Access to novel drugs and therapeutics for children and youth: Eliciting citizens' values to inform public funding decisions.

INTRODUCTION: The unique evidentiary, economic and ethical challenges associated with health technology assessment (HTA) of precision therapies limit access to novel drugs and therapeutics for children and youth, for whom such challenges are amplified. We elicited citizens' perspectives about values-based criteria relevant to the assessment of paediatric precision therapies to inform the development of a child-tailored HTA framework. METHODS: We held four citizen panels virtually in May-June 2021, informed by a plain-language citizen brief summarizing global and local evidence about the challenges, policy and programmatic options and implementation strategies related to enhancing access to precision therapies for Canadian children and youth. Panellists were recruited through a nationally representative database, medical/patient networks and social media. We inductively coded and thematically analysed panel transcripts to generate themes and identify priority values. RESULTS: The perspectives of panellists (n = 45) coalesced into four overlapping themes, with attendant subthemes, relevant to a child-tailored HTA framework: (1) Childhood Distinctions: vulnerability, 'fair innings', future potential, family impacts; (2) Voice: agency of children and youth; lived versus no lived experience; (3) One versus Many: disease severity, rarity, equity, unmet need and (4) Health System Governance: funding, implementation inequities, effectiveness and safety. Participants broadly agreed that childhood distinctions, particularly family impacts, justify child-tailored HTA. Dissent arose over whose voice should inform HTA and how such perspectives are best incorporated. CONCLUSIONS: Citizens can offer unique insights into criteria relevant to the development or revision of HTA frameworks to capture holistic, societally responsive dimensions of value attached to unique contexts or populations, including children. Balancing the hopes and expectations of patients and caregivers for access to expensive but potential life-altering therapies against the opportunity costs borne by encompassing health systems is a fundamental challenge that will require rigorous methods to elicit, weigh and reconcile varied views. PATIENT OR PUBLIC CONTRIBUTION: A patient advocate served on the steering committee of this study and co-authored this article. Key informants for the Citizen Brief included patient advocates and caregivers; a separate patient advocate reviewed the Brief before dissemination. Qualitative and quantitative data were collected from the general public and caregivers of children, with written consent.

Dynamic regulation of connexins in stem cell pluripotency.

Characterization of the pluripotent "ground state" has led to a greater understanding of species-specific stem cell differences and has imparted an appreciation of the pluripotency continuum that exists in stem cells in vitro. Pluripotent stem cells are functionally coupled via connexins that serve in gap junctional intercellular communication (GJIC) and here we report that the level of connexin expression in pluripotent stem cells depends upon the state in which stem cells exist in vitro. Human and mouse pluripotent stem cells stabilized in a developmentally primitive or "naïve" state exhibit significantly less connexin expression compared with stem cells which are "primed" for differentiation. This dynamic connexin expression pattern may be governed, in part, by differential regulation by pluripotency transcription factors expressed in each cell state. Species-specific differences do exist, however, with mouse stem cells expressing several additional connexin transcripts not found in human pluripotent stem cells. Moreover, pharmacological inhibition of GJIC shows limited impact on naïve human stem cell survival, self-renewal, and pluripotency but plays a more significant role in primed human pluripotent stem cells. However, CRISPR-Cas9 gene ablation of Cx43 in human and mouse primed and naïve pluripotent stem cells reveals that Cx43 is dispensable in each of these four pluripotent stem cell types.

Left atrial appendage aneurysm in pediatrics: Case study and literature review.

Left atrial appendage aneurysm (LAAA) is a rare cardiac pathology that is often identified in adulthood. There are a myriad of presentations related to atrial appendage enlargement, but most are asymptomatic. Pediatric cases of LAAA are extremely rare. We report a case of an incidental giant LAAA found in a healthy 6-year-old boy. He was successfully treated with surgical resection. A review of the literature shows that the presentation of LAAA in pediatrics likely involves cardiac or respiratory symptoms but can also be incidental findings. Similar to adults, diagnosis requires cardiac imaging, with echocardiography being the mainstay. Surgical intervention is indicated in symptomatic and most asymptomatic patients to prevent complications. More research is warranted into the optimal timing of surgery and alternative surgical approaches for complex cases.

Translating Precision Health for Pediatrics: A Scoping Review.

Precision health aims to personalize treatment and prevention strategies based on individual genetic differences. While it has significantly improved healthcare for specific patient groups, broader translation faces challenges with evidence development, evidence appraisal, and implementation. These challenges are compounded in child health as existing methods fail to incorporate the physiology and socio-biology unique to childhood. This scoping review synthesizes the existing literature on evidence development, appraisal, prioritization, and implementation of precision child health. PubMed, Scopus, Web of Science, and Embase were searched. The included articles were related to pediatrics, precision health, and the translational pathway. Articles were excluded if they were too narrow in scope. In total, 74 articles identified challenges and solutions for putting pediatric precision health interventions into practice. The literature reinforced the unique attributes of children and their implications for study design and identified major themes for the value assessment of precision health interventions for children, including clinical benefit, cost-effectiveness, stakeholder values and preferences, and ethics and equity. Tackling these identified challenges will require developing international data networks and guidelines, re-thinking methods for value assessment, and broadening stakeholder support for the effective implementation of precision health within healthcare organizations. This research was funded by the SickKids Precision Child Health Catalyst Grant.

Pharmacogenomic-based personalized medicine: Multistakeholder perspectives on implementational drivers and barriers in the Canadian healthcare system.

Pharmacogenomics (PGx)-based personalized medicine (PM) is increasingly utilized to guide treatment decisions for many drug-disease combinations. Notably, London Health Sciences Centre (LHSC) has pioneered a PGx program that has become a staple for London-based specialists. Although implementational studies have been conducted in other jurisdictions, the Canadian healthcare system is understudied. Herein, the multistakeholder perspectives on implementational drivers and barriers are elucidated. Using a mixed-method qualitative model, key stakeholders, and patients from LHSC's PGx-based PM clinic were interviewed and surveyed, respectively. Interview transcripts were thematically analyzed in a stepwise process of customer profiling, value mapping, and business model canvasing. Value for LHSC located specialist users of PGx was driven by the quick turnaround time, independence of the PGx clinic, and the quality of information. Engagement of external specialists was only limited by access and awareness, whereas other healthcare nonusers were limited by education and applicability. The major determinant of successful adoption at novel sites were institutional champions. Patients valued and approved of the service, expressed a general willingness to pay, but often traveled far to receive genotyping. This paper discusses the critical pillars of education, awareness, advocacy, and efficiency required to address implementation barriers to healthcare service innovation in Canada. Further adoption of PGx practices into Canadian hospitals is an important factor for advancing system-level changes in care delivery, patient experiences, and outcomes. The findings in this paper can help inform efforts to advance clinical PGx practices, but also the potential adoption and implementation of other innovative healthcare service solutions.

Assessing the Educational and Supportive Care Needs of Canadian Metastatic Melanoma Patients and Survivors Attending an Outpatient Clinic.

The rapid development of metastatic melanoma treatment options has significantly improved overall survival, but paralleled patient educational and supportive care resources have fallen behind. Particularly, the need for grassroots programs targeting environments outside urban centers has grown. Accordingly, an environmental scan of the Durham region in Ontario, Canada, showed the lack of melanoma-specific resources for outpatients. The goal of this study was to identify the needs of metastatic melanoma patients and survivors attending a large outpatient clinic in Durham, and then develop a patient-reviewed intervention plan. Needs were assessed in 5 domains through a melanoma-specific supportive care needs assessment survey. Among 75 surveyed melanoma patients and survivors, high-level needs were identified in 3 domains: psychological, health system information, and melanoma-specific information. Furthermore, domain-specific needs were heightened in specific sociodemographic groups. Based on these survey results, a multifaceted intervention plan was developed to mitigate future needs. The intervention plan was patient-reviewed in focus groups prior to implementation, refining the developed intervention plan.

Analysis of TERT Isoforms across TCGA, GTEx and CCLE Datasets.

Reactivation of the multi-subunit ribonucleoprotein telomerase is the primary telomere maintenance mechanism in cancer, but it is rate-limited by the enzymatic component, telomerase reverse transcriptase (TERT). While regulatory in nature, TERT alternative splice variant/isoform regulation and functions are not fully elucidated and are further complicated by their highly diverse expression and nature. Our primary objective was to characterize TERT isoform expression across 7887 neoplastic and 2099 normal tissue samples using The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression Project (GTEx), respectively. We confirmed the global overexpression and splicing shift towards full-length TERT in neoplastic tissue. Stratifying by tissue type we found uncharacteristic TERT expression in normal brain tissue subtypes. Stratifying by tumor-specific subtypes, we detailed TERT expression differences potentially regulated by subtype-specific molecular characteristics. Focusing on ß-deletion splicing regulation, we found the NOVA1 trans-acting factor to mediate alternative splicing in a cancer-dependent manner. Of relevance to future tissue-specific studies, we clustered cancer cell lines with tumors from related origin based on TERT isoform expression patterns. Taken together, our work has reinforced the need for tissue and tumour-specific TERT investigations, provided avenues to do so, and brought to light the current technical limitations of bioinformatic analyses of TERT isoform expression.

Cabozantinib real-world effectiveness in the first-through fourth-line settings for the treatment of metastatic renal cell carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium.

BACKGROUND: Cabozantinib is approved for metastatic renal cell carcinoma (mRCC) based on the METEOR and CABOSUN trials. However, real-world effectiveness and dosing patterns of cabozantinib are not well characterized. METHODS: Patients with mRCC treated with cabozantinib between 2011 and 2019 were identified and stratified using the International mRCC Database Consortium (IMDC) risk groups. First- (1L), second- (2L), third- (3L), and fourth-line (4L) overall response rate (ORR), time to treatment failure (TTF), and overall survival (OS) were analyzed. Dose reduction rates and their association with TTF and OS were determined. RESULTS: A total of 413 patients were identified. The ORRs across 1L to 4L were 32%, 26%, 25%, and 29%, respectively, and the median TTF rates were 8.3, 7.3, 7.0, and 8.0 months, respectively. The median OS (mOS) rates in 1L to 4L were 30.7, 17.8, 12.6, and 14.9 months, respectively. For patients treated with 1L PD(L)1 combination agent (n = 31), 2L cabozantinib had ORR of 22%, median TTF of 5.4 months, and mOS of 17.4 months. About 50% (129/258) of patients required dose reductions. The TTF and mOS were significantly longer for patients who required dose reduction vs. patients who did not, with an adjusted hazard ratio of 0.37 (95% CI 0.202-0.672, p < 0.01) and 0.46 (95% CI 0.215-0.980, p = 0.04), respectively. Limitations include the retrospective study design and the lack of central radiology review. CONCLUSION: The ORR and TTF of cabozantinib were maintained from the 1L to 4L settings. Dose reductions due to toxicity were associated with improved TTF and OS. Cabozantinib has clinical activity after 1L Immuno-oncology combination agents.