Publications by authors named "Michael Fisher"

361 Publications

Risk of Major Bleeding With Potent Antiplatelet Agents After an Acute Coronary Event: A Comparison of Ticagrelor and Clopidogrel in 5116 Consecutive Patients in Clinical Practice.

J Am Heart Assoc 2021 Apr 9:e019467. Epub 2021 Apr 9.

Liverpool University Hospitals NHS Foundation Trust Liverpool United Kingdom.

Background Major bleeding after acute coronary syndrome predicts a poor outcome but is challenging to define. The choice of antiplatelet influences bleeding risk. Methods and Results Major bleeding, subsequent myocardial infarction (MI), and all-cause mortality to 1 year were compared in consecutive patients with acute coronary syndrome treated with clopidogrel (n=2491 between 2011 and 2013) and ticagrelor (n=2625 between 2012 and 2015) in 5 English hospitals. Clinical outcomes were identified from national hospital episode statistics. Bleeding and MI events were independently adjudicated by 2 experienced clinicians, blinded to drug, sequence, and year. Bleeding events were categorized using Bleeding Academic Research Consortium 3 to 5 and PLATO (Platelet Inhibition and Patient Outcomes) criteria and MI by the Third Universal Definition. Multivariable regression analysis was used to adjust outcomes for case mix. The median age was 68 years and 34% were women. 39% underwent percutaneous coronary intervention and 13% coronary artery bypass graft surgery. Clinical outcome data were 100% complete for bleeding and 99.7% for MI. No statistically significant difference was seen in crude or adjusted major bleeding for ticagrelor compared with clopidogrel (Bleeding Academic Research Consortium 3-5, hazard ratio [HR], 1.23; 95% CI, 0.90-1.68; =0.2, PLATO major adjusted HR, 1.30; 95% CI, 0.98-1.74; =0.07) except in the non-coronary artery bypass graft cohort (n=4464), where bleeding was more frequent with ticagrelor (Bleeding Academic Research Consortium 3-5, adjusted HR, 1.58; 95% CI, 1.09-2.31; =0.017; and PLATO major HR, 1.67; 95% CI, 1.18-2.37; =0.004). There was no difference in crude or adjusted subsequent MI (adjusted HR, 1.20; 95% CI, 0.87-1.64; =0.27). Crude mortality was higher in the clopidogrel group but not after adjustment, using either Cox proportional hazards or propensity matched population (HR, 0.90; 95% CI, 0.76-1.10; =0.21) as was the case for stroke (HR, 0.82; 95% CI, 0.52-1.32; =0.42). Conclusions This observational study indicates that the apparent benefit of ticagrelor demonstrated in a clinical trial population may not be observed in the broader population encountered in clinical practice. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02484924.
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http://dx.doi.org/10.1161/JAHA.120.019467DOI Listing
April 2021

A Phase 2 Trial of Selumetinib in Children with Recurrent Optic Pathway and Hypothalamic Low-Grade Glioma without NF1: A Pediatric Brain Tumor Consortium Study.

Neuro Oncol 2021 Feb 25. Epub 2021 Feb 25.

Department of Radiology (JYJ) and Department of Hematology and Oncology (MF). Nationwide Children's Hospital, Columbus, OH.

Background: Pediatric low-grade gliomas (pLGGs) are the most common childhood brain tumor. Progression-free survival (PFS) is much lower than overall survival, emphasizing the need for alternative treatments. Sporadic (without neurofibromatosis type-1) optic pathway and hypothalamic glioma (OPHGs) are often multiply recurrent and cause significant visual deficits. Recently, there has been a prioritization of functional outcomes.

Methods: We present results from children with recurrent/progressive OPHGs treated on a PBTC phase 2 trial evaluating efficacy of selumetinib, (AZD6244, ARRY-142886) a MEK-1/2 inhibitor. Stratum 4 of PBTC-029 included patients with sporadic recurrent/progressive OPHGs treated with selumetinib at the recommended phase 2 dose (25mg/m 2 /dose BID) for a maximum of 26 courses.

Results: Twenty-five eligible and evaluable patients were enrolled with a median of 4 (1-11) previous therapies. Six of 25 (24%) had partial response, 14/25 (56%) had stable disease and 5 (20%) had progressive disease while on treatment. The median treatment courses were 26 (2-26); 14/25 patients completed all 26 courses. Two-year PFS was 78 ± 8.5%. Nineteen of 25 patients were evaluable for visual acuity which improved in 4/19 patients (21%), was stable in 13/19 (68%) and worsened in 2/19 (11%). Five of 19 patients (26%) had improved visual fields and 14/19 (74%) were stable. The most common toxicities were grade 1/2 CPK elevation, anemia, diarrhea, headache, nausea/emesis, fatigue, AST and ALT increase, hypoalbuminemia and rash.

Conclusions: Selumetinib was tolerable and led to responses and prolonged disease stability in children with recurrent/progressive OPHGs based upon radiographic response, PFS and visual outcomes.
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http://dx.doi.org/10.1093/neuonc/noab047DOI Listing
February 2021

Integrated molecular and clinical analysis of low-grade gliomas in children with neurofibromatosis type 1 (NF1).

Acta Neuropathol 2021 Apr 14;141(4):605-617. Epub 2021 Feb 14.

Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, Box 8111, St. Louis, MO, 63110, USA.

Low-grade gliomas (LGGs) are the most common childhood brain tumor in the general population and in individuals with the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome. Surgical biopsy is rarely performed prior to treatment in the setting of NF1, resulting in a paucity of tumor genomic information. To define the molecular landscape of NF1-associated LGGs (NF1-LGG), we integrated clinical data, histological diagnoses, and multi-level genetic/genomic analyses on 70 individuals from 25 centers worldwide. Whereas, most tumors harbored bi-allelic NF1 inactivation as the only genetic abnormality, 11% had additional mutations. Moreover, tumors classified as non-pilocytic astrocytoma based on DNA methylation analysis were significantly more likely to harbor these additional mutations. The most common secondary alteration was FGFR1 mutation, which conferred an additional growth advantage in multiple complementary experimental murine Nf1 models. Taken together, this comprehensive characterization has important implications for the management of children with NF1-LGG, distinct from their sporadic counterparts.
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http://dx.doi.org/10.1007/s00401-021-02276-5DOI Listing
April 2021

Molecular Characterization of Species Discovered in Ectoparasites Collected from Domestic Animals, Cuzco, Peru.

Vector Borne Zoonotic Dis 2021 Feb 9. Epub 2021 Feb 9.

Naval Medical Research Center, Silver Spring, Maryland, USA.

Rickettsiae and bartonellae are Gram-negative bacteria that can cause zoonotic and human diseases and are vectored by hematophagous arthropods. In the Americas, rickettsioses and bartonelloses have reemerged as significant public health threats. species have been identified as causing zoonotic infections responsible for a variety of clinical syndromes in humans and animals. The aim of this study was to investigate the distribution, prevalence, and molecular heterogeneity of spp. and spp. among ectoparasites collected from domestic animals in 14 farming communities in the Andes Mountains of Cuzco, Peru. A total of 222 domestic animals representing 8 different species (sheep, donkeys, goats, cattle, pigs, llamas, guinea pigs, and horses) were sampled. Nine species of ectoparasites ( = 1,697) collected from 122 animals were identified resulting in 1,657 chewing lice, 39 ticks, and 1 flea. DNA was individually extracted from a random sample of 600 (35.4%) considering variability of ectoparasite species, hosts, and sample location elevation. All 600 samples were negative for rickettsial DNA by a genus-specific molecular assay. A subset of 173 (28.8%) samples were selected based on variability of arthropods species, host, and location for testing. Ninety-one (52.6%) of these samples including (90/110) and (1/7) were positive for by a genus-specific molecular assay. Five genes of seven DNA samples from were analyzed by the multilocus sequence typing for characterization. We identified five identical specimens and two specimens with species related to from the seven The agents detected were widely distributed and frequent in multiple studied locations.
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http://dx.doi.org/10.1089/vbz.2020.2697DOI Listing
February 2021

NF106: A Neurofibromatosis Clinical Trials Consortium Phase II Trial of the MEK Inhibitor Mirdametinib (PD-0325901) in Adolescents and Adults With NF1-Related Plexiform Neurofibromas.

J Clin Oncol 2021 Mar 28;39(7):797-806. Epub 2021 Jan 28.

Children's Hospital of Philadelphia, Philadelphia, PA.

Purpose: Patients with neurofibromatosis type 1 (NF1) frequently develop plexiform neurofibromas (PNs), which can cause significant morbidity. We performed a phase II trial of the MAPK/ERK kinase inhibitor, mirdametinib (PD-0325901), in patients with NF1 and inoperable PNs. The primary objective was response rate based on volumetric magnetic resonance imaging analysis.

Methods: Inclusion criteria included age ≥ 16 years and a PN that was either progressive or causing significant morbidity. First-dose pharmacokinetics were performed. Patients completed patient-reported outcome measures. Patients received mirdametinib by mouth twice a day at 2 mg/m/dose (maximum dose = 4 mg twice a day) in a 3-week on/1-week off sequence. Each course was 4 weeks in duration. Evaluations were performed after four courses for the first year and then after every six courses. Patients could receive a maximum of 24 total courses.

Results: Nineteen patients were enrolled, and all 19 received mirdametinib. The median age was 24 years (range, 16-39 years); the median baseline tumor volume was 363.8 mL (range, 3.9-5,161 mL). Eight of the 19 patients (42%) achieved a partial response of the target PN by course 12, and 10 (53%) had stable disease. One patient (5%) developed progressive disease at course 8. Significant and durable decreases were observed in pain ratings.

Conclusion: To our knowledge, this analysis represents the first characterization of the activity and pharmacokinetics of mirdametinib in patients with NF1 and PNs and is the first published response study for MAPK/ERK kinase inhibitors in adults with NF1 and PNs. Mirdametinib given at 2 mg/m/dose (maximum dose, 4 mg) twice daily in a 3-week on/1-week off sequence resulted in a 42% partial response rate with preliminary evidence of reduction in pain.
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http://dx.doi.org/10.1200/JCO.20.02220DOI Listing
March 2021

Clinical Outcomes and Patient-Matched Molecular Composition of Relapsed Medulloblastoma.

J Clin Oncol 2021 Mar 27;39(7):807-821. Epub 2021 Jan 27.

Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN.

Purpose: We sought to investigate clinical outcomes of relapsed medulloblastoma and to compare molecular features between patient-matched diagnostic and relapsed tumors.

Methods: Children and infants enrolled on either SJMB03 (NCT00085202) or SJYC07 (NCT00602667) trials who experienced medulloblastoma relapse were analyzed for clinical outcomes, including anatomic and temporal patterns of relapse and postrelapse survival. A largely independent, paired molecular cohort was analyzed by DNA methylation array and next-generation sequencing.

Results: A total of 72 of 329 (22%) SJMB03 and 52 of 79 (66%) SJYC07 patients experienced relapse with significant representation of Group 3 and wingless tumors. Although most patients exhibited some distal disease (79%), 38% of patients with sonic hedgehog tumors experienced isolated local relapse. Time to relapse and postrelapse survival varied by molecular subgroup with longer latencies for patients with Group 4 tumors. Postrelapse radiation therapy among previously nonirradiated SJYC07 patients was associated with long-term survival. Reirradiation was only temporizing for SJMB03 patients. Among 127 patients with patient-matched tumor pairs, 9 (7%) experienced subsequent nonmedulloblastoma CNS malignancies. Subgroup (96%) and subtype (80%) stabilities were largely maintained among the remainder. Rare subgroup divergence was observed from Group 4 to Group 3 tumors, which is coincident with genetic alterations involving , , and . Subgroup-specific patterns of alteration were identified for driver genes and chromosome arms.

Conclusion: Clinical behavior of relapsed medulloblastoma must be contextualized in terms of up-front therapies and molecular classifications. Group 4 tumors exhibit slower biological progression. Utility of radiation at relapse is dependent on patient age and prior treatments. Degree and patterns of molecular conservation at relapse vary by subgroup. Relapse tissue enables verification of molecular targets and identification of occult secondary malignancies.
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http://dx.doi.org/10.1200/JCO.20.01359DOI Listing
March 2021

Cabozantinib for neurofibromatosis type 1-related plexiform neurofibromas: a phase 2 trial.

Nat Med 2021 01 13;27(1):165-173. Epub 2021 Jan 13.

Division of Hematology/Oncology, Department of Pediatrics, Indiana University School of Medicine, Riley Hospital for Children at Indiana University Health, Indianapolis, IN, USA.

Neurofibromatosis type 1 (NF1) plexiform neurofibromas (PNs) are progressive, multicellular neoplasms that cause morbidity and may transform to sarcoma. Treatment of Nf1;Postn-Cre mice with cabozantinib, an inhibitor of multiple tyrosine kinases, caused a reduction in PN size and number and differential modulation of kinases in cell lineages that drive PN growth. Based on these findings, the Neurofibromatosis Clinical Trials Consortium conducted a phase II, open-label, nonrandomized Simon two-stage study to assess the safety, efficacy and biologic activity of cabozantinib in patients ≥16 years of age with NF1 and progressive or symptomatic, inoperable PN ( NCT02101736 ). The trial met its primary outcome, defined as ≥25% of patients achieving a partial response (PR, defined as ≥20% reduction in target lesion volume as assessed by magnetic resonance imaging (MRI)) after 12 cycles of therapy. Secondary outcomes included adverse events (AEs), patient-reported outcomes (PROs) assessing pain and quality of life (QOL), pharmacokinetics (PK) and the levels of circulating endothelial cells and cytokines. Eight of 19 evaluable (42%) trial participants achieved a PR. The median change in tumor volume was 15.2% (range, +2.2% to -36.9%), and no patients had disease progression while on treatment. Nine patients required dose reduction or discontinuation of therapy due to AEs; common AEs included gastrointestinal toxicity, hypothyroidism, fatigue and palmar plantar erythrodysesthesia. A total of 11 grade 3 AEs occurred in eight patients. Patients with PR had a significant reduction in tumor pain intensity and pain interference in daily life but no change in global QOL scores. These data indicate that cabozantinib is active in NF1-associated PN, resulting in tumor volume reduction and pain improvement.
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http://dx.doi.org/10.1038/s41591-020-01193-6DOI Listing
January 2021

Outcomes by Clinical and Molecular Features in Children With Medulloblastoma Treated With Risk-Adapted Therapy: Results of an International Phase III Trial (SJMB03).

J Clin Oncol 2021 Mar 6;39(7):822-835. Epub 2021 Jan 6.

Division of Brain Tumor Research, Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN.

Purpose: SJMB03 (ClinicalTrials.gov identifier: NCT00085202) was a phase III risk-adapted trial that aimed to determine the frequency and clinical significance of biological variants and genetic alterations in medulloblastoma.

Patients And Methods: Patients 3-21 years old were stratified into average-risk and high-risk treatment groups based on metastatic status and extent of resection. Medulloblastomas were molecularly classified into subgroups (Wingless [WNT], Sonic Hedgehog [SHH], group 3, and group 4) and subtypes based on DNA methylation profiles and overlaid with gene mutations from next-generation sequencing. Coprimary study end points were (1) to assess the relationship between ERBB2 protein expression in tumors and progression-free survival (PFS), and (2) to estimate the frequency of mutations associated with WNT and SHH tumors. Clinical and molecular risk factors were evaluated, and the most robust were used to model new risk-classification categories.

Results: Three hundred thirty eligible patients with medulloblastoma were enrolled. Five-year PFS was 83.2% (95% CI, 78.4 to 88.2) for average-risk patients (n = 227) and 58.7% (95% CI, 49.8 to 69.1) for high-risk patients (n = 103). No association was found between ERBB2 status and PFS in the overall cohort ( = .74) or when patients were stratified by clinical risk ( = .71). Mutations in (96%), (37%), and (24%) were most common in WNT tumors and (38%), (21%), and (19%) in SHH tumors. Methylome profiling classified 53 WNT (17.4%), 48 SHH (15.7%), 65 group 3 (21.3%), and 139 group 4 (45.6%) tumors. A comprehensive clinicomolecular risk factor analysis identified three low-risk groups (WNT, low-risk SHH, and low-risk combined groups 3 and 4) with excellent (5-year PFS > 90%) and two very high-risk groups (high-risk SHH and high-risk combined groups 3 and 4) with poor survival (5-year PFS < 60%).

Conclusion: These results establish a new risk stratification for future medulloblastoma trials.
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http://dx.doi.org/10.1200/JCO.20.01372DOI Listing
March 2021

Visual outcomes following everolimus targeted therapy for neurofibromatosis type 1-associated optic pathway gliomas in children.

Pediatr Blood Cancer 2021 Apr 18;68(4):e28833. Epub 2020 Dec 18.

Dana-Farber/Boston Children's Cancer and Blood Disorder Center, Boston, Massachusetts.

Data for visual acuity (VA) after treatment of neurofibromatosis type 1-associated optic pathway gliomas (NF1-OPGs) are limited. We retrospectively collected VA, converted to logMAR, before and after targeted therapy with everolimus for NF1-OPG, and compared to radiologic outcomes (14/18 with NF1-OPG, 25 eyes [three without quantifiable vision]). Upon completion of treatment, VA was stable in 19 eyes, improved in four eyes, and worsened in two eyes; visual and radiologic outcomes were discordant. In summary, the majority of children with NF1-OPG exhibited stabilization of their VA after everolimus treatment. A larger, prospective study will help delineate visual outcomes after targeted therapy.
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http://dx.doi.org/10.1002/pbc.28833DOI Listing
April 2021

Visual field outcomes in children treated for neurofibromatosis type 1-associated optic pathway gliomas: a multicenter retrospective study.

J AAPOS 2020 12 20;24(6):349.e1-349.e5. Epub 2020 Nov 20.

Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.

Background: Optic pathway gliomas associated with neurofibromatosis type 1 (NF1-OPGs) may adversely affect visual acuity, but data regarding visual field (VF) outcomes after treatment in children are limited. The purpose of this study was to investigate the effects of NF1-OPGs on VF function in a large cohort of children after treatment with chemotherapy.

Methods: We performed a retrospective, international, multicenter study of VF outcomes in patients treated with chemotherapy for NF1-OPGs.

Results: A total of 25 participants underwent VF testing using formal perimetric techniques. At the end of treatment, 19 participants (76%) had persistent VF deficits. Formal VF testing was available for 16 participants (64%) at initiation and completion of treatment. Of the 16 children who underwent VF testing at initiation and completion of treatment, 7 (44%) showed stability of VF changes, 3 (19%) showed improvement of VF function, and 6 (38%) had worsening of VFs. Improvement or worsening of VF outcome did not always correlate with visual acuity outcome. Posterior tumor location involving the optic tracts and radiations was associated with more frequent and more profound VF defects.

Conclusions: In our study cohort, children undergoing initial chemotherapy for NF1-OPGs had a high prevalence of VF loss, which could be independent of visual acuity loss. A larger, prospective study is necessary to fully determine the prevalence of VF loss and the effects of chemotherapy on VF outcomes in children with NF1-OPGs.
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http://dx.doi.org/10.1016/j.jaapos.2020.07.013DOI Listing
December 2020

Sources of and Solutions to Toxic Metal and Metalloid Contamination in Small Rural Drinking Water Systems: A Rapid Review.

Int J Environ Res Public Health 2020 09 27;17(19). Epub 2020 Sep 27.

The Water Institute, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

Exposure to toxic metals and metalloids (TMs) such as arsenic and lead at levels of concern is associated with lifelong adverse health consequences. As exposure to TMs from paint, leaded gasoline, canned foods, and other consumer products has decreased in recent decades, the relative contribution of drinking water to environmental TM exposure and associated disease burdens has increased. We conducted a rapid review from June to September 2019 to synthesize information on the sources of TM contamination in small rural drinking water systems and solutions to TM contamination from these sources, with an emphasis on actionable evidence applicable to small rural drinking water systems worldwide. We reviewed publications from five databases (ProQuest, PubMed, Web of Science, Embase, and Global Health Library) as well as grey literature from expert groups including WHO, IWA, and others; findings from 61 eligible review publications were synthesized. Identified sources of TMs in included studies were natural occurrence (geogenic), catchment pollution, and corrosion of water distribution system materials. The review found general support for preventive over corrective actions. This review informs a useful planning and management framework for preventing and mitigating TM exposure from drinking water based on water supply characteristics, identified contamination sources, and other context-specific variables.
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http://dx.doi.org/10.3390/ijerph17197076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7579501PMC
September 2020

Antibody Responses Against Immunogenic Peptides in Infected Humans.

Front Cell Infect Microbiol 2020 31;10:455. Epub 2020 Aug 31.

Division of Parasitic Diseases and Malaria, Entomology Branch, Centers for Disease Control and Prevention, Atlanta, GA, United States.

Malaria is still an important vector-borne disease in the New World tropics. Despite the recent decline in malaria due to infection in Africa, a rise in infections has been detected in several low malaria transmission areas in Latin America. One of the main obstacles in the battle against malaria is the lack of innovative tools to assess malaria transmission risk, and the behavioral plasticity of one of the main malaria vectors in Latin America, . We used human IgG antibodies against mosquito salivary gland proteins as a measure of disease risk. Whole salivary gland antigen (SGA) from mosquitoes was used as antigen in Western blot experiments, in which a ~65 kDa protein was visualized as the main immunogenic band and sent for sequencing by mass spectrometry. Apyrase and peroxidase peptides were designed and used as antigens in an ELISA-based test to measure human IgG antibody responses in people with different clinical presentations of malaria. Liquid chromatography-mass spectrometry revealed 17 proteins contained in the ~65 kDa band, with an apyrase and a peroxidase as the two most abundant proteins. Detection of IgG antibodies against salivary antigens by ELISA revealed a significant higher antibody levels in people with malaria infection when compared to uninfected volunteers using the AnDar_Apy1 and AnDar_Apy2 peptides. We also detected a significant positive correlation between the anti-peptides IgG levels and antibodies against the and antigens PvMSP1 and PfMSP1. Odd ratios suggest that people with higher IgG antibodies against the apyrase peptides were up to five times more likely to have a malaria infection. Antibodies against salivary peptides from salivary gland proteins may be used as biomarkers for malaria risk.
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http://dx.doi.org/10.3389/fcimb.2020.00455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488213PMC
August 2020

Rationale and design of the Medical Research Council's Precision Medicine with Zibotentan in Microvascular Angina (PRIZE) trial.

Am Heart J 2020 11 17;229:70-80. Epub 2020 Jul 17.

British Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom. Electronic address:

Microvascular angina is caused by cardiac small vessel disease, and dysregulation of the endothelin system is implicated. The minor G allele of the non-coding single nucleotide polymorphism (SNP) rs9349379 enhances expression of the endothelin 1 gene in human vascular cells, increasing circulating concentrations of ET-1. The prevalence of this allele is higher in patients with ischemic heart disease. Zibotentan is a potent, selective inhibitor of the ET receptor. We have identified zibotentan as a potential disease-modifying therapy for patients with microvascular angina. METHODS: We will assess the efficacy and safety of adjunctive treatment with oral zibotentan (10 mg daily) in patients with microvascular angina and assess whether rs9349379 (minor G allele; population prevalence ~36%) acts as a theragnostic biomarker of the response to treatment with zibotentan. The PRIZE trial is a prospective, randomized, double-blind, placebo-controlled, sequential cross-over trial. The study population will be enriched to ensure a G-allele frequency of 50% for the rs9349379 SNP. The participants will receive a single-blind placebo run-in followed by treatment with either 10 mg of zibotentan daily for 12 weeks then placebo for 12 weeks, or vice versa, in random order. The primary outcome is treadmill exercise duration using the Bruce protocol. The primary analysis will assess the within-subject difference in exercise duration following treatment with zibotentan versus placebo. CONCLUSION: PRIZE invokes precision medicine in microvascular angina. Should our hypotheses be confirmed, this developmental trial will inform the rationale and design for undertaking a larger multicenter trial.
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http://dx.doi.org/10.1016/j.ahj.2020.07.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674581PMC
November 2020

Predicting pediatric optic pathway glioma progression using advanced magnetic resonance image analysis and machine learning.

Neurooncol Adv 2020 Jan-Dec;2(1):vdaa090. Epub 2020 Aug 1.

Center for Biomedical Image Computing and Analytics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Background: Optic pathway gliomas (OPGs) are low-grade tumors of the white matter of the visual system with a highly variable clinical course. The aim of the study was to generate a magnetic resonance imaging (MRI)-based predictive model of OPG tumor progression using advanced image analysis and machine learning techniques.

Methods: We performed a retrospective case-control study of OPG patients managed between 2009 and 2015 at an academic children's hospital. Progression was defined as radiographic tumor growth or vision decline. To generate the model, optic nerves were manually highlighted and optic radiations (ORs) were segmented using diffusion tractography tools. For each patient, intensity distributions were obtained from within the segmented regions on all imaging sequences, including derivatives of diffusion tensor imaging (DTI). A machine learning algorithm determined the combination of features most predictive of progression.

Results: Nineteen OPG patients with progression were matched to 19 OPG patients without progression. The mean time between most recent follow-up and most recently analyzed MRI was 3.5 ± 1.7 years. Eighty-three MRI studies and 532 extracted features were included. The predictive model achieved an accuracy of 86%, sensitivity of 89%, and specificity of 81%. Fractional anisotropy of the ORs was among the most predictive features (area under the curve 0.83, < 0.05).

Conclusions: Our findings show that image analysis and machine learning can be applied to OPGs to generate a MRI-based predictive model with high accuracy. As OPGs grow along the visual pathway, the most predictive features relate to white matter changes as detected by DTI, especially within ORs.
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http://dx.doi.org/10.1093/noajnl/vdaa090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455885PMC
August 2020

Low rate of bacterial co-infection in patients with COVID-19.

Lancet Microbe 2020 Jun 8;1(2):e62. Epub 2020 Jun 8.

Department of Microbiology, St Helens and Knowsley Teaching Hospitals NHS Trust, Prescot, L35 5DR, UK.

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http://dx.doi.org/10.1016/S2666-5247(20)30036-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279742PMC
June 2020

Efficacy and safety of once-daily nitisinone for patients with alkaptonuria (SONIA 2): an international, multicentre, open-label, randomised controlled trial.

Lancet Diabetes Endocrinol 2020 09 18;8(9):762-772. Epub 2020 Aug 18.

Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK.

Background: Alkaptonuria is a rare, genetic, multisystem disease characterised by the accumulation of homogentisic acid (HGA). No HGA-lowering therapy has been approved to date. The aim of SONIA 2 was to investigate the efficacy and safety of once-daily nitisinone for reducing HGA excretion in patients with alkaptonuria and to evaluate whether nitisinone has a clinical benefit.

Methods: SONIA 2 was a 4-year, open-label, evaluator-blind, randomised, no treatment controlled, parallel-group study done at three sites in the UK, France, and Slovakia. Patients aged 25 years or older with confirmed alkaptonuria and any clinical disease manifestations were randomly assigned (1:1) to receive either oral nitisinone 10 mg daily or no treatment. Patients could not be masked to treatment due to colour changes in the urine, but the study was evaluator-blinded as far as possible. The primary endpoint was daily urinary HGA excretion (u-HGA) after 12 months. Clinical evaluation Alkaptonuria Severity Score Index (cAKUSSI) score was assessed at 12, 24, 36, and 48 months. Efficacy variables were analysed in all randomly assigned patients with a valid u-HGA measurement at baseline. Safety variables were analysed in all randomly assigned patients. The study was registered at ClinicalTrials.gov (NCT01916382).

Findings: Between May 7, 2014, and Feb 16, 2015, 139 patients were screened, of whom 138 were included in the study, with 69 patients randomly assigned to each group. 55 patients in the nitisinone group and 53 in the control group completed the study. u-HGA at 12 months was significantly decreased by 99·7% in the nitisinone group compared with the control group (adjusted geometric mean ratio of nitisinone/control 0·003 [95% CI 0·003 to 0·004], p<0·0001). At 48 months, the increase in cAKUSSI score from baseline was significantly lower in the nitisinone group compared with the control group (adjusted mean difference -8·6 points [-16·0 to -1·2], p=0·023). 400 adverse events occurred in 59 (86%) patients in the nitisinone group and 284 events occurred in 57 (83%) patients in the control group. No treatment-related deaths occurred.

Interpretation: Nitisinone 10 mg daily was well tolerated and effective in reducing urinary excretion of HGA. Nitisinone decreased ochronosis and improved clinical signs, indicating a slower disease progression.

Funding: European Commission Seventh Framework Programme.
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http://dx.doi.org/10.1016/S2213-8587(20)30228-XDOI Listing
September 2020

Combat Stress Management and Resilience: Adapting Department of Defense Combat Lessons Learned to Civilian Healthcare during the COVID-19 Pandemic.

Health Secur 2020 Jul 17. Epub 2020 Jul 17.

Eric K. Wei, MD, MBA, is Chief Quality Officer; Jeremy Segall, MA, RDT, LCAT, is Chief Wellness Officer; and Hyung J. Cho, MD, is Chief Value Officer; all in the Office of Quality and Safety, New York City Health and Hospitals, New York, NY. Rebecca Linn-Walton, PhD, LCSW, is Assistant Vice President; Omar Fattal, MD, MPH, is Deputy Medical Director; and Charles Barron, MD, is Deputy Medical Officer; all in the Office of Behavioral Health, New York City Health and Hospitals, New York, NY. Hyung J. Cho and Omar Fattal are also Clinical Associate Professors, Department of Medicine, NYU Grossman School of Medicine, New York, NY. Monika Eros-Sarnyai, MD, MA, is a Best Practices Specialist, New York City Department of Health and Mental Hygiene, New York, NY. Olli Toukolehto, MD, is a Major, Medical Corps, United States Army, and Deputy Department Chief, Adult Behavioral Health, Fort Belvoir Community Hospital, Fort Belvoir, VA. Alison Burke, JD, is Vice President, Regulatory and Professional Affairs, Greater New York Hospital Association, New York, NY. David M. Benedek, MD, is Professor and Chair; and James C. West, MD, is an Associate Professor; both in the Department of Psychiatry, Uniformed Services University of the Health Sciences, Bethesda, MD. David M. Benedek is also a Colonel, United States Marine Corps. Michael Fisher, MSW, is Chief Readjustment Counseling Officer, Veterans Health Administration, Washington, DC. David Shmerler, PhD, is Director of Counseling Service Unit, Fire Department of the City of New York, New York, NY.

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http://dx.doi.org/10.1089/hs.2020.0091DOI Listing
July 2020

WaSH CQI: Applying continuous quality improvement methods to water service delivery in four districts of rural northern Ghana.

PLoS One 2020 15;15(7):e0233679. Epub 2020 Jul 15.

Public Health Leadership Program, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, United States of America.

Continuous, safely managed water is critical to health and development, but rural service delivery faces complex challenges in low- and middle-income countries (LMICs). We report the first application of continuous quality improvement (CQI) methods to improve the microbial quality of household water for consumption (HWC) and the functionality of water sources in four rural districts of northern Ghana. We further report on the impacts of interventions developed through these methods. A local CQI team was formed and trained in CQI methods. Baseline data were collected and analyzed to identify determinants of service delivery problems and microbial safety. The CQI team randomized communities, developed an improvement package, iteratively piloted it in intervention communities, and used uptake survey data to refine the package. The final improvement package comprised safe water storage containers, refresher training for community WaSH committees and replacement of missing maintenance tools. This package significantly reduced contamination of HWC (p<0.01), and significant reduction in contamination persisted two years after implementation. Repair times in both intervention and control arms decreased relative to baseline (p<0.05), but differences between intervention and control arms were not significant at endline. Further work is needed to build on the gains in household water quality observed in this work, sustain and scale these improvements, and explore applications of CQI to other aspects of water supply and sanitation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0233679PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7363065PMC
September 2020

Effect of age and neurofibromatosis type 1 status on white matter integrity in the optic radiations.

Neurooncol Adv 2020 Jul 25;2(Suppl 1):i150-i158. Epub 2020 Jun 25.

Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

Background: Adults with neurofibromatosis type 1 (NF1) have decreased white matter integrity, but differences in children with NF1 have not been described. Defining normal values for diffusion tensor imaging (DTI) measures, especially in the optic radiations, is important to the development of DTI as a potential biomarker of visual acuity in children with optic pathway glioma. This study examines the effect of age and NF1 status on DTI measures in children.

Methods: In this retrospective study, MR imaging including DTI was conducted in 93 children (40 children with NF1 and 53 healthy controls) between 0 and 14 years of age. Regression models of age, sex, and NF1 status on DTI measures were evaluated, and tract-based spatial statistics (TBSS) compared DTI measures in age-matched NF1 to non-NF1 cohorts.

Results: Fractional anisotropy, radial diffusivity, and mean diffusivity in white matter tracts of the optic radiations varied with age and were best modeled by a logarithmic function. Age-related DTI measure change was different in NF1 versus non-NF1 subjects. Normal values and 95% confidence intervals for age 0.5-12 years were derived for both groups. Differences in DTI measures between NF1 and non-NF1 groups at a range of ages were shown diffusely throughout the cerebral white matter using TBSS.

Conclusions: Children with NF1 demonstrate increased diffusion throughout the brain compared to children without NF1 suggesting a potentially altered developmental trajectory of optic radiation microstructure. Defining normal values for white matter integrity in children with NF1 may help target early intervention efforts in this vulnerable group.
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http://dx.doi.org/10.1093/noajnl/vdaa037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317057PMC
July 2020

Children drinking private well water have higher blood lead than those with city water.

Proc Natl Acad Sci U S A 2020 07 6;117(29):16898-16907. Epub 2020 Jul 6.

Sanford School of Public Policy, Duke University, Durham, NC 27708.

Although the Flint, Michigan, water crisis renewed concerns about lead (Pb) in city drinking water, little attention has been paid to Pb in private wells, which provide drinking water for 13% of the US population. This study evaluates the risk of Pb exposure in children in households relying on private wells. It is based on a curated dataset of blood Pb records from 59,483 North Carolina children matched with household water source information. We analyze the dataset for statistical associations between children's blood Pb and household drinking water source. The analysis shows that children in homes relying on private wells have 25% increased odds (95% CI 6.2 to 48%, < 0.01) of elevated blood Pb, compared with children in houses served by a community water system that is regulated under the Safe Drinking Water Act. This increased Pb exposure is likely a result of corrosion of household plumbing and well components, because homes relying on private wells rarely treat their water to prevent corrosion. In contrast, corrosion control is required in regulated community water systems. These findings highlight the need for targeted outreach to prevent Pb exposure for the 42.5 million Americans depending on private wells for their drinking water.
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http://dx.doi.org/10.1073/pnas.2002729117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7382258PMC
July 2020

Correction to: Health-related qualify of life, angina type and coronary artery disease in patients with stable chest pain.

Health Qual Life Outcomes 2020 06 29;18(1):205. Epub 2020 Jun 29.

Institute of Public Health, Charité-Universitätsmedizin Berlin, corporatemember of Freie Universität Berlin, Humboldt-Universität zu Berlin, and BerlinInstitute of Health, Berlin, Germany.

An amendment to this paper has been published and can be accessed via the original article.
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http://dx.doi.org/10.1186/s12955-020-01443-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322859PMC
June 2020

Late morbidity and mortality in adult survivors of childhood glioma with neurofibromatosis type 1: report from the Childhood Cancer Survivor Study.

Genet Med 2020 11 23;22(11):1794-1802. Epub 2020 Jun 23.

Departments of Epidemiology and Cancer Control, Oncology and Psychology, St. Jude Children's Research Hospital, Memphis, TN, USA.

Purpose: Neurofibromatosis type 1 (NF1) is associated with tumor predisposition and nonmalignant health conditions. Whether survivors of childhood cancer with NF1 are at increased risk for poor long-term health outcomes is unknown.

Methods: One hundred forty-seven 5+ year survivors of childhood glioma with NF1 from the Childhood Cancer Survivor Study were compared with 2629 non-NF1 glioma survivors and 5051 siblings for late mortality, chronic health conditions, and psychosocial, neurocognitive, and socioeconomic outcomes.

Results: Survivors with NF1 (age at diagnosis: 6.8 ± 4.8 years) had greater cumulative incidence of late mortality 30 years after diagnosis (46.3% [95% confidence interval: 23.9-62.2%]) compared with non-NF1 survivors (18.0% [16.1-20.0%]) and siblings (0.9% [0.6-1.2%]), largely due to subsequent neoplasms. Compared with survivors without NF1, those with NF1 had more severe/life-threatening chronic conditions at cohort entry (46.3% [38.1-54.4%] vs. 30.8% [29.1-32.6%]), but similar rates of new conditions during follow-up (rate ratio: 1.26 [0.90-1.77]). Survivors with NF1 were more likely to report psychosocial impairments, neurocognitive deficits, and socioeconomic difficulties compared with survivors without NF1.

Conclusions: Late mortality among glioma survivors with NF1 is twice that of other survivors, due largely to subsequent malignancies. Screening, prevention, and early intervention for chronic health conditions and psychosocial and neurocognitive deficits may reduce long-term morbidity in this vulnerable population.
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http://dx.doi.org/10.1038/s41436-020-0873-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606750PMC
November 2020

Identification of high-risk non-ST elevation myocardial infarction at presentation to emergency department. A prospective observational cohort study in North West England.

BMJ Open 2020 06 8;10(6):e030128. Epub 2020 Jun 8.

Liverpool Clinical Trials Centre, University of Liverpool, UK, Liverpool, England.

Objectives: Early access to invasive coronary angiography and revascularisation for high-risk non-ST elevation myocardial infarction (NSTEMI) improves outcomes and is supported by current guidelines. We sought to determine the most effective criteria at presentation to emergency department (ED) to identify high-risk NSTEMI.

Setting: Secondary care centre northwest England with national follow-up.

Participants: 1642 consecutive patients (median age 59, 52% male) presenting to ED with a primary symptom of chest pain in whom there is suspicion of NSTEMI.

Primary And Secondary Measures: Multivariate logistic regression analysis for the prediction of all-cause death (primary) and major adverse cardiac event (MACE defined as all-cause death, unplanned coronary revascularisation and adjudicated NSTEMI (third universal definition)) (secondary measure) at 1 year.

Results: The incidence of adjudicated NSTEMI was 10.7%, and 1-year mortality was 6.3%. Independent predictors for all-cause death at 1 year were Global Registry of Acute Coronary Events (GRACE) >140, age (per decade increase) and high-sensitive cardiac troponin T (hs-cTnT) >50 ng/L. hs-cTnT >50 ng/L was associated with adjudicated index presentation NSTEMI in the greatest proportion of patients (61.7%). When using MACE at 12 months, as opposed to all-cause death, as an end point History, ECG, Age, Risk factors and Troponin (HEART) score ≥7 was included in the multivariate model and had better prediction of index NSTEMI than GRACE>140. Combining hs-cTnT >50 ng/L and a second independent predictor identified both a high proportion of index NSTEMI and elevated risk of all-cause death at 1 year.

Conclusions: hs-cTnT >50 ng/L or HEART score ≥7 appear effective strategies to identify high-risk NSTEMI at presentation to emergency room with chest pain. Multicentre prospective studies enriched with early presenters, and with competitor high-sensitive and point-of-care troponins, are required to validate and extend these findings.

Trial Registration Number: NCT02581540.
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http://dx.doi.org/10.1136/bmjopen-2019-030128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7282291PMC
June 2020

Response assessment in paediatric low-grade glioma: recommendations from the Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group.

Lancet Oncol 2020 06;21(6):e305-e316

Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Dana-Farber Cancer Institute, Boston, MA, USA.

Paediatric low-grade gliomas (also known as pLGG) are the most common type of CNS tumours in children. In general, paediatric low-grade gliomas show clinical and biological features that are distinct from adult low-grade gliomas, and the developing paediatric brain is more susceptible to toxic late effects of the tumour and its treatment. Therefore, response assessment in children requires additional considerations compared with the adult Response Assessment in Neuro-Oncology criteria. There are no standardised response criteria in paediatric clinical trials, which makes it more difficult to compare responses across studies. The Response Assessment in Pediatric Neuro-Oncology working group, consisting of an international panel of paediatric and adult neuro-oncologists, clinicians, radiologists, radiation oncologists, and neurosurgeons, was established to address issues and unique challenges in assessing response in children with CNS tumours. We established a subcommittee to develop consensus recommendations for response assessment in paediatric low-grade gliomas. Final recommendations were based on literature review, current practice, and expert opinion of working group members. Consensus recommendations include imaging response assessments, with additional guidelines for visual functional outcomes in patients with optic pathway tumours. As with previous consensus recommendations, these recommendations will need to be validated in prospective clinical trials.
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http://dx.doi.org/10.1016/S1470-2045(20)30064-4DOI Listing
June 2020

Qualitative Methods in Health Policy and Systems Research: A Framework for Study Planning.

Qual Health Res 2020 10 25;30(12):1899-1912. Epub 2020 May 25.

University of Colorado School of Medicine, Aurora, Colorado, USA.

Qualitative methodologies and methods are commonly used in health policy and systems research but have not been extensively characterized. We describe how qualitative approaches are used within the field and present a framework to aid researchers in study planning. To achieve these aims, we conducted a scoping literature review of 1 year of selected health policy and systems research and then coded publications based on their primary analytical foci. Four core themes emerged: policy or program , an analysis of the substance of policies or program documents; policy or program , a study of the landscape of policies or programs; policy or program , a study of the planned or actual execution of a policy or program; and organization or system , a study of the structure or function of health organizations or systems. We provide guidance on utilizing the framework and adhering to qualitative best practices during the process.
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http://dx.doi.org/10.1177/1049732320921143DOI Listing
October 2020

Health-related qualify of life, angina type and coronary artery disease in patients with stable chest pain.

Health Qual Life Outcomes 2020 05 14;18(1):140. Epub 2020 May 14.

Institute of Public Health, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Background: Health-related quality of life (HRQoL) is impaired in patients with stable angina but patients often present with other forms of chest pain. The aim of this study was to compare the pre-diagnostic HRQoL in patients with suspected coronary artery disease (CAD) according to angina type, gender, and presence of obstructive CAD.

Methods: From the pilot study for the European DISCHARGE trial, we analysed data from 24 sites including 1263 patients (45.9% women, 61.1 ± 11.3 years) who were clinically referred for invasive coronary angiography (ICA; 617 patients) or coronary computed tomography angiography (CTA; 646 patients). Prior to the procedures, patients completed HRQoL questionnaires: the Short Form (SF)-12v2, the EuroQoL (EQ-5D-3 L) and the Hospital Anxiety and Depression Scale.

Results: Fifty-five percent of ICA and 35% of CTA patients had typical angina, 23 and 33% had atypical angina, 18 and 28% had non-anginal chest discomfort and 5 and 5% had other chest discomfort, respectively. Patients with typical angina had the poorest physical functioning compared to the other angina groups (SF-12 physical component score; 41.2 ± 8.8, 43.3 ± 9.1, 46.2 ± 9.0, 46.4 ± 11.4, respectively, all age and gender-adjusted p < 0.01), and highest anxiety levels (8.3 ± 4.1, 7.5 ± 4.1, 6.5 ± 4.0, 4.7 ± 4.5, respectively, all adjusted p < 0.01). On all other measures, patients with typical or atypical angina had lower HRQoL compared to the two other groups (all adjusted p < 0.05). HRQoL did not differ between patients with and without obstructive CAD while women had worse HRQoL compared with men, irrespective of age and angina type.

Conclusions: Prior to a diagnostic procedure for stable chest pain, HRQoL is associated with chest pain characteristics, but not with obstructive CAD, and is significantly lower in women.

Trial Registration: Clinicaltrials.gov, NCT02400229.
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http://dx.doi.org/10.1186/s12955-020-01312-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7222590PMC
May 2020

FGFR Inhibition Enhances Sensitivity to Radiation in Non-Small Cell Lung Cancer.

Mol Cancer Ther 2020 06 5;19(6):1255-1265. Epub 2020 May 5.

Department of Human Oncology, University of Wisconsin Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin.

FGFRs are commonly altered in non-small cell lung cancer (NSCLC). FGFRs activate multiple pathways including RAS/RAF/MAPK, PI3K/AKT, and STAT, which may play a role in the cellular response to radiation. We investigated the effects of combining the selective FGFR 1-3 tyrosine kinase inhibitor AZD4547 with radiation in cell line and xenograft models of NSCLC. NSCLC cell lines were assessed with proliferation, clonogenic survival, apoptosis, autophagy, cell cycle, and DNA damage signaling and repair assays. xenografts and IHC were used to confirm results. NSCLC cell lines demonstrated varying degrees of FGFR protein and mRNA expression. clonogenic survival assays showed radiosensitization with AZD4547 in two NSCLC cell lines. In these two cell lines, an increase in apoptosis and autophagy was observed with combined radiation and AZD4547. The addition of AZD4547 to radiation did not significantly affect γH2AX foci formation. Enhanced xenograft tumor growth delay was observed with the combination of radiation and AZD4547 compared with radiation or drug alone. IHC results revealed inhibition of pMAPK and pS6 and demonstrated an increase in apoptosis in the radiation plus AZD4547 group. This study demonstrates that FGFR inhibition by AZD4547 enhances the response of radiation in FGFR-expressing NSCLC and model systems. These results support further investigation of combining FGFR inhibition with radiation as a clinical therapeutic strategy.
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http://dx.doi.org/10.1158/1535-7163.MCT-19-0931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272291PMC
June 2020

Fibroblast Growth Factor Receptors as Targets for Radiosensitization in Head and Neck Squamous Cell Carcinomas.

Int J Radiat Oncol Biol Phys 2020 07 13;107(4):793-803. Epub 2020 Apr 13.

Department of Human Oncology, University of Wisconsin Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin. Electronic address:

Purpose: We examined the capacity of the pan-fibroblast growth factor receptor (FGFR) inhibitor AZD4547 to augment radiation response across a panel of head and neck squamous cell carcinoma (HNSCC) cell lines and xenografts.

Methods And Materials: FGFR1, FGFR2, and FGFR3 RNA in situ hybridization expression was assessed in a cohort of HNSCC patient samples, cell lines, and patient-derived xenografts (PDXs). In vitro effects of AZD4547 and radiation on cell survival, FGFR signaling, apoptosis, autophagy, cell cycle, and DNA damage repair were evaluated. Reverse phase protein array was used to identify differentially phosphorylated proteins in cells treated with AZD4547. In vivo tumor responses were evaluated in cell lines and PDX models.

Results: FGFR1, FGFR2, and FGFR3 RNA in situ hybridization were expressed in 41%, 81%, and 89% of 107 oropharynx patient samples. Sensitivity to AZD4547 did not directly correlate with FGFR protein or RNA expression. In sensitive cell lines, AZD4547 inhibited p-MAPK in a time-dependent manner. Significant radiosensitization with AZD4547 was observed in cell lines that were sensitive to AZD4547. The mechanism underlying these effects appears to be multifactorial, involving inhibition of the MTOR pathway and subsequent enhancement of autophagy and activation of apoptotic pathways. Significant tumor growth delay was observed when AZD4547 was combined with radiation compared with radiation or drug alone in an FGFR-expressing HNSCC cell line xenograft and PDX.

Conclusions: These findings suggest that AZD4547 can augment the response of radiation in FGFR-expressing HNSCC in vivo model systems. FGFR1 and FGFR2 may prove worthy targets for radiosensitization in HNSCC clinical investigations.
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http://dx.doi.org/10.1016/j.ijrobp.2020.03.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7321889PMC
July 2020

A phase II study of continuous oral mTOR inhibitor everolimus for recurrent, radiographic-progressive neurofibromatosis type 1-associated pediatric low-grade glioma: a Neurofibromatosis Clinical Trials Consortium study.

Neuro Oncol 2020 10;22(10):1527-1535

Department of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts.

Background: Activation of the mammalian target of rapamycin (mTOR) pathway is observed in neurofibromatosis type 1 (NF1) associated low-grade gliomas (LGGs), but agents that inhibit this pathway, including mTOR inhibitors, have not been studied in this population. We evaluate the efficacy of the orally administered mTOR inhibitor everolimus for radiographically progressive NF1-associated pediatric LGGs.

Methods: Children with radiologic-progressive, NF1-associated LGG and prior treatment with a carboplatin-containing chemotherapy were prospectively enrolled on this phase II clinical trial to receive daily everolimus. Whole blood was analyzed for everolimus and markers of phosphatidylinositol-3 kinase (PI3K)/mTOR pathway inhibition. Serial MRIs were obtained during treatment. The primary endpoint was progression-free survival at 48 weeks.

Results: Twenty-three participants (median age, 9.4 y; range, 3.2-21.6 y) were enrolled. All participants were initially evaluable for response; 1 patient was removed from study after development of a malignant peripheral nerve sheath tumor. Fifteen of 22 participants (68%) demonstrated a response, defined as either shrinkage (1 complete response, 2 partial response) or arrest of tumor growth (12 stable disease). Of these, 10/15 remained free of progression (median follow-up, 33 mo). All remaining 22 participants were alive at completion of therapy. Treatment was well tolerated; no patient discontinued therapy due to toxicity. Pharmacokinetic parameters and pre-dose concentrations showed substantial between-subject variability. PI3K/mTOR pathway inhibition markers demonstrating blood mononuclear cell mTOR pathway inactivation was achieved in most participants.

Conclusion: Individuals with recurrent/progressive NF1-associated LGG demonstrate significant disease stability/shrinkage during treatment with oral everolimus with a well-tolerated toxicity profile. Everolimus is well suited for future consideration as upfront or combination therapy in this patient population.
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http://dx.doi.org/10.1093/neuonc/noaa071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566451PMC
October 2020