Citations

Introduction: Minority communities have had limited access to advances in genomic medicine. Mayo Clinic and Mountain Park Health Center, a Federally Qualified Health Center in Phoenix, Arizona, partnered to assess the feasibility of offering genomic screening to Latino patients receiving care at a community-based health center. We examined primary care provider (PCP) experiences reporting genomic screening results and integrating those results into patient care. Methods: We conducted open-ended, semi-structured interviews with PCPs and other members of the health care team charged with supporting patients who received positive genomic screening results. Interviews were recorded, transcribed, and analyzed thematically. Results: Of the 500 patients who pursued genomic screening, 10 received results indicating a genetic variant that warranted clinical management. PCPs felt genomic screening was valuable to patients and their families, and that genomic research should strive to include underrepresented minorities. Providers identified multiple challenges integrating genomic sequencing into patient care, including difficulties maintaining patient contact over time; arranging follow-up medical care; and managing results in an environment with limited genetics expertise. Providers also reflected on the ethics of offering genomic sequencing to patients who may not be able to pursue diagnostic testing or follow-up care due to financial constraints. Conclusions: Our results highlight the potential benefits and challenges of bringing advances in precision medicine to community-based health centers serving under-resourced populations. By proactively considering patient support needs, and identifying financial assistance programs and patient-referral mechanisms to support patients who may need specialized medical care, PCPs and other health care providers can help to ensure that precision medicine lives up to its full potential as a tool for improving patient care.

Abstract Background: Adjuvant endocrine therapy (AET) improves outcomes in women with hormone receptor–positive (HR+) breast cancer. Suboptimal AET adherence is common, but data are lacking about symptoms and adherence in racial/ethnic minorities. We evaluated adherence by race and the relationship between symptoms and adherence. Methods: The Women's Hormonal Initiation and Persistence study included women diagnosed with nonrecurrent HR+ breast cancer who initiated AET. AET adherence was captured using validated items. Data regarding patient (e.g., race), medication-related (e.g., symptoms), cancer care delivery (e.g., communication), and clinicopathologic factors (e.g., chemotherapy) were collected via surveys and medical charts. Multivariable logistic regression models were employed to calculate odds ratios and 95% confidence intervals (CIs) associated with adherence. Results: Of the 570 participants, 92% were privately insured and nearly one of three were Black. Thirty-six percent reported nonadherent behaviors. In multivariable analysis, women less likely to report adherent behaviors were Black (vs. White; OR, 0.43; 95% CI, 0.27–0.67; P < 0.001) and with greater symptom burden (OR, 0.98; 95% CI, 0.96–1.00; P < 0.05). Participants more likely to be adherent were overweight (vs. normal weight) (OR, 1.58; 95% CI, 1.04–2.43; P < 0.05), sat ≤ 6 hours a day (vs. ≥6 hours; OR, 1.83; 95% CI, 1.25–2.70; P < 0.01), and were taking aromatase inhibitors (vs. tamoxifen; OR, 1.91; 95% CI, 1.28–2.87; P < 0.01). Conclusions: Racial differences in AET adherence were observed. Longitudinal assessments of symptom burden are needed to better understand this dynamic process and factors that may explain differences in survivor subgroups. Impact: Future interventions should prioritize Black survivors and women with greater symptom burden.

AbstractObjective Familial hypercholesterolemia (FH), a prevalent genomic disorder that increases risk of coronary heart disease, remains significantly underdiagnosed. Clinical decision support (CDS) tools have the potential to increase FH detection. We describe our experience in the development and implementation of a genomic CDS for FH at a large academic medical center.Methods CDS development and implementation were conducted in four phases: (1) development and validation of an algorithm to identify “possible FH”; (2) obtaining approvals from institutional committees to develop the CDS; (3) development of the initial prototype; and (4) use of an implementation science framework to evaluate the CDS.Results The timeline for this work was approximately 4 years; algorithm development and validation occurred from August 2018 to February 2020. During this 4-year period, we engaged with 15 stakeholder groups to build and integrate the CDS, including health care providers who gave feedback at each stage of development. During CDS implementation six main challenges were identified: (1) need for multiple institutional committee approvals; (2) need to align the CDS with institutional knowledge resources; (3) need to adapt the CDS to differing workflows; (4) lack of institutional guidelines for CDS implementation; (5) transition to a new institutional electronic health record (EHR) system; and (6) limitations of the EHR related to genomic medicine.Conclusion We identified multiple challenges in different domains while developing CDS for FH and integrating it with the EHR. The lessons learned herein may be helpful in streamlining the development and deployment of CDS to facilitate genomic medicine implementation.

AbstractCancer treatment has been transformed by checkpoint blockade therapies, with the highest anti-tumor activity of anti-programmed death 1 (PD-1) antibody therapy seen in Hodgkin lymphoma. Disappointingly, response rates have been low in the non-Hodgkin lymphomas, with no activity seen in relapsed/refractory chronic lymphocytic leukemia (CLL) with PD-1 blockade. Thus, identifying more powerful combination therapy is required for these patients. Here, we preclinically demonstrate enhanced anti-CLL activity following combinational therapy with anti-PD-1 or anti-PD-1 ligand (PD-L1) and avadomide, a cereblon E3 ligase modulator (CELMoD). Avadomide induced type I and II interferon (IFN) signaling in patient T cells, triggering a feedforward cascade of reinvigorated T-cell responses. Immune modeling assays demonstrated that avadomide stimulated T-cell activation, chemokine expression, motility and lytic synapses with CLL cells, as well as IFN-inducible feedback inhibition through upregulation of PD-L1. Patient-derived xenograft tumors treated with avadomide were converted to CD8+ T cell-inflamed tumor microenvironments that responded to anti-PD-L1/PD-1-based combination therapy. Notably, clinical analyses showed increased PD-L1 expression on T cells, as well as intratumoral expression of chemokine signaling genes in B-cell malignancy patients receiving avadomide-based therapy. These data illustrate the importance of overcoming a low inflammatory T-cell state to successfully sensitize CLL to checkpoint blockade-based combination therapy.

Abstract Pediatric solitary plasmacytomas are extremely rare, with only 14 cases previously reported. None of these reports included PET imaging findings. We present PET/CT and PET/MRI imaging findings in a 15-year-old boy with what was initially thought to be a solitary plasmacytoma, which later developed into multiple myeloma. The initial PET/CT of solitary plasmacytoma, as well as postradiotherapy PET/MRI findings with the new lesions suggestive of multiple myeloma, are presented.

Abstract Chronic lymphocytic leukemia (CLL) is characterized by the existence of subsets of patients with (quasi)identical, stereotyped B-cell receptor (BcR) immunoglobulins. Patients in certain major stereotyped subsets often display remarkably consistent clinicobiological profiles, suggesting that the study of BcR immunoglobulin stereotypy in CLL has important implications for understanding disease pathophysiology and refining clinical decision-making. Nevertheless, several issues remain open, especially pertaining to the actual frequency of BcR immunoglobulin stereotypy and major subsets, as well as the existence of higher-order connections between individual subsets. To address these issues, we investigated clonotypic IGHV-IGHD-IGHJ gene rearrangements in a series of 29 856 patients with CLL, by far the largest series worldwide. We report that the stereotyped fraction of CLL peaks at 41% of the entire cohort and that all 19 previously identified major subsets retained their relative size and ranking, while 10 new ones emerged; overall, major stereotyped subsets had a cumulative frequency of 13.5%. Higher-level relationships were evident between subsets, particularly for major stereotyped subsets with unmutated IGHV genes (U-CLL), for which close relations with other subsets, termed “satellites,” were identified. Satellite subsets accounted for 3% of the entire cohort. These results confirm our previous notion that major subsets can be robustly identified and are consistent in relative size, hence representing distinct disease variants amenable to compartmentalized research with the potential of overcoming the pronounced heterogeneity of CLL. Furthermore, the existence of satellite subsets reveals a novel aspect of repertoire restriction with implications for refined molecular classification of CLL.

As applications of genomic sequencing have expanded, offering genetic counseling support to all patients is arguably no longer practical. Additionally, whether individuals desire and value genetic counseling services for genomic screening is unclear. We offered elective genetic counseling to 5110 individuals prior to undergoing sequencing and 2310 participants who received neutral results to assess demand. A total of 0.2% of the study participants accessed genetic counseling services prior to sequencing, and 0.3% reached out after receiving neutral results. We later conducted 50 interviews with participants to understand why they did not access these services. Many interviewees did not recall the availability of genetic counseling and were unfamiliar with the profession. Interviewees described not needing counseling before sequencing because they understood the study and felt that they could cope with any result. Counseling was considered equally unnecessary after learning neutral results. Although the participants had questions about their results, they did not feel that speaking with a genetic counselor would be helpful. Genomic screening efforts that employ opt-in models of genetic counseling may need to clarify the potential value of genetic counseling support from the outset and feature genetic counseling services more prominently in program materials.

Abstract Zinc-finger protein 384 (ZNF384) gene fusions with EP300 have recently been described as a recurrent fusion in B-cell acute lymphoblastic leukemia (B-ALL) with a good response to conventional chemotherapy, suggesting a favorable prognosis. Herein, we report on a female patient aged 12 years with uninformative conventional chromosome and B-ALL panel fluorescence in situ hybridization studies with chromosomal microarray showing multiple copy number gains, including relative gains in the ZNF384 (12p13.31) and EP300 (22q13.2) gene regions, suggesting a cryptic EP300/ZNF384 fusion. Ultimately, a next-generation sequencing assay, mate pair sequencing, was utilized to confirm EP300/ZNF384 fusion in this B-ALL clone, which may confer a favorable overall prognosis and potential targeted therapy.

Electronic health record (EHR)-based clinical decision support (CDS) can address the low awareness and undertreatment of familial hypercholesterolemia (FH), a disorder associated with a markedly increased risk of coronary heart disease. We aimed to incorporate provider perspectives into the development and implementation of a CDS tool for FH. An implementation science framework and a user-centered design process were used to create a CDS tool for FH. Primary care physicians and specialist physicians participated in qualitative interviews, usability testing and an implementation survey. The CDS was configured in two formats—a best practice alert (BPA) and an in-basket message and subsequently deployed in the EHR in silent mode. The key themes that emerged from the analysis of interview transcripts included understanding and awareness of FH, clinical workflow, physician preferences and value of CDS tools, perspectives on patient needs and values and dissemination and implementation. Recommendations related to usability included preferred CDS format and placement, content, timing and frequency, and level of alert urgency/prioritization. In response to the survey, 84.6% of physicians agreed that the CDS would improve early FH diagnosis and 92.3% agreed that it would help them identify and manage FH patients. Physician feedback led to iterative CDS refinement. In summary, we developed a CDS tool for FH using an implementation science framework and physician feedback. Initial deployment revealed a significant burden of FH and the potential for the CDS tool to have a large impact.