Background
Embryonal tumor with multilayered rosettes (ETMR) is a deadly grade IV pediatric brain tumor. Despite an intensive multimodal treatment approach that includes surgical resection, high‐dose ...chemotherapy, and radiotherapy, the progression‐free survival at 5 years is less than 30%.
Case
We report a case of long‐term survival in a 5‐month old female with a large mass in the posterior fossa, diagnosed as ETMR, which subsequently underwent treatment‐induced maturation. Prior to chemotherapy, histopathology revealed an abundance of highly proliferative, undifferentiated cells and multilayered rosette structures. Conversely, post‐treatment histopathology revealed cell populations that differentiated into neuronal and ganglionic phenotypes. At 5‐year follow‐up, the patient remains progression‐free.
Conclusion
This finding contributes to the few reports to date of post‐treatment differentiation/maturation of ETMR cell populations, with an implication for less cytotoxic therapeutic interventions aimed at differentiation.
Abstract
Embryonal tumor with multilayer rosettes (ETMR) is a rare and highly-aggressive CNS neoplasm which occurs almost exclusively in young children and is associated with an extremely poor ...prognosis. Due to the rare nature of ETMR and its recent classification, no large clinical investigations have been conducted to determine the optimal therapy for these tumors. Historical data suggests that extensive surgical resection, radiotherapy, and high-dose chemotherapy are not sufficient treatment in the vast majority of cases with a reported 1-year EFS of 36% and 1-year OS of 45% using these approaches. New treatment regimens incorporating the known biology of ETMR must be investigated. Pre-clinical drug screens using the ETMR BT183 cell line and its xenograft have demonstrated responses to the chemotherapy agents topotecan, doxorubicin, and actinomycin D. Based on this data, a modified IRS-III chemotherapy regimen incorporating these active agents was developed and a small cohort of four children with ETMR were then treated. Three patients completed therapy without subsequent relapse and have EFS of >30 months. The ETMR One international registry and its associated consensus treatment protocol represent the first prospective evaluation of treatment outcomes for children with ETMR. The consensus regimen involves maximal feasible surgical resection, modified IRS-III chemotherapy, high-dose chemotherapy with autologous stem cell rescue, and radiotherapy (as indicated). Patients enrolled on the registry will have their cases periodically reviewed by a medical advisory board that will offer management recommendations, particularly regarding the use of radiotherapy or the need for additional surgical interventions. Through the procurement of patient tumor samples and development of additional cell lines and xenografts, the registry aims to serve as a platform for translational research. Pre-clinical findings will be used to modify the consensus protocol therapy as indicated or to generate additional biology-based phase I/II trials for ETMR.
Abstract
mRNA vaccines were the first to be authorized for use against SARS-CoV-2 and have since demonstrated high efficacy against serious illness and death. However, limitations in these vaccines ...have been recognized due to their requirement for cold storage, short durability of protection, and lack of access in low-resource regions. We have developed an easily-manufactured, potent self-amplifying RNA (saRNA) vaccine against SARS-CoV-2 that is stable at room temperature. This saRNA vaccine is formulated with a nanostructured lipid carrier (NLC), providing stability, ease of manufacturing, and protection against degradation. In preclinical studies, this saRNA/NLC vaccine induced strong humoral immunity, as demonstrated by high pseudovirus neutralization titers to the Alpha, Beta, and Delta variants of concern and induction of bone marrow-resident antibody-secreting cells. Robust Th1-biased T-cell responses were also observed after prime or homologous prime-boost in mice. Notably, the saRNA/NLC platform demonstrated thermostability when stored lyophilized at room temperature for at least 6 months and at refrigerated temperatures for at least 10 months. Taken together, this saRNA delivered by NLC represents a potential improvement in RNA technology that could allow wider access to RNA vaccines for the current COVID-19 and future pandemics.
Abstract
INTRODUCTION
There are few treatment options for pediatric patients with high grade gliomas Adult patients with newly diagnosed or recurrent glioblastoma multiforme have the option of ...treatment with tumor treating fields (TTFields), which have shown efficacy and safety in Phase 3 randomized trials. TTFields are a noninvasive anti-mitotic therapy administered via transducer arrays strategically arranged on the shaved scalp. TTFields are not approved for the treatment of high grade glioma in pediatric patients. Post-marketing surveillance data were collected for pediatric glioma patients receiving TTFields. Compiled safety data are presented for patients <18 years receiving TTFields for the treatment of glioma.
METHODS
A review of the clinical information for pediatric patients (<18 years of age) treated with TTFields in the United States and Europe identified 30 patients. The safety data obtained from post-market surveillance in all 30 patients were analyzed to identify adverse events (AEs) based on the MedDRA body system (system organ class) preferred terms.
RESULTS
Sixteen (53%) pediatric patients experienced at least 1 AE while receiving TTFields treatment. Patients reported general AEs include: electric sensations in 10% (3/30); fatigue in 10% (3/30), heat sensation in 10% (3/30) and 17% reported pain (5/30) in any location. Nervous system AEs included headache (10%), seizure (7%) and balance disorder (7%). The most common AE were skin reactions that were reported by 7 patients (23%). One patient reported hyperhidrosis (3%). CONCLUSIONS: There were no unexpected AEs associated with TTFields in pediatric patients. The most frequently reported AEs were skin reactions likely related to the placement of TTFields transducers on the scalp; incidence was comparable to the rate of skin reactions reported in adult GBM patients. The tolerability of TTFields in pediatric patients from this post-marketing surveillance data support further investigations to assess efficacy and safety of TTFields in pediatric glioma patients.
Abstract
High-grade gliomas (HGG) comprise 8–12% of brain tumors in children and include anaplastic astrocytoma or glioblastoma multiforme (GBM) pathology. Ependymoma is the third most common ...pediatric brain tumor accounting for 5–10% of all diagnoses. Treatment for these tumors involves surgical resection, adjuvant radiation and chemotherapy. The prognosis for high-grade glioma and recurrent ependymoma is poor and new therapies must be investigated to improve clinical outcomes for these patient populations. Tumor treating Fields (TTFs) is a non-invasive antimitotic treatment comprised of low-intensity alternating electric currents delivered through the Optune device approved for adults with GBM. This phase 1 study NCT03128047 will include 2 cohorts of pediatric patients (N= 6–12), age ≥1 and <18 years, with histologically-confirmed supratentorial newly-diagnosed or recurrent HGG and recurrent ependymoma. This study will have two safety endpoints to assess the safety and tolerability of TTFs for the treatment of pediatric HGG and ependymoma both alone and in combination with temozolomide (TMZ) and bevacizumab (BEV). Cohort 1 patients with recurrent HGG or ependymoma will receive TTFs (200 kHz 18 hours/day). Cohort 2 patients with newly-diagnosed or recurrent HGG or recurrent ependymoma will receive TTFs plus BEV 10 mg/kg/dose and TMZ 200 mg/m2/day. Safety endpoints will be determined by a standard 3 + 3 phase I study design based on the incidence and severity of adverse events and toxicities (CTCAE V4). There are no primary efficacy endpoints for this study. Patients will be followed to assess their progression-free and overall survival as the efficacy data gained from this study may be useful in designing future phase II/III investigations. The sample size will be determined by the number of observed severe adverse events related to therapy. A minimum of two and a maximum of twelve patients will be needed to complete this study.
Abstract
High-grade gliomas (HGG) comprise 8–12% of brain tumors in children and include anaplastic astrocytoma or glioblastoma multiforme (GBM) pathology. Treatment involves surgical resection, ...adjuvant radiation and chemotherapy. The prognosis of these tumors is poor and new therapies must be investigated to improve clinical outcomes for this patient population. Tumor Treating Fields (TTFs) is a non-invasive antimitotic treatment comprised of low-intensity alternating electric currents delivered through the Optune device approved for adults with GBM. This phase 1 study NCT03128047 will include 2 cohorts of pediatric patients (N= 6–12), age ≥1 and <18 years, with histologically-confirmed supratentorial newly-diagnosed or recurrent HGG. This study will have two safety endpoints to assess the safety and tolerability of TTFields for the treatment of pediatric HGG both alone and in combination with temozolomide (TMZ) and bevacizumab (BEV). Cohort 1 will receive TTFields (200kHz 18 hours/day). Cohort 2 will receive TTFs plus BEV 10mg/kg/dose and TMZ 200 mg/m2/day. Safety endpoints will be determined by a standard 3 + 3 phase I study design based on the incidence and severity of adverse events and toxicities (CTC V4). There are no primary efficacy endpoints for this study. Patients will be followed to assess their progression-free and overall survival as the efficacy data gained from this study may be useful in designing future phase II/III investigations. The sample size will be determined by the number of observed severe adverse events related to therapy. A minimum of two and a maximum of twelve patients will be needed to complete this study.
Pediatric neurological tumors are a heterogeneous group of cancers, many of which carry a poor prognosis and lack a "standard of care" therapy. While they have similar anatomic locations, pediatric ...neurological tumors harbor specific molecular signatures that distinguish them from adult brain and other neurological cancers. Recent advances through the application of genetics and imaging tools have reshaped the molecular classification and treatment of pediatric neurological tumors, specifically considering the molecular alterations involved. A multidisciplinary effort is ongoing to develop new therapeutic strategies for these tumors, employing innovative and established approaches. Strikingly, there is increasing evidence that lipid metabolism is altered during the development of these types of tumors. Thus, in addition to targeted therapies focusing on classical oncogenes, new treatments are being developed based on a broad spectrum of strategies, ranging from vaccines to viral vectors, and melitherapy. This work reviews the current therapeutic landscape for pediatric brain tumors, considering new emerging treatments and ongoing clinical trials. In addition, the role of lipid metabolism in these neoplasms and its relevance for the development of novel therapies are discussed.
Background
Survival for patients with high‐risk neuroblastoma (HRNB) remains poor despite aggressive multimodal therapies.
Aims
To study the feasibility and safety of incorporating a genomic‐based ...targeted agent to induction therapy for HRNB as well as the feasibility and safety of adding difluoromethylornithine (DFMO) to anti‐GD2 immunotherapy.
Methods
Twenty newly diagnosed HRNB patients were treated on this multicenter pilot trial. Molecular tumor boards selected one of six targeted agents based on tumor‐normal whole exome sequencing and tumor RNA‐sequencing results. Treatment followed standard upfront HRNB chemotherapy with the addition of the selected targeted agent to cycles 3–6 of induction. Following consolidation, DFMO (750 mg/m2 twice daily) was added to maintenance with dinutuximab and isotretinoin, followed by continuation of DFMO alone for 2 years. DNA methylation analysis was performed retrospectively and compared to RNA expression.
Results
Of the 20 subjects enrolled, 19 started targeted therapy during cycle 3 and 1 started during cycle 5. Eighty‐five percent of subjects met feasibility criteria (receiving 75% of targeted agent doses). Addition of targeted agents did not result in toxicities requiring dose reduction of chemotherapy or permanent discontinuation of targeted agent. Following standard consolidation, 15 subjects continued onto immunotherapy with DFMO. This combination was well‐tolerated and resulted in no unexpected adverse events related to DFMO.
Conclusion
This study demonstrates the safety and feasibility of adding targeted agents to standard induction therapy and adding DFMO to immunotherapy for HRNB. This treatment regimen has been expanded to a Phase II trial to evaluate efficacy.
Myeloma (MM) cells and osteoclasts are mutually interacted to enhance MM growth while creating acidic bone lesions. Here, we explored acid sensing of MM cells and its role in MM cell response to ...acidic conditions. Acidic conditions activated the PI3K-Akt signaling in MM cells while upregulating the pH sensor transient receptor potential cation channel subfamily V member 1 (TRPV1) in a manner inhibitable by PI3K inhibition. The acid-activated PI3K-Akt signaling facilitated the nuclear localization of the transcription factor Sp1 to trigger the expression of its target genes, including TRPV1 and HDAC1. Consistently, histone deacetylation was enhanced in MM cells in acidic conditions, while repressing a wide variety of genes, including DR4. Indeed, acidic conditions deacetylated histone H3K9 in a DR4 gene promoter and curtailed DR4 expression in MM cells. However, inhibition of HDAC as well as either Sp1 or PI3K was able to restore DR4 expression in MM cells suppressed in acidic conditions. These results collectively demonstrate that acid activates the TRPV1-PI3K-Akt-Sp1 signaling in MM cells while inducing HDAC-mediated gene repression, and suggest that a positive feedback loop between acid sensing and the PI3K-Akt signaling is formed in MM cells, leading to MM cell response to acidic bone lesions.
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