SUMMARY Interactions between tumorigenic cells and their surrounding microenvironment are critical for tumor progression yet remain incompletely understood. Germline mutations in the NF1 tumor suppressor gene cause neurofibromatosis type 1 (NF1), a common genetic disorder characterized by complex tumors called neurofibromas. Genetic studies indicate that biallelic loss of Nf1 is required in the tumorigenic cell of origin in the embryonic Schwann cell lineage. However, in the physiologic state, Schwann cell loss of heterozygosity is not sufficient for neurofibroma formation and Nf1 haploinsufficiency in at least one additional nonneoplastic lineage is required for tumor progression. Here, we establish that Nf1 heterozygosity of bone marrow-derived cells in the tumor microenvironment is sufficient to allow neurofibroma progression in the context of Schwann cell Nf1 deficiency. Further, genetic or pharmacologic attenuation of c-kit signaling in Nf1+/− hematopoietic cells diminishes neurofibroma initiation and progression. Finally, these studies implicate mast cells as critical mediators of tumor initiation.

Summary BACKGROUND Plexiform neurofibromas (PN) are slow growing chemoradiotherapy resistant tumours arising in patients with neurofibromatosis type I (NF1). Currently there are no viable therapeutic options for patients whose life-threatening plexiform neurofibromas cannot be surgically removed due to proximity to vital body structures. Based on identification of molecular targets in genetic mouse models of human NF1 tumours, we hypothesized that the oral kinase inhibitor, imatinib mesylate, may be effective in targeted treatment of these chemoradiotherapy-refractory tumours. METHODS An open-label pilot Phase II clinical trial was designed to test whether treatment with imatinib mesylate can decrease volume burden of clinically significant plexiform neurofibromas in NF1 patients. The entry criteria require patients only to have NF1 and a clinically significant plexiform neurofibroma with the specified age limitations (age 3–65). Patients were treated with daily oral imatinib at 440 mg/m2/day for children and 800 mg/day for adults divided twice daily for 6 months. The primary endpoint measure of significant response was a 20% or more reduction in plexiform size by sequential volumetric MRI imaging. Clinical data was analyzed on an intent to treat basis, however to determine the activity of imatinib on NF1-related plexiform tumours, patients able to take imatinib for 6 months were evaluated for their response. Secondary outcomes included evaluation of safety of imatinib mesylate in this group of patients. The trial is registered at http://clinicaltrials.gov/; study number 0512-25. The trial currently is closed to enrollment, however there is a single patient that continues to respond and remains on study. FINDINGS On an intent to treat basis, 6 out of 36 patients or 17% (95% CI: 6 – 33%) experienced objective response to imatinib mesylate. In the evaluable study population of patients (n=23) who received drug for at least six months, six patients (26%; 95% CI: 10 – 48%) experienced ≥ 20% decrease in volume of one or more plexiform tumours and 30% of study patients had symptomatic improvement. We noted significant inter-patient and intra-patient heterogeneity of plexiform neurofibroma response. Toxicity of drug was comparable to previous reports in patients with chronic myelogenous leukemia. The most common adverse events were reversible skin rash (5 patients) and edema with weight gain (6 patients). More serious adverse events included reversible grade 3 neutropenia (2 patients) and grade 4 transaminitis (one patient). INTERPRETATION Imatinib mesylate caused disease regression in 26% of evaluable patients with clinically significant plexiform neurofibromas due to neurofibromatosis type 1. These results warrant confirmation in a larger multi-institutional clinical trial aimed at this patient population. These findings provide the first demonstration of radiographic volumetric tumour reduction in response to medical therapy in patients with NF1 plexiform neurofibromas using imatinib mesylate based on studies...

Retinoic acid (RA) induces terminal granulocytic differentiation of the HL-60 promyelocytic leukemia cell line as well as certain other human myeloid leukemias. Specific RA receptors that are members of the steroid-thyroid hormone superfamily of nuclear transcription factors have recently been identified. We developed an HL-60 subclone that was relatively resistant to RA-induced differentiation. Specific nuclear RA receptors in this RA-resistant subclone had a decreased affinity for RA and exhibited a lower molecular weight compared with nuclear RA receptors from the RA-sensitive parental HL-60 cells. Retroviral vector-mediated transduction of a single copy of the RA receptor (RAR-alpha) into this RA-resistant HL-60 subclone restored the sensitivity of these cells to RA. These observations indicate that RAR-alpha plays a critical and central role in mediating RA-induced terminal differentiation of HL-60 leukemia cells.

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GCT patients require lifetime follow-up. At the time of LR, surgical resection alone remains our preferred therapy.

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Methods: Currently used imaging endpoints, designs of NF clinical trials, and knowledge of the natural history of NF-related tumors, in particular PN and VS, were reviewed. Consensus recommendations for response evaluation for future studies were developed based on this review and the expertise of group members.Results: MRI with volumetric analysis is recommended to sensitively and reproducibly evaluate changes in tumor size in clinical trials. Volumetric analysis requires adherence to specific imaging recommendations. A 20% volume change was chosen to indicate a decrease or increase in tumor size. Use of these criteria in future trials will enable meaningful comparison of results across studies. Conclusions:The proposed imaging response evaluation guidelines, along with validated clinical outcome measures, will maximize the ability to identify potentially active agents for patients with NF and benign tumors. 1,2 Linear measurements are performed for their ease of use and are suitable for most malignant lesions that rapidly change in size. Disease-specific recommendations have been developed for some diseases in which linear measurements are not practical or meaningful, such as the Response Assessment in Neuro-Oncology (RANO) criteria for brain tumors.3,4 In addition, an international effort is under way to develop measurement guidelines for pediatric brain tumors, which will be applicable to neurofibromatosis type 1 (NF1)-related gliomas.

Reliable, non-invasive methods for diagnosing and prognosing sinusoidal obstruction syndrome (SOS) early after hematopoietic cell transplantation (HCT) are needed. We used a quantitative mass spectrometry-based proteomics approach to identify candidate biomarkers of SOS by comparing plasma pooled from 20 patients with and 20 patients without SOS. Of 494 proteins quantified, we selected six proteins [L-Ficolin, vascular-cell-adhesion-molecule-1 (VCAM1), tissue-inhibitor of metalloproteinase-1, von Willebrand factor, intercellular-adhesion-molecule-1, and CD97] based on a differential heavy/light isotope ratio of at least 2 fold, information from the literature, and immunoassay availability. Next, we evaluated the diagnostic potential of these six proteins and five selected from the literature [suppression of tumorigenicity-2 (ST2), angiopoietin-2 (ANG2), hyaluronic acid (HA), thrombomodulin, and plasminogen activator inhibitor-1] in samples from 80 patients. The results demonstrate that together ST2, ANG2, L-Ficolin, HA, and VCAM1 compose a biomarker panel for diagnosis of SOS. L-Ficolin, HA, and VCAM1 also stratified patients at risk for SOS as early as the day of HCT. Prognostic Bayesian modeling for SOS onset based on L-Ficolin, HA, and VCAM1 levels on the day of HCT and clinical characteristics showed >80% correct prognosis of SOS onset. These biomarkers may provide opportunities for preemptive intervention to minimize SOS incidence and/or severity.