Single-agent Bevacizumab in the Treatment of Symptomatic Newly Diagnosed and Recurrent/Refractory Pediatric Cervicomedullary Brainstem Low-grade Gliomas: A Single Institutional Experience.

Bevacizumab-based therapies have been utilized as single or combination therapy of refractory/recurrent pediatric low-grade gliomas. Its efficacy for symptomatic cervicomedullary low-grade gliomas (cmLGGs) in the upfront and the recurrent setting is less known. We report our retrospective single institutional experience from 2015 to 2021 with single-agent bevacizumab for symptomatic cmLGG. Six consecutive patients (4 female, ages 2 to 12 y) with newly diagnosed (n=3) and recurrent/refractory (n=3) symptomatic nondisseminated cmLGG (5/6 biopsy-proven, 2 BRAFV600E, 2 BRAF-KIAA1549) were treated with single-agent bevacizumab. All demonstrated radiographic response most pronounced on post-gadolinium T1-weighted magnetic resonance imaging (2 complete, 4 partial) at a median of 8 weeks (range: 2 to 12 wk). Clinical response was seen in all patients with improvement in cranial nerve abnormalities (3 recurrent/refractory, 1 newly diagnosed), strength (2 recurrent/refractory, 2 newly diagnosed), pain (2 recurrent/refractory), and anorexia (1 newly diagnosed). Four patients (2 recurrent/refractory, 2 newly diagnosed) experienced disease progression on subsequent adjunct therapies, 2 of which (the 2 newly diagnosed patients) are currently being rechallenged. At a mean follow-up of 7 months, all patients are clinically stable without disease progression. Single-agent bevacizumab may be effective in the management of symptomatic newly diagnosed and recurrent/refractory cmLGG and warrants further evaluation in a clinical trial setting.

Deep Vein Thrombosis in a Young, Healthy Baseball Catcher: A Case Report and Review of the Literature.

Venous thromboembolism is becoming increasingly recognized as a significant cause of morbidity and mortality in the hospitalized pediatric population. However, young healthy athletes can present with unique risk factors for deep vein thrombosis (DVT) that can be overlooked. Here we report a case of an adolescent male with no inherited risk factors or prior history of DVTs who developed a right femoral vein DVT in the context of playing catcher in baseball after recovering from a bout of streptococcal pharyngitis. We review the evidence that suggests that repetitive squatting-induced compression of the femoral vein can cause the venous stasis and endothelial microtrauma that contributed to the formation of this thrombus.

Overview and recent advances in the targeting of medulloblastoma cancer stem cells.

Introduction: Medulloblastoma, an embryonal small round blue cell tumor primarily arising in the posterior fossa, is the most common malignancy of the central nervous system in children and requires intensive multi-modality therapy for cure. Overall 5-year survival is approximately 75% in children with primary disease, but outcomes for relapsed disease are very poor. Recent advances have identified molecular subgroups with excellent prognosis, with 5-year overall survival rates >90%, and subgroups with very poor prognosis with overall survival rates <50%. Molecular subtyping has allowed for more sophisticated risk stratification of patients, but new treatments for the highest risk patients have not yet improved outcomes. Targeting cancer stem cells may improve outcomes, and several candidate targets and novel drugs are under investigation.Areas covered: We discuss medulloblastoma epidemiology, biology, treatment modalities, risk stratification, and molecular subgroup analysis, links between subgroup and developmental biology, cancer stem cell biology in medulloblastoma including previously described cancer stem cell markers and proposed targeted treatments in the current literature.Expert opinion: The understanding of cancer stem cells in medulloblastoma will advance therapies targeting the most treatment-resistant cells within the tumor and therefore reduce the incidence of treatment refractory and relapsed disease.

Clinical and Neuroimaging Features of Magnetic Resonance-Guided Stereotactic Laser Ablation for Newly Diagnosed and Recurrent Pediatric Brain Tumors: A Single Institutional Series.

OBJECTIVE: We describe our single-institutional experience with magnetic resonance-guided stereotactic laser ablation (SLA) for the treatment of newly diagnosed and recurrent pediatric brain tumors. METHODS: Eighteen consecutive ablation procedures were performed in 17 patients from March 2016-April 2020. Patient demographics, indications, procedures, neuroimaging features, and outcomes were reviewed retrospectively. RESULTS: Seventeen patients (mean age of 11.4 years, 11 boys, 6 girls) underwent SLA with a mean follow-up of 24 months (range: 3-45 months). Tumor histologies included pilocytic astrocytoma (n = 5), ganglioglioma (n = 3), low-grade glioma not otherwise specified (n = 4), glioblastoma (n = 2), meningioma (n = 1), medulloblastoma (n = 1), and metastatic malignant peripheral nerve sheath tumor (n = 1). SLA was first-line therapy in 10 patients. Mean procedure duration including anesthesia time was 328 minutes (range: 244-529 minutes), and mean postoperative length of stay was 1.5 days (range 1-5 days). The complication rate was 29%, which included 3 patients who experienced postoperative motor changes, which resolved within several weeks of surgery, 1 patient with self-limited intraoperative bradycardia and hypotension, and 1 patient who died postoperatively due to intracranial hemorrhage from a distant lesion. Twelve of 17 patients had a neuroimaging response after SLA (4 complete responses, 8 partial responses, 1 stable disease). Percentage of tumor shrinkage from baseline ranged from 33%-100% (mean 75%). Patients with low-grade glioma exhibited the best responses to SLA (range 3%-100% decrease; mean 90%; 36% complete response rate). CONCLUSIONS: SLA is a minimally invasive modality for the treatment of newly diagnosed and recurrent low-grade pediatric brain tumors. Low-grade glioma exhibited the best responses. Identification of ideal candidates for SLA, mitigation of perioperative complications, and demonstration of long-term outcomes need to be better defined in a clinical trial setting.

Characterization of G-CSF receptor expression in medulloblastoma.

BACKGROUND: Identifying mechanisms of medulloblastoma recurrence is a key to improving patient survival, and targeting treatment-resistant subpopulations within tumors could reduce disease recurrence. Expression of the granulocyte colony-stimulating factor receptor (G-CSF-R, CD114) is a potential marker of cancer stem cells, and therefore we hypothesized that a subpopulation of medulloblastoma cells would also express CD114 and would demonstrate chemoresistance and responsiveness to G-CSF. METHODS: Prevalence of CD114-positive (CD114+) cells in medulloblastoma cell lines, patient-derived xenograft (PDX) tumors, and primary patient tumor samples were assessed by flow cytometry. Growth rates, chemoresistance, and responses to G-CSF of CD114+ and CD114-negative (CD114-) cells were characterized in vitro using continuous live cell imaging and flow cytometry. Gene expression profiles were compared between CD114+ and CD114- medulloblastoma cells using quantitative RT-PCR. RESULTS: CD114+ cells were identifiable in medulloblastoma cell lines, PDX tumors, and primary patient tumors and have slower growth rates than CD114- or mixed populations. G-CSF accelerates the growth of CD114+ cells, and CD114+ cells are more chemoresistant. The CD114+ population is enriched when G-CSF treatment follows chemotherapy. The CD114+ population also has higher expression of the CSF3R, NRP-1, TWIST1, and MYCN genes. CONCLUSIONS: Our data demonstrate that a subpopulation of CD114+ medulloblastoma cells exists in cell lines and tumors, which may evade traditional chemotherapy and respond to exogenous G-CSF. These properties invite further investigation into the role of G-CSF in medulloblastoma therapy and methods to specifically target these cells.

The multikinase inhibitor RXDX-105 is effective against neuroblastoma in vitro and in vivo.

Neuroblastoma is the most common extracranial solid tumor of childhood and accounts for 15% of all pediatric cancer-related deaths. New therapies are needed to improve outcomes for children with high-risk and relapsed tumors. Inhibitors of the RET kinase and the RAS-MAPK pathway have previously been shown to be effective against neuroblastoma, suggesting that combined inhibition may have increased efficacy. RXDX-105 is a small molecule inhibitor of multiple kinases, including the RET and BRAF kinases. We found that treatment of neuroblastoma cells with RXDX-105 resulted in a significant decrease in cell viability and proliferation in vitro and in tumor growth and tumor vascularity in vivo. Treatment with RXDX-105 inhibited RET phosphorylation and phosphorylation of the MEK and ERK kinases in neuroblastoma cells and xenograft tumors, and RXDX-105 treatment induced both apoptosis and cell cycle arrest. RXDX-105 also showed enhanced efficacy in combination with 13-cis-retinoic acid, which is currently a component of maintenance therapy for children with high-risk neuroblastoma. Our results demonstrate that RXDX-105 shows promise as a novel therapeutic agent for children with high-risk and relapsed neuroblastoma.

Challenges of assessing response to therapy in non-Hodgkin's lymphoma of the bone.

A 17-year-old male adolescent was diagnosed with diffuse large B cell lymphoma arising from the right humeral head. The lymphoma was found to be isolated to the bone, with a very small extraosseous component. After completion of a standard chemotherapy regimen, the Positron Emission Tomography-Computed Tomography (PET-CT) became PET negative but the CT and MRI appeared mostly unchanged in appearance, suggesting refractory disease. Repeat biopsy confirmed that no lymphoma remained, and he was in complete remission. Three months after completion of therapy, MRI continued to be abnormal. This case illustrates the unique challenges posed by the imaging characteristics of bone lymphoma, both during and after therapy. Biopsy is definitive but causes additional morbidity and may not be necessary. Imaging is done routinely to assess response to therapy, as with this patient, but in lymphomas of the bone imaging can be misleading and can lead to unnecessary procedures or follow-up imaging.

Severe Neuropathic Pain With Concomitant Administration of Vincristine and Posaconazole.

Vincristine is a chemotherapeutic agent with a potential toxicity of sensorimotor peripheral neuropathy. Patients receiving chemotherapy are in an immunocompromised state and may require antifungal agents. Triazole antifungals are known inhibitors of cytochrome P450 (CYP) enzymes. Vincristine is a known CYP3A4 and CYP3A5 substrate, and concomitant administration with fluconazole or voriconazole has been reported to increase vincristine toxicity and peripheral neuropathy, but there is limited literature on posaconazole in this regard. This 5-year-old girl with pre-B-cell acute lymphoblastic leukemia received vincristine while receiving posaconazole for a mucormycosis infection and developed unexpectedly severe peripheral neuropathy. After recovery, the child continued on mucormycosis prophylaxis with posaconazole with instructions to hold for 2 days before and on the day of vincristine administration. This case illustrates the potentiating effect that posaconazole had on vincristine-associated neurotoxicity, and our approach to mitigating that negative interaction.

Treatment of immune thrombocytopenic purpura associated with cytomegalovirus infection in a child with pre-B cell acute lymphoblastic leukaemia after central nervous system relapse.

A 13-year-old male patient with a history of pre-B cell acute lymphoblastic leukaemia (ALL) with isolated central nervous system relapse on maintenance chemotherapy presented with severe thrombocytopenia refractory to platelet transfusions. The patient showed only modest responses to two courses of intravenous immunoglobulin and steroids. He was found to be positive for cytomegalovirus (CMV) with modest viral load. His thrombocytopenia normalised with rituximab therapy and CMV treatment supporting the diagnosis of CMV-associated immune thrombocytopenic purpura (ITP). Following treatment, the patient continued to have a stable platelet count well above the threshold for transfusions. He continued to be intermittently treated for CMV when viral loads became detectable. This report discusses the unique management considerations of ITP in a patient undergoing therapy for ALL with a review of previously reported cases and discusses the possibility of CMV viraemia as a modulating factor.