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The 21st Century Cures Act passed by the United States (US) Congress in December 2016 requires the US Food and Drug Administration (FDA) shall establish a program to evaluate the potential use of real-world evidence (RWE) which is generated from real-world data (RWD) to (i) support approval of new indication for a drug approved under section 505 (c) and (ii) satisfy post-approval study requirements. RWE offers the opportunities to develop robust evidence using high-quality data and sophisticated methods for producing causal-effect estimates regardless randomization is feasible. In this article, we have demonstrated that the assessment of treatment effect (RWE) based on RWD could be biased due to the potential selection and information biases of RWD. Although fit-for-purpose RWE may meet regulatory standards under certain assumptions, it is not the same as substantial evidence (current regulatory standard in support of approval of regulatory submission). In practice, it is then suggested that when there are gaps between fit-for-purpose RWE and substantial evidence, we should make efforts to fill these gaps based on a comprehensive evaluation of the treatment effect. We also review two RWE examples to show some potential use of RWE in clinical studies. [ABSTRACT FROM AUTHOR]

Objective: To explore the clinical and genetic characteristics of five children with Catecholaminergic polymorphic ventricular tachycardia (CPVT)., Methods: Five children with clinical manifestations consistent with CPVT admitted to the Department of Cardiology of Children's Hospital Affiliated to Zhengzhou University from November 2019 to November 2021 were selected as the study subjects. Their clinical data were collected. Potential variants were detected by whole exome sequencing, and Sanger sequencing was used to verify the candidate variants. All patients were treated with β-blocker propranolol and followed up., Results: All patients had developed the disease during exercise and presented with syncope as the initial clinical manifestation. Electrocardiogram showed sinus bradycardia. The first onset age of the 5 patients were (10.4 ± 2.19) years, and the time of delayed diagnosis was (1.6 ± 2.19) years. All of the children were found to harbor de novo heterozygous missense variants of the RYR2 gene, including c.6916G>A (p.V2306I), c.527G>C (p.R176P), c.12271G>A (p.A4091T), c.506G>T (p.R169L) and c.6817G>A (p.G2273R). Among these, c.527G>C (p.R176P) and c.6817G>A (p.G2273R) were unreported previously. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c.527G>C (p.R176P) was classified as a pathogenic variant (PS2+PM1+PM2_Supporting+PM5+PP3+PP4), and the c.6817G>A (p.G2273R) was classified as a likely pathogenic variant (PS2+PM2_Supporting+PP3+PP4). The symptoms of all children were significantly improved with the propranolol treatment, and none has developed syncope during the follow up., Conclusion: Discovery of the c.527G>C (p.R176P) and c.6817G>A (p.G2273R) variants has expanded the mutational spectrum of the RYR2 gene. Genetic testing of CPVT patients can clarify the cause of the disease and provide a reference for their genetic counseling.

Objectives: To investigate the correlation between lymph node metastasis (LNM) and various clinicopathological features of pancreatic neuroendocrine tumors (pNETs) and its impact on prognosis., Methods: We searched the Surveillance Epidemiology and End Results database (2004-2015) for patients with surgically treated pNETs. Factors correlated with LNMs were analyzed by logistic regression and by Cox analysis., Results: For tumors of 1 to 4 cm, age (P < 0.001, P = 0.014), grade (P < 0.001, P < 0.001), LNMs (P = 0.008, P < 0.001), and size (P = 0.038, P = 0.002) predicted overall survival (OS) and disease-specific survival (DSS). For tumor greater than 4 cm, age (P < 0.001, P = 0.001) and grade (P = 0.011, P = 0.048) were independent prognostic factors of OS and DSS. Lymph node metastasis modestly predicted DSS (P = 0.028) but not OS (P = 0.218)., Conclusions: In pNETs greater than 4 cm, LNM is not a predictor of OS and modestly predicts DSS, and lymphadenectomy may be unhelpful in these patients. For pNETs 1 to 4 cm, LNM predicts poor OS and DSS, which supports lymphadenectomy in these patients. Pancreas-sparing resection with only limited peripancreatic node sampling needs to be questioned.