Targeted treatment of vascular anomalies.

Vascular anomalies comprise an array of congenital developmental disorders that can lead to significant disfigurement and physiologic disarray. The vast multitude of clinical phenotypes has inherently led to misdiagnosis and patients and families enduring long diagnostic odysseys of medical care. Although the observed variation in disease manifestations remains poorly understood, targeted next-generation sequencing has pivoted our understanding of the pathobiology of vascular anomalies and, for the first time, uncovered potential pharmacologic targets for these disorders. In this review article, we highlight current and developing targeted therapies for vascular anomalies, namely phosphoinositide 3-kinase and mitogen-activated protein kinase pathway inhibitors, and discuss the future directions of targeted therapies.

Targeted Inhibition of the Epidermal Growth Factor Receptor and Mammalian Target of Rapamycin Signaling Pathways in Olmsted Syndrome.

Importance: Olmsted syndrome is a rare and disabling genodermatosis for which no successful treatment is currently available. Objective: To evaluate the clinical response to the mammalian target of rapamycin (mTOR) inhibitor sirolimus and/or the epidermal growth factor receptor (EGFR) inhibitor erlotinib among patients with Olmsted syndrome. Design, Setting, and Participants: This case series focused on 4 children with treatment-refractory Olmsted syndrome. These children received treatments (initiated in 2017 and 2018) at the outpatient dermatology clinic at the Children's Hospital of Wisconsin in Milwaukee, Wisconsin; Children's National Hospital in Washington, DC; and Hospital Infantil Pequeno Príncipe, Curitiba in Paraná, Brazil. Exposures: Immunohistochemical analyses for mTOR and EGFR activation were performed on skin biopsy specimens from 2 patients. Oral sirolimus was administered to these 2 patients at a dosage of 0.8 mg/m2 twice daily, titrated to a goal trough whole-blood concentration of 10 to 15 ng/mL. Erlotinib was administered to all 4 patients at a dosage of 2 mg/kg/d. Main Outcomes and Measures: Clinical responses were assessed with visual analog scales for pruritus and pain and/or the Children's Dermatology Life Quality Index. Adverse effects were monitored throughout treatment. Results: Four patients (mean [SD] age, 7 [6] years; 2 boys and 2 girls) were analyzed. Lesional skin immunostaining showed increased phosphorylated ribosomal protein S6 (RPS6) and phosphorylated EGFR staining in the epidermis, indicating enhanced mTOR and EGFR signaling activation. Patients 1 and 2 were initially treated with sirolimus, displaying substantial clinical improvement in erythema and periorificial hyperkeratosis afterward. When switched to erlotinib, these patients showed substantial palmoplantar keratoderma (PPK) improvement. Patients 3 and 4 were treated with erlotinib only and later showed rapid and near complete resolution of PPK and substantial improvement in Children's Dermatology Life Quality Index scores. All 4 patients had sustained improvements in pruritus and pain. No severe adverse effects were reported. Conclusions and Relevance: This study's findings suggest that the EGFR-mTOR cascade may play a substantial role in the pathophysiological process of Olmsted syndrome and may serve as a major therapeutic target. Oral sirolimus and erlotinib may be a promising, life-altering treatment for pediatric patients with Olmsted syndrome.

Administration of Dexrazoxane Improves Cardiac Indices in Children and Young Adults With Acute Myeloid Leukemia (AML) While Maintaining Survival Outcomes.

Anthracycline-induced cardiotoxicity remains a significant contributor to late morbidity/mortality in children and young adults with acute myeloid leukemia (AML). The cardioprotectant dexrazoxane can be used as prophylaxis to diminish risk for cardiomyopathy but whether it affects risk of relapse in pediatric AML is unclear. Our institution adopted the use of dexrazoxane before anthracyclines administration for all oncology patients in 2011. We compared patients with AML (ages, 0 to 21 y) who received or did not receive dexrazoxane during the years 2008 to 2013. In total, 44 patients with AML (ages, 4.5 mo to 21.7 y) were included. We identified no statistical difference in 2-year event rate (62% vs. 50%, P=0.41) or 2-year overall survival (69% vs. 69%, P=0.53) between patients receiving (n=28) or not receiving (n=16) dexrazoxane. Ejection fraction (P=0.0262) and shortening fraction (P=0.0381) trended significantly higher in patients that received dexrazoxane compared with those that did not receive dexrazoxane. Utilization of the cardioprotectant dexrazoxane before anthracycline chemotherapy in pediatric patients with AML demonstrated no significant difference in either event rate or overall survival relative to institutional controls and seems to improve cardiac function indices. Further studies in this patient population are needed to confirm these findings.

Pure Erythroid Leukemia Mimicking Ewing Sarcoma/Primitive Neuroectodermal Tumor in an Infant.

Pure erythroid leukemia (PEL) is a rare type of acute myeloid leukemia (AML) with a very aggressive clinical course. Presentation as a myeloid/erythroid sarcoma is exceedingly rare. We describe an infantile PEL presenting as a multifocal myeloid sarcoma, clinically and pathologically mimicking Ewing sarcoma/PNET family of tumors. The patient died 8 weeks after the initial presentation due to widespread disease. Our case shows that PEL needs to be considered in the differential diagnosis of small round blue cell tumors in infancy. A meticulous workup including immunohistochemistry, flow cytometry, molecular, and cytogenetic studies was required to reach the diagnosis.

Dose intensification of methotrexate and cytarabine during intensified continuation chemotherapy for high-risk B-precursor acute lymphoblastic leukemia: POG 9406: a report from the Children's Oncology Group.

PURPOSE: To determine the efficacy and toxicity of higher dose versus standard dose intravenous methotrexate (MTX) and pulses of high-dose cytosine arabinoside with asparaginase versus standard dose cytosine arabinoside and teniposide during intensified continuation therapy for higher risk pediatric B-precursor acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: From 1994 to 1999, the Pediatric Oncology Group conducted a randomized phase III clinical trial in higher risk pediatric B-precursor ALL. A total of 784 patients were randomized in a 2×2 factorial design to receive MTX 1 g/m versus 2.5 g/m and to cytosine arabinoside/teniposide versus high-dose cytosine arabinoside/asparaginase during intensified continuation therapy. RESULTS: Patients receiving standard dose MTX had a 5-year disease-free survival (DFS) of 71.8±2.4%; patients receiving higher dose MTX had a 5-year DFS of 71.7±2.4% (P=0.55). Outcomes on cytosine arabinoside/teniposide (DFS of 70.4±2.4) were similar to higher dose cytosine arabinoside/asparaginase (DFS of 73.1±2.3%) (P=0.41). Overall survival rates were not different between MTX doses or cytosine arabinoside/teniposide versus cytosine arabinoside/asparaginase. CONCLUSIONS: Increasing MTX dosing to 2.5 g/m did not improve outcomes in higher risk pediatric B-precursor ALL. Giving high-dose cytarabine and asparaginase pulses instead of standard dose cytarabine and teniposide produced nonsignificant differences in outcomes, allowing for teniposide to be removed from ALL therapy.

Significant response to oral Etoposide in the treatment of an unresectable cardiac sarcoma.

Primary cardiac sarcomas are rare and carry a poor prognosis. The standard of care is complete resection. Outcomes for patients without complete resection are dismal, and the benefit of adjuvant therapy is uncertain. A 9-year-old girl presented with a large right-sided cardiac mass. After biopsy, the tumor was classified as an undifferentiated sarcoma. Resection was not feasible due to apparent invasion of the right ventricle and atrioventricular groove. Treatment with oral etoposide resulted in a 97% reduction in tumor volume and allowed for complete resection of residual tumor. She is alive with no evidence of disease 25 months from diagnosis.

Genetic variants modify susceptibility to leukemia in infants: a Children's Oncology Group report.

BACKGROUND: The mixed lineage leukemia (MLL) gene is commonly rearranged in infant leukemia (IL). Genetic determinants of susceptibility to IL are unknown. Recent genome-wide association studies for childhood acute lymphoblastic leukemia (ALL) have identified susceptibility loci at IKZF1, ARID5B, and CEBPE. PROCEDURE: We genotyped these loci in 171 infants with leukemia and 384 controls and evaluated associations overall, by subtype [ALL, acute myeloid leukemia (AML)], and by presence (+) or absence (-) of MLL rearrangements. RESULTS: Homozygosity for a variant IKZF1 allele (rs11978267) increased risk of infant AML [Odds ratio (OR) = 3.9, 95% confidence interval (CI) = 1.8-8.4]; the increased risk was similar for AML/MLL+ and MLL- cases. In contrast, risk of ALL/MLL- was increased in infants homozygous for the IKZF1 variant (OR = 5.1, 95% CI = 1.8-14.5) but the variant did not modify risk of ALL/MLL+. For ARID5B (rs10821936), homozygosity for the variant allele increased risk for the ALL/MLL- subgroup only (OR = 7.2, 95% CI = 2.5-20.6). There was little evidence of an association with the CEBP variant (rs2239633). CONCLUSION: IKZF1 is expressed in early hematopoiesis, including precursor myeloid cells. Our data provide the first evidence that IKZF1 modifies susceptibility to infant AML, irrespective of MLL rearrangements, and could provide important new etiologic insights into this rare and heterogeneous hematopoietic malignancy.

Case report: giant cardiac malignancy in a nine-year-old female.

PURPOSE: To describe the management of a giant cardiac malignancy initially diagnosed as an anterior mediastinal mass. CLINICAL FEATURES: A nine-year-old female with right facial swelling and chronic cough was diagnosed with a large right mediastinal mass. Intermittent ventricular and supraventricular arrhythmias were noted on admission electrocardiograms. Empiric corticosteroid and radiation therapy did not reduce the size of the tumour, and initial tissue biopsies were non-diagnostic. Due to worsening tamponade physiology and persistent arrhythmias, the patient was scheduled for tumour debulking with potential resection. Prior to surgery, a multidisciplinary team was assembled to delineate team member responsibilities and treatment algorithms. The procedure was performed under general anesthesia with spontaneous ventilation preserved during endotracheal intubation and invasive line placement. The team was prepared to provide extracorporeal mechanical support if needed. The child required inotropic and vasoactive medications after transitioning to positive pressure ventilation, but her hemodynamics improved with sternotomy. The lesion was identified as a malignant cardiac clear-cell tumour that was unresectable. Her sternum was left open, as attempted closure led to the re-creation of tamponade physiology. She underwent delayed sternal closure days later. After months of chemotherapy that resulted in significant tumour involution, she underwent successful surgical resection. CONCLUSION: Giant primary cardiac tumours may present similarly to large anterior mediastinal masses. The care of patients with these lesions requires an understanding of the risks associated with mediastinal masses as well as those unique to cardiac tumours. A multidisciplinary approach is critical to providing safe and effective care throughout this process.

A composite pheochromocytoma/ganglioneuroblastoma of the adrenal gland.

A 9-year-old female presented with a large abdominal mass. At surgery, the mass was noted to arise from the right adrenal gland. As the mass was manipulated, the patient developed severe hypertension. The final diagnosis was a cystic composite-pheochromocytoma/ganglioneuroblastoma. This compound adrenal tumor is only the fourth case reported in a child. Because composite pheochromocytomas are rare in the pediatric population, the management, optimal surveillance schedule and outcomes have not been characterized.

The epidemiology of childhood leukemia with a focus on birth weight and diet.

Leukemia is the most common childhood cancer and a major source of morbidity and mortality. The etiology of childhood leukemia remains largely unknown. Cytogenetic abnormalities determine disease subtypes, prognosis, clinical presentation, and course and may help in discovering etiological factors. Epidemiologic investigations of leukemia are complicated by many factors, including the rarity of the disease, necessitating careful study design. Two emerging areas of interest in leukemia etiology are birth weight and diet. High birth weight has been associated with increased risk of childhood leukemia. The biological mechanism behind this association may involve insulin-like growth factor I (IGF-I), which is associated with high birth weight. IGF-I may act by increasing the absolute number of stem cells available for transformation, stimulating the growth of cells that are already transformed, or a combination of effects. Diet has been linked with leukemia. Maternal dietary DNA topoisomerase II (DNAt2) inhibitor intake is associated with infant acute myeloid leukemia (AML) with the MLL gene translocation. Increased intake of fruits and vegetables has been associated with decreased leukemia risk and, relatedly, lack of maternal folate supplementation has been associated with increased childhood leukemia risk, possibly by causing DNA hypomethylation and increased DNA strand breaks. Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms modify this risk.