Development and Clinical Validation of a Large Fusion Gene Panel for Pediatric Cancers.

2019

2019 Jun 27

1943-7811

<p>Gene fusions are one of the most common genomic alterations in pediatric cancer. Many fusions encode oncogenic drivers and play important roles in cancer diagnosis, risk stratification, and treatment selection. We report the development and clinical validation of a large custom-designed RNA sequencing panel, CHOP Fusion panel, using anchored multiplex PCR technology. The panel interrogates 106 cancer genes known to be involved in nearly 600 different fusions reported in hematological malignancies and solid tumors. The panel works well with different types of samples including formalin-fixed, paraffin-embedded samples. The panel demonstrated excellent analytic accuracy with 100% sensitivity and specificity on 60 pediatric tumor validation samples. In addition to identifying all known fusions in the validation samples, three unrecognized yet clinically significant fusions were also detected. Two-hundred and sevety-six clinical cases were analyzed after the validation and 51 different fusions were identified in 104 cases. Of these, 16 fusions were not previously reported at the time of discovery. These fusions provided genomic information useful for clinical management. Our experience demonstrates that CHOP Fusion panel can detect the vast majority of known and certain novel clinically relevant fusion genes in pediatric cancers accurately, efficiently, and cost effectively, and provides an excellent tool for new fusion gene discovery.</p>

10.1016/j.jmoldx.2019.05.006

J Mol Diagn

31255796

Clinical utility of custom-designed NGS panel testing in pediatric tumors.

2019

32

2019 May 28

1756-994X

<p><strong>BACKGROUND: </strong>Somatic genetic testing is rapidly becoming the standard of care in many adult and pediatric cancers. Previously, the standard approach was single-gene or focused multigene testing, but many centers have moved towards broad-based next-generation sequencing (NGS) panels. Here, we report the laboratory validation and clinical utility of a large cohort of clinical NGS somatic sequencing results in diagnosis, prognosis, and treatment of a wide range of pediatric cancers.</p>

<p><strong>METHODS: </strong>Subjects were accrued retrospectively at a single pediatric quaternary-care hospital. Sequence analyses were performed on 367 pediatric cancer samples using custom-designed NGS panels over a 15-month period. Cases were profiled for mutations, copy number variations, and fusions identified through sequencing, and their clinical impact on diagnosis, prognosis, and therapy was assessed.</p>

<p><strong>RESULTS: </strong>NGS panel testing was incorporated meaningfully into clinical care in 88.7% of leukemia/lymphomas, 90.6% of central nervous system (CNS) tumors, and 62.6% of non-CNS solid tumors included in this cohort. A change in diagnosis as a result of testing occurred in 3.3% of cases. Additionally, 19.4% of all patients had variants requiring further evaluation for potential germline alteration.</p>

<p><strong>CONCLUSIONS: </strong>Use of somatic NGS panel testing resulted in a significant impact on clinical care, including diagnosis, prognosis, and treatment planning in 78.7% of pediatric patients tested in our institution. Somatic NGS tumor testing should be implemented as part of the routine diagnostic workup of newly diagnosed and relapsed pediatric cancer patients.</p>

10.1186/s13073-019-0644-8

Genome Med

31133068

Disease Burden and Outcome in Pediatric and Young Adults with Concurrent Graves Disease and Differentiated Thyroid Carcinoma.

2018

2018 May 18

1945-7197

<p><strong>Context: </strong>Adults with differentiated thyroid carcinoma (DTC) and Graves Disease (GD) demonstrate a greater reported disease burden and aggressive DTC behavior. To date, no studies have examined the impact and long-term outcome of concurrent GD and DTC (GD-DTC) in pediatric and young adults.</p>

<p><strong>Design: </strong>Single institution, retrospective longitudinal cohort study between 1997-2016.</p>

<p><strong>Participants: </strong>139 pediatric and young adults with DTC, diagnosed at median age 15 (range 5-23) years compared to 12 GD-DTC patients, median age 18 (range 12-20) years.</p>

<p><strong>Major Outcome Measures: </strong>Patient demographics, pre-operative imaging, fine needle aspiration (FNA) cytology, operative and pathological reports, laboratory studies, treatment, and subsequent 2-year outcomes.</p>

<p><strong>Results: </strong>Compared to DTC, GD-DTC were significantly older at the time of DTC diagnosis (p&lt;0.01). GD-DTC were more likely to exhibit micro-carcinoma (p&lt;0.01) and 2/12 (17%) demonstrated tall-cell variant PTC vs 2/139 (2%) in DTC alone (p=0.03). While DTC patients showed greater lymphovascular invasion (60% vs 25%; p=0.03), no group differences were noted in extra-thyroidal extension, regional lymph node, distant or lung metastasis. There were no group differences in the 2-year outcome for remission, persistent disease, or recurrence.</p>

<p><strong>Conclusions: </strong>Concurrent DTC in pediatric GD patients is not associated with a greater disease burden at presentation and shows no significant difference in 2-year outcomes compared to DTC alone. Similar to adults, micro-carcinoma and tall-cell variant PTC is prevalent in pediatric GD-DTC. For GD-DTC patients with an identified nodule on ultrasound imaging prior to definitive therapy, FNA biopsy is recommended to guide definitive treatment.</p>

10.1210/jc.2018-00026

J. Clin. Endocrinol. Metab.

29788090

Characteristics of Follicular Variant Papillary Thyroid Carcinoma in a Pediatric Cohort.

2018

1639-1648

2018 Apr 1

1945-7197

<p><strong>Context: </strong>In adults, non-invasive follicular variant papillary thyroid carcinoma (FVPTC) is considered low risk for metastasis and persistent/recurrent disease.</p>

<p><strong>Objective: </strong>The goal of this study was to assess the clinical, sonographic, and histopathological features of FVPTC in a pediatric cohort.</p>

<p><strong>Design: </strong>A retrospective review of subjects &lt; 19 years of age with papillary thyroid carcinoma (PTC) who underwent thyroidectomy between January 2010 and July 2015.</p>

<p><strong>Setting: </strong>Multidisciplinary, academic referral center.</p>

<p><strong>Patients: </strong>Patients with FVPTC, defined as a tumor ≥1.0 cm in largest dimension with predominant follicular growth, complete lack of well-formed papillae, and nuclear features of PTC.</p>

<p><strong>Main Outcome Measure: </strong>Tumor size and location, presence of a tumor capsule, capsule and vascular invasion, lymph node and distant metastasis.</p>

<p><strong>Results: </strong>Eighteen patients with FVPTC were identified from a case cohort of 110 patients with PTC. On histopathology, 13 (72%) had unifocal nodules and 14 (78%) were completely encapsulated. Capsule invasion was frequent (9/14; 64%) and vascular invasion was found in one third of patients (6/18; 33%). No lymph node metastases were found in the 13 (72%) patients who had a central neck lymph node dissection. One patient with vascular invasion had distant metastases.</p>

<p><strong>Conclusion: </strong>When strictly defined, FVPTC in pediatric patients has a low risk for bilateral disease and metastasis. Prospective studies are needed to confirm whether lobectomy with surveillance is sufficient to achieve remission in pediatric patients with low risk FVPTC.</p>

10.1210/jc.2017-02454

29438531

Defining the role of liver biopsy in the assessment of liver fibrosis in patients with Fontan circulation-reply.

2017

2017 Jun 08

1532-8392

10.1016/j.humpath.2017.04.029

Hum. Pathol.

28603067

Hepatic Fibrosis Is Universal Following Fontan Operation, and Severity is Associated With Time From Surgery: A Liver Biopsy and Hemodynamic Study.

2017

2017 Apr 26

2047-9980

<p><strong>BACKGROUND: </strong>Congestive hepatopathy is a recognized complication of Fontan physiology. Data regarding the incidence of hepatopathy and risk factors are lacking.</p>

<p><strong>METHODS AND RESULTS: </strong>Liver biopsies and cardiac catherizations were performed as part of an evaluation offered to all patients ≥10&nbsp;years after Fontan. Quantitative determination of hepatic fibrosis was performed using Sirius red staining with automated calculation of collagen deposition per slide (%CD). Biopsies from included subjects were compared to stained specimens from controls without known fibrotic liver disease. Patient characteristics, echocardiographic findings, and hemodynamic measures were evaluated as potential risk factors. The cohort consisted of 67 patients (31 female) at mean age of 17.3±4.5&nbsp;years and mean time from Fontan of 14.9±4.5&nbsp;years. Right ventricular morphology was present in 37 subjects. Median %CD by Sirius red staining was 21.6% (range 8.7% to 49.4%) compared to 2.6% (range 2.2% to 3.0%) in controls. There was a significant correlation between time from Fontan and degree of Sirius red staining (r=0.33, P&lt;0.01). Serum liver enzymes and platelet count did not correlate with %CD. The median inferior vena cava pressure was 13&nbsp;mm&nbsp;Hg (range 6-24&nbsp;mm&nbsp;Hg) and did not correlate with %CD. There was no difference in %CD based on ventricular morphology or severity of atrioventricular valve insufficiency.</p>

<p><strong>CONCLUSIONS: </strong>In this cohort of predominantly asymptomatic children and adolescents electively evaluated after a Fontan operation, all exhibited evidence for hepatic fibrosis as measured by collagen deposition in the liver. Time from Fontan was the only factor significantly associated with collagen deposition. These findings demonstrate that liver fibrosis is an inherent feature of Fontan physiology and that the degree of fibrosis increases over time.</p>

10.1161/JAHA.116.004809

J Am Heart Assoc

28446492

Prevalence and characterization of fibrosis in surveillance liver biopsies of patients with Fontan circulation.

2016

2016 Jul 27

1532-8392

<p>The Fontan operation is a widely used palliative procedure in patients with single ventricle anatomy that results in liver injury. As timely identification of liver fibrosis may result in management changes to Fontan patients, the aim of our study was to identify clinically meaningful semi-quantitative/quantitative pathologic parameters for biopsy assessment. We performed a retrospective review of 74 liver needle biopsies from Fontan patients. Fibrosis was assessed using quantitative % collagen deposition (%CD) by Sirius red image analysis, METAVIR, congestive hepatic fibrosis score (CHFS), sinusoidal fibrosis (SF) score, and sinusoidal dilation score. Contemporaneous laboratory, hemodynamic, and ultrasound data were collected. Centrilobular and peri-sinusoidal fibrosis was observed in all cases, with 39.2% high grade. Portal fibrosis was observed in 93.2%, with 36.2% high grade (METAVIR F3-F4). Cirrhosis was observed in 5.4%. %CD was increased over control tissue (p&lt;0.001) and correlated with time from Fontan (r=0.3, p=0.009) and prothrombin time (PT) (r=0.25, p=0.034). Mildly elevated PT/INR was the only measure of liver function consistently associated with multiple high-grade fibrosis scores (METAVIR p=0.046, SF p=0.018). Abnormal liver echotexture on ultrasound was associated with high grade CHFS (p=0.03). Pathologic gradings and %CD correlated with each other (r=0.48-0.8, p&lt;0.001). Hepatic fibrosis in Fontan patients in our study is universally present, appears to be time dependent, and correlates with few laboratory measurements of liver function. Careful assessment of needle liver biopsies lends a more meaningful measure of liver fibrosis in the Fontan patient than clinical and laboratory data, allowing for appropriate changes to patient management.</p>

10.1016/j.humpath.2016.07.006

Hum. Pathol.

27476041