive digital imaging analysis technique for fibrosis quantification in chronic hepatitis B patients. MATERIAL AND METHODS: In total, 142 chronic hepatitis B patients who underwent liver biopsy and analysis of serum fibrosis markers were included. Images of Sirius red stain sections were captured and processed using Adobe Photoshop CS3 software. The percentage of fibrosis (fibrosis index) was determined by the ratio of the fibrosis area to the total sample area, expressed in pixels, and calculated automatically. RESULTS: A strong correlation between the fibrosis index and the Ishak, Metavir, and Laennec histological staging systems were observed (r = 0.83, 0.86, and 0.84, respectively; < 0.001). The cutoff value associated with cirrhosis was 7.7% with an area under the receiver operating characteristic curve (AUROC) of 0.95 (95% confidence interval [CI], 0.92-0.99, p < 0.001). Furthermore, the fibrosis index yielded a cutoff value of 8.9% (AUROC, 0.74; 95% CI, 0.66-0.86), 12% (AUROC, 0.84; 95% CI, 0.75-0.93), and 14% (AUROC, 0.97; 95% CI, 0.92-1.0) for the diagnosis of cirrhosis 4a, 4b, and 4c, respectively. No serum markers or fibrosis models were correlated with the fibrosis index in Metavir F2-F4. CONCLUSIONS: The present digital imaging analysis technique is reproducible and available worldwide, allowing its use in clinical practice, and can be considered as a complementary tool to traditional histological methods.

Histologic Disease in Chinese Chronic Hepatitis B Patients With Low Viral Loads and Persistently Normal Alanine Aminotransferase Levels.

BACKGROUND/AIM: We aimed to evaluate the histopathologic characteristics of HBeAg-negative chronic hepatitis B patients with low hepatitis B virus (HBV) DNA levels (<2000 IU/mL) and persistently normal ALT levels and to determine indicators of significant liver disease. METHODS: We examined 102 consecutive subjects who underwent percutaneous liver biopsy. Significant predictors of liver disease (stage ≥2 fibrosis or stage 1 fibrosis plus grade ≥2 inflammation), including demographic, clinical, and laboratory variables, were evaluated by means of univariate and multivariate logistic regression analyses. RESULTS: Among the patients, 75.5% (77/102) had grade 0-1 inflammation and 77.5% (79/102) had stage 0-1 fibrosis. However, 38.2% (39/102) had significant liver disease. There were no statistically significant differences in clinical parameters such as age, biochemical profile, HBV DNA levels, HBsAg levels, and platelet count between patients with significant and those with nonsignificant liver disease. Patients with significant liver disease had higher values of aspartate transferase-to-platelet ratio index (APRI) and FIB-4 index compared with those with nonsignificant liver disease (0.35±0.21 vs. 0.27±0.12, P=0.02; 1.58±0.97 vs. 1.13±0.54, P=0.009, respectively). The area under the receiver operating characteristic (AUROC) curve of APRI for identifying active liver histology was 0.64 (95% CI, 0.53-0.75; P=0.019); the cutoff value was 0.24 with a sensitivity of 74% and specificity of 55%. In comparison, FIB-4 had equal power (the AUROC was 0.66) in predicting active liver histology. CONCLUSION: Among patients presenting with low HBV DNA levels and normal ALT levels, about 38.2% had significant liver disease. Neither serum HBsAg nor HBV DNA levels correlate with liver histology. However, APRI≥0.24 might be considered an indicator of liver biopsy.

MiR-125b promotes cell migration and invasion by targeting PPP1CA-Rb signal pathways in gastric cancer, resulting in a poor prognosis.

BACKGROUND: MiR-125b functions as an oncogene in many cancers; however, its clinical significance and molecular mechanism in gastric cancers have never been sufficiently investigated. Here, we elucidated the functions and molecular regulated pathways of MiR-125b in gastric cancer. METHODS: We investigated MiR-125b expression in fresh tissues from 50 gastric cancer patients and 6 gastric cancer cell lines using RT-PCR, and explored its prognostic value by hybridizing MiR-125b in situ for 300 clinical gastric tumor tissues with pathological diagnosis and clinical parameters. The effects of MiR-125b on gastric cancer cells and downstream target genes and proteins were analyzed by MTT, transwell assay, RT-PCR, and western blot on the basis of silencing MiR-125b in vitro. Luciferase reporter plasmid was constructed to demonstrate MiR-125b's direct target. RESULTS: MiR-125b was upregulated in gastric cancer tissues and cell lines, and significantly promoted cellular proliferation, migration, and invasion by downregulating the expression of PPP1CA and upregulating Rb phosphorylation. MiR-125b expression was significantly correlated with tumor size and depth of invasion, lymph nodes, distant metastasis, and TNM stage. The high-MiR-125b-expression group had a significantly poorer prognosis than the low-expression group (P < 0.05) in stages I, II, and III, and the 5-year survival rate in of the high-expression group was significantly lower than that of the low-expression group. CONCLUSIONS: MiR-125b functions as an oncogene by targeting downregulated PPP1CA and upregulated Rb phosphorylation in gastric cancer. MiR-125b not only promotes cellular proliferation, migration, and invasion in vitro, but also acts as an independent prognostic factor in gastric cancer.

Analyzing the correlation between low proportion of hobnail features in papillary thyroid carcinoma and clinical aggressiveness risk.

PURPOSE: Hobnail features may enhance the clinical aggressiveness of papillary thyroid carcinoma (PTC). However, whether a low proportion (<30%) of these features contributes to increased PTC aggressiveness remains unclear. This study investigated whether PTC cases with a low proportion hobnail features (<30%) exhibit clinical invasiveness and pathological features of aggressiveness. METHODS: Pathological specimens from patients with postoperatively diagnosed PTC were retrospectively analyzed. Among them, 29 PTC cases with a low proportion of hobnail features (<30%) were compared with 173 consecutive classical PTC (cPTC) cases. Data regarding age at presentation, sex, tumor size, number of tumors, and histological characteristics were obtained by reviewing electronic medical records. Postoperative information was obtained during follow-up visits and telephone interviews. RESULTS: Twenty-nine patients with PTC with a low proportion of hobnail features (<30%) were identified, exhibiting a median age of 34 years. At a median follow-up of 31 (IQR, 23-37) months, two patients had recurrent disease in the PTC with a low proportion of hobnail features (<30%) group, whereas there was no recurrence in the cPTC group. No distant metastasis and postoperative mortality were observed in either group. Compared with the cPTC group, patients with PTC and a low proportion of hobnail features exhibited larger tumor volumes and higher susceptibility to capsular invasion and lymph node metastasis. Tumor size and hobnail features emerged as independent risk factors for lymph node metastasis. CONCLUSION: PTC with a low proportion hobnail features (<30%) and larger tumor volumes are associated with the occurrence of lymph node metastasis. A low proportion of hobnail features (<30%) in PTC may heighten invasiveness, elevating the risk of recurrence.

TyG-GGT is a Reliable Non-Invasive Predictor of Advanced Liver Fibrosis in Overweight or Obese Individuals.

BACKGROUND: Liver fibrosis is a predisposing factor for liver cancer. This study will investigate the predictive role of the Triglyceride-glucose and Gamma-glutamyl transferase index (TyG-GGT) as a non-invasive indicator of advanced liver fibrosis in individuals with obesity or overweight. METHOD: We enrolled patients who underwent metabolic and bariatric surgery as well as intraoperative liver biopsies at Zhejiang provincial people's hospital from August 2020 to March 2023. Clinical characteristics, comorbidities, laboratory data, and pathological variables of patients were collected and analysed. Then, we conducted logistics regression model to compare the performance of the TyG-GGT index with other 4 non-invasive models. RESULTS: A total of 65 patients were included in this study. 43(66.2%) of them were female, with the mean body mass index (BMI) of 39.0 ± 7.3 kg/m2. Meanwhile, 24(36.9%) patients were diagnosed with diabetes. Advanced liver fibrosis were observed in 16.9% of patients, while liver cirrhosis was found in 4.6% of patients. The multivariable logistics regression showed that TyG-GGT was an independent risk factor of advanced liver fibrosis (OR = 6.989, P = 0.049). Additionally, compared to another 4 non-invasive liver fibrosis models (NFS = 0.66, FIB4 = 0.65, METS-IR = 0.68, APRI = 0.65), TyG-GGT exhibits the highest AUC value of 0.75. CONCLUSIONS: More than one-third of patients undergoing metabolic and bariatric surgery are afflicted with nonalcoholic steatohepatitis (NASH), and a significant proportion exhibit advanced fibrosis. TyG-GGT was a potentially reliable predictor for screening individuals with overweight or obesity at high risk of advanced liver fibrosis, thus providing clinical guidance for early intervention in this targeted group.

ZNF521 Is Correlated with Tumor Immune Cell Infiltration and Act as a Valuable Prognostic Biomarker in Gastric Cancer.

Aim: To explore the correlations between the expression of zinc finger protein 521 (ZNF521) with immune invasion and prognosis of gastric cancer. Methods: Expression of ZNF521 was examined by immunohistochemistry in gastric cancer cases. Kaplan-Meier plotter was used to determine the relationships between ZNF521 and prognosis. TIMER and GEPIA were used to analyze the correlation between ZNF521 expression and gene markers of immune cell infiltration. Results: The expression of ZNF521 was up-regulated in gastric cancer samples. Kaplan-Meier analysis indicated that higher expression of ZNF521 was associated with poor prognosis. The expression of ZNF521 was correlated with infiltrating levels of CD4+ T and CD8+ T cells, macrophages, neutrophils, and dendritic cells in gastric cancer, which also correlated with diverse immune marker sets. Conclusions: ZNF521 is correlated significantly with immune cell infiltration and is a valuable biomarker for prognosis in gastric cancer.

Low expression of citron kinase is associated with poor patient outcomes in hepatocellular carcinoma.

BACKGROUND: Citron kinase (CIT) is a protein related to cytokinesis and is an important abscission regulator. However, the relationship between CIT and hepatocellular carcinoma (HCC) is unclear. The aim of this study was to investigate the expression CIT in HCC tissues, and explore the connection between this expression and clinicopathological characteristics of HCC. METHODS: Immunohistochemistry staining on 235 HCC tissues and 96 non-tumorous liver tissues controls was performed to examine the CIT protein expression. We then analyzed the correlation between protein expression and clinicopathological parameters via χ2 tests, and we performed overall survival analyses via the Kaplan-Meier survival approach. Based on the online Oncomine Expression Array and UALCAN databases, we more broadly compared CIT mRNA expression between normal and HCC tissues. Finally, we compared CIT mRNA expression in these databases to protein expression in our study and explored potential sources for any observe differences. RESULTS: Compared to normal tissues, CIT expression was significantly lower in HCC tissues. Low CIT expression was found to be related to gender, tumor size, Edmondson Grade, Microvascular invasion, serum AFP levels and poor overall survival. Based on the online databases, CIT mRNA expression was found to be high in HCC tissues and decreased in normal tissues. We hypothesize that this unexpected result is due to a negative feedback loop whereby low protein CIT levels mediate increased CIT mRNA levels. CONCLUSIONS: Lower CIT protein levels are associated with a poorer prognosis in HCC patients, and lower CIT protein levels may mediate a negative feedback loop leading to increased CIT mRNA levels.

Pegylated-interferon consolidation treatment versus nucleos(t)ide analogue consolidation treatment in non-cirrhotic hepatitis B patients with hepatitis B e antigen seroconversion: an open-label pilot trial.

BACKGROUND: The safety of nucleos(t)ide analogue (NA) treatment cessation remains one of the most controversial topics in the management of chronic hepatitis B (CHB) patients. This study investigated the efficiency of 48-week pegylated-interferon (peg-IFN) alfa-2a consolidation therapy on viral relapse after discontinued NA treatment in CHB patients who achieved hepatitis B e antigen (HBeAg) seroconversion for > 1 year. METHODS: NA-treated HBeAg-positive patients who achieved the standard of discontinued NA treatment (i.e. time of HBeAg seroconversion > 1 year) were randomly assigned to receive peg-IFN consolidation (n = 24) treatment or continue original NA therapy (n = 24) for 48 weeks. The treatments were then discontinued, and the patients were observed up to 144 weeks. The primary endpoint was the proportion of patients with viral relapse at week 144 among those who received at least one dose of study drug or had at least one study visit [modified intention-to-treat population (mITT)]. RESULTS: Of the 24 patients who received peg-IFN treatment, 6 (25%) experienced viral relapse and 8 (36.3%) showed HBsAg loss during 96 weeks of treatment-free follow-up. Of the patients who underwent NA consolidation treatment, only 1 (4.3%) of 23 patients showed HBsAg loss and 14 (58.3%) of 24 patients experienced viral relapse during follow-up. HBsAg level decline < 0.25 log10 IU/mL at week 96 was significantly associated with viral relapse. CONCLUSION: A 48-week peg-IFN alfa-2a consolidation therapy increased the rate of HBsAg loss and sustained viral replication suppression in HBeAg-positive patients who achieved HBeAg seroconversion for > 1 year after NA treatment discontinuation.

[mRNA expression of basic fibroblast growth factor and hepatocyte growth factor in gastric carcinoma and significance thereof].

OBJECTIVE: To investigate the mRNA expression of basic fibroblast growth factor (bFGF) and hepatocyte growth factor (HGF) in gastric carcinoma and correlation thereof with intratumoral microvascular density (IMD), proliferating cell nuclear antigen labeling index (PCNA LI), tumor invasion and metastasis, and patients' survival. METHODS: In situ hybridization and immunohistochemistry were used to test the expression of bFGF and HGF mRNA and protein expression of CD34 and PCNA in 118 specimens of gastric carcinoma. RESULTS: The positive rates of bFGF mRNA and HGF mRNA were 57.6% and 52.5% respectively; the positive expression rates of bFGF mRNA and HGF mRNA of the cases at the stage T3-T4, and those with vessel invasion, lymph node metastasis, and distant metastasis were all significantly higher than the positive expression rates of the cases at the stage T1-T2, and those without lymph node metastasis, vessel invasion, and distant metastasis (all P < 0.05). The mean IMD levels of the patients positive in bFGF and HGF mRNA expression were (46.63 +/- 13.96) and (46.73 +/- 13.34) pieces/0.72 mm2, both significantly higher than those of the patients negative in bFGF and HGF mRNA expression [(34.56 +/- 15.16) and (35.98 +/- 14.92) pieces/0.72 mm2) respectively, t = 4.62, P = 0.000, and t = 4.01, P = 0.000]. The PCNA LI of the of the patients positive in bFGF and HGF mRNA expression was (66.53 +/- 13.61) and (67.56 +/- 13.41) respectively, both significantly higher5 than those of patients negative in bFGF and HGF mRNA expression [(54.79 +/- 10.57) and (55.04 +/- 11.01) respectively, t = 5.83, P = 0.000, and t = 4.91, P = 0.000]. The 5-year survival rates of the patients negative in bFGF and HGF mRNA expression were 60.00% and 67.90% respectively, both significantly higher than those of the patients positive in bFGF and HGF mRNA expression (30.90% and 21.00% respectively, both P = 0.000). IMD, PCNA LI, and bFGF mRNA were all positively related to HGF mRNA (all P = 0.000). CONCLUSIONS: bFGF and HGF promote angiogenesis and proliferation of gastric cancer, and in involved in tumor invasion and metastasis. They can be used as markers of prognosis of gastric cancer in clinical practice.

Decreased CRHBP expression is predictive of poor prognosis in patients with hepatocellular carcinoma.

Corticotropin releasing hormone binding protein (CRHBP) mediates the reaction between corticotropin releasing hormone (CRH) and corticotropin releasing hormone receptors (CRHRs). It is expressed in a number of organs, and the expression of CRHBP is associated with tumorigenesis and cancer progression. The aim of the present study was to investigate CRHBP expression levels in hepatocellular carcinoma (HCC) and its association with patient clinicopathological characteristics as well as prognosis. The expression of CRHBP was examined by immunohistochemistry in 169 HCC tissues and 151 adjacent non-tumorous tissues. The results were validated by western blotting using patient tissues and liver cancer cell lines. The association of CRHBP expression with clinicopathological patient characteristics and survival rate was analyzed statistically. Expression of CRHBP was detected in 142/151 (94.0%) non-tumorous liver tissues, and 84/169 (49.7%) HCC tissues (P<0.001). The expression of CRHBP was negatively associated with tumor size (P=0.013), Edmondson Grade (P=0.002), hepatitis B virus antigen (P=0.020), and α-fetoprotein levels (P=0.014). Patients exhibiting low CRHBP expression were associated with shorter survival time compared with those exhibiting high CRHBP expression (P=0.012). The results of western blotting analysis suggest that reduced CRHBP expression is frequently observable in patients with HCC. Low CRHBP expression in HCC tissues may be a predictor of clinical prognosis and a potential therapeutic target for HCC.

Upregulation of hypoxia inducible factor 1alpha mRNA is associated with elevated vascular endothelial growth factor expression and excessive angiogenesis and predicts a poor prognosis in gastric carcinoma.

AIM: To investigate the implication of the hypoxia inducible factor HIF-1alpha mRNA in gastric carcinoma and its relation to the expression of vascular endothelial growth factor (VEGF) protein, tumor angiogenesis invasion/metastasis and the patient's survival. METHODS: In situ hybridization was used to examine expression of HIF-1alpha mRNA, and immunohistochemical staining was used to examine expression of VEGF protein and CD34 in 118 specimens from patients with gastric carcinoma. RESULTS: The positive rates of HIF-1alpha mRNA and VEGF protein were 49.15% and 55.92%, respectively. Positive expressions of HIF-1alpha and VEGF in stage T3-T4 tumors and those with vessel invasion, lymph node metastasis and distant metastasis were dramatically stronger than stage T1-T2 cases and those without vessel invasion, lymph node metastasis and distant metastasis. The mean microvascular density (MVD) in stage T3-T4 tumors and those with vessel invasion, lymph node metastasis and distant metastasis was significantly higher than stage T1-T2 tumors and those without vessel invasion, lymph node metastasis and distant metastasis. The mean MVD in tumors with positive HIF-1alpha and VEGF expression was significantly higher than that in tumors with negative HIF-1alpha and VEGF expression. The expression of HIF-1alpha was positively correlated with VEGF protein. There were positive correlations between MVD and expression of HIF-1alpha and VEGF. The mean survival time and the 5-year survival rate in cases with positive expression HIF-1alpha and VEGF and MVD value >or= 41.5/0.72 mm2 were significantly lower than those with negative expression of HIF-1alpha and VEGF and MVD value < 41.5/0.72 mm2. CONCLUSION: Overexpression of HIF-1alpha is found in gastric carcinoma. HIF-1alpha may induce the angiogenesis in gastric carcinoma by upregulating the transcription of VEGF gene, and take part in tumor invasion and metastasis. They can be used as prognostic markers of gastric cancer in clinical practice.

[Expressions of hypoxia inducible factor-1alpha and insulin-like growth factor-II in gastric carcinoma: correlation with angiogenesis and prognosis].

OBJECTIVE: To investigate relationship between expressions of hypoxia inducible factor-1alpha (HIF-1alpha) and insulin-like growth factor-II (IGF-II) as well as their correlation with angiogenesis and prognosis in gastric carcinoma. METHODS: HIF-1alpha and IGF-II mRNA expression were analyzed using in situ hybridization, microvessel density (MVD) was determined by anti-CD34 immunostaining in 118 cases gastric carcinoma. RESULTS: The positive rates of HIF-1alpha mRNA and IGF-II mRNA were 49.2% and 47.4%, respectively. In stage T3-T4 cases, positive rates of HIF-1alpha and IGF-II mRNA expression, the frequencies of vessel invasion, lymph node and distant metastasis were significantly higher than those in stage T1-T2 cases. The mean MVD in stage T3-T4 tumors, vessel invasion, lymph node metastasis and distant metastasis were significantly more frequent than those in stage T1-T2 tumors. The mean MVD in tumors with positive HIF-1alpha and IGF-II mRNA expression was significantly higher than those in tumors without HIF-1alpha and IGF-II mRNA expression. The expression of HIF-1alpha was positively correlated with IGF-II mRNA. There were positive correlations between MVD and expression of HIF-1alpha and IGF-II mRNA, respectively. The mean survival time and 5-year survival rate in cases with positive HIF-1alpha and VEGF expression and MVD value >/= 41.5 were significantly shorter than those in cases with negative HIF-1alpha and VEGF expression and MVD value < 41.5. CONCLUSIONS: HIF-1alpha and IGF-II play an important role in tumor invasion and metastasis, especially in tumor angiogenesis. So test of the expression of HIF-1alpha and IGF-II may act as a useful index of treatment and prognosis.

Development and validation of a model for staging hepatic fibrosis for chronic hepatitis B patients with E antigen-positive.

BACKGROUND: Interest is growing in the use of non-invasive techniques for complementing liver biopsy for liver fibrosis assessment. We aimed to prospectively evaluate liver histology in chronic hepatitis B (CHB) patients with e-antigen positivity, and develop and validate a novel scoring system-e-antigen-positive CHB liver fibrosis (EPLF) score-for noninvasively predicting the fibrosis stages. METHODS: We identified the baseline variables associated with fibrosis stage (MATAVIR score, F0-F4) in 212 CHB patients with e-antigen positivity. These significant variables were used to develop the EPLF scoring system. The EPLF score equation was developed based on the prediction of fibrosis stages via multivariate ordered logistic regression analysis. The diagnostic powers of the EPLF score and several non-invasive markers were assessed through an area under the receiver operating characteristic curve (AUROC) analyses. This EPLF score model was validated in another set of 208 similar patients. RESULTS: The natural logarithms of serum albumin, HBeAg, and HBsAg levels were selected as significant independent variables for the EPLF score equation. The EPLF score had good diagnostic power (AUROC, 0.72-0.90, p<0.001) and good diagnostic accuracy (72-85%), with a high positive predictive value (80.8-92.8%) for each fibrosis stage in the test group. Similar results were observed in the validation group (AUROC, 0.73-0.89, p<0.001). The EPLF score exhibited a strong correlation with fibrosis stage (r=0.67, p<0.001), and was the preferable non-invasive marker for staging liver fibrosis. CONCLUSION: In e-antigen-positive patients with CHB, the EPLF score could serve as a potential non-invasive marker of liver fibrosis stage.

High level of homeobox A9 and PBX homeobox 3 expression in gastric cancer correlates with poor prognosis.

The homeobox protein homeobox (HOXA9) is a transcriptional factor that regulates patterning during embryogenesis and controls cell differentiation. HOXA9 dysfunction has been implicated in certain cancers. However, the role of HOXA9 in gastric cancer is poorly understood. The present study investigated HOXA9 and its cofactor PBX homeobox 3 (PBX3) expression in patients with gastric cancer. Paired tissue samples from 24 patients and paraffin embedded tissues of gastric cancer patients (104 males and 24 females) were included. HOXA9 and PBX3 expression levels were determined by reverse transcription quantitative polymerase chain reaction in fresh tissues, and by immunohistochemical staining in paraffin embedded tissues. The association between HOXA9/PBX3 expression and clinicopathological features was established. The results demonstrated that HOXA9 and PBX3 mRNA levels were significantly upregulated (P=0.032 for HOXA9 and P=0.031 for PBX3) in gastric cancer tissue. Immunohistochemical staining revealed that HOXA9 expression was associated with differentiation, lymph node metastasis and tumor-node-metastasis (TNM) stage, and PBX3 expression was associated with lymph node metastasis and TNM stage. Correlation analysis revealed a high coincidental expression of HOXA9 and PBX3 levels in gastric cancer (r=0.391; P<0.001). Survival analysis showed that high expression of HOXA9 or PBX3 was associated with poor survival of gastric cancer, and multivariate analysis using Cox's regression model showed that PBX3 expression was an independent prognostic factor in gastric cancer. There was elevated expression of HOXA9 and PBX3 in gastric cancer patients, and high-level expression of those proteins was associated with poor prognosis of gastric cancer. The present study underlines the significance of HOXA9/PBX3 in the development of gastric cancer.

CEACAM6 is a prognostic biomarker and potential therapeutic target for gastric carcinoma.

This study aims to investigate the prognostic power of carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) in gastric cancer (GC) and its potential role in cancer development and progression. Data mining results show that CEACAM6 is overexpressed in gastric cancer and is correlated with lymph node metastasis. Subsequently, immunohistochemical staining was performed to determine CEACAM6 protein levels in paraffin gastric tumor specimens. Real-time reverse-transcription-polymerase chain reaction (RT-PCR) was conducted to detect CEACAM6 mRNA levels in fresh GC samples. CEACAM6 protein and mRNA levels were significantly up regulated in GC compared with paired normal mucosa. The IHC staining intensity of CEACAM6 was positively correlated with tumor size, Lauren's classification, vascular invasion, lymph node metastasis, distant metastasis, and TNM stage. CEACAM6 expression was inversely correlated with the five-year survival rate of GC patients. Cox multivariate analysis results demonstrated that the overall survival was independently correlated with CEACAM6 expression. A significant association was observed between CEACAM6 and distant metastases. Network analysis of downstream gene signatures revealed several hub genes such as SRC and DNM1L etc. which may mediating tumor promoting functions of CEACAM6. Further data mining discovered that Tamoxifen etc. could be therapeutic alternatives for gastric patients with CEACAM6 overexpression. Collectively, CEACAM6 overexpression is a common characteristic of GC and is associated with poor 5 year survival rate in GC. Besides, potential molecular mechanisms and treatment options were also provided.

Correlative studies on uPA mRNA and uPAR mRNA expression with vascular endothelial growth factor, microvessel density, progression and survival time of patients with gastric cancer.

AIM: To investigate the correlations between the expression of urokinase-type plasminogen activator (uPA) mRNA, uPA receptor (uPAR) mRNA and vascular endothelial growth factor (VEGF) protein and clinicopathologic features, microvessel density (MVD) and survival time. METHODS: In situ hybridization and immuno-histochemistry techniques were used to study the expressions of uPA mRNA, uPAR mRNA, VEGF and CD34 protein in 105 gastric carcinoma specimens. RESULTS: Expressions of uPA mRNA, uPAR mRNA and VEGF protein were observed in 61 (58.1%) cases, 70 (66.7%) cases and 67 (63.8%) cases, respectively. The uPA mRNA and uPAR mRNA positive expression rates in infiltrating-type cases (73.7%, 75.4%), stage III-IV (72.1%, 75.4%), vessel invasion (63.2%, 69.9%), lymphatic metastasis (67.1%, 74.4%) and distant metastasis (88.1%, 85.7%) were significantly higher than those of the expanding-type (chi2 = 15.57, P = 0.001; chi2 = 6.91, P = 0.046), stage I-II (chi2 = 19.22, P = 0.001; chi2 = 16.75, P = 0.001), non-vessel invasion (chi2 = 11.92, P = 0.006; chi2 = 14.15, P = 0.002), non-lymphatic metastasis (chi2 = 28.41, P = 0.001; chi2 = 22.5, P = 0.005) and non-distant metastasis (chi2 = 12.32, P = 0.004; chi2 = 17.42, P = 0.002; chi2 = 11.25, P = 0.012; chi2 = 18.12, P = 0.002). The VEGF positive expression rates in infiltrating-type cases (75.4%), stage III-IV (88.5%), vessel invasion (82.9%), lymphatic metastasis (84.3%) and distant metastasis (95.2%) were significantly higher than those of the expanding-type (chi2 = 9.61, P = 0.021), stage I-II (chi2 = 16.66, P = 0.001), non-vessel invasion (chi2 = 29.38, P = 0.001), non-lymphatic metastasis (chi2 = 18.68, P = 0.005), and non-distant metastasis (chi2 = 22.72, P = 0.007; chi2 = 21.62, P = 0.004). The mean MVD in the specimens positive for the uPA mRNA, uPAR mRNA and VEGF protein was markedly higher than those with negative expression groups. Moreover, a positive relation between MVD and uPA mRNA (rs = 0.199, P = 0.042), uPAR mRNA (rs = 0.278, P = 0.035), and VEGF (rs = 0.398, P = 0.048) expressions was observed. The mean survival time in cases with positive uPA mRNA, uPAR mRNA and VEGF protein expression or MVD value > or = 54.9 was significantly shorter than those in cases with negative expression or MVD value < 54.9. CONCLUSION: uPA and uPAR expressions are correlated with enhanced VEGF-induced tumor angiogenesis and may play a role in invasion and nodal metastasis of gastric carcinoma, thereby serving as prognostic markers of gastric cancer.