ABSTRACT
In cancer, recurrent somatic single-nucleotide variants-which are rare in most paediatric cancers-are confined largely to protein-coding genes1-3. Here we report highly recurrent hotspot mutations (r.3A>G) of U1 spliceosomal small nuclear RNAs (snRNAs) in about 50% of Sonic hedgehog (SHH) medulloblastomas. These mutations were not present across other subgroups of medulloblastoma, and we identified these hotspot mutations in U1 snRNA in only <0.1% of 2,442 cancers, across 36 other tumour types. The mutations occur in 97% of adults (subtype SHHδ) and 25% of adolescents (subtype SHHα) with SHH medulloblastoma, but are largely absent from SHH medulloblastoma in infants. The U1 snRNA mutations occur in the 5' splice-site binding region, and snRNA-mutant tumours have significantly disrupted RNA splicing and an excess of 5' cryptic splicing events. Alternative splicing mediated by mutant U1 snRNA inactivates tumour-suppressor genes (PTCH1) and activates oncogenes (GLI2 and CCND2), and represents a target for therapy. These U1 snRNA mutations provide an example of highly recurrent and tissue-specific mutations of a non-protein-coding gene in cancer.
Subject(s)
Cerebellar Neoplasms/genetics , Hedgehog Proteins/genetics , Medulloblastoma/genetics , RNA, Small Nuclear/genetics , Adolescent , Adult , Alternative Splicing , Hedgehog Proteins/metabolism , Humans , Mutation , RNA Splice Sites , RNA SplicingABSTRACT
Pediatric hematologists/oncologists face complex situations such as breaking bad news, treatment/clinical trials discussions, and end-of-life/hospice care. With increasing diversity in patient and physician populations, cultural competency and sensitivity training covering different aspects of pediatric hematology/oncology (PDHO) care can help improve health care delivery and reduce disparities. Though it is considered a required component of fellowship training, there is no clearly defined curriculum meant specifically for PDHO fellows-in-training (PDHO-F). A national online survey of 356 PDHO-F and 67 PDHO program directors (PDHO-PD) was conducted to assess the educational experience, perceptions about identifying barriers including one's own biases and trainee comfort in delivering culturally sensitive care in various PDHO relevant clinical situations. One hundred and eleven (31.2%) PDHO-F and 27 (40.3%) PDHO-PD responded. 30.6% of PDHO-F "strongly agreed/agreed" they received comprehensive cross-cultural communication (CCC) training. The top two teaching methods were faculty role modeling and informal teaching. Majority of CCC training is in medical school or residency and only 10.8% of PDHO-F reported that most of their CCC training was in fellowship. In most clinical situations, there was a modest direct correlation between the fellow's level of agreement that they received comprehensive CCC training and their comfort level. Comfort level with some clinical situations was also significantly different based on year of training. Fellowship training programs should have CCC curricula which use experiential learning models and lay the foundation for promoting cultural awareness, self-reflection, and better patient-physician partnerships which can eventually adapt to and surmount the challenges unique to the physician's chosen field of practice.
Subject(s)
Cultural Diversity , Delivery of Health Care/standards , Faculty, Medical/standards , Fellowships and Scholarships/standards , Hematology/education , Medical Oncology/education , Pediatrics/education , Adult , Child , Communication , Curriculum , Education, Medical, Graduate , Female , Humans , Male , Middle Aged , Physician-Patient Relations , Surveys and QuestionnairesABSTRACT
Rates of venous thromboembolism have increased in the adolescent population over the last two decades, likely due to advanced diagnostics, increased use of central venous catheters, chronic medical conditions, obesity, and oral contraceptive use. Of these factors, a modifiable risk factor for adolescents is obesity. Sedentary lifestyle and prolonged immobilization are additional prothrombotic risk factors that are often associated with obesity. With ever-increasing screen time, sedentary behavior has risen accordingly, especially among gamers. We present four cases of adolescents who developed life-threatening venous thromboembolic events in the setting of obesity, sedentary lifestyle and/or immobilization, and prolonged video game use.
Subject(s)
Obesity/complications , Sedentary Behavior , Thrombophilia/etiology , Venous Thromboembolism/etiology , Video Games/adverse effects , Adolescent , Adolescent Behavior , Humans , MaleABSTRACT
The risk of viral infections and reactivation occurring in the setting of pediatric allogeneic hematopoietic stem cell transplantation is a concern in the pediatric patient, especially with the use of Alemtuzumab (Campath) as a conditioning agent. The purpose of this study was to determine the incidence of Epstein-Barr virus posttransplant lymphoproliferative disorder (EBV-PTLD), cytomegalovirus (CMV), and adenovirus among pediatric recipients of alemtuzumab at our institution. We found that EBV-PTLD occurred in 2.1% of transplants (1 matched unrelated donor [MUD] recipient), CMV reactivation occurred in 12.5% of transplants (4 MUD and 2 matched related donor [MRD] recipients) with disseminated CMV in 2.1% of cases (1 MRD recipient), and adenovirus infection occurred in 8.3% of the total transplants (2 MUD and 2 MRD recipients). Alemtuzumab continues to be used as a method of graft-versus-host disease and graft failure prevention among pediatric recipients of hematopoietic stem cell transplantation and seems to be safer than previously reported. At our institution, alemtuzumab has not increased the risk for EBV-PTLD, CMV infection, or adenovirus.
Subject(s)
Adenoviridae Infections/epidemiology , Alemtuzumab/administration & dosage , Cytomegalovirus Infections/epidemiology , Epstein-Barr Virus Infections/epidemiology , Lymphoproliferative Disorders/epidemiology , Transplantation Conditioning , Unrelated Donors , Adenoviridae , Adenoviridae Infections/etiology , Adolescent , Adult , Alemtuzumab/adverse effects , Allografts , Child , Child, Preschool , Cytomegalovirus , Cytomegalovirus Infections/etiology , Epstein-Barr Virus Infections/etiology , Female , Follow-Up Studies , Graft Rejection/epidemiology , Graft Rejection/prevention & control , Graft vs Host Disease/epidemiology , Graft vs Host Disease/prevention & control , Herpesvirus 4, Human , Humans , Infant , Infant, Newborn , Lymphoproliferative Disorders/etiology , Male , Retrospective Studies , Risk FactorsABSTRACT
Lemierre syndrome (LS) is a multisystemic infection beginning in the oropharynx and leading to thrombosis of the internal jugular vein (IJV) with septic emboli and potential thrombotic extension to the central nervous system. Although patient outcomes have improved with early initiation of antimicrobial therapies, there is no consensus regarding the role of anticoagulation in LS. To better define the role of anticoagulation therapy in LS and determine whether anticoagulation improves thrombosis outcomes, we conducted a retrospective chart review of pediatric and adult patients diagnosed with LS and managed at our institution from January 1998 to December 2014. Eighteen patients (9 females and 9 males) were included in this analysis, 6 of whom received ≥4 weeks of anticoagulation therapy (median 23.1 weeks, range 6.9-32.9 weeks). Six patients were in the pediatric age group (<18 years). All patients received broad-spectrum antibiotics. All patients had improvement in their thrombi by 3 months (nonanticoagulated patient group: complete response [CR], n = 9; partial response [PR], n = 3; anticoagulated patient group: CR, n = 2; PR, n = 4). No patient developed recurrent thrombosis or progression during the follow-up period, regardless of anticoagulation status. Our study suggests that anticoagulation in LS may not affect thrombosis outcomes.
Subject(s)
Anti-Bacterial Agents/administration & dosage , Anticoagulants/administration & dosage , Lemierre Syndrome/drug therapy , Adolescent , Adult , Aged , Child , Female , Follow-Up Studies , Humans , Male , Middle Aged , Retrospective StudiesABSTRACT
HCC is rare in the pediatric population, but is the second most common liver malignancy in children. Survival rates for primary unresectable HCC have been dismal. The objective of this study was to describe our experience with a multimodal approach for the management of unresectable HCC in two adolescent patients and to review the literature. Both patients are currently alive with no recurrence at 51 and 29 months post-transplant. Multimodality treatment involving chemotherapy with doxorubicin, cisplatin, and sorafenib; TACE; timely liver transplantation; and post-transplant therapy with sorafenib and mTOR inhibitors may help improve outcomes and prolong survival in pediatric patients with unresectable HCC.
Subject(s)
Carcinoma, Hepatocellular/therapy , Liver Neoplasms/therapy , Adolescent , Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Chemoembolization, Therapeutic , Chemotherapy, Adjuvant , Child , Female , Hepatectomy , Humans , Liver TransplantationABSTRACT
Neonatal renal vein thrombosis (NRVT) is a rare thromboembolic complication in the neonatal period, and sequelae from renal dysfunction can cause significant morbidity. The authors retrospectively reviewed 10 patients with NRVT treated at their institution. The majority of the cohort were male (n = 9), preterm (n = 6), and had unilateral NRVT (n = 6). Six patients received thrombolysis and/or anticoagulation, and 4 patients received supportive care only. Two of the 6 patients treated with anticoagulation who had bilateral NRVT and anuria received thrombolysis with low-dose tissue plasminogen activator. Thrombolysis was not associated with any major adverse events, and both patients had marked improvement of renal function. Eight patients subsequently developed renal atrophy (3 received anticoagulation, 2 received thrombolysis with anticoagulation, and 3 received supportive care). Anticoagulation/thrombolysis did not appear to prevent renal atrophy. The role of thrombolysis needs to be further studied and considered in the setting of bilateral NRVT and acute renal failure.
Subject(s)
Anticoagulants/administration & dosage , Renal Veins , Thrombolytic Therapy/methods , Tissue Plasminogen Activator/administration & dosage , Venous Thrombosis/therapy , Female , Humans , Infant , Infant, Newborn , Male , Retrospective StudiesABSTRACT
BACKGROUND: Humanism and professionalism are virtues intrinsic to the practice of medicine, for which we lack a standard, evidence-based approach for teaching and evaluation. Pediatric hematology-oncology (PHO) fellowship training brings new and significant stressors, making it an attractive setting for innovation in humanism and professionalism training. PROCEDURE: We electronically surveyed a national sample of PHO fellows to identify fellows' educational needs in humanism and professionalism. Next, we developed a case-based, faculty-facilitated discussion curriculum to teach this content within pilot fellowship programs. We assessed whether fellowships would decide to offer the curriculum, feasibility of administering the curriculum, and satisfaction of fellow and faculty participants. RESULTS: Surveys were completed by 187 fellows (35%). A minority (29%) reported that their training program offers a formal curriculum in humanism and/or professionalism. A majority desires more formal teaching on balancing clinical practice and research (85%), coping with death/dying (85%), bereavement (78%), balancing work and personal life (75%), navigating challenging relationships with patients (74%), and depression/burn out (71%). These six topics were condensed into four case-based modules, which proved feasible to deliver at all pilot sites. Ten fellowship programs agreed to administer the novel curriculum. The majority (90%) of responding fellows and faculty reported the sessions touched on issues important for training, stimulated reflective communication, and were valuable. CONCLUSIONS: Pediatric hematology-oncology fellows identify numerous gaps in their training related to humanism and professionalism. This curriculum offers an opportunity to systematically address these educational needs and can serve as a model for wider implementation. Pediatr Blood Cancer 2015;62:335-340. © 2014 Wiley Periodicals, Inc.
Subject(s)
Education, Medical, Graduate/methods , Hematology/education , Humanism , Medical Oncology/education , Professionalism/education , Adult , Attitude of Health Personnel , Curriculum , Female , Humans , Male , Surveys and QuestionnairesABSTRACT
BACKGROUND: Survival rates for children with medulloblastoma have risen over the past decade, in part due to the addition of cisplatin-containing adjuvant chemotherapy. Total dose of cisplatin required for optimal treatment is unknown. The purpose of this study was to evaluate the survival outcomes based on cumulative cisplatin doses (CCD) in children with newly diagnosed average-risk medulloblastoma. PROCEDURE: CCD data were reviewed for 363 patients in a prospective study evaluating patients between 3 and 21 years with a newly diagnosed average-risk medulloblastoma and treated with craniospinal radiation and post-radiation cisplatin based adjuvant chemotherapy. RESULTS: Eight-year event-free survival (EFS) and overall survival (OS) estimates were 78.2 ± 2.6% and 83.9 ± 2.4%, respectively. Only 73 patients received the protocol specified CCD of 600 mg/m(2), primarily due to mandated cisplatin toxicity-related dose reductions. The median CCD given to those without relapse or death on treatment was 487.5 mg/m(2). CCD, as a time-dependent covariate, was not associated with EFS (P = 0.54) or OS (P = 0.11). The 343 patients who completed chemotherapy failure-free were categorized into four groups according to CCD (n = 10; 75-150 mg/m(2)), (n = 26; 151-300 mg/m(2)), (n = 113; 301-450 mg/m(2)), and (n = 194; 451-600 mg/m(2)). There were no statistically significant differences in distributions of EFS (P = 0.53) or OS (P = 0.49) among these four groups. CONCLUSION: CCD is not associated with EFS or OS suggesting that lower doses of cisplatin may be incorporated into future medulloblastoma trials, thereby limiting its toxicity profile without affecting survival. If ototoxicity is encountered, more stringent cisplatin dose modification/cessation rules seem warranted.
Subject(s)
Antineoplastic Agents/administration & dosage , Cerebellar Neoplasms/drug therapy , Cisplatin/administration & dosage , Medulloblastoma/drug therapy , Adolescent , Cerebellar Neoplasms/mortality , Chemoradiotherapy , Chemotherapy, Adjuvant , Child , Child, Preschool , Disease-Free Survival , Dose-Response Relationship, Drug , Female , Humans , Kaplan-Meier Estimate , Maintenance Chemotherapy , Male , Medulloblastoma/mortality , Proportional Hazards Models , Risk Factors , Young AdultABSTRACT
Low-grade gliomas (LGGs) represent the most common childhood brain tumors and are a histologically heterogenous group of tumors. Most LGGs are surgically resectable with excellent 10-year overall survival outcomes of more than 90 % with surgery alone. Tumors not amenable to surgical resection and those with an aggressive biology are more challenging to treat. Conventional radiotherapy is a more efficacious method of long-term tumor control than chemotherapy. However, radiation is associated with significant cognitive, endocrine, and cerebrovascular late effects, making chemotherapy an often-preferred modality over radiotherapy, especially in younger children. Multiple chemotherapy regimens have been evaluated over the past few decades with comparable survival outcomes and differing toxicity profiles. Newer regimens containing antiangiogenic agents also show promise. Recent molecular studies have implicated the BRAF oncogene, a key regulator of the MAPK pathway, and the AKT/mTOR pathway in pediatric LGG tumorigenesis. This has opened up promising new avenues for targeted therapy, with many agents currently under investigation.
Subject(s)
Central Nervous System Neoplasms/therapy , Glioma/therapy , Antineoplastic Agents/therapeutic use , Central Nervous System Neoplasms/pathology , Child , Clinical Trials as Topic , Combined Modality Therapy , Glioma/pathology , Humans , Molecular Targeted Therapy/methodsABSTRACT
Pediatric brain tumors are the second most common form of childhood malignancy. Brain tumors are a very heterogenous group of tumors and the pathogenesis of many of these tumors is yet to be clearly elucidated. Current diagnostic tools include histopathology and immunohistochemistry, but classification based on these means has significant limitations. As our understanding of the molecular biology of individual tumors continues to increase it has led to the identification of reliable and increasingly available molecular biomarkers. Molecular techniques are likely to complement current standard means of investigation and help not only overcome diagnostic challenges but may also result in better disease classification and risk stratification, leading to more personalized therapeutic approaches.
Subject(s)
Biomarkers, Tumor/genetics , Brain Neoplasms/genetics , Glioma/genetics , Rhabdoid Tumor/genetics , Teratoma/genetics , Adolescent , Biomarkers, Tumor/metabolism , Brain Neoplasms/metabolism , Child , Child, Preschool , Female , Gene Expression Regulation , Glioma/metabolism , Humans , Infant , Male , Molecular Biology/methods , Rhabdoid Tumor/metabolism , Teratoma/metabolismABSTRACT
Graft versus host disease (GVHD) remains a major cause of mortality and morbidity after matched unrelated hematopoietic stem cell transplantation (HSCT). Campath-1 H (alemtuzumab), a humanized monoclonal antibody to CD52 antigen, is thought to reduce GVHD incidence through in vivo T-cell depletion. Through the same mechanism it can potentially increase the risk of relapse by reducing the graft versus leukemia effect and possibly increase the risk of infection due to delayed immune recovery. A retrospective case analysis of 17 pediatric matched unrelated HSCTs done in our institution between January 2003 and June 2009 with Campath-1H as part of the pretransplant conditioning regimen was conducted. Grade I-II acute GVHD was noted in 29.4% of the HSCTs. No patient developed chronic GVHD. All but one patient with severe aplastic anemia engrafted. A relapse of primary disease was noted in 35.3% of the transplants. Three patient deaths were due to relapse and 1 due to disseminated varicella infection. Overall survival was 100% and 94% at 100 days and 1 year, respectively. Our experience suggests Campath-1H used as part of pretransplant conditioning regimen in pediatric unrelated HSCTs effectively reduces the risk of serious GVHD with no apparent increase in life-threatening infections or relapse compared with that reported with conventional regimens. Larger studies, with longer duration of follow-up, are required to further assess its role with regards to graft versus leukemia effect and to establish if the decreased incidence of GVHD and infectious complications is sustained in larger cohorts.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents/therapeutic use , Graft vs Host Disease/prevention & control , Hematopoietic Stem Cell Transplantation/adverse effects , Transplantation Conditioning/methods , Adolescent , Alemtuzumab , Child , Child, Preschool , Disease-Free Survival , Female , Graft vs Host Disease/mortality , Hematologic Diseases/mortality , Hematologic Diseases/surgery , Humans , Infant , Kaplan-Meier Estimate , Male , Retrospective Studies , Young AdultSubject(s)
Bone Neoplasms/radiotherapy , Sarcoma, Ewing/radiotherapy , Adolescent , Adult , Bone Neoplasms/diagnostic imaging , Bone Neoplasms/pathology , Child , Female , Humans , Lumbosacral Region/pathology , Magnetic Resonance Imaging , Male , Middle Aged , Neuroectodermal Tumors, Primitive, Peripheral/diagnostic imaging , Sarcoma, Ewing/diagnostic imaging , Sarcoma, Ewing/pathology , Treatment Failure , Young AdultABSTRACT
Over the past decade, wingless-activated (WNT) medulloblastoma has been identified as a candidate for therapy de-escalation based on excellent survival; however, a paucity of relapses has precluded additional analyses of markers of relapse. To address this gap in knowledge, an international cohort of 93 molecularly confirmed WNT MB was assembled, where 5-year progression-free survival is 0.84 (95%, 0.763-0.925) with 15 relapsed individuals identified. Maintenance chemotherapy is identified as a strong predictor of relapse, with individuals receiving high doses of cyclophosphamide or ifosphamide having only one very late molecularly confirmed relapse (p = 0.032). The anatomical location of recurrence is metastatic in 12 of 15 relapses, with 8 of 12 metastatic relapses in the lateral ventricles. Maintenance chemotherapy, specifically cumulative cyclophosphamide doses, is a significant predictor of relapse across WNT MB. Future efforts to de-escalate therapy need to carefully consider not only the radiation dose but also the chemotherapy regimen and the propensity for metastatic relapses.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cerebellar Neoplasms/drug therapy , Medulloblastoma/drug therapy , Neoplasm Recurrence, Local/drug therapy , Adolescent , Biomarkers, Tumor/metabolism , Child , Cyclophosphamide/therapeutic use , Female , Humans , Ifosfamide/therapeutic use , Male , Medulloblastoma/metabolism , Middle Aged , Neoplasm Recurrence, Local/metabolism , Progression-Free SurvivalABSTRACT
Catastrophic antiphospholipid syndrome (CAPS) is a life-threatening condition characterized by small-vessel thrombi and a rapid onset of multiorgan system failure associated with systemic inflammatory response syndrome. Current treatment options include anticoagulants, corticosteroids, plasma exchange, and intravenous immunoglobulin, but these are not always effective. Rituximab, a chimeric anti-CD20 monoclonal antibody, may help eliminate autoreactive B cells and thus limit the rapid inflammatory process involved in CAPS. We describe the use of rituximab in the successful initial management of a probable case of pediatric CAPS.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents/therapeutic use , Antiphospholipid Syndrome/drug therapy , Antiphospholipid Syndrome/physiopathology , Adolescent , Antibodies, Monoclonal, Murine-Derived , Catastrophic Illness , Female , Humans , Rituximab , Tomography, X-Ray ComputedABSTRACT
Although typically a disorder of adults, acquired von Willebrand syndrome (AVWS) is increasingly being recognized in the pediatric population in association with congenital cardiac diseases, certain neoplasia, and hypothyroidism. Transplacental transfer of maternal immunoglobulin G (IgG) antibodies as a cause of neonatal disorders in infants born to mothers with autoimmune conditions has been reported. We describe the diagnosis and peripartum clinical management of AVWS due to monoclonal gammopathy of undetermined significance (MGUS) and the first reported case of transient neonatal AVWS due to transplacental transfer of maternal IgG antibodies.
Subject(s)
Antibodies, Monoclonal/metabolism , Maternal-Fetal Exchange , von Willebrand Diseases/etiology , Adult , Female , Humans , Immunoglobulin G/metabolism , Infant, Newborn , PregnancyABSTRACT
Atypical teratoid/rhabdoid tumor (AT/RT) is a rare CNS cancer that typically occurs in children younger than 3 years of age. Histologically, AT/RTs are embryonal tumors that contain a rhabdoid component as well as areas with primitive neuroectodermal, mesenchymal, and epithelial features. Compared to other CNS tumors of childhood, AT/RTs are characterized by their rapid growth, short symptomatic prodrome, and large size upon presentation, often leading to brain compression and intracranial hypertension requiring urgent intervention. For decades, the mainstay of care has been a combination of maximal safe surgical resection followed by adjuvant chemotherapy and radiotherapy. Despite advances in each of these modalities, the relative paucity of data on these tumors, their inherently aggressive course, and a lack of molecular data have limited advances in treatment over the past 3 decades. Recent large-scale, multicenter interdisciplinary studies, however, have significantly advanced our understanding of the molecular pathogenesis of these tumors. Multiple clinical trials testing molecularly targeted therapies are underway, offering hope for patients with AT/RT and their families.
ABSTRACT
MAPK pathway activation has been recurrently observed in desmoplastic infantile ganglioglioma/astrocytoma (DIG/DIA) with reported disproportionally low mutation allele frequencies relative to the apparent high tumor content, suggesting that MAPK pathway alterations may be subclonal. We sought to expand the number of molecularly profiled cases and investigate if tumor cell composition could account for the observed low mutation allele frequencies. Molecular (targeted neuro-oncology next-generation sequencing/RNA sequencing and OncoScan microarray) and immunohistochemical (CD68-PGM1/CD163/CD14/CD11c/lysozyme/CD3/CD20/CD34/PD-L1) studies were performed in 7 DIG. Activating MAPK pathway alterations were identified in 4 (57%) cases: 3 had a BRAF mutation (V600E/V600D/V600_W604delinsDQTDG, at 8%-27% variant allele frequency) and 1 showed a TPM3-NRTK1 fusion. Copy number changes were infrequent and nonrecurrent. All tumors had at least 30% of cells morphologically and immunophenotypically consistent with microglial/macrophage lineage. Two subtotally resected tumors regrew; 1 was re-excised and received adjuvant treatment (chemotherapy/targeted therapy), with clinical response to targeted therapy only. Even with residual tumor, all patients are alive (median follow-up, 83 months; 19-139). This study further supports DIG as another MAPK pathway-driven neuroepithelial tumor, thus expanding potential treatment options for tumors not amenable to surgical cure, and suggests that DIG is a microglia/macrophage-rich neuroepithelial tumor with frequent low driver mutation allele frequencies.
Subject(s)
Brain Neoplasms/metabolism , Ganglioglioma/metabolism , Ganglioglioma/pathology , MAP Kinase Signaling System , Macrophages/metabolism , Microglia/metabolism , Neoplasms, Neuroepithelial/metabolism , Brain/pathology , Brain Neoplasms/pathology , Female , Humans , Infant , Macrophages/pathology , Male , Microglia/pathology , Neoplasms, Neuroepithelial/pathologyABSTRACT
Pleomorphic xanthoastrocytoma (PXA) is a rare localized glioma characterized by frequent BRAF V600E mutation and CDKN2A/B deletion. We explored the association of copy-number variants (CNVs) with BRAF mutations, tumor grade, and patient survival in a cohort of 41 PXA patients using OncoScan chromosomal microarray. Primary resection specimens were available in 38 cases, including 24 PXA and 14 anaplastic PXA (A-PXA), 23 BRAF V600E mutant tumors (61%). CNVs were identified in all cases and most frequently involved chromosome 9 with homozygous CDKN2A/B deletion (n = 33, 87%), a higher proportion than previously detected by comparative genomic hybridization (50%-60%) (37). CDKN2A/B deletion was present in similar proportion of PXA (83%), A-PXA (93%), BRAF V600E (87%), and wild-type (87%) tumors. Whole chromosome gains/losses were frequent, including gains +7 (n = 15), +2 (n = 11), +5 (n = 10), +21 (n = 10), +20 (n = 9), +12 (n = 8), +15 (n = 8), and losses -22 (n = 11), -14 (n = 7), -13 (n = 5). Losses and copy-neutral loss of heterozygosity were significantly more common in A-PXA, involving chromosomes 22 (P = 0.009) and 14 (P = 0.03). Amplification of 8p and 12q was identified in a single tumor. Histologic grade was a robust predictor of overall survival (P = 0.003), while other copy-number changes, including CDKN2A/B deletion, did not show significant association with survival. Distinct histologic patterns of anaplasia included increased mitotic activity in an otherwise classic PXA or associated with small cell, fibrillary, or epithelioid morphology, with loss of SMARCB1 expression in one case. In 10 cases, matched specimens were compared, including A-PXA with areas of distinct low- and high-grade morphology (n = 2), matched primary/tumor recurrence (n = 7), or both (n = 1). Copy-number changes on recurrence/anaplastic transformation were complex and highly variable, from nearly identical profiles to numerous copy-number changes. Overall, we confirm CDKN2A/B deletion as key a feature of PXA not associated with tumor grade or BRAF mutation, but central to the underlying genetics of PXA.