Background: Irritable bowel syndrome (IBS) is a common gastrointestinal disorder without obvious structural abnormalities or consistent associated biomarkers, making its diagnosis difficult. In the present study, we used a urine-based metabolomics approach to identify IBS biomarkers. Methods: We used an ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) on urine samples from patients suffering from IBS and healthy controls. Data were coupled for multivariate statistical analysis methods. Results: We selected 30 differential metabolites associated with IBS and found steroid hormone biosynthesis and histidine metabolism alterations in patients with IBS that may be involved in the pathogenesis of the disease. In addition, we identified a panel of five metabolite markers composed of cortisone, citric acid, tiglylcarnitine, N6,-N6,-N6-trimethyl-L-lysine and L-histidine that could be used to discriminate between patients and healthy controls and may be appropriate as IBS diagnosis biomarkers. Conclusion: Our findings indicate that metabolomics combined with pattern recognition can be useful to identify disease diagnostic IBS markers.
Background: The aim of the current systematic review and network meta-analysis (NMA) was to assess the diagnostic characteristics of the gastroesophageal reflux disease questionnaire (GERDQ), proton-pump inhibitor (PPI) test, baseline impedance, mucosal impedance, dilated intercellular spaces (DIS), salivary pepsin, esophageal pH/pH impedance monitoring and endoscopy for gastroesophageal reflux disease (GERD). Methods: We searched PubMed and the Cochrane Controlled Trial Register database (from inception to 10 April 2018) for studies assessing the diagnostic characteristics of the GERDQ, PPI test, baseline impedance, mucosal impedance, DIS, or salivary pepsin and esophageal pH/pH impedance monitoring/endoscopy in patients with GERD. Direct pairwise comparison and a NMA using Bayesian methods under random effects were performed. We also assessed the ranking probability. Results: A total of 40 studies were identified. The NMA found no significant difference among the baseline impedance, mucosal impedance, and esophageal pH/pH impedance monitoring and endoscopy in terms of both sensitivity and specificity. It was also demonstrated that the salivary pepsin detected by the Peptest device had comparable specificity to esophageal pH/pH impedance monitoring and endoscopy. Results of ranking probability indicated that esophageal pH/pH impedance monitoring and endoscopy had highest sensitivity and specificity, followed by mucosal impedance and baseline impedance, whereas GERDQ had the lowest sensitivity and PPI test had the lowest specificity. Conclusions: In a systematic review and NMA of studies of patients with GERD, we found that baseline impedance and mucosal impedance have relatively high diagnostic performance, similar to esophageal pH/pH impedance monitoring and endoscopy.
Liver cancer is one of the most common malignant tumors and prognosis remains poor. It has been increasingly recognized that liver cancer stem cells (LCSCs) are responsible for the carcinogenesis, recurrence, metastasis and chemoresistance of hepatocellular carcinoma (HCC). Targeting LCSCs is promising to be a new direction for the treatment of HCC. Herein, we summarize the potentially therapeutic targets in LCSCs at the level of genes, molecules and cells, such as knockout of oncogenes or oncoproteins, restoring the silent tumor suppressor genes, inhibition of the transcription factors and regulation of noncoding RNAs (including microRNAs and long noncoding RNAs) in LCSCs at the genetic level; inhibition of markers and blockade of the key signaling pathways of LCSCs at the molecular level; and inhibiting autophagy and application of oncolytic adenoviruses in LCSCs at the cellular level. Moreover, we analyze the potential targets in LCSCs to eliminate chemoresistance of HCC. Thereinto, the suppression of autophagy and Nanog by chloroquine and shRNA respectively may be the most promising targeting approaches. These targets may provide novel therapeutic strategies for the treatment of HCC by targeting LCSCs.
Background: An overview of systematic reviews (SRs) and a network meta-analysis (NMA) were conducted to evaluate the comparative effectiveness of acupuncture and related therapies used either alone, or as an add-on to other irritable bowel syndrome (IBS) treatments. Methods: A total of eight international and Chinese databases were searched for SRs of randomized controlled trials (RCTs). The methodological quality of SRs was appraised using the AMSTAR instrument. From the included SRs, data from RCTs were extracted for the random-effect pairwise meta-analyses. An NMA was used to evaluate the comparative effectiveness of different treatment options. The risk of bias among included RCTs was assessed using the Cochrane risk of bias tool. Results: From 15 SRs of mediocre quality, 27 eligible RCTs (n = 2141) were included but none performed proper blinding. Results from pairwise meta-analysis showed that both needle acupuncture and electroacupuncture were superior in improving global IBS symptoms when compared with pinaverium bromide. NMA results showed needle acupuncture plus Geshanxiaoyao formula had the highest probability of being the best option for improving global IBS symptoms among 14 included treatment options, but a slight inconsistency exists. Conclusion: The risk of bias and NMA inconsistency among included trials limited the trustworthiness of the conclusion. Patients who did not respond well to first-line conventional therapies or antidepressants may consider acupuncture as an alternative. Future trials should investigate the potential of (1) acupuncture as an add-on to antidepressants and (2) the combined effect of Chinese herbs and acupuncture, which is the norm of routine Chinese medicine practice.
Background: The clinical relevance and biological role of tissular AOC4P in gastric cancer (GC) remains to be clarified. Methods: The association between AOC4P expression and clinicopathological characteristics was investigated. In vitro, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation, wound healing and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays were performed to explore the biological effects of AOC4P on GC cell proliferation, migration, invasion, and apoptosis in MGC-803 and BGC-823 cell lines. In vivo, animal experiments were conducted to confirm the in vitro findings. Quantitative real-time polymerase chain reaction, western blotting, and immunofluorescence were used to investigate the potential mechanisms. Results: Expression levels of AOC4P were significantly higher in tumor tissues than in noncancerous tissues, and patients with high levels of AOC4P had poor overall and disease-free survival. AOC4P expression was correlated with lymphovascular invasion. In vitro, knockdown of AOC4P inhibited tumor cell proliferation, migration, and invasion, and promoted apoptosis of MGC-803 and BGC-823 cells. In vivo, BGC-823 cells transfected with AOC4P siRNA formed smaller and lighter tumors than BGC-823 cells transfected with negative control siRNA in severe combined immunodeficiency mice. Additionally, the si-AOC4P group had less proliferating cells and more apoptotic cells in tumor xenografts compared with the negative control. Mechanistically, knockdown of AOC4P decreased the expression of vimentin and MMP9, while increasing the expression of E-cadherin. Immunofluorescence confirmed the relationship between AOC4P expression and E-cadherin, vimentin, and MMP9 levels in clinical GC specimens. Conclusions:AOC4P promotes tumorigenesis and progression partly through epithelial-mesenchymal transition in GC. Additionally, AOC4P may serve as a prognostic biomarker for clinical decision making.
Gastric cancer remains one of the leading cancers in the world with a high mortality, particularly in East Asia. Helicobacter pylori infection accounts for the majority of the noncardia gastric cancers by triggering gastric inflammation and subsequent neoplastic progression. Eradication of H. pylori can reduce, but not totally eliminate, subsequent risk of developing gastric cancer. Proton-pump inhibitors (PPIs) are one of the most widely prescribed medications worldwide. With their profound gastric-acid suppression, there are concerns about a possible carcinogenic role in gastric cancer, due to induced hypergastrinemia, gastric atrophy and bacterial overgrowth in the stomach. While randomized clinical trials to establish causality between long-term PPI use and gastric cancer are lacking, current evidence based on observational studies suggests PPIs are associated with an increased gastric cancer risk. However, opinions on causality remain divergent due to unmeasured and possible residual confounding in various studies. Our recent study has showed that even after H. pylori eradication, long-term PPI use is still associated with an increased risk of gastric cancer by more than twofold. Hence, long-term PPIs should be used judiciously after considering individual's risk-benefit profile, particularly among those with history of H. pylori infection. Further well-designed prospective studies are warranted to confirm the potential role of PPIs in gastric cancer according to baseline gastric histology and its interaction with other chemopreventive agents like aspirin, statins and metformin.
Background: In our previous dose-escalation study, we uncovered the maximum tolerated dose (MTD) of weekly irinotecan was escalated to 80 mg/m(2) and 65 mg/m(2) for UDP glucuronosyltransferase family 1 member A1 (UGT1A1) *1*1 and *1*28 rectal cancer patients in neoadjuvant chemoradiotherapy (nCRT). This is an expansion study for *1*1 patients. Methods: Patients with clinical stage T3-4, N0-2 rectal cancer eligible for preoperative chemoradiotherapy were screened for the UGT1A1*28 genotype. A total of 52 patients with the *1*1 genotype were enrolled. Whole-pelvic intensity-modulated radiation therapy was given in 50 Gy/25 fractions. Concurrently, irinotecan of 80 mg/m(2) and capecitabine of 625 mg/m(2) twice daily from Monday to Friday were administered weekly. Primary endpoint was toxicities; secondary endpoints included pathological complete response (pCR), tumour-regression grading, treatment compliance, overall survival, local recurrence and disease-free survival. Results: All patients completed capecitabine-based radiotherapy as scheduled, and 42 (81%) patients completed more than three cycles of weekly irinotecan. Overall, grade 3/4 toxicities were observed in 20 cases, including 11 leucopenia, 10 neutropenia and 12 diarrhoea. Forty-three patients (83%) underwent a radical surgery, and 12 were evaluated as pCR. Another four patients accepted a watch-and-wait strategy because of clinical complete response (CCR). Conclusions: Our data demonstrated manageable toxicities and an encouraging CCR rate for UGT1A1 *1*1 genotype in an enhanced neoadjuvant therapy. A phase III trial is ongoing to evaluate the value of irinotecan in neoadjuvant therapy (CinClare) [ClinicalTrials.gov identifier: NCT02605265].
Background: The prevalence of diverticulosis has increased in our aging population, but the risk factors for diverticulosis are not fully understood. The role of hypertension in the risk of diverticulosis remains uncertain. This study investigated whether hypertension is associated with asymptomatic colorectal diverticulosis. Methods: This study enrolled asymptomatic patients who received a colonoscopy as part of a health check. Hypertension was defined by actual measured blood pressure. Logistic regression models were used to examine the relationship between hypertension and diverticulosis. In addition, we established three logistic regression models for covariate adjustment, and further stratified patients with hypertension into three subgroups based on their type of hypertension. Results: The study group consisted of 2748 participants, including 141 participants with diverticulosis and 2607 participants without diverticulosis. After adjustments for potential covariates, the odds ratio (OR) for having diverticulosis was 1.83 (95% confidence interval, 1.21-2.75, p = 0.004) in the hypertension group compared with the group without hypertension. In subgroup analyses, hypertension without antihypertensive medication use, and hypertension despite the use of antihypertensive medication were also significantly associated with the occurrence of asymptomatic diverticulosis (OR = 1.73, p = 0.028; OR = 2.07, p = 0.013, respectively). Current normal blood pressure under antihypertensive drug therapy was not associated with diverticulosis (OR = 1.74, p = 0.092). Conclusions: Our findings suggest a positive association between hypertension and diverticulosis. Participants with poorly controlled blood pressure were found to have a higher risk of asymptomatic diverticulosis. Our study presents epidemiologic evidence for future prevention strategies against diverticulosis.
Background: Endoscopic resection has been increasingly adopted for neoplasms in the major duodenal papilla. Previous studies have reached varying conclusions on whether prophylactic pancreatic stent (PS) placement is an effective measure against post-procedure complications. We aimed to investigate whether PS could reduce the incidence of post-procedure complications. Methods: The PubMed, Cochrane Library, and EMBASE databases were systematically searched from the inception dates to 25 December 2018 to identify all randomized controlled trials (RCTs) and retrospective cohort studies (RCSs) comparing prophylactic PS and no PS against post-procedure complications. The main outcomes measurements were post-procedure pancreatitis, bleeding, perforation and late papillary stenosis. Results: 23 RCSs (1001 subjects) and 2 RCTs met the inclusion criteria. Meta-analysis of the RCSs showed that prophylactic PS decreased the odds of post-procedure pancreatitis (OR, 0.71; 95% CI, 0.36-1.40; p = 0.325) as well as late papillary stenosis (OR, 0.35; 95% CI, 0.07-1.75; p = 0.200; I-2 =0%) and increased the odds of bleeding (OR, 1.32; 95% CI, 0.50-3.46; p = 0.572; I-2 = 0%) and perforation (OR, 2.25; 95% CI, 0.33-15.50; p = 0.412; I-2 = 0%) but not significantly. Sensitivity analysis illustrated prophylactic PS significantly decreased the risk of post-procedure pancreatitis (OR, 0.44; 95% CI, 0.24-0.80; p = 0.007). Conclusions: PS placement was prophylactic against post-procedure complications although not significantly. Sensitivity analysis suggests the significant effect of prophylactic PS against post-procedure pancreatitis. More RCTs are required to validate the statistical significance of our results and potentially relevant characteristics improving the prophylactic efficacy of stents.
Background: The N-myc downstream-regulated gene (NDRG) family, NDRG1-4, has been involved in a wide spectrum of biological functions in multiple cancers. However, their prognostic values remain sparse in gastric cancer (GC). Therefore, it is crucial to systematically investigate the prognostic values of the NDRG family in GC. Methods: The prognostic values of the NDRG family were evaluated by Kaplan-Meier Plotter and SurvExpress. The mRNA of the NDRG family was investigated in The Cancer Genome Atlas (TCGA). Transcription factors (TFs) and miRNAs associated with the NDRG family were predicted by NetworkAnalysis. The prognostic values of DNA methylation levels were analyzed by MethSurv. The correlation between immune cells and the NDRG family was evaluated by the Tumor Immune Estimation Resource (TIMER) database. Results: High levels of mRNA expression of NDRG2 and NDRG3 were associated with a favorable prognosis in all GCs. In HER2(-) GC, NDRG1 was significantly associated with a poor prognosis of GC [hazard ratio (HR) = 1.65, 95% confidence interval (CI) = 1.16-2.33, p = 0.0046]. In HER2(+) GC, NDRG4 showed a poor prognosis (HR = 1.4, 95% CI: 1.06-1.85, p = 0.017). NDRG4 was an independent prognostic factor in recurrence-free survival by TCGA cohort. The low-risk NDRG-signature group displayed a significantly favorable survival outcome than the high-risk group (HR = 1.76, 95% CI: 1.2-2.59, p = 0.00385). The phosphorylated protein NDRG1 (NDRG1_pT346) displayed a favorable overall survival and was significantly associated with HER2 and phosphorylated HER2. Epidermis development was the top biological process (BP) for coexpressed genes associated with NDRG1 and NDRG4, while mitotic nuclear division and mitotic cell processes were the top BPs for NDRG2 and NDRG3, respectively. Overall, 6 CpGs of NDRG1, 4 CpGs of NDRG2, 3 CpGs of NDRG3 and 24 CpGs of NDRG4 were associated with significant prognosis. CD4(+) T-cells showed the highest correlation with NDRG4 (correlation = 0.341, p = 2.14e(-11)). Furthermore, BCL6 in follicular helper T-cells (Tfh) cells showed the highest association with NDRG4 (correlation = 0.438, p = 00e(+)00). Conclusions: This study analyzed the multilevel prognostic values and biological roles of the NDRG family in GC.
Background: There is no conclusion about the most important contributor to the upswing of locally advanced colorectal cancer (LACRC) survival. Methods: Data from the Surveillance, Epidemiology, and End Results (SEER) database was extracted to identify colorectal adenocarcinoma cancer patients at stage II and III diagnosed in the two periods 1989-1990 and 2009-2010. The statistical methods included Pearson's chi-squared test, log-rank test, Cox regression model and propensity score matching. Results: The Cox regression model showed that hazard ratio (HR) of non-surgery dropped from 11.529 to 3.469 in right colon cancer (RCC), 5.214 to 2.652 in left colon cancer (LCC) and 3.275 to 3.269 in rectal cancer (RC) from 1989-1990 to 2009-2010. The 95% confidence intervals (CIs) for surgical resection in 2009-2010 were narrower than those in 1989-1990. HR became greater in LACRC without chemotherapy (from 1.337 to 1.779 in RCC, 1.269 to 2.017 in LCC, 1.317 to 1.811 in RC). There was no overlapping about the 95% CI of chemotherapy between the two groups. The progress of surgery was not linked to the improvement of overall survival (OS) of RCC (p = 0.303) and RC (p = 0.660). Chemotherapy had a significant association with OS of all colorectal cancer (CRC) patients (p = 0.017 in RCC; p = 0.006 in LCC; p = 0.001 in RC). Conclusions: Advancements in chemotherapy regimen were the main contributor to the upswing of CRC survival. The improvements in surgery had a limited effect on improvements in CRC survival.
Background: In patients with a large, unresectable hepatocellular carcinoma (HCC), the primary recommendation is for transarterial chemoembolization (TACE) but used alone TACE is not typically curative. Combinations of TACE followed in a delayed fashion by single-applicator thermal ablation have also been suboptimal. As an alternative, we investigated the combination of TACE followed within 1-3 days by multi-antenna microwave ablation (MWA) in patients with a large HCC, to determine the feasibility, safety, local control, and short-term survival rates of this approach. Methods: We retrospectively studied 43 patients with a large HCC (mean diameter, 8.8 cm; SD, 2.8 cm) treated between July 2015 and July 2018, who underwent TACE followed within 3 days by multi-antenna simultaneous MWA. We measured the liver and renal function before and after treatment, recorded complications, used three-dimensional software and imaging to calculate tumor necrosis rates at 1 month after therapy, and calculated overall survival (OS) and progression-free survival (PFS) using the Kaplan-Meier method. Results: Mean follow up was 12.2 (range, 3.5-35.6) months. All patients completed the treatment protocol. At 1 month after combined therapy, tumor necrosis was complete in 16 (37.2%), nearly complete in 19 (44.2%), and partial in 8 (18.6%) patients. The 1- and 2-year OS rates were 64.0% and 46.8%, respectively, with a median OS of 23.0 months; and the 1- and 2-year PFS rates were 19.9% and 4.4%, respectively, with a median PFS of 4.2 months. A transient change in liver function occurred 3 days after MWA but resolved within 1 month. Only two patients had major complications, which were treatable and resolved. Conclusion: Multi-antenna MWA-oriented combined therapy is feasible and well tolerated, and it results in satisfactory initial local control and short-term survival in some but not all patients with a large HCC.
Background: Although adjuvant chemotherapy is recommended for patients with stage II colon cancer characterized by poor prognostic features, its pros and cons remain a controversial issue. We aim to evaluate the real effectiveness of chemotherapy on stage II colon cancer as well as select suitable patients. Methods: Patients during 1988-2013 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. The competing risk regression model and propensity score matching method were used to evaluate colon-cancer-specific death (CCSD) and non-CCSD. Also, a competing-risk nomogram was constructed to identify risk of patients. Risk score (RS) was calculated according to nomogram. Results: A total of 58,133 patients were included, 25.66% received chemotherapy, and 74.34% were without chemotherapy. In total, 19.95% and 25.78% of patients died of CCSD and non-CCSD, respectively. Univariate and multivariate analyses showed that receiving chemotherapy appears to be associated with more CCSD and less non-CCSD (HR 1.23, 95% CI 1.18-1.28; HR 0.45, 95% CI 0.43-0.47, respectively), even after adjustment for covariates and propensity score weighting. A competing-risk nomogram was established; the model was relatively good with a C-index of 0.661. Based on the RS, risk stage could only predict prognosis but failed to predict the benefit from chemotherapy. Conclusions: The value of chemotherapy is much less than we thought. It is time to de-escalate chemotherapy for stage II colon cancer. CCSD, rather than overall survival, should be considered as an appropriate primary end point for future trials in stage II colon cancer.
Background: After achieving a clinical complete response through neoadjuvant chemoradiotherapy, a nonoperative management approach for rectal cancer patients known as Wait and Watch (W&W) has gained increasing attention. However, the W&W strategy has been related to higher local recurrence and ambiguous long-term survival. This meta-analysis compared key prognosis indicators between W&W and surgical treatment in an effort to clarify some long-standing points of confusion. Methods: Pubmed, Web of Science, EMbase, Cochrane Library were searched for relevant researches comparing W&W with surgery treatment, with a time criteria set from 1 January 2002 to 4 July 2019. Endpoints were 2-year local regrowth/recurrence, 2-year distant metastasis (plus local regrowth/recurrence), 3- and 5-year disease-free survival (DFS), and overall survival (OS). Results: In total, nine studies with 801 patients were enrolled, of which 348 were managed by W&W and 453 by surgery. Surgery patients were further divided into a pathological complete response (pCR) group (all included patients achieved pCR) and a surgery group (consisting of both pCR and non-pCR patients without deliberate screening). Compared with the surgery group, W&W patients have higher 3- and 5-year OS, and are not inferior on 2-year local regrowth (LR), 2-year distant metastasis (DM)/DM+LR, and 3- and 5-year DFS. On the other hand, compared with the pCR group, the W&W group is inferior on 2-year LR, 3- and 5-year DFS, and 5-year OS, and not inferior on 2-year DM/DM+LR and 3-year OS. Conclusions: In contrast with patients undergoing surgical treatment, the W&W group has higher 3- and 5-year OS, and is not inferior on other major prognostic indicators, which, however, is based on the fact that the tumor stage in the W&W group is generally earlier. Versus surgically treated patients who acquired pCR, W&W group is inferior on all major prognostic indicators except 2-year DM/DM+LR and 3-year OS. Additionally, by comparison of cCR definitions across different studies, we conclude that implementation of the strictest cCR criteria is critical for W&W patients to acquire maximum prognostic benefit.
Background: Physicians and medical students in the world do not have high awareness of fecal microbiota transplantation (FMT). This study aimed to explore the recognition and attitude of postgraduate medical students towards FMT and to create awareness for it. Methods: A self-administered questionnaire was distributed to first-year Chinese postgraduate medical students across six medical universities. Basic descriptive statistical analyses were performed. Results: A total of 1828 eligible questionnaires were included into analysis. 47.76% of students did not know FMT prior to this survey. Respondents with a high-level recognition of FMT were more willing to donate feces or receive FMT therapy than those with a low-level recognition (80.26% vs. 69.62%, p = 0.000 and 56.80% vs. 41.45%, p = 0.000). The respondents from a leading institution of FMT in China showed better awareness compared with others, and 42.26% of them knew about FMT from medical lectures. The main reasons for respondents not supporting FMT were: limited reported clinical evidence (67.94%), raw technology (42.56%), and lack of analysis of patient willingness or cost-effectiveness (36.71%). However, the life-saving value (84.41%), the automatic purification system (38.68%), low expenses (36.00%), and convenient delivering ways (35.67%) were the major considerations for supporting FMT. Conclusions: This study revealed the low recognition level of postgraduate medical students about FMT. Therefore, medical education should not neglect the knowledge of FMT. Studies of FMT and standardized FMT should be carried out to promote its development.