Preemptive Pharmacogenetic-Guided Metoprolol Management for Postoperative Atrial Fibrillation in Cardiac Surgery: The Preemptive Pharmacogenetic-Guided Metoprolol Management for Atrial Fibrillation in Cardiac Surgery Pilot Trial.

OBJECTIVES: To test the hypothesis that implementation of a cytochrome P-450 2D6 (CYP2D6) genotype-guided perioperative metoprolol administration will reduce the risk of postoperative atrial fibrillation (AF), the authors conducted the Preemptive Pharmacogenetic-Guided Metoprolol Management for Atrial Fibrillation in Cardiac Surgery pilot study. DESIGN: Clinical pilot trial. SETTING: Single academic center. PARTICIPANTS: Seventy-three cardiac surgery patients. MEASUREMENTS AND MAIN RESULTS: Patients were classified as normal, intermediate, poor, or ultrarapid metabolizers after testing for their CYP2D6 genotype. A clinical decision support tool in the electronic health record advised providers on CYP2D6 genotype-guided metoprolol dosing. Using historical data, the Bayesian method was used to compare the incidence of postoperative AF in patients with altered metabolizer status to the reference incidence. A logistic regression analysis was performed to study the association between the metabolizer status and postoperative AF while controlling for the Multicenter Study of Perioperative Ischemia AF Risk Index. Of the 73 patients, 30% (n = 22) developed postoperative AF; 89% (n = 65) were normal metabolizers; 11% (n = 8) were poor/intermediate metabolizers; and there were no ultrarapid metabolizer patients identified. The estimated rate of postoperative AF in patients with altered metabolizer status was 30% (95% CI 8%-60%), compared with the historical reference incidence (27%). In the risk-adjusted analysis, there was insufficient evidence to conclude that modifying metoprolol dosing based on poor/intermediate metabolizer status was associated significantly with the odds of postoperative AF (odds ratio 0.82, 95% CI 0.15-4.55, p = 0.82). CONCLUSIONS: A CYP2D6 genotype-guided metoprolol management was not associated with a reduction of postoperative AF after cardiac surgery.

Assessments of Somatic Variant Classification Using the Association for Molecular Pathology/American Society of Clinical Oncology/College of American Pathologists Guidelines: A Report from the Association for Molecular Pathology.

To assess the clinical implementation of the 2017 Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer: A Joint Consensus Recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists, identify content that may result in classification inconsistencies, and evaluate implementation barriers, an Association for Molecular Pathology Working Group conducted variant interpretation challenges and a guideline implementation survey. A total of 134 participants participated in the variant interpretation challenges, consisting of 11 variants in four cancer cases. Results demonstrate 86% (range, 54% to 94%) of the respondents correctly classified clinically significant variants, variants of uncertain significance, and benign/likely benign variants; however, only 59% (range, 39% to 84%) of responses agreed with the working group's consensus intended responses regarding both tiers and categories of clinical significance. In the implementation survey, 71% (157/220) of respondents have implemented the 2017 guidelines for variant classification and reporting either with or without modifications. Collectively, this study demonstrates that, although they may not yet be optimized, the 2017 guideline recommendations are being adopted for standardized somatic variant classification. The working group identified significant areas for future guideline improvement, including the need for a more granular and comprehensive classification system and education resources to meet the growing needs of both laboratory professionals and medical oncologists.

Impairments to executive function in emerging adults with Huntington disease.

BACKGROUND AND OBJECTIVES: The clinical diagnosis of Huntington disease (HD) is typically made once motor symptoms and chorea are evident. Recent reports highlight the onset of cognitive and psychiatric symptoms before motor manifestations. These findings support further investigations of cognitive function across the lifespan of HD sufferers. METHODS: To assess cognitive symptoms in the developing brain, we administered assessments from the National Institutes of Health Toolbox Cognitive Battery, an age-appropriate cognitive assessment with population norms, to a cohort of children, adolescents and young adults with (gene-expanded; GE) and without (gene-not-expanded; GNE) the trinucleotide cytosine, adenine, guanine (CAG) expansion in the Huntingtin gene. These five assessments that focus on executive function are well validated and form a composite score, with population norms. We modelled these scores across age, and CAP score to estimate the slope of progression, comparing these results to motor symptoms. RESULTS: We find significant deficits in the composite measure of executive function in GE compared with GNE participants. GE participant performance on working memory was significantly lower compared with GNE participants. Modelling these results over age suggests that these deficits occur as early as 18 years of age, long before motor manifestations of HD. CONCLUSIONS: This work provides strong evidence that impairments in executive function occur as early as the second decade of life, well before anticipated motor onset. Future investigations should delineate whether these impairments in executive function are due to abnormalities in neurodevelopment or early sequelae of a neurodegenerative process.

The first report of a JAK2 V617F-positive myeloproliferative neoplasm with initial manifestation as a rare pampiniform venous plexus thrombosis and review of the literature.

Pampiniform venous plexus (PVP) thrombosis is exceedingly rare, with fewer than 25 cases described. Thus, the etiology and pathophysiology remain largely unknown. A 38-year-old male with no known risk factors incidentally noted a 10-day history of right testicular discomfort prompting evaluation. Findings included extensive right PVP thrombus, critically elevated hematocrit, and a JAK2 V617F gene variant. Despite no treatment guidelines, conservative management was initiated with therapeutic apixaban, and therapeutic phlebotomy and hydroxyurea for newly diagnosed primary polycythemia vera (PV), sparing exploratory genitourinary surgery. This represents the first reported case of PVP thrombosis as the initial manifestation of a JAK2 V617F positive PV and the first documented report of PVP thrombosis associated with an acquired hypercoagulable state. Of the 8 previous cases with hypercoagulable testing performed, 2 involved inherited hypercoagulable states, suggesting hereditary and acquired prothrombotic disorders should be considered as predisposing factors. Testing for the JAK2 V617F variant in patients with mesenteric, cerebral, and splanchnic venous thromboses is currently recommended, but testing patients with venous thromboses in other anatomical locations remains controversial. We reviewed all previously described cases to expound upon this diagnosis, potential association with hypercoagulable disorders, treatment options, and observed clinical outcomes. This case adds to the minimal literature and supports genetic testing all patients with spontaneous PVP thrombosis for the JAK2 V617F variant and other hypercoagulable conditions. Additionally, conservative management with therapeutic anticoagulation and treatment of the underlying precipitating disease state may be acceptable in select patients, following exclusion of surgical emergencies.

Impact of Updating Pharmacogenetic Results: Lessons Learned from the PREDICT Program.

Pharmacogenomic (PGx) evidence for selective serotonin reuptake inhibitors (SSRIs) continues to evolve. For sites offering testing, maintaining up-to-date interpretations and implementing new clinical decision support (CDS) driven by existing results creates practical and technical challenges. Vanderbilt University Medical Center initiated panel testing in 2010, added CYP2D6 testing in 2017, and released CDS for SSRIs in 2020. We systematically reinterpreted historic CYP2C19 and CYP2D6 genotypes to update phenotypes to current nomenclature and to launch provider CDS and patient-oriented content for SSRIs. Chart review was conducted to identify and recontact providers caring for patients with current SSRI therapy and new actionable recommendations. A total of 15,619 patients' PGx results were reprocessed. Of the non-deceased patients reprocessed, 21% (n = 3278) resulted in CYP2C19*1/*17 reinterpretations. Among 289 patients with an actionable recommendation and SSRI medication prescription, 31.8% (n = 92) did not necessitate contact of a clinician, while 43.2% (n = 125) resulted in clinician contacted, and for 25% (n = 72) no appropriate clinician was able to be identified. Maintenance of up-to-date interpretations and recommendations for PGx results over the lifetime of a patient requires continuous effort. Reprocessing is a key strategy for maintenance and expansion of PGx content to be periodically considered and implemented.

A Tutorial for Pharmacogenomics Implementation Through End-to-End Clinical Decision Support Based on Ten Years of Experience from PREDICT.

Vanderbilt University Medical Center implemented pharmacogenomics (PGx) testing with the Pharmacogenomic Resource for Enhanced Decisions in Care and Treatment (PREDICT) initiative in 2010. This tutorial reviews the laboratory considerations, technical infrastructure, and programmatic support required to deliver panel-based PGx testing across a large health system with examples and experiences from the first decade of the PREDICT initiative. From the time of inception, automated clinical decision support (CDS) has been a critical capability for delivering PGx results to the point-of-care. Key features of the CDS include human-readable interpretations and clinical guidance that is anticipatory, actionable, and adaptable to changes in the scientific literature. Implementing CDS requires that structured results from the laboratory be encoded in standards-based messages that are securely ingested by electronic health records. Translating results to guidance also requires an informatics infrastructure with multiple components: (1) to manage the interpretation of raw genomic data to "star allele" results to expected phenotype, (2) to define the rules that associate a phenotype with recommended changes to clinical care, and (3) to manage and update the knowledge base. Knowledge base management is key to processing new results with the latest guidelines, and to ensure that historical genomic results can be reinterpreted with revised CDS. We recommend that these components be deployed with institutional authorization, programmatic support, and clinician education to govern the CDS content and policies around delivery.

Acute Myeloid Leukemia Case Harboring Unusual FLT3 Variant: Somatic vs Germline?

FLT3 mutations are considered a prognostic and predictive marker. Here we report on a patient with a rare FLT3 germline variant in the context of relapsed acute myeloid leukemia (AML). A female patient aged 57 years presented with AML with mutations in the IDH2, ASXL1, and DNMT3A genes. She underwent allogenic hematopoietic stem cell transplant but relapsed 2 years posttransplant. Targeted next generation sequencing identified a new missense variant in the FLT3 tyrosine kinase domain c.2440G > T (p.A814S). The treating team considered the possibility of patient eligibility for an FLT3 inhibitor. Because both somatic and germline mutations can be identified in tumor tissue with high-throughput sequencing, it becomes important to distinguish the origin of these alterations when possible-especially, in this challenging case, to define the treatment modality. Simultaneous tumor/germline sequencing allows for the identification of rare germline mutations and may help in determining their significance in the pathogenesis of disease.

CYP2D6 Genotype-guided Metoprolol Therapy in Cardiac Surgery Patients: Rationale and Design of the Pharmacogenetic-guided Metoprolol Management for Postoperative Atrial Fibrillation in Cardiac Surgery (PREEMPTIVE) Pilot Study.

OBJECTIVES: The Preemptive Pharmacogenetic-guided Metoprolol Management for Atrial Fibrillation in Cardiac Surgery (PREEMPTIVE) pilot trial aims to use existing institutional resources to develop a process for integrating CYP2D6 pharmacogenetic test results into the patient electronic health record, to develop an evidence-based clinical decision support tool to facilitate CYP2D6 genotype-guided metoprolol administration in the cardiac surgery setting, and to determine the impact of implementing this CYP2D6 genotype-guided integrated approach on the incidence of postoperative atrial fibrillation (AF), provider, and cost outcomes. DESIGN: One-arm Bayesian adaptive design clinical trial. SETTING: Single center, university hospital. PARTICIPANTS: The authors will screen (including CYP2D6 genotype) up to 600 (264 ± 144 expected under the adaptive design) cardiac surgery patients, and enroll up to 200 (88 ± 48 expected) poor, intermediate, and ultrarapid CYP2D6 metabolizers over a period of 2 years at a tertiary academic center. INTERVENTIONS: All consented and enrolled patients will receive the intervention of CYP2D6 genotype-guided metoprolol management based on CYP2D6 phenotype classified as a poor, intermediate, extensive (normal), or ultrarapid metabolizer. MEASUREMENTS AND MAIN RESULTS: The primary outcome will be the incidence of postoperative AF. Secondary outcomes relating to rates of CYP2D6 genotype-guided prescription changes, costs, lengths of stay, and implementation metrics also will be investigated. CONCLUSIONS: The PREEMPTIVE pilot study is the first perioperative pilot trial to provide essential information for the design of a future, large-scale trial comparing CYP2D6 genotype-guided metoprolol management with a nontailored strategy in terms of managing AF. In addition, secondary outcomes regarding implementation, clinical benefit, safety, and cost-effectiveness in patients undergoing cardiac surgery will be examined.

Clinicopathologic correlates of MYD88 L265P mutation and programmed cell death (PD-1) pathway in primary central nervous system lymphoma.

Primary central nervous system lymphoma (PCNSL) patients have a poorer prognosis than systemic lymphoma. Gain-of-function MYD88 c.794T > C (p. L265P) mutation and programed cell death-1 (PD-1) pathway alterations are potential targetable pathways. Our study objective was to determine the clinicopathologic correlates of MYD88 mutation and PD-1 alterations in PCNSL and the impact of Epstein-Barr virus (EBV) infection. We studied 53 cases including 13 EBV-associated (EBVpos) PCNSL, 49% harbored MYD88 mutation, none seen in EBVpos PCNSL. MYD88 protein expression did not correlate with MYD88 mutation. T-cell and macrophage infiltration was common. All PD-L1-positive tumors were EBVpos. Two PD-L1 positive tumors showed 9p24.1/PD-L1 locus alterations by Fluorescence In Situ Hybridization. T cells and macrophages expressed PD-1 and/or PD-L1 in 98% and 83% cases, respectively. MYD88 mutation or protein expression and PD-1 or PD-L1 expression did not predict outcome. We hypothesize that EBVpos PCNSL has a distinct activation mechanism, independent of genetic alterations.

PD-L1 Expression Patterns in Microsatellite Instability-High Intestinal Adenocarcinoma Subtypes.

OBJECTIVES: To investigate patterns of programmed death protein-1 (PD-L1) expression in microsatellite instability (MSI)-high intestinal carcinomas and correlate them with pathologic and molecular features. METHODS: One hundred and fifteen MSI-high and 41 microsatellite stable carcinomas were included. Tumor sections were immunohistochemically labeled for PD-L1. The results were correlated with histologic subtypes, MSI, and BRAF status. RESULTS: As expected, MSI status was associated with PD-L1 expression. Among 115 MSI-high tumors, PD-L1 expression was observed on tumor cells in 28 tumors and on tumor-associated inflammatory cells in 77 tumors. Medullary carcinoma demonstrated more frequent PD-L1 expression on tumor cells than mucinous and typical adenocarcinoma. PD-L1 expression was more frequent in medullary and typical adenocarcinoma than in mucinous adenocarcinoma based on combined positive scores. Tumors with more nucleotide shifts by PCR-based MSI testing were more likely to express PD-L1. CONCLUSIONS: Expression of PD-L1 is different among different histologic subtypes of MSI-high intestinal carcinomas.

The impact of variant classification on the clinical management of hereditary cancer syndromes.

PURPOSE: The reclassification of genetic variants poses a significant challenge for laboratories and clinicians. Variant review has resulted in the reclassification of variants of unknown significance as well as the reclassification of previously established pathogenic and likely pathogenic variants. These reclassifications have the potential to alter the clinical management of patients with hereditary cancer syndromes. METHODS: Results were reviewed for 1694 patients seen for hereditary cancer evaluation between August 2012 and May 2017 to determine the frequency and types of variant reclassification. Patients with reclassifications with high potential for impact were monitored for alterations in organ surveillance, prophylactic surgery, and cascade testing. RESULTS: One hundred forty-two variants were reclassified representing 124/1694 (7.3%) patients; 11.3% of reclassifications (16/142) had a high potential for clinical impact with 94% (15/16) altering clinical management of patients with 56% (9/16) changing multiple areas of management. CONCLUSION: While reclassifications are rare, the impact on clinical management is profound. In many cases, patients with downgraded pathogenic/likely pathogenic variants had years of unnecessary organ surveillance and underwent unneeded surgical intervention. In addition, cascade testing misidentified those at risk for developing cancers, thereby altering the management across generations. The frequency and types of alterations to clinical management highlight the need for timely variant reclassification.

Clinical prognostic value of the isocitrate dehydrogenase 1 single-nucleotide polymorphism rs11554137 in glioblastoma.

The presence of the single-nucleotide polymorphism (SNP) rs11554137:C>T in the IDH1 gene is associated with a significantly lower survival in acute myeloid leukemia patients. The impact of its presence in glioblastoma on patient survival is unclear. We retrospectively reviewed 171 adult (> 18 years of age) patients treated at a single, tertiary academic center for supratentorial glioblastoma (WHO grade IV) between 2013 and 2017. We conducted Kaplan-Meier overall and progression free survival analyses based on the IDH1 and IDH2 gene status of patients' glioblastoma (IDH wild type, mutant, and IDH1 rs11554137:C>T SNP). Multivariate Cox survival analyses were conducted accounting for age at diagnosis, preoperative Karnofsky performance status score, treatment (extent of resection, postoperative radiotherapy, and temozolomide), IDH gene variant, and MGMT promoter methylation status. Presence of rs11554137:C>T SNP in glioblastoma samples did not correlate with presence of IDH1 mutation. Patients with rs11554137:C>T SNP did not have histories of prior lower-grade gliomas. Patients with IDH mutant glioblastoma had a distinctly higher survival profile than both rs11554137:C>T SNP and IDH wild type glioblastomas. No survival difference was noted between patients with glioblastoma harboring the SNP and patients with IDH wild type glioblastoma. In this study, clinical prognostication in glioblastoma patients was largely dependent on the classification of IDH mutant and wild type glioblastoma, and not on the presence of IDH1 rs11554137:C>T SNP in the tumor.

Deciphering Elevated Microsatellite Alterations at Selected Tetra/Pentanucleotide Repeats, Microsatellite Instability, and Loss of Heterozygosity in Colorectal Cancers.

Elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) are common in colorectal cancers (CRCs). The association between EMAST and classic mono/dinucleotide microsatellite instability (MSI) is unknown. We assessed the stability of 13 tetranucleotide and three pentanucleotide repeat markers in tumor and normal tissue from 22 MSI-high and 107 microsatellite-stable CRC samples. When present, instability was observed at tetra/pentanucleotide repeats and was defined as elevated microsatellite alterations at selected tetra/pentanucleotide repeats-high (EMASTP-H; ≥30% instability), -low (EMASTP-L; <30% instability), or -stable (EMASTP-S). EMASTP instability, including high and low, was observed in 50 of 123 CRCs (41%), including all MSI-high tumors and 28 of 101 microsatellite-stable tumors (28%). MSI-high CRCs were more likely to be EMASTP-H compared with microsatellite-stable tumors with EMASTP instability. Tetranucleotide markers VWA and D13S317 were the two most frequently altered loci. Loss of heterozygosity was more common in EMASTP-L/S than in EMASTP-H CRCs. Frequencies of loss of heterozygosity at three loci were different between EMASTP-L and EMASTP-S tumors. In addition, right-sided tumor site, large tumor size, high tumor grade, and the presence of Crohn-like reaction were significantly associated with EMASTP-H CRCs. However, there were no differences in clinicopathologic features between EMASTP-L and EMASTP-S tumors. In summary, more CRCs exhibited genomic instability as EMASTP than as MSI. EMASTP instability may prove to be an important prognostic/therapeutic indicator in CRCs.

Genotypic and clinical heterogeneity within NCCN favorable-risk acute myeloid leukemia.

The National Comprehensive Cancer Network (NCCN) defines the following types of acute myeloid leukemia (AML) as favorable-risk: acute promyelocytic leukemia with t(15;17) (APL); AML with core-binding factor (CBF) rearrangements, including t(8;21) and inv(16) or t(16;16) without mutations in KIT (CBF-KITwt); and AML with normal cytogenetics and mutations in NPM1 (NPM1mut); or biallelic mutations in CEBPA (CEBPAmut/mut), without FLT3-ITD. Although these AMLs are categorized as favorable risk by NCCN, clinical experience suggests that there are differences in clinical outcome amongst these cytogenetically and molecularly distinct leukemias. This study compared clinical and genotypic characteristics of 60 patients with favorable-risk AML, excluding APL, and demonstrated significant differences between them. Patients with NPM1mut AML were significantly older than those in the other groups. Targeted next-generation sequencing on DNA from peripheral blood or bone marrow revealed significantly more mutations in NPM1mut AML than the other favorable-risk diseases, especially in genes related to DNA splicing and methylation. CEBPAmut/mut AMLs exhibited more mutations in transcription-related genes. Patients with NPM1mut AML and CEBPAmut/mut AML show significantly reduced overall survival in comparison with CBF-KITwt AML. These findings emphasize that favorable-risk AML patients have divergent outcomes and that differences in clinical and genotypic characteristics should be considered in their evaluation and management.

Authors' Reply.

Authors' Reply to the Letter to the Editor by Montgomery et al (Identification of Germline Variants in Tumor Genomic Sequencing Analysis. J Mol Diagn 2017, 19:XXXX-XXXX).

Primary Carcinoid Tumor of the Renal Pelvis Arising From Intestinal Metaplasia: An Unusual Histogenetic Pathway?

OBJECTIVES: Primary carcinoid tumor of the renal pelvis is a rare neoplasm with few cases reported in the literature. Here we present the clinical and histopathologic findings of a primary carcinoid tumor arising in the left renal pelvis of a horseshoe kidney in a 61-year-old female patient. MATERIALS AND METHODS: Pathologic features were evaluated with standard hematoxylin and eosin sections and immunohistochemical studies. A literature review was performed to place our case in context to previous reports. RESULTS: The tumor was associated with intestinal metaplasia with high-grade dysplasia and neuroendocrine hyperplasia. Molecular testing for microsatellite instability and loss of heterozygosity were negative. CONCLUSIONS: This report portrays a unique presentation of carcinoid tumor arising from intestinal metaplasia of the pelvic urothelium, and supports its histogenesis from urothelial intestinal metaplasia and neuroendocrine hyperplasia.

Differences in Microsatellite Instability Profiles between Endometrioid and Colorectal Cancers: A Potential Cause for False-Negative Results?

Colorectal (CRCs) and endometrioid (EMCs) cancers in patients with Lynch syndrome exhibit microsatellite instability (MSI) detected by PCR or immunohistochemistry (IHC). While both assays are equally sensitive for CRCs, some suggest that PCR has a higher false-negative rate than IHC in EMCs. We assessed the MSI profiles of 91 EMC and 311 CRC specimens using five mononucleotide repeat markers: BAT25, BAT26, NR21, NR24, and MONO27. EMCs with high MSI (MSI-H) showed a mean left shift of 3 nucleotides (nt), which was significantly different from 6 nt in CRCs. A shift of 1 nt was observed in multiple markers in 76% of MSI-H EMCs, whereas only 12% of MSI-H CRCs displayed a 1-nt shift in one of five markers. IHC against four mismatch repair proteins was performed in 78 EMCs. Loss of staining in one or more proteins was detected in 18 of 19 tumors that were MSI-H by PCR. When EMC tumor cell burden was diluted to <30%, MSI-H was no longer observed in two of three EMCs with a mean nucleotide shift of 1 nt. These results indicate that EMC and CRC MSI profiles are different and that caution should be exercised when interpreting the results, as subtle, 1-nt changes may be missed. These findings provide a potential cause of previously reported discordant MSI and IHC results in EMCs.