Leukemic Optic Neuropathy in Pediatric Patients: A Case Series.

PURPOSE: To characterize the presentation, clinical course, and treatment of a series of children with leukemic optic neuropathy. METHODS: Patients with leukemia who were treated at a tertiary children's hospital for optic nerve infiltration were included (n = 11). Demographic information, cancer history, ophthalmologic examination findings, treatment, and outcomes were retrospectively collected. RESULTS: Mean age was 10.0 ± 4.8 years, and 63.6% were male and 36.4% were female. The most common underlying oncologic diagnosis was B-precursor acute lymphoblastic leukemia (n = 7, 63.6%). Notably, the majority presented with optic nerve infiltration during presumed remission (n = 9, 81.8%), but 2 patients (18.2%) presented with optic nerve infiltration at their initial leukemia diagnosis. Cerebrospinal fluid was positive for leukemic cells in 36.4% of patients. Magnetic resonance imaging demonstrated optic nerve enhancement and/or enlargement in only 8 patients (72.7%). In addition to other leukemia-directed treatment, 8 patients (72.7%) received emergent local radiation within 1.5 ± 1.2 days of initial ophthalmology examination. CONCLUSIONS: The largely negative cerebrospinal fluid results and variable magnetic resonance imaging findings in this study emphasize the importance of clinical context for this diagnosis. Clinicians should consider optic nerve infiltration in patients with leukemia and visual or ocular complaints, because urgent treatment is required to preserve vision and manage systemic disease. [J Pediatr Ophthalmol Strabismus. 2024;61(1):67-72.].

Intensive Multimodality Therapy for Extraocular Retinoblastoma: A Children's Oncology Group Trial (ARET0321).

PURPOSE: Metastatic retinoblastoma has a poor prognosis when treated with conventional chemotherapy and radiation therapy (RT). Intensified therapy may improve the outcome. METHODS: A prospective, international trial enrolled patients with extraocular retinoblastoma. Patients with stage II or III (locoregional) retinoblastoma received four cycles of chemotherapy, followed by involved field RT (45 Gy). Patients with stage IVa or IVb (metastatic or trilateral) retinoblastoma also received four cycles of chemotherapy and those with ≥ partial response then received one cycle of high-dose carboplatin, thiotepa, and etoposide with autologous hematopoietic stem-cell support. Patients with stage IVa or IVb with residual tumor postchemotherapy received RT. The proportion of patients who achieved event-free survival would be reported and compared with historical controls separately for each of the three groups of patients. RESULTS: Fifty-seven eligible patients were included in the analyses. Event-free survival at 1 year was 88.1% (90% CI, 66.6 to 96.2) for stage II-III, 82.6% (90% CI, 61.0 to 92.9) for stage IVa, and 28.3% (90% CI, 12.7 to 46.2) for stage IVb/trilateral. Toxicity was significant as expected and included two therapy-related deaths. CONCLUSION: Intensive multimodality therapy is highly effective for patients with regional extraocular retinoblastoma and stage IVa metastatic retinoblastoma. Although the study met its aim for stage IVb, more effective therapy is still required for patients with CNS involvement (ClinicalTrials.gov identifier: NCT00554788).

Pediatric Aggressive Mature B-Cell Lymphomas, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology.

Pediatric aggressive mature B-cell lymphomas are the most common types of non-Hodgkin lymphoma in children, and they include Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL). These diseases are highly aggressive but curable, the treatment is complex, and patients may have many complicated supportive care issues. The NCCN Guidelines for Pediatric Aggressive Mature B-Cell Lymphomas provide guidance regarding pathology and diagnosis, staging, initial treatment, disease reassessment, surveillance, therapy for relapsed/refractory disease, and supportive care for clinicians who treat sporadic pediatric BL and DLBCL.

Novel miRNA-31 and miRNA-200a-Mediated Regulation of Retinoblastoma Proliferation.

Retinoblastoma is the most common intraocular tumor in children. Current management includes broad-based treatments such as chemotherapy, enucleation, laser therapy, or cryotherapy. However, therapies that target specific pathways important for retinoblastoma progression could provide valuable alternatives for treatment. MicroRNAs are short, noncoding RNA transcripts that can regulate the expression of target genes, and their aberrant expression often facilitates disease. The identification of post-transcriptional events that occur after the initiating genetic lesions could further define the rapidly aggressive growth displayed by retinoblastoma tumors. In this study, we used two phenotypically different retinoblastoma cell lines to elucidate the roles of miRNA-31 and miRNA-200a in tumor proliferation. Our approach confirmed that miRNAs-31 and -200a expression is significantly reduced in human retinoblastomas. Moreover, overexpression of these two miRNAs restricts the expansion of a highly proliferative cell line (Y79), but does not restrict the growth rate of a less aggressive cell line (Weri1). Gene expression profiling of miRNA-31 and/or miRNA-200a-overexpressing cells identified differentially expressed mRNAs associated with the divergent response of the two cell lines. This work has the potential to enhance the development of targeted therapeutic approaches for retinoblastoma and improve the efficacy of treatment.

Salvage therapy of refractory hemophagocytic lymphohistiocytosis with alemtuzumab.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome that remains difficult to treat. Even with current standard HLH therapy, only approximately half of patients will experience complete resolution of disease, and early mortality remains a significant problem. Salvage therapies have been described only in limited case reports, and there are no large studies of second-line therapies. PROCEDURE: We reviewed the charts of 22 pediatric and adult patients who received alemtuzumab for the treatment of refractory HLH at our center or in consultation with our group. RESULTS: Patients had received conventional therapies for a median of 8 weeks (range: 2-70) prior to alemtuzumab, and treatment immediately prior to alemtuzumab included dexamethasone (100%), etoposide (77%), cyclosporine (36%), intrathecal hydrocortisone ± methotrexate (23%), methylprednisolone (9%), and rituximab (14%). Patients received a median dose of 1 mg/kg alemtuzumab (range: 0.1-8.9 mg/kg) divided over a median of 4 days (range: 2-10). Fourteen patients experienced an overall partial response, defined as at least a 25% improvement in two or more quantifiable symptoms or laboratory markers of HLH 2 weeks following alemtuzumab (64%). Five additional patients had a 25% or greater improvement in a single quantifiable symptom or laboratory marker of HLH (23%). Seventy-seven percent of patients survived to undergo allogeneic hematopoietic cell transplantation. Patients experienced an acceptable spectrum of complications, including CMV and adenovirus viremia. CONCLUSION: Alemtuzumab appears to be an effective salvage agent for refractory HLH, leading to improvement and survival to HCT in many patients. Prospective trials to define optimal dosing levels, schedules, and responses are needed.

Medical radiation exposure and risk of retinoblastoma resulting from new germline RB1 mutation.

Although ionizing radiation induces germline mutations in animals, human studies of radiation-exposed populations have not detected an effect. We conducted a case-control study of sporadic bilateral retinoblastoma, which results from a new germline RB1 mutation, to investigate gonadal radiation exposure of parents from medical sources before their child's conception. Parents of 206 cases from nine North American institutions and 269 controls participated; fathers of 184 cases and 223 friend and relative controls and mothers of 204 cases and 260 controls provided information in telephone interviews on their medical radiation exposure. Cases provided DNA for RB1 mutation testing. Of common procedures, lower gastrointestinal (GI) series conferred the highest estimated dose to testes and ovaries. Paternal history of lower GI series was associated with increased risk of retinoblastoma in the child [matched odds ratio (OR) = 3.6, 95% confidence interval (CI) = 1.2-11.2, two-sided p = 0.02], as was estimated total testicular dose from all procedures combined (OR for highest dose=3.9, 95% CI = 1.2-14.4, p = 0.02). Maternal history of lower GI series was also associated with increased risk (OR = 7.6, 95% CI = 2.8-20.7, p < 0.001) as was the estimated total dose (OR for highest dose = 3.0, 95% CI = 1.4-7.0, p = 0.005). The RB1 mutation spectrum in cases of exposed parents did not differ from that of other cases. Some animal and human data support our findings of an association of gonadal radiation exposure in men and women with new germline RB1 mutation detectable in their children, although bias, confounding, and/or chance may also explain the results.

Sudden dispersion of retinoblastoma shortly after initial chemotherapy treatment.

PURPOSE: To present 3 cases of unilateral retinoblastoma that demonstrated unusual tumor dispersion shortly after initial chemotherapy treatment. DESIGN: Observational case series. METHODS: Review of medical records of patients in whom intraocular dissemination of retinoblastoma occurred after initial treatment with chemotherapy. RESULTS: Three patients demonstrated an atypical response with intraocular dissemination of retinoblastoma shortly after 1 cycle of chemotherapy. All cases had unilateral retinoblastoma with no vitreous seeding or subretinal fluid at presentation. In 2 cases (Cases 2 and 3), there were a few distant subretinal seeds. Per the International Classification of Retinoblastoma, 1 tumor was group E (Case 1), and the other 2 tumors were group D1 (Cases 2 and 3). In 2 cases (Cases 1 and 2), chemotherapy included a 2-drug regimen of carboplatin and etoposide; in the third case, a 3-drug regimen of carboplatin, etoposide, and vincristine was used. In each case, the retinoblastoma dispersed with tumor cells in the vitreous shortly after initial chemotherapy treatment, leading to subsequent enucleation of the eye. CONCLUSIONS: Retinoblastoma can exhibit an unexpected and sudden dispersion of the tumor shortly after chemotherapy is initiated.

Outcomes of a two-drug chemotherapy regimen for intraocular retinoblastoma.

BACKGROUND: Retinoblastoma is the most common intraocular tumor of childhood. Vision salvage rates in advanced cases are less than ideal, and the optimal treatment for intraocular retinoblastoma has not been established. We report the results of an institutional retinoblastoma treatment trial to determine the vision salvage rates and toxicity of a regimen combining carboplatin and etoposide with focal retinal therapy. PROCEDURE: Twenty-nine patients diagnosed with retinoblastoma in 48 eyes were treated between 1992 and 2004 with at least six cycles of carboplatin and etoposide combined with focal retinal therapy. RESULTS: The response rate of eyes after six cycles of chemotherapy was 85.4%. Twenty-two eyes were enucleated, but only seven eyes received EBRT. The vision salvage rate without EBRT was 82.6% for eyes with Reese-Ellsworth (R-E) groups I-IV tumors and 20% for eyes with R-E group V tumors. The vision salvage rate without EBRT for eyes with Murphree groups A and B tumors was 77.3% but was only 26.9% for eyes with groups C and D tumors. Acute side effects were minimal. CONCLUSIONS: The combination of carboplatin and etoposide with focal therapy is a well-tolerated regimen that has acceptable vision salvage rates for R-E groups I-IV and Murphree groups A and B retinoblastoma. This combination avoids the use of EBRT and the toxicity of additional chemotherapy agents. However, patients with R-E group V and Murphree groups C and D retinoblastoma have poorer outcomes and require more intensive therapy.

Advances in the diagnosis and treatment of neuroblastoma.

Neuroblastoma, a childhood neoplasm arising from neural crest cells, is characterized by a diversity of clinical behavior ranging from spontaneous remission to rapid tumor progression and death. To a large extent, outcome can be predicted by the stage of disease and the age at diagnosis. However, the molecular events responsible for the variability in response to treatment and the rate of tumor growth remain largely unknown. Over the past decade, transformation-linked genetic changes have been identified in neuroblastoma tumors that have contributed to the understanding of tumor predisposition, metastasis, treatment responsiveness, and prognosis. The Children's Oncology Group recently developed a Neuroblastoma Risk Stratification System that is currently in use for treatment stratification purposes, based on clinical and biologic factors that are strongly predictive of outcome. This review discusses the current risk-based treatment approaches for children with neuroblastoma and recent advances in biologic therapy.