Efficacy of keverprazan for duodenal ulcer: A phase II randomized, double-blind, parallel-controlled trial.

BACKGROUND AND AIM: Considering the limitation of varying acid suppression of proton pump inhibitors, this study was aimed to assess the efficacy, safety, and dose-effect relationship of keverprazan, a novel potassium-competitive acid blocker, in the treatment of duodenal ulcer (DU) compared with lansoprazole. METHODS: A randomized, double-blind, double-dummy, multicenter, low-dose, high-dose, and positive-drug parallel-controlled study was conducted to verify the non-inferiority of keverprazan (20 or 30 mg) to lansoprazole of 30 mg once daily for 4 to 6 weeks and dose-effect relationship of keverprazan in the treatment of patients with active DU confirmed by endoscopy. RESULTS: Of the 180 subjects randomized, including 55 cases in the keverprazan_20 mg group, 61 cases in the keverprazan_30 mg group, and 64 cases in the lansoprazole_30 mg group, 168 subjects (93.33%) completed the study. The proportions of healed DU subjects in the keverprazan_20 mg, keverprazan_30 mg, and lansoprazole_30 mg groups were respectively 87.27%, 90.16%, and 79.69% at week 4 (P = 0.4595) and were respectively 96.36%, 98.36%, and 92.19% at week 6 (P = 0.2577). The incidence of adverse events in the keverprazan_20 mg group was lower than that in the lansoprazole_30 mg (P = 0.0285) and keverprazan_30 mg groups (P = 0.0398). CONCLUSIONS: Keverprazan was effective and non-inferior to lansoprazole in healing DU. Based on the comparable efficacy and safety data, keverprazan of 20 mg once daily is recommended for the follow-up study of acid-related disorders. (Trial registration number: ChiCTR2100043455.).

Imbalance of tumor necrosis factor-α, interleukin-8 and interleukin-10 production evokes barrier dysfunction, severe abdominal symptoms and psychological disorders in patients with irritable bowel syndrome-associated diarrhea.

The present study aimed to explore the correlation between cytokine expression of tumor necrosis factor α (TNF­α), interleukin (IL)­8 and IL­10 with occludin production, abdominal symptoms and psychological factors in patients with irritable bowel syndrome­associated diarrhea (IBS­D). A total of 42 IBS­D patients and 20 healthy controls were included, which were recruited from QiLu Hospital in China. ELISA and immunohistochemical analysis were performed for evaluating the cytokines (TNF­α, IL­8 and IL­10) and occludin protein levels in the peripheral blood mononuclear cells (PBMCs) of all subjects. In addition, the abdominal symptoms and psychological status were assessed in IBS­D patients. Levels of TNF­α and IL­8 in the PBMCs of patients with IBS­D were significantly higher than those in the controls (P<0.001 and P=0.007, respectively), while IL­10 levels were significantly reduced in patients with IBS­D (P=0.047). Occludin production was significantly reduced in patients with IBS­D as compared with that in the controls (P<0.001). In patients with IBS­D, levels of TNF­α and IL­8 were negatively correlated with occludin levels (r=­0.34, P=0.028; r=­0.52, P<0.001, respectively). IL­10 showed a negative correlation with occludin production (r=0.05, P=0.748). Furthermore, TNF­α, IL­8 and IL­10 levels were significantly correlated with symptoms scores (r=0.74, P<0.001; r=0.55, P<0.001; r=­0.80, P<0.001, respectively) in patients with IBS­D. Within the IBS­D group, TNF­α expression was significantly increased in patients with a self­rating depression scale (SDS) score ≥50 (P=0.004) as compared with that in patients with an SDS score <50. Furthermore, IL­8 was significantly increased in IBS­D patients with a self­rating anxiety scale (SAS) or SDS score ≥50 (P=0.016, P=0.008, respectively) as compared with that in patients scoring <50. In conclusion, the results of the present study suggested that in IBS­D, an imbalance of cytokine production evoked colonic epithelial barrier dysfunction, abdominal symptoms and psychological disorders.

Functional dosimetric metrics for predicting radiation-induced lung injury in non-small cell lung cancer patients treated with chemoradiotherapy.

BACKGROUND: Radiation-induced lung injury (RILI) is an important dose-limiting toxicity during thoracic radiotherapy. The purpose of this study is to investigate single photon emission computed tomography (SPECT) perfusion-weighted functional dose-volume histogram (FDVH) for predicting RILI in non-small cell lung cancer (NSCLC) patients treated with definitive chemoradiotherapy. METHODS: Fifty-seven locally advanced NSCLC patients receiving chemoradiotherapy were enrolled prospectively. Patients had treatment scans and dose calculations to provide a standard dose-volume histogram (DVH). Fusion of SPECT and computed tomography scans provided perfusion-weighted FDVH and associated functional dosimetric parameters (relative volumes of functional lung receiving more than a threshold dose of 5 - 60 Gy at increments of 5 Gy [FV5 - FV60]). The predictive abilities of FDVH and DVH were calculated and compared based on the area under receiver operating characteristic (ROC) curve (AUC). RESULTS: The accumulative incidence of ≥ 2 grade RILI was 19.3% with a median follow-up of 12 months. Univariate analysis showed that the functional (FV5 - FV60) and standard (V5 - V40) parameters were associated with RILI (all value of p < 0.05). Close correlations between a variety of functional and standard parameters were found. By ROC curve analysis, functional metrics (AUCs were 0.784 - 0.869) provided similarly (p value 0.233 - 1.000) predictive outcome to standard metrics (AUCs were 0.695 - 0.902) in lower - median dose level parameters (FV5 - FV40). However, FDVH seemed to add some predictive value in higher dose level, the best statistical significance for comparing FV60 with V60 was 0.693 vs. 0.511 (p = 0.055). CONCLUSIONS: Functional metrics are identified as reliable predictors for RILI, however, this observation still needs to be further verified using a larger sample size.

Microalterations of esophagus in patients with non-erosive reflux disease: in-vivo diagnosis by confocal laser endomicroscopy and its relationship with gastroesophageal reflux.

OBJECTIVES: Objectively diagnosing non-erosive reflux disease (NERD) is still a challenge. We aimed to evaluate the use of in-vivo confocal laser endomicroscopy (CLE) to examine the microalterations of the esophagus in patients with NERD and its relationship with reflux episodes monitored by multiple intraluminal impedance-pH (MII-pH). METHODS: Patients with gastroesophageal reflux symptoms completed reflux disease questionnaires. NERD was determined by negative gastroscopy. Patients without reflux symptoms were recruited as controls. Pilot clinical study was followed by prospective controlled blinded study. All subjects were examined by white-light mode of the endoscopy followed by the standard CLE mode and then MII-pH monitoring. The microalterations seen on CLE images and the correlation between CLE features and reflux episodes were evaluated, the correlation between CLE and transmission electron microscope (TEM) data was also analyzed. RESULTS: On CLE images, NERD patients had more intrapapillary capillary loops (IPCLs) per image than did controls (8.29 ± 3.52 vs. 5.69 ± 2.31, P=0.010), as well as the diameter of IPCLs (19.48 ± 3.13 vs. 15.87 ± 2.21 µm, P=0.041) and intercellular spaces of squamous cells (3.40 ± 0.82 vs. 1.90 ± 0.53 µm, P=0.042). The receiver operating characteristic analysis indicated that IPCLs number (optimal cutoff >6 per image, area under the curve (AUC) 0.722, 95% confidence interval (CI) 0.592-0.853, sensitivity 67.7%, specificity 71.6%), IPCLs diameter (optimal cutoff >17.2 µm, AUC 0.847, 95% CI 0.747-0.947, sensitivity 81%, specificity 76%), and the intercellular spaces of squamous cells (optimal cutoff >2.40 µm, AUC 0.935, 95% CI 0.875-0.995, sensitivity 85.7%, specificity 90.5%) diagnosed NERD with reasonable accuracy. Combined features of dilatation of intercellular space plus increased IPCLs provided 100% specificity in the diagnosis of NERD patients. The intercellular spaces of squamous cells observed on CLE were highly related to that on TEM findings (r=0.75, P<0.001). Multivariate progressive regression analysis showed that acidic reflux, especially in the supine position, was related to the increased number and dilation of IPCLs in the squamous epithelium (ß=0.063, t=2.895, P=0.038 and ß=0.156, t=1.023, P=0.04). CONCLUSIONS: CLE represents a useful and potentially significant improvement over standard endoscopy to examine the microalterations of the esophagus in vivo. Acidic reflux is responsible for the microalterations in the esophagus of patients with NERD.

Transient receptor potential ankyrin-1 participates in visceral hyperalgesia following experimental colitis.

Transient receptor potential ankyrin-1 (TRPA1) is an important receptor that contributes to inflammatory pain. However, previous studies were mainly concerned with its function in somatic hyperalgesia while few referred to visceral, especially colonic inflammatory hyperalgesia. The present study was aimed to investigate the role of TRPA1 in visceral hyperalgesia after trinitrobenzene sulfonic acid (TNBS)-induced colitis. Results indicate that TNBS induced a significant increase in visceral sensitivity to colonic distension and chemical irritation accompanied by up-regulation of TRPA1 in colonic afferent dorsal root ganglia (DRG). Intrathecal administration of TRPA1 antisense (AS) oligodeoxynucleotide (ODN) reduced the TRPA1 expression in DRG as well as suppressed the colitis-induced hyperalgesia to nociceptive colonic distension and intracolonic allyl isothiocyanate (AITC). Meanwhile the TRPA1 antisense ODN had no effect on transient receptor potential vanilloid-1 (TRPV1) expression, which was proposed to highly co-express with TRPA1, and no effect on the response to TRPV1 agonist, capsaicin. These data suggest an apparent role of TRPA1 in visceral hyperalgesia following colitis that might provide a novel therapeutic target for the relief of pain.