Use of Maribavir for Multidrug Resistant Cytomegaloviremia in a Pediatric Oncology Patient.

Resistant and refractory cytomegalovirus (CMV) viremia can limit the provision of chemotherapy due to myelosuppression and end-organ dysfunction. Few therapies are available for children with clinically significant CMV viremia. We successfully used maribavir for a 4-year-old patient with lymphoma to complete his chemotherapy course. Resistance to maribavir did result after many months of therapy.

Extracranial medulloepithelioma: a review of the literature.

PURPOSE: Medulloepithelioma is a rare, malignant tumor that typically arises in the periventricular region of the cerebral hemispheres or the ciliary body of the eye. Even rarer still is the extracranial manifestation of medulloepithelioma with only 12 cases reported to date. Our purpose is to report a case of an intradural, extra-medullary medulloepithelioma and review the limited literature about diagnosis and treatment of this extremely rare pathology. METHODS: PubMed was queried using search terms "peripheral medulloepithelioma" and "pre-sacral medulloepithelioma." Medulloepitheliomas which were intraocular or occurred in reproductive organs were excluded. Patients' age, sex, the symptomatic period prior to diagnosis, primary tumor site, stage, treatment regimen, pathologic description, and survival outcomes were collected. RESULTS: We present a case of extracranial medulloepithelioma in an 8-year-old male. Morphology of the neoplasm was representative of medulloepithelioma but there was no amplification of C19MC. Additionally, the neoplasm stained positive for CD99. Twelve other cases of extracranial medulloepithelioma were found in literature review. CONCLUSIONS: The rarity of extracranial medulloepithelioma makes for a challenging diagnosis. Designing an optimal treatment strategy is difficult because of a scarcity of cases and wide variety in locations and treatments. Our case provides an example of treatment including resection, intense induction chemotherapy, consolidation with high-dose chemotherapy and stem cell rescue, craniospinal proton radiation therapy, and metronomic chemotherapy.

The potential global distribution of the papaya mealybug, Paracoccus marginatus, a polyphagous pest.

BACKGROUND: The papaya mealybug, Paracoccus marginatus, is a highly polyphagous invasive pest that affects more than 200 plants, many of which are of economic importance. We modelled the potential distribution of P. marginatus using CLIMEX, a process-oriented, climate-based niche model. We combined this model with spatial data on irrigation and cropping patterns to increase the real-world applicability of the model. RESULTS: The resulting model agreed with known distribution points for this pest and with broad areas where P. marginatus has been reported, but for which no GPS data were available. Our model highlights the potential expansion of P. marginatus into novel areas in Central and East Africa, as well as further expansion in Central America and Asia, as these areas are highly climatically suitable, and have large expanses of suitable crop hosts. It also highlights areas, such as the central and eastern states of the USA as well as the western provinces of China, that are suitable for seasonal invasions of P. marginatus. CONCLUSION: Our results offer refined resolution on areas with high potential for invasion by P. marginatus. © 2020 Society of Chemical Industry.

Outcomes of BRAF V600E Pediatric Gliomas Treated With Targeted BRAF Inhibition.

PURPOSE: Children with pediatric gliomas harboring a BRAF V600E mutation have poor outcomes with current chemoradiotherapy strategies. Our aim was to study the role of targeted BRAF inhibition in these tumors. PATIENTS AND METHODS: We collected clinical, imaging, molecular, and outcome information from patients with BRAF V600E-mutated glioma treated with BRAF inhibition across 29 centers from multiple countries. RESULTS: Sixty-seven patients were treated with BRAF inhibition (pediatric low-grade gliomas [PLGGs], n = 56; pediatric high-grade gliomas [PHGGs], n = 11) for up to 5.6 years. Objective responses were observed in 80% of PLGGs, compared with 28% observed with conventional chemotherapy (P < .001). These responses were rapid (median, 4 months) and sustained in 86% of tumors up to 5 years while receiving therapy. After discontinuation of BRAF inhibition, 76.5% (13 of 17) of patients with PLGG experienced rapid progression (median, 2.3 months). However, upon rechallenge with BRAF inhibition, 90% achieved an objective response. Poor prognostic factors in conventional therapies, such as concomitant homozygous deletion of CDKN2A, were not associated with lack of response to BRAF inhibition. In contrast, only 36% of those with PHGG responded to BRAF inhibition, with all but one tumor progressing within 18 months. In PLGG, responses translated to 3-year progression-free survival of 49.6% (95% CI, 35.3% to 69.5%) versus 29.8% (95% CI, 20% to 44.4%) for BRAF inhibition versus chemotherapy, respectively (P = .02). CONCLUSION: Use of BRAF inhibition results in robust and durable responses in BRAF V600E-mutated PLGG. Prospective studies are required to determine long-term survival and functional outcomes with BRAF inhibitor therapy in childhood gliomas.

NCI-CONNECT: Comprehensive Oncology Network Evaluating Rare CNS Tumors-Histone Mutated Midline Glioma Workshop Proceedings.

Histone mutations occur in approximately 4% of different cancer types. In 2012, mutations were found in the gene encoding histone variant H3.3 (H3F3A gene) in pediatric diffuse intrinsic pontine gliomas and pediatric hemispheric gliomas. Tumors with mutations in the H3F3A gene are generally characterized as histone mutated gliomas (HMGs) or diffuse midline gliomas. HMGs are a rare subtype of glial tumor that is malignant and fast growing, carrying a poor prognosis. In 2017, the Beau Biden Cancer Moonshot Program appropriated $1.7 billion toward cancer care in 10 select areas. The National Cancer Institute (NCI) was granted support to focus specifically on rare central nervous system (CNS) tumors through NCI-CONNECT. Its mission is to address the challenges and unmet needs in CNS cancer research and treatment by connecting patients, providers, researchers, and advocacy organizations to work in partnership. On September 27, 2018, NCI-CONNECT convened a workshop on histone mutated midline glioma, one of the 12 CNS cancers included in its initial portfolio. Three leaders in the field provided an overview of advances in histone mutated midline glioma research. These experts shared observations and experiences related to common scientific and clinical challenges in studying these tumors. Although the clinical focus of this workshop was on adult patients, one important objective was to start a collaborative dialogue between pediatric and adult clinicians and researchers. Meeting participants identified needs for diagnostic and treatment standards, disease biology and biological targets for this cancer, disease-specific trial designs, and developed a list of action items and future direction.

Immunotherapy Approaches for Pediatric CNS Tumors and Associated Neurotoxicity.

Treatment for brain tumors has recently shifted to using the power of the immune system to destroy cancer cells with promising results. Many immunotherapeutic approaches that have been used in adults, including checkpoint inhibitors, vaccine therapy, adoptive immunotherapy, such as chimeric antigen receptor T cell therapy, and viral therapy, are now being evaluated in children. Although these treatments work through different mechanisms, they all activate the immune system and can result in inflammation at the site of disease. This can be especially problematic in the confined area of the brain causing potentially severe neurological side effects, which are of special concern in children with central nervous system malignancies. Steroids can be helpful in the management of neurological complications but carry the risk of making immunotherapeutic approaches less effective. Alternative therapeutic interventions to mitigate side effects are being evaluated. This review describes the most common immunotherapeutic modalities that are now under study for the treatment of pediatric brain tumors, their rationale, associated neurotoxicities, and current management.

Long-term Efficacy of Single-agent Vemurafenib for Pleomorphic Xanthoastrocytoma.

Pleomorphic xanthoastrocytoma is a malignant brain tumor that has a good prognosis with complete resection but does not respond well to chemotherapy if there is residual tumor. BRAF V600E mutations are common in pleomorphic xanthoastrocytomas and provide an additional means for treatment when excision is not possible. Monotherapy with the BRAF V600E inhibitor vemurafenib has only been reported in a small number of cases and mostly in adults. We present the case of a 16-year-old male who responded to vemurafenib monotherapy initially and had an additional response to vemurafenib following progression after a brief time off the medication.

Therapeutic and Prognostic Implications of BRAF V600E in Pediatric Low-Grade Gliomas.

Purpose BRAF V600E is a potentially highly targetable mutation detected in a subset of pediatric low-grade gliomas (PLGGs). Its biologic and clinical effect within this diverse group of tumors remains unknown. Patients and Methods A combined clinical and genetic institutional study of patients with PLGGs with long-term follow-up was performed (N = 510). Clinical and treatment data of patients with BRAF V600E mutated PLGG (n = 99) were compared with a large international independent cohort of patients with BRAF V600E mutated-PLGG (n = 180). Results BRAF V600E mutation was detected in 69 of 405 patients (17%) with PLGG across a broad spectrum of histologies and sites, including midline locations, which are not often routinely biopsied in clinical practice. Patients with BRAF V600E PLGG exhibited poor outcomes after chemotherapy and radiation therapies that resulted in a 10-year progression-free survival of 27% (95% CI, 12.1% to 41.9%) and 60.2% (95% CI, 53.3% to 67.1%) for BRAF V600E and wild-type PLGG, respectively ( P < .001). Additional multivariable clinical and molecular stratification revealed that the extent of resection and CDKN2A deletion contributed independently to poor outcome in BRAF V600E PLGG. A similar independent role for CDKN2A and resection on outcome were observed in the independent cohort. Quantitative imaging analysis revealed progressive disease and a lack of response to conventional chemotherapy in most patients with BRAF V600E PLGG. Conclusion BRAF V600E PLGG constitutes a distinct entity with poor prognosis when treated with current adjuvant therapy.

STIM1-Ca(2+) signaling is required for the hypertrophic growth of skeletal muscle in mice.

Immediately after birth, skeletal muscle must undergo an enormous period of growth and differentiation that is coordinated by several intertwined growth signaling pathways. How these pathways are integrated remains unclear but is likely to involve skeletal muscle contractile activity and calcium (Ca(2+)) signaling. Here, we show that Ca(2+) signaling governed by stromal interaction molecule 1 (STIM1) plays a central role in the integration of signaling and, therefore, muscle growth and differentiation. Conditional deletion of STIM1 from the skeletal muscle of mice (mSTIM1(-/-) mice) leads to profound growth delay, reduced myonuclear proliferation, and perinatal lethality. We show that muscle fibers of neonatal mSTIM1(-/-) mice cannot support the activity-dependent Ca(2+) transients evoked by tonic neurostimulation, even though excitation contraction coupling (ECC) remains unperturbed. In addition, disruption of tonic Ca(2+) signaling in muscle fibers attenuates downstream muscle growth signaling, such as that of calcineurin, mitogen-activated protein (MAP) kinases, extracellular signal-regulated kinase 1 and 2 (ERK1/2), and AKT. Based on our findings, we propose a model wherein STIM1-mediated store-operated calcium entry (SOCE) governs the Ca(2+) signaling required for cellular processes that are necessary for neonatal muscle growth and differentiation.