Neurofibromatosis 2 Patients Research Articles

NFS-05. INCIDENCE OF BEVACIZUMAB ASSOCIATED TOXICITY IN CHILDREN WITH LOW GRADE GLIOMA WITH AND WITHOUT NF1

Abstract BACKGROUND Low grade gliomas (LGG), both sporadic & Neurofibromatosis1 (NF1) associated, are the commonest pediatric brain tumors. When surgically unresectable, they may become progressive/ symptomatic and require chronic oncological treatment. Bevacizumab (BVZ; Avastin), a recombinant humanized monoclonal antibody to VEGF, has shown efficacy both as a single agent or combined with chemotherapy as second/ third line treatment of progressive LGG especially in the optic pathway. BVZ can be associated with adverse effects including hypertension (HTN) and proteinuria. Children with NF1 have known increased tendency to hypertension however there is no data comparing the frequency of side effects from BVZ in patients with or without NF1. METHODS Retrospective study of all LGG cases treated with BVZ diagnosed 2010-2023 in a tertiary oncology center. We graded hypertension, proteinuria, cardiac function, retinopathy & bleeding according to the CTCAE v5.0 in NF1 and non-NF1 patients. RESULTS 16 children with LGG were treated with BVZ; 7 had NF1. 75% optic glioma, 25% other. All received BVZ as second or third line treatment in combination with chemotherapy. In the non NF1 group, 77% patients developed grade 2 HTN on BVZ treatment; none required medical intervention. 6 had grade 1 elevation of protein-creatinine ratio (median 0.38). In the NF1 group, 71% developed grade 2 or 3 HTN on BVZ treatment including a patient with aortic coarctation (CoA) who had worsening of previous HTN, 2 required antihypertensive therapy (p non-significant HTN non NF1 vs. NF1). Only 1 NF1 patient developed proteinuria. No patients in either group stopped BVZ prematurely for toxicity. Hypertension was reversible after cessation of BVZ in all except the patient with CoA. CONCLUSIONS Hypertension is more common than previously reported in both NF1 and non-NF1 patients treated with BVZ for LGG. Blood pressure should be monitored and treated appropriately. BVZ is safe in young patients with NF1.

Using Qualitative Interviews to Improve Quantitative Assessments of Quality of Life in Patients with Neurofibromatosis 2 (P7-13.006)

<h3>Objective:</h3> To use qualitative interviews to elucidate seemingly discordant quantitative ratings in patient reported outcomes for quality of life (QOL). <h3>Background:</h3> Neurofibromatosis 2 (NF2) is a progressive, neurogenetic disease. Assessing QOL is important in demonstrating that new drugs improve how NF2 patients feel and function. The NFTI-QOL is the currently recommended measure to assess NF2-specific QOL in clinical trials. <h3>Design/Methods:</h3> We interviewed 16 participants enrolled in stage one of the brigatinib arm of INTUITT-NF2 (NCT04374305) –a multicenter, adaptive platform-basket trial targeting progressive NF2-related tumors – after one year of treatment or at time of trial discontinuation. Interviews included cognitive debriefings of the NFTI-QoL and global impression of change (GIC) scale. We also analyzed NFTI-QoL scores collected over the same time period, using a MCID of ±2 points to classify improvement or worsening in QOL. <h3>Results:</h3> 11/16 (69%) participants reported a GIC rating discordant with their change in NFTI-QoL scores. 8/13 (62%) of participants who improved on their GIC had stable (N=6) or worsened (N=2) NFTI-QoL scores. This group cited tumor stability as a major contributor to improved GIC ratings and also had lower baseline NFTI-QoL scores (median=8) than those with concordant ratings (median=12). Participants with lower NFTI-QoL scores disproportionally reported that a meaningful improvement in their symptoms would not lead to an accompanying score improvement due to inadequate NFTI-QOL response options. <h3>Conclusions:</h3> Qualitative interviews revealed two reasons for conflicting patient reported outcome results. In the setting of a progressive disease, participants can view tumor volume stability as an improvement, even with stable or worsening symptoms. Also, the NFTI-QoL may not be capturing improvement in people with a lower symptom burden. In order for the NFTI-QoL and GIC to better reflect changes in NF2 patients QOL, we recommend adding another response option to the NFTI-QoL and altering the instructions of the GIC. <b>Disclosure:</b> Ms. Von Imhof has nothing to disclose. Dr. Plotkin has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for NFlection Therapeutics. Dr. Plotkin has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Akouos. Dr. Plotkin has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for SonALAsense. Dr. Plotkin has stock in NFlection Therapeutics. Dr. Plotkin has stock in NF2 Therapeutics. Dr. Plotkin has stock in SonALAsense. Dr. Plotkin has received research support from Children’s Tumor Foundation. Dr. Plotkin has received research support from Department of Defense. Dr. Plotkin has received research support from National Institutes of Health. Dr. Plotkin has received intellectual property interests from a discovery or technology relating to health care. Dr. Yohay has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Astra Zeneca. Dr. Yohay has received publishing royalties from a publication relating to health care. An immediate family member of Dr. Yohay has received publishing royalties from a publication relating to health care. Dr. Nghiemphu has received research support from Erasca. Dr. Nghiemphu has received research support from Springswork. Dr. Nghiemphu has received research support from Children’s Tumor Foundation. Dr. Nghiemphu has received research support from NIH-NCI . Dr. Nghiemphu has received research support from Genentech. Dr. Nghiemphu has received research support from DOD. Dr. Nghiemphu has received research support from Millenium. Dr. Nghiemphu has received research support from GCAR. Dr. Nghiemphu has received research support from Novartis. Dr. Nghiemphu has received research support from BMS. Dr. Nghiemphu has received personal compensation in the range of $500-$4,999 for serving as a advisory board with Alexion. Dr. Babovic-Vuksanovic has received personal compensation for serving as an employee of AstraZeneka. Dr. Babovic-Vuksanovic has received personal compensation for serving as an employee of Alexion. Dr. Babovic-Vuksanovic has received personal compensation in the range of $500-$4,999 for serving as a Consultant for AstraZeneca. Dr. Babovic-Vuksanovic has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alexion. Dr. Babovic-Vuksanovic has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for AstraZeneca . Dr. Babovic-Vuksanovic has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Loeb&amp;Loeb. The institution of Dr. Babovic-Vuksanovic has received research support from DOD. Dr. Babovic-Vuksanovic has received publishing royalties from a publication relating to health care. The institution of Vanessa Merker has received research support from Children’s tumor foundation . The institution of Vanessa Merker has received research support from NF Northeast. Vanessa Merker has received personal compensation in the range of $10,000-$49,999 for serving as a science writer with Neurofibromatosis Network.

Ischemic Cerebellar Stroke in a Young Patient with Neurofibromatosis Type 2, a Case Report (P12-5.026)

<h3>Objective:</h3> We present a case of brainstem ischemia in a young patient with neurofibromatosis 2 (NF2) and review the existing literature on similar cases, which together suggest a possible NF2-associated syndrome of which stroke neurologists and pediatric neurologists should be aware. <h3>Background:</h3> NF2 is a multifaceted disease characterized primarily by benign CNS tumors, especially meningiomas and vestibular schwannomas. There have been several cases of brainstem ischemic stroke in young NF2 patients reported in the literature. To date, there is no unified theory about the connection between NF2 and pediatric stroke. <h3>Design/Methods:</h3> We present a case of ischemia in the left cerebellar peduncle of a young patient with NF2, as well as a narrative review of the literature on previous cases. <h3>Results:</h3> The patient presented to the Emergency Department with left facial paresthesia and dizziness. Serial Magnetic Resonance Images (MRI’s) displayed an initial area of restricted diffusion in the left cerebellar peduncle with peripheral enhancement which did improve over several months, consistent with maturing infarct. <h3>Conclusions:</h3> Our case joins several others with similar presentations and findings, including pediatric patients for whom brainstem ischemia was the presenting symptom of NF2. The primary theory for the cause of brainstem ischemia in juvenile NF2 is a microvascular cause due to genetic deficiency of <i>neurofibromin 2</i>, a regulator of endothelial development, whose absence is likely to disrupt vascular homeostatic mechanisms. Multicenter studies with large NF2 cohorts are needed to better characterize this syndrome. Understanding brainstem ischemia in young NF2 patients will inform the development of treatment guidelines for such patients. <b>Disclosure:</b> An immediate family member of Mrs. Trautman has received personal compensation for serving as an employee of Hydro Extrusions. Mrs. Trautman has received personal compensation for serving as an employee of University of South Dakota. Dr. Sandhu has nothing to disclose.

Proteasomal pathway inhibition as a potential therapy for NF2-associated meningioma and schwannoma.

Neurofibromatosis 2 (NF2) is an inherited disorder caused by bi-allelic inactivation of the NF2 tumor suppressor gene. NF2-associated tumors, including schwannoma and meningioma, are resistant to chemotherapy, often recurring despite surgery and/or radiation, and have generally shown cytostatic response to signal transduction pathway inhibitors, highlighting the need for improved cytotoxic therapies. Leveraging data from our previous high-throughput drug screening in NF2 preclinical models, we identified a class of compounds targeting the ubiquitin-proteasome pathway (UPP), and undertook studies using candidate UPP inhibitors, ixazomib/MLN9708, pevonedistat/MLN4924, and TAK-243/MLN7243. Employing human primary and immortalized meningioma (MN) cell lines, CRISPR-modified Schwann cells (SCs), and mouse Nf2-/- SCs, we performed dose response testing, flow cytometry-based Annexin V and cell cycle analyses, and RNA-sequencing to identify potential underlying mechanisms of apoptosis. In vivo efficacy was also assessed in orthotopic NF2-deficient meningioma and schwannoma tumor models. Testing of three UPP inhibitors demonstrated potent reduction in cell viability and induction of apoptosis for ixazomib or TAK-243, but not pevonedistat. In vitro analyses revealed that ixazomib or TAK-243 downregulates expression of c-KIT and PDGFRα, as well as the E3 ubiquitin ligase SKP2 while upregulating genes associated with endoplasmic reticulum stress-mediated activation of the unfolded protein response (UPR). In vivo treatment of mouse models revealed delayed tumor growth, suggesting a therapeutic potential. This study demonstrates the efficacy of proteasomal pathway inhibitors in meningioma and schwannoma preclinical models and lays the groundwork for use of these drugs as a promising novel treatment strategy for NF2 patients.

Prospective phase II trial of the dual mTORC1/2 inhibitor vistusertib for progressive or symptomatic meningiomas in persons with neurofibromatosis 2.

Meningiomas occur in 80% of persons with neurofibromatosis 2 (NF2) and cause significant mortality and morbidity, yet there are no effective medical treatments. NF2-deficient tumors have constitutive activation of mammalian/mechanistic target of rapamycin (mTOR), and treatment with mTORC1 inhibitors results in growth arrest in a minority of tumors, with paradoxical activation of the mTORC2/AKT pathway. We studied the effect of vistusertib, a dual mTORC1/mTORC2 inhibitor, in NF2 patients with progressive or symptomatic meningiomas. Vistusertib was administered orally at 125 mg twice daily for 2 consecutive days each week. The primary endpoint was the imaging response in the target meningioma, defined as a volume decrease of 20% compared with the baseline. Secondary endpoints included toxicity, imaging response of nontarget tumors, quality of life, and genetic biomarkers. Eighteen participants (13 female), median age of 41 (range, 18-61) years, were enrolled. In target meningiomas, the best response was partial response (PR) in 1/18 tumors (6%) and stable disease (SD) in 17/18 tumors (94%). For all measured intracranial meningiomas and vestibular schwannomas, the best imaging response was PR in 6/59 tumors (10%) and SD in 53 (90%). Treatment-related grade 3/4 adverse events occurred in 14 (78%) participants, and 9 participants discontinued treatment due to side effects. Although the study did not meet the primary endpoint, vistusertib treatment was associated with high rates of SD in progressive NF2-related tumors. However, this dosing regimen for vistusertib was poorly tolerated. Future studies of dual mTORC inhibitors for NF2 should focus on optimizing tolerability and evaluating the relevance of tumor stability in participants.

Extensive glandular and neuroendocrine differentiation of a malignant peripheral nerve sheath tumor in a neurofibromatosis-1 patient

The histologic diagnosis of a malignant peripheral nerve sheath tumor (MPNST) is complex with no defining biomarkers or generally accepted diagnostic criteria, but based on whether it is identified arising from a peripheral nerve, arising from a benign nerve sheath tumor, in the setting of neurofibroma or when its constellation of features suggest a Schwann-cell differentiation [1- 3]. Further complicating the histologic diagnosis is the small subset of these tumors with divergent differentiation demonstrating various heterologous elements [4]. Divergent differentiation presenting in a glandular form in MPNST is particularly rare, though has been described, usually in context of Neurofibromatosis I (NF1) patients, as discrete localized areas occasionally associated with neuroendocrine features [3,5,6]. Being aware of the possible extent of variable histologic features is critical for diagnosis, particularly if only a needle core biopsy is provided. We present a case of MPNST arising in a 20-year-old woman with NF1 found to have an unusual extensive glandular and neuroendocrine divergent differentiation comprising more the 75% of the tumor, arising from a plexiform neurofibroma. The patient had a prior MPNST resected without evidence of divergent differentiation, and then a subsequent metastasis to the base of the skull with similar glandular histology following our presenting case. To our knowledge, such extensive glandular and neuroendocrine differentiation has not been previously described in these tumors.

CLRM-16 PATIENT-FOCUSED DRUG DEVELOPMENT IN NEURO-ONCOLOGY: A PILOT STUDY OF QUALITATIVE PATIENT INTERVIEWS EMBEDDED WITHIN A NEUROFIBROMATOSIS 2 CLINICAL TRIAL

BACKGROUNDThe Food and Drug Administration recently issued guidance on conducting qualitative research to support patient-focused drug development. In prior FDA submissions, qualitative data has been critical to demonstrate the content validity of and meaningfulness of change in quantitative trial endpoints. Qualitative patient interviews embedded within neuro-oncology trials can supplement traditional quantitative measures by providing nuanced information on patients’ treatment priorities, benefit/risk assessments, and quality of life. METHODSWe interviewed people with neurofibromatosis 2 (NF2) in stage one of the brigatinib arm of a multicenter, phase II, adaptive platform-basket trial for progressive NF2-related tumors (NCT04374305). Transcripts were coded by two analysts using a hybrid inductive/deductive framework; cross-cutting themes were generated using the Framework Method. RESULTS16/20 trial enrollees participated in interviews May 2021-March 2022. The radiographic response rate (volume shrinkage ≥20% from baseline) at 6 months for target and non-target tumors was 5% and 22%, respectively. However, most participants rated their change in overall status as minimally (10/16) or much (3/16) improved. Several participants acknowledged their tumor size had not changed significantly but felt tumor stability was an improvement over previously accelerated growth rates; this importantly allowed them to avoid or postpone future surgery. Participants also valued prevention of symptomatic decline, minimal impact of side effects on social roles and activities, the convenience of oral medication, and the sense of hope and agency gained from participating in a trial. CONCLUSIONSVirtual, in-depth qualitative interviews were feasible across multiple sites and provided unique information on NF2 patients’ conceptualization of clinical benefit. Qualitative interviews embedded within neuro-oncology trials can reveal 1) whether trial design and choice of outcome measures align with patient priorities; 2) whether and how new treatments improve patients’ quality of life; and 3) what degree of change in quantitative measures such as radiographic progression are clinically meaningful.

Cochlear Implantation in Vestibular Schwannoma: A Systematic Literature Review.

Objective Ipsilateral cochlear implantation (CI) in vestibular schwannoma (VS) has been an emerging trend over the last two decades. We conducted the first systematic review of hearing outcomes comparing neurofibromatosis 2 (NF2) and sporadic VS undergoing CI. A comparison of the two populations and predictor of outcome was assessed. This is an update to a previously presented study. Data Sources Systemic data searches were performed in PubMed NCBI and Scopus by an academic librarian. No restrictions based on the year of publication were used. Study Selection Studies were selected if patients had a diagnosis of NF2 and a CI placed in the affected side with reports of hearing outcome. Two independent reviewers screened each abstract and full-text article. Data Extraction Studies were extracted at the patient level, and the assessment of quality and bias was evaluated according to the National Institutes of Health Quality Assessment Tool. Main Outcome Measures Outcome predictors were determined by using the chi-square test and Student's t -test. Results Overall, most CI recipients functioned in the high-to-intermediate performer category for both sporadic and NF2-related VS. Median AzBio (Arizona Biomedical Institute Sentence Test) was 72% (interquartile range [IQR]: 50) in NF2 patients and 70% (IQR: 7.25) in sporadic patients. Larger tumor size predicted a poorer final audiometric outcome. Conclusions Categorization of hearing outcome into superior performance and inferior performance based on sentence recognition revealed a generally good hearing outcome regardless of treatment or patient population. Select patients with sporadic and NF2 VS may benefit from CI.

Cochlear Implantation in NF2 Patients Without Intracochlear Schwannoma Removal.

To determine if cochlear implantation without removal of inner ear schwannomas (IES) is an effective treatment option for Neurofibromatosis 2 (NF2) patients. To determine how the presence of an intracochlear schwannoma might impact cochlear implant (CI) outcomes and programming parameters. Retrospective chart review. Tertiary center for cochlear and auditory brainstem implantation. Of 10 NF2 patients with IES, 8 are reported with no previous tumor removal on the implanted ear. Cochlear implant without tumor removal. Performance outcomes with CI at least 1-year post intervention. Programming parameters, including impedances, for patients with IES. All patients had full insertion of the electrode arrays with round window approaches. Performance outcomes ranged from 0 to 100% for Bamford-Kowal-Bench sentences. Impedance measurements for active electrodes for patients with IES were comparable to those measured in patients without vestibular schwannoma (VS). Only patients who had radiation treatment before receiving their implant had elevated threshold requirements for CI programming compared with CI recipients without VS. Cochlear implantation without tumor removal is an effective option for treating NF2 patients with IES. The presence of an intracochlear tumor did not have an impact on CI performance or programming requirements compared with patients without VS; however, previous treatment with radiation may be related to elevated current requirements in the CI settings.

Global microRNA profiling identified miR-10b-5p as a regulator of neurofibromatosis 1 (NF1)-glioma migration.

Neurofibromatosis 1 (NF1) is an autosomal-dominant cancer predisposition syndrome caused by loss of function alterations involving the NF1 locus on chromosome 17. The most common brain tumours encountered in affected patients are low-grade gliomas (pilocytic astrocytomas), although high-grade gliomas are also observed at increased frequency. While bi-allelic NF1 loss characterizes these tumours, previous studies have suggested noncoding RNA molecules (microRNA, miR) may have important roles in dictating glioma biology. To explore the contributions of miRs in NF1-associated gliomas, we analysed five high-grade gliomas (NF1-HGG) and five PAs (NF1-PA) using global microRNA profiling with NanoString-based microarrays followed by functional experiments with glioma cell lines. miR-10b-5p, miR-135b-5p, miR-196a-5p, miR-196b-5p, miR-1247-5p and miR-320a (adjusted P<0.05) were increased>3-fold in NF1-HGG relative to NF1-PA tumours. In addition, miR-378b and miR-1305 were decreased 6.8- and 6-fold, respectively, whereas miR-451a was increased 2.7-fold (adjusted P<0.05) in NF1-PAs compared to non-neoplastic NF1 patient brain specimens (n=2). As miR-10b-5p was the microRNA overexpressed the most in NF1-high-grade glioma compared to NF1-low-grade glioma (5.76 fold), we examined its levels in glioma cell lines. miR-10b-5p levels were highest in adult glioma cell lines and lowest in paediatric low-grade glioma lines (P=0.02). miR-10b-5p knockdown resulted in decreased invasion in NF1-deficient LN229 high-grade glioma line, whereas its overexpression in the NF1-PA derived line (JHH-NF1-PA1) led to increased invasion. There was no change in cell growth (viability and proliferation). These proof-of-concept experiments support a role for microRNA regulation in NF1-glioma biology.

Malignant Peripheral Nerve Sheath Tumor of the Thigh Invading the Superficial Femoral Artery, with Necrotic Lung Metastases as Presenting Symptoms

A NF1 (neurofibromatosis 1) patient developed multiple necrotic lung metastases from a sciatic malignant peripheral nerve sheath tumor (MPNST) invading the superficial femoral artery. The first diagnosis was metastases of a non-small-cell adenocarcinoma because the right calf MPNST was not clinically noticeable ant that the chest/abdomen PET/CT did not include the region of the legs. When the MPNST was diagnosed, new histological analysis on the metastases changed the diagnosis to that of epithelioid undifferentiated sarcoma. The article deals with the sometimes-delayed diagnosis in those NF1 patients with large palpable masses and chronic pain pre-existing the malignant transformation, and discusses the difficulty of the biopsy of necrotic metastases.

Various Retinal Vascular Manifestations of Neurofibromatosis-1 in a Single Patient

Objectives: To report an Iranian woman with a variety of retinal vascular manifestations secondary to Neurofibromatosis -1.Case Report: A 49 years old woman known case of Neurofibromatosis-1 (NF-1) presented with decreased vision in her right eye. We found peculiar retinal and choroidal findings. Mild vascular tortuosity and few hard exudates were the prominent finding in right eye fundus examination; however, left eye showed inferior hemi retinal artery macro aneurysm. Fluorescein angiography, revealed multiple bright choroidal nodules in both eyes. Left eye findings were in favor of branch retinal artery occlusion and branch retinal vein occlusion. Discussion: As vascular and microvascular manifestations of NF-1 are being reported recently, further investigational studies for retinal vascular associations in NF-1 patients appears reasonable. Complete ophthalmic examinations in each NF-1 patient seems essential to prevent potential threatening complications of vascular events in these patients.

Clinical Presentation and Novel Pathogenic Variants among 68 Chinese Neurofibromatosis 1 Children.

Background: Neurofibromatosis 1 (NF1) is one of the most common dominantly inherited genetic disorders worldwide, with an age-dependent phenotypic expression. Exploring the mutational spectrum and clinical presentation of NF1 patients at different ages from a diverse population will aid the understanding of genotype–phenotype correlations. Methods: In this study, 95 Chinese children with clinical suspicion of NF1 mainly due to the presence of multiple café-au-lait macules (CALMs) were subjected to medical exome-sequencing analysis and Sanger confirmation of pathogenic variants. Clinical presentations were evaluated regarding dermatological, ocular, neurological, and behavioral features. Results: Pathogenic or likely pathogenic NF1 variants were detected in 71.6% (68/95) of patients; 20 pathogenic variants were not previously reported, indicating that Chinese NF1 patients are still understudied. Parental Sanger sequencing confirmation revealed 77.9% of de novo variants, a percentage that was much higher than expected. The presence of a higher number of NF1-related features at young ages was correlated with positive diagnostic findings. In addition to CALMs, neurological and behavioral features had a high expression among Chinese NF1 children. We attempted to correlate short stature with the locations of the pathogenic variants across the NF1 gene. It is interesting to notice that variants detected in the C-terminal region of the NF1 gene were less likely to be associated with short stature among the NF1 patients, whereas variants at the N-terminal were highly penetrant for the short stature phenotype. Conclusion: Novel NF1 pathogenic variants are yet to be uncovered in under-studied NF1 patient populations; their identification will help to reveal novel genotype–phenotype correlations.

Angiosarcoma arising in a neurofibromatosis-1 patient as a de novo malignancy?

Background: Neurofibromatosis-1 (NF-1) is the most common genetic disease belonging to the group of neural tissue cell growth disorders, known to be complicated by malignant peripheral nerve sheath tumors or MPNST. On the contrary, angiosarcoma is rarely associated with NF-1. Only few cases reported angiosarcoma arising as a sarcomatous transformation within a preexisting MPNST.Methods and results: We report here the remarkable case of a 35-year-old NF-1 woman, with a history of excised MPNST 8 years before a new hospitalization for the development of multi localized angiosarcoma, whose discovery is related to an oropharyngeal involvement, with a dramatic presentation. Review of the literature and differences from previous reports are discussed.Conclusion: Our case report supports the hypothesis of an angiosarcoma developing as a malignant proliferation apparently not arising from contiguous neurofibroma or MPNST lesions, but representing a second de novo malignancy.

18F]fluorothymidine and [18F]fluorodeoxyglucose PET Imaging Demonstrates Uptake and Differentiates Growth in Neurofibromatosis 2 Related Vestibular Schwannoma.

To investigate whether [F]fluorothymidine (FLT) and/or [F]fluorodeoxyglucose (FDG) positron emission tomography (PET) can differentiate growth in neurofibromatosis 2 (NF2) related vestibular schwannomas (VS) and to evaluate the importance of PET scanner spatial resolution on measured tumor uptake. Six NF2 patients with 11 VS (4 rapidly growing, 7 indolent), were scanned with FLT and FDG using a high-resolution research tomograph (HRRT, Siemens) and a Siemens Biograph TrueV PET-CT, with and without resolution modeling image reconstruction. Mean, maximum, and peak standardised uptake values (SUV) for each tumor were derived and the intertumor correlation between FDG and FLT uptake was compared. The ability of FDG and FLT SUV values to discriminate between rapidly growing and slow growing (indolent) tumors was assessed using receiver operator characteristic (ROC) analysis. Tumor uptake was seen with both tracers, using both scanners, with and without resolution modeling. FDG and FLT uptake was correlated (R = 0.67-0.86, p < 0.01) and rapidly growing tumors displayed significantly higher uptake (SUVmean and SUVpeak) of both tracers (p < 0.05, one tailed t test). All of the PET analyses performed demonstrated better discriminatory power (AUCROC range = 0.71-0.86) than tumor size alone (AUCROC = 0.61). The use of standard resolution scanner with standard reconstruction did not result in a notable deterioration of discrimination accuracy. NF2 related VS demonstrate uptake of both FLT and FDG, which is significantly increased in rapidly growing tumors. A short static FDG PET scan with standard clinical resolution and reconstruction can provide relevant information on tumor growth to aid clinical decision making.

Malignant peripheral nerve sheath tumor presenting as pathological fracture of femur in neurofibromatosis patient

Malignant peripheral nerve sheath tumors (MPNSTs) are rare soft tissue sarcomas that arise from a peripheral nerve or cells associated with the nerve sheath, such as Schwann cells, perineural cells, or fibroblasts. MPNSTs account for 5%–10% of all soft tissue sarcomas. Neurofibromas in Neurofibromatosis-1 (NF-1) may undergo malignant transformation in 2%–5% of patients. We are reporting a very rare case in NF-1 patient who, presented with pathological intertrochanteric fracture of femur and liver metastasis. X-ray from left hip joint shows lytic lesion which on histopathology turned out to be MPNST. S-100 was positive confirming its neural origin. Elbow lesion which was excised later, also showed similar features with S-100 positivity. Ultrasonography abdomen showed target lesions in liver. Fine-needle aspiration cytology from liver showed scattered malignant spindle cells. A final diagnosis of metastatic MPNST was made. Although malignant transformation in neurofibromas is extremely rare when it occurs, it is associated with NF-1 in 75% of patients. This case highlights the possibility of fracture femur as the presenting complains, in patients of NF with malignant transformation. The case is unique with regard to its presentation and rarity of metastatic sites.

Immortalization of human normal and NF1 neurofibroma Schwann cells

Neurofibromas, which are benign Schwann cell tumors, are the hallmark feature in the autosomal dominant condition neurofibromatosis 1 (NF1) and are associated with biallelic loss of NF1 gene function. There is a need for effective therapies for neurofibromas, particularly the larger, plexiform neurofibromas. Tissue culture is an important tool for research. However, it is difficult to derive enriched human Schwann cell cultures, and most enter replicative senescence after 6–10 passages, impeding cell-based research in NF1. Through exogenous expression of human telomerase reverse transcriptase and murine cyclin-dependent kinase (mCdk4), normal (NF1 wild-type), neurofibroma-derived Schwann cells heterozygous for NF1 mutation, and neurofibroma-derived Schwann cells homozygous for NF1 mutation were immortalized, including some matched samples from the same NF1 patient. Initial experiments employed retroviral vectors, while subsequent work utilized lentiviral vectors carrying these genes because of improved efficiency. Expression of both transgenes was required for immortalization. Molecular and immunohistochemical analysis indicated that these cell lines are of Schwann cell lineage and have a range of phenotypes, many of which are consistent with their primary cultures. This is the first report of immortalization and detailed characterization of multiple human NF1 normal nerve and neurofibroma-derived Schwann cell lines, which will be highly useful research tools to study NF1 and other Schwann tumor biology and conditions.

The Outcome of Hypofractionated Stereotactic Radiosurgery for Large Vestibular Schwannomas

Stereotactic radiosurgery (SRS) for large vestibular schwannomas (VS) remains controversial. We studied the tumor local control and toxicity rates after hypofractionated SRS for VS > 3 cm. A total of 587 patients with VS treated with SRS between 1998 and 2014 were reviewed retrospectively, and 30 Koos grade IV VSs were identified. There were 6 patients with neurofibromatosis 2 (NF2), 8 with cystic tumors, 22 with solid tumors, 19 who underwent primary CyberKnife (CK), and 11 with >3 cm after previous resection. Patients were treated by a median of 3 fractions at 18 Gy. After a median 97 months, the 3- and 10-year Kaplan-Meier estimates of local control were 85% and 80%, respectively, with 20% requiring salvage treatment. For patients who had previous tumor resection rather than primary CK, the estimates were 46% and 5%, respectively, with progression, and 3-year control rates of 71% and 94% (P= 0.008). Tumor control was also lower among NF2 versus non-NF2 patients (40% vs. 95%; P= 0.0014). Among patients with good clinical baselines before CK, 88% were functionally independent (modified Rankin Scale score, 0-2), 88% had good facial function (House-Brackmann grade I-II), and 38% had serviceable hearing (Gardner-Robertson grade I-II) at last follow-up. Hearing worsening was more likely among patients treated with primary CK (33% vs. 90%; P= 0.04). Overall, 80% of large VSs were adequately controlled by CK with 97 months of median follow-up. Patients with previous surgery and NF2 also appeared to have higher rates of tumor progression, and less favorable functional outcomes.

Surgical management of an appendiceal neurofibroma in a neurofibromatosis-1 patient: A case report

Abstract Neurofibromatosis-1 (NF1) is an autosomal dominant disease with an incidence of 1 in every 2500 to 3000 births [1]. Although neurofibromas that result from the NF1 gene mutation are typically benign, they may cause complications by compressing neighboring structures or undergoing malignant transformation. The various manifestations and symptoms of NF1 may cause a number of complications throughout childhood and into adulthood, and patients often require surgical management of these complications. A young adult with a previous NF1 diagnosis presented with symptoms concerning for appendicitis. Subsequent imaging and biopsy revealed a rare appendiceal neurofibroma. The patient underwent an ileocecectomy and pathology confirmed the diagnosis of appendiceal neurofibroma. The variety of symptoms and complications associated with NF1, such as vascular abnormalities and airway obstruction, create unique surgical risks for these patients. These risks should be understood and accounted for by surgeons who may encounter NF1 patients.

Natural history of vestibular schwannomas and hearing loss in NF2 patients

Context and objectiveBilateral vestibular schwannomas are the hallmark of neurofibromatosis 2 (NF2), occurring in 95% of patients. These tumors are associated with significant morbidity due to hearing loss, tinnitus, imbalance and facial weakness. As radiosurgery and chemotherapy have been recently introduced in the treatment armamentarium in addition to surgery, a thorough evaluation of vestibular schwannoma natural history is mandatory to determine the role and timing of each treatment modality. MethodsAn exhaustive review of the literature was performed using the PubMed database concerning the natural history of tumor growth and hearing loss in NF2 patients with vestibular schwannomas. ResultsAlthough some aspects of vestibular schwannoma natural history remain uncertain (pattern of tumor growth, mean tumor growth rate), factors influencing growth such as age at presentation and paracrine factors are well established. Studies focusing on the natural history of hearing have highlighted different patterns of hearing loss and the possible role of intralabyrinthine tumors. The polyclonality of vestibular schwannomas in NF2 was recently unveiled, giving a new perspective to their growth mechanisms. ConclusionAn uniform evaluation of tumor growth using volumetric evaluation and hearing with standard classifications will ensure the use of common endpoints and should improve the quality of clinical trials as well as foster comparison among studies while ensuring more consistency in decision-making.