Malignant peripheral nerve sheath tumors in neurofibromatosis type 1: a multicenter project with 3 clinical trials

ReportA major goal of this CTDA proposal is to optimize subject recruitment in each of the clinical trials. Using the prevalence estimate for NF1 as 1 in 3,500 individuals in the population at large coupled with the cross-sectional estimate of 5% affected by MPNST, we acknowledge that few centers will have more than 2 patients with MPNST and NF1 in any given year. We anticipate 1 in 1,750,000 people will develop MPNST and NF1 on an annual basis, thus the populations of the US, Canada, and Europe will provide a maximum of 50 cases per year. Our goal is to recruit at least 2/3 of this cohort for enrollment in at least 1 of the 3 clinical trials. By developing a well-publicized network of NF1 Clinic Centers and Sarcoma Centers, we plan to offer enrollment to every individual in North America and Europe who has MPNST and NF1 into the case-control trial to identify risk factors for MPNST (clinical trial project 1). Based on inclusion and exclusion criteria, some individuals will be eligible for the clinical trial of neoadjuvant chemotherapy, and this will be offered to them as a treatment option (clinical trial project 3)

Malignant Peripheral Nerve Sheath Tumors State of the Science: Leveraging Clinical and Biological Insights into Effective Therapies.

Malignant peripheral nerve sheath tumor (MPNST) is the leading cause of mortality in patients with neurofibromatosis type 1. In 2002, an MPNST consensus statement reviewed the current knowledge and provided guidance for the diagnosis and management of MPNST. Although the improvement in clinical outcome has not changed, substantial progress has been made in understanding the natural history and biology of MPNST through imaging and genomic advances since 2002. Genetically engineered mouse models that develop MPNST spontaneously have greatly facilitated preclinical evaluation of novel drugs for translation into clinical trials led by consortia efforts. Continued work in identifying alterations that contribute to the transformation, progression, and metastasis of MPNST coupled with longitudinal follow-up, biobanking, and data sharing is needed to develop prognostic biomarkers and effective prevention and therapeutic strategies for MPNST

Malignant Peripheral Nerve Sheath Tumors State of the Science: Leveraging Clinical and Biological Insights into Effective Therapies.

Malignant peripheral nerve sheath tumor (MPNST) is the leading cause of mortality in patients with neurofibromatosis type 1. In 2002, an MPNST consensus statement reviewed the current knowledge and provided guidance for the diagnosis and management of MPNST. Although the improvement in clinical outcome has not changed, substantial progress has been made in understanding the natural history and biology of MPNST through imaging and genomic advances since 2002. Genetically engineered mouse models that develop MPNST spontaneously have greatly facilitated preclinical evaluation of novel drugs for translation into clinical trials led by consortia efforts. Continued work in identifying alterations that contribute to the transformation, progression, and metastasis of MPNST coupled with longitudinal follow-up, biobanking, and data sharing is needed to develop prognostic biomarkers and effective prevention and therapeutic strategies for MPNST

Phase 2 randomized, flexible crossover, double-blinded, placebo-controlled trial of the farnesyltransferase inhibitor tipifarnib in children and young adults with neurofibromatosis type 1 and progressive plexiform neurofibromas

Background RAS is dysregulated in neurofibromatosis type 1 (NF1) related plexiform neurofibromas (PNs). The activity of tipifarnib, which blocks RAS signaling by inhibiting its farnesylation, was tested in children and young adults with NF1 and progressive PNs. Methods Patients aged 3–25 years with NF1-related PNs and imaging evidence of tumor progression were randomized in a double-blinded fashion to receive tipifarnib (200 mg/m2 orally every 12 h) or placebo (phase A) and crossed over to the opposite treatment arm at the time of tumor progression (phase B). PN volumes were measured with MRI, and progression was defined as ≥20% volume increase. Time to progression (TTP) in phase A was the primary endpoint, and the trial was powered to detect whether tipifarnib doubled TTP compared with placebo. Toxicity, response, and quality of life were also monitored. Results Sixty-two patients were enrolled. Tipifarnib and placebo were well tolerated. On phase A, the median TTP was 10.6 months on the placebo arm and 19.2 months on the tipifarnib arm (P = .12; 1-sided). Quality of life improved significantly compared with baseline on the tipifarnib arm but not on the placebo arm. Volumetric tumor measurement detected tumor progression earlier than conventional 2-dimensional (WHO) and 1-dimensional (RECIST) methods. Conclusions Tipifarnib was well tolerated but did not significantly prolong TTP of PNs compared with placebo. The randomized, flexible crossover design and volumetric PN assessment provided a feasible and efficient means of assessing the efficacy of tipifarnib. The placebo arm serves as an historical control group for phase 2 single-arm trials directed at progressive PNs

Growth dynamics of plexiform neurofibromas: a retrospective cohort study of 201 patients with neurofibromatosis 1

BACKGROUND: To examine the natural growth dynamics of internal plexiform neurofibromas (PNs) in patients with neurofibromatosis 1 (NF1). METHODS: Two hundred and one NF1 patients underwent whole body MRI (WBMRI). Tumour burden was estimated volumetrically. Non-parametric Spearman’s rho correlation coefficients were used to analyse the relationship of growth rate to tumour volume and age. Chi-squared and Mann–Whitney U tests were used for analysing the association of tumour occurrence with sex or age. Chi-squared tests were used to analyse the association of tumour growth with age group. RESULTS: Seventy-one of 171 patients with serial WBMRI exams had internal PNs (median follow up 2.2 years [1.1 to 4.9 years]). Median whole body tumour volume was 86.4 mL [5.2 to 5878.5 mL]) with a median growth rate of 3.7%/year (−13.4 to 111%/year) that correlated with larger whole body tumour volume (P<0.001) and lower age (P=0.004). No new PNs developed in 273.0 patient-years among patients without tumours. Rate of new tumour development among patients with PNs was 0.6%/year (95% confidence interval 0.02 to 3.4%). Twenty-seven (13.5%) tumours increased significantly and were more frequent among children (P<0.001). Growth rate of tumours was inversely correlated with age (Spearman’s rho=−0.330, P<0.001). Seventy-one (35.5%) tumours had smaller volumes on follow up (median −3.4%/year [−0.07% to −35.9%/year]). CONCLUSION: Children with NF1 and internal PNs are at risk for tumour growth. Most PNs grow slowly or not at all, and some decrease in size. New tumours are infrequent in NF1 patients with PNs and unlikely in patients without PNs

Whole Body MRI at 3T with Quantitative Diffusion Weighted Imaging and Contrast-Enhanced Sequences for the Characterization of Peripheral Lesions in Patients with Neurofibromatosis Type 2 and Schwannomatosis

Purpose. WB-MRI is mainly used for tumor detection and surveillance. The purpose of this study is to establish the feasibility of WB-MRI at 3T for lesion characterization, with DWI/ADC-mapping and contrast-enhanced sequences, in patients with neurofibromatosis type 2 (NF-2) and schwannomatosis. Materials and Methods. At 3T, WB-MRI was performed in 11 subjects (10 NF-2 and 1 schwannomatosis) with STIR, T1, contrast-enhanced T1, and DWI/ADC mapping (b = 50, 400, 800 s/mm2). Two readers reviewed imaging for the presence and character of peripheral lesions. Lesion size and features (signal intensity, heterogeneity, enhancement characteristics, and ADC values) were recorded. Descriptive statistics were reported. Results. Twenty-three lesions were identified, with average size of 4.6 ± 2.8 cm. Lesions were characterized as tumors (21/23) or cysts (2/23) by contrast-enhancement properties (enhancement in tumors, no enhancement in cysts). On T1, tumors were homogeneously isointense (5/21) or hypointense (16/21); on STIR, tumors were hyperintense and homogeneous (10/21) or heterogeneous (11/21); on postcontrast T1, tumors enhanced homogeneously (14/21) or heterogeneously (7/21); on DWI, tumor ADC values were variable (range 0.8–2.7), suggesting variability in intrinsic tumor properties. Conclusion. WB-MRI with quantitative DWI and contrast-enhanced sequences at 3T is feasible and advances the utility of WB-MRI not only to include detection, but also to provide additional metrics for lesion characterization

Genetically engineered minipigs model the major clinical features of human neurofibromatosis type 1.

Neurofibromatosis Type 1 (NF1) is a genetic disease caused by mutations in Neurofibromin 1 (NF1). NF1 patients present with a variety of clinical manifestations and are predisposed to cancer development. Many NF1 animal models have been developed, yet none display the spectrum of disease seen in patients and the translational impact of these models has been limited. We describe a minipig model that exhibits clinical hallmarks of NF1, including café au lait macules, neurofibromas, and optic pathway glioma. Spontaneous loss of heterozygosity is observed in this model, a phenomenon also described in NF1 patients. Oral administration of a mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor suppresses Ras signaling. To our knowledge, this model provides an unprecedented opportunity to study the complex biology and natural history of NF1 and could prove indispensable for development of imaging methods, biomarkers, and evaluation of safety and efficacy of NF1-targeted therapies