Bonnie Cole

Improving the Value of Costly Genetic Reference Laboratory Testing With Active Utilization Management

CONTEXT Tests that are performed outside of the ordering institution, send-out tests, represent an area of risk to patients because of complexity associated with sending tests out. Risks related to send-out tests include increased number of handoffs, ordering the wrong or unnecessary test, specimen delays, data entry errors, preventable delays in reporting and acknowledging results, and excess financial liability. Many of the most expensive and most misunderstood tests are send-out genetic tests. OBJECTIVE To design and develop an active utilization management program to reduce the risk to patients and improve value of genetic send-out tests. DESIGN Send-out test requests that met defined criteria were reviewed by a rotating team of doctoral-level consultants and a genetic counselor in a pediatric tertiary care center. RESULTS Two hundred fifty-one cases were reviewed during an 8-month period. After review, nearly one-quarter of genetic test requests were modified in the downward direction, saving a total of 2% of the entire send-out bill and 19% of the test requests under management. Ultimately, these savings were passed on to patients. CONCLUSIONS Implementing an active utilization strategy for expensive send-out tests can be achieved with minimal technical resources and results in improved value of testing to patients.

Inflammatory myofibroblastic tumor with thrombocytosis and a unique chromosomal translocation With ALK rearrangement.

We describe a case of inflammatory myofibroblastic tumor with an unusual constellation of clinical, pathologic, and genetic findings. A 7-year-old girl had an 11-cm abdominopelvic mass accompanied by thrombocytosis, anemia, elevated erythrocyte sedimentation rate, and elevated C-reactive protein. The inflammatory myofibroblastic tumor displayed unusual histologic features of zonal coagulative necrosis, high cellularity with a herringbone pattern, and tumor-associated osteoclast-like giant cells. The complex tumor karyotype included a translocation t(1;2)(q21; p23). Following resection, the laboratory abnormalities resolved. The patient is well and free of recurrence at 3 years following resection. This case raises interesting questions about clinical, pathologic, prognostic, and molecular genetic interrelationships in inflammatory myofibroblastic tumor.

Another laboratory test utilization program: our approach to reducing unnecessary 1,25-dihydroxyvitamin D orders with a simple intervention.

To the Editor We were very interested in the report by Jeffrey Warren1 outlining a comprehensive laboratory test utilization program in a large academic medical center. The report highlighted the implementation of an interdisciplinary committee to review utilization patterns, appropriateness, and new test requests in combination with significant information technology (IT) resources dedicated to computerized provider order entry decision tools. Over 5 years, they decreased send-out testing expenses normalized to clinical laboratory expenses. We implemented a similar laboratory test utilization program in a 250-bed pediatric hospital that processes approximately 1,000 requisitions daily. Send-out expenses are a proportionally large burden on clinical laboratory and hospital budgets.2 We developed a strategy to manage “flagged” test requests with minimal IT resources. Our utilization committee operates similarly to the committee …

A prospective tool for risk assessment of sendout testing

OBJECTIVE Errors associated with laboratory testing can cause significant patient harm. Sendout testing refers to tests sent by a primary lab to a reference lab when testing is unavailable at the primary lab. Sendout testing is particularly high risk for patient harm, due to many factors including increased hand-offs, manual processes, and complexity associated with rare, low-volume tests. No published prospective tools exist for sendout risk assessment. METHODS A novel prospective tool was developed to assess risk of diagnostic errors involving laboratory sendout testing. This tool was successfully piloted at nine sites. RESULTS Marked diversity was noted among survey respondents, particularly in the sections on quality metrics and utilization management. Of note, most sites had committees who managed rules for test ordering, but few places reported enforcing these rules. Only one site claimed to routinely measure the frequency clinicians failed to retrieve test results. An evaluation of the tool indicated that it was both useful and easy to use. CONCLUSIONS This tool could be used by other laboratories to identify the areas of highest risk to patients, which in turn may guide them in focusing their quality improvement efforts and resources.

Placental mesenchymal dysplasia and fetal renal-hepatic-pancreatic dysplasia: androgenetic-biparental mosaicism and pathogenesis of an autosomal recessive disorder.

Androgenetic-biparental mosaicism (ABM) denotes an embryo in which a subset of cells contains a diploid chromosomal complement derived entirely from the father. Such embryos have a high incidence of placental mesenchymal dysplasia (PMD) and paternal imprinting disorders because the androgenetic cells have pangenomic paternal uniparental disomy. Uniparental disomy also poses a theoretical risk for paternally transmitted autosomal recessive disorders, if both chromosomes of each autosomal pair are identical (isodisomy). We present the 1st example of a recessive disorder, renal-hepatic-pancreatic dysplasia, in a pregnancy complicated by PMD and ABM. Androgenetic-biparental mosaicism was demonstrated in fetal DNA, extracted from multiple organs, by quantitative polymerase chain reaction–based methods that detected allelic imbalances at the differentially methylated SNRPN locus (chromosome 15); polymorphic short tandem repeat microsatellite markers located on chromosomes 4, 7, 8, 13, 18, and 21; and single nucleotide polymorphisms on chromosomes 1 and 19. Laser capture microdissection was performed to isolate specific placental and renal cell populations and document selective enrichment of androgenetic cells in the stroma of PMD and the epithelium of renal cysts. Mutational analysis of coding sequences did not reveal any mutations in NPHP3, a ciliopathy gene implicated in some cases of renal-hepatic-pancreatic dysplasia. Nonetheless, the fetal phenotype and laser capture data support the model of a paternally transmitted autosomal recessive disorder, which occurred because of ABM.

Targeted Sequencing of Malignant Supratentorial Pediatric Brain Tumors Demonstrates a High Frequency of Clinically Relevant Mutations

Pediatric brain tumors cause more deaths than any other childhood malignancy, and the identification of potentially actionable genomic alterations in this rare heterogeneous group of tumors may improve treatment and outcome. The genetic landscape of common posterior fossa tumors has been described in the past several years, yet the classification of malignant pediatric supratentorial tumors remains controversial. Next-generation sequencing (NGS) is a promising tool to evaluate multiple genes concurrently. The clinical utility of NGS has not been proven in pediatric brain tumors. We identified patients diagnosed with high-grade supratentorial pediatric brain tumors resected between 2008 and 2012 at our institution. DNA from 12 formalin-fixed paraffin-embedded tumor samples from 9 patients was analyzed, including 3 paired samples from diagnosis and relapse. A panel of 194 cancer-related genes was sequenced using targeted next-generation deep sequencing. Genetic findings were correlated with histology, immunohistochemistry, treatment, and survival. We found one or more pathologic genetic change (mutation, amplification, or deletion) in 8 of 9 (89%) of patients studied. Epidermal Growth Factor Receptor (EGFR) mutations were found in 3 patients, 2 of which had an exon 20 insertion not previously described in pediatric malignancy. Additional genetic changes were found in EGFR and Platelet-Derived Growth Factor Receptor Alpha (PDGFRA) at relapse not present in the initial samples. Familial cancer predisposition syndromes were suggested by mutations found in 3 genes in 4 patients, including TP53, MSH2, and CHEK2. Seven of 9 patients in this study died of their disease. In summary, targeted deep sequencing may be used in rare pediatric brain tumors to identify driver mutations for targeted therapy, suggest constitutional and familial testing for cancer predisposition syndromes, and select molecular targets worthy of further study.

A biobank of patient-derived pediatric brain tumor models

Brain tumors are the leading cause of cancer-related death in children. Genomic studies have provided insights into molecular subgroups and oncogenic drivers of pediatric brain tumors that may lead to novel therapeutic strategies. To evaluate new treatments, better preclinical models adequately reflecting the biological heterogeneity are needed. Through the Children’s Oncology Group ACNS02B3 study, we have generated and comprehensively characterized 30 patient-derived orthotopic xenograft models and seven cell lines representing 14 molecular subgroups of pediatric brain tumors. Patient-derived orthotopic xenograft models were found to be representative of the human tumors they were derived from in terms of histology, immunohistochemistry, gene expression, DNA methylation, copy number, and mutational profiles. In vivo drug sensitivity of targeted therapeutics was associated with distinct molecular tumor subgroups and specific genetic alterations. These models and their molecular characterization provide an unprecedented resource for the cancer community to study key oncogenic drivers and to evaluate novel treatment strategies.A resource of preclinical pediatric brain tumor models with detailed molecular characterization provides a platform for the community to test novel therapeutic approaches.

Year 1 in the Molecular Era of Pediatric Brain Tumor Diagnosis: Application of Universal Clinical Targeted Sequencing in an Unselected Cohort of Children

PurposeNext-generation sequencing is gaining acceptance as a clinical tool to aid diagnosis and guide treatment of pediatric cancer. Prior pilot studies have evaluated the feasibility and utility of clinical genomic profiling in a subset of selected patients with brain tumors. Here, we report an unselected prospective cohort study to evaluate the clinical use of universal targeted sequencing in pediatric patients with brain tumors.MethodsWe applied a universal sequencing protocol for all tumors of the CNS undergoing diagnostic workup at Seattle Children’s Hospital during the study period of November 2015 to November 2016. All tumors were sequenced using the UW-OncoPlex platform, which is a multiplexed targeted deep gene sequencing panel that detects genetic alterations in 262 cancer-related genes performed in a College of American Pathologists–accredited Clinical Laboratory Improvements Amendments–certified laboratory.ResultsEighty-eight patients underwent diagnostic evaluation during the study period, of...

Another laboratory test utilization program

To the Editor We were very interested in the report by Jeffrey Warren1 outlining a comprehensive laboratory test utilization program in a large academic medical center. The report highlighted the implementation of an interdisciplinary committee to review utilization patterns, appropriateness, and new test requests in combination with significant information technology (IT) resources dedicated to computerized provider order entry decision tools. Over 5 years, they decreased send-out testing expenses normalized to clinical laboratory expenses. We implemented a similar laboratory test utilization program in a 250-bed pediatric hospital that processes approximately 1,000 requisitions daily. Send-out expenses are a proportionally large burden on clinical laboratory and hospital budgets.2 We developed a strategy to manage “flagged” test requests with minimal IT resources. Our utilization committee operates similarly to the committee …

Another Laboratory Test Utilization Program: Our Approach to Reducing Unnecessary 1,25-Dihydroxyvitamin D Orders With a Simple InterventionThe Author’s Reply

To the Editor We were very interested in the report by Jeffrey Warren1 outlining a comprehensive laboratory test utilization program in a large academic medical center. The report highlighted the implementation of an interdisciplinary committee to review utilization patterns, appropriateness, and new test requests in combination with significant information technology (IT) resources dedicated to computerized provider order entry decision tools. Over 5 years, they decreased send-out testing expenses normalized to clinical laboratory expenses. We implemented a similar laboratory test utilization program in a 250-bed pediatric hospital that processes approximately 1,000 requisitions daily. Send-out expenses are a proportionally large burden on clinical laboratory and hospital budgets.2 We developed a strategy to manage “flagged” test requests with minimal IT resources. Our utilization committee operates similarly to the committee …