scholarly journals Safe marginal resection of atypical neurofibromas in neurofibromatosis type 1

2020 ◽  
Vol 133 (5) ◽  
pp. 1516-1526 ◽  
Author(s):  
Charlie N. Nelson ◽  
Eva Dombi ◽  
Jared S. Rosenblum ◽  
Markku M. Miettinen ◽  
Tanya J. Lehky ◽  
...  
Keyword(s):  
Neurofibromatosis Type 1 ◽  
Fdg Pet ◽  
Standardized Uptake Value ◽  
Neurofibromatosis Type ◽  
Subtotal Resection ◽  
Histopathological Analysis ◽  
Low Grade ◽  
Surgical Morbidity ◽  
Peripheral Nerve Sheath Tumors

OBJECTIVEPatients with neurofibromatosis type 1 (NF1) are predisposed to visceral neurofibromas, some of which can progress to premalignant atypical neurofibromas (ANFs) and malignant peripheral nerve sheath tumors (MPNSTs). Though subtotal resection of ANF may prevent malignant transformation and thus deaths with no neural complications, local recurrences require reoperation. The aim of this study was to assess the surgical morbidity associated with marginal resection of targeted ANF nodules identified via preoperative serial volumetric MRI and 18F-FDG-PET imaging.METHODSThe authors analyzed clinical outcomes of 16 NF resections of 21 tumors in 11 NF1 patients treated at the NIH Clinical Center between 2008 and 2018. Preoperative volumetric growth rates and 18F-FDG-PET SUVMax (maximum standardized uptake value within the tumor) of the target lesions and any electromyographic or nerve conduction velocity abnormalities of the parent nerves were measured and assessed in tandem with postoperative complications, histopathological classification of the resected tumors, and surgical margins through Dunnett’s multiple comparisons test and t-test. The surgical approach for safe marginal resection of ANF was also described.RESULTSEleven consecutive NF1 patients (4 male, 7 female; median age 18.5 years) underwent 16 surgical procedures for marginal resections of 21 tumors. Preoperatively, 13 of the 14 (93%) sets of serial MRI studies and 10 of the 11 (91%) 18F-FDG-PET scans showed rapid growth (≥ 20% increase in volume per year) and avidity (SUVMax ≥ 3.5) of the identified tumor, respectively (median tumor size 48.7 cm3; median growth rate 92% per year; median SUVMax 6.45). Most surgeries (n = 14, 88%) resulted in no persistent postoperative parent nerve–related complications, and to date, none of the resected tumors have recurred. The median length of postoperative follow-up has been 2.45 years (range 0.00–10.39 years). Histopathological analysis confirmed significantly greater SUVMax among the ANFs (6.51 ± 0.83, p = 0.0042) and low-grade MPNSTs (13.8, p = 0.0001) than in benign neurofibromas (1.9).CONCLUSIONSThis report evaluates the utility of serial imaging (MRI and 18F-FDG-PET SUVMax) to successfully detect ANF and demonstrates that safe, fascicle-sparing gross-total, extracapsular resection of ANF is possible with the use of intraoperative nerve stimulation and microdissection of nerve fascicles.

scholarly journals Fascicle Sparing Capsular Resections of Atypical Neurofibromas in Neurofibromatosis 1

Neurosurgery ◽  
2019 ◽  
Vol 66 (Supplement_1) ◽  
Author(s):  
Charlie Nelson ◽  
Eva Dombi ◽  
Jared S Rosenblum ◽  
Markku Miettenen ◽  
Tanya Lehky ◽  
...  
Keyword(s):  
Rapid Growth ◽  
Fdg Pet ◽  
Subtotal Resection ◽  
Low Grade ◽  
Volumetric Growth ◽  
Surgical Morbidity ◽  
Histopathological Classification ◽  
Peripheral Nerve Sheath Tumors ◽  
18F Fdg ◽  
Extracapsular Resection

Abstract INTRODUCTION Neurofibromatosis type 1 (NF1) patients are predisposed to neurofibromas (NF), which can progress to premalignant atypical neurofibromas (ANF) and malignant peripheral nerve sheath tumors (MPNST). Subtotal resection of ANF may prevent metastases and deaths, but local recurrences require reoperation. Here, we assess the surgical morbidity associated with gross total, extracapsular resection of targeted ANF nodules identified via serial volumetric magnetic resonance imaging (MRI) and 18F-FDG-PET imaging. METHODS We retrospectively analyzed the clinical outcomes of 11 NF1 patients following 16 NF surgical resections of 21 tumors at the NIH Clinical Center between 2008 and 2018. Preoperative volumetric growth rates and 18F-FDG-PET SUVMAX of the target lesions were measured and assessed in tandem with postoperative complications, histopathological classification of the resected tumors, and surgical margins through Dunnett's multiple comparison tests and t-tests. RESULTS Preoperatively, 13 of the 14 (93%) sets of serial preoperative MRI scans showed rapid growth ( = 20% increase in volume per year), and 10 of the 11 (91%) 18F-FDG-PET scans indicated increased positron emission tomography (PET) avidity (median SUVMax = 6.45). Gross total, extracapsular resections of the targeted neurofibroma nodules were annotated by the surgeon in all 16 (100%) surgeries, and most surgeries (n = 14, 88%) resulted in no persistent postoperative parent nerve-related complications. SUVMax was significantly greater in the ANF (6.51 ± 0.83, P = .0042) and low grade MPNST (13.8, P = .0001) strata than in the benign NF (1.9) stratum. To date, none of the resected NF have recurred. CONCLUSION This study confirms that the combination of increased 18F-FDG-PET SUVMax, rapid growth, and pain can serve as reliable indicators of atypical transformation and the need for surgical intervention. We also demonstrate the ability to achieve safe, fascicle-sparing gross total, extracapsular resection of ANF using intraoperative nerve stimulation, histological verification, and continued monitoring for tumor recurrence.

scholarly journals Malignant peripheral nerve sheath tumor with and without neurofibromatosis type 1

2017 ◽  
Vol 75 (6) ◽  
pp. 366-371 ◽  
Author(s):  
Roberto André Torres de Vasconcelos ◽  
Pedro Guimarães Coscarelli ◽  
Regina Papais Alvarenga ◽  
Marcus André Acioly
Keyword(s):  
Overall Survival ◽  
Peripheral Nerve ◽  
Neurofibromatosis Type 1 ◽  
Tumor Size ◽  
Retrospective Chart Review ◽  
Neurofibromatosis Type ◽  
Nerve Sheath Tumor ◽  
Peripheral Nerve Sheath Tumors ◽  
Nerve Sheath

ABSTRACT Objective In this study, we review the institution’s experience in treating malignant peripheral nerve sheath tumors (MPNSTs). A secondary aim was to compare outcomes between MPNSTs with and without neurofibromatosis type 1 (NF1). Methods Ninety-two patients with MPNSTs, over a period of 20 years, were reviewed. A retrospective chart review was performed. The median age was 43.5 years (range, 3–84 years) and 55.4% were female; 41 patients (44.6%) had NF1-associated tumors. Results Mean tumor sizes were 15.8 ± 8.2 cm and 10.8 ± 6.3 cm for patients with and without NF1, respectively. Combined two- and five-year overall survival was 48.5% and 29%. Multivariate analysis confirmed the association of tumor size greater than 10 cm (hazard ratio (HR) 2.99; 95% confidence interval (CI) 1.14–7.85; p = 0.0258) and presence of NF1 (HR 3.41; 95%CI 1.88–6.19; p < 0.001) with a decreased overall survival. Conclusion Tumor size and NF1 status were the most important predictors of overall survival in our population.

scholarly journals New Model Systems and the Development of Targeted Therapies for the Treatment of Neurofibromatosis Type 1-Associated Malignant Peripheral Nerve Sheath Tumors

Genes ◽  
2020 ◽  
Vol 11 (5) ◽  
pp. 477 ◽  
Author(s):  
Kyle B. Williams ◽  
David A. Largaespada
Keyword(s):  
Schwann Cell ◽  
Peripheral Nerve ◽  
Neurofibromatosis Type 1 ◽  
Single Agent ◽  
Neurofibromatosis Type ◽  
Mek Inhibitors ◽  
Nerve Sheath Tumors ◽  
Peripheral Nerve Sheath Tumors ◽  
Nerve Sheath

Neurofibromatosis Type 1 (NF1) is a common genetic disorder and cancer predisposition syndrome (1:3000 births) caused by mutations in the tumor suppressor gene NF1. NF1 encodes neurofibromin, a negative regulator of the Ras signaling pathway. Individuals with NF1 often develop benign tumors of the peripheral nervous system (neurofibromas), originating from the Schwann cell linage, some of which progress further to malignant peripheral nerve sheath tumors (MPNSTs). Treatment options for neurofibromas and MPNSTs are extremely limited, relying largely on surgical resection and cytotoxic chemotherapy. Identification of novel therapeutic targets in both benign neurofibromas and MPNSTs is critical for improved patient outcomes and quality of life. Recent clinical trials conducted in patients with NF1 for the treatment of symptomatic plexiform neurofibromas using inhibitors of the mitogen-activated protein kinase (MEK) have shown very promising results. However, MEK inhibitors do not work in all patients and have significant side effects. In addition, preliminary evidence suggests single agent use of MEK inhibitors for MPNST treatment will fail. Here, we describe the preclinical efforts that led to the identification of MEK inhibitors as promising therapeutics for the treatment of NF1-related neoplasia and possible reasons they lack single agent efficacy in the treatment of MPNSTs. In addition, we describe work to find targets other than MEK for treatment of MPNST. These have come from studies of RAS biochemistry, in vitro drug screening, forward genetic screens for Schwann cell tumors, and synthetic lethal screens in cells with oncogenic RAS gene mutations. Lastly, we discuss new approaches to exploit drug screening and synthetic lethality with NF1 loss of function mutations in human Schwann cells using CRISPR/Cas9 technology.

scholarly journals A phase II study of continuous oral mTOR inhibitor everolimus for recurrent, radiographic-progressive neurofibromatosis type 1–associated pediatric low-grade glioma: a Neurofibromatosis Clinical Trials Consortium study

2020 ◽  
Vol 22 (10) ◽  
pp. 1527-1535 ◽  
Author(s):  
Nicole J Ullrich ◽  
Sanjay P Prabhu ◽  
Alyssa T Reddy ◽  
Michael J Fisher ◽  
Roger Packer ◽  
...  
Keyword(s):  
Phase Ii ◽  
Neurofibromatosis Type 1 ◽  
Mtor Inhibitor ◽  
Neurofibromatosis Type ◽  
Mtor Pathway ◽  
Pharmacokinetic Parameters ◽  
Low Grade ◽  
Nerve Sheath Tumor ◽  
Pathway Inhibition

Abstract Background Activation of the mammalian target of rapamycin (mTOR) pathway is observed in neurofibromatosis type 1 (NF1) associated low-grade gliomas (LGGs), but agents that inhibit this pathway, including mTOR inhibitors, have not been studied in this population. We evaluate the efficacy of the orally administered mTOR inhibitor everolimus for radiographically progressive NF1-associated pediatric LGGs. Methods Children with radiologic-progressive, NF1-associated LGG and prior treatment with a carboplatin-containing chemotherapy were prospectively enrolled on this phase II clinical trial to receive daily everolimus. Whole blood was analyzed for everolimus and markers of phosphatidylinositol-3 kinase (PI3K)/mTOR pathway inhibition. Serial MRIs were obtained during treatment. The primary endpoint was progression-free survival at 48 weeks. Results Twenty-three participants (median age, 9.4 y; range, 3.2–21.6 y) were enrolled. All participants were initially evaluable for response; 1 patient was removed from study after development of a malignant peripheral nerve sheath tumor. Fifteen of 22 participants (68%) demonstrated a response, defined as either shrinkage (1 complete response, 2 partial response) or arrest of tumor growth (12 stable disease). Of these, 10/15 remained free of progression (median follow-up, 33 mo). All remaining 22 participants were alive at completion of therapy. Treatment was well tolerated; no patient discontinued therapy due to toxicity. Pharmacokinetic parameters and pre-dose concentrations showed substantial between-subject variability. PI3K/mTOR pathway inhibition markers demonstrating blood mononuclear cell mTOR pathway inactivation was achieved in most participants. Conclusion Individuals with recurrent/progressive NF1-associated LGG demonstrate significant disease stability/shrinkage during treatment with oral everolimus with a well-tolerated toxicity profile. Everolimus is well suited for future consideration as upfront or combination therapy in this patient population.

Imaging biomarkers for malignant peripheral nerve sheath tumors in neurofibromatosis type 1

Neurology ◽  
2019 ◽  
Vol 93 (11) ◽  
pp. e1076-e1084 ◽  
Author(s):  
Shivani Ahlawat ◽  
Jaishri O. Blakeley ◽  
Fausto J. Rodriguez ◽  
Laura M. Fayad
Keyword(s):  
Fdg Pet ◽  
Neurofibromatosis Type ◽  
Nerve Sheath Tumors ◽  
Peripheral Nerve Sheath Tumors ◽  
Pet Ct ◽  
Adc Values ◽  
Adc Mapping ◽  
Fdg Pet Ct

ObjectiveTo determine the utility of quantitative metrics obtained from fMRI using diffusion-weighted imaging (DWI)/apparent diffusion coefficient (ADC) mapping compared with metabolic (18F-fluorodeoxyglucose [FDG]-PET/CT) imaging in patients with neurofibromatosis type 1 (NF1) for the characterization of peripheral nerve sheath tumors (PNSTs) as benign or malignant.MethodsThis Institutional Review Board–approved, Health Insurance Portability and Accountability Act–compliant study retrospectively reviewed imaging of 55 PNSTs in 21 patients with NF1. Imaging included anatomic (unenhanced T1, fluid-sensitive, contrast-enhanced T1-weighted), functional DWI (b = 50, 400, 800 s/mm2) and ADC mapping, magnetic resonance sequences, and FDG-PET/CT imaging. Anatomic (size), functional (minimum ADC values), and metabolic (maximum standardized uptake values [SUVmax]) imaging characteristics were recorded. ADC values were correlated with SUVmax. With histologic correlation for all malignant PNSTs (MPNSTs) or clinical or imaging stability (>12 months) for benign lesions used as reference standards, diagnostic accuracy was calculated.ResultsOf 55 PNSTs, there were 19 (35%) malignant and 36 (65%) benign PNSTs. Benign PNSTs were overall smaller than MPNSTs (largest diameter 4.3 ± 1.3 vs 8.2 ± 3.3 cm, respectively, p = 0.014). Benign PNSTs had higher ADCmin (×10−3 mm2/s) than MPNSTs (1.6 ± 0.4 vs 0.6 ± 0.2, respectively, p < 0.0001) and lower SUVmax than MPNSTs (3.2 ± 1.8 vs 8 ± 3.9, p < 0.0001, respectively). ADCmin correlated inversely with SUVmax (correlation coefficient r = −0.0.58, p < 0.0001). Maintaining a sensitivity of 100% with threshold values of ADCmin ≤1 or SUVmax >3.2, DWI yielded a specificity of 94% while FDG-PET/CT offered a specificity of 83%.ConclusionsBoth quantitative metabolic imaging and functional imaging offer high sensitivity for the characterization of PNSTs in NF1; however, DWI/ADC mapping offers increased specificity and may be a more useful modality.Classification of evidenceThis study provides Class II evidence that for patients with NF1, MRI using DWI/ADC mapping accurately distinguishes malignant and benign PNSTs.

scholarly journals Brain tumors in neurofibromatosis type 1

2019 ◽  
Vol 2 (Supplement_1) ◽  
pp. i85-i97
Author(s):  
Amanda De Andrade Costa ◽  
David H Gutmann
Keyword(s):  
Tumor Growth ◽  
Neurofibromatosis Type 1 ◽  
Vision Loss ◽  
Critical Role ◽  
Neurofibromatosis Type ◽  
Therapeutic Drug ◽  
Low Grade ◽  
Increased Risk ◽  
Genetically Engineered Mice

Abstract AbstractAs a cancer predisposition syndrome, individuals with neurofibromatosis type 1 (NF1) are at increased risk for the development of both benign and malignant tumors. One of the most common locations for these cancers is the central nervous system, where low-grade gliomas predominate in children. During early childhood, gliomas affecting the optic pathway are most frequently encountered, whereas gliomas of the brainstem and other locations are observed in slightly older children. In contrast, the majority of gliomas arising in adults with NF1 are malignant cancers, typically glioblastoma, involving the cerebral hemispheres. Our understanding of the pathogenesis of NF1-associated gliomas has been significantly advanced through the use of genetically engineered mice, yielding new targets for therapeutic drug design and evaluation. In addition, Nf1 murine glioma models have served as instructive platforms for defining the cell of origin of these tumors, elucidating the critical role of the tumor microenvironment in determining tumor growth and vision loss, and determining how cancer risk factors (sex, germline NF1 mutation) impact on glioma formation and progression. Moreover, these preclinical models have permitted early phase analysis of promising drugs that reduce tumor growth and attenuate vision loss, as an initial step prior to translation to human clinical trials.

Neurofibromatosis-associated nerve sheath tumors

2006 ◽  
Vol 20 (1) ◽  
pp. 1-10 ◽  
Author(s):  
Judith A. Murovic ◽  
Daniel H. Kim ◽  
David G. Kline
Keyword(s):  
Diagnostic Criteria ◽  
Current Literature ◽  
Neurofibromatosis Type 1 ◽  
Neurofibromatosis Type ◽  
Imaging Findings ◽  
Nerve Sheath Tumors ◽  
Peripheral Nerve Sheath Tumors ◽  
Examination Protocol ◽  
Nerve Sheath

In this paper the authors describe a patient with neurofibromatosis Type 1 (NF1) who presented with sequelae of this disease. They also review the current literature on NF1 and NF2 published between 2001 and 2005. The method used to obtain information for the case report consisted of a family member interview and a review of the patient's chart. For the literature review the authors used the search engine Ovid Medline to identify papers published on the topic between 2001 and 2005. Neurofibromatosis Type 1 appears in approximately one in 2500 to 4000 births, is caused by a defect on 17q11.2, and results in neurofibromin inactivation. The authors reviewed the current literature with regard to the following aspects of this disease: 1) diagnostic criteria for NF1; 2) criteria for other NF1-associated manifestations; 3) malignant peripheral nerve sheath tumors (PNSTs); 4) the examination protocol for a patient with an NF1-related NST; 5) imaging findings in patients with NF1; 6) other diagnostic studies; 7) surgical and adjuvant treatment for NSTs and malignant PNSTs; and 8) hormone receptors in NF1-related tumors. Pertinent illustrations are included. Neurofibromatosis Type 2 occurs much less frequently than NF1, that is, in one in 33,000 births. Mutations in NF2 occur on 22q12 and result in inactivation of the tumor suppressor merlin. The following data on this disease are presented: 1) diagnostic criteria for NF2; 2) criteria for other NF2 manifestations; 3) malignant PNSTs in patients with NF2; 4) examination protocol for the patient with NF2 who has an NST; and 5) imaging findings in patients with NF2. Relevant illustrations are included. It is important that neurosurgeons be aware of the sequelae of NF1 and NF2, because they may be called on to treat these conditions.

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