Malignant Peripheral Nerve Sheath Research Articles

Clinical Outcome After Pencil Beam Scanning Proton Therapy of Patients With Non-Metastatic Malignant and Benign Peripheral Nerve Sheath Tumors

ObjectivePeripheral nerve sheath tumors (PNSTs) commonly arise from peripheral nerve roots and grow locally invasive. Malignant PNSTs (mPNSTs) represent aggressive sarcomas of neural origin that can originate from PNSTs. Radiation therapy is commonly used as part of the required multimodal treatment. However, both entities tend to occur early in life and are associated with the genetic disorder neurofibromatosis type 1 (NF-1), which is known to cause increased radiosensitivity. Pencil beam scanning proton therapy (PBSPT) allows for a minimization of the dose delivered to organs at risk and the integral dose and, thus, potentially also a reduction of radiation-induced adverse events. We report the clinical outcome and toxicity rates of patients with (m)PNSTs treated with PBSPT.MethodsWe retrospectively reviewed 36 patients who received PBSPT (median dose, 64 GyRBE) with curative intent for (m)PNSTs between 1999 and 2020 at our institute. Twenty-eight (78%) and 8 (22%) patients were treated at diagnosis and for tumor recurrence/progression, respectively. The median age was 32 years (range, 3–75), and 25 (69%) patients were male. mPNST and PNST were diagnosed in 31 (86%) and 5 (14%) patients, respectively. Underlying NF-1 disease was found in 8 (22%) patients. Acute and late toxicities were recorded according to Common Terminology Criteria for Adverse Events, version 4.1 (CTCAE v4.1). Overall survival (OS), local control (LC), and distant control (DC) were estimated using the Kaplan–Meier method.ResultsWith a median follow-up time of 31 months (range, 4–194), 13 (36%) patients died from a progressive disease, 8 (22%) experienced local failure, and 14 (39%) experienced distant failure after PBSPT. Estimated 2-year OS, LC, and DC were 75.5%, 73.5%, and 61.2%, respectively. Acute grade 3 toxicity (dermatitis, mucositis, and pain) was observed in 5 (14%) patients. Late grade 3 cataract and osteonecrosis were both observed in 1 (3%) patient at 34 and 194 months after PBSPT, respectively. There was no late grade >3 toxicity or radiation-induced secondary cancer.ConclusionTo our knowledge, this is the first study to analyze the outcome of (m)PNSTs treated with proton therapy using a PBS delivery paradigm. In our cohort, consisting mainly of patients with mPNSTs, we report reasonable oncological outcomes and low toxicity rates after PBSPT.

MO-0148 Clinical outcome after proton therapy for malignant and benign peripheral nerve sheath tumors

MO-0148 Clinical outcome after proton therapy for malignant and benign peripheral nerve sheath tumors

Patient-derived iPSC-cerebral organoid modeling of the 17q11.2 microdeletion syndrome establishes CRLF3 as a critical regulator of neurogenesis.

SUMMARYNeurodevelopmental disorders are often caused by chromosomal microdeletions comprising numerous contiguous genes. A subset of neurofibromatosis type 1 (NF1) patients with severe developmental delays and intellectual disability harbors such a microdeletion event on chromosome 17q11.2, involving the NF1 gene and flanking regions (NF1 total gene deletion [NF1-TGD]). Using patient-derived human induced pluripotent stem cell (hiPSC)-forebrain cerebral organoids (hCOs), we identify both neural stem cell (NSC) proliferation and neuronal maturation abnormalities in NF1-TGD hCOs. While increased NSC proliferation results from decreased NF1/RAS regulation, the neuronal differentiation, survival, and maturation defects are caused by reduced cytokine receptor-like factor 3 (CRLF3) expression and impaired RhoA signaling. Furthermore, we demonstrate a higher autistic trait burden in NF1 patients harboring a deleterious germline mutation in the CRLF3 gene (c.1166T>C, p.Leu389Pro). Collectively, these findings identify a causative gene within the NF1-TGD locus responsible for hCO neuronal abnormalities and autism in children with NF1.

Soft-tissue sarcoma in adolescents and young adults compared with older adults: A report among 5000 patients from the Scandinavian Sarcoma Group Central Register.

In recent years, there has been growing awareness of the distinct characteristics of adolescents and young adults (AYA) diagnosed with cancer. Soft-tissue sarcoma (STS) accounts for approximately 1% of all cancers diagnosed in adults and 8% of cancers diagnosed in AYA. To the best of our knowledge, only a few sarcoma registers include data regarding histological subtype, age at diagnosis, and detailed clinical information. Therefore, little is known regarding clinical presentation and outcomes in AYA diagnosed with STS. Using the Scandinavian Sarcoma Group Central Register, data were obtained regarding 4977 patients who were diagnosed with STS for the period between 1986 and 2011. AYA (those aged 18-39years) were compared with older adults (OA; those aged 40-80years) with respect to clinical presentation, treatment, and outcome. There were 868 AYA and 4109 OA. Overall and by STS subtype, there were significant differences noted between AYA and OA with regard to presentation, treatment, and survival. The distribution of STS subtypes was different between OA and AYA (eg, OA were more likely to be diagnosed with malignant fibrous histiocytoma compared with AYA [34% vs 16%; P<.001]). OA also were more likely to have tumors measuring ≥5cm (68% vs 56%; P<.001) and a higher malignancy grade (75% vs 67%; P<.001). In the majority of STS subtypes AYA had significantly better overall survival and less disease recurrence compared with OA, but this finding was not true for those with malignant peripheral nerve sheath tumors. There are several differences between AYA and OA with STS with regard to presentation, treatment, and survival, and such differences must be taken into consideration when designing clinical trials. Additional work also is needed to characterize the potential biological mechanisms underlying these differences.

Abstract 2748: A population-based survey of excess cancers observed in Ewing's sarcoma and in their first-, second-, and third-degree relatives

Abstract Purpose: The purpose of this study is to investigate whether individuals with Ewing's sarcoma are at increased risk of developing other cancers. The presence of excess cancers in first-, second-, and third-degree relatives of ES cases is also investigated. Background: Ewing's sarcoma (ES) is a rare, aggressive bone cancer that affects children and young adults. In 85% of ES cases, a chromosomal translocation between the EWSR1 gene on chromosome 22 and the FLI1 gene on chromosome 7 is observed in somatic cells. In the remainder of cases, the EWSR1 gene fuses to other ETS family gene members. The resulting EWS/ETS fusion protein formed in ES cases dysregulates target genes–thereby promoting oncogenesis. Methods: The Utah Population Database (UPDB) is a population-based genealogy linked to both the Utah Cancer Registry and to hospital data from the University of Utah Health Sciences Center. We used the UPDB to calculate the relative risks (RR) of 35 cancer sites in ES cases and in their relatives. RR was calculated using age-, birth-state- (Utah vs. non-Utah), birth county- (urban vs. rural) and birth-year-specific cancer rates. Results: We identified 133 individuals with ES who had ancestors in the UPDB. Brain cancer and complex genotype/karyotype sarcomas were observed at significant excess in more than one ES case (RR = 10.26; 95% CI: 1.24, 37.05; RR = 28.33, 95%CI: 3.43, 102.33, respectively). Individuals with ES had 695 first-degree, 2129 second-degree, and 6285 third-degree relatives in the UPDB. RRs for four cancer sites were significantly elevated in first-degree relatives: prostate (1.75; 1.06, 2.94), female genital (6.38; 1.13, 23.06), brain (3.68; 1.26, 9.42), and lung (2.31; 1.01, 5.04). In second-degree relatives, there was a significantly increased risk of four cancers: Non-Hodgkins lymphoma (2.07; 1.16, 3.42), breast (1.47; 1.11, 2.01), malignant peripheral nerve sheath (15.63; 1.89, 56.45), and tongue (4.02; 1.10, 11.75). Lastly, third-degree relatives had a significantly increased risk for five cancer sites: acute lymphocytic leukemia (3.74; 1.75, 7.70), stomach (1.87; 1.17, 3.03), prostate (1.23; 1.04, 1.49), brain (1.86; 1.07, 3.24), and gallbladder (2.73; 1.08, 6.37). Conclusion: The increased risk of several cancers other than ES in ES cases and in their relatives suggests the possibility of an inherent genetic predisposition to mutagenesis that predisposes both to observed mutations and chromosomal rearrangements seen in ES cases and to additional cancers (primarily brain and prostate) in individuals who do not have ES. Citation Format: Diana Abbott, R. Lor Randall, Joshua Schiffman, Stephen Lessnick, Lisa A. Cannon-Albright. A population-based survey of excess cancers observed in Ewing's sarcoma and in their first-, second-, and third-degree relatives. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2748. doi:10.1158/1538-7445.AM2015-2748

Non-Rhabdomyosarcoma Soft Tissue Sarcomas in Children: A Surveillance, Epidemiology, and End Results Analysis Validating COG Risk Stratifications

Non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) are a heterogeneous group of sarcomas that encompass over 35 histologies. With an incidence of ∼500 cases per year in the United States in those <20 years of age, NRSTS are rare and therefore difficult to study in pediatric populations. We used the large Surveillance, Epidemiology, and End Results (SEER) database to validate the prognostic ability of the Children's Oncology Group (COG) risk classification system and to define patient, tumor, and treatment characteristics. From SEER data from 1988 to 2007, we identified patients ≤18 years of age with NRSTS. Data for age, sex, year of diagnosis, race, registry, histology, grade, primary size, primary site, stage, radiation therapy, and survival outcomes were analyzed. Patients with nonmetastatic grossly resected low-grade tumors of any size or high-grade tumors ≤5 cm were considered low risk. Cases of nonmetastatic tumors that were high grade, >5 cm, or unresectable were considered intermediate risk. Patients with nodal or distant metastases were considered high risk. A total of 941 patients met the review criteria. On univariate analysis, black race, malignant peripheral nerve sheath (MPNST) histology, tumors >5 cm, nonextremity primary, lymph node involvement, radiation therapy, and higher risk group were associated with significantly worse overall survival (OS) and cancer-specific survival (CSS). On multivariate analysis, MPNST histology, chemotherapy-resistant histology, and higher risk group were significantly poor prognostic factors for OS and CSS. Compared to low-risk patients, intermediate patients showed poorer OS (hazard ratio [HR]: 6.08, 95% confidence interval [CI]: 3.53-10.47, P<.001) and CSS (HR: 6.27; 95% CI: 3.44-11.43, P<.001), and high-risk patients had the worst OS (HR: 13.35, 95% CI: 8.18-21.76, P<.001) and CSS (HR: 14.65, 95% CI: 8.49-25.28, P<.001). The current COG risk group stratification for children with NRSTS has been validated with a large number of children in the SEER database.

MS-01 * DEVELOPMENT OF MALIGNANT PERIPHERAL NERVE TUMOR MODEL FOR EVALUATING A TUMOR TARGETED LIPOSOME-BASED THERAPY

In our previous studies we demonstrated the expression of IL-13Rα2 receptor in several malignant and benign peripheral nerve sheath tumors. In a subsequent study we investigated the specific binding of the IL-13 conjugated liposomal doxorubicin (IL13LIPDXR) to the MPNST cells and their cytotoxic property in the monolayer and spheroid model. To demonstrate the in vivo therapeutic efficacy, a sciatic nerve tumor model was developed in nude mice using STS26T, a MPNST cell line. The STS26T cell line was stably transfected with a luciferase expressing plasmid using a nanoliposome technology developed in our laboratory. These luciferase transfected cells were injected in the sciatic nerve in NIH III nude mice and allowed to grow for 2-4 weeks. To confirm the tumor formation intravital imaging spectroscopy (IVIS) and MR imaging were performed after injection of luciferin-D, a substrate for the luciferase. For our pathological studies, the mice were sacrificed and the tumor along with the nerve was dissected and paraffin embedded. The tumor was sectioned and the sections were subjected to immunohistochemistry (IHC) for the presence of IL-13Rα2 receptor protein, ki-67 a cell proliferation marker, heavy chain ferritin and S100 (myelin forming Schwann cells). Our experiment demonstrated the presence of IL-13R2 receptor, ki-67, H-ferritin and S100 at variable levels in the tumor. Experiments are in progress to develop an effective therapeutic strategy using IL-13 targeted liposomes.

Malignant Peripheral Nerve Sheath Tumors of the Scalp: Case Report and Review of Literature

Malignant peripheral nerve sheath tumors of the scalp are rare lesions of the nervous system. Only 16 cases have been reported to date. In this report, we present a case of a malignant peripheral nerve sheath tumor (MPNST) of the scalp and retrospectively analyze the clinical features, imaging findings, pathological features, and prognoses of these tumors.

Abstract 5210: KPT-330, a selective small molecule inhibitor of nuclear export, is active in bone and soft tissue sarcoma.

Abstract KPT-330 is a small molecule Selective Inhibitor of Nuclear Export (SINE) that irreversibly block the major nuclear export protein CRM1 (exportin 1, XPO1). The Chromosome Region Maintenance 1 (CRM1) protein is responsible for the nuclear export of snRNAs and of proteins bearing a leucine-rich nuclear export signal (NES). This class of drugs is expected to induce forced nuclear accumulation of tumor suppressor proteins (TSPs) and is believed to initiate a ‘genome survey’ leading to the death of cancer cells with normal cells undergoing transient, reversible cell cycle arrest. Our effort was to investigate the effects of KPT-330 in sarcomas and the mechanism by which it exerts the effect of tumor suppression. Our data clearly shows KPT-330 as active against a broad panel of human bone and soft tissue sarcoma cell lines at low nanomolar concentrations. The effect was mainly due to the induction of apoptosis. Target specificity of the drug was confirmed by the decrease in CRM1 protein level. An induction of p53 and p21 protein levels was observed. However, the effect of apoptosis or inhibition in proliferation seems to be independent of p53 status of the cell line. The effect of KPT-330 was further tested in xenograft models using malignant peripheral nerve sheath (MPNST) and de-differentiated liposarcoma (LS141) cell lines. Tumor suppression was observed in both the sarcoma models and its target specificity was confirmed in the xenografts. KPT-330 may represent a new drug for the treatment of bone and soft tissue sarcoma. Citation Format: Jayasree S. Nair, William Tap, Shyamprasad Deraje Vasudeva, Jason K. Sicklick, Michael Kauffman, Sharon Shacham, Gary K. Schwartz. KPT-330, a selective small molecule inhibitor of nuclear export, is active in bone and soft tissue sarcoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5210. doi:10.1158/1538-7445.AM2013-5210

Serum vascular endothelial growth factor in dogs with soft tissue sarcomas

This work aimed to evaluate serum vascular endothelial growth factor (VEGF) in 25 dogs with soft tissue sarcoma, and in 30 healthy dogs. Blood was collected once time from the control animals and three times, in the same way, from animals with sarcoma. Blood count was performed in the blood collected, and serum VEGF was measured by enzyme-linked immunosorbent assay quantitative method. Serum VEGF in control animals was similar to patients with soft tissue sarcoma. There was a reduction in serum VEGF after the sarcoma resection. There was positive correlation between serum VEGF and neutrophil counts, and negative between VEGF and hemoglobin content in animals with sarcoma. Animals with hemangiopericytoma showed higher serum VEGF levels compared to the patients with malignant peripheral nerve sheath. Circulating blood cells can contribute to elevate VEGF serum concentrations in dogs with soft tissue sarcomas and a possible role of VEGF in the angiogenesis of these tumors.

Aberrant cAMP Metabolism in NF1 Malignant Peripheral Nerve Sheath Tumor Cells

Malignant peripheral nerve sheath (MPNST) cell lines derived from patients with neurofibromatosis type 1 (NF!) were found to have basal cAMP levels which are two-fold higher than cAMP levels in normal human adult Schwann cells (nHSC). PCR analysis also revealed that normal adult human Schwann cells express mRNA for types Ill, IV, and IX adenylyl cyclase (AC) while NF1 MPNST cells express AC mRNA of types II, V, and VIII in addition to expressing all the isoforms of normal adult human Schwann cells. Further PCR analysis revealed that NF1 MPNST lines express mRNA for EP2 and EP4 prostaglandin receptors whereas nHSC only express mRNA for the EP2 receptor. Exogenous prostaglandins alone or in combination with PDGF BB induced greater increases in cAMP levels and proliferation of NF1 MPNST cells compared to nHSC. We conclude that aberrant cAMP signaling in NF1 MPNST cells contributes to tumor formation in NF1 patients.

Chronic renal failure and macrogenitalia associated with genitourinary neurofibromatosis

Neurofibromatosis (NF) is a genetic disorder of the nervous system that primarily affects the development and growth of neural cell tissues. This disorder is characterized by the development of various tumors, including neurofibromas, neuroniomas, malignant and benign peripheral nerve sheath tumors, and meningiomas. Accompanying skin changes and bone deformities are also common in NF. However, genitourinary involvement in NF is a rare condition, and penile enlargement has been reported only in a few males with plexiform NF. We report a 6-year-old boy with chronic renal failure associated with plexiform neurofibromas of the bladder and prostatic urethra which led to urinary obstruction and macrogenitalia due to genitourinary NF.

Phase II trial of cetuximab in patients (pts) with metastatic and/or locally advanced soft tissue and bone sarcomas

10537 Background: Cytotoxic therapy has resulted in limited improvement in outcomes of pts with advanced sarcoma. The epidermal growth factor receptor (EGFR) pathway plays a role in tumorigenicity and is expressed in many sarcoma subtypes. Blockade of EGFR in certain sarcoma cell lines has decreased cell growth and increased tumor apoptosis. Therefore, we conducted a phase II trial of the anti-EGFR monoclonal antibody cetuximab in EGFR positive(+) and negative sarcoma and report here results of the EGFR+ group. Methods: Pts ≥ 16 years old with advanced sarcoma who progressed on ≥ 1 prior therapy were eligible. Cetuximab was administered at 400mg/m2 on day 1 and 250mg/m2 during subsequent weekly infusions. A cycle was defined as 4 weeks of therapy with radiographic assessment every 2 cycles. The primary objective was 4-month progression-free survival (PFS) rate in EGFR+ pts. Using a Simon two-stage design and a 10 and 30% rate as the null and alternative hypothesis, 22 pts were to be accrued in the first stage, with an additional 11 pts if ≥ 3 pts met primary endpoint. EGFR+ was defined by immunohistochemistry (IHC) as 1+, 2+, or 3+. Secondary objectives included assessment of response rate and evaluation of molecular alterations in EGFR pathway by IHC and mutational analysis using PCR/direct sequencing. Results: 22 evaluable pts with EGFR+ sarcoma were enrolled. Subtypes included synovial (32%), liposarcoma (27%), malignant fibrous histiocytoma (18%), leiomyosarcoma (14%), myxofibrosarcoma (4%), and malignant peripheral nerve sheath (4%). The median number of prior therapies was 2; the median number of cycles was 2; the median PFS was 52 days (95% CI: 48 - 54). One patient was free of progression for over 4 months. No objective responses were seen. Two patients withdrew from study due to ileus and acute renal failure. MAP-K, PTEN, and phospho-EGFR staining revealed variable expression without discernible pattern. No EGFR mutations were detected in exons tested in available specimens. Conclusions: Cetuximab has minimal activity in advanced EGFR+ sarcoma, and further investigation as a single agent is not indicated. Cetuximab in combination with cytotoxic therapy or following definition of specific molecular abnormalities in sarcoma requires further study. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bristol-Myers Squibb

Mouse double minute antagonist Nutlin-3a enhances chemotherapy-induced apoptosis in cancer cells with mutant p53 by activating E2F1

MDM2 is a critical negative regulator of the p53 tumor suppressor protein. Recently, small-molecule antagonists of MDM2, the Nutlins, have been developed to inhibit the p53-MDM2 interaction and activate p53 signaling. However, half of human cancers have mutated p53 and they are resistant to Nutlin treatment. Here, we report that treatment of the p53-mutant malignant peripheral nerve sheath (MPNST) and p53-null HCT116 cells with cisplatin (Cis) and Nutlin-3a induced a degree of apoptosis that was significantly greater than either drug alone. Nutlin-3a also increased the cytotoxicity of both carboplatin and doxorubicin in a series of p53-mutant human tumor cell lines. In the human dedifferentiated liposarcoma cell line (LS141) and the p53 wild-type HCT116 cells, Nutlin-3a induced downregulation of E2F1 and this effect appeared to be proteasome dependent. In contrast, in MPNST and HCTp53-/- cells, Nutlin-3a inhibited the binding of E2F1 to MDM2 and induced transcriptional activation of free E2F1 in the presence of Cis-induced DNA damage. Downregulation of E2F1 by small interfering RNA significantly decreased the level of apoptosis induced by Cis and Nutlin-3a treatment. Moreover, expression of a dominant-negative form of E2F1 rescued cells from apoptosis, whereas cells overexpressing wild-type E2F1 showed an increase in cell death. This correlated with the induction of the proapoptotic proteins p73alpha and Noxa, which are both regulated by E2F1. These results indicate that antagonism of MDM2 by Nutlin-3a in cells with mutant p53 enhances chemosensitivity in an E2F1-dependent manner. Nutlin-3a therefore may provide a therapeutic benefit in tumors with mutant p53 provided it is combined with chemotherapy.

Unilateral Limb Enlargement in a Dog with a Malignant Peripheral Nerve Sheath Tumor

A 3- to 4-month-old female Golden Retriever dog presented with right hind limb enlargement. Physical examination of the limb and radiographic findings initially included soft tissue swelling with elongation, bowing, and cortical irregularity of the femur and tibia. During a period of approximately 7 months, pathology in the limb progressed to include tarsal laxity, muscle atrophy, avulsion of the gastrocnemius muscle, and luxation of the patella. During surgical intervention to shorten the limb and repair the patellar luxation, a large soft tissue cyst was identified along the caudal aspect of the femur and stifle. The limb was later amputated, and a final diagnosis of malignant peripheral nerve sheath (PNS) tumor of the sciatic nerve and surrounding soft tissues was made. The unilateral limb enlargement in this dog appears to have been because of the development and progression of a malignant PNS tumor. The presentation and associated pathologic changes in the limb are unusual for canine PNS tumor but have similarities with neurofibromatosis in the limbs of humans.

Malignant peripheral nerve sheath tumor of the orbit

Malignant peripheral nerve sheath (MPNS) tumor is a rare neoplasm of the orbit. The authors report a 78-year-old woman with an anaplastic MPNS tumor of the orbit that arose from a pre-existing encapsulated tumor composed of cells having a low mitotic index and displaying ultrastructural features of Schwann cells. The encapsulated tumor was unusual for a schwannoma because of its greater cellularity, absence of Antoni B tissue, and rarity of nuclear palisading. This combination of morphologic findings has two possible interpretations: (1) the anaplastic portion of the tumor arose from a variant of benign schwannoma known as a cellular schwannoma, or (2) the entire tumor was an MPNS tumor with variable differerentiation and extensive growth within markedly thickened perineurium.