Methods for conducting international Delphi surveys to optimise global participation in core outcome set development: a case study in gastric cancer informed by a comprehensive literature review

Copyright © 2021, The Author(s) Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background: Core outcome sets (COS) should be relevant to key stakeholders and widely applicable and usable. Ideally, they are developed for international use to allow optimal data synthesis from trials. Electronic Delphi surveys are commonly used to facilitate global participation; however, this has limitations. It is common for these surveys to be conducted in a single language potentially excluding those not fluent in that tongue. The aim of this study is to summarise current approaches for optimising international participation in Delphi studies and make recommendations for future practice. Methods: A comprehensive literature review of current approaches to translating Delphi surveys for COS development was undertaken. A standardised methodology adapted from international guidance derived from 12 major sets of translation guidelines in the field of outcome reporting was developed. As a case study, this was applied to a COS project for surgical trials in gastric cancer to translate a Delphi survey into 7 target languages from regions active in gastric cancer research. Results: Three hundred thirty-two abstracts were screened and four studies addressing COS development in rheumatoid and osteoarthritis, vascular malformations and polypharmacy were eligible for inclusion. There was wide variation in methodological approaches to translation, including the number of forward translations, the inclusion of back translation, the employment of cognitive debriefing and how discrepancies and disagreements were handled. Important considerations were identified during the development of the gastric cancer survey including establishing translation groups, timelines, understanding financial implications, strategies to maximise recruitment and regulatory approvals. The methodological approach to translating the Delphi surveys was easily reproducible by local collaborators and resulted in an additional 637 participants to the 315 recruited to complete the source language survey. Ninety-nine per cent of patients and 97% of healthcare professionals from non-English-speaking regions used translated surveys. Conclusion: Consideration of the issues described will improve planning by other COS developers and can be used to widen international participation from both patients and healthcare professionals.This study is funded by the National Institute for Health Research (NIHR) Doctoral Research Fellowship Grant (DRF-2015-08-023). JMB is partially funded by the NIHR Bristol Biomedical Research Centre and the MRC ConDUCT-II Hub for Trials Methodology Research. PRW was funded by the MRC North West Hub for Trials Methodology Research (Grant ref: MR/K025635/01).info:eu-repo/semantics/publishedVersio

Norepinephrine Enhances Aerobic Glycolysis and May Act as a Predictive Factor for Immunotherapy in Gastric Cancer

Objective/Background and Aims. The gastrointestinal tract is rich in neurotransmitters, which play an essential role in the occurrence and development of gastrointestinal tumors. We aimed to explore the function of neurotransmitters in gastric cancer and identify a suitable target to treat gastric cancer patients in the future. Methods. Monoamine neurotransmitters were detected in gastric cancer tissue and paired normal tissue, and The Cancer Genome Atlas was used to identify differentially expressed norepinephrine-degrading and synthetic enzymes. Quantitative real-time PCR and the Seahorse assay were used to determine the effect of norepinephrine on gastric cancer cell glycolysis. MAOA expression in cancer tissues was analyzed by immunohistochemistry and was compared with the patient SUVmax value of PET-CT and other clinicopathological characteristics. Results. The norepinephrine levels were markedly high in gastric cancer tissue, while the norepinephrine-degrading enzymes MAOA and MAOB showed low expression. High norepinephrine levels were associated with activated glycolysis. The MAOA or MAOB expression levels in tumor tissue were closely correlated with the patient SUV max values of PET-CT and immunotherapy evaluation indices, such as PD-L1 and the microsatellite status. Conclusions. Norepinephrine shows relatively higher expression in gastric cancer tissue than in normal tissue, and its expression level is associated with the glycolysis levels in patients. The norepinephrine-degrading enzymes MAOA and MAOB have significant expression differences in cancer and normal tissue, and their missing or low expression may predict immune therapy outcomes for gastric cancer patients. High norepinephrine levels with metabolic abnormalities may be more suitable for metabolic targeted therapy or immunotherapy

Somatic mutation of DNAH genes implicated higher chemotherapy response rate in gastric adenocarcinoma patients

Abstract Background The dynein axonemal heavy chain (DNAH) family of genes encode the dynein axonemal heavy chain, which is involved in cell motility. Genomic variations of DNAH family members have been frequently reported in diverse kinds of malignant tumors. In this study, we analyzed the genomic database to evaluate the mutation status of DNAH genes in gastric adenocarcinoma and further identified the significance of mutant DNAH genes as effective molecular biomarkers for predicting chemotherapy response in gastric cancer patients. Methods We analyzed the clinical and genomic data of gastric cancer patients published in The Cancer Genome Atlas (TCGA) project. Data on chemotherapy response, overall survival (OS) and chemotherapy-free survival were retrieved. Then, we verified the results via targeted sequencing of gastric cancer patients with similar clinical characteristics but different chemotherapeutic outcomes. Results In total, 132 gastric adenocarcinoma patients undergoing chemotherapy treatment from TCGA were included in our study. Somatic mutations in all 13 members of the DNAH family of genes were associated with different chemotherapy responses. Compared with patients with wild-type DNAH genes (n = 59), a significantly higher proportion of those with mutations in DNAH genes (n = 73) (55.9% vs 80.8%) responded to chemotherapy (P = 0.002). Moreover, DNAH mutations were correlated with significantly better OS (P = 0.027), chemotherapy-free survival (P = 0.027), fluoropyrimidine-free survival (P = 0.048) and platinum-free survival (P = 0.014). DNAH mutation status was an independent risk factor for OS (P = 0.015), chemotherapy-free survival (P = 0.015) and platinum-free survival (P = 0.011). We identified somatic mutations in 27 (42.2%) of the 64 stage III gastric adenocarcinoma patients receiving fluoropyrimidine-based chemotherapy by targeted exon sequencing with strict screening conditions. In our own cohort, a significantly higher proportion of patients (n = 32) with DNAH mutations than patients with wild-type DNAH genes (n = 32) had a good prognosis (OS > 48 months) (70.4% vs 35.1%) (P = 0.005). Conclusions Dynein axonemal heavy chain gene mutations contribute positively to chemotherapy sensitivity in gastric cancer patients

hsa-miR-376c-3p Regulates Gastric Tumor Growth Both In Vitro and In Vivo

Background. In recent studies, aberrant expression of various microRNAs (miRNAs) is reported to be associated with gastric cancer metastasis. Method. Overexpression construct and inhibitor of hsa-miR-376c-3p were expressed in human gastric adenocarcinoma cell line SGC-7901. The expression level of tumor related genes was detected by qPCR, western blot, and immunostaining. Cell apoptosis was determined by flow cytometry. Xenograft of SGC-7901 cells was used to elucidate the function of hsa-miR-376c-3p in gastric tumor growth in vivo. Result. Expression of hsa-miR-376c-3p was detected in SGC-7901 cells. Downregulation of hsa-miR-376c-3p increased the expression level of BCL-2 and decreased the expression of smad4 and BAD. On the contrary, overexpression of hsa-miR-376c-3p increased the expression of BAD and smad4, while it led to the decreasing expression level of BCL-2. Overexpression of hsa-miR-376c-3p also promoted cell apoptosis in vitro and inhibited gastric tumor growth in vivo. Furthermore, the expression of BCL-2 was higher and expression of smad4 and BAD was lower in tumor tissue than the tissue adjacent to tumor from gastric cancer patients. Conclusion. This study demonstrated that hsa-miR-376c-3p plays an important role in the inhibition of gastric tumor growth and tumor related gene expression both in vitro and in vivo

Turning left or right? A comparative analysis in adenocarcinomas of the esophagogastric junction according to the seventh AJCC TNM classification for cancers of the esophagus and stomach: experience in a Chinese single institution

The seventh AJCC TNM classification defines rules for classifying adenocarcinomas of esophagogastric junction (AEG II and III) as a part of esophageal cancer. But there are still many controversies over the classification system. The study aims to evaluate and compare whether AEG should be classified as cancers of esophagus or stomach. A single-center cohort of patients with AEG or proximal third gastric adenocarcinoma underwent surgical resection with curative intent in Shanghai from November 2004 to July 2011. We compared the clinicopathologic features between AEG (n=291) and proximal third gastric adenocarcinoma (n=176) and analyzed overall survival probabilities of AEG using the latest seventh AJCC TNM classification for cancers. Patients with AEG not only show more advanced diseases, but also have a significantly worse 5-year survival rate than those with proximal third gastric adenocarcinoma (P=0.027). In 291 patients with AEG, the gastric T classification is monotone but indistinct except for pT2 versus pT3 (P=0.001) and pT4a versus pT4b (P=0.012). The esophageal T classification is neither monotone nor distinct. For the N classification, both schemes are monotone and distinct. The gastric scheme is indistinctive for stages IA versus IB (P=0.428), for IIA versus IIB (P=0.376), for IIB versus IIIA (P=0.086), for IIIA versus IIIB (P=0.087), and for IIIC versus IV (P=0.928). The esophageal scheme is indistinct only except for IIIB versus IIIC (P=0.002). The gastric scheme includes one heterogeneous stage group (stage IIIC, P<0.001), whereas all stage groups are homogeneous in the esophageal scheme. Although AEG shows different clinicopathological features and surgical outcomes of patients, the current seventh AJCC TNM classification which stages the AEG in the esophageal scheme does not demonstrate the advantages in the assessment of the patient prognosis. We propose a revised staging system to clarify the AEG with esophageal invasion

Should we still use prophylactic drain in gastrectomy for cancer? A systematic review and meta-analysis

Prophylactic drain in gastrectomy for cancer is still widely used, although some evidence has disputed this practice and spreading enhanced recovery protocol has been pushing towards surgical simplification. This study aimed at assessing the impact of drain placement on important clinical outcomes, evaluating the results of randomised controlled trials (RCTs), or cohort studies whenever information provided by the former was scarce. PubMed, PMC, Cochrane Library, CNKI and Wanfang databases were searched from January 1990 to February 2019, both for RCTs and cohort studies comparing use or avoidance of prophylactic drain in gastric cancer patients undergoing gastrectomy. All RCTs and cohort studies were rated according to Jadad score and Newcastle-Ottawa-Scale, respectively. Meta-analysis was separately performed on RCTs and cohort studies. The following clinical outcomes were considered: anastomotic leak, reoperation rate, additional drain procedure, length of stay, postoperative morbidity, postoperative mortality, readmission rate and drain related complications. Overall, 3 RCTs (330 patients) and 7 cohort studies (2897 patients) were included. Seven studies came from Eastern Countries. Meta-analysis on RCTs evidenced that drain avoidance halves overall morbidity (RR&nbsp;=&nbsp;0.47, 95%CI 0.26-0.86, p&nbsp;=&nbsp;0.014) and slightly reduces length of stay (SMD -0.24, 95%CI -0.51-0.03, p&nbsp;=&nbsp;0.083). Only one postoperative death occurred in the drain group. The other outcomes were either not reported or reported just by one RCT each. Meta-analysis on cohort studies, despite higher statistical power, did not highlight any significant difference. This meta-analysis showed that prophylactic drain avoidance can reduce morbidity and length of stay, while not significantly affecting other major surgical outcomes

Production of Aryl Oxygen-Containing Compounds by the Pyrolysis of Bagasse Alkali Lignin Catalyzed by LaM0.2Fe0.8O3 (M = Fe, Cu, Al, Ti)

A series of LaM0.2Fe0.8O3 (M = Fe, Cu, Al, Ti) samples synthesized by the sol-gel method were used to catalyze the pyrolysis of bagasse alkali lignin (BAL) to produce aryl oxygen-containing compounds. The effects of doping metal ions in the B-site of LaFeO3 were investigated by X-ray diffraction, scanning electron microscopy, Brunauer-Emmett-Teller, and X-ray photoelectron spectrometer. Furthermore, the catalytic pyrolysis performances of the perovskites were evaluated by thermogravimetric analysis and the fixed-bed microreactor, and the gaseous and liquid pyrolysis products were analyzed by GC and gas chromatography/mass spectrometry (GC/MS), respectively. The results indicated that the perovskites have a cubic crystal phase, porous structure, and large specific surface area. After doping Cu, Al, and Ti ions in the B-site of perovskites, the grain sizes were refined, the performance of catalyzing BAL pyrolysis was improved, and the yields of liquid pyrolysis products increased by 24.1-39.1%. The selectivities of CO2 and CO in gaseous products decreased by 5.8-16.3 and 26.0-34.8%, respectively, which resulted from the inhibition of decarboxylation and decarbonylation. The total selectivities of target products, i.e., aryl oxygen-containing compounds (including phenolics, guaiacols, syringols, and phenylates) obtained from BAL pyrolysis catalyzed using perovskites were all greater than 74 wt %, which was higher than that obtained from the pyrolysis of pure BAL (62 wt %) in the absence of catalyst. After 5 cycles of redox reaction, the perovskite still showed a well-maintained structural and catalytic stability

HUNK inhibits epithelial-mesenchymal transition of CRC via direct phosphorylation of GEF-H1 and activating RhoA/LIMK-1/CFL-1

Abstract Epithelial-mesenchymal transition (EMT) is associated with the invasive and metastatic phenotypes in colorectal cancer (CRC). However, the mechanisms underlying EMT in CRC are not completely understood. In this study, we find that HUNK inhibits EMT and metastasis of CRC cells via its substrate GEF-H1 in a kinase-dependent manner. Mechanistically, HUNK directly phosphorylates GEF-H1 at serine 645 (S645) site, which activates RhoA and consequently leads to a cascade of phosphorylation of LIMK-1/CFL-1, thereby stabilizing F-actin and inhibiting EMT. Clinically, the levels of both HUNK expression and phosphorylation S645 of GEH-H1 are not only downregulated in CRC tissues with metastasis compared with that without metastasis, but also positively correlated among these tissues. Our findings highlight the importance of HUNK kinase direct phosphorylation of GEF-H1 in regulation of EMT and metastasis of CRC