A case series of pediatric survivors of anaplastic pleomorphic xanthoastrocytoma

Abstract Background Anaplastic pleomorphic xanthoastrocytoma (APXA) is a rare subtype of CNS astrocytoma. They are generally treated as high-grade gliomas; however, uncertainty exists regarding the optimal therapy. Here, we report on 3 pediatric cases of APXA. Methods Our institutional database was queried for cases of APXA and 3 cases were identified. Surgical samples were processed for methylation profiling and chromosomal microarray analysis. Methylation data were uploaded to the online CNS tumor classifier to determine methylation-based diagnoses to determine copy number variations (CNVs). Results Two patients were male, 1 female, and all were aged 12 years at diagnosis. All underwent a gross total resection (GTR) and were diagnosed with an APXA. Immunohistochemical analysis demonstrated that 2 cases were BRAF V600E positive. Methylation-based tumor classification supported the APXA diagnosis in all cases. CNV analyses revealed homozygous CKDN2A deletions in all and chromosome 9p loss in 2 cases. All patients received radiation therapy (54 Gy in 30 fractions) with concurrent temozolomide. Two patients received maintenance chemotherapy with temozolomide and lomustine for 6 cycles as per the Children’s Oncology Group ACNS0423. The third patient recurred and went on to receive a second GTR and 6 cycles of lomustine, vincristine, and procarbazine. All are alive with no evidence of disease >4 years post-treatment completion (overall survival = 100%, event free survival = 67%). Conclusions The natural history and optimal treatment of this rare pediatric tumor are not well understood. This case series supports the use of adjuvant chemoradiotherapy in the treatment of APXA. The genetic landscape may be informative for optimizing treatment and prognosis.

Download Full-text

HGG-35. PEDIATRIC PLEOMORPHIC XANTHOASTROCYTOMA WITH ANAPLASIA TREATED WITH SURGERY AND ADJUVANT CHEMOTHERAPY: A CASE SERIES OF 3 LONG-TERM SURVIVORS

Neuro-Oncology ◽

10.1093/neuonc/noaa222.316 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii350-iii350

Author(s):

Rebecca Ronsley ◽

Christopher Dunham ◽

Stephen Yip ◽

Juliette Hukin ◽

Sylvia Cheng

Keyword(s):

Case Series ◽

Complete Response ◽

Pleomorphic Xanthoastrocytoma ◽

Braf V600e ◽

Pediatric Tumor ◽

Molecular Features ◽

End Of Treatment ◽

Genetic Landscape ◽

Long Term Survivors

Abstract OBJECTIVE Pleomorphic xanthoastrocytoma (PXA) with anaplasia is a rare histological subtype of central nervous system astrocytoma and generally treated as high grade gliomas. The optimal extent of therapy required is unknown. Here we report on 3 pediatric cases of PXA with anaplasia. We also describe molecular features and methylation profile of PXA with anaplasia compared to age-matched PXA without anaplasia. METHODS Our institutional database was queried for cases of PXA since 1998 and 3 cases with anaplasia were identified and records reviewed. RESULTS 2/3 patients were male and all were aged 12 at diagnosis. All underwent a gross total resection (GTR), where the diagnosis of PXA with anaplasia was made. Immunohistochemistry demonstrated that two cases were BRAF V600E positive and two were CD34 positive. Methylation profiling revealed unique pattern of CpG methylation/unmethylation. All patients underwent 5400cGy radiation to the surgical bed. 2/3 patients received concurrent temozolamide with radiation followed by maintenance chemotherapy with temozolamide and lomustine for 6 cycles as per the Children’s Oncology Group Protocol ACNS0423. These two patients had a continued complete response. The third patient received temozolamide following radiation and subsequently had recurrent disease at the end of treatment and went on to have a re-resection GTR and achieved complete response after 6 cycles of lomustine, vincristine and procarbazine. All are alive with no evidence of disease at more than 2 years post treatment completion (OS=100%,EFS=67%). CONCLUSIONS This rare pediatric tumor is not well understood. The genetic landscape may be informative for optimizing treatment and prognosis.

Download Full-text

Identification of copy number variations associated with congenital heart disease by chromosomal microarray analysis and next-generation sequencing

Prenatal Diagnosis ◽

10.1002/pd.4782 ◽

2016 ◽

Vol 36 (4) ◽

pp. 321-327 ◽

Cited By ~ 34

Author(s):

Xiangyu Zhu ◽

Jie Li ◽

Tong Ru ◽

Yaping Wang ◽

Yan Xu ◽

...

Keyword(s):

Congenital Heart Disease ◽

Heart Disease ◽

Next Generation Sequencing ◽

Microarray Analysis ◽

Copy Number ◽

Congenital Heart ◽

Copy Number Variations ◽

Chromosomal Microarray ◽

Chromosomal Microarray Analysis ◽

Generation Sequencing

Download Full-text

Comprehensive Evaluation of Non-invasive Prenatal Screening to Detect Fetal Copy Number Variations

Frontiers in Genetics ◽

10.3389/fgene.2021.665589 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jing Wang ◽

Bin Zhang ◽

Lingna Zhou ◽

Qin Zhou ◽

Yingping Chen ◽

...

Keyword(s):

Prenatal Diagnosis ◽

Pregnant Women ◽

Copy Number ◽

Prenatal Screening ◽

Comprehensive Evaluation ◽

Copy Number Variations ◽

Chromosomal Microarray ◽

Chromosomal Microarray Analysis ◽

Non Invasive ◽

Pathogenic Cnvs

ObjectiveTo evaluate the effectiveness of non-invasive prenatal screening (NIPS) in prenatal screening of fetal pathogenic copy number variants (CNVs).Materials and MethodsWe evaluated the prenatal screening capacity using traditional and retrospective approaches. For the traditional method, we evaluated 24,613 pregnant women who underwent NIPS; cases which fetal CNVs were suggested underwent prenatal diagnosis with chromosomal microarray analysis (CMA). For the retrospective method, we retrospectively evaluated 47 cases with fetal pathogenic CNVs by NIPS. A systematic literature search was performed to compare the evaluation efficiency.ResultsAmong the 24,613 pregnant women who received NIPS, 124 (0.50%) were suspected to have fetal CNVs. Of these, 66 women underwent prenatal diagnosis with CMA and 13 had true-positive results. The positive predictive value (PPV) of NIPS for fetal CNVs was 19.7%. Among 1,161 women who did not receive NIPS and underwent prenatal diagnosis by CMA, 47 were confirmed to have fetal pathogenic CNVs. Retesting with NIPS indicated that 24 of these 47 cases could also be detected by NIPS, representing a detection rate (DR) of 51.1%. In total, 10 publications, namely, six retrospective studies and four prospective studies, met our criteria and were selected for a detailed full-text review. The reported DRs were 61.10–97.70% and the PPVs were 36.11–80.56%. The sizes of CNVs were closely related to the accuracy of NIPS detection. The DR was 41.9% (13/31) in fetuses with CNVs ≤ 3 Mb, but was 55.0% (11/20) in fetuses with CNVs > 3 Mb. Finally, to intuitively show the CNVs accurately detected by NIPS, we mapped all CNVs to chromosomes according to their location, size, and characteristics. NIPS detected fetal CNVs in 2q13 and 4q35.ConclusionThe DR and PPV of NIPS for fetal CNVs were approximately 51.1% and 19.7%, respectively. Follow-up molecular prenatal diagnosis is recommended in cases where NIPS suggests fetal CNVs.

Download Full-text

Subependymoma involving multiple spinal cord levels: A clinicopathological case series with chromosomal microarray analysis

Neuropathology ◽

10.1111/neup.12543 ◽

2019 ◽

Vol 39 (2) ◽

pp. 97-105 ◽

Cited By ~ 1

Author(s):

Anthony L. Mikula ◽

Michael A. Paolini ◽

William R. Sukov ◽

Michelle J. Clarke ◽

Aditya Raghunathan

Keyword(s):

Spinal Cord ◽

Microarray Analysis ◽

Case Series ◽

Chromosomal Microarray ◽

Chromosomal Microarray Analysis

Download Full-text

Application of Chromosome Microarray Analysis in the Investigation of Developmental Disabilities and Congenital Anomalies: Single Center Experience and Review of NRXN3 and NEDD4L Deletions

Molecular Syndromology ◽

10.1159/000509645 ◽

2020 ◽

Vol 11 (4) ◽

pp. 197-206

Author(s):

Alper Han Çebi ◽

Şule Altıner

Keyword(s):

Developmental Disabilities ◽

Microarray Analysis ◽

Congenital Anomalies ◽

Copy Number Variations ◽

Step Test ◽

Chromosomal Microarray ◽

Chromosomal Microarray Analysis ◽

Multiple Congenital Anomalies ◽

Single Center Experience ◽

Genome Wide

Chromosomal microarray analysis (CMA) is a first step test used for the diagnosis of patients with developmental delay, intellectual disability, autistic spectrum disorder, and multiple congenital anomalies. Its widespread usage has allowed genome-wide identification of copy number variations (CNVs). In our study, we performed a retrospective study on clinical and microarray data of 237 patients with developmental disabilities and/or multiple congenital anomalies and investigated the clinical utility of CMA. Phenotype-associated CNVs were detected in 15.18% of patients. Besides, we detected submicroscopic losses on 14q24.3q31.1 in a patient with speech delay and on 18q21.31q21.32 in twin patients with seizures. Deletions of <i>NRXN3</i> and <i>NEDD4L</i> were responsible for the phenotypes, respectively. This study showed that CMA is a powerful diagnostic tool in this patient group and expands the genotype-phenotype correlations on developmental disabilities.

Download Full-text

Simultaneous Detection of CNVs and SNVs Improves the Diagnostic Yield of Fetuses with Ultrasound Anomalies and Normal Karyotypes

Genes ◽

10.3390/genes11121397 ◽

2020 ◽

Vol 11 (12) ◽

pp. 1397

Author(s):

Qingwei Qi ◽

Yulin Jiang ◽

Xiya Zhou ◽

Hua Meng ◽

Na Hao ◽

...

Keyword(s):

Exome Sequencing ◽

Diagnostic Yield ◽

Simultaneous Detection ◽

Genetic Diagnosis ◽

Copy Number Variations ◽

Molecular Diagnostic ◽

Chromosomal Microarray ◽

Chromosomal Microarray Analysis ◽

Single Nucleotide Variants ◽

Sequential Approach

The routine assessment to determine the genetic etiology for fetal ultrasound anomalies follows a sequential approach, which usually takes about 6–8 weeks turnaround time (TAT). We evaluated the clinical utility of simultaneous detection of copy number variations (CNVs) and single nucleotide variants (SNVs)/small insertion-deletions (indels) in fetuses with a normal karyotype with ultrasound anomalies. We performed CNV detection by chromosomal microarray analysis (CMA) or low pass CNV-sequencing (CNV-seq), and in parallel SNVs/indels detection by trio-based clinical exome sequencing (CES) or whole exome sequencing (WES). Eight-three singleton pregnancies with a normal fetal karyotype were enrolled in this prospective observational study. Pathogenic or likely pathogenic variations were identified in 30 cases (CNVs in 3 cases, SNVs/indels in 27 cases), indicating an overall molecular diagnostic rate of 36.1% (30/83). Two cases had both a CNV of uncertain significance (VOUS) and likely pathogenic SNV, and one case carried both a VOUS CNV and an SNV. We demonstrated that simultaneous analysis of CNVs and SNVs/indels can improve the diagnostic yield of prenatal diagnosis with shortened reporting time, namely, 2–3 weeks. Due to the relatively long TAT for sequential procedure for prenatal genetic diagnosis, as well as recent sequencing technology advancements, it is clinically necessary to consider the simultaneous evaluation of CNVs and SNVs/indels to enhance the diagnostic yield and timely TAT, especially for cases in the late second trimester or third trimester.

Download Full-text

High Detection Rate of Copy Number Variations Using Capture Sequencing Data: A Retrospective Study

Clinical Chemistry ◽

10.1093/clinchem/hvz033 ◽

2020 ◽

Vol 66 (3) ◽

pp. 455-462 ◽

Cited By ~ 1

Author(s):

Yu Sun ◽

Xiantao Ye ◽

Yanjie Fan ◽

Lili Wang ◽

Xiaomei Luo ◽

...

Keyword(s):

Copy Number ◽

Diagnostic Yield ◽

Copy Number Variations ◽

Systematic Evaluation ◽

High Yield ◽

Chromosomal Microarray ◽

Chromosomal Microarray Analysis ◽

Large Sample Size ◽

Analytical Sensitivity ◽

Capture Sequencing

Abstract Background Capture sequencing (CS) is widely applied to detect small genetic variations such as single nucleotide variants or indels. Algorithms based on depth comparison are becoming available for detecting copy number variation (CNV) from CS data. However, a systematic evaluation with a large sample size has not been conducted to evaluate the efficacy of CS-based CNV detection in clinical diagnosis. Methods We retrospectively studied 3010 samples referred to our diagnostic laboratory for CS testing. We used 68 chromosomal microarray analysis–positive samples (true set [TS]) and 1520 reference samples to build a robust CS-CNV pipeline. The pipeline was used to detect candidate clinically relevant CNVs in 1422 undiagnosed samples (undiagnosed set [UDS]). The candidate CNVs were confirmed by an alternative method. Results The CS-CNV pipeline detected 78 of 79 clinically relevant CNVs in TS samples, with analytical sensitivity of 98.7% and positive predictive value of 49.4%. Candidate clinically relevant CNVs were identified in 106 UDS samples. CNVs were confirmed in 96 patients (90.6%). The diagnostic yield was 6.8%. The molecular etiology includes aneuploid (n = 7), microdeletion/microduplication syndrome (n = 40), and Mendelian disorders (n = 49). Conclusions These findings demonstrate the high yield of CS-based CNV. With further improvement of our CS-CNV pipeline, the method may have clinical utility for simultaneous evaluation of CNVs and small variations in samples referred for pre- or postnatal analysis.

Download Full-text

Dual BRAF/MEK therapy in BRAF V600E-mutated primary brain tumors: a case series showing dramatic clinical and radiographic responses and a reduction in cutaneous toxicity

Journal of Neurosurgery ◽

10.3171/2019.8.jns19643 ◽

2020 ◽

Vol 133 (6) ◽

pp. 1704-1709 ◽

Cited By ~ 3

Author(s):

Aaron Bernstein ◽

Oliver D. Mrowczynski ◽

Amrit Greene ◽

Sandra Ryan ◽

Catherine Chung ◽

...

Keyword(s):

Brain Tumors ◽

Pilocytic Astrocytoma ◽

Case Series ◽

Mek Inhibitor ◽

Pleomorphic Xanthoastrocytoma ◽

Inhibitor Therapy ◽

Braf V600e ◽

Dual Inhibitor ◽

Cutaneous Toxicity ◽

Primary Brain Tumors

OBJECTIVEBRAF V600E is a common oncogenic driver in a variety of primary brain tumors. Dual inhibitor therapy using dabrafenib (a selective oral inhibitor of several mutated forms of BRAF kinase) and trametinib (a reversible inhibitor of MEK1 and MEK2) has been used successfully for treatment of metastatic melanoma, anaplastic thyroid cancer, and other tumor types, but has been reported in only a few patients with primary brain tumors and none with pleomorphic xanthoastrocytoma. Here, the authors report on the substantial clinical response and reduction in cutaneous toxicity in a case series of BRAF V600E primary brain cancers treated with dual BRAF/MEK inhibitor therapy.METHODSThe authors treated 4 BRAF V600E patients, each with a different type of primary brain tumor (pilocytic astrocytoma, papillary craniopharyngioma, ganglioglioma, and pleomorphic xanthoastrocytoma) with the combination of dabrafenib and trametinib.RESULTSThe patients with pilocytic astrocytoma, pleomorphic xanthoastrocytoma, and papillary craniopharyngioma experienced near-complete radiographic and complete clinical responses after 8 weeks of therapy. A substantial partial response (by RANO [Response Assessment in Neuro-Oncology] criteria) was observed in the patient with ganglioglioma. The patient with craniopharyngioma developed dramatic, diffuse verrucal keratosis within 2 weeks of starting dabrafenib. This completely resolved within 2 weeks of adding trametinib.CONCLUSIONSDual BRAF/MEK inhibitor therapy represents an exciting treatment option for patients with BRAF V600E primary brain tumors. In addition to greater efficacy than single-agent dabrafenib, this combination has the potential to mitigate cutaneous toxicity, one of the most common and concerning BRAF inhibitor–related adverse events.

Download Full-text

Rapid Diagnosis of Imprinting Disorders Involving Copy Number Variation and Uniparental Disomy Using Genome-Wide SNP Microarrays

Cytogenetic and Genome Research ◽

10.1159/000435847 ◽

2015 ◽

Vol 146 (1) ◽

pp. 9-18 ◽

Cited By ~ 10

Author(s):

Weiqiang Liu ◽

Rui Zhang ◽

Jun Wei ◽

Huimin Zhang ◽

Guojiu Yu ◽

...

Keyword(s):

Copy Number ◽

Snp Array ◽

Uniparental Disomy ◽

Copy Number Variations ◽

Chromosomal Microarray ◽

Chromosomal Microarray Analysis ◽

Imprinting Disorders ◽

Genome Wide ◽

Number Variation ◽

Efficient Alternative

Imprinting disorders, such as Beckwith-Wiedemann syndrome (BWS), Prader-Willi syndrome (PWS) and Angelman syndrome (AS), can be detected via methylation analysis, methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA), or other methods. In this study, we applied single nucleotide polymorphism (SNP)-based chromosomal microarray analysis to detect copy number variations (CNVs) and uniparental disomy (UPD) events in patients with suspected imprinting disorders. Of 4 patients, 2 had a 5.25-Mb microdeletion in the 15q11.2q13.2 region, 1 had a 38.4-Mb mosaic UPD in the 11p15.4 region, and 1 had a 60-Mb detectable UPD between regions 14q13.2 and 14q32.13. Although the 14q32.2 region was classified as normal by SNP array for the 14q13 UPD patient, it turned out to be a heterodisomic UPD by short tandem repeat marker analysis. MS-MLPA analysis was performed to validate the variations. In conclusion, SNP-based microarray is an efficient alternative method for quickly and precisely diagnosing PWS, AS, BWS, and other imprinted gene-associated disorders when considering aberrations due to CNVs and most types of UPD.

Download Full-text