Raman difference spectroscopy and U-Net convolutional neural network for molecular analysis of cutaneous neurofibroma.

In Neurofibromatosis type 1 (NF1), peripheral nerve sheaths tumors are common, with cutaneous neurofibromas resulting in significant aesthetic, painful and functional problems requiring surgical removal. To date, determination of adequate surgical resection margins-complete tumor removal while attempting to preserve viable tissue-remains largely subjective. Thus, residual tumor extension beyond surgical margins or recurrence of the disease may frequently be observed. Here, we introduce Shifted-Excitation Raman Spectroscopy in combination with deep neural networks for the future perspective of objective, real-time diagnosis, and guided surgical ablation. The obtained results are validated through established histological methods. In this study, we evaluated the discrimination between cutaneous neurofibroma (n = 9) and adjacent physiological tissues (n = 25) in 34 surgical pathological specimens ex vivo at a total of 82 distinct measurement loci. Based on a convolutional neural network (U-Net), the mean raw Raman spectra (n = 8,200) were processed and refined, and afterwards the spectral peaks were assigned to their respective molecular origin. Principal component and linear discriminant analysis was used to discriminate cutaneous neurofibromas from physiological tissues with a sensitivity of 100%, specificity of 97.3%, and overall classification accuracy of 97.6%. The results enable the presented optical, non-invasive technique in combination with artificial intelligence as a promising candidate to ameliorate both, diagnosis and treatment of patients affected by cutaneous neurofibroma and NF1.

High-Grade Astrocytoma with Piloid Features: A Dual Institutional Review of Imaging Findings of a Novel Entity.

High-grade astrocytoma with piloid features (HGAP) is a recently identified brain tumor characterized by a distinct DNA methylation profile. Predominantly located in the posterior fossa of adults, HGAP is notably prevalent in individuals with neurofibromatosis type 1. We present an image-centric review of HGAP and explore the association between HGAP and neurofibromatosis type 1. Data were collected from 8 HGAP patients treated at two tertiary care institutions between January 2020 and October 2023. Demographic details, clinical records, management, and tumor molecular profiles were analyzed. Tumor characteristics, including location and imaging features on MR imaging, were reviewed. Clinical or imaging features suggestive of neurofibromatosis 1 or the presence of NF1 gene alteration were documented. The mean age at presentation was 45.5 years (male/female = 5:3). Tumors were midline, localized in the posterior fossa (n = 4), diencephalic/thalamic (n = 2), and spinal cord (n = 2). HGAP lesions were T1 hypointense, T2-hyperintense, mostly without diffusion restriction, predominantly peripheral irregular enhancement with central necrosis (n = 3) followed by mixed heterogeneous enhancement (n = 2). Two NF1 mutation carriers showed signs of neurofibromatosis type 1 before HGAP diagnosis, with one diagnosed during HGAP evaluation, strengthening the HGAP-NF1 link, particularly in patients with posterior fossa masses. All tumors were IDH1 wild-type, often with ATRX, CDKN2A/B, and NF1 gene alteration. Six patients underwent surgical resection followed by adjuvant chemoradiation. Six patients were alive, and two died during the last follow-up. Histone H3 mutations were not detected in our cohort, such as the common H3K27M typically seen in diffuse midline gliomas, linked to aggressive clinical behavior and poor prognosis. HGAP lesions may involve the brain or spine and tend to be midline or paramedian in location. Underlying neurofibromatosis type 1 diagnosis or imaging findings are important diagnostic cues.

Brain injury drives optic glioma formation through neuron-glia signaling.

Tissue injury and tumorigenesis share many cellular and molecular features, including immune cell (T cells, monocytes) infiltration and inflammatory factor (cytokines, chemokines) elaboration. Their common pathobiology raises the intriguing possibility that brain injury could create a tissue microenvironment permissive for tumor formation. Leveraging several murine models of the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome and two experimental methods of brain injury, we demonstrate that both optic nerve crush and diffuse traumatic brain injury induce optic glioma (OPG) formation in mice harboring Nf1-deficient preneoplastic progenitors. We further elucidate the underlying molecular and cellular mechanisms, whereby glutamate released from damaged neurons stimulates IL-1ß release by oligodendrocytes to induce microglia expression of Ccl5, a growth factor critical for Nf1-OPG formation. Interruption of this cellular circuit using glutamate receptor, IL-1ß or Ccl5 inhibitors abrogates injury-induced glioma progression, thus establishing a causative relationship between injury and tumorigenesis.

Impact of neurofibromatosis type 1 on quality of life using the Skindex-29 questionnaire quality of life in NF1.

BACKGROUND: Neurofibromatosis type 1 (NF1) is one of the most common RASopathies predisposing affected patients to melanic lesions and benign tumors. NF1 is associated with considerable esthetic and functional burden negatively affecting the patient's quality of life (QoL). This study aims to assess the clinical features of NF1 patients and evaluate their impact on QoL. We identified NF1 patients from a public health database of a region in Spain. All patients underwent clinical and ophthalmological evaluation for NF1 features. We measured QoL using the Spanish version of the Skindex-29. RESULTS: Forty patients fulfilled the NF1 National Institute of Health criteria when we recruited patients. The median age was 42.00 years (IQR 26.5 -53.75). The median total Skindex-29 score was 12.3 (IQR 5.9-22.4); (emotion: 15.0, IQR 5.0-37.5; symptoms 8.9, IQR 0.0-17.9 and functioning 8.3; IQR 0.5-18.3). Women and NF1 patients with lower educational levels were associated with poorer QoL scores. We identified itching and sleep troubles to influence NF1 patients' QoL negatively. CONCLUSION: NF1 considerably influences the psychological well-being of NF1 patients. We observed that female and low-educated patients scored higher on the emotional dimension of the Skindex-29 and could, therefore, be more at risk of depression. We also pointed out some "minor symptoms" that negatively impact NF1 patients' QoL such, as itching and sleep troubles which doctors could treat if sought by doctors.

A Giant Scrotal Neurofibroma in a Child Masquerading as Filariasis: Uncommon Presentation of a Common Disease.

Neurofibroma of the scrotum is a very uncommon benign neoplasm, specifically when it affects teenagers and is not associated with neurofibromatosis type I. To the best of our knowledge, only a couple of cases of neurofibroma in children have been documented. Here, we report a case study of a 17-year-old boy who had a giant scrotal lump for ten years masquerading clinically as filariasis. A provisional diagnosis of benign nerve sheath neoplasm was made based on cytology findings. The lump was surgically removed from the patient, and a histopathological and immunohistochemistry examination established the diagnosis of neurofibroma. The combined clinical, preoperative cytological, histological, and immunohistochemistry findings were not presented in the literature in any of the formerly documented cases of scrotal neurofibroma. The current case expands the spectrum of differential diagnoses for scrotal tumours that clinicians have previously observed.

[Gene therapy strategies and prospects for neurofibromatosis type 1].

Objective: To summarize the gene therapy strategies for neurofibromatosis type 1 (NF1) and related research progress. Methods: The recent literature on gene therapy for NF1 at home and abroad was reviewed. The structure and function of the NF1 gene and its mutations were analyzed, and the current status as well as future prospects of the transgenic therapy and gene editing strategies were summarized. Results: NF1 is an autosomal dominantly inherited tumor predisposition syndrome caused by mutations in the NF1 tumor suppressor gene, which impair the function of the neurofibromin and lead to the disease. It has complex clinical manifestations and is not yet curable. Gene therapy strategies for NF1 are still in the research and development stage. Existing studies on the transgenic therapy for NF1 have mainly focused on the construction and expression of the GTPase-activating protein-related domain in cells that lack of functional neurofibromin, confirming the feasibility of the transgenic therapy for NF1. Future research may focus on split adeno-associated virus (AAV) gene delivery, oversized AAV gene delivery, and the development of new vectors for targeted delivery of full-length NF1 cDNA. In addition, the gene editing tools of the new generation have great potential to treat monogenic genetic diseases such as NF1, but need to be further validated in terms of efficiency and safety. Conclusion: Gene therapy, including both the transgenic therapy and gene editing, is expected to become an important new therapeutic approach for NF1 patients.

Unbalancing cAMP and Ras/MAPK pathways as a therapeutic strategy for cutaneous neurofibromas.

Cutaneous neurofibromas (cNFs) are benign Schwann cell (SC) tumors arising from subepidermal glia. Individuals with neurofibromatosis type 1 (NF1) may develop thousands of cNFs, which greatly affect their quality of life. cNF growth is driven by the proliferation of NF1-/- SCs and their interaction with the NF1+/- microenvironment. We analyzed the crosstalk between human cNF-derived SCs and fibroblasts (FBs), identifying an expression signature specific to the SC-FB interaction. We validated the secretion of proteins involved in immune cell migration, suggesting a role of SC-FB crosstalk in immune cell recruitment. The signature also captured components of developmental signaling pathways, including the cAMP elevator G protein-coupled receptor 68 (GPR68). Activation of Gpr68 by ogerin in combination with the MEK inhibitor (MEKi) selumetinib reduced viability and induced differentiation and death of human cNF-derived primary SCs, a result corroborated using an induced pluripotent stem cell-derived 3D neurofibromasphere model. Similar results were obtained using other Gpr68 activators or cAMP analogs/adenylyl cyclase activators in combination with selumetinib. Interestingly, whereas primary SC cultures restarted their proliferation after treatment with selumetinib alone was stopped, the combination of ogerin-selumetinib elicited a permanent halt on SC expansion that persisted after drug removal. These results indicate that unbalancing the Ras and cAMP pathways by combining MEKi and cAMP elevators could be used as a potential treatment for cNFs.

Giant gluteal and vesical plexiform neurofibromas in a patient with neurofibromatosis type 1: a case report.

BACKGROUND: Neurofibromatosis type 1 is a neurocutaneous genetic disorder caused by mutations in the NF1 gene, resulting in the formation of benign tumors called neurofibromas. The most common type of tumor seen in patients with neurofibromatosis type 1 is the slow-growing and benign neurofibroma, with a subtype called plexiform neurofibroma being particularly common and causing pain, functional impairment, and cosmetic disfigurement. CASE PRESENTATION: We report the case of a 20-year-old North African female patient with a history of neurofibromatosis type 1 who presented with a growing mass in her right gluteal region, which was later diagnosed as a giant cutaneous neurofibroma. Imaging studies revealed infiltration in several regions, including the urinary bladder wall, resulting in significant bilateral hydronephrosis. The patient is currently being monitored, and no excisional procedures are planned. CONCLUSIONS: Neurofibromatosis type 1 can cause a variety of clinical symptoms, including the development of large plexiform neurofibromas. It is important to closely monitor patients with neurofibromatosis type 1 for the early detection of neurofibromas. Early detection and prompt surgical intervention are essential for preventing complications.

Perspectives of adolescents with neurofibromatosis 1 and cutaneous neurofibromas: Implications for clinical trials.

BACKGROUND/AIMS: More than 99% of individuals with neurofibromatosis 1 develop cutaneous neurofibromas, benign nerve sheath tumors that manifest as nodules on the skin. These cutaneous neurofibromas emerge with age, appearing most commonly in adolescence. Nevertheless, few data have been published on how adolescents with neurofibromatosis 1 feel about cutaneous neurofibromas. The purpose of this study was to assess the perspectives of adolescents with neurofibromatosis 1 and their caregivers regarding cutaneous neurofibroma morbidity, treatment options, and acceptable risks-benefits of treatment. METHODS: An online survey was distributed through the world's largest NF registry. Eligibility criteria included self-reported neurofibromatosis 1 diagnosis, adolescent child ages 12-17 years, ≥1 cutaneous neurofibroma, and ability to read English. The survey was designed to collect details about the adolescent's cutaneous neurofibromas, views on morbidity related to cutaneous neurofibromas, social and emotional impact of cutaneous neurofibromas, communication regarding cutaneous neurofibromas, and views regarding current and potential future cutaneous neurofibroma treatment. RESULTS: Survey respondents included 28 adolescents and 32 caregivers. Adolescents reported having several negative feelings about cutaneous neurofibromas, particularly feeling worried about the potential progression of their cutaneous neurofibromas (50%). Pruritus (34%), location (34%), appearance (31%), and number (31%) were the most bothersome cutaneous neurofibroma features. Topical medication (77%-96%), followed by oral medication (54%-93%), was the most preferred treatment modality. Adolescents and caregivers most often replied that cutaneous neurofibroma treatment should be initiated when cutaneous neurofibromas become bothersome. The majority of respondents were willing to treat cutaneous neurofibromas for at least 1 year (64%-75%). Adolescent and caregivers were least willing to risk pain (72%-78%) and nausea/vomiting (59%-81%) as a cutaneous neurofibroma treatment side effect. CONCLUSIONS: These data indicate that adolescents with neurofibromatosis 1 are negatively impacted by their cutaneous neurofibromas, and that both adolescents and their caregivers would be willing to try longer-term experimental treatments.

Direct comparison of the diagnostic accuracy of 2-[18F]-fluoro-2-deoxy-d-glucose PET/CT and MRI for the differentiation of malignant peripheral nerve sheath tumour in neurofibromatosis type I: a meta-analysis.

AIM: To compare the diagnostic test of integrated 2-[18F]-fluoro-2-deoxy-d-glucose positron-emission tomography/computed tomography (FDG PET/CT) with that of magnetic resonance imaging (MRI) for the differentiation of malignant peripheral nerve sheath tumours (MPNSTs) in neurofibromatosis type 1 (NF1) patients. MATERIALS AND METHODS: A systematic search was performed in PubMed and EMBASE (last updated in 30 November 2022). Studies investigating the performance of FDG PET/CT and MRI for differentiation of MPNSTs were eligible for inclusion. Only studies reporting a direct comparison between these imaging methods were considered to establish precise summary estimates in the same setting of patients. RESULTS: The pooled estimate of sensitivity of FDG PET/CT was 0.99 and a pooled specificity of 0.53. The pooled estimate of sensitivity of MRI was 0.85 and a pooled specificity of 0.85. CONCLUSION: Analysis of the available studies indicated that FDG PET/CT and MRI had similar diagnostic performances for differentiation of MPNSTs in patients with NF1; however, either technique can be a complement to the other rather than being used singly.

Characterization of Immune Cell Populations of Cutaneous Neurofibromas in Neurofibromatosis 1.

Cutaneous neurofibromas (cNFs) are characteristic of neurofibromatosis 1 (NF1), yet their immune microenvironment is incompletely known. A total of 61 cNFs from 10 patients with NF1 were immunolabeled for different types of T cells and macrophages, and the cell densities were correlated with clinical characteristics. Eight cNFs and their overlying skin were analyzed for T cell receptor CDR domain sequences, and mass spectrometry of 15 cNFs and the overlying skin was performed to study immune-related processes. Intratumoral T cells were detected in all cNFs. Tumors from individuals younger than the median age of the study participants (33 years), growing tumors, and tumors smaller than the data set median showed increased T cell density. Most samples displayed intratumoral or peritumoral aggregations of CD3-positive cells. T cell receptor sequencing demonstrated that the skin and cNFs host distinct T cell populations, whereas no dominant cNF-specific T cell clones were detected. Unique T cell clones were fewer in cNFs than in skin, and mass spectrometry suggested lower expression of proteins related to T cell-mediated immunity in cNFs than in skin. CD163-positive cells, suggestive of M2 macrophages, were abundant in cNFs. Human cNFs have substantial T cell and macrophage populations that may be tumor-specific.

Neurofibroma: Case Series with Clinical Features and Recommendations.

Neurofibroma is an autosomal benign disorder. It can be localized, diffuse or invasive like plexiform neurofibroma that involves the nerves, muscle, tissues, skeleton. It represents itself as a destructive variant of neurofibroma, mostly present as orbital or periorbital neurofibroma or may be associated with autosomal dominant disease. Clinical diagnosis of neurofibromatosis (NF) according to National Institutes of Health (NIH) criteria should have more than two of the seven features including lisch nodules, cafe'- au-lait spots, plexiform neurofibroma, optic glioma, freckling, first degree relative with NF or dysplasia of cortical bones. However, proper early diagnosis is still crucial due to its various presentation such as cheek mass, painless swelling on skin, chalazion, intratracheal tumor, genital swelling or ptosis. It is reported that neurofibroma often represents as ocular or facial swelling. Here we are presenting features of neurofibroma of eight cases of patients from Civil Hospital, Karachi. These cases had main complain of overhanging skin mass mainly on orbital or periorbital region that damage the area and with poor daily activities. Multiple nodules on face and body along with them Cafe'-au-lait spots and lisch nodules were main signs. While, other signs i.e. ptosis, pterygium, telecanthus and muddy discoloration of conjunctiva need further evaluation for correlation with neurofibromatosis. Debulking surgery was planned for most of the cases but the huge disfigurement caused by overhanging skin mass and nodules made it a challenge for plastic surgeons to provide good outcomes with minimum damage. Keywords: neurofibroma; lisch nodules; ptosis; Cafe'-au-lait spot; periorbital; overhanging skin.

Quality of life in patients with neurofibromatosis type 1: a nationwide database study in Japan from 2015 to 2019.

BACKGROUND: This study examined the association between dermatological, neurological, and bone manifestations of neurofibromatosis type 1 (NF1) and quality of life (QoL) in patients with NF1 using a nationwide database of all patients who newly claimed for medical expense subsidies in Japan from 2015 to 2019. METHODS: The Japanese Ministry of Health, Labour and Welfare provided the "National Database of Designated Intractable Diseases of Japan" containing clinical and personal records ("Medical Certificates of Designated Intractable Diseases") of all patients with NF1 following approval of the study protocol. To examine the association between the severity of symptoms and QoL, multinominal logistic regression analyses were performed, adjusted for potential confounders. RESULTS: The final study population consisted of 1,487 patients (775 females and 712 males; mean (standard deviation) age, 45.4 (17.9) years). More than 50% and nearly 45% of participants were recorded as having moderate or severe "pain/discomfort" and "anxiety/depression," respectively. The severity of neurological symptoms was significantly associated with all components of QoL, whereas the severity of dermatological symptoms was significantly associated with only moderate or severe subjective and mental health-related components of QoL, and the severity of bone lesions was associated with only moderate or severe physical health-related components of QoL. Subjective and mental health-related components of QoL tended to be deteriorated more than physical health-related components of QoL in younger and female patients. CONCLUSIONS: Severities of neurological and dermatological symptoms were significantly associated with subjective and mental health-related components of QoL, while the severity of bone symptoms was associated with only moderate and severe deterioration of physical health-related components of QoL.

Automatic Visual Acuity Loss Prediction in Children with Optic Pathway Gliomas using Magnetic Resonance Imaging.

Children with optic pathway gliomas (OPGs), a low-grade brain tumor associated with neurofibromatosis type 1 (NF1-OPG), are at risk for permanent vision loss. While OPG size has been associated with vision loss, it is unclear how changes in size, shape, and imaging features of OPGs are associated with the likelihood of vision loss. This paper presents a fully automatic framework for accurate prediction of visual acuity loss using multi-sequence magnetic resonance images (MRIs). Our proposed framework includes a transformer-based segmentation network using transfer learning, statistical analysis of radiomic features, and a machine learning method for predicting vision loss. Our segmentation network was evaluated on multi-sequence MRIs acquired from 75 pediatric subjects with NF1-OPG and obtained an average Dice similarity coefficient of 0.791. The ability to predict vision loss was evaluated on a subset of 25 subjects with ground truth using cross-validation and achieved an average accuracy of 0.8. Analyzing multiple MRI features appear to be good indicators of vision loss, potentially permitting early treatment decisions.Clinical relevance- Accurately determining which children with NF1-OPGs are at risk and hence require preventive treatment before vision loss remains challenging, towards this we present a fully automatic deep learning-based framework for vision outcome prediction, potentially permitting early treatment decisions.

Multiple GISTand pheochromocytoma -A rare associationin neurofibromatosis type 1 / GIST múltipley feocromocitoma -Una asociación raraen neurofibromatosis tipo 1

We describe a case of coexistence of multiple gastrointestinal stromal tumors (GIST) and pheochromocytoma in a 32-year-old patient with neurofibromatosis type 1. The coexistence of these two conditions in patients with this syndrome is extremely rare.(AU)

[Symptomatic tumors in neurofibromatosis type 1: a diagnostic challenge]. / Symptomatische tumoren bij neurofibromatose type 1.

Neurofibromatosis type 1 (NF1) is a hereditary, progressive and unpredictable disease, which can involve many organs. Benign and malignant tumors arise due to unrestrained cell division and cell growth. Recognizing the symptoms of these tumors and using the correct diagnostics is of great importance. In this clinical lesson we show the disease course of 3 patients with NF1. In all 3, the disease course was complicated by a symptomatic tumor. Characteristic in these patients is the relatively long interval between the onset of symptoms and the final tumor diagnosis. In this clinical lesson we examine the causes of this in more detail and we emphasize the importance of the specific knowledge within the Dutch national NF1 care network.

Structural brain network changes in patients with neurofibromatosis type 1: A retrospective study.

We investigated the changes in structural connectivity (using diffusion tensor imaging [DTI]) and the structural covariance network based on structural volume using graph theory in patients with neurofibromatosis type 1 (NF1) compared to a healthy control group. We included 14 patients with NF1, according to international consensus recommendations, and 16 healthy individuals formed the control group. This was retrospectively observational study followed STROBE guideline. Both groups underwent brain magnetic resonance imaging including DTI and 3-dimensional T1-weighted imaging. We analyzed structural connectivity using DTI and Diffusion Spectrum Imaging Studio software and evaluated the structural covariance network based on the structural volumes using FreeSurfer and Brain Analysis Using Graph Theory software. There were no differences in the global structural connectivity between the 2 groups, but several brain regions showed significant differences in local structural connectivity. Additionally, there were differences between the global structural covariance networks. The characteristic path length was longer and the small-worldness index was lower in patients with NF1. Furthermore, several regions showed significant differences in the local structural covariance networks. We observed changes in structural connectivity and covariance networks in patients with NF1 compared to a healthy control group. We found that global structural efficiency is decreased in the brains of patients with NF1, and widespread changes in the local structural network were found. These results suggest that NF1 is a brain network disease, and our study provides direction for further research to elucidate the biological processes of NF1.

Perinatal folate levels do not influence tumor latency or multiplicity in a model of NF1 associated plexiform-like neurofibromas.

OBJECTIVE: In epidemiological and experimental research, high folic acid intake has been demonstrated to accelerate tumor development among populations with genetic and/or molecular susceptibility to cancer. Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder predisposing affected individuals to tumorigenesis, including benign plexiform neurofibromas; however, understanding of factors associated with tumor risk in NF1 patients is limited. Therefore, we investigated whether pregestational folic acid intake modified plexiform-like peripheral nerve sheath tumor risk in a transgenic NF1 murine model. RESULTS: We observed no significant differences in overall survival according to folate group. Relative to controls (180 days), median survival did not statistically differ in deficient (174 days, P = 0.56) or supplemented (177 days, P = 0.13) folate groups. Dietary folate intake was positively associated with RBC folate levels at weaning, (P = 0.023, 0.0096, and 0.0006 for deficient vs. control, control vs. supplemented, and deficient vs. supplemented groups, respectively). Dorsal root ganglia (DRG), brachial plexi, and sciatic nerves were assessed according to folate group. Mice in the folate deficient group had significantly more enlarged DRG relative to controls (P = 0.044), but no other groups statistically differed. No significant differences for brachial plexi or sciatic nerve enlargement were observed according to folate status.

Surgical management of craniospinal axis malignant peripheral nerve sheath tumors: a single-institution experience and literature review.

BACKGROUND: Malignant peripheral nerve sheath tumor (MPNST) is an exceedingly rare and aggressive tumor, with limited literature on its management. Herein, we present our series of surgically managed craniospinal MPNSTs, analyze their outcomes, and review the literature. METHODS: We retrospectively reviewed surgically managed primary craniospinal MPNSTs treated at our institution between January 2005 and May 2023. Patient demographics, tumor features, and treatment outcomes were assessed. Neurological function was quantified using the Frankel grade and Karnofsky performance scores. Descriptive statistics, rank-sum tests, and Kaplan-Meier survival analyses were performed. RESULTS: Eight patients satisfied the inclusion criteria (4 male, 4 female). The median age at presentation was 38 years (range 15-67). Most tumors were localized to the spine (75%), and 3 patients had neurofibromatosis type 1. The most common presenting symptoms were paresthesia (50%) and visual changes (13%). The median tumor size was 3 cm, and most tumors were oval-shaped (50%) with well-defined borders (75%). Six tumors were high grade (75%), and gross total resection was achieved in 5 patients, with subtotal resection in the remaining 3 patients. Postoperative radiotherapy and chemotherapy were performed in 6 (75%) and 4 (50%) cases, respectively. Local recurrence occurred in 5 (63%) cases, and distant metastases occurred in 2 (25%). The median overall survival was 26.7 months. Five (63%) patients died due to recurrence. CONCLUSIONS: Primary craniospinal MPNSTs are rare and have an aggressive clinical course. Early diagnosis and treatment are essential for managing these tumors. In this single-center study with a small cohort, maximal resection, low-grade pathology, young age (< 30), and adjuvant radiotherapy were associated with improved survival.

Integration of single-nuclei RNA-sequencing, spatial transcriptomics and histochemistry defines the complex microenvironment of NF1-associated plexiform neurofibromas.

Plexiform neurofibroma (PN) is a leading cause of morbidity in children with the genetic condition Neurofibromatosis Type 1 (NF1), often disfiguring or threatening vital structures. During formation of PN, a complex tumor microenvironment (TME) develops, with recruitment of neoplastic and non-neoplastic cell types being critical for growth and progression. Due to the cohesive cellularity of PN, single-cell RNA-sequencing is difficult and may result in a loss of detection of critical cellular subpopulations. To bypass this barrier, we performed single-nuclei RNA-sequencing (snRNA-seq) on 8 frozen PN samples, and integrated this with spatial transcriptomics (ST) in 4 PN samples and immunohistochemistry to provide morphological context to transcriptomic data. SnRNA-seq analysis definitively charted the heterogeneous cellular subpopulations in the PN TME, with the predominant fraction being fibroblast subtypes. PN showed a remarkable amount of inter-sample homogeneity regarding cellular subpopulation proportions despite being resected from a variety of anatomical locations. ST analysis identified distinct cellular subpopulations which were annotated using snRNA-seq data and correlated with histological features. Schwann cell/fibroblast interactions were identified by receptor/ligand interaction analysis demonstrating a high probability of Neurexin 1/Neuroligin 1 (NRXN1/NLGN1) receptor-ligand cross-talk predicted between fibroblasts and non-myelinated Schwann cells (NM-SC) and subtypes, respectively. We observed aberrant expression of NRXN1 and NLGN1 in our PN snRNA-seq data compared to a normal mouse sciatic nerve single-cell RNA-seq dataset. This pathway has never been described in PN and may indicate a clear and direct communication pathway between putative NM-SC cells of origin and surrounding fibroblasts, potentially driving disease progression. SnRNA-seq integrated with spatial transcriptomics advances our understanding of the complex cellular heterogeneity of PN TME and identify potential novel communication pathways that may drive disease progression, a finding that could provide translational therapy options for patients with these devastating tumors of childhood and early adulthood.