NF1-associated Tumors Research Articles

Plastic surgical treatment of neurofibromatosis type 1

Neurofibromatosis type1 (NF1, formerly Recklinghausen's disease) is a genetic tumor predisposition syndrome in which the mutation of atumor suppressor gene (neurofibromin) leads to the development of mostly benign neurofibromas of the skin and the central and peripheral nervous systems and malformations or tumors of other organ systems. Patients with NF1 should receive lifelong interdisciplinary care in specialized centers and important treatment decisions should be made by a regularly meeting interdisciplinary panel of experts. Plastic surgery plays an important role in the multidisciplinary management of all clinical forms of NF1-associated peripheral nerve sheath tumors, from cutaneous and subcutaneous to deep nodular and diffuse plexiform neurofibromas. Each patient requires individualized surgical planning, whereby the timing and extent of surgery are determined by the accompanying symptoms, functional and esthetic limitations, disease progression and potential malignant transformation. As any region of the body can be affected, the esthetic and reconstructive procedures required include awide range of interventions, such as eyelid surgery and facial restoration to breast shaping and nerve reconstruction or motor replacement surgery. A timely surgical intervention can have aprofoundly positive effect on the course of the disease and the quality of life of those affected and, in the case of transformation into amalignant peripheral nerve sheath tumor (MPNST), can even be lifesaving.

Overall survival and progression-free survival in pediatric meningiomas: a systematic review and individual patient-level meta-analysis.

Pediatric meningiomas (PMs) are rare central nervous system tumors, accounting for 1-5% of all meningiomas, and differ from adult meningiomas in clinical, histopathological, and molecular features. Current guidelines primarily focus on adults, leaving a gap in evidence-based management for PMs. This study presents the largest meta-analysis of longitudinal individual patient data (IPD) to date, addressing progression-free survival (PFS) and overall survival (OS) in pediatric patients. Data from 20 studies (2011-2023), including 1010 pediatric meningioma cases, were analyzed to assess PFS and OS stratified by WHO grade, NF1/NF2 status, extent of resection (EOR), and adjuvant radiotherapy. Longitudinal survival data were reconstructed from Kaplan-Meier curves using IPD extraction methods. PMs affect males and females nearly equally (52.1% vs. 47.9%). WHO grade 3 tumors had significantly shorter PFS (72.1months) compared to grades 1 (209.8months) and 2 (137.5months) (p < 0.001). No significant OS difference between WHO grades 1 and 2 PMs were observed. NF1- and NF2-associated tumors showed shorter PFS (59.7 and 138.4months) than sporadic cases (180.6months) (p = 0.02). GTR significantly improved PFS (113.8 vs. 40.1months, p < 0.001) and OS (602.9 vs. 173.8months, p < 0.001). Radiotherapy enhanced PFS (72.5 vs. 23.8months, p = 0.009) and OS (140.7 vs. 63.0months, p = 0.002) in grade 3 tumors but not in WHO grade 2 PMs (p = 0.43). This largest meta-analysis highlights the critical roles of GTR and adjuvant radiotherapy in improving outcomes for high-grade PMs and underscores the urgent need for pediatric-specific management guidelines based on robust longitudinal data.

PATH-25. CONSENSUS RECOMMENDATIONS FOR AN INTEGRATED DIAGNOSTIC APPROACH TO NERVE SHEATH TUMORS ARISING IN THE SETTING OF NEUROFIBROMATOSIS TYPE 1

Abstract NF1-associated nerve sheath tumors exist on a morphologically and molecularly diverse spectrum. Criteria for diagnosing neurofibroma, atypical neurofibromatous neoplasm of uncertain biologic potential (ANNUBP), and malignant peripheral nerve sheath tumor (MPNST) developed by consensus in 2017 were codified in recent WHO guidelines. However, incorporation of molecular strata should be formalized to aid in early identification and appropriate intervention for patients with lesions at increased risk for malignant transformation. Here, we assembled a multi-institutional expert pathology working group to review molecular literature and formalize classification recommendations. In collaboration with clinical/surgical, imaging, and pre-clinical working groups during the “Symposium on Atypical Neurofibroma: State of the Science” held April 2024, we reached consensus on a potential integrated diagnostic approach. Based on strong preclinical and clinical evidence, we propose CDKN2A homozygous deletion as a sufficient molecular feature for diagnosing ANNUBP and either SUZ12, EED, or TP53 inactivating mutations or significant aneuploidy as sufficient molecular features for diagnosing MPNST, even in the absence of high-grade histologic features. In the absence of MPNST-defining molecular alterations, we also recommend reclassifying “low grade MPNST” as “ANNUBP with increased proliferation”. To facilitate molecular characterization of concerning tumors, we recommend at least six core biopsies be obtained and divided into two cores per block at time of grossing. Worrisome immunohistochemical features including reduced SOX10 or S100 immunoreactivity, decreased CD34 lattice-like network, minimal p16 expression, loss of H3K27me3 immunoreactivity, p53 overexpression, and increased Ki-67 labeling can guide region selection. A comprehensive next-generation sequencing panel that includes copy number and zygosity assessment is the preferred single assay, though a combination of multiple molecular techniques may provide similar information. In the spirit of the prior 2017 consensus agreement, we hope this refined integrated diagnostic approach for NF1-associated nerve sheath tumors will continue to evolve alongside our understanding of the spectrum of these neoplasms.

CTNI-46. WINDOW-OF-OPPORTUNITY TRIAL OF ULIXERTINIB FOR MAPK-ACTIVATED LOWER GRADE GLIOMAS IN ADULTS

Abstract Overexpression of MAPK (Ras-Raf-MEK-ERK) signaling is well known in NF1-associated tumors. MEK inhibition has shown promising results in pediatrics NF1-associated tumors. In addition, we have observed augmented MAPK signaling and anti-tumor activity with MAPK inhibition in preclinical models of CIC-mutated vs. wild-type oligodendroglioma. Ulixertinib is a small molecule inhibitor of ERK that is being developed as a novel anti-cancer drug. A phase I study of ulixertinib in advanced solid malignancies had shown two central nervous system responses. We hypothesized that ulixertinib crosses the blood-brain barrier (BBB) and it will result in improved responses in MAPK-activated lower-grade gliomas in adults (recurrent NF1-mutated gliomas grade 1,2,3 and oligodendrogliomas grade 2,3 which are enriched in CIC-mutation). This is a window-of-opportunity study of ulixertinib in patients ≥18 yo. Twenty patients who are candidates for non-emergent surgical resection will be enrolled (10 in each cohort). Patients will receive neoadjuvant ulixertinib at 600mg BID. Selected patients will undergo CSF collection 1-week after and all will undergo surgical intervention 2-weeks after initiation of ulixertinib. Patients will then continue treatment until disease progression or unacceptable toxicity. Primary endpoints are ulixertinib tumor concentration and tumor/plasma ratio in enhancing and non-enhancing disease. Secondary endpoints include median PFS, overall response rate (ORR) and disease control rate at 12mo, duration of response, time-to-next intervention and time-to-response, safety profile, and ulixertinib CSF and tumor/CSF ratio. Exploratory endpoint includes ORR of plexiform neurofibromas in NF1 patients. To date, 4 patients have been dosed; 3 CIC-mutated oligodendroglioma and 1 NF1-mutated glioma. A fifth patient with NF1-mutated glioma has been consented. Upon collection of tumor tissue on all 5 patients, initial assessment of tumor and CSF drug concentration will be conducted and presented at the conference. Ulixertinib’s ability to cross the BBB could influence what tumor types may be explored for further patient benefit.

Consensus recommendations for an integrated diagnostic approach to peripheral nerve sheath tumors arising in the setting of Neurofibromatosis type 1 (NF1).

Consensus recommendation published in 2017 histologically defining atypical neurofibromatous neoplasm of uncertain biologic potential (ANNUBP) and malignant peripheral nerve sheath tumor (MPNST) were codified in the 2021 WHO Classification of Tumors of the Central Nervous System and the 2022 WHO Classification of Tumors of Soft Tissue and Bone. However, given the shift in diagnostic pathology toward the use of integrated histopathologic and genomic approaches, the incorporation of additional molecular strata in the classification of Neurofibromatosis Type 1 (NF1)-associated peripheral nerve sheath tumors should be formalized to aid in accurate diagnosis and early identification of malignant transformation to enable appropriate intervention for affected patients. To this end, we assembled a multi-institutional expert pathology working group as part of a "Symposium on Atypical Neurofibroma: State of the Science". Herein, we provide a suggested framework for adequate interventional radiology and surgical sampling, and recommend molecular profiling for clinically or radiologically worrisome non-cutaneous lesions in patients with NF1 to identify diagnostically-relevant molecular features, including CDKN2A/B inactivation for ANNUBP, as well as SUZ12, EED, or TP53 inactivating mutations, or significant aneuploidy for MPNST. We also propose renaming "low-grade MPNST" to "ANNUBP with increased proliferation" to avoid the use of the "malignant" term in this group of tumors with persistent unknown biologic potential. This refined integrated diagnostic approach for NF1-associated peripheral nerve sheath tumors should continue to evolve in concert with our understanding of these neoplasms.

Presenting characteristics and clinical outcomes of idiopathic versus neurofibromatosis type 2-associated spinal meningiomas: a retrospective institutional experience.

Spinal meningioma (SM) is a pathology with an estimated incidence of nearly 1000 diagnoses per year in the United States and presents in 20% of patients with neurofibromatosis type 2 (NF2). This multi-institutional retrospective cohort study aimed to assess clinical outcomes for patients with SM who underwent surgery between 1998 and 2020 with stratification by NF2 mutation status. Medical records were reviewed retrospectively to collect data on patient demographics, clinical presentation, tumor characteristics, treatment, and outcomes. Analyses were done to determine radiographic predictors of gross-total resection (GTR) and tumor recurrence, to assess radiographic characteristics of NF2-associated tumors, and to determine progression-free survival between groups. A total of 166 patients who received surgery for SM during the study period were included, of whom 133 were women (80%). Fifteen (9%) patients had a concurrent NF2 diagnosis. The mean age at surgery was 58 (SD 18) years. The mean presenting Karnofsky Performance Status score was 76 (SD 11), and the most common presenting symptoms were sensation changes (60%) and weakness (59%). Most tumors were in the thoracic spine (72%). GTR was achieved in 154 cases (93%). Eight patients with subtotal resection were treated with radiation therapy, and none received chemotherapy. Eighteen patients (11%) experienced radiographic recurrence of disease following surgery, with a mean time to recurrence of 4.2 years. NF2 patients were diagnosed at a significantly earlier mean age (33.3 [SD 15.4] years) compared with other patients. NF2 patients experienced progression at a significantly higher rate than other patients (40%), and in less time (mean 2.8 [SD 3.7] years). Radiographic characteristics, including tumor volume, T2 cord edema, dural tail sign, and calcification, were similar between NF2 and non-NF2 patients, between patients who underwent gross-total versus subtotal resection, and between patients who experienced tumor recurrence and those who did not. In this study of 166 surgically treated patients with SM, patients with NF2 presented earlier, experienced earlier progression, and experienced progression more frequently compared with those without NF2. Radiographic characteristics of tumors were relatively consistent between groups. While idiopathic SMs remain a relatively benign and highly manageable disease, considering tumor molecular characteristics and broader clinical history is paramount in providing efficacious and individualized patient care.

Pharmacogenomic synthetic lethal screens reveal hidden vulnerabilities and new therapeutic approaches for treatment of NF1-associated tumors.

Neurofibromatosis Type 1 (NF1) is a common cancer predisposition syndrome, caused by heterozygous loss of function mutations in the tumor suppressor gene NF1. Individuals with NF1 develop benign tumors of the peripheral nervous system (neurofibromas), originating from the Schwann cell linage after somatic loss of the wild type NF1 allele, some of which progress further to malignant peripheral nerve sheath tumors (MPNST). There is only one FDA approved targeted therapy for symptomatic plexiform neurofibromas and none approved for MPNST. The genetic basis of NF1 syndrome makes associated tumors ideal for using synthetic drug sensitivity approaches to uncover therapeutic vulnerabilities. We developed a drug discovery pipeline to identify therapeutics for NF1-related tumors using isogeneic pairs of NF1-proficient and deficient immortalized human Schwann cells. We utilized these in a large-scale high throughput screen (HTS) for drugs that preferentially kill NF1-deficient cells, through which we identified 23 compounds capable of killing NF1-deficient Schwann cells with selectivity. Multiple hits from this screen clustered into classes defined by method of action. Four clinically interesting drugs from these classes were tested in vivo using both a genetically engineered mouse model of high-grade peripheral nerve sheath tumors and human MPNST xenografts. All drugs tested showed single agent efficacy in these models as well as significant synergy when used in combination with the MEK inhibitor Selumetinib. This HTS platform yielded novel therapeutically relevant compounds for the treatment of NF1-associated tumors and can serve as a tool to rapidly evaluate new compounds and combinations in the future.

Leveraging Neural Crest-Derived Tumors to Identify NF1 Cancer Stem Cell Signatures.

Neurofibromatosis type 1 (NF1) is a genetic disorder that predisposes individuals to develop benign and malignant tumors of the nerve sheath. Understanding the signatures of cancer stem cells (CSCs) for NF1-associated tumors may facilitate the early detection of tumor progression. Background: Neural crest cells, the cell of origin of NF1-associated tumors, can initiate multiple tumor types, including melanoma, neuroblastoma, and schwannoma. CSCs within these tumors have been reported; however, identifying and targeting CSC populations remains a challenge. Results: This study aims to leverage existing studies on neural crest-derived CSCs to explore markers pertinent to NF1 tumorigenesis. By focusing on the molecular and cellular dynamics within these tumors, we summarize CSC signatures in tumor maintenance, progression, and treatment resistance. Conclusion: A review of these signatures in the context of NF1 will provide insights into NF1 tumor biology and pave the way for developing targeted therapies and improving treatment outcomes for NF1 patients.

Multidimensional Immunotyping of Human NF1-Associated Peripheral Nerve Sheath Tumors Uncovers Tumor-Associated Macrophages as Key Drivers of Immune Evasion in the Tumor Microenvironment.

Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft-tissue sarcomas and the leading cause of mortality in individuals with neurofibromatosis type 1 (NF1). Despite many clinical trials, outcomes for patients with MPNST have remained stagnant, and most succumb to their disease; thus, novel therapeutic approaches are needed. A better understanding of the MPNST immune ecosystem will aid in the development of strategies to activate the immune system against the tumor. In this study, we profile the tumor immune microenvironment (TIME) in NF1-associated peripheral nerve sheath tumors (PNST) to discover insights on the role played by tumor-infiltrating immune cells in malignant transformation. Using fresh and formalin-fixed paraffin-embedded tissue from patients diagnosed with NF1-PNST, we dissected the TIME through IHC, multiparameter flow cytometry, and comparative transcriptomic studies. Immunophenotyping confirmed increased immune cell infiltration during malignant progression, with a predominance of infiltrating myeloid cells, particularly CD163+ tumor-associated macrophages (TAM). The T cells within MPNST exhibited signs of tumor activation, characterized by high programmed cell death 1 expression. Additionally, MPNST specimens demonstrated elevated levels of immunosuppressive TAM, with heightened PD-L1 expression. The proportion of CD163+ myeloid cells within the TIME correlated with poorer progression-free survival. Notably, loss of H3K27 trimethylation correlated with low immune cell infiltration in MPNST. Malignant transformation of NF1-PNST is characterized by an immunosuppressive microenvironment comprising TAM with high expression of PD-L1, which is associated with inferior outcomes. These findings suggest the clinical potential of immune-modulating therapeutics that can unleash an antitumor immune response.

Cold Atmospheric Plasma Induces Growth Arrest and Apoptosis in Neurofibromatosis Type 1-Associated Peripheral Nerve Sheath Tumor Cells.

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder resulting from mutations in the NF1 gene. Patients harboring these mutations are predisposed to a spectrum of peripheral nerve sheath tumors (PNSTs) originating from Schwann cells, of which malignant peripheral nerve sheath tumors (MPNSTs) are the deadliest, with limited treatment options. Therefore, an unmet need still exists for more effective therapies directed at these aggressive malignancies. Cold atmospheric plasma (CAP) is a reactive oxygen species (ROS) and reactive nitrogen species (RNS) generating ionized gas that has been proposed to be a potential therapeutic modality for cancer. In this study, we sought to determine the effects of CAP on NF1-associated PNSTs. Utilizing established mouse and human cell lines to interrogate the effects of CAP in both in vitro and in vivo settings, we found that NF1-associated PNSTs were highly sensitive to CAP exposure, resulting in cell death. To our knowledge, this is the first application of CAP to NF1-associated PNSTs and provides a unique opportunity to study the complex biology of NF1-associated tumors.

Inhibition of autophagy as a novel treatment for neurofibromatosis type 1 tumors.

Neurofibromatosis type 1 (NF1) is a genetic disorder caused by mutation of the NF1 gene that is associated with various symptoms, including the formation of benign tumors, called neurofibromas, within nerves. Drug treatments are currently limited. The mitogen-activated protein kinase kinase (MEK) inhibitor selumetinib is used for a subset of plexiform neurofibromas (PNs) but is not always effective and can cause side effects. Therefore, there is a clear need to discover new drugs to target NF1-deficient tumor cells. Using a Drosophila cell model of NF1, we performed synthetic lethal screens to identify novel drug targets. We identified 54 gene candidates, which were validated with variable dose analysis as a secondary screen. Pathways associated with five candidates could be targeted using existing drugs. Among these, chloroquine (CQ) and bafilomycin A1, known to target the autophagy pathway, showed the greatest potential for selectively killing NF1-deficient Drosophila cells. When further investigating autophagy-related genes, we found that 14 out of 30 genes tested had a synthetic lethal interaction with NF1. These 14 genes are involved in multiple aspects of the autophagy pathway and can be targeted with additional drugs that mediate the autophagy pathway, although CQ was the most effective. The lethal effect of autophagy inhibitors was conserved in a panel of human NF1-deficient Schwann cell lines, highlighting their translational potential. The effect of CQ was also conserved in a Drosophila NF1 in vivo model and in a xenografted NF1-deficient tumor cell line grown in mice, with CQ treatment resulting in a more significant reduction in tumor growth than selumetinib treatment. Furthermore, combined treatment with CQ and selumetinib resulted in a further reduction in NF1-deficient cell viability. In conclusion, NF1-deficient cells are vulnerable to disruption of the autophagy pathway. This pathway represents a promising target for the treatment of NF1-associated tumors, and we identified CQ as a candidate drug for the treatment of NF1 tumors.

PET Imaging of Neurofibromatosis Type 1 with a Fluorine-18 Labeled Tryptophan Radiotracer.

Neurofibromatosis type 1 (NF1) is a neurocutaneous disorder. Plexiform neurofibromas (PNFs) are benign tumors commonly formed in patients with NF1. PNFs have a high incidence of developing into malignant peripheral nerve sheath tumors (MPNSTs) with a 5-year survival rate of only 30%. Therefore, the accurate diagnosis and differentiation of MPNSTs from benign PNFs are critical to patient management. We studied a fluorine-18 labeled tryptophan positron emission tomography (PET) radiotracer, 1-(2-[18F]fluoroethyl)-L-tryptophan (L-[18F]FETrp), to detect NF1-associated tumors in an animal model. An ex vivo biodistribution study of L-[18F]FETrp showed a similar tracer distribution and kinetics between the wild-type and triple mutant mice with the highest uptake in the pancreas. Bone uptake was stable. Brain uptake was low during the 90-min uptake period. Static PET imaging at 60 min post-injection showed L-[18F]FETrp had a comparable tumor uptake with [1⁸F]fluorodeoxyglucose (FDG). However, L-[18F]FETrp showed a significantly higher tumor-to-brain ratio than FDG (n = 4, p < 0.05). Sixty-minute-long dynamic PET scans using the two radiotracers showed similar kidney, liver, and lung kinetics. A dysregulated tryptophan metabolism in NF1 mice was further confirmed using immunohistostaining. L-[18F]FETrp is warranted to further investigate differentiating malignant NF1 tumors from benign PNFs. The study may reveal the tryptophan-kynurenine pathway as a therapeutic target for treating NF1.

116 The Role of Spinal Surgery Among NF2 Patients With Spinal Tumors: Surgery-associated Characteristics and Response to Bevacizumab

INTRODUCTION: Neurofibromatosis type 2 (NF2) patients develop spinal neoplasms. Determining indications for spine surgery remains challenging, as localization of spine related symptoms can be confounded by intracranial or peripheral neuropathology. Additionally, patient selection must be balanced with pre-existing comorbidities NF2 incurs with the goal to maintain or improve quality of life. METHODS: Seventy-nine patients were enrolled retrospectively based upon NF2 diagnosis and radiographic presence of spine tumors from three tertiary academic centers. Demographic data, clinical findings, treatment course, and spine tumor pathology were collected for all patients. RESULTS: Forty-eight percent of patients received spine surgery (38/79, 48.1%). Patients undergoing spine surgery had lower age of symptom onset (15.4 vs. 25.6, p = 0.015), increased cervical (4.2 vs 2.4, p = 0.005) and overall spine tumor burden (10.3 vs 6.2, p &lt; 0.001) and presence of neck (9 vs 1, p = 0.006) and radicular pain (8 vs 1, p = 0.012). Over a quarter of our patients received BEV (25/79, 31.6%), with majority experiencing symptom onset before age 20 (17/19, 89.5%). Schwannoma was the most common BEV-treated pathology. Only one patient experienced worsening of tumor burden at one year while on BEV, and five patients required spine surgery after receiving BEV. CONCLUSIONS: NF2 patients who require spine surgery typically present at younger ages with large cervical spine tumor burden and associated symptomology. It is crucial that surgery-associated demographics and symptomology are identified. BEV was utilized in patients with aggressive, early-onset spine disease. Further, BEV halted spine disease progression in all patients except one, with minimal additional spine surgery required. Its ability to slow aggressive, NF2-associated spine tumors should be considered for clinical trial.

Deciphering the Immune Microenvironment of NF1-associated Peripheral Nerve Sheath Tumors: Identifying Early Biomarkers of Disease Progression and Malignant Transformation

Background/Objective:Neurofibromatosis type 1 (NF1) is a multisystem disorder that affects ~1/3000 newborns. Plexiform neurofibromas (PN) are present in about half of cases and can transform (lifetime risk of 8-13%) into malignant peripheral nerve sheath tumor (MPNST), a highly aggressive and metastatic sarcoma with poor survival. Unfortunately, there are currently no reliable biomarkers to identify PN at risk of undergoing malignant transformation. Our research has revealed that a subset of benign-appearing and atypical PN exhibit deregulated immune surveillance and T-cell infiltration that precede malignant transformation. In this study, we are analyzing tumor microenvironment and immune landscape in NF1-related tissue specimens to identify biomarkers of disease progression. To power these studies, this project focused on constructing a dataset of NF1-related samples to be analyzed. Methods:701 patients were identified via Cerner billing codes and pathology archives. De-identified clinical data, including presenting symptoms, relevant clinical history, pathology diagnoses, disease features, prior chemotherapeutics/radiation, prior gene profiling, and imaging features were collected. Results: We selected 86 patients with a total of 175 samples. 81% of patients had a clinical diagnosis of NF1, and 6% had a history of MPNST. Out of the 175 samples, 54 were in the head and neck, 42 in the thorax, 28 in the lower extremity, 27 in the upper extremity, 26 in the pelvis/abdomen, and 15 in the paraspinal region. The leading causes of procedures were pain (41%), growth (40%), and concern for malignancy (27%). The most common tissue diagnoses were neurofibroma (51.4%), PN (20%), and undefined-grade MPNST (11%). Out of the 46 MPNSTs, 30 were primary tumors, 4 metastases, and 12 local recurrences. Conclusion and Potential Impact:The results of this study will provide valuable insights to inform preclinical models of NF1-tumorigenesis to validate these findings and identify novel treatment approaches for individuals affected by these rare but devastating tumors.

Case report of selumetinib as a novel therapy in a neurofibromatosis type 2-associated ependymoma

We report partial response (PR) to novel therapy with selumetinib in a patient with Neurofibromatosis type 2 (NF2). A 25-year-old male presented with bilateral vestibular schwannomas, spinal cord intramedullary ependymomas, cranial and spinal meningiomas, spinal nerve root mixed schwannoma-neurofibromas, and peripheral nerve sheath tumors. He tested negative for germline NF2, SWItch/Sucrose Non-Fermentable-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 (SMARCB1), and leucine zipper like transcription regulator 1 (LZTR1) mutations. Molecular analysis of a resected cervical spine schwannoma-neurofibroma demonstrated an isolated somatic SMARCB1 mutation. Due to progression of all tumors, he was treated medically with both everolimus (10 mg/day) and selumetinib (25 mg/kg BID), but rapidly transitioned to selumetinib monotherapy due to everolimus toxicity. Three months of treatment resulted in PR in one spinal ependymoma and stable disease in other tumors. This partial response was quantified by the differences in units of intensity in pre- and post-treatment MR image. To the best of our knowledge, this is the first reported case for using selumetinib in NF2-associated tumors or ependymomas.

Asymmetry of thalamic hypometabolism on FDG-PET/CT in neurofibromatosis type 1: Association with peripheral tumor burden.

Thalamic hypometabolism is a consistent finding in brain PET with F-18 fluorodeoxyglucose (FDG) in patients with neurofibromatosis type 1 (NF1). However, the pathophysiology of this metabolic alteration is unknown. We hypothesized that it might be secondary to disturbance of peripheral input to the thalamus by NF1-characteristic peripheral nerve sheath tumors (PNSTs). To test this hypothesis, we investigated the relationship between thalamic FDG uptake and the number, volume, and localization of PNSTs. This retrospective study included 22 adult NF1 patients (41% women, 36.2±13.0years) referred to whole-body FDG-PET/contrast-enhanced CT for suspected malignant transformation of PNSTs and 22 sex- and age-matched controls. Brain FDG uptake was scaled voxelwise to the individual median uptake in cerebellar gray matter. Bilateral mean and left-right asymmetry of thalamic FDG uptake were determined using a left-right symmetric anatomical thalamus mask. PNSTs were manually segmented in contrast-enhanced CT. Thalamic FDG uptake was reduced in NF1 patients by 2.0 standard deviations (p<.0005) compared to controls. Left-right asymmetry was increased by 1.3 standard deviations (p=.013). Thalamic hypometabolism was higher in NF1 patients with ≥3 PNSTs than in patients with ≤2 PNSTs (2.6 vs. 1.6 standard deviations, p=.032). The impact of the occurrence of paraspinal/paravertebral PNSTs and of the mean PNST volume on thalamic FDG uptake did not reach statistical significance (p=.098 and p=.189). Left-right asymmetry of thalamic FDG uptake was not associated with left-right asymmetry of PNST burden (p=.658). This study provides first evidence of left-right asymmetry of thalamic hypometabolism in NF1 and that it might be mediated by NF1-associated peripheral tumors.

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.

A Call for Discovery and Therapeutic Development for Cutaneous Neurofibromas

A Call for Discovery and Therapeutic Development for Cutaneous Neurofibromas

Basement membrane proteins in extracellular matrix characterize NF1 neurofibroma development and response to MEK inhibitor.

Neurofibromatosis Type 1 (NF1) is one of the most common tumor-predisposing genetic disorders. Neurofibromas are NF1-associated benign tumors. A hallmark feature of neurofibromas is an abundant collagen-rich extracellular matrix (ECM) that constitutes >50% of the tumor dry weight. However, little is known about the mechanism underlying ECM deposition during neurofibroma development and treatment response. We performed a systematic investigation of ECM enrichment during plexiform neurofibroma (pNF) development, and identified basement membrane (BM) proteins, rather than major collagen isoforms, as the most upregulated ECM component. Following MEK inhibitor treatment, the ECM profile displayed an overall down-regulation signature, suggesting ECM reduction as a therapeutic benefit of MEK inhibition. Through these proteomic studies, TGF-β1 signaling was identified as playing a role in ECM dynamics. Indeed, TGF-β1 overexpression promoted pNF progression in vivo. Furthermore, by integrating single-cell RNA-sequencing, we found that immune cells including macrophages and T cells produce TGF-β1 to induce Schwann cells to produce and deposit BM proteins for ECM remodeling. Following Nf1 loss, neoplastic Schwann cells further increased BM protein deposition in response to TGF-β1. Our data delineate the regulation governing ECM dynamics in pNF and suggest that BM proteins could serve as markers for disease diagnosis and treatment response.

A basket-platform trial for neurofibromatosis type 1: A potential model for rare cancer predisposition syndromes.

e22550 Background: Neurofibromatosis Type 1 (NF1) is a rare hereditary condition that predisposes to the development of a variety of tumors. Variability in disease manifestation, prevalence and severity, in combination with a low prevalence complicates the efficient conduct of clinical trials in NF1. NF1-associated tumors mainly but not exclusively affect the nervous system as well as the skin, and a percentage of those tumors exhibit a significantly increased risk of malignant transformation. There is an urgent need to identify effective treatments for NF1-associated tumors. The development of innovative trial designs that accelerate the ability to assess new investigational agents is essential. The European Patient-Centric Clinical Trial Platforms (EU-PEARL) is an Innovative Medicines Initiative (IMI) project, aiming to create platform trials for diseases with high unmet medical need. As part of EU-PEARL, we designed a basket-platform trial in NF1 that could serve as a prototype for accelerating drug studies in rare cancer predisposition syndromes. Methods: The trial was designed by NF1 experts, a dedicated statistician and a trial designer. Subprotocols were written for previously prioritized manifestations including plexiform neurofibroma, cutaneous neurofibroma, low-grade glioma, and optic pathway glioma. Collaboration with NF1 experts from the USA was sought to ensure alignment with trials for NF1 in the USA. Results: To optimally learn from a small number of potential participants, patients should be able to participate in both an observational and a treatment phase. The observational phase will serve as longitudinal natural history study, providing data that can be used as a comparator for the treatment arms. To enter the treatment phase, patients must meet additional eligibility criteria. Patients will be randomized to a sequence of available drugs, rather than one single drug. This may allow for the addition of newly identified drugs during the course of the trial. If a drug concept fails or unacceptable toxicity arises, patients may re-enter the observational phase or be re-randomized to a different treatment arm if eligible. Drug-specific eligibility criteria and endpoints are listed separately in Intervention-Specific-Appendices (ISAs), allowing flexibility and adaptability that is needed for a highly variable and progressive rare disorder like NF1. This trial design allows optimal learning from a limited number of patients. Conclusions: We designed a basket-platform trial for four manifestations of NF1. This trial design addresses challenges that may be encountered when designing a clinical trial for NF1. This trial will be the future of clinical trials for NF1 in Europe. Its design could serve as a prototype for other rare diseases: it enhances the chances of finding beneficial treatments by optimizing patient inclusion and invigorating international collaborations.