Prognostic relevance of UCH-L1 and α-internexin in pancreatic neuroendocrine tumors.

Prognostic biomarkers for the pancreatic neuroendocrine tumors are needed. Proteomic study on insulinoma has been rarely reported. We identified the differential expression of proteins between insulinoma and their paired tissues by proteomic analysis, and evaluated the prognostic significance of specific proteins in pancreatic neuroendocrine tumors including insulinoma. The differential expression of select proteins was validated in more than 300 tumors using immunohistochemical staining and western blot. Methylation of UCH-L1 promoter in tumors was examined by methylation specific PCR and validated by sequencing. The concurrent expression of UCH-L1 and α-internexin was correlated with the prognosis in 2 independent collectives of patients with tumors. Sixty-two and 219 proteins were significantly down-regulated and up-regulated in insulinomas, respectively. Demethylation of UCH-L1 promoter was associated with UCH-L1 expression in tumors (p = 0.002). The concurrent expression of UCH-L1 and α-internexin in pancreatic neuroendocrine tumors was significantly associated with better overall survival and disease-free survival in the combination of both cohorts (log rank p = 3.90 × 10-4 and p = 3.75 × 10-5, respectively) and in each of cohorts. The prognostic value of both proteins was also validated in patients with stage II and III tumors (p = 0.017 and p = 0.006, respectively). The proteins UCH-L1 and α-internexin could be independent prognostic biomarkers of pancreatic neuroendocrine tumors.

High expression of PTBP1 promote invasion of colorectal cancer by alternative splicing of cortactin.

Polypyrimidine tract-binding protein 1 (PTBP1) involving in almost all steps of mRNA regulation including alternative splicing metabolism during tumorigenesis due to its RNA-binding activity. Initially, we found that high expressed PTBP1 and poor prognosis was interrelated in colorectal cancer (CRC) patients with stages II and III CRC, which widely different in prognosis and treatment, by immunohistochemistry. PTBP1 was also upregulated in colon cancer cell lines. In our study, knockdown of PTBP1 by siRNA transfection decreased cell proliferation and invasion in vitro. Denovirus shRNA knockdown of PTBP1 inhibited colorectal cancer growth in vivo. Furthermore, PTBP1 regulates alternative splicing of many target genes involving in tumorgenesis in colon cancer cells. We confirmed that the splicing of cortactin exon 11 which was only contained in cortactin isoform-a, as a PTBP1 target. Knockdown of PTBP1 decreased the expression of cortactin isoform-a by exclusion of exon 11. Also the mRNA levels of PTBP1 and cortactin isoform-a were cooperatively expressed in colorectal cancer tissues. Knocking down cortactin isoform-a significantly decreased cell migration and invasion in colorectal cancer cells. Overexpression of cortactin isoform-a could rescue PTBP1-knockdown effect of cell motility. In summary the study revealed that PTBP1 facilitates colorectal cancer migration and invasion activities by inclusion of cortactin exon 11.

Differences and Similarities in the Clinicopathological Features of Pancreatic Neuroendocrine Tumors in China and the United States: A Multicenter Study.

The presentation, pathology, and prognosis of pancreatic neuroendocrine tumors (PNETs) in Asian patients have not been studied in large cohorts. We hypothesized that the clinicopathological features of PNETs of Chinese patients might be different from those of US patients. The objectives of this study were to address whether PNETs in Chinese patients exhibit unique clinicopathological features and natural history, and can be graded and staged using the WHO/ENETS criteria. This is a retrospective review of medical records of patients with PNETs in multiple academic medical centers in China (7) and the United States (2). Tumor grading and staging were based on WHO/ENETS criteria. The clinicopathological features of PNETs of Chinese and US patients were compared. Univariate and multivariate analyses were performed to find associations between survival and patient demographics, tumor grade and stage, and other clinicopathological characteristics. A total of 977 (527 Chinese and 450 US) patients with PNETs were studied. In general, Chinese patients were younger than US patients (median age 46 vs 56 years). In Chinese patients, insulinomas were the most common (52.2%), followed by nonfunctional tumors (39.7%), whereas the order was reversed in US patients. Tumor grade distribution was similar in the 2 countries (G1: 57.5% vs 55.0%; G2: 38.5% vs 41.3%; and G3: 4.0% vs 3.7%). However, age, primary tumor size, primary tumor location, grade, and stage of subtypes of PNETs were significantly different between the 2 countries. The Chinese nonfunctional tumors were significantly larger than US ones (median size 4 vs 3 cm) and more frequently located in the head/neck region (54.9% vs 34.8%). The Chinese and US insulinomas were similar in size (median 1.5 cm) but the Chinese insulinomas relatively more frequently located in the head/neck region (48.3% vs 26.1%). Higher grade, advanced stage, metastasis, and larger primary tumor size were significantly associated with unfavorable survival in both countries. Several clinicopathological differences are found between Chinese and US PNETs but the PNETs of both countries follow a similar natural history. The WHO tumor grading and ENETS staging criteria are applicable to both Chinese and US patients.

Chromogranin A is a reliable serum diagnostic biomarker for pancreatic neuroendocrine tumors but not for insulinomas.

BACKGROUND: Pancreatic neuroendocrine tumors (PNETs) are a group of rare tumors. Chromogranin A (CgA) was considered as the most practical and useful serum tumor marker in PNET patients. But peripheral blood levels of CgA are not routinely tested in Chinese patients with PNETs. This study was to assess the diagnostic value of CgA in Chinese patients with PNETs especially in patients with insulinomas. METHODS: Eighty-nine patients with PNETs including 57 insulinomas and 32 non-insulinoma PNETs as well as 86 healthy participants were enrolled in this study between September 2003 and June 2013. Serum levels of CgA were measured by ELISA method. Expression of CgA protein was detected in 26 PNET tissues including 14 insulinomas by immunohistochemical staining. RESULTS: Serum levels of CgA in 89 PNET patients were significantly higher than that in healthy controls (P = 7.2 × 10-9). Serum levels of CgA in 57 patients with insulinomas (median 64.8 ng/ml, range 25-164) were slightly higher than the levels in healthy controls (median 53.4 ng/ml, range 39-94) but much lower than the levels in 32 patients with non-insulinoma PNETs (median 193 ng/ml, range 27-9021), P = 0.001. The serum CgA levels were reduced in 16 of 17 patients with insulinomas after tumor resection. ROC curve showed that CgA values at 60 ng/ml distinguished patients with insulinomas from healthy controls but its sensitivity and specificity were 66.7% and 73.3%, respectively. In contrast, CgA values at 74 ng/ml distinguished patients with non-insulinoma PNETs from healthy controls, and the sensitivity and specificity were 65.6% and 91.9%, respectively. Except for two insulinomas with negative staining of CgA, 12 insulinoma tissues showed positive staining of CgA. CONCLUSION: CgA is a reliable serum diagnostic biomarker for PNETs but not for insulinomas.

α-Internexin: a novel biomarker for pancreatic neuroendocrine tumor aggressiveness.

PURPOSE: We aimed to test whether α-internexin could be a molecular biomarker of tumor aggressiveness and prognosis in pancreatic neuroendocrine tumors (PNETs). PATIENTS AND METHODS: Using immunohistochemical staining and Western blot, we detected the expression of α-internexin in 350 tumors from 343 patients, of whom 257 were followed up. Methylation of α-internexin promoter was examined by bisulfite sequencing to identify the crucial region that determines gene expression. Methylation of gene promoter in tumors was quantitatively measured by denaturing high performance liquid chromatography (DHPLC). We correlated α-internexin expression with clinicopathological characteristics. RESULTS: α-Internexin was expressed in 53% of 350 PNETs. The reduced expression of α-internexin was significantly associated with advanced stage (P < .0001), metastases (P < .0001), and recurrence (P = .003). α-Internexin expression was found in 57.1% of 212 surviving patients and in 17.1% of 35 deceased patients (P < .0001). Reduced expression of α-internexin was associated with shorter overall survival in PNET patients (log rank P < .0001) as well as in patients with noninsulinoma and nonfunctional (NF)-PNETs (log rank P = 0.0073 and P = 0.010, respectively). The crucial region of α-internexin promoter (-149 to +96 nucleotides [nt]) was identified, and the hypomethylation of this area in PNETs was significantly associated with gene expression (P = .015). CONCLUSION: α-Internexin can be a useful prognostic biomarker for PNETs.

S100P, a potential novel prognostic marker in colorectal cancer.

Previous studies have shown that S100P contributes to the development of a number of tumors. However, its prognostic significance in colorectal cancer (CRC) has not been demonstrated. This study aimed to confirm the expression of S100P in colorectal cancer as well as the epigenetic mechanism underlying its gene expression, and to demonstrate whether S100P could be used to predict prognosis as a biomarker. We tested the expression of S100P in 96 CRCs and their paired tissue controls, as well as 13 colon cancer cell lines by RT-PCR and western blotting. Expression of the S100P protein and mRNA was significantly higher in cancerous regions compared to that in paired non-cancerous tissues (P=4.59 x 10(-17), 0.005 respectively). The expression was significantly correlated with the hypomethylation of the S100P promoter (P=4.92 x 10(-5)), which was detected by bisulphite sequencing PCR (BSP) and quantitative methylation-specific real-time PCR (QMSP). In stages I to III, the patients with positive expression of S100P protein showed poorer overall survival compared to those with S100P negative expression, P=0.031. We also measured the preoperative serum S100P levels by ELISA. The patients with normal serum levels of S100P showed favorable prognosis compared with patients with elevated S100P levels (P=0.008). These data suggest that S100P protein may be a potential novel prognostic biomarker in CRC patients.

[Effectiveness of educational interventions in children with chronic diseases and their parents].

OBJECTIVE: To evaluate the effectiveness of educational interventions in children with chronic illness and their parents. METHODS: Fifty children with chronic illness and 75 parents participated in the study. Children who were hospitalized between August 2007 and January 2008 and their parents received educational sessions and those who were hospitalized between February and July 2007 and who did not receive the sessions served as the control group. The content of the educational sessions included knowledge of chronic disease, drugs and self-care, and coping skills. The knowledge level, stressors, coping strategies, and psychological conditions of children with chronic illness and their parents were evaluated before discharge and three months after discharge. RESULTS: After educational interventions, the knowledge levels of children and their parents increased and the stressors decreased significantly in the intervention group compared with those in the control group. The children's parents in the intervention group used more active coping strategies (understanding the medical situations through communication with medical staff) than those in the control group. The differences in the medication compliance of children between the two groups were not found. CONCLUSIONS: The educational interventions may result in an improved knowledge level and decrease stressors in children and their parents, and improve stress coping strategies in parents. There is no evidence that the educational intervention can improve the psychosocial conditions of children and their parents.

Clinical implications of microsatellite instability and MLH1 gene inactivation in sporadic insulinomas.

CONTEXT: The molecular pathogenesis of sporadic insulinomas is unknown. There is a lack of biomarker to distinguish benign and malignant form of insulinoma. OBJECTIVE: Our objective was to confirm the occurrence of microsatellite instability (MSI) in insulinomas, to identify alterations of mismatch repair (MMR) genes in the tumors, and to evaluate the possibility to distinguish benign and malignant insulinoma or to predict the clinical outcome of patients with these alterations. DESIGN AND PATIENTS: We detected MSI and inactivation of MLH1 gene in 55 sporadic insulinomas by PCR, immunohistochemical staining, allelic typing, analysis of promoter methylation, and exon mutations. Their correlations with clinicopathological characteristics were analyzed with univariate and multivariate statistic analysis. RESULTS: A high rate of MSI (MSI-H) was found in 33% of sporadic insulinomas. Reduced expression of mutL homolog 1 (MLH1) protein was observed in 36% of insulinomas and correlated with MSI-H (P = 0.008). Promoter methylation and loss of heterozygosity of MLH1 gene was found in 31 and 49% of insulinomas, respectively. Reduced expression of MLH1 and MSI-H were significantly associated with both tumor malignancy (P = 0.033 and P = 4.8 x 10(-6), respectively) and incurable disease (P = 0.006 and P = 0.001, respectively). CONCLUSION: High frequency of MSI occurred in sporadic insulinomas. The silencing of MLH1 gene may partially contribute to the MSI-H in the tumors. Assessing MSI-H and expressions of MLH1 could be used to distinguish benign and malignant insulinomas and to predict the outcome of patients.

Eosinophilia associated with chronic pancreatitis.

OBJECTIVES: Eosinophilia (>0.5 x 10/L eosinophils [EOSs] in the peripheral blood) has been overlooked in the study of chronic pancreatitis (CP). The purpose of this study was to investigate the clinical significance and causes of eosinophilia by analyzing the features of CP cases with eosinophilia. METHODS: We retrospectively analyzed the clinical features of CP patients with eosinophilia and compared them with CP patients without eosinophilia. RESULTS: There were 28 cases (15.6%) of CP with eosinophilia among 180 CP patients. The ratio of male to female patients was 8.3:1. The mean patient age at the time of diagnosis was 49.0 (+/- 16.2) years. The peak value of EOSs in the patients' peripheral blood was 0.935 (+/- 0.600) x 10/L. The incidence of eosinophilia in autoimmune pancreatitis was significantly higher than in non-autoimmune pancreatitis CP cases. The incidence of pancreatic ascites, pancreatic enlargement, or jaundice in CP cases with eosinophilia was significantly higher than in those without eosinophilia. There was no obvious infiltration of EOSs in the pancreatic tissues of 16 pathology or cytology specimens. CONCLUSIONS: The occurrence of eosinophilia during the course of CP is not unusual. This may be related to autoimmune mechanisms, serous membrane response, or the progression of pancreatic inflammation and fibrosis.

[Prevalence of human papillomavirus infection in women in Tibet Autonomous Region of China.].

OBJECTIVE: To determine the prevalence of cervical type-specific human papillomavirus (HPV) infection as well as risk factors associated in Tibet Autonomous Region of China. METHODS: A cluster sampling study was performed in Lasa, Rikaze and Naqu of Tibet. An epidemiological questionnaire was applied and 3036 cervical specimens were obtained for liquid-based cytology and HPV DNA detection. Statistical analysis included Wald Chi-square and stepwise logistic regression model. RESULTS: The overall HPV prevalence of involved 3036 women was 9.19% (279/3036), of which 7.05% (214/3036) of the women were infected by high-risk types (including 14 sorts of types) and 2.14% (65/3036) by low-risk types (including 6 sorts of types). There were no significant differences of HPV prevalence between age groups (P = 0.936), race (P = 0.718) and areas (P = 0.746), respectively. Twenty-one types of HPV were detected, of which HPV16 (1.52%) was the most common type, followed by HPV33 (1.42%), HPV58 (1.22%), HPV52 (1.15%), and HPV31 (1.05%). HPV type distribution was varied by age. Of the 279 HPV infected women, 14.3% (40/279) exhibited multiple HPV infections. Independent risk factors for HPV infection were smoking (P = 0.027), number of sex partners (P = 0.198) and early age of first intercourse (P = 0.237). CONCLUSION: The overall prevalence of HPV infection in Tibet Autonomous Region is lower than that in China or abroad, in which the most common genotype is HPV16 and the independent risk factors for HPV infection included early age of first intercourse, smoking, and number of sex partners.

[Analysis of clinical features of autoimmune disease-related pancreatitis].

OBJECTIVE: To improve the understanding of autoimmune disease related pancreatitis by analyzing their clinical features. METHODS: The clinical features were analyzed retrospectively in 28 autoimmune disease related pancreatitis cases from Peking Union Medical College Hospital (PUMCH), according to the associated autoimmune diseases. RESULTS: (1) The average age was (40.0 +/- 16.1) years, and the ratio of male to female patients was 1:6. There were 24 acute and 4 chronic pancreatitis in the 28 cases. (2) The common related autoimmune diseases were systemic lupus erythematosus (20/28) and Sjögren's syndrome (6/28). (3) The characteristics of the autoimmune diseases was multi-system involvement, such as hematologic system, kidney, liver, etc. (4) Clinical features of those acute pancreatitis shown that no distinct trigger exist for acute pancreatitis, and the radiological changing was not prominent. (5) In laboratory examination, an obvious increase of CA199 could be seen, paralleling the severity of pancreatitis. (6) Glucocorticoids or immunosuppressors was effective, and the mortality rate of acute pancreatitis cases was 33.3%. CONCLUSIONS: Autoimmune disease related pancreatitis is dominant with acute pancreatitis and females is common, which may reflect the activity of autoimmune diseases. Autoimmune disease related acute pancreatitis has a high mortality rate. Glucocorticoids and/or immunosuppressors may be useful to relieve the pancreatitis.