Improved clinical investigation and evaluation of high-risk medical devices: the rationale and objectives of CORE-MD (Coordinating Research and Evidence for Medical Devices)

: In the European Union (EU) the delivery of health services is a national responsibility but there are concerted actions between member states to protect public health. Approval of pharmaceutical products is the responsibility of the European Medicines Agency, whereas authorizing the placing on the market of medical devices is decentralized to independent 'conformity assessment' organizations called notified bodies. The first legal basis for an EU system of evaluating medical devices and approving their market access was the medical device directives, from the 1990s. Uncertainties about clinical evidence requirements, among other reasons, led to the EU Medical Device Regulation (2017/745) that has applied since May 2021. It provides general principles for clinical investigations but few methodological details-which challenges responsible authorities to set appropriate balances between regulation and innovation, pre- and post-market studies, and clinical trials and real-world evidence. Scientific experts should advise on methods and standards for assessing and approving new high-risk devices, and safety, efficacy, and transparency of evidence should be paramount. The European Commission recently awarded a Horizon 2020 grant to a consortium led by the European Society of Cardiology and the European Federation of National Associations of Orthopaedics and Traumatology, that will review methodologies of clinical investigations, advise on study designs, and develop recommendations for aggregating clinical data from registries and other real-world sources. The CORE-MD project (Coordinating Research and Evidence for Medical Devices) will run until March 2024; here we describe how it may contribute to the development of regulatory science in Europe

High throughput techniques for characterizing the expression profile of Barrett's esophagus

Barrett's esophagus (BE) is the metaplastic change of the normal lined squamous epithelium of the distal esophagus to a columnar type of epithelium as a result of chronic long-standing gastroesophageal reflux disease. Patients with BE have a significantly increased risk of developing an esophageal adenocarcinoma, with an estimated annual incidence varying from 0.4 to 1.8%. Over the last 3 decades, the incidence of BE and its associated adenocarcinoma has increased in Western countries at a rate that exceeds that of any other malignancy. Despite all the research performed on BE, there is still an inadequate understanding of the biological basis of this mucosal transformation. With the upcoming modern high throughput technologies, important progression has been made in unraveling the expression profiles and gaining more insight in the biology of BE and esophageal adenocarcinoma. Several studies reported genome, transcriptome, proteome, and kinome investigations using high throughput techniques. These studies were conducted to find biomakers that can be used to detect BE patients with increased risk for malignant progression or to obtain more insight in the mechanism underlying BE development. In the following review, we first discuss the different techniques that are currently available and summarize findings in this field, including several recent publications of our grou

Transcatheter aortic valve replacement: clinical safety and performance data.

Introduction: Patients with severe aortic stenosis and regurgitation who are inoperable or at high-risk for surgery can be treated with transcatheter aortic valve replacement (TAVR). The aim of this study was to provide a comprehensive overview of the literature of TAVR and reported clinical and performance outcomes. Areas covered: A total of 16 devices, described in 204 articles describing clinical and performance outcomes, were included. The most frequently observed outcome was 30-day mortality, ranging between 0-23%. Other commonly reported clinical outcomes were 30-day stroke, ranging between 0-14.3% and pacemaker implantation, ranging from 0-44.9%. The most common valve performance outcome was aortic valve regurgitation, however, mostly reported at 7 days follow-up. Next to a follow-up period of 30 days, numerous articles reported outcomes at 6 months and 1 year. The numbers of articles describing outcomes with a longer follow-up as well as including intermediate and low-risk patients were limited. Expert commentary: This literature review provided a clear overview of the reported clinical and performance outcomes of TAVR devices. Despite the frequently used VARC-2 definitions, we identified a huge variation across studies. Future studies using standardized definitions of study set-ups and outcomes are essential and might lead to better insights of TAVR

Transcatheter aortic valve replacement: clinical safety and performance data.

Introduction: Patients with severe aortic stenosis and regurgitation who are inoperable or at high-risk for surgery can be treated with transcatheter aortic valve replacement (TAVR). The aim of this study was to provide a comprehensive overview of the literature of TAVR and reported clinical and performance outcomes. Areas covered: A total of 16 devices, described in 204 articles describing clinical and performance outcomes, were included. The most frequently observed outcome was 30-day mortality, ranging between 0-23%. Other commonly reported clinical outcomes were 30-day stroke, ranging between 0-14.3% and pacemaker implantation, ranging from 0-44.9%. The most common valve performance outcome was aortic valve regurgitation, however, mostly reported at 7 days follow-up. Next to a follow-up period of 30 days, numerous articles reported outcomes at 6 months and 1 year. The numbers of articles describing outcomes with a longer follow-up as well as including intermediate and low-risk patients were limited. Expert commentary: This literature review provided a clear overview of the reported clinical and performance outcomes of TAVR devices. Despite the frequently used VARC-2 definitions, we identified a huge variation across studies. Future studies using standardized definitions of study set-ups and outcomes are essential and might lead to better insights of TAVR

Patients With Barrett's Esophagus and Persistent Low-grade Dysplasia Have an Increased Risk for High-grade Dysplasia and Cancer

Background & Aims: In some patients with Barrett's esophagus (BE) and a confirmed diagnosis of low-grade dysplasia (LGD), the LGD is not detected during follow-up examinations. We would like to avoid the unnecessary risks and costs of ablative treatment for these patients. Therefore, we investigated whether persistent LGD increases risk for high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC) and what proportion of patients are no longer found to have dysplasia after an initial diagnosis of LGD. Methods: In a retrospective study, we collected information on 1579 patients with BE and LGD from 2005 through 2010 by using a nationwide registry of histopathology diagnoses in the Netherlands (PALGA). Confirmed LGD was defined as a diagnosis of LGD that was confirmed by any other pathologist. Persistent LGD was defined as LGD detected at the first and follow-up endoscopy. Data were collected on patients until treatment for HGD, detection of EAC, or the last endoscopy at which a biopsy was collected (through July 2014). We evaluated whether persistent LGD was a risk factor for malignant progression by using univariable and multivariable Cox regression analyses. Results: Of individuals with BE and LGD in the database, the diagnosis of LGD was confirmed for 161 patients (10% of total). In these patients, the incidence of HGD and/or EAC was 5.18/100 person-years (95% confidence interval [CI], 4.32-8.10/100 person-years) compared with 1.85/100 person-years (95% CI, 1.52-2.22/100 person-years) in patients for whom LGD was not confirmed at the first endoscopy. The incidence of EAC alone in patients with confirmed LGD was 2.51/100 person-years (95% CI, 1.46-3.99/100 person-years), compared with 1.01/per 100 person-years (95% CI, 0.41-2.10/100 person-years) in patients for whom LGD was not confirmed at the first endoscopy. Of patients in whom LGD was confirmed at the first endoscopic examination, 51% were not found to have dysplasia at the first follow-up endoscopy, and 30% had persistent LGD. In patients with persistent LGD, the incidence of HGD and/or EAC was 7.65/100 person-years (95% CI, 4.45-12.34) and of only EAC was 2.04/100 person-years (95% CI, 0.65-4.92); in patients without persistent LGD, the incidence of HGD and/or EAC was 2.32/100 person-years (95% CI, 1.08-4.40/100 person-years) and of only EAC was 1.45 (95% CI, 0.53-3.21/100 person-years). Persistent LGD was found to be an independent risk factor for the development of HGD and/or EAC, with hazard ratio of 3.5 (95% CI, 1.48-8.28). Conclusions: In a large population-based cohort study of patients with BE and LGD, the risk of progression to HGD and/or EAC was higher in patients with confirmed LGD and highest in those with confirmed and persistent LGD

Correction: BMP4 Signaling Is Able to Induce an Epithelial-Mesenchymal Transition-Like Phenotype in Barrett's Esophagus and Esophageal Adenocarcinoma through Induction of SNAIL2

[This corrects the article DOI: 10.1371/journal.pone.0155754.]

BMP4 signaling is able to induce an epithelial-mesenchymal transition-like phenotype in Barrett's esophagus and esophageal adenocarcinoma through induction of SNAIL2

Background: Bone morphogenetic protein 4 (BMP4) signaling is involved in the development of Barrett's esophagus (BE), a precursor of esophageal adenocarcinoma (EAC). In various cancers, BMP4 has been found to induce epithelial-mesenchymal transition (EMT) but its function in the development of EAC is currently unclear. Aim: To investigate the expression of BMP4 and several members of the BMP4 pathway in EAC. Additionally, to determine the effect of BMP4 signaling in a human Barrett's esophagus (BAR-T) and adenocarcinoma (OE33) cell line. Methods: Expression of BMP4, its downstream target ID2 and members of the BMP4 pathway were determined by Q-RT-PCR, immunohistochemistry and Western blot analysis using biopsy samples from EAC patients. BAR-T and OE33 cells were incubated with BMP4 or the BMP4 antagonist, Noggin, and cell viability and migration assays were performed. In addition, expression of factors associated with EMT (SNAIL2, CDH1, CDH2 and Vimentin) was evaluated by Q-RT-PCR and Western blot analysis. Results: Compared to squamous epithelium (SQ), BMP4 expression was significantly upregulated in EAC and BE. In addition, the expression of ID2 was significantly upregulated in EAC and BE compared to SQ. Western blot analysis confirmed our results, showing an upregulated expression of BMP4 and ID2 in both BE and EAC. In addition, more phosphorylation of SMAD1/5/8 was observed. BMP4 incubation inhibited cell viability, but induced cell migration in both BAR-T and OE33 cells. Upon BMP4 incubation, SNAIL2 expression was significantly upregulated in BAR-T and OE33 cells while CDH1 expression was significantly downregulated. These results were confirmed by Western blot analysis. Conclusion: Our results indicate active BMP4 signaling in BE and EAC and suggest that this results in an invasive phenotype by inducing an EMT-like response through upregulation of SNAIL2 and subsequent downregulation of CDH1

Risk of neoplastic progression in Barrett's esophagus diagnosed as indefinite for dysplasia : A nationwide cohort study

Background and study aims: A histological diagnosis of indefinite for dysplasia (IND) in Barrett's esophagus is used when a diagnosis of genuine dysplasia is equivocal. The aim of the present study was to assess the risk of progression to high grade dysplasia (HGD) or esophageal adenocarcinoma (EAC) after a diagnosis of IND in a nationwide cohort of patients with Barrett's esophagus. Patients and methods: Patients with a first diagnosis of IND in Barrett's esophagus between 2002 and 2011 were selected from a nationwide registry of histopathology diagnoses in The Netherlands. Patients were followed up until treatment for HGD, detection of EAC, or date of last endoscopy contact with biopsy sampling. Results: In total, 1258 patients met the inclusion criteria, of whom 842 (66.9%) underwent endoscopic follow-up. Patients were followed for a total of 2585 person-years (mean ± SD 3.01 ± 2.6). Median duration until first follow-up endoscopy was 1.2 years (interquartile range 0.3a-1.8 years). The progression rate from IND to the combined end point of HGD or EAC was 2.0 (95% confidence interval [CI] 1.5-2.6) per 100 person-years and progression to EAC was 1.2 (95%CI 0.8-1.6). After excluding cases with HGD or EAC within 1 year after IND diagnosis (na=16), the progression rates were 1.4 (95%CI 1.01.9) and 0.8 (95%CI 0.5-1.2) per 100 person-years for HGD or EAC and EAC, respectively. Conclusion: In this large, population-based, cohort of patients with Barrett's esophagus, the incidence rate of HGD or EAC following a diagnosis of IND was 1.4 per 100 person-years. The results demonstrate the need for additional studies to select the subgroup of IND patients with an increased risk of neoplastic progression

Risk of neoplastic progression in Barrett's esophagus diagnosed as indefinite for dysplasia : A nationwide cohort study

Background and study aims: A histological diagnosis of "indefinite for dysplasia" (IND) in Barrett's esophagus is used when a diagnosis of genuine dysplasia is equivocal. The aim of the present study was to assess the risk of progression to high grade dysplasia (HGD) or esophageal adenocarcinoma (EAC) after a diagnosis of IND in a nationwide cohort of patients with Barrett's esophagus. Patients and methods: Patients with a first diagnosis of IND in Barrett's esophagus between 2002 and 2011 were selected from a nationwide registry of histopathology diagnoses in The Netherlands. Patients were followed up until treatment for HGD, detection of EAC, or date of last endoscopy contact with biopsy sampling. Results: In total, 1258 patients met the inclusion criteria, of whom 842 (66.9%) underwent endoscopic follow-up. Patients were followed for a total of 2585 person-years (mean ± SD 3.01±2.6). Median duration until first follow-up endoscopy was 1.2 years (interquartile range 0.3-1.8 years). The progression rate from IND to the combined end point of HGD or EAC was 2.0 (95% confidence interval [CI] 1.5-2.6) per 100 person-years and progression to EAC was 1.2 (95%CI 0.8-1.6). After excluding cases with HGD or EAC within 1 year after IND diagnosis (n=16), the progression rates were 1.4 (95%CI 1.0-1.9) and 0.8 (95%CI 0.5-1.2) per 100 person-years for HGD or EAC and EAC, respectively. Conclusion: In this large, population-based, cohort of patients with Barrett's esophagus, the incidence rate of HGD or EAC following a diagnosis of IND was 1.4 per 100 person-years. The results demonstrate the need for additional studies to select the subgroup of IND patients with an increased risk of neoplastic progression