Individual Response to Radiation of Individuals with Neurofibromatosis Type I: Role of the ATM Protein and Influence of Statins and Bisphosphonates.

Neurofibromatosis type 1 (NF1) is a disease characterized by high occurrence of benign and malignant brain tumours and caused by mutations of the neurofibromin protein. While there is an increasing evidence that NF1 is associated with radiosensitivity and radiosusceptibility, few studies have dealt with the molecular and cellular radiation response of cells from individuals with NF1. Here, we examined the ATM-dependent signalling and repair pathways of the DNA double-strand breaks (DSB), the key-damage induced by ionizing radiation, in skin fibroblast cell lines from 43 individuals with NF1. Ten minutes after X-rays irradiation, quiescent NF1 fibroblasts showed abnormally low rate of recognized DSB reflected by a low yield of nuclear foci formed by phosphorylated H2AX histones. Irradiated NF1 fibroblasts also presented a delayed radiation-induced nucleoshuttling of the ATM kinase (RIANS), potentially due to a specific binding of ATM to the mutated neurofibromin in cytoplasm. Lastly, NF1 fibroblasts showed abnormally high MRE11 nuclease activity suggesting a high genomic instability after irradiation. A combination of bisphosphonates and statins complemented these impairments by accelerating the RIANS, increasing the yield of recognized DSB and reducing genomic instability. Data from NF1 fibroblasts exposed to radiation in radiotherapy and CT scan conditions confirmed that NF1 belongs to the group of syndromes associated with radiosensitivity and radiosusceptibility.

Vision Outcomes for Pediatric Patients With Optic Pathway Gliomas Associated With Neurofibromatosis Type I: A Systematic Review of the Clinical Evidence.

Children with neurofibromatosis type I (NF1) have a higher predisposition for low-grade astrocytomas of the optic pathway, commonly referred to as optic pathway gliomas (OPGs). OPGs can result in visual deterioration. Treatment outcomes in OPG-NF1 management are often reported around tumor stabilization. We sought to compare vision outcomes associated with different OPG treatment strategies to inform about this important functional metric. A meta-analysis exploring the different modalities to treat children with OPG-NF1 was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines using multiple databases. Of the 113 articles identified in the search, 23 full text articles, representing 564 patients, were included for review. These articles included retrospective, prospective, and randomized controlled studies on observation (n=9), chemotherapy (n=19), radiation therapy (n=6), and surgery (n=7). Of the patients undergoing observation, 87% (60/69) demonstrated stable acuity. In the chemotherapy studies, 27.3% (72/264) demonstrated improved acuity/visual field and/or visual-evoked potential amplitudes, 39.4% (104/264) stable acuity, and 33.3% (88/264) deterioration. Both the radiation and surgical treatments reported worsening acuity at 90.9% (10/11) and 73.3% (11/15), respectively. Causal associations are not known. Indications for and timing of treatment choice warrant larger scale study to provide further understanding.

Radiation Therapy for Optic Pathway and Hypothalamic Low-Grade Gliomas in Children.

PURPOSE: The long-term survival of pediatric patients with optic pathway or hypothalamic low-grade glioma (LGG) who receive radiation therapy (RT) has not been previously assessed. METHODS AND MATERIALS: A retrospective study was performed of all patients with optic-hypothalamic pediatric LGG treated with RT at a single institution. Eligible patients were aged ≤21 years at the time of RT and had localized LGG diagnosed by neuroimaging or histology. The median RT dose was 54 Gy, delivered in 30 fractions. Event-free survival (EFS) was defined as survival without progression or secondary high-grade glioma. Days were counted from the first day of RT. RESULTS: Eighty-nine patients were included in the study, with a median follow-up period of 12.5 years. Of the patients, 14 had neurofibromatosis type 1 (NF-1). The 10-year EFS rate was 61.9% (95% confidence interval [CI], 31.2%-82.1%) for patients with NF-1 and 67.5% (95% CI, 54.8%-77.3%) for those without NF-1. The 10-year overall survival rate was 92.3% (95% CI, 56.6%-98.9%) for patients with NF-1 and 98.4% (95% CI, 89.1%-99.8%) for those without NF-1. Pre-RT chemotherapy (which was more commonly given to younger patients) was associated with reduced EFS, whereas younger age was associated with reduced overall survival. Possible RT-induced neoplasms developed in 8 patients, including 4 with NF-1. The 10-year cumulative incidence of clinically significant vasculopathy was 7.1% (95% CI, 2.9%-13.9%); vasculopathy did not develop in any child aged >10 years at the commencement of RT. CONCLUSIONS: RT is an effective treatment for optic-hypothalamic LGG. Older children without NF-1 have a low risk of late toxicity. RT can be considered for selected younger patients or individuals with NF-1 as a salvage treatment after progression.

Radiation-induced gliomas in 2 pediatric patients with neurofibromatosis type 1: case study and summary of the literature.

Neurofibromatosis type 1 (NF1) is a genetic disorder that predisposes patients to the formation of sporadic tumors and also increases the risk of radiation-induced malignancies. The most commonly described radiation-induced tumor in NF1 patients is a malignant peripheral nerve sheath tumor. We present 2 children with NF1 who received radiation therapy and subsequently developed high-grade gliomas. We then review the current literature on radiation-induced tumors in NF1 patients. Although radiation may be the most appropriate therapy in specific situations for children with NF1, the secondary tumor risk should be carefully considered.

Narrowband ultraviolet B irradiation increases the serum level of vitamin D3 in patients with neurofibromatosis 1.

The serum vitamin D3 levels in patients with neurofibromatosis 1 has been reported to be significantly lower than that in control subjects, and the level of vitamin D3 reversely correlates with the severity of neurofibroma formation. We found that narrowband ultraviolet B (NB-UVB) irradiation increased the serum level of 1,25(OH)2 vitamin D3 in patients with neurofibromatosis 1. The difference in the 1,25(OH)2 vitamin D3 levels between patients who had received irradiation for more than 18 months and those who had no irradiation was highly significant. Time-course analyses of the serum vitamin D3 levels in the patients who were enrolled after informed consent revealed that the levels became higher significantly after 6 months of irradiation. It is suggested that NB-UVB irradiation is effective for increasing the serum level of vitamin D3 in patients with neurofibromatosis 1, which may be of benefit for skin symptoms such as pigmented macules or neurofibromas.

In vitro responses of neurofibroma fibroblasts, mast cells and Schwann cells obtained from patients with neurofibromatosis 1 to 308-nm excimer light and/or vitamin D3.

Fibroblasts, mast cells and Schwann cells were isolated from neurofibromas of patients with neurofibromatosis 1, and their responses to 308-nm excimer light irradiation and/or vitamin D3 or an analog (tacalcitol; 1,24-dihydroxyvitamin D3 ) were examined in vitro. Excimer light irradiation (300 mJ/cm(2) ) suppressed the growth of all three cell types. Exposure to 10(-7)  mol/L of 1α,25(OH)2 D3 (VD3 ) or tacalcitol suppressed the growth of fibroblasts and mast cells, but not Schwann cells. These results suggest that the different neurofibroma cell types show different responses to VD3 . A combination of excimer light irradiation and VD3 is necessary to suppress the growth of neurofibroma cells in vivo.

[A young woman with progressive cerebral atrophy]. / Een jonge vrouw met progressieve cerebrale atrofie.

A 21-year-old patient suffering from neurofibromatosis type 1 had received radiotherapy for a chiasm glioma 17 years ago. Fourteen years later, there was progressive deterioration of several neurological functions. MRI scans showed a progressively increasing volume loss of the left hemisphere and stenoses around the circle of Willis with secondary parenchymal effects. Based on conventional cerebral angiography, the diagnosis 'moyamoya syndrome' was made.

Malignant peripheral nerve sheath tumor of intracranial nerve: a case series review.

OBJECTIVES: The incidence of malignant peripheral nerve sheath tumor (MPNST) is approximately 0.001%. Those involving intracranial nerves are even more exceptional. Little information is available concerning work up and management. Our objective is: (1) to review all cases of intracranial MPNST described in the literature, (2) to highlight the suspicion of intracranial MPNST, (3) to identify the gross pathology, the histopathology, the immunohistochemistry, (4) to discuss the differential diagnosis, the treatment, the recurrence rate, the follow-up, the incidence of metastasis and the prognosis. METHODS: We reviewed English, Spanish and French literature published from 1950 to date. We used the following Keywords: "malignant peripheral nerve sheath tumor", "cranial nerve", "neurosarcoma", "malignant schwannoma", "neurofibroma", "malignant neurofibroma" and "nerve tumor". We considered cases where MPNST involved an intracranial cranial nerve. The results yielded 20 relevant studies, in which 31 patient's records were transcribed. We also added our case to this series. RESULTS: We identified 32 cases of cranial MPNST including our case. The age ranged from 5 to 75 years old with most patients being in the 5th and 6th decade. Male to female ratio is 2.5:1. Most cases are developed sporadically (50%), 31% arise from a malignant transformation of schwannoma and 19% from a neurofibroma. Imaging findings were not specific. The cranial nerve VIII is the most involved (15/32), followed by the Vth (10/32) and the VIIth (5/32). 4 cases had neurofibromatosis type 1 and 2 had neurofibromatosis type 2. MPNST will strongly express protein S-100 and collagen IV-laminin. 13 cases were treated with radiotherapy for tumor recurrence and metastasis. In these cases the survival rate was better than the cases without radiotherapy. Fatal outcome occurred in 66% of patients whereas 19% were reported alive with or without complications. The seven cases reported to have metastasis were entirely to the spine. The mean time of recurrence or metastasis is 12.2 months. CONCLUSION: MPNST of cranial nerves are very rare. In neurofibroma, even though MPNST is mainly associated to type 1, we should keep in mind its association to NF2. Mainstay of treatment is radical resection with adjuvant radiotherapy. Inaccessibility of cranial MPNST may explain the subtotal resection and thus the poor prognosis. Metastasis to the spinal cord is the most frequent one. A close postoperative follow-up is mandatory to eliminate recurrence.

[Optic pathway gliomas--current position and future directions].

Optic pathway gliomas (OPG) are the most common primary tumors of the visual pathways, and constitute 1% of all brain tumors and 5% of all brain tumors in children. Among Neurofibromatosis type 1 patients (a hereditary genetic disorder which is characterized by higher incidence of tumors from a neurocutaneous origin) it is the most frequent tumor and it constitutes between 15 to 20 percent of all nervous system tumors. These tumors are stable most of the time and remain indolent for many years after diagnosis, especially in patients suffering from Neurofibromatosis type 1. However, amongst some of the patients suffering from OPG, these tumors develop progressive characteristics and can cause visual disturbances, endocrine dysfunction, blindness and even death. Patients with aggressive tumors will need treatment, which can be either surgery, chemotherapy or radiation therapy. Today, the treating physicians face substantial difficulty in estimating the course the tumor will take, choosing the right candidates for oncological treatment and the type of therapy most suited to the case, due to lack of reliable information in the relevant literature. This article characterizes the tumors, presents updates from recent literature, as well as recommendations for treatment and follow-up.

Radiation-sensitive genetically susceptible pediatric sub-populations.

Major advances in pediatric cancer treatment have resulted in substantial improvements in survival. However, concern has emerged about the late effects of cancer therapy, especially radiation-related second cancers. Studies of childhood cancer patients with inherited cancer syndromes can provide insights into the interaction between radiation and genetic susceptibility to multiple cancers. Children with retinoblastoma (Rb), neurofibromatosis type 1 (NF1), Li-Fraumeni syndrome (LFS), and nevoid basal cell carcinoma syndrome (NBCCS) are at substantial risk of developing radiation-related second and third cancers. A radiation dose-response for bone and soft-tissue sarcomas has been observed in hereditary Rb patients, with many of these cancers occurring in the radiation field. Studies of NF1 patients irradiated for optic pathway gliomas have reported increased risks of developing another cancer associated with radiotherapy. High relative risks for second and third cancers were observed for a cohort of 200 LFS family members, especially children, possibly related to radiotherapy. Children with NBCCS are very sensitive to radiation and develop multiple basal cell cancers in irradiated areas. Clinicians following these patients should be aware of their increased genetic susceptibility to multiple primary malignancies enhanced by sensitivity to ionizing radiation.

Case report on a patient with neurofibromatosis type 1 and a frontal cystic glioblastoma.

Neurofibromatosis type 1 (NF1) is one of the most common dominantly inherited disorders. Astrocytomas, especially low-grade optic nerve tumours, are frequently harboured in these patients. In this paper, a case of a lobar cystic glioblastoma and NF1 in a 28-year-old woman is presented. This patient underwent a resection of the glioblastoma, followed a multimodal therapy including radiotherapy and chemotherapy, and survived 41 months. Neurofibromatosis is a multifaceted disease in which primary malignant CNS tumours, such as glioblastoma, can be identified. Glioblastomas in these patients should be managed like the usual ones. They may benefit from treatment with temozolomide, as can GBM patients without NF, thus potentially increasing the patient's overall survival.

A case of neurofibromatosis 1 presenting with optic pathway glioma with an early onset and an aggressive course.

Optic pathway glioma associated with neurofibromatosis 1 has a classically indolent course. However, involvement of the optic radiations is relatively rare and is associated with a more aggressive course. A three-year-old girl presented with strabismus and loss of vision in the left eye with relative afferent pupillary defect and optic disc pallor. She had multiple cafiota au lait spots. Visually evoked potential was suggestive of an optic nerve conduction defect and magnetic resonance imaging of the brain was suggestive of an optic pathway glioma involving the optic nerves, the optic chiasma and the optic tracts. The optic radiations and the dendate nuclei had hamartomas. Optic nerve biopsy confirmed pilocytic astrocytoma. Radical radiotherapy under general anesthesia was subsequently given. This case report aims to highlight the involvement of the optic radiations and the unusually aggressive clinical course in this case.

Moyamoya following cranial irradiation for primary brain tumors in children.

OBJECTIVE: To study the risk factors for the development of moyamoya syndrome after cranial irradiation for primary brain tumors in children. METHODS: We reviewed neuroimaging studies and dosimetry data for 456 children who were treated with radiation for a primary brain tumor and who were prospectively evaluated with serial neuroimaging studies and neurologic evaluations. A total of 345 patients had both adequate neuroimaging and radiation dosimetry data for further analysis. We used survival analysis techniques to examine the relationship of clinically important variables as risk factors for the development of moyamoya over time. RESULTS: Overall, 12 patients (3.5%) developed evidence of moyamoya. The onset of moyamoya was more rapid for patients with neurofibromatosis type 1 (NF1) (median of 38 vs 55 months) and for patients who received >5,000 cGy of radiation (median of 42 vs 67 months). In a multiple Cox proportional hazards regression analysis controlling for age at start of radiation, each 100-cGy increase in radiation dose increased the rate of moyamoya by 7% (hazard ratio [HR] = 1.07, 95% CI: 1.02 to 1.13, p = 0.01) and the presence of NF1 increased the rate of moyamoya threefold (HR = 3.07, 95% CI: 0.90 to 10.46, p = 0.07). CONCLUSIONS: Moyamoya syndrome is a potentially serious complication of cranial irradiation in children, particularly for those patients with tumors in close proximity to the circle of Willis, such as optic pathway glioma. Patients who received higher doses of radiation to the circle of Willis and with neurofibromatosis type 1 have increased risk of the development of moyamoya syndrome.

Anterior visual pathway gliomas: The last 30 years.

Modern neuroimaging provides excellent characterization of anterior visual pathway gliomas, often obviating the need for biopsy of the tumor. Management remains controversial, but if there is progression, chemotherapy is preferred for young patients. Stereotactically guided conformal radiotherapy and proton beam radiotherapy allow smaller, more precise doses of radiation to be administered and can be considered in older children with progressive disease. A mouse model of NF-1 with optic pathway gliomas has the potential to provide important insights into the development of gliomas as well as serving as a model for their effective treatment.

Assessment of sacrum scalloping in neurofibromatosis type 1 caused by a giant cell lesion of the sacrum.

BACKGROUND: Neurofibromatosis type 1 (NF-1) is the most common of the neurocutaneous disorders. It leads to significant orthopedic complications and spinal deformities. Scalloping in NF-1 may be caused by weakness of the mesodermal dysplasia, which develops through the inherited mutation of chromosome 17. Aneurysmal bone cysts (ABCs) are rare, rapidly expanding, locally destructive, and often misdiagnosed lesions. Assessment of sacrum scalloping in NF-1 caused by aneurysmal bone cyst is described. CASE DESCRIPTION: A 15-year-old male was a patient with NF-1. He presented with cramping pain of the left soleus muscle, which had developed over the previous 3 months. The magnetic resonance imaging of the lumbar-sacrum region revealed a well-circumscribed multiloculated lesion located in the dorsal sacrum region and causing posterior vertebral scalloping and compression of nerve roots. The preoperative clinical suspicion was of a neurofibroma, a giant cell granuloma, or a lymphoma. However, the histopathologic diagnosis was consistent with ABC of the sacrum. This differed from our preoperative suspicion. CONCLUSION: The etiology of ABCs is still unknown. Some researchers have described ABCs with chromosomal abnormalities of 16q22 and/or 17p13. This is consistent with NF-1, which develops through the inherited mutation of chromosome 17. Therefore, mutation of the chromosome may play an important role in the development of NF-1 and ABCs. Adequate diagnosis is necessary before treatment or biopsy of ABCs because bleeding may occur during operation or biopsy. Surgery is the treatment of choice for most ABCs. Adjuvant megavoltage radiotherapy is indicated for patients with recurrent tumors and whose tumors are inoperable.

Extended remission of a recurrent median nerve malignant peripheral nerve sheath tumor after multimodal treatment. Case report.

Malignant peripheral nerve sheath tumors (MPNSTs) are difficult to control despite aggressive treatment. In this report the authors describe the treatment and follow-up review of a patient with neurofibromatosis Type I who harbored a recurrent median nerve MPNST. The man underwent preoperative intraarterial and intravenous chemotherapy followed by additional surgery for gross-total removal and postoperative radiotherapy. Two courses of preoperative intraarterial cisplatin and intravenous Adriamycin produced significant tumor shrinkage. Gross-total removal of the remaining tumor without amputation of the arm was followed by fractionated radiotherapy (total minimum tumor dose 6485 cGy, maximal dose 6575 cGy). The patient is alive 9.5 years after treatment without evidence of tumor recurrence and with only focal median nerve functional deficits. A review of the patient's treatment is warranted to provide a description of a regimen that may be useful in the treatment of similar patients in the future.

Ophthalmic artery occlusion secondary to radiation-induced vasculopathy.

A 35-year-old man with neurofibromatosis type 1 (NF1) had a left ophthalmic artery occlusion that caused no light perception OS 28 years after having been treated with external beam radiation therapy for a presumed glioma of the right optic nerve and chiasm. Clinical and imaging findings were consistent with radiation-induced cerebral vasculopathy. This ophthalmic complication has never been reported, despite the common occurrence of severe carotid-ophthalmic artery junction stenosis after radiation in NF1 patients. Even though modern radiation techniques limit collateral damage, this modality should be used with discretion in NF1 patients, given the vulnerability of their immature cerebral vasculature to radiation.

Malignant peripheral nerve sheath tumors.

The rarity of MPNSTs and the lack of any singular diagnostic radiologic or pathologic signature lead to several management challenges. These tumors are best managed as part ofa multidisciplinary team so as to optimize patient care and facilitate research. Suspicion of an MPNST based on clinical or radiologic alteration of a soft tissue mass in proximity to a peripheral nerve, especially in the context of NF I, should lead to referral to such a tertiary center. Early diagnosis followed by oncologic surgery to obtain tumor-free margins provides the best chance for long-term cure. Psychologic support and occupational rehabilitation are vital components of the overall care of these relatively young patients faced with often disabling surgery. Current adjuvant therapy with radiation and chemotherapy is suboptimal. There have been major inroads toward the molecular biologic understanding of MPNSTs,with several biologic targets that are of potential therapeutic interest. Proper evaluation of these novel and promising management strategies requires a concerted effort to refer these patients to the tertiary centers through which multi-institutional clinical trials can be undertaken.

Malignant peripheral nerve sheath tumor in the anterior skull base associated with neurofibromatosis type 1--case report.

A 36-year-old man presented with a tumor in the anterior skull base manifesting as headache and visual disturbance. Neurofibromatosis type 1 (NF-1) was identified in early childhood in the patient, and also in his father. Subtotal excision of the tumor was performed, leaving the portion extending outside of the cranium. The histological diagnosis was malignant peripheral nerve sheath tumor. Local radiotherapy was instituted postoperatively. Facial paralysis and dysphagia appeared 7 months after the first operation. Magnetic resonance imaging revealed new lesions in the lateral ventricle and around the brainstem. These tumors were also subtotally excised, but the patient died 10 months after the first operation. The tumor very likely originated from the meningeal branch of the trigeminal nerve. Treatment of such tumors developing inside the cranium should include the widest resection possible, followed by irradiation of the entire neuraxis including the spinal cord to inhibit dissemination through the cerebrospinal fluid. Treatment should be started as quickly as possible if the tumor is associated with NF-1, because of the poor prognosis associated with this condition.