Comparing 3D imaging devices for the measurement of cutaneous neurofibromas in patients with Neurofibromatosis Type 1.

BACKGROUND: Cutaneous neurofibromas (cNFs) are a major cause of disfigurement in patients with Neurofibromatosis Type 1 (NF1). However, clinical trials investigating cNF treatments lack standardised outcome measures to objectively evaluate changes in cNF size and appearance. 3D imaging has been proposed as an objective standardised outcome measure however various systems exist with different features that affect useability in clinical settings. The aim of this study was to compare the accuracy, precision, feasibility, reliability and accessibility of three imaging systems. MATERIALS AND METHODS: We compared the Vectra-H1, LifeViz-Micro and Cherry-Imaging systems. A total of 58 cNFs from 13 participants with NF1 were selected for imaging and analysis. The primary endpoint was accuracy as measured by comparison of measurements between imaging systems. Secondary endpoints included reliability between two operators, precision as measured with the average coefficient of variation, feasibility as determined by time to capture and analyse an image and accessibility as determined by cost. RESULTS: There was no significant difference in accuracy between the three devices for length or surface area measurements (p > 0.05), and reliability and precision were similar. Volume measurements demonstrated the most variability compared to other measurements; LifeViz-Micro demonstrated the least measurement variability for surface area and image capture and analysis were fastest with LifeViz-Micro. LifeViz-Micro was better for imaging smaller number of cNFs (1-3), Vectra-H1 better for larger areas and Cherry for uneven surfaces. CONCLUSIONS: All systems demonstrated excellent reliability but possess distinct advantages and limitations. Surface area is the most consistent and reliable parameter for measuring cNF size in clinical trials.

A High-Throughput Screening Platform Identifies Novel Combination Treatments for Malignant Peripheral Nerve Sheath Tumors.

Malignant peripheral nerve sheath tumors (MPNST) are soft-tissue sarcomas that are the leading cause of mortality in patients with Neurofibromatosis type 1 (NF1). Single chemotherapeutic agents have shown response rates ranging from 18% to 44% in clinical trials, so there is still a high medical need to identify chemotherapeutic combination treatments that improve clinical prognosis and outcome. We screened a collection of compounds from the NCATS Mechanism Interrogation PlatE (MIPE) library in three MPNST cell lines, using cell viability and apoptosis assays. We then tested whether compounds that were active as single agents were synergistic when screened as pairwise combinations. Synergistic combinations in vitro were further evaluated in patient-derived orthotopic xenograft/orthoxenograft (PDOX) athymic models engrafted with primary MPNST matching with their paired primary-derived cell line where synergism was observed. The high-throughput screening identified 21 synergistic combinations, from which four exhibited potent synergies in a broad panel of MPNST cell lines. One of the combinations, MK-1775 with Doxorubicin, significantly reduced tumor growth in a sporadic PDOX model (MPNST-SP-01; sevenfold) and in an NF1-PDOX model (MPNST-NF1-09; fourfold) and presented greater effects in TP53 mutated MPNST cell lines. The other three combinations, all involving Panobinostat (combined with NVP-BGT226, Torin 2, or Carfilzomib), did not reduce the tumor volume in vivo at noncytotoxic doses. Our results support the utility of our screening platform of in vitro and in vivo models to explore new therapeutic approaches for MPNSTs and identified that combination MK-1775 with Doxorubicin could be a good pharmacologic option for the treatment of these tumors.

Neurofibromatosis Type 1-Associated MPNST State of the Science: Outlining a Research Agenda for the Future.

Malignant peripheral nerve sheath tumor (MPNST) is an aggressive soft tissue sarcoma for which the only effective therapy is surgery. In 2016, an international meeting entitled "MPNST State of the Science: Outlining a Research Agenda for the Future" was convened to establish short- and long-term research priorities. Key recommendations included the: 1) development of standardized, cost-efficient fluorodeoxyglucose positron emission tomography and whole-body magnetic resonance imaging guidelines to evaluate masses concerning for MPNST; 2) development of better understanding and histologic criteria for the transformation of a plexiform neurofibroma to MPNST; 3) establishment of a centralized database to collect genetic, genomic, histologic, immunohistochemical, molecular, radiographic, treatment, and related clinical data from MPNST subspecialty centers in a standardized manner; 4) creation of accurate mouse models to study the plexiform neurofibroma-to-MPNST transition, MPNST metastasis, and drug resistance; 5) use of trial designs that minimize regulatory requirements, maximize availability to patients, consider novel secondary end points, and study patients with newly diagnosed disease. Lastly, in order to minimize delays in developing novel therapies and promote the most efficient use of research resources and patient samples, data sharing should be incentivized.

Magnetic resonance neurography of peripheral nerve tumors and tumorlike conditions.

Peripheral nerve enlargement may be seen in multiple conditions including hereditary or inflammatory neuropathies, sporadic or syndromic peripheral nerve sheath tumors, perineurioma, posttraumatic neuroma, and intraneural ganglion. Malignancies such as neurolymphoma, intraneural metastases, or sarcomas may also affect the peripheral nervous system and result in nerve enlargement. The imaging appearance and differentiating factors become especially relevant in the setting of tumor syndromes such as neurofibromatosis type 1, neurofibromatosis type 2, and schwannomatosis. This article reviews the typical magnetic resonance neurography imaging appearances of neurogenic as well as nonneurogenic neoplasms and tumorlike lesions of peripheral nerves, with emphasis on distinguishing factors.