Systematic review of the perioperative classification, diagnosis, description and repair of hiatus hernias in randomized controlled trials.

Hiatus hernias (HH) are a common cause of symptoms and complications, with considerable variation in anatomy, function, diagnosis and treatment. We undertook the first systematic review to appraise how HH are diagnosed and classified in the literature, using randomized controlled trials as a sample. A search was performed in July 2021of the PubMed, EMBASE and Cochrane Central Register of Controlled Trials, and 2832 articles were identified and 64 were included. Median Jadad score was 2. Studies demonstrated considerable variation in diagnosis, classification and minimum surgical steps. The commonest classifications before surgery were axial length and the Type I-IV classification, variably assessed by endoscopy and contrast swallow. Intra-operatively, the commonest classification was type I-IV. A minority used more than one classification, or alternatives such as defect size and Hill classification. Most studies reported minimum steps, but these varied. Only a minority reported criteria for diagnosing recurrence. Using randomized controlled trials to appraise the highest quality evidence in the literature, we found considerable variation and inconsistency in the way HH are diagnosed and classified. This lack of a 'common language' has significant impacts for the generalizability of evidence, study synthesis and design. We propose the development of an internationally accepted classification. We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us.

Management of intraoperatively identified small bile duct stones in patients undergoing cholecystectomy.

INTRODUCTION: The management of CBDS (common bile duct stones) in patients with co-existing gallbladder stones has been debated. Guidelines recommend patients with CBDS identified on imaging should be offered duct clearance; however, this is based on low-quality evidence. This study aimed to investigate the natural history of small CBDS identified using IOUS (intraoperative ultrasound) in patients undergoing cholecystectomy. This may provide evidence to support a short-term expectant management approach in such patients. METHODS: Patients with CBDS diagnosed on IOUS during cholecystectomy were identified from a database of consecutive patients undergoing surgery. Patients with CBDS identified were divided into small stone (SS, ≤5 mm) and large stone (LS, >5 mm) groups. Intraoperative CBDS management, postoperative investigations, postoperative bile duct clearance, re-admissions, complications, length of stay (LOS) and follow-up are described. RESULTS: Fifty-nine of 427 patients had CBDS identified on IOUS. In the SS group (n=51), 46 patients underwent short-term expectant management rather than immediate/planned bile duct clearance. Following short-term expectant management, 41/46 patients (89.1%) did not require postoperative endoscopic retrograde cholangiopancreatography and at >3 year follow-up, none has since presented with residual CBDS. Median LOS was 0 days in the short-term expectant management group and 2 days in the immediate/planned bile duct clearance group, P=0.039. CONCLUSIONS: This study reports the natural history of small CBDS identified on IOUS in patients undergoing cholecystectomy. Such patients were safely treated with short-term expectant management associated with a reduced hospital LOS. This provides rationale for undertaking further research to establish this as a preferred management strategy.

The genome sequence of a riffle beetle, Elmis aenea (Müller, 1806).

We present a genome assembly from an individual female Elmis aenea (a riffle beetle; Arthropoda; Insecta; Coleoptera; Elmidae). The genome sequence is 516.5 megabases in span. Most of the assembly is scaffolded into 9 chromosomal pseudomolecules, including the X sex chromosome. The mitochondrial genome has also been assembled and is 18.06 kilobases in length.

G protein-coupled receptor 21 in macrophages: An in vitro study.

GPR21 is an orphan and constitutively active receptor belonging to the superfamily of G-Protein Coupled Receptors (GPCRs). GPR21 couples to the Gq family of G proteins and is expressed in macrophages. Studies of GPR21 knock-out mice indicated that GPR21 may be involved in promoting macrophage migration. The aim of this study was to evaluate the role of GPR21 in human macrophages, analyzing (i) its involvement in cell migration and cytokine release and (ii) the consequence of its pharmacological inhibition by using the inverse agonist GRA2. THP-1 cells were activated and differentiated into either M1 or M2 macrophages. GPR21 expression was evaluated at gene and protein level, the signalling pathway was investigated by an IP1 assay, and cytokine release by ELISA. Cell migration was detected by the Boyden chamber migration assay, performed on macrophages derived from both the THP-1 cell line and human peripheral blood monocytes. In addition, we compared the effect of the pharmacological inhibition of GPR21 with the effect of the treatment with a specific GPR21 siRNA to downregulate the receptor expression, thus confirming that GRA2 acts as an inverse agonist of GPR21. GRA2 does not affect cell viability at the tested concentrations, but significantly reduces the release of TNF-α and IL-1ß from M1 macrophages. The analysis of the migratory ability highlighted opposite effects of GRA2 on M1 and M2 macrophages since it decreased M1, while it promoted M2 cell migration. Therefore, the pharmacological inhibition of GPR21 could be of interest for pathological conditions characterized by low grade chronic inflammation.

Lasting Symptoms After Esophageal Resection (LASER): European Multicenter Cross-sectional Study.

OBJECTIVE: To identify the most prevalent symptoms and those with greatest impact upon health-related quality of life (HRQOL) among esophageal cancer survivors. BACKGROUND: Long-term symptom burden after esophagectomy, and associations with HRQOL, are poorly understood. PATIENTS AND METHODS: Between 2010 and 2016, patients from 20 European Centers who underwent esophageal cancer surgery, and were disease-free at least 1 year postoperatively were asked to complete LASER, EORTC-QLQ-C30, and QLQ-OG25 questionnaires. Specific symptom questionnaire items that were associated with poor HRQOL as identified by EORTC QLQ-C30 and QLQ-OG25 were identified by multivariable regression analysis and combined to form a tool. RESULTS: A total of 876 of 1081 invited patients responded to the questionnaire, giving a response rate of 81%. Of these, 66.9% stated in the last 6 months they had symptoms associated with their esophagectomy. Ongoing weight loss was reported by 10.4% of patients, and only 13.8% returned to work with the same activities.Three LASER symptoms were correlated with poor HRQOL on multivariable analysis; pain on scars on chest (odds ratio (OR) 1.27; 95% CI 0.97-1.65), low mood (OR 1.42; 95% CI 1.15-1.77) and reduced energy or activity tolerance (OR 1.37; 95% CI 1.18-1.59). The areas under the curves for the development and validation datasets were 0.81 ±â€Š0.02 and 0.82 ±â€Š0.09 respectively. CONCLUSION: Two-thirds of patients experience significant symptoms more than 1 year after surgery. The 3 key symptoms associated with poor HRQOL identified in this study should be further validated, and could be used in clinical practice to identify patients who require increased support.

GPR21 Inhibition Increases Glucose-Uptake in HepG2 Cells.

GPR21 is a constitutively active, orphan, G-protein-coupled receptor, with in vivo studies suggesting its involvement in the modulation of insulin sensitivity. However, its precise contribution is not fully understood. As the liver is both a major target of insulin signalling and critically involved in glucose metabolism, the aim of this study was to examine the role of GPR21 in the regulation of glucose uptake and production in human hepatocytes. In particular, HepG2 cells, which express GPR21, were adopted as cellular models. Compared with untreated cells, a significant increase in glucose uptake was measured in cells treated with siRNA to downregulate GPR21 expression or with the GPR21-inverse agonist, GRA2. Consistently, a significantly higher membrane translocation of GLUT-2 was measured under these conditions. These effects were accompanied by an increased ratio of phAKT(Ser473)/tot-AKT and phGSK-3ß(Ser9)/tot-GSK-3ß, thus indicating a marked activation of the insulin signalling pathway. Moreover, a significant reduction in ERK activation was observed with GPR21 inhibition. Collectively, these results indicate that GPR21 mediates the negative effects on glucose uptake by the liver cells. In addition, they suggest that the pharmacological inhibition of GPR21 could be a novel strategy to improve glucose homeostasis and counteract hepatic insulin resistance.

Secondary progressive multiple sclerosis: a systematic review of costs and health state utilities.

Objective: To identify evidence in the literature presenting the economic and humanistic (based on health state utility values [HSUVs]) burden of multiple sclerosis (MS) and report the incremental burden of secondary progressive MS (SPMS) compared with relapsing-remitting MS (RRMS).Methods: Electronic databases (Embase, MEDLINE, MEDLINE In-Process, Cochrane Library) and other relevant repositories were systematically searched from the date of inception until November 2019 for evidence on the economic burden of MS, or HSUVs in patients with MS. Data were extracted from studies investigating cost data or HSUVs for patients with SPMS compared with RRMS.Results: In total, 25 studies were identified that reported data on the economic and HSUV burden of SPMS versus RRMS: 18 studies reported cost data and nine presented HSUVs. Overall, costs associated with SPMS were consistently higher than those for RRMS. Major cost drivers appeared to shift following transition from RRMS to SPMS, with higher direct medical costs associated with RRMS than with SPMS, while the opposite was true for direct non-medical costs and indirect costs. In all studies presenting HSUVs specifically in patients with SPMS, the disease burden was greater (indicated by lower HSUV scores or a negative regression coefficient vs RRMS) for patients with SPMS than for those with RRMS. Fatigue and psychological stress (including depression) were identified as key drivers of this reduced health-related quality of life (HRQoL).Conclusions: Our findings indicate that SPMS is associated with higher costs and more substantial HRQoL decrements than RRMS. These results highlight the substantial unmet need for effective treatments that can slow disease progression in patients with SPMS, which, in turn, would reduce the rate of HRQoL deterioration and increasing healthcare costs.

A multicenter prospective audit to investigate the current management of patients undergoing anti-reflux surgery in the UK: Audit & Review of Anti-Reflux Operations & Workup.

BACKGROUND: There are a variety of surgical and endoscopic interventions available to treat gastroesophageal reflux disease. There is, however, no consensus on which approach is best.The aim of this national audit is to describe the current variation in the UK clinical practice in relation to anti-reflux surgery (ARS) and to report adherence to available clinical guidelines. METHODS: This national audit will be conducted at centers across the UK using the secure online web platform ALEA. The study will comprise two parts: a registration questionnaire and a prospective multicenter audit of ARS. All participating centers will be required to complete the registration questionnaire comprising details regarding pre-, peri-, and post-operative care pathways and whether or not these are standardized within each center. Following this, a 12-month multicenter prospective audit will be undertaken to capture data including patient demographics, predominant symptoms, preoperative investigations, surgery indication, intraoperative details, and postoperative outcomes within the first 90 days.Local teams will retain access to their own data to facilitate local quality improvement. The full dataset will be reported at national and international scientific congresses and will contribute to peer-reviewed publications and national quality improvement initiatives. CONCLUSIONS: This study will identify and explore variation in the processes and outcomes following ARS within the UK using a collaborative cohort methodology. The results generated by this audit will facilitate local and national quality improvement initiatives and generate new possibilities for future research in anti-reflux interventions.

Correction to: Use of an Integrated Pan-Cancer Oncology Enrichment Next-Generation Sequencing Assay to Measure Tumour Mutational Burden and Detect Clinically Actionable Variants.

This article was originally published under a [CC BY NC 4.0] license.

Use of an Integrated Pan-Cancer Oncology Enrichment Next-Generation Sequencing Assay to Measure Tumour Mutational Burden and Detect Clinically Actionable Variants.

INTRODUCTION: The identification of tumour mutational burden (TMB) as a biomarker of response to programmed cell death protein 1 (PD-1) immunotherapy has necessitated the development of genomic assays to measure this. We carried out comprehensive molecular profiling of cancers using the Illumina TruSight Oncology 500 (TSO500) panel and compared these to whole-genome sequencing (WGS). METHODS: Cancer samples derived from formalin-fixed material were profiled on the TSO500 panel, sequenced on an Illumina NextSeq 500 instrument and processed through the TSO500 Docker pipeline. Either FASTQ files (PierianDx) or vcf files (OncoKDM) were processed to understand clinical actionability. RESULTS: In total, 108 samples (a mixture of colorectal, lung, oesophageal and control samples) were processed via the DNA panel. There was good correlation between TMB, single-nucleotide variants (SNVs), indels and copy-number variations as predicted by TSO500 and WGS (R2 > 0.9) and good reproducibility, with less than 5% variability between repeated controls. For the RNA panel, 13 samples were processed, with all known fusions observed via orthogonal techniques. For clinical actionability, 72 tier 1 variants and 297 tier 2 variants were detected, with clinical trials identified for all patients. CONCLUSIONS: The TSO500 assay accurately measures TMB, microsatellite instability, SNVs, indels, copy-number/structural variation and gene fusions when compared to WGS and orthogonal technologies. Coupled with a clinical annotation pipeline, this provides a powerful methodology for identification of clinically actionable variants.

Temporal validation of metabolic nodal response of esophageal cancer to neoadjuvant chemotherapy as an independent predictor of unresectable disease, survival, and recurrence.

OBJECTIVES: We recently described metabolic nodal stage (mN) and response (mNR) of cancer of the esophagus and gastro-esophageal junction (GEJ) to neoadjuvant chemotherapy (NAC) using 18F-FDG PET-CT as new markers of disease progression, recurrence, and death. We aimed to validate our findings. METHODS: Our validation cohort comprised all patients consecutive to our discovery cohort, staged before and after NAC using PET-CT from 2014 to 2017. Multivariate binary logistic and Cox regression were performed. RESULTS: Fifty-one of the 200 patients had FDG-avid nodes after NAC (25.5%; i.e., lack of complete mNR), and were more likely to progress during NAC to incurable disease on PET-CT or at surgery: odds ratio 3.84 (1.46-10.1; p = 0.006). In 176 patients undergoing successful resection, patients without complete mNR had a worse prognosis: disease-free survival hazard ratio 2.46 (1.34-4.50); p = 0.004. These associations were independent of primary tumor metabolic, pathological response, and stage. In a hybrid pathological/metabolic nodal stage, avid nodal metastases conferred a worse prognosis than non-avid metastases. Lack of complete mNR predicted recurrence or death at 1 and 2 years: positive predictive values 44.4% (31.7-57.8) and 74.1% (56.6-86.3) respectively. CONCLUSIONS: This study provides temporal validation for mNR as a new and independent predictive and prognostic marker of esophageal and GEJ cancer treated with NAC and surgery, although external validation is required to assess generalizability. mNR may provide surrogate information regarding the phenotype of metastatic cancer clones beyond the mere presence of nodal metastases, and might be used to better inform patients, risk stratify, and personalize management, including adjuvant therapy. KEY POINTS: • We previously described metabolic nodal response (mNR) of esophageal cancer to neoadjuvant chemotherapy using 18 F-FDG PET-CT as a predictor of unresectable disease, early recurrence, and death. • We report the first validation of these findings. In an immediately consecutive cohort, we found consistent proportions of patients with and without mNR, and associations with abandoned resection, early recurrence, and death. • This supports mNR as a new and actionable biomarker in esophageal cancer. Although external validation is required, mNR may provide surrogate information about the chemosensitivity of metastatic subclones, and the means to predict treatment success, guide personalized therapy, and follow-up.

Real-world persistence and benefit-risk profile of fingolimod over 36 months in Germany.

Objective: To assess the long-term real-world benefit-risk profile of fingolimod in patients with relapsing MS in Germany. Methods: This analysis used data from the noninterventional real-world study, Post-Authorization Non-interventional German sAfety study of GilEnyA (PANGAEA), to assess prospectively the persistence, effectiveness, and safety of fingolimod over 36 months (±90 days) in Germany. For inclusion in the effectiveness analysis (n = 2,537), patients were required to have received fingolimod for the first time in PANGAEA, to have at least 12 months of data, and to have completed each 12-month follow-up period. For the safety analysis (n = 3,266), patients were additionally allowed to have received fingolimod before enrollment. Results: At baseline, 94.7% of patients in the effectiveness analysis had received a previous disease-modifying therapy. After 36 months, 70.4% of patients were still receiving fingolimod. Over this period, annualized relapse rates decreased to 0.265 (95% CI: 0.244-0.286) from 1.79 (95% CI: 1.75-1.83), and mean Expanded Disability Status Scale scores remained stable (mean change from baseline: +0.049 [95% CI: -0.015 to +0.114]). In total, 16% of patients had 6-month confirmed disability improvement, 12.5% had 6-month confirmed disability worsening, and 52.4% were free from relapses and 6-month confirmed disability worsening. Adverse events (AEs) and serious AEs were experienced by up to 23.4% and 3.9% of patients, respectively, during any of the 12-month follow-up periods. The frequency and nature of AEs were in line with previous findings. Conclusions: Using systematically collected data from PANGAEA, this analysis demonstrates the sustained effectiveness, high persistence, and manageable safety profile of fingolimod over 36 months.

Routinely staging gastric cancer with 18F-FDG PET-CT detects additional metastases and predicts early recurrence and death after surgery.

OBJECTIVES: Fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET-CT) is typically considered to have minimal yield in gastric cancer, and so is not consistently recommended by international guidelines. However, its yield is considerable in esophageal and junctional cancer, identifying unsuspected metastases and risk-stratifying patients using metabolic nodal stage (mN). We aimed to determine the contemporary utility of routine 18F-FDG PET-CT in gastric cancer. METHODS: We routinely stage patients with non-junctional gastric cancer with PET-CT, provided initial CT does not demonstrate unequivocal metastases. We performed a retrospective study of all such patients staged in our institution from January 2007 to July 2016. Our primary endpoint was detection of incurable disease. Our secondary endpoint was disease-free survival following gastrectomy. Decision theory, economic, and predictive models were generated. RESULTS: The primary tumor was FDG-avid in 225/279 patients (80.6%). Seventy-two (25.8%) had FDG-avid nodes (resectable by D2 lymphadenectomy). This was not influenced by the Lauren classification. Unsuspected metastases were identified in 20 patients (7.2%). In 13 (4.7%), these would not have been otherwise identified. Decision theory and economic modeling supported routine PET-CT. Patients with FDG-avid nodes were more likely to have incurable disease (51.4% versus 15.5%; p < 0.001), and a worse prognosis if not: multivariate hazard ratio 2.19 (1.23-3.91; p = 0.008). Prognosis worsened with mN stage. CONCLUSIONS: PET-CT appears useful when used routinely for non-junctional gastric cancer, and should be considered in international recommendations. Any extra costs appear small and offset by avoiding futile investigations and radical treatment. mN stage identifies patients at risk of early recurrence and death. KEY POINTS: • PET-CT is typically not considered useful when staging gastric cancer. We describe a retrospective study of 279 patients routinely staged with PET-CT in the absence of metastases on CT. • The primary tumor was avid in 80% of patients. Twenty-five percent had resectable avid nodes. PET-CT identified previously unsuspected metastases in 7% of patients, which would likely not have been identified by conventional staging without PET-CT in 5%. These patients were much more likely to have avid nodes. • Beyond avoiding futile investigations and radical treatment in this 5%, we found patients with FDG-avid nodes (metabolic nodal stage, mN) to have a worse disease-free survival after gastrectomy.

Novel imaging techniques in staging oesophageal cancer.

The survival of oesophageal cancer is poor as most patients present with advanced disease. Radiological staging of oesophageal cancer is complex but is fundamental to clinical management. Accurate staging investigations are vitally important to guide treatment decisions and optimise patient outcomes. A combination of baseline computed tomography (CT), endoscopic ultrasound (EUS) and positron emission tomography (PET) are currently used for initial treatment decisions. The potential value of these imaging modalities to re-stage disease, monitor response and alter treatment is currently being investigated. This review presents an essential update on the accuracy of oesophageal cancer staging investigations, their use in re-staging after neo-adjuvant therapy and introduces evolving imaging techniques, including novel biomarkers that have clinical potential in oesophageal cancer.

The signalling mechanisms of a novel mitochondrial complex I inhibitor prevent lipid accumulation and attenuate TNF-α-induced insulin resistance in vitro.

RTC-1 has recently been identified as a member of a new class of anti-diabetic compounds acting through the inhibition of complex I of the mitochondrial respiratory chain (NADH:ubiquinone oxidoreductase) to improve glucose handling and inhibit weight gain in mice fed a high-fat diet (HFD). The exact mechanism by which the reduced activity of NADH:ubiquinone oxidoreductase, in response to RTC-1, promotes these improved metabolic parameters remains to be established. Through extensive in vitro analysis, new molecular insights into these downstream signalling pathways have been obtained. RTC-1-induced inhibition of NADH:ubiquinone oxidoreductase was found to promote glucose uptake in C2C12 myotubes in vitro, through the activation of the Akt substrate of 160kDa (AS160), in response to the increased activity of Akt and AMP-activated protein kinase (AMPK). RTC-1-induced phosphorylation of the AMPK substrate, acetyl-CoA carboxylase (ACC) in vitro, was associated with a decrease in lipid accumulation in 3T3-L1 adipocytes and murine mesenchymal stromal cells (MSC). The novel compound also prevented tumour necrosis factor-alpha (TNF-α)-induced insulin resistance and demonstrated insulin sensitising effects in C2C12 myotubes. Taken together, these results present a systematic analysis of the signalling mechanisms responsible for the potent anti-diabetic and anti-obesogenic effects of this modulator of mitochondrial function, strengthening the potential use of such compounds for the treatment of type 2 diabetes mellitus (T2DM).

Predicting Pathologic Response of Esophageal Cancer to Neoadjuvant Chemotherapy: The Implications of Metabolic Nodal Response for Personalized Therapy.

Only a minority of esophageal cancers demonstrates a pathologic tumor response (pTR) to neoadjuvant chemotherapy (NAC). 18F-FDG PET/CT is often used for restaging after NAC and to assess response. Increasingly, it is used during therapy to identify unresponsive tumors and predict pTR, using avidity of the primary tumor alone. However, definitions of such metabolic tumor response (mTR) vary. We aimed to comprehensively reevaluate metabolic response assessment using accepted parameters, as well as novel concepts of metabolic nodal stage (mN) and metabolic nodal response (mNR). METHODS: This was a single-center retrospective U.K. cohort study. All patients with esophageal cancer staged before NAC with PET/CT and after with CT or PET/CT and undergoing resection from 2006 to 2014 were identified. pTR was defined as Mandard tumor regression grade 1-3; imaging parameters included metrics of tumor avidity (SUVmax/mean/peak), composites of avidity and volume (including metabolic tumor volume), nodal SUVmax, and our new concepts of mN stage and mNR. RESULTS: Eighty-two (27.2%) of 301 patients demonstrated pTR. No pre-NAC PET parameters predicted pTR. In 220 patients restaged by PET/CT, the optimal tumor ΔSUVmax threshold was a 77.8% reduction. This was as sensitive as the current PERCIST 30% reduction, but more specific with a higher negative predictive value (P < 0.001). ΔSUVmax and Δlength independently predicted pTR, and composite avidity/spatial metrics outperformed avidity alone. Although both mTR and mNR were associated with pTR, in 82 patients with 18F-FDG-avid nodes before NAC we observed mNR in 10 (12.2%) not demonstrating mTR. CONCLUSION: Current definitions of metabolic response are suboptimal and too simplistic. Composite avidity/volume measures improve prediction. mNR may further improve response assessment, by specifically assessing metastatic tumor subpopulations, likely responsible for disease relapse, and should be urgently assessed when considering aborting therapy on the basis of mTR alone.