Development of international consensus recommendations using a modified Delphi approach

Funding Information: This work was supported by BioMarin Pharmaceutical Inc . Funding Information: The content of this manuscript was based on preparatory pre-meeting activities and presentations and discussions during two advisory board meetings that were coordinated and funded by BioMarin Pharmaceutical Inc. All authors or their institutions received funding from BioMarin to attend at least one or both meetings. Additional disclosures: BKB received consulting payments from BioMarin, Shire, Genzyme, Alexion, Horizon Therapeutics, Denali Therapeutics, JCR Pharma, Moderna, Aeglea BioTherapeutics, SIO Gene Therapies, Taysha Gene Therapy, Ultragenyx, and Inventiva Pharma, participated as clinical trial investigator for BioMarin, Shire, Denali Therapeutics, Homology Medicines, Ultragenyx, and Moderna as well as received speaker fees from BioMarin, Shire, Genzyme, and Horizon Therapeutics. AH received consulting payments from BioMarin, Chiesi, Shire, Genzyme, Amicus, and Ultragenyx, participated as clinical trial investigator for Ultragenyx as well as received speaker fees from Alexion, Amicus, BioMarin, Genzyme, Nutricia, Sobi, and Takeda. ABQ received consulting payments from BioMarin, speaker fees from BioMarin, Nutricia, Vitaflo, Sanofi, Takeda, Recordati, and travel support from Vitaflo . SEC received consulting payments and speaker fees from BioMarin as well as consulting payments from Synlogic Therapeutics. COH was clinical trial investigator for BioMarin and received consulting and speaker payments from BioMarin. SCJH received consulting payments and travel support from BioMarin and Homology Medicines. NL received consulting payments from Alnylam, Amicus, Astellas, BioMarin, BridgeBio, Chiesi, Genzyme/Sanofi, HemoShear, Horizon Therapeutics, Jaguar, Moderna, Nestle, PTC Therapeutics, Reneo, Shire, Synlogic, and Ultragenyx, participated as clinical trial investigator for Aeglea, Amicus, Astellas, BioMarin, Genzyme/Sanofi, Homology, Horizon, Moderna, Pfizer, Protalix, PTC Therapeutics, Reneo, Retrophin/Travere therapeutics, Shire, and Ultragenyx, as well as received speaker fees from Cycle Pharmaceuticals, Leadiant and Recordati. MCM II received consulting payments from BioMarin, Horizon Therapeutics, Rhythm Pharmaceuticals, Applied Therapeutics, Cycle Therapeutics, and Ultragenyx. ALSP received speaker fees from BioMarin. JCR received consulting payments from Applied Pharma Research, Merck Serono, BioMarin, Vitaflo, and Nutricia, speaker fees from Applied Pharma Research, Merck Serono, BioMarin Pharmaceutical, Vitaflo, Cambrooke, PIAM, LifeDiet, and Nutricia, as well as travel support from Applied Pharma Research, Merck Serono, BioMarin, Vitaflo, Cambrooke, PIAM, and Nutricia. SS received consulting payments, research grants, speaker fees, and travel support from BioMarin and participated as clinical trials investigator for BioMarin. ASV received consulting payments from BioMarin, Horizon Therapeutics, and Ultragenyx and participated as clinical trial investigator for Acadia, Alexion, BioMarin, Genzyme, Homology Medicines, Kaleido, Mallinckrodt, and Ultragenyx. JV received consulting payments from BioMarin, LogicBio Pharmaceuticals, Sangamo Therapeutics, Orphan Labs, Synlogic Therapeutics, Sanofi, Axcella Health, Agios Pharmaceuticals, and Applied Therapeutics as well as travel grants from BioMarin and LogicBio Pharmaceuticals. MW received consulting payments, speaker fees, and travel support from BioMarin, and participated as clinical trial investigator for Mallinckrodt, Roche, Wave, Cycle Therapeutics, and Intrabio. ACM participated in strategic advisory boards and received honoraria as a consultant and as a speaker for Merck Serono, BioMarin, Nestlé Health Science (SHS), Applied Pharma Research, Actelion, Retrophin, Censa, PTC Therapeutics, and Arla Food. Funding Information: Ideally, access to (neuro)psychological/psychiatric support should assist adolescents with identifying, understanding, and reporting of PKU-specific challenges (Table 3), offering individualized recommendations on managing these challenges. Although there is no replacement for mental health services for patients with identified needs, psychosocial support from PKU peers, e.g., through PKU camps, virtual social events, etc., can at least in the short-term help to improve metabolic control by providing individuals an opportunity to participate in supportive PKU-related educational activities potentially reducing perceived social isolation [91]. In addition to PKU camps, which may be very specific to certain regions or countries, HCPs should consider encouraging involvement in local, regional, national and international PKU patient/family advocacy and social support organizations, introducing adolescents and young adults to national/international patient registries [92,93]. Besides support from PKU peers, patients can benefit from non-PKU peer support, although some adolescents and young adults with PKU may not disclose to others and may avoid eating in with others or eating in public due to potential feelings of anxiety or feelings of being ashamed of their disease. In addition, patients with PKU of all ages, but particularly vulnerable adolescents and young adults, can benefit from having the opportunity to learn about and practice strategies that help promote feelings of empowerment and self-efficacy that can be used in both familiar and unfamiliar environments where they may experience peer pressure and feel the need to ‘fit in’. For example, a role-play approach involving behavioral rehearsal, self-monitoring, goal setting, and training in problem-solving skills with emphasis on initiation and inhibition (i.e., how to say no) could be provided by parents, PKU peers, or even members of the PKU team. These types of activities can be used to teach adolescents with PKU how to react in social situations, such as dining out, helping to avoid indulging and increased risk-taking behavior, a hallmark of the adolescent period [94].This work was supported by BioMarin Pharmaceutical Inc.The content of this manuscript was based on preparatory pre-meeting activities and presentations and discussions during two advisory board meetings that were coordinated and funded by BioMarin Pharmaceutical Inc. All authors or their institutions received funding from BioMarin to attend at least one or both meetings. Additional disclosures: BKB received consulting payments from BioMarin, Shire, Genzyme, Alexion, Horizon Therapeutics, Denali Therapeutics, JCR Pharma, Moderna, Aeglea BioTherapeutics, SIO Gene Therapies, Taysha Gene Therapy, Ultragenyx, and Inventiva Pharma, participated as clinical trial investigator for BioMarin, Shire, Denali Therapeutics, Homology Medicines, Ultragenyx, and Moderna as well as received speaker fees from BioMarin, Shire, Genzyme, and Horizon Therapeutics. AH received consulting payments from BioMarin, Chiesi, Shire, Genzyme, Amicus, and Ultragenyx, participated as clinical trial investigator for Ultragenyx as well as received speaker fees from Alexion, Amicus, BioMarin, Genzyme, Nutricia, Sobi, and Takeda. ABQ received consulting payments from BioMarin, speaker fees from BioMarin, Nutricia, Vitaflo, Sanofi, Takeda, Recordati, and travel support from Vitaflo. SEC received consulting payments and speaker fees from BioMarin as well as consulting payments from Synlogic Therapeutics. COH was clinical trial investigator for BioMarin and received consulting and speaker payments from BioMarin. SCJH received consulting payments and travel support from BioMarin and Homology Medicines. NL received consulting payments from Alnylam, Amicus, Astellas, BioMarin, BridgeBio, Chiesi, Genzyme/Sanofi, HemoShear, Horizon Therapeutics, Jaguar, Moderna, Nestle, PTC Therapeutics, Reneo, Shire, Synlogic, and Ultragenyx, participated as clinical trial investigator for Aeglea, Amicus, Astellas, BioMarin, Genzyme/Sanofi, Homology, Horizon, Moderna, Pfizer, Protalix, PTC Therapeutics, Reneo, Retrophin/Travere therapeutics, Shire, and Ultragenyx, as well as received speaker fees from Cycle Pharmaceuticals, Leadiant and Recordati. MCM II received consulting payments from BioMarin, Horizon Therapeutics, Rhythm Pharmaceuticals, Applied Therapeutics, Cycle Therapeutics, and Ultragenyx. ALSP received speaker fees from BioMarin. JCR received consulting payments from Applied Pharma Research, Merck Serono, BioMarin, Vitaflo, and Nutricia, speaker fees from Applied Pharma Research, Merck Serono, BioMarin Pharmaceutical, Vitaflo, Cambrooke, PIAM, LifeDiet, and Nutricia, as well as travel support from Applied Pharma Research, Merck Serono, BioMarin, Vitaflo, Cambrooke, PIAM, and Nutricia. SS received consulting payments, research grants, speaker fees, and travel support from BioMarin and participated as clinical trials investigator for BioMarin. ASV received consulting payments from BioMarin, Horizon Therapeutics, and Ultragenyx and participated as clinical trial investigator for Acadia, Alexion, BioMarin, Genzyme, Homology Medicines, Kaleido, Mallinckrodt, and Ultragenyx. JV received consulting payments from BioMarin, LogicBio Pharmaceuticals, Sangamo Therapeutics, Orphan Labs, Synlogic Therapeutics, Sanofi, Axcella Health, Agios Pharmaceuticals, and Applied Therapeutics as well as travel grants from BioMarin and LogicBio Pharmaceuticals. MW received consulting payments, speaker fees, and travel support from BioMarin, and participated as clinical trial investigator for Mallinckrodt, Roche, Wave, Cycle Therapeutics, and Intrabio. ACM participated in strategic advisory boards and received honoraria as a consultant and as a speaker for Merck Serono, BioMarin, Nestlé Health Science (SHS), Applied Pharma Research, Actelion, Retrophin, Censa, PTC Therapeutics, and Arla Food. Publisher Copyright: © 2022 The AuthorsBackground: Early treated patients with phenylketonuria (PKU) often become lost to follow-up from adolescence onwards due to the historical focus of PKU care on the pediatric population and lack of programs facilitating the transition to adulthood. As a result, evidence on the management of adolescents and young adults with PKU is limited. Methods: Two meetings were held with a multidisciplinary international panel of 25 experts in PKU and comorbidities frequently experienced by patients with PKU. Based on the outcomes of the first meeting, a set of statements were developed. During the second meeting, these statements were voted on for consensus generation (≥70% agreement), using a modified Delphi approach. Results: A total of 37 consensus recommendations were developed across five areas that were deemed important in the management of adolescents and young adults with PKU: (1) general physical health, (2) mental health and neurocognitive functioning, (3) blood Phe target range, (4) PKU-specific challenges, and (5) transition to adult care. The consensus recommendations reflect the personal opinions and experiences from the participating experts supported with evidence when available. Overall, clinicians managing adolescents and young adults with PKU should be aware of the wide variety of PKU-associated comorbidities, initiating screening at an early age. In addition, management of adolescents/young adults should be a joint effort between the patient, clinical center, and parents/caregivers supporting adolescents with gradually gaining independent control of their disease during the transition to adulthood. Conclusions: A multidisciplinary international group of experts used a modified Delphi approach to develop a set of consensus recommendations with the aim of providing guidance and offering tools to clinics to aid with supporting adolescents and young adults with PKU.publishersversionpublishe

Identifying core MRI sequences for reliable automatic brain metastasis segmentation

BACKGROUND Many automatic approaches to brain tumor segmentation employ multiple magnetic resonance imaging (MRI) sequences. The goal of this project was to compare different combinations of input sequences to determine which MRI sequences are needed for effective automated brain metastasis (BM) segmentation. METHODS We analyzed preoperative imaging (T1-weighted sequence ± contrast-enhancement (T1/T1-CE), T2-weighted sequence (T2), and T2 fluid-attenuated inversion recovery (T2-FLAIR) sequence) from 339 patients with BMs from seven centers. A baseline 3D U-Net with all four sequences and six U-Nets with plausible sequence combinations (T1-CE, T1, T2-FLAIR, T1-CE + T2-FLAIR, T1-CE + T1 + T2-FLAIR, T1-CE + T1) were trained on 239 patients from two centers and subsequently tested on an external cohort of 100 patients from five centers. RESULTS The model based on T1-CE alone achieved the best segmentation performance for BM segmentation with a median Dice similarity coefficient (DSC) of 0.96. Models trained without T1-CE performed worse (T1-only: DSC = 0.70 and T2-FLAIR-only: DSC = 0.73). For edema segmentation, models that included both T1-CE and T2-FLAIR performed best (DSC = 0.93), while the remaining four models without simultaneous inclusion of these both sequences reached a median DSC of 0.81-0.89. CONCLUSIONS A T1-CE-only protocol suffices for the segmentation of BMs. The combination of T1-CE and T2-FLAIR is important for edema segmentation. Missing either T1-CE or T2-FLAIR decreases performance. These findings may improve imaging routines by omitting unnecessary sequences, thus allowing for faster procedures in daily clinical practice while enabling optimal neural network-based target definitions

Significant benefits of AIP testing and clinical screening in familial isolated and young-onset pituitary tumors

Context Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are responsible for a subset of familial isolated pituitary adenoma (FIPA) cases and sporadic pituitary neuroendocrine tumors (PitNETs). Objective To compare prospectively diagnosed AIP mutation-positive (AIPmut) PitNET patients with clinically presenting patients and to compare the clinical characteristics of AIPmut and AIPneg PitNET patients. Design 12-year prospective, observational study. Participants & Setting We studied probands and family members of FIPA kindreds and sporadic patients with disease onset ≤18 years or macroadenomas with onset ≤30 years (n = 1477). This was a collaborative study conducted at referral centers for pituitary diseases. Interventions & Outcome AIP testing and clinical screening for pituitary disease. Comparison of characteristics of prospectively diagnosed (n = 22) vs clinically presenting AIPmut PitNET patients (n = 145), and AIPmut (n = 167) vs AIPneg PitNET patients (n = 1310). Results Prospectively diagnosed AIPmut PitNET patients had smaller lesions with less suprasellar extension or cavernous sinus invasion and required fewer treatments with fewer operations and no radiotherapy compared with clinically presenting cases; there were fewer cases with active disease and hypopituitarism at last follow-up. When comparing AIPmut and AIPneg cases, AIPmut patients were more often males, younger, more often had GH excess, pituitary apoplexy, suprasellar extension, and more patients required multimodal therapy, including radiotherapy. AIPmut patients (n = 136) with GH excess were taller than AIPneg counterparts (n = 650). Conclusions Prospectively diagnosed AIPmut patients show better outcomes than clinically presenting cases, demonstrating the benefits of genetic and clinical screening. AIP-related pituitary disease has a wide spectrum ranging from aggressively growing lesions to stable or indolent disease course

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts