Citations

Abstract Background To protect minors’ future autonomy, professional organizations have historically discouraged returning predictive adult-onset genetic test results and carrier status to children. Recent clinical guidance diverges from this norm, suggesting that when minors have genomic sequencing performed for clinical purposes, parents and children should have the opportunity to learn secondary findings, including for some adult-onset conditions. While parents can currently opt in or out of receiving their child’s secondary findings, the American Society of Human Genetics Workgroup on Pediatric Genetic and Genomic Testing suggests including adolescents in the decision-making process. However, it is not clear what factors young people consider when given the opportunity to learn genetic findings for themselves. We are examining adolescents’, young adults’, and parents’ (if applicable) decisions about learning genomic information for the adolescent. Methods We are enrolling assenting (ages 13–17) adolescents and consenting (ages 18–21) young adults in a prospective genomic screening study to assess the choices they make about receiving individual genomic results. Participants use an online tool to indicate whether they want to learn their personal genetic risk for specific preventable, treatable, and adult-onset conditions, as well as carrier status for autosomal recessive conditions. We are examining 1) how choices differ between adolescent and young adult cohorts (as well as between adolescents/young adults and parents) and 2) decisional conflict and stability across study timepoints. Results are returned based on participants’ choices. Qualitative interviews with a subset of participants explore decisional stability, adolescent/young adult engagement with parents in decision-making, and the impact of learning pathogenic/likely pathogenic and carrier results. Discussion This study explores decision making and decision stability between adolescents and parents (where applicable), as well as the ethical implications and impact of return of clinical-grade genetic research results to adolescents and young adults. The results of this study will contribute empirical evidence to support best practices and guidance on engaging young people in genetic research studies and clinical care that offer return of results. Trial Registration: ClinicalTrials.gov Identifier: NCT04481061. Registered 22 July 2020.

Introduction While neurovascular surgeries have largely been performed by neurosurgeons, the advent of endovascular procedures has produced increasing involvement of other specialists in this arena (i.e. neurologists and radiologists).This study aims to analyzethe involvement of different specialties within theneuroendovascular workforce by characterizingthem by their primary specialty. Methods The Medicare Provider Utilization Database was queried from 2013 to 2019 for all primary Current Procedural Terminology (CPT) codes identified by the American Medical Association as pertaining to endovascular procedures of the nervous system (61623, 61624, 61630, 61635, 61626, 61645, and 61650). We counted the number of unique providers in respective fields (neurology, neurosurgery, and radiology) who performed these procedures. Statistical analyses, including data aggregation, exploratory analysis, and propensity adjustment, were performed using R, version 4.0.1 (The R Foundation, Vienna, Austria). The two‐sided Mann‐Kendall trend test, a non‐parametric statistical test that assesses for monotonic trends in either an upward or downward trend, was utilized to assess for trends over time. Within each year analyzed, a Chi‐squared test for trend in proportions was used. A significance level of 0.05 was used. Results In 2013, neurosurgeons comprised 45% of the workforce performing these procedures, neurologists were 9%, and radiologists were 47%. By 2019, neurosurgeons decreased to 34.5% of the workforce, while neurologists increased to 21.5%, and radiologists decreased slightly to 44%. Neurologists were the only field in which the proportional shift in providers was noted to have a significant change in trajectory (p:0.04), an upward trajectory. Overall proportional differences between respective specialists were statistically significant each year (p< 0.01). Conclusions Neurologists are increasingly performing endovascular procedures. Increased communication and coordination between specialties can improve disparities in care to ensure adequate access to neurovascular care across the US.

Introduction Endovascular procedures have become increasingly popular in recent years due to preference of minimally invasive approaches and technological advancement.This study aims to characterize the trends in procedural rates of common neuro‐endovascular procedures performed by neurologists, neurosurgeons, and radiologists. Methods The Medicare Provider Utilization Database was queried from 2013 to 2019 for all primary Current Procedural Terminology codes identified by the American Medical Association as pertaining to endovascular procedures of the nervous system (61623, 61624, 61630, 61635, 61626, 61645, and 61650). Statistical analyses, including data aggregation, exploratory analysis, and propensity adjustment, were performed using R, version 4.0.1 (The R Foundation, Vienna, Austria). The two‐sided Mann‐Kendall trend test, a non‐parametric statistical test that assesses for monotonic trends in either an upward or downward trend, was utilized to assess for trends over time. A significance level of 0.05 was used. Results Between 2013 to 2019 a total of 40,730 endovascular procedures were performed by neurosurgeons, neurologists and radiologists treating Medicare patients. When all codes were combined, there was a significant increase in the number of procedures done by all specialists: Radiology (2013:1080; 2019:4938; p:0.02), Neurosurgery (2013:1230; 2019:4508; p< 0.01), and Neurology (2013:205; 2019:2397; p:0.04). Significant increases in mechanical thrombectomy (CPT61645) were observed in all fields: Radiology (2016:1287, 2019:3542; p< 0.01), Neurosurgery (2016:610; 2019:2326; p< 0.01), Neurology (2016:569; 2019:1951; p< 0.01). Increases in transcatheter permanent occlusion (CPT61624) were observed in neurosurgery (2013:1230; 2019:2049; p:0.04). Increases in temporary balloon artery occlusion (CPT61623) were noted in neurology (2013:21; 2019:27; p:0.04). Conclusions Endovascular procedures have seen a dramatic rise in utilization over a short amount of time, particularly mechanical thrombectomy. Future investigation should include more inclusive datasets beyond the Medicare population.

VEXAS is caused by somatic mutations in UBA1 (UBA1mut) and characterized by heterogenous systemic auto-inflammation and progressive hematologic manifestations, meeting criteria for myelodysplastic syndrome (MDS) and plasma cell dyscrasias. The landscape of myeloid-related gene mutations leading to typical clonal hematopoiesis (CH) in these patients is unknown. Retrospectively, we screened 80 VEXAS patients for CH in their peripheral blood (PB) and correlated findings with clinical outcomes in 77. UBA1mutwere most common at hotspot p.M41 (median variant allele frequency/VAF = 75%). Typical CH mutations co-occurred with UBA1mut in 60% of patients, mostly in DNMT3A and TET2, and were not associated with inflammatory or hematologic manifestations. In prospective single-cell proteogenomic sequencing (scDNA), UBA1mutwas the dominant clone, present mostly in branched clonal trajectories. Based on integrated bulk and scDNA analyses, clonality in VEXAS followed two major patterns: with either typical CH preceding UBA1mutselection in a clone (Pattern 1), or occurring as an UBA1mutsubclone or in independent clones (Pattern 2). VAF in PB differed markedly between DNMT3A and TET2 clones (median VAF of 25% vs 1%). DNMT3A and TET2 clones associated with hierarchies representing patterns 1 and 2, respectively. Overall survival for all patients was 60% at 10 years. Transfusion-dependent anemia, moderate thrombocytopenia, and typical CH mutations, each correlated with poor outcome. In VEXAS, UBA1mut cells are the primary cause of systemic inflammation and marrow failure, being a new molecularly defined somatic entity associated with MDS. VEXAS-associated MDS is distinct from classical MDS in its presentation and clinical course.

Chronic hepatitis B (CHB) is the most common cause of hepatocellular carcinoma (HCC) worldwide. Antiviral treatment reduces the risk of HCC and mortality; nonetheless, globally in 2019, only 2.2% of CHB patients received treatment. Current international CHB guidelines recommend antiviral treatment only in subsets of patients with clear evidence of liver damage. This contrasts with hepatitis C or HIV where early treatment is recommended in all infected patients, regardless of end-organ damage. This narrative review aims to provide an overview of data on the early initiation of antiviral treatment and its related potential economic impact. Literature searches were performed using PubMed and abstracts from international liver congresses (2019–2021). Data on risk of disease progression and HCC and the impact of antiviral treatment in currently ineligible patients were summarized. Cost-effectiveness data on early antiviral treatment initiation were also collated. Accumulating molecular, clinical, and economic data suggest that early initiation of antiviral treatment could save many lives through HCC prevention in a highly cost-effective manner. In light of these data, we consider several alternative expanded treatment strategies that might further a simplified ‘treatment as prevention’ approach.

Abstract Introduction: Tegavivint is a first in class small molecule inhibitor of Wnt-ß-catenin signaling that functions by disrupting the interaction of ß-catenin and TBL1/TBLR1 resulting in degradation of nuclear ß-catenin. Aberrant Wnt signaling has been identified as a key mechanism of cancer biology, resulting in uncontrolled transcription of pro-oncogenic Wnt target genes. Pre-clinical in vivo studies of tegavivint demonstrated anti-tumor activity in a variety of pediatric solid tumors, including osteosarcoma, Ewing sarcoma, and lymphoma. Methods: We conducted a phase 1 dose-escalation study of single agent tegavivint in children aged ≥12 months to ≤21 years with relapsed or refractory solid tumors including lymphoma and desmoid tumors. The dose escalation was conducted using a rolling six design starting with the recommended phase 2 dose (RP2D) in adults, 5 mg/kg, administered intravenously over four hours on days 1, 8 and 15 of a 28 day cycle. A single de-escalation to 4 mg/kg and escalations to 6.5 mg/kg and 8 mg/kg if pharmacokinetic (PK) parameters indicated were planned. Once the RP2D is defined a PK cohort and phase 2 cohorts including Ewing sarcoma, desmoid tumor, osteosarcoma, liver tumors, Wilms tumor and a disease agnostic cohort including cancers with Wnt alterations will be evaluated. Results: A total of 15 patients were enrolled on the phase 1 part of the study. Two patients were not treated due to pre-therapy DEXA scan demonstrating grade 1 osteoporosis; therefore, 13 patients received treatment with tegavivint on 2 dose levels (5 mg/kg and 6.5 mg/kg). The median age of treated patients was 16 years (range 3-21). Patient diagnoses included desmoid tumor (5), Wilms tumor (3), and one each of Ewing sarcoma, osteosarcoma, CIC::DUX4 sarcoma, neuroblastoma, and hepatocellular carcinoma. There were no dose limiting toxicities among 4 DLT-evaluable patients at DL1 and 6 at DL2. The maximum tolerated dose was not determined. Grade three or higher adverse events at least possibly related to treatment included anemia (2) and lymphopenia (2). A single patient had a grade 3 QT prolongation requiring cessation of tegavivint after cycle 3. At 5 mg/kg, the mean AUC was 94,900 hr*ng/mL (range 52,000-136,000), and at 6.5 mg/kg was 91,200 hr*ng/mL (range 28,400-144,000). The pediatric RP2D dose was determined to be 6.5 mg/kg based on the pre-specified objective of achieving pharmacologically relevant plasma concentrations and less than 20% difference in mean AUC between the two tested dose levels. Conclusions: Tegavivint is well tolerated in children with refractory solid tumors, the pediatric RP2D is 6.5 mg/kg demonstrating pharmacologically relevant plasma concentrations. The study is currently enrolling patients to a pharmacokinetic expansion cohort and will then proceed to phase 2. Citation Format: Sarah B. Whittle, Joseph G. Pressey, Xiaowei Liu, Charles G. Minard, Kristina Z. Denic, Joel M. Reid, Stacey L. Berg, Elizabeth Fox, Brenda J. Weigel. PEPN2011: a phase 1/2 study of tegavivint in children, adolescents, and young adults with recurrent or refractory solid tumors, including lymphomas and desmoid tumors: a report from the pediatric early phase clinical trials network [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT090.

AbstractIntroductionNasal symptoms are frequently reported by patients undergoing chemotherapy.MethodsEligible patients planning to receive paclitaxel, docetaxel, nab‐paclitaxel, bevacizumab without a concomitant taxane, or “other” (non‐taxane, non‐bevacizumab) chemotherapy regimens were invited to participate in this prospective study. Patients reported nasal symptoms prior to each dose of chemotherapy.ResultsThe percentage of patients (95% CI) who reported nasal symptoms was the same for patients who received bevacizumab or nab‐paclitaxel, 82.6% (61.2%, 95.1%). There were no significant differences among the proportions of patients experiencing nasal symptoms within the paclitaxel, nab‐paclitaxel, and bevacizumab cohorts. Patients in the nab‐paclitaxel cohort were more likely to experience symptoms than those in the non‐taxane non‐bevacizumab cohort or docetaxel cohort (p = 0.001, p = 0.001). Patients in the bevacizumab cohort were more likely to experience nasal symptoms than those in the non‐taxane non‐bevacizumab cohort (p = 0.03).ConclusionNasal vestibulitis symptoms are common in patients receiving chemotherapy, especially those receiving paclitaxel, docetaxel, and bevacizumab. Further investigations into treatments of this symptom complex are warranted.

AbstractBackgroundObesity and inactivity are poor prognostic factors in breast cancer, but less is known regarding physical activity (PA) and weight patterns in young breast cancer survivors.MethodsThe Young and Strong Study was a cluster‐randomized trial evaluating education and support interventions for young women (age <45 years) with newly diagnosed breast cancer. Sites were randomized 1:1 to a Young Women's Intervention (YWI) or a contact‐time control physical activity intervention (PAI). Changes in PA and weight were compared between groups using general estimating equations to evaluate clustered binary and Gaussian data.ResultsA total of 467 patients enrolled between July 2012 and December 2013 across 54 sites. Median age at diagnosis was 40 years (range, 22–45). At baseline, median body mass index (BMI) was 25.4 kg/m2 (range, 16.1–61.1), and participants reported a median of 0 minutes (range, 0–2190) of moderate/vigorous PA/week. PA increased significantly over time in both groups (p < .001), with no difference between groups at any time point. BMI increased modestly but significantly (p < .001) over time in both groups. Provider attention to PA was observed in 74% of participants on PAI and 61% on YWI (p = .145) and correlated with PA at 12 months (median 100 min/week of PA in participants with provider attention to PA vs. 60 min/week in those without, p = .016).ConclusionsIn a cohort of young women with breast cancer, rates of obesity and inactivity were high. PA and BMI increased over time and were not impacted by an educational PA intervention. Findings provide important information for developing lifestyle interventions for young breast cancer survivors.

Purpose: Treatment sequelae compromising reproductive health are highly prevalent in childhood cancer survivors, and a main determinant of health and quality of life. Follicular reserve determines ovarian function life span; thus, its preservation is important in the care of female survivors. Anti-Müllerian hormone (AMH) is a biomarker to measure functional ovarian reserve. We aimed to evaluate the effect of leuprolide during gonadotoxic therapy on pubertal females' post-treatment functional ovarian reserve using AMH levels. Methods: We conducted a single-center retrospective study including all pubertal females who had undergone gonadotoxic treatments between January 2010 and April 2020, and had an AMH level after completion of therapy. We used multivariable linear regressions to compare AMH-level beta coefficients in patients stratified by gonadotoxic risk, adjusting for leuprolide use. Results: Fifty-two females meeting study eligibility were included, of which 35 received leuprolide. The use of leuprolide was associated with higher post-treatment AMH levels in the lower gonadotoxic risk group (beta 2.74, 95% CI 0.97–4.51; p = 0.004). This association was lost in the higher gonadotoxic risk groups. Conclusions: Leuprolide may have a protective effect on the functional ovarian reserve. However, this is limited by increasing treatment gonadotoxicity. Larger, prospective studies are needed to elucidate the potential benefits of gonadotropin-releasing hormone agonist on preservation of ovarian reserve among children receiving gonadotoxic therapies, as cancer survivors.