Citations

Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predisposes both hematologic malignancy and CAD. TERT (which encodes telomerase reverse transcriptase) is the most significantly associated germline locus for CHIP in genome-wide association studies. Here, we investigated the relationship between CHIP, LTL, and CAD in the Trans-Omics for Precision Medicine (TOPMed) program ( n = 63,302) and UK Biobank ( n = 47,080). Bidirectional Mendelian randomization studies were consistent with longer genetically imputed LTL increasing propensity to develop CHIP, but CHIP then, in turn, hastens to shorten measured LTL (mLTL). We also demonstrated evidence of modest mediation between CHIP and CAD by mLTL. Our data promote an understanding of potential causal relationships across CHIP and LTL toward prevention of CAD.

P10 Coronary artery calcification (CAC), quantified by electron beam computed tomography, provides a measure of extent of coronary atherosclerosis in asymptomatic and symptomatic individuals. It is well recognized that coronary artery disease and CAC are complex processes that are influenced by many genetic and environmental factors. Several aspects of CAC quantity make genetic studies of it particularly challenging. These include the non-normality of CAC frequency distributions and the strong age- and sex-dependence of CAC levels. To search for regions that may contain genes influencing CAC quantity, a genome-wide scan was conducted on a sample enriched for hypertension from the Epidemiology of Coronary Artery Calcification Study. The genome-wide linkage scan was based on 370 anonymous markers spanning the 22 autosomal chromosomes in 29 families. The analysis sample consisted of 20 affected sib-pairs, 8 affected sib-trios and 1 family with 6 affected siblings. Here, affection status was defined as being above the 70th sex- and age-specific percentile based on a reference population. Mode-of-inheritance-free qualitative linkage analysis was used to analyze sib-pair data. Maximum multipoint lod scores were calculated using the computer software Genehunter-2. Weighted analyses were conducted using Holmans “possible triangle” constraint. The overall maximum lod scores were observed on chromosomes 6 (lod=2.22) and 10 (lod=3.24). Additional lod scores greater than 1.0 were observed on chromosomes 2, 14, 15 and 17. These results identify regions that may harbor genes involved in high sex- and age-specific levels of CAC (supported by HL46292).

The NCCN Guidelines for Head and Neck Cancers address tumors arising in the oral cavity (including mucosal lip), pharynx, larynx, and paranasal sinuses. Occult primary cancer, salivary gland cancer, and mucosal melanoma (MM) are also addressed. The specific site of disease, stage, and pathologic findings guide treatment (eg, the appropriate surgical procedure, radiation targets, dose and fractionation of radiation, indications for systemic therapy). The NCCN Head and Neck Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel’s most recent recommendations regarding management of HPV-positive oropharynx cancer and ongoing research in this area.

Objective To provide evidence‐based recommendations and expert guidance for the management of Kawasaki disease (KD), focusing on clinical scenarios more commonly addressed by rheumatologists. Methods Sixteen clinical questions regarding diagnostic testing, treatment, and management of KD were developed in the Patient/Population, Intervention, Comparison, and Outcomes (PICO) question format. Systematic literature reviews were conducted for each PICO question. We used the Grading of Recommendations, Assessment, Development and Evaluation method to assess the quality of evidence and formulate recommendations. Each recommendation required consensus from at least 70% of the Voting Panel. Results We present 1 good practice statement, 11 recommendations, and 1 ungraded position statement to guide the management of KD and clinical scenarios of suspected KD. These recommendations for KD are focused on situations in which input from rheumatologists may be requested by other managing specialists, such as in cases of treatment‐refractory, severe, or complicated KD. The good practice statement affirms that all patients with KD should receive initial treatment with intravenous immunoglobulin (IVIG). In addition, we developed 7 strong and 4 conditional recommendations for the management of KD or suspected KD. Strong recommendations include prompt treatment of incomplete KD, treatment with aspirin, and obtaining an echocardiogram in the setting of unexplained macrophage activation syndrome or shock. Conditional recommendations include use of IVIG with other adjuvant agents for patients with KD and high‐risk features of IVIG resistance and/or coronary artery aneurysms. These recommendations endorse minimizing risk to the patient by using established therapy promptly at disease onset and identifying situations in which adjunctive therapy may be warranted. Conclusion These recommendations provide guidance regarding diagnostic strategies, use of pharmacologic agents, and use of echocardiography in patients with suspected or confirmed KD.

Objective To provide evidence‐based recommendations and expert guidance for the management of Kawasaki disease (KD), focusing on clinical scenarios more commonly addressed by rheumatologists. Methods Sixteen clinical questions regarding diagnostic testing, treatment, and management of KD were developed in the Patient/Population, Intervention, Comparison, and Outcomes (PICO) question format. Systematic literature reviews were conducted for each PICO question. We used the Grading of Recommendations, Assessment, Development and Evaluation method to assess the quality of evidence and formulate recommendations. Each recommendation required consensus from at least 70% of the Voting Panel. Results We present 1 good practice statement, 11 recommendations, and 1 ungraded position statement to guide the management of KD and clinical scenarios of suspected KD. These recommendations for KD are focused on situations in which input from rheumatologists may be requested by other managing specialists, such as in cases of treatment‐refractory, severe, or complicated KD. The good practice statement affirms that all patients with KD should receive initial treatment with intravenous immunoglobulin (IVIG). In addition, we developed 7 strong and 4 conditional recommendations for the management of KD or suspected KD. Strong recommendations include prompt treatment of incomplete KD, treatment with aspirin, and obtaining an echocardiogram in the setting of unexplained macrophage activation syndrome or shock. Conditional recommendations include use of IVIG with other adjuvant agents for patients with KD and high‐risk features of IVIG resistance and/or coronary artery aneurysms. These recommendations endorse minimizing risk to the patient by using established therapy promptly at disease onset and identifying situations in which adjunctive therapy may be warranted. Conclusion These recommendations provide guidance regarding diagnostic strategies, use of pharmacologic agents, and use of echocardiography in patients with suspected or confirmed KD.

AbstractThe Three-Clinic Hearing Aid Selection Profile (HASP) was developed to assess a patient's beliefs about a number of basic considerations felt to be critical to the hearing aid selection (HAS) process. These characteristics are felt to be key to the acceptance of amplification and include motivation, expectations, cost of goods and services, appearance (cosmesis), attitudes about technology, physical function/limitations, communication needs, and lifestyle. The results of the first investigation suggest that we have been successful in developing a 40–item metric with adequate internal consistency reliability that assesses the aforementioned characteristics. Second, results of the administration of this tool to a large group of individuals indicated that (1) age impacted scores on the Technology, Physical Function, and Communicative Needs subscales; (2) gender impacted scores on the Motivation, Expectation, Technology, Communicative Needs, and Appearance subscales; (3) previous hearing aid use affected scores on the Motivation subscale; (4) level of education impacted scores on the Physical Function and Lifestyle subscales; and (5) self-perceived hearing handicap had an effect on Motivation and Communicative Needs subscale scores. Percentile data collected from this subject sample are presented as a benchmark against which to evaluate responses from individual patients. Case studies are presented to illustrate the potential clinical utility of this device. Abbreviations: ANOVA = analysis of variance, CIC = completely in the canal, COSI = Client Oriented Scale of Improvement, DSP = digital signal processing, HAS = hearing aid selection, HASP = Hearing Aid Selection Profile, HHIA = Hearing Handicap Inventory for Adults, HHIE = Hearing Handicap Inventory for the Elderly

Cardiovascular disease remains the leading cause of death in women. Given accumulating evidence on sex- and gender-based differences in cardiovascular disease development and outcomes, the need for more effective approaches to screening for risk factors and phenotypes in women is ever urgent. Public health surveillance and health care delivery systems now continuously generate massive amounts of data that could be leveraged to enable both screening of cardiovascular risk and implementation of tailored preventive interventions across a woman’s life span. However, health care providers, clinical guidelines committees, and health policy experts are not yet sufficiently equipped to optimize the collection of data on women, use or interpret these data, or develop approaches to targeting interventions. Therefore, we provide a broad overview of the key opportunities for cardiovascular screening in women while highlighting the potential applications of artificial intelligence along with digital technologies and tools.

PURPOSE Chemotherapy outcomes in older patients with Philadelphia (Ph) chromosome–negative B-acute lymphoblastic leukemia (ALL) are very poor. Here, we evaluated blinatumomab as induction and consolidation therapy followed by prednisone, vincristine, 6-mercaptopurine, and methotrexate (POMP) maintenance chemotherapy in this patient population. PATIENTS AND METHODS Patients were treated at National Clinical Trial Network sites. Eligibility criteria included age ≥ 65 years and newly diagnosed Ph chromosome–negative B-ALL. Patients received blinatumomab as induction for one-two cycles until attainment of response (complete remission (CR) and CR with incomplete count recovery). Patients then received three cycles of consolidation with blinatumomab followed by 18 months of POMP maintenance chemotherapy. Eight doses of intrathecal methotrexate were administered as central nervous system prophylaxis. RESULTS Twenty-nine eligible patients were enrolled. The median age was 75 years, and the median bone marrow blast count at diagnosis was 87%. Cytogenetic risk was poor in 10 patients (34%), and five of 14 patients (36%) tested had the Ph-like ALL gene signature. Nineteen patients (66%; 95% CI, 46 to 82) achieved CR. Kaplan-Meier 3-year disease-free survival and overall survival estimates were 37% (95% CI, 17 to 57) and 37% (95% CI, 20 to 55), respectively. CONCLUSION Blinatumomab was well tolerated and effective in the treatment of older patients with newly diagnosed Ph chromosome–negative B-ALL, including patients with poor-risk cytogenetics. The 3-year disease-free survival and overall survival results are encouraging and suggest that this approach should be further explored.

Abstract Background Diffuse Midline Glioma (DMG) with the H3K27M mutation is a lethal childhood brain cancer, with patients rarely surviving 2 years from diagnosis. Methods We conducted a multi-site Phase 1 trial of the imipridone ONC201 for children with H3K27M-mutant glioma (NCT03416530). Patients enrolled on Arm D of the trial (n = 24) underwent serial lumbar puncture for cell-free tumor DNA (cf-tDNA) analysis and patients on all arms at the University of Michigan underwent serial plasma collection. We performed digital droplet polymerase chain reaction (ddPCR) analysis of cf-tDNA samples and compared variant allele fraction (VAF) to radiographic change (maximal 2D tumor area on MRI). Results Change in H3.3K27M VAF over time (“VAF delta”) correlated with prolonged PFS in both CSF and plasma samples. Nonrecurrent patients that had a decrease in CSF VAF displayed a longer progression free survival (P = .0042). Decrease in plasma VAF displayed a similar trend (P = .085). VAF “spikes” (increase of at least 25%) preceded tumor progression in 8/16 cases (50%) in plasma and 5/11 cases (45.4%) in CSF. In individual cases, early reduction in H3K27M VAF predicted long-term clinical response (>1 year) to ONC201, and did not increase in cases of later-defined pseudo-progression. Conclusion Our work demonstrates the feasibility and potential utility of serial cf-tDNA in both plasma and CSF of DMG patients to supplement radiographic monitoring. Patterns of change in H3K27M VAF over time demonstrate clinical utility in terms of predicting progression and sustained response and possible differentiation of pseudo-progression and pseudo-response.

OBJECTIVE Suprasellar meningioma resection via either the transcranial approach (TCA) or the endoscopic endonasal approach (EEA) is an area of controversy and active evaluation. Skull base surgeons increasingly consider patient-reported outcomes (PROs) when choosing an approach. No PRO measure currently exists to assess quality of life for suprasellar meningiomas. METHODS Adult patients undergoing suprasellar meningioma resection between 2013 and 2019 via EEA (n = 14) or TCA (n = 14) underwent semistructured interviews. Transcripts were coded using a grounded theory approach to identify themes as the basis for a PRO measure that includes all uniquely reported symptoms. To assess content validity, 32 patients and 15 surgeons used a Likert scale to rate the relevance of items on the resulting questionnaire and the general Patient-Reported Outcomes Measurement Information System–29 (PROMIS29). The mean scores were calculated for all items and compared for TCA versus EEA patient cohorts by using unpaired t-tests. Items on either questionnaire with mean scores ≥ 2.0 from patients were considered meaningful and were aggregated to form the novel Suprasellar Meningioma Patient-Reported Outcome Survey (SMPRO) instrument. RESULTS Qualitative analyses resulted in 55 candidate items. Relative to patients who underwent the EEA, those who underwent the TCA reported significantly worse future outlook before surgery (p = 0.01), tiredness from medications 2 weeks after surgery (p = 0.001), and word-finding and memory difficulties 3 months after surgery (p = 0.05 and < 0.001, respectively). The items that patients who received a TCA were most concerned about included medication-induced lethargy after surgery (2.9 ± 1.3), blurry vision before surgery (2.7 ± 1.5), and difficulty reading due to blurry vision before surgery (2.7 ± 2.7). Items that patients who received an EEA were most concerned about included blurry vision before surgery (3.5 ± 1.3), difficulty reading due to blurry vision before surgery (2.4 ± 1.3), and problems with smell postsurgery (2.9 ± 1.3). Although surgeons overall overestimated how concerned patients were about questionnaire items (p < 0.0005), the greatest discrepancies between patient and surgeon relevance scores were for blurry vision pre- and postoperatively (p < 0.001 and < 0.001, respectively) and problems with taste postoperatively (p < 0.001). Seventeen meningioma-specific items were considered meaningful, supplementing 8 significant PROMIS29 items to create the novel 25-item SMPRO. CONCLUSIONS The authors developed a disease- and approach-specific measure for suprasellar meningiomas to compare quality of life by operative approach. If demonstrated to be reliable and valid in future studies, this instrument may assist patients and providers in choosing a personalized surgical approach.