Role of the Mean Nocturnal Baseline Impedance in Identifying Evidence Against Pathologic Reflux in Patients With Refractory Gastroesophageal Reflux Disease Symptoms as Classified by the Lyon Consensus

Background/Aims@#Mean nocturnal baseline impedance (MNBI) is a new reflux metric for mucosal integrity. It remains unclear whether MNBI can help identify evidence against pathological reflux by the Lyon Consensus in patients with refractory gastroesophageal reflux disease (GERD) symptoms. @*Methods@#Three hundred and forty-nine patients with refractory GERD symptoms enrolled in this study were subjected to high-resolution manometry, 24-hour multichannel intraluminal impedance-pH (MII-pH) monitoring, and endoscopy. Conventional indexes (ie, reflux events and acid exposure time) and the novel index (MNBI) of MII-pH monitoring were extracted and analyzed. The value of MNBI in diagnosing patients with evidence against pathologic reflux was evaluated by receiver-operating-characteristic analysis. @*Results@#There were 102 (29.2%) patients with evidence against pathologic reflux, 149 (42.7%) with inconclusive or borderline evidence and 98 (28.1%) with conclusive evidence for pathologic reflux. The MNBI was significantly higher while the proportion of pathological MNBI was significantly lower in subjects with evidence against pathologic reflux than in patients with inconclusive or borderline evidence and in patients with conclusive evidence for pathologic reflux (2444.3 [1977.9-2997.4] vs 1992.8 [1615.5-2253.6] and vs 1772.3 [758.6-2161.3], both P < 0.001; 42.2% vs 79.7% and vs 80.0%, both P < 0.05). When identifying evidence against pathologic reflux in patients with refractory GERD symptoms, the MNBI yielded an area under the curve of 0.749 (P < 0.001) at a cutoff value of 1941.8 Ω. @*Conclusions@#The MNBI has a good diagnostic value for evidence against pathological reflux in patients with refractory GERD symptoms. For its simplicity and reproducibility, we believe that MNBI should be referred to in reports of impedance-pH tracings by physicians.

MUC13 promotes intrahepatic cholangiocarcinoma progression via EGFR/PI3K/AKT pathways.

BACKGROUND & AIMS: Mucin 13 (MUC13) is reportedly overexpressed in human malignancies. However, the clinicopathological and biological significance of MUC13 in human intrahepatic cholangiocarcinoma (iCCA) remain unclear. The aim of this study was to define the role of MUC13 in the progression of iCCA. METHODS: Expression levels of MUC13 in human iCCA samples were evaluated by immunohistochemistry, western blot, and real-time PCR. In vitro and in vivo experiments were used to assess the effect of MUC13 on iCCA cell growth and metastasis. Crosstalk between MUC13 and EGFR/PI3K/AKT signaling was analyzed by molecular methods. The upstream regulatory effects of MUC13 were evaluated by Luciferase and DNA methylation assays. RESULTS: MUC13 was overexpressed in human iCCA specimens and iCCA cells. MUC13 overexpression positively correlated with clinicopathological characteristics of iCCA, such as vascular invasion and lymph node metastasis, and was independently associated with poor survival. Results from loss-of-function and gain-of-function experiments suggested that knockdown of MUC13 attenuated, while overexpression of MUC13 enhanced, the proliferation, motility, and invasiveness of iCCA cells in vitro and in vivo. Mechanistically, we found that the phosphatidylinositol 3-kinase-AKT signal pathway and its downstream effectors, such as tissue inhibitor of metalloproteinases 1 and matrix metallopeptidase 9, were required for MUC13-mediated tumor metastasis of iCCA. MUC13 interacted with epidermal growth factor receptor (EGFR) and subsequently activated the EGFR/PI3K/AKT signaling pathway by promoting EGFR dimerization and preventing EGFR internalization. We also found that MUC13 was directly regulated by miR-212-3p, whose downregulation was related to aberrant CpG hypermethylation in the promoter area. CONCLUSIONS: These findings suggest that aberrant hypermethylation-induced downregulation of miR-212-3p results in overexpression of MUC13 in iCCA, leading to metastasis via activation of the EGFR/PI3K/AKT signaling pathway. LAY SUMMARY: Mucin 13 overexpression has been implicated in the development of malignancies, although its role in intrahepatic cholangiocarcinoma has not been studied. Herein, we show that mucin 13 plays a critical role in intrahepatic cholangiocarcinoma. Mucin 13 could have therapeutic value both as a prognostic marker and as a treatment target.

Study on the quality of life and psychological factors of 159 patients with different subtypes of refractory gastroesophageal reflux disease / 中华消化杂志

Objective:To explore the quality of life and psychological factors of patients with refractory gastroesophageal reflux disease (rGERD).Methods:From September 2016 to March 2019, 159 rGERD patients visiting the Department of Gastroenterology, Beijing Tongren Hospital Affiliated to Capital Medical University were retrospectively selected. According to the presence or absence of distal esophageal mucosal injury under gastroscopy, the patients were divided into refractory reflux esophagitis (RE) group (58 cases) and refractory non-erosive reflux disease (NERD) group (101 cases). The general data, the results of 24 h esophageal impedance pH, esophageal high-resolution manometry (HRM) and the scores of gatroesophageal reflux disease-questionnaire (GerdQ), 36-item short-form health survey (SF-36), self-rating anxiety scale(SAS) and self-rating depression scale (SDS) were recorded and compared between the two groups. Independent sample t test, rank sum test, chi-square test and multiple linear regression analysis were used for statistical analysis. Results:There were no significant differences in gender, age, abdominal circumference or body mass index between the two groups (all P>0.05). The incidence of extraesophageal symptoms of refractory NERD group was higher than that of refractory RE group (45.5%, 46/101 vs. 24.1%, 14/58), and the difference was statistically significant ( χ2=7.185, P=0.010). The episodes of gas reflux, weak-acid reflux and non-acid reflux were all more than those of refractory RE group (66.20 times, 45.20 times to 111.60 times vs. 38.40 times, 23.50 times to 59.63 times; 34.70 times, 9.05 times to 52.75 times vs. 6.35 times, 3.10 times to 24.00 times; 12.60 times, 2.15 times to 24.20 times vs. 2.15 times, 0 times to 10.30 times), GerdQ score of refractory NERD group was higher than that of refractory RE group (8.9±2.5 vs. 7.8±2.3), and DeMeester score, the symptom index and symptom association probability of refractory NERD group were all lower than those of refractory RE group (5.16, 1.75 to 14.48 vs. 15.19, 2.78 to 45.96; 33.3%, 0 to 60.0% vs. 57.5%, 40.5% to 78.0%; 87.8%, 0 to 97.8% vs. 94.0%, 82.7% to 98.2%); and the differences were statistically significant ( Z=-5.548, -5.384 and -4.338, t=3.306, Z=-2.607, -4.313 and -2.468; all P<0.05). The esophageal distal contractile integral of refractory NERD group was lower than that of refractory RE group (334.0 mmHg·s·cm, 182.5 mmHg·s·cm to 492.0 mmHg·s·cm vs. 399.0 mmHg·s·cm, 216.5 mmHg·s·cm to 756.3 mmHg·s·cm, 1 mmHg=0.133 kPa), and the difference was statistically significant ( Z=-2.204, P=0.030). There were no significant differences in lower escophageal sphincter or the length of peristaltic interruption between the two groups (both P>0.05). There were no significant differences in physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, mental health or reported health transition of SF-36 score between refractory NERD group and refractory RE group (all P>0.05). Among 159 patients with rGERD, 98 patients (61.6%) had anxiety and 55 patients (34.6%) had depression. The SAS score of refractory NERD group was higher than that of refractory RE Group (52.6±5.8 vs. 47.0±8.8), and the difference was statistically significant ( t=4.794, P<0.05), however there was no significant difference in SDS score between the two groups ( P>0.05). The results of multiple linear regression analysis showed that GerdQ score in rGERD patients was positively correlated with DeMeester score, gas reflux, weak acid reflux, SAS score and SDS score ( r=0.201, 0.228, 0.171, 0.229 and 0.276; all P<0.05). Conclusions:Among the patients with rGERD, the reflux symptoms are more severe in refractory NERD patients, which may be related to non-acid reflux, gas reflux, esophageal motor disorders, and psychological abnormalities, especially anxiety.

Results of 24-hour esophageal impedance-pH monitoring in 141 patients with gastroesophageal reflux disease / 中华消化杂志

Objective To analyze the relationship between body type,age,gender,esophageal motility function,lower esophageal sphincter pressure (LESP) and clinical classification and type of reflux contents of patients with gastroesophageal reflux disease (GERD).Methods From September 2015 to July 2016,at Beijing Tongren Hospital of China Capital Medical University,the results of 24-hour esophageal impedance-pH monitoring of 141 patients with GERD were retrospectively analyzed.The differences of reflux contents were compared in patients with GERD among different body type,age,gender,esophageal motility function,LESP and clinical classification.Mann-Whitney test was performed for comparison between groups.Results Acid reflux was more common in obese patients (body mass index more than 23.9 kg/m2) compared with patients with normal body type (body mass index from 18.5 to 23.9 kg/m2) (18.5,7.0 to 45.3 vs.10.0,2.0 to 32.0),and the difference was statistically significant (Z =-2.320,P =0.020).Patients under 65 years old had more numbers of weak acid reflux,non-acid reflux and gas reflux than patients over 65 years old (58.5,32.8 to95.0 vs.40.0,24.0to71.0;19.5,6.0to47.5 vs.8.0,3.0 to19.0;46.0,23.8to79.3 vs.35.0,11.0 to 56.0),and the differences were statistically significant (Z =-2.690,-3.286 and-2.091,all P＜0.05).Male patients had more gas and mixed reflux compared with female patients (53.5,24.0 to 122.8 vs.36.0,19.0 to 67.0;34.0,20.8 to 50.0 vs.27.0,14.0 to 43.0),and the differences were statistically significant (Z =-2.424 and-1.961,both P ＜ 0.05).There was no statistically significant difference in reflux contents between patients with normal esophageal motility and patients with esophageal motility disorder (weak or interrupted peristalsis) (all P ＞ 0.05).Patients with reflux esophagitis(RE) and/or Barrett's esophagus (BE) had more weak acid reflux,non-acid reflux and gas reflux compared with patients with non-erosive reflux disease (NERD) (61.0,31.3 to 102.5 vs.44.0,24.5 to 66.5;18.0,8.0 to 36.5 vs.8.0,2.0 to 22.0;49.5,27.5 to 86.5 vs.26.0,11.0 to 47.0),and the differences were statistically significant (Z =-2.585,-2.942 and-3.278,all P ＜ 0.05).Patients with lower esophageal sphincter (LES) relaxation were more likely to have weak acid reflux than patients with normal LES function (57.0,32.3 to 87.0 vs.40.0,21.0 to 73.0),the difference was statistically significant (Z =-2.065,P =0.039).Conclusion Body type,age,gender,LESP and clinical classification are related to type of reflux contents in GERD patients,while esophageal peristalsis is irrelevant.

Correlation between esophageal motility abnormalities and characteristics of esophageal reflux in patients with different subtypes of refractory gastroesophageal reflux disease / 中华消化杂志

Objective To investigate the correlation between esophageal motility abnormalities and the characteristics of gastroesophageal reflux in patients with different subtypes of refractory gastroesophageal reflux disease (rGERD).Methods From September 2015 to May 2016,a total of 100 rGERD patients were collected,all of whom received gastroendoscopy examination,high resolution manometry (HRM) and 24 h impedance-pH monitoring.According to the results of gastroendoscopy examination,the patients were divided into refractory non-erosive reflux disease (NERD) group and refractory reflux esophagitis (RE) group.Abnormal esophageal motility and pathological gastroesophageal reflux of each group were analyzed.Chi-square test,t test and sum-rank test were performed for comparison,the correlation factors were analyzed by multivariate unconditional Logistic regression.Results Among the 100 patients with rGERD,there were 83 cases in refractory NERD group and 17 in refractory RE group.The episodes of weak acid and gas-liquid mixed reflux of refractory NERD group were both significantly higher than those of refractory RE group (80.2±56.9 vs 44.8± 13.7,56.0± 25.6 vs 25.2±16.1);and the differences were statistically significant (t=3.202 and 2.229,both P＜ 0.05).The DeMeester score,acid reflux episodes and the percentage of reflux time of refractory NERD group were all significantly lower than those of refractory RE group (24.2±8.5 vs 56.8±3.0,21.4± 11.8 vs 35.9 ± 32.6,(7.1 ± 1.6) ％ vs (16.2 ± 8.8) ％),and the differences were statistically significant (t=-2.820,-2.230 and-2.604;all P＜0.05).However,the average resting pressure of lower esophageal sphincter was higher than that of refractory RE group ((7.9±5.6) mmHg (1 mmHg=0.133 kPa) vs (4.5±2.2) mmHg),and the difference was statistically significant (t=2.443,P＜0.05).Patients with esophageal motility disorders of refractory NERD group and refractory RE group were 58 cases (69.9 ％) and 12 cases (12/17),respectively,and the difference was not significant (P＞0.05).Compared with refractory RE group,the ratio of intermittent contraction was higher (1/17 vs 26.5％,22/83) and the peristaltic contraction disorder was lower in refractory NERD group (11/17 vs 43.4％,36/83);and the differences were statistically significant (x2 =3.389 and 2.587,both P ＜ 0.05).The results of multivariate non-conditional Logistic regression analysis showed that intermittent contraction and gas reflux were risk factors of the incidence of pathological weak acid reflux (odd ratio (OR) =3.139 and 1.254,both P＜0.05),while body mass index and gas-liquid mixed reflux were the risk factors of the occurrence of pathological acid reflux (OR =1.302 and 1.026,both P＜ 0.05),whereas the distal contractile integral was a protective factor (OR=0.998,P＜0.05).Conclusion Esophageal dysmotility is common in patients with rGERD,and the dysmotility disorders are different in patients with different subtypes,which may be related to the different reflux characteristics.

Analyzing S100A6 expression in endoscopic ultrasonography-guided fine-needle aspiration specimens: a promising diagnostic method of pancreatic cancer.

BACKGROUND AND GOALS: Endoscopic ultrasonography-guided fine-needle aspiration (EUS-FNA) cytology in combination with other tests is necessary to improve diagnostic accuracy. We evaluated the diagnostic utility of S100A6 expression in EUS-FNA tissue samples in pancreatic ductal adenocarcinoma (PDA). METHODS: RNA was extracted from 36 PDA and 44 nontumor pancreatic tissues obtained during surgery. S100A6 expression was quantified by real-time reverse transcription-polymerase chain reaction, and receiver operating characteristic analysis was performed to determine the cutoff value for PDA. We preoperatively performed EUS-FNA in 52 patients with pancreatic masses, then prospectively evaluated the diagnostic value of S100A6 expression of EUS-FNA samples in pancreatic cancer diagnosis. S100A6 immunohistology was conducted to validate the S100A6 expression data in PDA samples. RESULTS: Of the 52 EUS-FNA patients with pancreatic masses, RNA was successfully extracted from 44, which comprised 34 pancreatic cancer patients and 10 patients with benign pancreatic diseases. Cytology results were malignant in 23 cases, benign in 9, and atypical or abnormal in 12. The sensitivity, specificity, and accuracy of cytology for diagnosis of pancreatic cancer were 67.65%, 100%, and 75%, respectively. When an S100A6 expression >0.005248 was defined as positive for malignancy, the sensitivity, specificity, and accuracy of S100A6 expression of EUS-FNA for diagnosis of pancreatic cancer were 88.24%, 90.00%, and 88.64%, respectively. CONCLUSIONS: Quantification of S100A6 expression in EUS-FNA samples had a high sensitivity and specificity for the diagnosis of PDA.

Diagnostic value of S100A6 mRNA expression level in endoscopic ultrasonography guided fine needle aspiration specimens in pancreatic cancer / 中华消化杂志

ObjectiveTo investigate the feasibitity of detecting S100A6 expression at mRNA level in endoscopic ultrasonography guided fine needle aspiration (EUS-FNA) pancreatic ductal adenocarcinoma (PDA) specimens and its diagnostic value in PDA.MethodsA total of 18 PDA specimens and 22 normal pancreatic specimens were collected. RNA was extracted for reverse transcription.The expression of S100A6 gene was examined by real-time polymerase chain reaction.The cut-off value of S100A6 expression at mRNA level in PDA diagnosis was established through receiver operating characteristic (ROC) analysis. 28 patients with pancreatic head masses were selected for EUS-FNA examination,and the value of S100A6 mRNA expression level in PDA diagnosis was prospectively evaluated. The expression of S100A6 protein in PDA tissue was determined by immunohistochemistry staining.ResultsS100A6 mRNA expression in EUS-FNA and surgical PDA specimens (0.05023±0.10120,0.02083 ± 0.02848) was significantly higher than that of normal pancreatic tissues (0.00164±0.00202),both P＜0.01.The expression of S100A6 in 22 EUS-FNA PDA specimens was significantly higher than that of 6 pancreatic benign disease biopsy specimens (0.00193 ± 0.00278,P =0.0009). There was no significant difference in S100A6 expression between 6 pancreatic benign disease biopsy specimens and normal surgical pancreatic samples (P=0.6143).When S100A6 mRNA expression in EUS-FNA specimens over 0.00525 was taken as positive diagnostic value,the sensitivity,specificity and accuracy in prospective pancreatic cancer diagnosis were 90.01％,100 ％ and 92.85 ％,respectively.ConclusionThe high expression of S100A6 mRNA in EUS-FNA specimens of PDA has good preoperative diagnostic value.