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.

Treatment evaluation by volumetric segmentation in pediatric optic pathway glioma: evaluation of the effect of bevacizumab on intra-tumor components.

PURPOSE: Progressive pediatric optic pathway gliomas (OPGs) are treated by diverse systemic antitumor modalities. Refined insights on the course of intra-tumoral components are limited. METHODS: We performed an exploratory study on the longitudinal volumetric course of different (intra-)tumor components by manual segmentation of MRI at the start and after 3, 6 and 12 months of bevacizumab (BVZ) treatment. RESULTS: Thirty-one patients were treated with BVZ (median 12 months, range: 2-39 months). During treatment the total tumor volume decreased with median 19.9% (range: - 62.3 to + 29.7%; n = 30) within the first 3 months, decreased 19.0% (range: - 68.8 to + 96.1%; n = 28) between start and 6 months and 27.2% (range: -73.4 to + 36.0%; n = 21) between start and 12 months. Intra-tumoral cysts were present in 12 OPGs, all showed a decrease of volume during treatment. The relative contrast enhanced volume of NF1 associated OPG (n = 11) showed an significant reduction compared to OPG with a KIAA1549-BRAF fusion (p < 0.01). Three OPGs progressed during treatment, but were not preceded by an increase of relative contrast enhancement. CONCLUSION: Treatment with BVZ of progressive pediatric OPGs leads to a decrease of both total tumor volume and cystic volume for the majority of OPGs with emphasis on the first three months. NF1 and KIAA1549-BRAF fusion related OPGs showed a different (early) treatment effect regarding the tumor enhancing component on MRI, which did not correlate with tumor volume changes. Future research is necessary to further evaluate these findings and its relevance to clinical outcome parameters.

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.

[Characteristics of primary ocular symptoms in children with optic pathway glioma at different ages].

Objective: To investigate the characteristics of initial ocular symptoms in children with optic pathway glioma (OPG) at different age stages. Methods: A retrospective case series study was conducted. Clinical data of 16 children with OPG who were diagnosed and treated in the Department of Ophthalmology, Beijing Children's Hospital, Capital Medical University from April 2017 to July 2021 were collected. The initial ocular symptoms, clinical manifestations of the eyes and nervous system, imaging and histopathological features were analyzed, and the differences in initial ocular symptoms between infants and young children aged≤36 months and older children aged>36 months were compared. Results: Of all 16 children included, 9 were male and 7 were female. The onset age was 15.0 (6.3, 56.5) months, and the diagnosis age was 48.0 (11.3, 78.0) months. There were 11 infants and young children, and 5 older children. Eye symptoms were the initial manifestation in 11 cases, including 8 cases of infants and young children (5 cases presented with irregular nystagmus, 2 cases with strabismus, and 1 case with failure to chase visual target), and 3 cases of older children (2 cases presented with decreased vision and 1 case with optic disc edema). The imaging findings showed that optic chiasm-involved OPG accounted for the highest proportion, with 3 cases in older children and 8 cases in infants and young children. Among the 8 children with optic chiasm-involved OPG who underwent surgical treatment, 5 were diagnosed with pilocytic astrocytoma according to histopathological results. Seven children had useful vision saved after treatment, and 1 child had visual loss accompanied by cognitive impairment due to surgery after 4 years of nystagmus. Conclusion: OPG in children often manifests as initial ocular symptoms, with irregular nystagmus being more common in infants and young children, and vision loss being the main symptom in older children.

[Clinical diagnosis and treatment of optic nerve glioma: a review].

Optic nerve glioma (ONG) is a relatively rare central nervous system tumor that mainly affects children and adolescents. It can be classified into sporadic and neurofibromatosis type 1 (NF1)-associated types. The histological type is mainly a low-grade pilocytic astrocytoma. The typical clinical manifestations are visual impairment and painless eye protrusion, and the imaging features mainly present as fusiform swelling or irregular masses. Chemotherapy is still the first-line treatment for ONG, and other treatment options include radiotherapy, surgical resection, and molecular targeted therapy. Screening and monitoring of NF1 patients are also crucial. The prognosis of ONG is difficult to predict, and close monitoring and timely effective intervention are necessary.

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.

Tumor load rather than contrast enhancement is associated with the visual function of children and adolescents with optic pathway glioma - a retrospective Magnetic Resonance Imaging study.

INTRODUCTION: Optic pathway gliomas are often asymptomatic tumors occurring in children with neurofibromatosis type 1 (NF1 + OPG) or sporadically (spOPG). Treatment is usually prompted by visual loss and/or tumor progression on MRI. The aim of this study was to investigate the relationship between visual acuity (VA), tumor growth, and contrast enhancement to provide more distinct indications for the administration of gadolinium-based contrast agents. METHODS: Tumor load was retrospectively measured and enhancement semi-quantitatively scored on 298 MRIs of 35 patients (63% NF1 + OPG). Spearman rank correlation between tumor load and enhancement was calculated and a linear mixed model used to examine the influence of tumor load and enhancement on corresponding VA tests (LogMAR). RESULTS: The optic nerve width in NF1 + OPGs was strongly associated with VA (regression coefficient 0.75; confidence interval 0.61-0.88), but weakly with enhancement (0.06; -0.04-0.15). In spOPGs, tumor volume and optic nerve width were more relevant (0.31; -0.19-0.81 and 0.39; 0.05-0.73) than enhancement (0.09; -0.09-0.27). CONCLUSIONS: Tumor load measures may be more relevant for the surveillance of optic pathway gliomas than enhancement, given that VA is the relevant outcome parameter. Regular contrast administration should therefore be questioned in these patients.

Correlation Between Ophthalmologic and Neuroradiologic Findings in Type 1 Neurofibromatosis.

BACKGROUND: Neurofibromatosis Type 1 (NF-1) is a genetic disease affecting the eye, and ocular findings such as Lisch nodules (LN) or optic pathway gliomas (OPGs) are a part of its diagnostic criteria. Recent imaging technologies such as infrared (IR) imaging and optical coherence tomography (OCT) have highlighted the visualization of choroidal focal abnormalities in these patients, even in the absence of other ocular lesions. This study aimed to establish a morphological multimodal evaluation of choroidal findings in patients with NF-1, correlating them with central nervous system (CNS) findings. METHODS: This retrospective study included 44 eyes from 22 patients with NF-1. Central 30° IR imaging was obtained, and the number and total area of detectable lesions were calculated. Both macular and optic disc scanning with OCT were performed, with and without the enhanced depth imaging technique, to assess the presence of choroidal focal hyperreflective lesions. Central macular thickness, ganglion cell layer, and outer nuclear layer thickness were assessed, as well as subfoveal choroidal thickness. The peripapillary retinal nerve fiber layer (RNFL) thickness was also assessed. Patients' magnetic resonance images (MRI) were reviewed and categorized by a neuroradiology specialist, determining the presence of OPGs and CNS hamartomas. Correlations between the ophthalmological and neuroradiological findings were established. RESULTS: Patients' mean age was 16.4 ± 7.3 years and 59.1% were women. On the MRI, 86.4% of the patients had CNS hamartomas, and 34.1% of the eyes had OPGs. LN were described in 29.5% of the eyes, whereas a total of 63.4% of the eyes presented the characteristic hyperreflective lesions in IR imaging, all of them matching the underlying choroidal lesions. A mean of 2.9 ± 3.3 lesions per eye and a median total lesion area of 1.52 mm2 were found. The presence of OPGs was correlated with a greater number (P = 0.004) and a larger area (P = 0.006) of IR lesions. For a cut-off of 3.5 lesions per eye, the sensitivity and specificity for the presence of OPGs were 75% and 80%, respectively. For a total lesion area of 2.77 mm2, the sensitivity and specificity for the presence of OPGs were 69.2% and 93.1%, respectively. Eyes with OPGs presented a significant reduction in the temporal RNFL (P = 0.018) thickness, as well as a reduction in subfoveal choroid thickness (P = 0.04). No relations were found between CNS hamartomas and ophthalmological findings. CONCLUSIONS: This study suggests that focal choroidal abnormalities are correlated with the presence of CNS lesions as OPGs in patients with NF-1, and it might be a surrogate for the need for CNS imaging in these patients.

Asthma reduces glioma formation by T cell decorin-mediated inhibition of microglia.

To elucidate the mechanisms underlying the reduced incidence of brain tumors in children with Neurofibromatosis type 1 (NF1) and asthma, we leverage Nf1 optic pathway glioma (Nf1OPG) mice, human and mouse RNAseq data, and two different experimental asthma models. Following ovalbumin or house dust mite asthma induction at 4-6 weeks of age (WOA), Nf1OPG mouse optic nerve volumes and proliferation are decreased at 12 and 24 WOA, indicating no tumor development. This inhibition is accompanied by reduced expression of the microglia-produced optic glioma mitogen, Ccl5. Human and murine T cell transcriptome analyses reveal that inhibition of microglia Ccl5 production results from increased T cell expression of decorin, which blocks Ccl4-mediated microglia Ccl5 expression through reduced microglia NFκB signaling. Decorin or NFκB inhibitor treatment of Nf1OPG mice at 4-6 WOA inhibits tumor formation at 12 WOA, thus establishing a potential mechanistic etiology for the attenuated glioma incidence observed in children with asthma.

Optic pathway glioma and the sex association in neurofibromatosis type 1: a single-center study.

BACKGROUND: Low-grade optic pathway glioma (OPG) develops in 15-20% of children with neurofibromatosis type 1 (NF1). OPGs are symptomatic in 30-50% and one-third of these require treatment. A few studies have suggested female sex as a risk factor for visual impairment associated with NF1-OPG. This descriptive study investigated the correlation between NF1-OPG growth, sex and visual impairment. METHOD: We based our cross-sectional study on a systematic, retrospective data collection in a NF1 cohort of children and adolescents below 21 years of age followed at Center for Rare Diseases, Aarhus University Hospital, Denmark. For each patient with OPG a medical chart review was performed including demographics, ophthalmological examinations and magnetic resonance imaging (MRI) of OPG. RESULTS: Of 176 patients with NF1 (85 females, 91 males), we identified 21 patients with OPG (11.9%) with a preponderance of females, p = 0.184. Eight females (62%) and one male (13%) had visual impairment at the last ophthalmological evaluation. Five out of 21 children with OPG (24%) underwent diagnostic MRI because of clinical findings at the ophthalmological screening. Nine children (43%) had symptoms suggestive of OPG and seven (33%) experienced no OPG-related symptoms before the diagnostic MRI. Of eight children diagnosed with OPG ≤ two years of age, one had visual impairment. Of 13 children diagnosed > two years of age, eight had visual impairment; in each group, four of the children were treated with chemotherapy. The study suggested no correlation between NF1-OPG growth and sex. CONCLUSION: Our data suggest sex as a risk factor for visual impairment, while an OPG diagnose ≤ two years of age was a protective factor for visual impairment. Females with NF1-OPG had a higher prevalence of visual impairment outcome compared to males. Interestingly, our data also suggest a better response to treatment in children with OPG diagnosed ≤ two years of age compared to older children. The findings in our study suggest sex as a potential prognostic factor for visual impairment.

Treatment during a developmental window prevents NF1-associated optic pathway gliomas by targeting Erk-dependent migrating glial progenitors.

The mechanism of vulnerability to pediatric low-grade gliomas (pLGGs)-the most common brain tumor in children-during development remains largely unknown. Using mouse models of neurofibromatosis type 1 (NF1)-associated pLGGs in the optic pathway (NF1-OPG), we demonstrate that NF1-OPG arose from the vulnerability to the dependency of Mek-Erk/MAPK signaling during gliogenesis of one of the two developmentally transient precursor populations in the optic nerve, brain-derived migrating glial progenitors (GPs), but not local progenitors. Hyperactive Erk/MAPK signaling by Nf1 loss overproduced GPs by disrupting the balance between stem-cell maintenance and gliogenesis of hypothalamic ventricular zone radial glia (RG). Persistence of RG-like GPs initiated NF1-OPG, causing Bax-dependent apoptosis in retinal ganglion cells. Removal of three Mek1/Mek2 alleles or transient post-natal treatment with a low-dose MEK inhibitor normalized differentiation of Nf1-/- RG-like GPs, preventing NF1-OPG formation and neuronal degeneration. We provide the proof-of-concept evidence for preventing pLGGs before tumor-associated neurological damage enters an irreversible phase.

NF1 mutation drives neuronal activity-dependent initiation of optic glioma.

Neurons have recently emerged as essential cellular constituents of the tumour microenvironment, and their activity has been shown to increase the growth of a diverse number of solid tumours1. Although the role of neurons in tumour progression has previously been demonstrated2, the importance of neuronal activity to tumour initiation is less clear-particularly in the setting of cancer predisposition syndromes. Fifteen per cent of individuals with the neurofibromatosis 1 (NF1) cancer predisposition syndrome (in which tumours arise in close association with nerves) develop low-grade neoplasms of the optic pathway (known as optic pathway gliomas (OPGs)) during early childhood3,4, raising  the possibility that postnatal light-induced activity of the optic nerve drives tumour initiation. Here we use an authenticated mouse model of OPG driven by mutations in the neurofibromatosis 1 tumour suppressor gene (Nf1)5 to demonstrate that stimulation of optic nerve activity increases optic glioma growth, and that decreasing visual experience via light deprivation prevents tumour formation and maintenance. We show that the initiation of Nf1-driven OPGs (Nf1-OPGs) depends on visual experience during a developmental period in which Nf1-mutant mice are susceptible to tumorigenesis. Germline Nf1 mutation in retinal neurons results in aberrantly increased shedding of neuroligin 3 (NLGN3) within the optic nerve in response to retinal neuronal activity. Moreover, genetic Nlgn3 loss or pharmacological inhibition of NLGN3 shedding blocks the formation and progression of Nf1-OPGs. Collectively, our studies establish an obligate role for neuronal activity in the development of some types of brain tumours, elucidate a therapeutic strategy to reduce OPG incidence or mitigate tumour progression, and underscore the role of Nf1mutation-mediated dysregulation of neuronal signalling pathways in mouse models of the NF1 cancer predisposition syndrome.

Grating visual acuity impairment assessed by sweep visually evoked potentials in children with optic pathway tumors unable to perform optotype acuity tests / Deficiência na acuidade visual de grades avaliada pelos potenciais visuais evocados de varredura em crianças com tumores da via óptica incapazes de informar a acuidade de optotipos

ABSTRACT Purpose: To determine visual impairment due to optic pathway tumors in children unable to perform recognition acuity tests. Methods: Grating visual acuity scores, in logMAR, were obtained by sweep visually evoked potentials (SVEP) in children with optic pathway tumors. The binocular grating visual acuity deficit was calculated by comparison with age-based norms and then assigned to categories of visual impairment as mild (from 0.10 to 0.39 logMAR), moderate (from 0.40 to 0.79 logMAR), or severe (≥0.80 logMAR). Interocular differences were calculated by subtraction and considered increased if >0.10 logMAR. Results: The participants were 25 children (13 boys; mean ± SD age, 35.1 ± 25.9 months; median age, 32.0 months) with optic pathway tumors (24 gliomas and 1 embryonal tumor), mostly located at the hypothalamic-chiasmatic transition (n=21; 84.0%) with visual abnormalities reported by parents (n=17; 68.0%). The mean grating acuity deficit was 0.60 ± 0.36 logMAR (median, 0.56 logMAR). Visual impairment was detected in all cases and was classified as mild in 10 (40.0%), moderate in 8 (32.0%), and severe in 7 (28.0%) children, along with increased interocular differences (>0.1 logMAR) (n=16; 64.0%). The remarkable ophthalmological abnormalities were nystagmus (n=17; 68.0%), optic disc cupping and/or pallor (n=13; 52.0%), strabismus (n=12; 48.0%), and poor visual behavior (n=9; 36.0%). Conclusion: In children with optic pathway tumors who were unable to perform recognition acuity tests, it was possible to quantify visual impairment by sweep-visually evoked potentials and to evaluate interocular differences in acuity. The severity of age-based grating visual acuity deficit and interocular differences was in accordance with ophthalmological abnormalities and neuroimaging results. Grating visual acuity deficit is useful for characterizing visual status in children with optic pathway tumors and for supporting neuro-oncologic management.(AU)

RESUMO Objetivo: Determinar o grau de deficiência visual em crianças com tumores da via óptica incapazes de informar a acuidade visual de reconhecimento. Método: A acuidade visual de grades, em logMAR, foi estimada por potenciais visuais evocados de varredura em crianças com tumores das vias ópticas. O déficit da acuidade visual de grades binocular foi calculado em relação ao valor mediano normativo esperado para a idade e a deficiência visual, classificada como leve (0,10 a 0,39 logMAR), moderada (0,40 a 0,79 logMAR) ou grave (≥0,80 logMAR). Diferenças inter-oculares foram calculadas por subtração e consideradas aumentadas se >0,10 logMAR. Resultados: Foram avaliadas 25 crianças (13 meninos; média de idade ± DP=35,1± 25,9 meses; mediana=32,0 meses) com tumores da via óptica (24 gliomas e 1 tumor embrionário) localizados particularmente na transição hipotalâmico-quiasmática (n=21; 84,0%) e com anormalidades visuais detectadas pelos pais (n=17; 68,0%). A média do déficit da acuidade de grades foi 0,60 ± 0,36 logMAR (mediana=0,56 logMAR). Observou-se deficiência visual leve em 10 (40,0%), moderada em 8 (32,0%) e grave em 7 (28,0%), além de aumento da diferença interocular da acuidade visual (n=16; 64,0%). As principais alterações oftalmológicas encontradas foram: nistagmo (n=17; 68,0%), aumento da escavação do disco óptico e/ou palidez (n=13; 52,0%), estrabismo (n=12; 48,0%) e comportamento visual pobre (n=9; 36,0%). Conclusão: Em crianças com tumor da via óptica e incapazes de responder aos testes de acuidade visual de reconhecimento, foi possível quantificar deficiência visual por meio dos potenciais visuais evocados de varredura e avaliar a diferença interocular da acuidade visual de grades. A gravidade do déficit da acuidade visual de grades relacionado à idade e a diferença interocular da acuidade visual de grades foram congruentes com alterações oftalmológicas e neuroimagem. O déficit da acuidade visual de grades foi útil à caracterização do estado visual em crianças com tumores da via óptica e ao embasamento da assistência neuro-oncológica.(AU)

Genetic characterization of an aggressive optic nerve pilocytic glioma.

Optic nerve glioma (ONG) is a rare, typically slow-growing WHO I grade tumor that affects the visual pathways. ONG is most commonly seen in the pediatric population, in association with neurofibromatosis type 1 syndrome. However, sporadic adult cases may also occur and may clinically behave more aggressively, despite benign histopathology. Genetic characterization of these tumors, particularly in the adult population, is lacking. A 39-year-old female presented with 1 month of progressive left-sided visual loss secondary to a enhancing mass along the left optic nerve sheath. Initial empiric management with focal radiotherapy failed to prevent tumor progression, prompting open biopsy which revealed a WHO I pilocytic astrocytoma of the optic nerve. Whole-exome sequencing of the biopsy specimen revealed somatic mutations in NF1,FGFR1 and PTPN11 that may provide actionable targets for molecularly guided therapies. Genetic characterization of ONG is lacking but is needed to guide the management of these rare but complex tumors. The genomic alterations reported in this case contributes to understanding the pathophysiology of adult sporadic ONG and may help guide future clinical prognostication and development of targeted therapies.

Neurofibromatosis Type 1-Associated Optic Pathway Glioma in Children: A Follow-Up of 10 Years or More.

PURPOSE: This study reports on neurofibromatosis type 1 (NF1)-associated optic pathway gliomas (OPGs) and a follow-up period of at least 10 years in a cohort of children. OPGs are a common manifestation of NF1 and can cause significant visual morbidity. Long-term follow-up in children with NF1-associated OPGs has not been reported previously. DESIGN: Retrospective observational case series. METHODS: This study included children with a documented follow-up of at least 10 years. Three final outcomes were evaluated: visual acuity (VA) per eye (i.e., in the more severely affected eye), VA per patient (i.e., VA when both eyes were open), and the presence of optic nerve head pallor. RESULTS: A total of 45 children were included, followed for a mean of 14 years (range, 10-21 years). At the end of follow-up, abnormal VA (considered moderate to severe impairment) in the more severely affected eye was present in 36% of the patients and in both eyes in 11%. Optic nerve head pallor of 1 or both nerves was present in 62%. In multivariate analysis, only initial VA and optic nerve head appearance at presentation were found to predict the final outcomes. All patients, except for 1, were asymptomatic at presentation and had normal VA and nerves that appeared normal, preserved their good vision in both eyes. Only 1 patient, who had normal VA and normal appearing nerves at presentation, had moderate to severe VA loss at long term follow-up. CONCLUSIONS: In this study, children with NF1-associated OPG whose examination signs and symptoms were normal had a normal initial examination and excellent long-term visual and anatomical outcomes. VA and the appearance of the optic nerve head at presentation predict long-term outcome.

Co-occurrence of neurofibromatosis type 1 and optic nerve gliomas with autosomal dominant polycystic kidney disease type 2.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) and neurofibromatosis type 1 (NF1) are both autosomal dominant disorders with a high rate of novel mutations. However, the two disorders have distinct and well-delineated genetic, biochemical, and clinical findings. Only a few cases of coexistence of ADPKD and NF1 in a single individual have been reported, but the possible implications of this association are unknown. METHODS: We report an ADPKD male belonging to a family of several affected members in three generations associated with NF1 and optic pathway gliomas. The clinical diagnosis of ADPKD and NF1 was performed by several image techniques. RESULTS: Linkage analysis of ADPKD family was consistent to the PKD2 locus by a nonsense mutation, yielding a truncated polycystin-2 by means of next-generation sequencing. The diagnosis of NF1 was confirmed by mutational analysis of this gene showing a 4-bp deletion, resulting in a truncated neurofibromin, as well. The impact of this association was investigated by analyzing putative genetic interactions and by comparing the evolution of renal size and function in the proband with his older brother with ADPKD without NF1 and with ADPKD cohorts. CONCLUSION: Despite the presence of both conditions there was not additive effect of NF1 and PKD2 in terms of the severity of tumor development and/or ADPKD progression.

Midkine activation of CD8+ T cells establishes a neuron-immune-cancer axis responsible for low-grade glioma growth.

Brain tumors (gliomas) are heterogeneous cellular ecosystems, where non-neoplastic monocytic cells have emerged as key regulators of tumor maintenance and progression. However, relative to macrophages/microglia, comparatively less is known about the roles of neurons and T cells in glioma pathobiology. Herein, we leverage genetically engineered mouse models and human biospecimens to define the axis in which neurons, T cells, and microglia interact to govern Neurofibromatosis-1 (NF1) low-grade glioma (LGG) growth. NF1-mutant human and mouse brain neurons elaborate midkine to activate naïve CD8+ T cells to produce Ccl4, which induces microglia to produce a key LGG growth factor (Ccl5) critical for LGG stem cell survival. Importantly, increased CCL5 expression is associated with reduced survival in patients with LGG. The elucidation of the critical intercellular dependencies that constitute the LGG neuroimmune axis provides insights into the role of neurons and immune cells in controlling glioma growth, relevant to future therapeutic targeting.