Neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis (SWN) are tumor-suppressor syndromes. Each syndrome is an orphan disease; however, the tumors that arise within ...them represent the most common tumors of the nervous system worldwide. Systematic investigation of the pathways impacted by the loss of function of neurofibromin (encoded byNF1) and merlin (encoded byNF2) have led to therapeutic advances for patients with NF1 and NF2. In the syndrome of SWN, the genetic landscape is more complex, with 2 known causative genes (SMARCB1andLZTR1) accounting for up to 50% of familial SWN patients. The understanding of the molecular underpinnings of these syndromes is developing rapidly and offers more therapeutic options for the patients. In addition, common sporadic cancers harbor somatic alterations inNF1(ie, glioblastoma, breast cancer, melanoma),NF2(ie, meningioma, mesothelioma) andSMARCB1(ie, atypical teratoid/rhabdoid tumors) such that advances in management of syndromic tumors may benefit patients both with and without germline mutations. In this review, we discuss the clinical and genetic features of NF1, NF2 and SWN, the therapeutic advances for the tumors that arise within these syndromes and the interaction between these rare tumor syndromes and the common tumors that share these mutations.
To determine the utility of quantitative metrics obtained from fMRI using diffusion-weighted imaging (DWI)/apparent diffusion coefficient (ADC) mapping compared with metabolic (
F-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.
This 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/mm
) 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.
Of 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,
= 0.014). Benign PNSTs had higher ADCmin (×10
mm
/s) than MPNSTs (1.6 ± 0.4 vs 0.6 ± 0.2, respectively,
< 0.0001) and lower SUVmax than MPNSTs (3.2 ± 1.8 vs 8 ± 3.9,
< 0.0001, respectively). ADCmin correlated inversely with SUVmax (correlation coefficient
= -0.0.58,
< 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%.
Both 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.
This study provides Class II evidence that for patients with NF1, MRI using DWI/ADC mapping accurately distinguishes malignant and benign PNSTs.
Purpose
To assess amide proton transfer‐weighted (APTW) imaging features in patients with malignant gliomas after chemoradiation and the diagnostic performance of APT imaging for distinguishing true ...progression from pseudoprogression.
Materials and Methods
After approval by the Institutional Review Board, 32 patients with clinically suspected tumor progression in the first 3 months after chemoradiation were enrolled and scanned at 3T. Longitudinal routine magnetic resonance imaging (MRI) changes and medical records were assessed to confirm true progression versus pseudoprogression. True progression was defined as lesions progressing on serial imaging over 6 months, and pseudoprogression was defined as lesions stabilizing or regressing without intervention. The APTWmean and APTWmax signals were obtained from three to five regions of interests for each patient and compared between the true progression and pseudoprogression groups. The diagnostic performance was assessed with receiver operating characteristic curve analysis.
Results
The true progression was associated with APTW hyperintensity (APTWmean = 2.75% ± 0.42%), while pseudoprogression was associated with APTW isointensity to mild hyperintensity (APTWmean = 1.56% ± 0.42%). The APTW signal intensities were significantly higher in the true progression group (n = 20) than in the pseudoprogression group (P < 0.001; n = 12). The cutoff APTWmean and APTWmax intensity values to distinguish between true progression and pseudoprogression were 2.42% (with a sensitivity of 85.0% and a specificity of 100%) and 2.54% (with a sensitivity of 95.0% and a specificity of 91.7%), respectively.
Conclusion
The APTW‐MRI signal is a valuable imaging biomarker for distinguishing pseudoprogression from true progression in glioma patients. J. Magn. Reson. Imaging 2016;44:456–462.
Isocitrate dehydrogenase (IDH)-mutant gliomas are usually treated with radiotherapy and chemotherapy, which increases the risk for neurocognitive sequelae during patients' most productive years. We ...report our experience using off-label first-in-class mutant IDH1 inhibitor ivosidenib and its impact on tumor volume in IDH-mutant gliomas.
We retrospectively analyzed patients ages ≥18 years with radiation/chemotherapy-naïve, mutant IDH1, nonenhancing, radiographically active, grade 2/3 gliomas, and ≥2 pretreatment and ≥2 on-treatment ivosidenib MRIs. T2/FLAIR-based tumor volumes, growth rates, and progression-free survival (PFS) were analyzed. log-linear mixed-effect modeling of growth curves adjusted for grade, histology, and age was performed.
We analyzed 116 MRIs of 12 patients 10 males, median age 46 years (range: 26-60): 8 astrocytomas (50% grade 3) and 4 grade 2 oligodendrogliomas. Median on-drug follow-up was 13.2 months interquartile range (IQR): 9.7-22.2. Tolerability was 100%. A total of 50% of patients experienced ≥20% tumor volume reduction on-treatment and absolute growth rate was lower during treatment (-1.2 ± 10.6 cc/year) than before treatment (8.0 ± 7.7 cc/year; P ≤ 0.05). log-linear models in the Stable group (n = 9) showed significant growth before treatment (53%/year; P = 0.013), and volume reduction (-34%/year; P = 0.037) after 5 months on treatment. After treatment, volume curves were significantly lower than before treatment (after/before treatment ratio 0.5; P < 0.01). Median time-to-best response was 11.2 (IQR: 1.7-33.4) months, and 16.8 (IQR: 2.6-33.5) months in patients on drug for ≥1 year. PFS at 9 months was 75%.
Ivosidenib was well tolerated and induced a high volumetric response rate. Responders had significant reduction in tumor growth rates and volume reductions observed after a 5-month delay. Thus, ivosidenib appears useful to control tumor growth and delay more toxic therapies in IDH-mutant nonenhancing indolently growing gliomas. See related commentary by Lukas and Horbinski, p. 4709.
No approved therapies exist for inoperable plexiform neurofibromas in patients with neurofibromatosis type 1.
We conducted an open-label, phase 2 trial of selumetinib to determine the objective ...response rate among patients with plexiform neurofibromas and to assess clinical benefit. Children with neurofibromatosis type 1 and symptomatic inoperable plexiform neurofibromas received oral selumetinib twice daily at a dose of 25 mg per square meter of body-surface area on a continuous dosing schedule (28-day cycles). Volumetric magnetic resonance imaging and clinical outcome assessments (pain, quality of life, disfigurement, and function) were performed at least every four cycles. Children rated tumor pain intensity on a scale from 0 (no pain) to 10 (worst pain imaginable).
A total of 50 children (median age, 10.2 years; range, 3.5 to 17.4) were enrolled from August 2015 through August 2016. The most frequent neurofibroma-related symptoms were disfigurement (44 patients), motor dysfunction (33), and pain (26). A total of 35 patients (70%) had a confirmed partial response as of March 29, 2019, and 28 of these patients had a durable response (lasting ≥1 year). After 1 year of treatment, the mean decrease in child-reported tumor pain-intensity scores was 2 points, considered a clinically meaningful improvement. In addition, clinically meaningful improvements were seen in child-reported and parent-reported interference of pain in daily functioning (38% and 50%, respectively) and overall health-related quality of life (48% and 58%, respectively) as well as in functional outcomes of strength (56% of patients) and range of motion (38% of patients). Five patients discontinued treatment because of toxic effects possibly related to selumetinib, and 6 patients had disease progression. The most frequent toxic effects were nausea, vomiting, or diarrhea; an asymptomatic increase in the creatine phosphokinase level; acneiform rash; and paronychia.
In this phase 2 trial, most children with neurofibromatosis type 1 and inoperable plexiform neurofibromas had durable tumor shrinkage and clinical benefit from selumetinib. (Funded by the Intramural Research Program of the National Institutes of Health and others; ClinicalTrials.gov number, NCT01362803.).
Abstract
Background
Understanding the natural history of non-malignant peripheral nerve sheath tumors (PNSTs) in neurofibromatosis type 1 (NF1) is critical to optimal clinical care and the ...development of meaningful clinical trials.
Methods
We longitudinally analyzed growth of plexiform neurofibromas (PNs) and of PNSTs with distinct nodular appearance (distinct nodular lesions DNLs) using volumetric MRI analysis in patients enrolled on a natural history study (NCT00924196).
Results
DNLs were observed in 58/122 (45.6%) patients (median 2 DNLs/patient). In DNLs that developed during follow-up, median age of development was 17 years. A moderate negative correlation was observed between the estimated PN growth rate and patients’ age at initial MRI (Spearman’s r 95% CI: −0.60 −0.73, −0.43, n = 70), whereas only a weak correlation was observed for DNLs (Spearman’s r 95% CI: −0.25 −0.47, 0.004; n = 61). We observed a moderate negative correlation between tumor growth rate and baseline tumor volume for PNs and DNLs (Spearman’s r 95% CI: −0.52 −0.67, −0.32 and −0.61 −0.75, −0.42, respectively). Spontaneous tumor volume reduction was observed in 10 PNs and 7 DNLs (median decrease per year, 3.6% and 7.3%, respectively).
Conclusion
We corroborate previously described findings that most rapidly growing PNs are observed in young children. DNLs tend to develop later in life and their growth is minimally age related. Distinct growth characteristics of PNs and DNLs suggest that these lesions have a different biology and may require different clinical management and clinical trial design. In a subset of PNs and DNLs, slow spontaneous regression in tumor volume was seen.
Constitutional SMARCB1 mutations at 22q11.23 have been found in ∼50% of familial and <10% of sporadic schwannomatosis cases. We sequenced highly conserved regions along 22q from eight individuals ...with schwannomatosis whose schwannomas involved somatic loss of one copy of 22q, encompassing SMARCB1 and NF2, with a different somatic mutation of the other NF2 allele in every schwannoma but no mutation of the remaining SMARCB1 allele in blood and tumor samples. LZTR1 germline mutations were identified in seven of the eight cases. LZTR1 sequencing in 12 further cases with the same molecular signature identified 9 additional germline mutations. Loss of heterozygosity with retention of an LZTR1 mutation was present in all 25 schwannomas studied. Mutations segregated with disease in all available affected first-degree relatives, although four asymptomatic parents also carried an LZTR1 mutation. Our findings identify LZTR1 as a gene predisposing to an autosomal dominant inherited disorder of multiple schwannomas in ∼80% of 22q-related schwannomatosis cases lacking mutation in SMARCB1.
Neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis (SWN) are three clinically distinct tumor predisposition syndromes with a shared tendency to develop peripheral and ...central nervous system neoplasms. Disease expression and complications of NF1, NF2, and SWN are highly variable, necessitating a multidisciplinary approach to care in order to optimize outcomes. This review will discuss the imaging appearance of NF1, NF2, and SWN and highlight the important role that imaging plays in informing management decisions in people with tumors associated with these syndromes. Recent technological advances, including the role of both whole-body and localized imaging strategies, routine anatomic and advanced magnetic resonance (MR) imaging sequences such as diffusion-weighted imaging (DWI) with quantitative apparent diffusion coefficient (ADC) mapping, and metabolic imaging techniques (MR spectroscopy and positron emission testing) are discussed in the context of the diagnosis and management of people with NF1, NF2, and SWN based on the most up-to-date clinical imaging studies.
Abstract
The COVID-19 outbreak is posing unprecedented risks and challenges for all communities and health care systems, worldwide. There are unique considerations for many adult patients with ...gliomas who are vulnerable to the novel coronavirus due to older age and immunosuppression. As patients with terminal illnesses, they present ethical challenges for centers that may need to ration access to ventilator care due to insufficient critical care capacity. It is urgent for the neuro-oncology community to develop a proactive and coordinated approach to the care of adults with gliomas in order to provide them with the best possible oncologic care while also reducing their risk of viral infection during times of potential health care system failure. In this article, we present an approach developed by an international multidisciplinary group to optimize the care of adults with gliomas during this pandemic. We recommend measures to promote strict physical distancing and minimize exposures for patients, address risk and benefit of all therapeutic interventions, proactively develop end-of-life plans, educate patients and caregivers, and ensure the health of the multidisciplinary neuro-oncology workforce. This pandemic is already changing neuro-oncologic care delivery around the globe. It is important to highlight opportunities to maximize the benefit and minimize the risk of glioma management during this pandemic and potentially, in the future.
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