Germline cancer susceptibility in individuals with melanoma.

BACKGROUND: Prior studies have estimated a small number of individuals with melanoma (2%-2.5%) have germline cancer predisposition, yet a recent twin study suggested melanoma has the highest hereditability among cancers. OBJECTIVE: To determine the incidence of hereditary melanoma and characterize the spectrum of cancer predisposition genes that may increase the risk of melanoma. METHODS: Four hundred individuals with melanoma and personal or family history of cancers underwent germline testing of >80 cancer predisposition genes. Comparative analysis of germline data was performed on 3 additional oncologic and dermatologic data sets. RESULTS: Germline pathogenic/likely pathogenic (P/LP) variants were identified in 15.3% (61) individuals with melanoma. Most variants (41, 67%) involved genes considered unrelated to melanoma (BLM, BRIP1, CHEK2, MLH1, MSH2, PMS2, RAD51C). A third (20, 33%) were in genes previously associated with familial melanoma (BAP1, BRCA2, CDKN2A, MITF, TP53). Nearly half (30, 46.9%) of P/LP variants were in homologous repair deficiency genes. Validation cohorts demonstrated P/LP rates of 10.6% from an unselected oncologic cohort, 15.8% from a selected commercial testing cohort, and 14.5% from a highly selected dermatologic study. LIMITATIONS: Cohorts with varying degrees of selection, some retrospective. CONCLUSION: Germline predisposition in individuals with melanoma is common, with clinically actionable findings diagnosed in 10.6% to 15.8%.

Utility, Appropriateness, and Content of Electronic Consultations Across Medical Subspecialties.

BACKGROUND: Electronic consultations (e-consults) can facilitate patient access to specialists, minimize travel, and reduce unnecessary in-person visits. However, metrics to enable study of e-consults and their effect on processes and patient care are lacking. OBJECTIVE: To assess novel metrics of e-consult appropriateness and utility. DESIGN: Retrospective cohort study. SETTING: Primary and specialty care practices at 2 large academic and 2 community hospitals of an integrated health system. PARTICIPANTS: Patients with e-consult requests to 5 specialties-hematology, infectious disease, dermatology, rheumatology, and psychiatry-between October 2017 and November 2018. MEASUREMENTS: The appropriateness of e-consult inquiries was assessed by review of medical records and defined as meeting the following 4 criteria: not answerable by reviewing evidence-based summary sources ("point-of-care resource test"), not merely requesting logistic information, having appropriate clinical urgency, and having appropriate patient complexity. Interrater agreement in assessments of e-consult appropriateness was assessed by the κ statistic. Utility of e-consults was assessed by the rate of avoided visits (AVs), defined by the absence of an in-person visit to the same specialty within 120 days. RESULTS: Overall, 6512 eligible e-consults were made by 1096 referring providers to 121 specialist consultants. Inquiries were characterized as diagnostic, therapeutic, for provider education, or at the request of the patient. Most consultations were answered within 1 day, with variation across specialties (73.1% for psychiatry to 87.8% for infectious disease). Overall, 70.2% of e-consults met all 4 criteria for appropriateness; the frequency of unmet criteria varied among specialties. Raters agreed on the appropriateness of 94% of e-consults (κ = 0.57 [95% CI, 0.36 to 0.79]), indicating moderate agreement. The overall rate of AVs across the 5 specialties was 81.2%; the highest rate was in psychiatry (92.6%) and the lowest in dermatology (61.9%). LIMITATION: Generalizability is unknown outside a single integrated health system, where requesting and consulting providers share a common electronic health record. CONCLUSION: Novel metrics to assess the appropriateness and utility of e-consults provide meaningful insight into practice, provide a rubric for comparison in future studies in additional settings, and suggest areas to improve resource use and patient care. PRIMARY FUNDING SOURCE: None.

Influence of Killer Immunoglobulin-Like Receptors and Somatic Mutations on Transplant Outcomes in Acute Myeloid Leukemia.

Natural killer (NK) cells are regulated by killer immunoglobulin-like receptor (KIR) interactions with human leukocyte antigen class I ligands. Various models of NK cell alloreactivity have been associated with outcomes after allogeneic hematopoietic cell transplant (alloHCT), but results have varied widely. We hypothesized that somatic mutations in acute myeloid leukemia (AML) in the context of KIR profiles may further refine their association with transplant outcomes. In this single-center, retrospective, observational study, 81 AML patients who underwent matched-related donor alloHCT were included. Post-HCT outcomes were assessed based on mutational status and KIR profiles with the Kaplan-Meier method and log-rank test. On multivariable analysis those with any somatic mutations and C1/C2 heterozygosity had less acute graft-versus-host disease (GvHD) (hazard ratio [HR], 0.32; 95% confidence interval [CI], 0.14-0.75; P = .009), more relapse (HR, 3.02; 95% CI, 1.30-7.01; P = .010), inferior relapse-free survival (RFS; HR, 2.22; 95% CI, 1.17-4.20; P = .014), and overall survival (OS; HR, 2.21; 95% CI, 1.17-4.20; P = .015), whereas those with a missing KIR ligand had superior RFS (HR, 0.53; 95% CI, 0.30-0.94; P = .031). The presence of a somatic mutation and donor haplotype A was also associated with less acute GvHD (HR, 0.38; 95% CI, 0.16-0.92; P = .032), more relapse (HR, 2.72; 95% CI, 1.13-6.52; P = .025), inferior RFS (HR, 2.11; 95% CI, 1.07-4.14; P = .030), and OS (HR, 2.20; 95% CI, 1.11-4.38; P = .024). Enhanced NK cell alloreactivity from more KIR activating signals (donor B haplotype) and fewer inhibitory signals (recipient missing KIR ligand or C1 or C2 homozygosity) may help mitigate the adverse prognosis associated with some AML somatic mutations. These results may have implications for improving patient risk stratification prior to transplant and optimizing donor selection.