Advancing the Real-World Evidence for Medical Devices through Coordinated Registry Networks.

Objectives: Generating and using real-world evidence (RWE) is a pragmatic solution for evaluating health technologies. RWE is recognized by regulators, health technology assessors, clinicians, and manufacturers as a valid source of information to support their decision-making. Well-designed registries can provide RWE and become more powerful when linked with electronic health records and administrative databases in coordinated registry networks (CRNs). Our objective was to create a framework of maturity of CRNs and registries, so guiding their development and the prioritization of funding. Design setting and participants: We invited 52 stakeholders from diverse backgrounds including patient advocacy groups, academic, clinical, industry and regulatory experts to participate on a Delphi survey. Of those invited, 42 participated in the survey to provide feedback on the maturity framework for CRNs and registries. An expert panel reviewed the responses to refine the framework until the target consensus of 80% was reached. Two rounds of the Delphi were distributed via Qualtrics online platform from July to August 2020 and from October to November 2020. Main outcome measures: Consensus on the maturity framework for CRNs and registries consisted of seven domains (unique device identification, efficient data collection, data quality, product life cycle approach, governance and sustainability, quality improvement, and patient-reported outcomes), each presented with five levels of maturity. Results: Of 52 invited experts, 41 (79.9%) responded to round 1; all 41 responded to round 2; and consensus was reached for most domains. The expert panel resolved the disagreements and final consensus estimates ranged from 80.5% to 92.7% for seven domains. Conclusions: We have developed a robust framework to assess the maturity of any CRN (or registry) to provide reliable RWE. This framework will promote harmonization of approaches to RWE generation across different disciplines and health systems. The domains and their levels may evolve over time as new solutions become available.

Host conditioning and rejection monitoring in hepatocyte transplantation in humans.

BACKGROUND & AIMS: Hepatocyte transplantation partially corrects genetic disorders and has been associated anecdotally with reversal of acute liver failure. Monitoring for graft function and rejection has been difficult, and has contributed to limited graft survival. Here we aimed to use preparative liver-directed radiation therapy, and continuous monitoring for possible rejection in an attempt to overcome these limitations. METHODS: Preparative hepatic irradiation was examined in non-human primates as a strategy to improve engraftment of donor hepatocytes, and was then applied in human subjects. T cell immune monitoring was also examined in human subjects to assess adequacy of immunosuppression. RESULTS: Porcine hepatocyte transplants engrafted and expanded to comprise up to 15% of irradiated segments in immunosuppressed monkeys preconditioned with 10Gy liver-directed irradiation. Two patients with urea cycle deficiencies had early graft loss following hepatocyte transplantation; retrospective immune monitoring suggested the need for additional immunosuppression. Preparative radiation, anti-lymphocyte induction, and frequent immune monitoring were instituted for hepatocyte transplantation in a 27year old female with classical phenylketonuria. Post-transplant liver biopsies demonstrated multiple small clusters of transplanted cells, multiple mitoses, and Ki67+ hepatocytes. Mean peripheral blood phenylalanine (PHE) level fell from pre-transplant levels of 1343±48µM (normal 30-119µM) to 854±25µM (treatment goal ≤360µM) after transplant (36% decrease; p<0.0001), despite transplantation of only half the target number of donor hepatocytes. PHE levels remained below 900µM during supervised follow-up, but graft loss occurred after follow-up became inconsistent. CONCLUSIONS: Radiation preconditioning and serial rejection risk assessment may produce better engraftment and long-term survival of transplanted hepatocytes. Hepatocyte xenografts engraft for a period of months in non-human primates and may provide effective therapy for patients with acute liver failure. LAY SUMMARY: Hepatocyte transplantation can potentially be used to treat genetic liver disorders but its application in clinical practice has been impeded by inefficient hepatocyte engraftment and the inability to monitor rejection of transplanted liver cells. In this study, we first show in non-human primates that pretreatment of the host liver with radiation improves the engraftment of transplanted liver cells. We then used this knowledge in a series of clinical hepatocyte transplants in patients with genetic liver disorders to show that radiation pretreatment and rejection risk monitoring are safe and, if optimized, could improve engraftment and long-term survival of transplanted hepatocytes in patients.

Cutting balloon angioplasty in children with resistant renal artery stenosis.

Children with systemic hypertension resulting from a renovascular stenosis commonly have fibromuscular dysplasia and respond to percutaneous transluminal renal angioplasty (PTRA). There is a subset of children, however, with conditions that appear to be resistant to PTRA (eg, syndromic renal artery stenosis and arteritis). These patients are often treated surgically. The development of the cutting balloon may provide a minimally invasive alternative to surgery in these individuals. Associated adverse events may include recurrent stenosis, arterial occlusion with renal loss, and arterial rupture with extravasation and pseudoaneurysm formation. Some of these adverse events can be successfully treated with percutaneous interventional techniques. The authors present four cases of cutting balloon angioplasty performed at two large metropolitan children's hospitals in children with resistant renal artery stenosis.

Pseudoaneurysm in children: diagnosis and interventional management.

Pseudoaneurysms (PAn) are uncommon in adults and even less common in children. They are most often encountered after iatrogenic arterial injury. Presentation may be substantially delayed after the iatrogenic event, and diagnosis can be difficult, especially when the PAn occurs in an unexpected location. Treatment of PAn has evolved during the last two decades from a reliance on surgical resection to US-guided compression, coil embolization, covered stents, and stent-graft exclusion. More recently, direct percutaneous US-guided thrombin injection has been used in the treatment of PAn. We present three cases of successful PAn thrombosis by US-guided percutaneous thrombin injection in children, one of the epigastric artery and two of the femoral artery.

CT-guided percutaneous lung biopsy in children.

PURPOSE: To describe techniques and evaluate outcomes of computed tomography (CT)-guided percutaneous lung biopsy in children. MATERIALS AND METHODS: Between April 1992 and June 2003, 64 patients (32 male, 32 female) with a mean age of 10.8 years (0.6-20 years) were referred for 75 lung biopsies. Most biopsies were performed for suspected malignancy (n = 24; 32%) or to distinguish posttransplantation lymphoproliferative disorder from fungal infection in immunocompromised patients (n = 17; 23%). All children referred to the pediatric interventionalists in two children's hospitals for CT-guided biopsy of parenchymal or pleural-based lesions in the thorax were studied. Prospectively gathered procedural data were reviewed for medical history and indications for procedure, admission status, type of anesthesia, technical approach (core vs aspiration biopsy), procedural modifications, lesion size, number of passes required, and immediate complications. Medical records were retrospectively reviewed for diagnostic outcome, impact on patient management, and delayed complications. RESULTS: Procedures were performed under deep sedation whenever possible (n = 61; 81%) with use of a coaxial core biopsy technique (n = 56; 75%), a fine needle aspiration biopsy technique (n = 15; 20%), or both (n = 4; 5%). Mean lesion diameters were 2.5 cm (range, 1-10 cm) in the core biopsy group and 1.0 cm (range, 0.5-1.7 cm) in the aspiration biopsy group. Sixty-four biopsies (85%) were diagnostic. There was one major complication (1.3%), a tension pneumothorax treated with intraprocedural placement of a chest tube. CONCLUSION: Percutaneous CT-guided lung biopsy is a safe and accurate diagnostic procedure in children that obviates open surgical biopsy in most patients.