Citations

AbstractBackgroundChildren with chest wall Ewing sarcoma with malignant pulmonary effusion or pleural stranding require hemithorax radiation, often with plans that exceed lung constraints. We investigated disease control and pneumonitis in children requiring hemithorax radiation.ProcedureEleven children (median age 13 years) received hemithorax radiotherapy. Symptomatic radiation pneumonitis was considered National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) grade 1+ with respiratory symptoms. Mean lung dose (MLD), volume of lung exposed to a dose ≥5 Gy (V5), ≥20 Gy (V20), and ≥35 Gy (V35) were recorded. Adult and pediatric lung constraints were obtained from Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) guidelines and Children's Oncology Group (COG) protocols, respectively.ResultsMedian hemithorax dose was 15 Gy (1.5 Gy/fraction). Median total dose was 51 Gy (1.8 Gy/fraction). Most plans delivered both protons and photons. The ipsilateral MLD, V5, and V20 were 27.2 Gy, 100%, and 48.3%; the bilateral MLD, V20, and V35 were 14.1 Gy, 22.8%, and 14.3%, respectively. One hundred percent, 36%, and 91% of treatments exceeded recommended adult ipsilateral lung constraints of V5 <65%, V20 <52%, and MLD of 22 Gy; 64%, 45%, and 82% exceeded COG bilateral lung constraints of V20 <20%, MLD <15 Gy, and MLD <12 Gy, respectively; 82% of treatments exceeded the COG ipsilateral lung constraint of V20 <30%. At a median 36 months (range 12–129), the symptomatic radiation pneumonitis incidence was 0%. Two patients progressed with nonpulmonary metastatic disease and died at a median 12 months following radiotherapy.ConclusionsExisting guidelines may overestimate pneumonitis risk, even among young children receiving multiagent chemotherapy. For children with chest wall Ewing sarcoma and other thoracic malignancies, more data are needed to refine pediatric dose–effect models for pulmonary toxicity.

Therapeutic drug monitoring (TDM) of biologics is a rapidly evolving field. We aimed to provide a consensus statement regarding the clinical utility of TDM for biologics in inflammatory bowel disease (IBD). A modified Delphi method was applied to develop consensus statements. A comprehensive literature review was performed regarding TDM of biologic therapies in IBD, and 45 statements were subsequently formulated on the potential application of TDM in IBD. The statements, along with literature, were then presented to a panel of 10 gastroenterologists with expertise in IBD and TDM who anonymously rated them on a scale of 1–10 (1 = strongly disagree and 10 = strongly agree). An expert consensus development meeting was held virtually to review, discuss, refine, and reformulate statements that did not meet criteria for agreement or that were ambiguous. During the meeting, additional statements were proposed. Panelists then confidentially revoted, and statements rated ≥7 by 80% or more of the participants were accepted. During the virtual meeting, 8 statements were reworded, 7 new statements were proposed, and 19 statements were rerated. Consensus was finally reached in 48/49 statements. The panel agreed that reactive TDM should be used for all biologics for both primary nonresponse and secondary loss of response. It was recommended that treatment discontinuation should not be considered for infliximab or adalimumab until a drug concentration of at least 10–15 μg/mL was achieved. Consensus was also achieved regarding the utility of proactive TDM for anti–tumor necrosis factor therapy. It was recommended to perform proactive TDM after induction and at least once during maintenance. Consensus was achieved in most cases regarding the utility of TDM of biologics in IBD, specifically for reactive and proactive TDM of anti–tumor necrosis factors.

Abstract Carotid artery angioplasty and stenting (CAS) has been shown to be equally effective as carotid endarterectomy (CEA) for carotid stenosis in both symptomatic and asymptomatic disease. 1 In patients who are considered high risk for endarterectomy, CAS is safe and effective. 2 While this is a common procedure, proper technique is crucial to ensure that the procedure is safe with minimal risk of stroke. This patient consented to treatment. The following is a video detailing the CAS procedure in a 77-yr-old male with a symptomatic 65% carotid stenosis (by NASCET criteria 3 ) in a patient with prior CEA.

Abstract Since the International Subarachnoid Aneurysm Trial, 1 endovascular treatment has been the favored treatment for appropriate ruptured intracranial aneurysms. While our endovascular technology has advanced to allow us to treat the majority of intracranial aneurysms, simple coil embolization is still the most common modality. This video demonstrates the fundamentals of aneurysm catheterization and coiling for safe treatment. In addition, the set-up and devices are detailed. This video is to add to the library of basic techniques that will aid a large number of practitioners. This patient consented to endovascular treatment. The video demonstrates endovascular coil embolization of a posterior communicating artery aneurysm in a 76-yr-old female who presented with a subarachnoid hemorrhage. Image of biplane suite in video used courtesy of Siemens Medical Solutions USA, Inc. Illustration at 5:12 reprinted from Yasargil MG, et al, Microneurosurgery IV B , p. 9, Thieme, New York, 1995.

Abstract The burden of senescent cells (SnCs), which do not divide but are metabolically active and resistant to death by apoptosis, is increased in older adults and those with chronic diseases. These individuals are also at the greatest risk for morbidity and mortality from SARS‐CoV‐2 infection. SARS‐CoV‐2 complications include cytokine storm and multiorgan failure mediated by the same factors as often produced by SnCs through their senescence‐associated secretory phenotype (SASP). The SASP can be amplified by infection‐related pathogen‐associated molecular profile factors. Senolytic agents, such as Fisetin, selectively eliminate SnCs and delay, prevent, or alleviate multiple disorders in aged experimental animals and animal models of human chronic diseases, including obesity, diabetes, and respiratory diseases. Senolytics are now in clinical trials for multiple conditions linked to SnCs, including frailty; obesity/diabetes; osteoporosis; and cardiovascular, kidney, and lung diseases, which are also risk factors for SARS‐CoV‐2 morbidity and mortality. A clinical trial is underway to test if senolytics decrease SARS‐CoV‐2 progression and morbidity in hospitalized older adults. We describe here a National Institutes of Health‐funded, multicenter, placebo‐controlled clinical trial of Fisetin for older adult skilled nursing facility (SNF) residents who have been, or become, SARS‐CoV‐2 rtPCR‐positive, including the rationale for targeting fundamental aging mechanisms in such patients. We consider logistic challenges of conducting trials in long‐term care settings in the SARS‐CoV‐2 era, including restricted access, consent procedures, methods for obtaining biospecimens and clinical data, staffing, investigational product administration issues, and potential solutions for these challenges. We propose developing a national network of SNFs engaged in interventional clinical trials.

AbstractObjectiveWith COVID-19, there was a need for a rapidly scalable annotation system that facilitated real-time integration with clinical decision support systems (CDS). Current annotation systems suffer from a high-resource utilization and poor scalability limiting real-world integration with CDS. A potential solution to mitigate these issues is to use the rule-based gazetteer developed at our institution.Materials and MethodsPerformance, resource utilization, and runtime of the rule-based gazetteer were compared with five annotation systems: BioMedICUS, cTAKES, MetaMap, CLAMP, and MedTagger.ResultsThis rule-based gazetteer was the fastest, had a low resource footprint, and similar performance for weighted microaverage and macroaverage measures of precision, recall, and f1-score compared to other annotation systems.DiscussionOpportunities to increase its performance include fine-tuning lexical rules for symptom identification. Additionally, it could run on multiple compute nodes for faster runtime.ConclusionThis rule-based gazetteer overcame key technical limitations facilitating real-time symptomatology identification for COVID-19 and integration of unstructured data elements into our CDS. It is ideal for large-scale deployment across a wide variety of healthcare settings for surveillance of acute COVID-19 symptoms for integration into prognostic modeling. Such a system is currently being leveraged for monitoring of postacute sequelae of COVID-19 (PASC) progression in COVID-19 survivors. This study conducted the first in-depth analysis and developed a rule-based gazetteer for COVID-19 symptom extraction with the following key features: low processor and memory utilization, faster runtime, and similar weighted microaverage and macroaverage measures for precision, recall, and f1-score compared to industry-standard annotation systems.

Abstract Context Hypoparathyroidism is characterized by insufficient levels of parathyroid hormone (PTH). TransCon PTH is an investigational long-acting prodrug of PTH(1-34) for the treatment of hypoparathyroidism. Objective This work aimed to investigate the safety, tolerability, and efficacy of daily TransCon PTH in adults with hypoparathyroidism. Methods This phase 2, randomized, double-blind, placebo-controlled 4-week trial with open-label extension enrolled 59 individuals with hypoparathyroidism. Interventions included TransCon PTH 15, 18, or 21 µg PTH(1-34)/day or placebo for 4 weeks, followed by a 22-week extension during which TransCon PTH dose was titrated (6-60 µg PTH[1-34]/day). Results By Week 26, 91% of participants treated with TransCon PTH achieved independence from standard of care (SoC, defined as active vitamin D = 0 μg/day and calcium [Ca] ≤ 500 mg/day). Mean 24-hour urine Ca (uCa) decreased from a baseline mean of 415 mg/24h to 178 mg/24h by Week 26 (n = 44) while normal serum Ca (sCa) was maintained and serum phosphate and serum calcium-phosphate product fell within the normal range. By Week 26, mean scores on the generic 36-Item Short Form Health Survey domains increased from below normal at baseline to within the normal range. The Hypoparathyroidism Patient Experience Scale symptom and impact scores improved through 26 weeks. TransCon PTH was well tolerated with no treatment-related serious or severe adverse events. Conclusion TransCon PTH enabled independence from oral active vitamin D and reduced Ca supplements (≤ 500 mg/day) for most participants, achieving normal sCa, serum phosphate, uCa, serum calcium-phosphate product, and demonstrating improved health-related quality of life. These results support TransCon PTH as a potential hormone replacement therapy for adults with hypoparathyroidism.

Abstract Acute carotid terminus occlusion (CTO) is responsible for up to 5% of acute ischemic strokes secondary to emergent large vessel occlusion (ELVO) and up to 20% of acute internal carotid artery (ICA) occlusions. 1 The term “CTO” has also been used to describe occlusions in the supra-clinoid segment or at the bifurcation of the ICA. Compared to other ELVOs, patients with CTO present with higher stroke severity and larger infarct volume, likely to be a result of disruption of direct Circle of Willis collaterals across the anterior communicating artery (AComA) and posterior communicating artery (PComA). 2,3 Similary, CTO is usually associated with worse prognosis compared to other ELVOs in general. With regard to response to treatment, previous studies have reported significantly lower recanalization rates with intravenous alteplase with CTO compared to M1 segment occlusion. With regard to the safety and efficacy of mechanical thrombectomy, prior reports provide conflicting results with some reporting lower successful recanalization rates with CTO compared to M1 occlusion, and others reporting similar results. In our experience, we have found that successful recanalization of CTO can be achieved with a similar approach to M1 occlusions utilizing a direct aspiration first pass technique (ADAPT). 3,4 Herein, we present a case of CTO for which we performed mechanical thrombectomy using ADAPT. This procedure was an emergent standard of care procedure for which a consent was not required and so not obtained.

The mammalian liver's regenerative ability has led researchers to engineer animals as incubators for expansion of human hepatocytes. The expansion properties of human hepatocytes in immunodeficient mice are well known. However, little has been reported about larger animals that are more scalable and practical for clinical purposes. Therefore, we engineered immunodeficient swine to support expansion of human hepatocytes and identify barriers to their clinical application. Immunodeficient swine were engineered by knockout of the recombinase-activating gene 2 ( RAG2 ) and fumarylacetoacetate hydrolase (FAH). Immature human hepatocytes (ihHCs) were injected into fetal swine by intrauterine cell transplantation (IUCT) at day 40 of gestation. Human albumin was measured as a marker of engraftment. Cytotoxicity against ihHCs was measured in transplanted piglets and control swine. We initially detected higher levels of human albumin in cord blood of newborn FAH/ RAG2 -deficient (FR) pigs compared with immunocompetent controls (196.26 ng/dL vs. 39.29 ng/dL, p = 0.008), indicating successful engraftment of ihHCs after IUCT and adaptive immunity in the fetus. Although rare hepatocytes staining positive for human albumin were observed, levels of human albumin did not rise after birth, but declined, suggesting rejection of xenografted ihHCs. Cytotoxicity against ihHCs increased after birth by 3.8% (95% CI: [2.1%–5.4%], p < 0.001) and inversely correlated with declining levels of human albumin ( p = 2.1 × 10 −5 , R 2 = 0.17). Circulating numbers of T cells and B cells were negligible in FR pigs. However, circulating natural killer (NK) cells exerted cytotoxicity against ihHCs. NK cell activity was lower in immunodeficient piglets after IUCT than in naive controls (30.4% vs. 40.1%, p = 0.011, 95% CI for difference [2.7%–16.7%]). In conclusion, ihHCs were successfully engrafted in FR swine after IUCT. NK cells were a significant barrier to expansion of hepatocytes. New approaches are needed to overcome this hurdle and allow large-scale expansion of human hepatocytes in immunodeficient swine. Impact statement There is currently a need for robust expansion of human hepatocytes. We describe an immunodeficient swine model into which we engrafted immature human hepatocytes (ihHCs). We identified the mechanism of the eventual graft rejection by the intact NK cell population, which has not been previously shown to have a significant role in xenograft rejection. By both improving engraftment and reducing NK cell-mediated cytotoxicity toward the graft through intrauterine cell transfer, we confirmed the presence of residual adaptive immunity in this model of immunodeficiency and the ability to induce hyposensitization in the NK cell population by taking advantage of the fetal microenvironment.