Tumors Of Peripheral Nervous System Research Articles

Low-grade glioma in children with neurofibromatosis type 1: surveillance, treatment indications, management, and future directions.

Neurofibromatosis type 1 (NF1) is an autosomal dominant cancer predisposition syndrome characterized by the development of both central and peripheral nervous system tumors. Low-grade glioma (LGG) is the most prevalent central nervous system tumor occurring in children with NF1, arising most frequently within the optic pathway, followed by the brainstem. Historically, treatment of NF1-LGG has been limited to conventional cytotoxic chemotherapy and surgery. Despite treatment with chemotherapy, a subset of children with NF1-LGG fail initial therapy, have a continued decline in function, or recur. The recent development of several preclinical models has allowed for the identification of novel, molecularly targeted therapies. At present, exploration of these novel precision-based therapies is ongoing in the preclinical setting and through larger, collaborative clinical trials. Herein, we review the approach to surveillance and management of NF1-LGG in children and discuss upcoming novel therapies and treatment protocols.

Biological Implications and Functional Significance of Transglutaminase Type 2 in Nervous System Tumors.

Transglutaminase type 2 (TG2) is the most ubiquitously expressed member of the transglutaminase family. TG2 catalyzes the transamidation reaction leading to several protein post-translational modifications and it is also implicated in signal transduction thanks to its GTP binding/hydrolyzing activity. In the nervous system, TG2 regulates multiple physiological processes, such as development, neuronal cell death and differentiation, and synaptic plasticity. Given its different enzymatic activities, aberrant expression or activity of TG2 can contribute to tumorigenesis, including in peripheral and central nervous system tumors. Indeed, TG2 dysregulation has been reported in meningiomas, medulloblastomas, neuroblastomas, glioblastomas, and other adult-type diffuse gliomas. The aim of this review is to provide an overview of the biological and functional relevance of TG2 in the pathogenesis of nervous system tumors, highlighting its involvement in survival, tumor inflammation, differentiation, and in the resistance to standard therapies.

Neurofibromatosis type 1 and pneumoconiosis: A case report on a coincidence.

Neurofibromatosis (NF) is a neurocutaneous syndrome characterized by the development of central or peripheral nervous system tumors. The most common form, known as NF1 or Von Recklinghausen's disease, presents with distinct clinical features, including cutaneous and ocular manifestations, along with various other organ and systemic symptoms. While the lung findings associated with neurofibromatosis lack specificity, they can include parenchymal cysts and bullae formation, primarily in the upper-apical regions. Additionally, progressive fibrotic changes, such as ground-glass areas, consolidations, and paving stone patterns, may manifest in the basal parts of the lungs. In this case report, a case of NF1 diagnosed in adulthood and accompanying pneumoconiosis was discussed as a coincidence.

Specifics of spinal neuropathology in the molecular age

Abstract Tumors located in the spinal cord and its coverings can be diagnostically challenging and require special consideration regarding treatment options. During the last decade, important advances regarding the molecular characterization of central and peripheral nervous system tumors were achieved, resulting in improved diagnostic precision, and understanding of the tumor spectrum of this compartment. In particular, array-based global DNA methylation profiling has emerged as a valuable tool to delineate biologically and clinically relevant tumor subgroups and has been incorporated in the current WHO classification for central nervous system tumors of 2021. In addition, several genetic drivers have been described, which may also help to define distinct tumor types and subtypes. Importantly, the current molecular understanding not only sharpens diagnostic precision but also provides the opportunity to investigate both targeted therapies as well as risk-adapted changes of treatment intensity. Here, we discuss the current knowledge and the clinical relevance of molecular neuropathology in spinal tumor entities.

Cancer Predisposition Syndromes in Neuro-oncology.

Although most primary central and peripheral nervous system (NS) tumors occur sporadically, there are a subset that may arise in the context of a cancer predisposition syndrome. These syndromes occur due to a pathogenic mutation in a gene that normally functions as a tumor suppressor. With increased understanding of the molecular pathogenesis of these tumors, more people have been identified with a cancer predisposition syndrome. Identification is crucial, as this informs surveillance, diagnosis, and treatment options. Moreover, relatives can also be identified through genetic testing. Although there are many cancer predisposition syndromes that increase the risk of NS tumors, in this review, we focus on three of the most common cancer predisposition syndromes, neurofibromatosis type 1, neurofibromatosis type 2, and tuberous sclerosis complex type 1 and type 2, emphasizing the clinical manifestations, surveillance guidelines, and treatment options.

Management of Central and Peripheral Nervous System Tumors in Patients with Neurofibromatosis.

Neurofibromatosis type I (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis represent a diverse group of genetic tumor predisposition syndromes with a shared feature of tumors affecting the peripheral nerve sheaths. PURPOSE OF REVIEW: Many advancements have been made in understanding the biologic underpinnings of these conditions, and in 2016 the first drug was approved by the FDA to treat pediatric symptomatic unresectable plexiform neurofibromas. RECENT FINDINGS: Mek inhibitors have provided a much-needed therapeutic avenue for NF1 patients with unresectable plexiform neurofibromas (PN), both for reduction of tumor bulk and for improvement in symptoms. Selumetinib is the first FDA approved drug for PN, but is only approved for children. Some research suggests that alternative Mek inhibitors and other mixed tyrosine kinase inhibitors may have better efficacy in adults. Vascular endothelial growth factor (VEGF) inhibitor bevacizumab can prolong hearing and delay the need for surgery in NF2 patients with bilateral vestibular schwannomas. This article provides an update regarding considerations and approaches when treating the tumors associated with the neurofibromatoses (NF), including risk and prognosis metrics, clinical trial results, surgical techniques, and radiation therapy recommendations.

Management of neurofibromatosis type 1 associated tumors of central and peripheral nervous system.

In recent years emerging evidence suggests that some tumor types, extremely rare in general population and understudied, can be observed in NF1 and neoplasms related with this condition harbor peculiar genetic and epigenetic features. The aim of this review is to summarize recent advances that, delving into the tumor complexity, have identified new diagnostic tools and potential tumor subtype that may have been associated with clinical implications. The available data confirmed the presence of peculiar molecular signatures in those tumors, different from those observed in sporadic neoplasms and suggest that a specific reference to NF1 associated neoplasms would deserve to be mentioned in tumor WHO classification. Comprehensive multiomic analysis shows that the histologic assessment does not always match the methylation group assignment and facilitates tumor subclassification into categories predictive of clinical behavior. The non-invasive assessment of tumor genetic profiles by the analysis of plasma ctDNA is representative of tumor features, may help differential diagnosis and may identify malignant transformation, sparing the patient from repeated biopsies. A better knowledge of NF1 associated tumors at the molecular level may suggest changes in the clinical management of the disease and open new frontiers of personalized treatment.

Lower extremity peripheral nerve pathology: Utility of preoperative ultrasound-guided needle localization before operative intervention.

Historically, the use of ultrasound (US) in the management of peripheral nervous system (PNS) pathology has been limited to diagnostic confirmation or guidance for interventional injections. This technical case series will demonstrate the utility and versatility of preoperative US-guided needle localization for the excision of lower extremity neuromas and other pathology of the PNS. Five patients with symptomatic lower extremity PNS tumors were retrospectively reviewed. This case series corroborates the technical nuances of localizing lower extremity neuromas by US-guided needle and wire placement prior to operative excision. This was achieved by a multidisciplinary team that included plastic surgery, neurosurgery, and radiology. Five patients had US-guided needle localization of a lower extremity PNS target prior to operative intervention. Three patients had lower extremity neuromas of varying origins, including the lateral femoral cutaneous nerve (LFCN), saphenous nerve, and sural nerve. The remaining two patients had a sciatic nerve sheath Schwannoma and a femoral nerve glomus tumor. Under sonographic visualization, a needle was advanced to the target perimeter and withdrawn, leaving behind a percutaneous guidewire. This technique simplified the marking of the nerve course prior to dissection and led to efficient intraoperative identification of all five PNS tumors without any complications. Preoperative US-guided needle localization led to safe, accurate, and efficient perioperative and intraoperative identification of neuromas and other PNS tumors of the lower extremity prior to excision. By reducing the challenges of nerve identification in a scarred tissue bed, this multidisciplinary approach may decrease postoperative patient morbidity.

Combined exploratory laparotomy, transpsoas, and thoracic approach to resection of a giant spinal ganglioneuroma: illustrative case.

Ganglioneuromas are rare peripheral nervous system tumors of neural crest origin. Most are often asymptomatic and incidentally found, but large tumors can cause mass effect. Herein, the authors report a case of a giant ganglioneuroma that arose from the lumbar foramina into the retroperitoneal and thoracic cavities. A 62-year-old female presented with low back pain, left lower extremity swelling, and increased sensation of an abdominal mass. Surgical treatment options were reviewed with the patient and coordinated care was planned by surgical oncological specialists. The patient opted for multistage exploratory laparotomy for abdominal mobilization, diaphragm resection, and en bloc resection with neuromonitoring. After surgery, the patient experienced significant improvement in symptoms. A combined surgical exposure involving gastrointestinal, thoracic, and neurological surgeons can be important in the safe resection of ganglioneuromas that span multiple body cavities. Hence, a thorough preoperative assessment could help plan surgery accordingly.

Thromboembolic toxicity observed with concurrent trametinib and lenalidomide therapy.

The event-free survival of pediatric low-grade gliomas is poor, and patients often require multiple treatment strategies. While MEK and RAF inhibitors are efficacious in early-phase trials, not all patients respond, and many experience progression following completion of therapy. Evaluating combination therapies that may enhance efficacy or prolong disease stabilization is warranted. We report our institutional experience using concurrent trametinib and lenalidomide in the treatment of primary pediatric central and peripheral nervous system tumors. Two of four patients using this combination therapy experienced severe thromboembolic events, necessitating discontinuation of therapy. This combination requires further investigation, and we urge caution if used.

Low-pass whole-genome and targeted sequencing of cell-free DNA from cerebrospinal fluid in pediatric patients with central nervous system tumors.

Central nervous system tumors are the most common pediatric solid tumors and the most frequent cause of cancer-related morbidity in childhood. Significant advances in understanding the molecular features of these tumors have facilitated the development of liquid biopsy assays that may aid in diagnosis and monitoring response to therapy. In this report, we describe our comprehensive liquid biopsy platform for detection of genome-wide copy number aberrations, sequence variants, and gene fusions using cerebrospinal fluid (CSF) from pediatric patients with brain, spinal cord, and peripheral nervous system tumors. Cell-free DNA was isolated from the CSF from 55 patients, including 47 patients with tumors and 8 controls. Abnormalities in cell-free DNA were detected in 24 (51%) patients including 11 with copy number alterations, 9 with sequence variants, and 7 with KIAA1549::BRAF fusions. Positive findings were obtained in patients spanning histologic subtypes, tumor grades, and anatomic locations. This study demonstrates the feasibility of employing this platform in routine clinical care in upfront diagnostic and monitoring settings. Future studies are required to determine the utility of this approach for assessing response to therapy and long-term surveillance.

CSIG-01. EGFR AND AXL RECEPTOR TYROSINE KINASES DRIVE ONCOGENESIS BY LZTR1 MUTATION

Abstract LZTR1, the substrate-specific adaptor of a CUL3-dependent ubiquitin ligase is among the most frequently mutated ubiquitin ligase coding gene in syndromic and sporadic human cancers including glioblastoma multiforme, in which approximately 27% of cases harbor inactivating mutations and copy number loss. However, both the identity of the protein substrates targeted by LZTR1-mediated ubiquitylation and the biological contexts regulated by specific LZTR1-substrate(s) interactions remain uncertain. Here, we combined biochemical and genetic studies to identify LZTR1 substrates and interrogated their tumor-driving function in the context of LZTR1 loss-of-function mutations and in a new conditional Lztr1 knockout mouse. Multiple screens converged on the receptor tyrosine kinases EGFR and AXL as LZTR1 interactors targeted for ubiquitin-dependent degradation in the lysosome by LZTR1-CUL3 complexes. Pathogenic mutations affecting LZTR1 failed to promote degradation of EGFR and AXL in human tumors. Mice harboring conditional deletion of the LZTR1 gene combined with loss of CDKN2A in the neural progenitor compartment generated peripheral nervous system tumors including schwannoma like and malignant peripheral nervous system tumors (MPNST). Tumors from the LZTR1-mutant mouse model accumulated very high levels of EGFR and AXL and exhibited potent and specific vulnerability to the combinatorial inhibition of EGFR and AXL kinases. These findings explain the mechanism of tumorigenesis associated with LZTR1 inactivation and offer a therapeutic strategy to patients affected by tumors carrying mutations of LZTR1.

EPCO-27. REVEALING TUMOR HETEROGENEITY AND IMMUNE MICROENVIRONMENT IN NF-1 GLIOMA BY SINGLE-CELL GENE EXPRESSION PROFILING

Abstract Germline mutations in the NF1 tumor suppressor gene cause neurofibromatosis type 1 (NF-1), the most common human genetic cancer predisposition syndrome. NF1 patients are prone to develop peripheral and central nervous system tumors, with glioma occurring in 15-20% of patients. The molecular profiles of glioma from patients with NF-1 have been previously explored by large scale DNA and RNA bulk analyses, providing the first comprehensive genetic landscape of NF-1 glioma. However, the intra-tumoral architecture and the microenvironment organization remained largely concealed within the global bulk profile. Here, to characterize the complexity of molecular states of both malignant and non-malignant cells, we profiled NF-1 glioma gene expression at individual cell resolution. We performed single-nuclei RNA sequencing (Nucseq) on frozen NF-1 glioma specimens, including high-grade and low-grade tumors. The functional classification of the transcriptional programs activated in the individual tumor cells identified three main molecular states that partially overlapped with the cellular subtypes of sporadic glioblastoma. Tumor cells of low-grade NF-1 glioma exhibited marked enrichment of neuronal functions, suggesting that the gliomagenesis process in the context of NF1 inactivation might be supported by specialized neuronal activities. Conversely, the proliferative state characterized high-grade NF-1 glioma, indicating that cell cycle-associated pathways are drivers of tumor progression. The single-cell deconvolution of immune microenvironment in NF-1 low grade glioma revealed infiltration of CD8+ T lymphocytes and the active crosstalk of these cells with pro-inflammatory macrophages and mature dendritic cells, supporting a possible anti-tumor cell-mediated response. The identification of divergent tumor cell states as well as the characterization of the immune infiltrates provide new insights for accurate stratification of NF-1 glioma patients and to inform personalized therapeutics.

P04.02.A Integrated diagnosis and therapeutic decision of pediatric nervous system tumors using a comprehensive genomic profiling test

Abstract Background Nervous system tumors (NST) are one of the leading causes of cancer-related death in children. Next-generation sequencing has enabled the identification of an increasing number of genetic markers, allowing for a more accurate diagnosis, and may help guide clinicians towards a more specific therapeutic approach. Material and Methods Retrospective cohort study of pediatric and young adult patients with NST analyzed with FoundationOneHeme® (FOH) panel from March 2020 to April 2021. This panel was requested, in addition to previously performed pathological reviews and routine genetic tests, in order to obtain more accurate diagnoses and/or possible therapeutic targets. Results Fifty NST were analyzed with FOH panel, corresponding to 49 patients. Median age at NST diagnosis was 13 years (range 0-23 years); 50% were females. Initial diagnoses were: 10 pilocytic astrocytomas, 10 diffuse gliomas, 5 ependymomas, 6 mixed neuronal-glial tumors, 7 embryonal tumors, 3 meningeal tumors, 5 peripheral nervous system tumors (PNST) and 4 other types of tumors. There was a change in the final integrated diagnosis after performing the FOH panel in 10 patients (1 pilocytic astrocytoma, 3 diffuse gliomas, 4 mixed neuronal-glial tumors and 1 PNST). In thirty patients, at least one possible therapeutic target was identified: in 5 patients the target therapies are approved for the patients’ tumor type; in 20 patients, target therapies are approved for the same mutations in other tumor types; and in 30 patients target therapies are still being evaluated in ongoing clinical trials. After the results of the FOH panel were known, the previous therapeutic approach was changed in 15 patients, but in only 4 this was attributed to the new genomic findings. Conclusion Comprehensive genomic profiling tests can improve diagnostic accuracy and allow for a more reliable approach to the management of pediatric patients with nervous system tumors. Although in most patients there was no immediate therapeutic application of the potential targets found, the genomic data obtained could be very useful to patients who may have tumor progressions in the future.

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

LGG-42. Thromboembolic toxicity observed with concurrent trametinib and lenalidomide therapy

INTRODUCTION: Event-free survival of pediatric low-grade glioma (pLGG) is poor, and patients often require multiple treatment strategies. The hallmark of pLGGs are genetic aberrations of the mitogen-activated protein kinase pathway, which lead to constitutive pathway activation. MEK and RAF inhibitors target this pathway and are efficacious in early phase trials in recurrent pLGGs. However, not all patients respond to monotherapy, and many experience progression after completion of therapy. Evaluating combination therapies that may enhance efficacy or prolong disease stabilization is warranted. Lenalidomide is an immunomodulatory agent with an anti-tumor effect demonstrated in phase 1 trials in recurrent pediatric central nervous system (CNS) tumors. OBJECTIVE: To describe our institutional experience using concurrent trametinib and lenalidomide in the treatment of primary pediatric central and peripheral nervous system (PNS) tumors. METHODS: Retrospective review of patients’ medical records. RESULTS: Four patients with locally recurrent primary CNS or PNS tumors, three with WHO grade II pilomyxoid astrocytomas and one with a plexiform neurofibroma, were treated with trametinib and lenalidomide concurrently. Two patients developed severe thromboembolic events. One patient was treated with combination therapy for seven months until trametinib and lenalidomide were held after urgent ventriculoperitoneal shunt revision. Shortly following shunt revision, he experienced near-complete vision loss. MRI of the brain demonstrated a left posterior watershed territory hypoxic-ischemic injury. In a second patient, after four months of combination therapy, surveillance echocardiogram showed an incidental finding of severe biventricular dysfunction with a left ventricular ejection fraction (LVEF) of 17.7% and two mural thrombi in the left ventricular apex. She started losartan and enoxaparin and discontinued trametinib and lenalidomide. Her LVEF normalized four months later, and the mural thrombi resolved. CONCLUSIONS: Given the severe thromboembolic events experienced by these patients treated with concomitant trametinib and lenalidomide, this combination requires further investigation, and we urge caution if used concurrently.

Neuronal hyperexcitability drives central and peripheral nervous system tumor progression in models of neurofibromatosis-1

Neuronal activity is emerging as a driver of central and peripheral nervous system cancers. Here, we examined neuronal physiology in mouse models of the tumor predisposition syndrome Neurofibromatosis-1 (NF1), with different propensities to develop nervous system cancers. We show that central and peripheral nervous system neurons from mice with tumor-causing Nf1 gene mutations exhibit hyperexcitability and increased secretion of activity-dependent tumor-promoting paracrine factors. We discovered a neurofibroma mitogen (COL1A2) produced by peripheral neurons in an activity-regulated manner, which increases NF1-deficient Schwann cell proliferation, establishing that neurofibromas are regulated by neuronal activity. In contrast, mice with the Arg1809Cys Nf1 mutation, found in NF1 patients lacking neurofibromas or optic gliomas, do not exhibit neuronal hyperexcitability or develop these NF1-associated tumors. The hyperexcitability of tumor-prone Nf1-mutant neurons results from reduced NF1-regulated hyperpolarization-activated cyclic nucleotide-gated (HCN) channel function, such that neuronal excitability, activity-regulated paracrine factor production, and tumor progression are attenuated by HCN channel activation. Collectively, these findings reveal that NF1 mutations act at the level of neurons to modify tumor predisposition by increasing neuronal excitability and activity-regulated paracrine factor production.

211 Deep Phenotyping Reveals Germline Determinants of Disease Severity in Neurofibromatosis Type 2

INTRODUCTION: Neurofibromatosis type 2 (NF2) is an autosomal dominant tumor predisposition syndrome with central and peripheral nervous system tumors and non-neoplastic manifestations including peripheral neuropathy. NF2 presents with a large variation in penetrance and severity. Although germline nonsense and frameshift NF2mutations are hypothesized to confer severe disease, the relationship between mutation type and manifestations of this disease is not completely understood. METHODS: Patients (n = 169) with NF2 (Manchester criteria) were enrolled in a Natural History protocol (NCTNCT00598351). Deep phenotypic profiles were created (serially for 5 years) including clinical evaluations, self-reported functional measures, lifetime interventions (surgical, radiation and drug treatments), and imaging (tumor number, type and volume using volumetric MRI of the neuroaxis). Validated germline mutation data (n = 68) was used to examine relationships between genotype and phenotype with attention to NF2 mutation type (indel/large deletion), genomic effect (missense/nonsense/frameshift), predicted protein effect (truncating/non-truncating) and location (exonic/intronic/splice-site). RESULTS: Tumor burden varied greatly between patients (tumor number range 1-165, median 25). We found that cranial meningiomas were a major determinant of total tumor burden. Total tumor burden (number and volume) was associated with worse KPS and decline in KPS over the study protocol (p < 0.001). We found that truncating mutations in exons 11-12 were associated with more severe disease in terms of tumor number on MRI (p = 0.0439). CONCLUSION: This is the first large scale study to deeply phenotype patients with NF2 including longitudinal analysis and demonstrates several previously unrecognized trends related to germline mutations type, imaging findings, and measures of disease severity.

Neurofibromatosis: analysis of clinical cases and new diagnostic criteria

Neurofibromatoses are a group of genetic disorders with predisposing for central and peripheral nervous system tumor development. The group includes three entities: neurofibromatosis type I, neurofibromatosis type II and schwannomatosis, which are characterized by gradual phenotype development and have a partially overlapping spectrum of manifestations, which complicates diagnosis establishing, especially at the stage of clinical onset. At the same time, the emergence of new pathogenetic therapy and the high risk of transmission to descendants actualize the necessity of early diagnosis. DNA tests allow us to reliably confirm the presumed diagnosis. This article presents a review of neurofibromatoses, their clinical features and courses, modern diagnostic criteria and indications for DNA tests.

Assessment of Mosaicism and Detection of Cryptic Alleles in CRISPR/Cas9-Engineered Neurofibromatosis Type 1 and TP53 Mutant Porcine Models Reveals Overlooked Challenges in Precision Modeling of Human Diseases.

Genome editing in pigs has been made efficient, practical, and economically viable by the CRISPR/Cas9 platform, representing a promising new era in translational modeling of human disease for research and preclinical development of therapies and devices. Porcine embryo microinjection provides a universally available, efficient option over somatic-cell nuclear transfer, but requires that critical considerations be made in genotypic validation of the models that routinely go unaddressed. Accurate validation of genotypes is especially important when modeling genetic disorders, such as neurofibromatosis type 1 (NF1) that exhibits complex genotype–phenotypic relationships. NF1, an autosomal dominant disorder, is particularly hard to model as it manifests very differently across patients, and even within families, with over 3,000 disease-associated mutations of the neurofibromin 1 (NF1) gene identified. The precise nature of the mutations plays a role in the complex phenotypic presentation of the disorder that includes benign and malignant peripheral and central nervous system tumors, a variety of motor deficits and debilitating cognitive impairments and musculoskeletal, cardiovascular, and gastrointestinal disorders. NF1 can also often involve mutations in passenger genes such as TP53. In this manuscript, we describe the creation of three novel porcine models of NF1 and a model additionally harboring a mutation in TP53 by embryo microinjection of CRISPR/Cas9. We present the challenges encountered in validation of genotypes and the methodological strategies developed to counter the hurdles. We present simple options for quantifying level of mosaicism: a quantitative method (targeted amplicon sequencing) for small edits such as SNPs and indels and a semiquantitative method (competitive PCR) for large edits. Characterization of mosaicism allowed for strategic selection of founder pigs for rapid, economical expansion of genetically defined lines. We also present commonly observed unexpected DNA repair products (i.e., structural variants or cryptic alleles) that are refractory to PCR amplification and thus evade detection. We present the use of copy number variance assays to overcome hurdles in detecting cryptic alleles. The report provides a framework for genotypic validation of porcine models created by embryo microinjection and the expansion of lines in an efficient manner.