Citations

Abstract Pharmacogenomics (PGx) is focused on the relationship between an individual's genetic makeup and their response to medications, with the overarching aim of guiding prescribing decisions to improve drug efficacy and reduce adverse events. The PGx and genomic medicine communities have worked independently for over 2 decades, developing separate standards and terminology, making implementation of PGx across all areas of genomic medicine difficult. To address this issue, the Clinical Genome Resource (ClinGen) Pharmacogenomics Working Group (PGxWG) was established by the National Institutes of Health (NIH)-funded ClinGen to initially create frameworks for evaluating gene–drug response clinical validity and actionability aligned with the ClinGen frameworks for evaluating monogenic gene–disease relationships, and a framework for classifying germline PGx variants similar to the American College of Medical Genetics (ACMG) and Association of Molecular Pathology (AMP) system for interpretation of disease-causing variants. These frameworks will leverage decades of work from well-established PGx resources facilitating buy-in among PGx stakeholders. In this report, we describe the background and major activities of the ClinGen PGxWG, and how this initiative will facilitate the critical inclusion of PGx into the larger context of genomic medicine.

AbstractBackgroundIndividuals meeting neuropathological criteria for Alzheimer’s disease (AD) may manifest with atypical clinical syndromes. Past work showed that the neurobiological basis for these differences is related to specific neuronal vulnerabilities for tau pathology. For instance, amnestic cases have a higher burden of neurofibrillary changes in CA1. In contrast, logopenic variant primary progressive aphasia (lvPPA) cases have a higher tau burden in the superior temporal gyrus (STG). Single‐cell technology enables investigations on the molecular basis of differential neuronal vulnerability in AD. Consequently, we delved into the factors that underlie this selective vulnerability by analyzing brain samples from individuals exclusively afflicted with AD but exhibiting diverse clinical manifestations.MethodsnRNA Sequencing using the Chromium Single Cell 3′ (10X Genomics, USA) on nuclei cells extracted from the CA1 sector and posterior STG of postmortem brain tissue of 48 individuals either meeting pathological criteria for AD (A3B3C3; 24 amnestic and eleven lvPPA) and healthy controls (A≤1B≤1C≤1; n = 13) (Table 1, Fig. 1A/B). Bioinformatics analyses were conducted using Cell Ranger and R software. Comparisons between cell subpopulations were conducted with the Wald statistical test, and p‐values < .05 were considered significant.ResultAfter quality control, we recovered more than 250k nuclei with a mean of 2,130 genes per nuclei. Upon cross‐sample alignment and t‐stochastic neighborhood embedding clustering (Fig. 1C), we found 21 excitatory neuronal subpopulations (Exc‐sub) in CA1 and 26 in STG, and 22 and 25 inhibitory neuronal subpopulations (Inh‐sub) in CA1 and STG, respectively; 16 astrocytes subpopulations in both areas and 20 microglia subpopulations in CA1 and 17 in STG (Fig. 2). One STG Exc‐sub, expressing CUX2 and LAMP5 genes showed vulnerability in lvPPA patients. Also, one STG Inh‐sub, expressing the ADARB2 gene, showed vulnerability for all AD patients.ConclusionOur preliminary study identified a vulnerable population of excitatory neurons related to lvPPA. We are conducting validation studies using quantitative pathology to confirm these results. Furthermore, analysis of a higher number of cases is ongoing and will continue to inform on factors associated with neuronal vulnerability.

AbstractBackgroundLate Onset Alzheimer’s Disease (LOAD) is the most common neurodegenerative disorder. Carriers of an ɛ4 allele of the apolipoprotein E gene (APOE) have significantly increased risk of developing LOAD. LOAD is also strongly sex biased. Besides the well‐established role of sex hormones, the impact of genetic sex combined with APOE genotypes has not been studied. Sex chromosome dosage (SCD) is the main genetic difference between females (XX) and males (XY). Despite dosage compensation by X chromosome inactivation (XCI), some X‐linked genes remain expressed from the inactive X (Xi) and are female biased in expression. Many of these genes are related to neurological and immune functions and could contribute to neuroinflammation in AD.MethodTo understand the genetic interactions between autosomal risk (APOE) and sex‐bias in AD, we are generating isogenic sets of hiPSCs with various sex chromosome complements and APOE genotypes. We have derived XXY/XY, XY/X, and XX/X isogenic pairs by reprogramming cells from naturally mosaic individuals or by selective removal of the Xi in vitro. These lines uniquely position us to differentiate the effects of X chromosome dosage and/or presence of a Y chromosome, while minimizing genetic variability and environmental or hormonal confounders. Currently, we are also constructing APOE ɛ3 and ɛ4 alleles in our paired hiPSC lines with differing sex chromosome content using gene editing.ResultStarting from an XXY/XY isogenic pair, we have generated an hiPSC series with six different genotypes of APOE ɛ3/ɛ3, ɛ3/ɛ4 or ɛ4/ɛ4 alleles with either the XXY or XY genotype. Preliminary results in differentiated neural precursor cells show differential expression of sex‐linked genes in relation to SCD. We also observed genome‐wide changes in gene expression and DNA methylation. Subsets of autosomal sex‐biased genes were differentially affected either by X chromosome dosage, presence of a Y, or both.ConclusionThe new hiPSC lines are being differentiated to AD‐relevant cell types, including neurons, microglia, and cortical organoids, for transcriptomic and functional analyses to elucidate how APOE alleles and genetic sex interact to modulate risk in LOAD pathology.

Abstract Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that profoundly impacts the lives of people with the condition and their family caregivers. Little is known about the experiences of care at home among individuals with ALS and their family caregivers. This qualitative study explored these experiences in 14 in-depth interviews that included seven persons with ALS and 13 family caregivers. The findings were organized based on the Salutogenic Model of Health. The main sources of stress reported included the overwhelming nature of getting an ALS diagnosis, inadequacy of health care teams in providing emotional support and promoting shared decision-making in regard to the management of ALS, high level of illness acuity, the intense nature of caregiving involved in ALS, high cost of treatments and equipment, difficulties navigating the healthcare system, unavailability of suitable medical equipment, scarcity of paid caregivers competent in managing ALS, and lack of adequate training for family caregivers. Perspectives on positive coping included mental toughness, maintaining a positive outlook about life and the future, being proactive in seeking support to maintain function and quality of life, proactively communicating with care teams, advanced care planning, having a sense of control over ALS management plan of care, and taking a break from caregiving. Instrumental and emotional support from family, friends, community organizations, and healthcare teams, as well as sufficient insurance and financial coverage for ALS treatments, facilitated better coping. Future research and policies should focus on identifying effective multisectoral strategies for supporting people with ALS and their caregivers.

Trends in diagnostic biopsy sample collection approaches for primary bone sarcomas have shifted in the past 2 decades. Although open/incisional biopsies used to be the predominant approach to obtain diagnostic material for Ewing sarcoma and osteosarcoma, image-guided core needle biopsies have increased in frequency and are safe for patients. These procedures are less invasive and reduce recovery times but have potential limitations. The quantity and quality of tissue obtained through these procedures vary between institutions. Acquired viable tissue volumes can be low, limiting the conduct of downstream expanded clinical workup, molecular analyses, and research. Patients with advanced Ewing sarcoma and osteosarcoma continue to have overall poor outcomes despite dose-intensive cytotoxic chemotherapy. The biology of treatment resistance is not currently well understood, partly due to limited availability of relevant tissue to study. There is a need for access to quality tumor specimens for molecular and other analyses to identify high-risk tumor subsets and drive discovery to improve patient outcomes. Given broad variability in bone tumor tissue procurement and processing across member institutions, the Children’s Oncology Group Bone Tumor Committee convened a multidisciplinary group of experts to outline the current and near-future tissue needs for optimal clinical care and access to research platforms. The goal of this working group was to provide high-level guidance on biopsy practices that safely meet these evolving needs. Harmonizing tissue collection practices is paramount to improving the care of children, adolescents, and young adults diagnosed with Ewing sarcoma and osteosarcoma.

Abstract Background Benign breast disease (BBD) increases breast cancer (BC) risk progressively for women diagnosed with nonproliferative change, proliferative disease without atypia (PDWA), and atypical hyperplasia (AH). Leveraging data from 18 704 women in the Mayo BBD Cohort (1967-2013), we evaluated temporal trends in BBD diagnoses and how they have influenced associated BC risk over 4 decades. Methods BC risk trends associated with BBD were evaluated using standardized incidence ratios (SIRs) and age–period–cohort modeling across 4 eras—premammogram (1967-1981), precore needle biopsy (CNB) (1982-1992), transition to CNB (1993-2001), and CNB era (2002-2013). Results With a median follow-up of 15.8 years, 9.9% of women were diagnosed with BC (invasive and/or DCIS). From the premammogram era to the CNB era, we observed a significant increase in BC risk, rising from an SIR of 1.61 to 1.99. The proportion of proliferative BBD diagnoses (PDWA or AH) increased markedly over time (28.1%-49.7%), as did the proportion of DCIS events (11%-28%; χ2 P &lt; .001). Within specific BBD categories, the risk of invasive BC increased modestly. Conclusions Absolute risk of BC within BBD categories remained stable, but the relative risk of BC after BBD increased over time due to notable increases in higher risk BBD lesions, specifically PDWA and AH. These findings illustrate how evolving screening practices have changed the risk profile of BBD and should inform management strategies for patients with BBD in modern clinical settings.

PURPOSE Teclistamab is initiated with a step-up dosing (SUD) schedule to mitigate the risk of cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS). Early teclistamab users commonly received SUD in a hospital setting. This study aimed to evaluate safety and health care resource utilization (HRU) in real-world patients with multiple myeloma who initiated teclistamab SUD in an outpatient setting. METHODS This was a retrospective study using Mayo Clinic's electronic medical records from October 26, 2022, to October 31, 2023. Patient characteristics were summarized for all patients treated with teclistamab and separately for patients who started SUD outpatient. SUD pattern, safety, HRU, and post-SUD dosing schedule were described in patients with complete SUD. RESULTS At data cutoff, 65 patients received ≥1 teclistamab dose, including 58 patients who initiated SUD outpatient (median age, 69.2 years; male, 63.8%; White, 89.7%). Among 57 patients who completed SUD in an outpatient setting, all received premedications on the days of teclistamab administrations per label recommendation; 18 (31.6%) developed CRS (13 grade 1, four grade 2, and one grade 4) and two developed ICANS (one each with grade 2 and 4). All CRS and ICANS resolved with supportive care and all patients continued treatment. Eighteen patients were admitted to the hospital for CRS treatment, with a median CRS-related hospital stay of 2 days per admission. Most (60%) doses during SUD required <1 hour clinic time between administration and checkout. Post-SUD, clinic time for treatment doses decreased to <30 minutes for most doses (82%). CONCLUSION Outcomes of this study support outpatient administration as a safe and feasible option for teclistamab SUD to potentially reduce HRU and improve patient experiences.

Abstract The immune system is a key player in the onset and progression of neurodegenerative disorders. While brain resident immune cell‐mediated neuroinflammation and peripheral immune cell (eg, T cell) infiltration into the brain have been shown to significantly contribute to Alzheimer's disease (AD) pathology, the nature and extent of immune responses in the brain in the context of AD and related dementias (ADRD) remain unclear. Furthermore, the roles of the peripheral immune system in driving ADRD pathology remain incompletely elucidated. In March of 2023, the Alzheimer's Association convened the Alzheimer's Association International Conference (AAIC), Advancements: Immunity, to discuss the roles of the immune system in ADRD. A wide range of topics were discussed, such as animal models that replicate human pathology, immune‐related biomarkers and clinical trials, and lessons from other fields describing immune responses in neurodegeneration. This manuscript presents highlights from the conference and outlines avenues for future research on the roles of immunity in neurodegenerative disorders. Highlights The immune system plays a central role in the pathogenesis of Alzheimer's disease. The immune system exerts numerous effects throughout the brain on amyloid‐beta, tau, and other pathways. The 2023 AAIC, Advancements: Immunity, encouraged discussions and collaborations on understanding the role of the immune system.

Objective Describe surgical decision making and outcomes in a series of patients with persistent VPI after pharyngeal flap placement that were all treated with revision palatoplasty. Design Retrospective, case series. Participants Five patients with nonsyndromic cleft palate and persistent hypernasality following a pharyngeal flap. On MRI, 3 patients presented with an incohesive levator veli palatini muscle, and 4 patients had a pharyngeal flap that was below the palatal plane. Interventions One patient underwent straight-line intravelar veloplasty (IVVP), 2 patients underwent pharyngeal flap take-down and IVVP, and 2 patients underwent pharyngeal flap take-down and palate lengthening with buccal myomucosal flaps. Main Outcome Measure Pre- and postoperative resonance. Results Four of five patients (80%) achieved normal resonance 12 months postoperation. Conclusions Revision palatoplasty may be an effective approach for treating patients with persistent hypernasality following a pharyngeal flap. MRI may aid in surgical selection based on patient-specific anatomical findings.