Association of plexiform and diffuse neurofibromas with malignant peripheral nerve sheath tumor in NF I patients: a whole-body MRI assessment.

OBJECTIVE: The aim of this study is to evaluate neurofibromatosis type 1 (NF1) patients with whole-body MRI (WBMRI) to investigate the frequency of plexiform neurofibromas (pNFs), diffuse neurofibromas (dNFs), and malignant peripheral nerve sheath tumors (MPNSTs). MATERIALS AND METHODS: In this retrospective cross-sectional study, between the years 2015 and 2023, 83 consecutive patients with known NF1 underwent a total of 110 WBMRI screenings for MPNST using a standardized institutional protocol. The lesions are categorized as discrete lesions, pNFs, dNFs, and MPNSTs. Histopathology served as the reference standard for all MPNSTs. RESULTS: Among the 83 patients analyzed, 53 (64%) were women and 30 were men (36%) of ages 36.94±14.43 years (range, 15-66 years). Of the 83 patients, 33 have a positive family history of NF1 and positive genetic studies. Seven of 83 (8%) have only dNF, 20/83 (24%) have pNF, 28/83 (34%) have both dNF and pNF, and 28/83 (34%) have neither. Of the 83 patients, eight (9.6%) were diagnosed with nine total MPNSTs. Age range for patients with MPNSTs at time of diagnosis was 22-51, with an average age of 33.4 years. Only one MPNST (11%) developed from underlying pNF 4 years after WBMRI along the right bronchial tree. Three of eight (37.5%) patients with MPNST died within 5 years of pathologic diagnosis. CONCLUSION: This study suggests the absence of a predisposition for development of MPNST from pNFs and dNFs in the setting of NF1. As such, these lesions may not need special surveillance compared to discrete peripheral nerve sheath tumors.

Vaginal malignant peripheral nerve sheath tumor treated with complete surgical resection and postoperative radiation therapy.

Malignant peripheral nerve sheath tumors (MPNSTs) are neoplasms originating from or differentiating into nerve sheaths of peripheral nerves. Vaginal origin is rare, with only six vaginal primary cases reported to date. A 55-year-old woman presented to our hospital with a 7 cm vulvar mass. Tumor biopsy results were suspicious of sarcoma, and pelvic magnetic resonance imaging and hysterofiberscopy showed that the tumor originated from the lower vagina. The mass was transvaginally excised, and histological examination confirmed the diagnosis of a vaginal MPNST with negative surgical margins. The patient underwent radiotherapy because the risk of recurrence was high, owing to the large tumor size and high mitotic index. The patient remained recurrence-free for 1 year after the primary treatment. This is the first case of a high-risk vaginal MPNST that avoided early disease recurrence with additional radiotherapy after complete tumor resection.

Malignant Peripheral Nerve Sheath Tumors of the Brachial Plexus: A Single-Center Experience on Diagnosis, Management, and Outcomes.

INTRODUCTION: The incidence of malignant peripheral nerve sheath tumors (MPNSTs) is 0.001%. Commonly, MPNST arise in neurofibromatosis; however, they can occur sporadically, de novo or from a preexisting neurofibroma. Malignant peripheral nerve sheath tumors are aggressive tumors with high rates of local recurrence and metastasis. The prognosis is poor with 5-year survival rates of 15% to 50%. Unfortunately, given the rarity of these tumors, it is not clear how to best manage these patients. The purposes of this study were (1) to discuss our experience with MPNST and particularly our difficulties with diagnosis and management, and (2) to review the literature. MATERIALS AND METHODS: We report on all tumors of the brachial plexus excised between 2013 and 2019. We report 3 cases of MPNST, their treatment, and their outcomes. RESULTS: Thirteen patients underwent surgical excision of an intrinsic brachial plexus mass. Three of these patients (2 male, 1 female; average age, 36 years) were diagnosed with an MPNST. Two patients with an MPNST had neurofibromatosis type 1. All patients with an MPNST had a tumor >8 cm, motor and sensory deficits, and pain. All 3 patients with MPNST underwent a magnetic resonance imaging (MRI) before diagnosis. The average time from initial symptom onset to MRI was 12.3 months. Only 1 of the MRIs suggested a malignant tumor, with no MRI identifying an MPNST. One patient underwent an excisional biopsy, and 2 had incisional biopsies. Because of the lack of diagnosis preoperatively, all patients had positive margins given the limited extent of surgery. Returning for excision in an attempt to achieve negative margins in a large oncologically contaminated field was not possible because defining the boundaries of the initial surgical field was unachievable; therefore, the initial surgery was their definitive surgical management. All patients were referred to oncology and received radiation therapy. CONCLUSIONS: Malignant peripheral nerve sheath tumors must be suspected in enlarging masses (>5 cm) with the constellation of pain, motor, and sensory deficits. Computed tomography- or ultrasound-guided core needle biopsy under brachial plexus block or sedation is required for definitive diagnosis to allow for a comprehensive approach to the patient's tumor with a higher likelihood of disease-free survival.

Risk of Malignant Transformation Arising From Giant Congenital Melanocytic Nevi: A 20-year Single-center Study.

BACKGROUND: Although giant congenital melanocytic nevus (GCMN) is regarded as premalignant, the incidence and risk factors of malignant transformation are controversial. OBJECTIVE: This study aimed to share the authors' surgical experience with GCMNs and provide data on their demographics, malignant transformation, and prognosis. METHODS: This single-center, consecutive study included 152 patients with GCMN who visited this center from March 2000 to February 2020. Their medical documentation was reviewed retrospectively, and the nevi were classified according to the size as follows: Group 1, 10 to 19.9 cm (n = 45); Group 2, 20 to 39.9 cm (n = 62); and Group 3, ≥40 cm (n = 45). RESULTS: Seven malignancies were found (4.6%; 4 melanomas, 2 rhabdomyosarcomas [RMS], and 1 malignant peripheral nerve sheath tumor [MPNST]). The risk increased according to the nevus size (2.2% in Group 1, 3.2% in Group 2, and 8.9% in Group 3) but the difference was not statistically significant (p = .3305). CONCLUSION: Malignant transformation from GCMN cannot be ignored. It can include transformation into melanoma, RMS, and MPNST. Early surgical resection and regular follow-up should be performed in patients with nevi ≥10 cm.

Neurofibromatosis-associated malignant peripheral nerve sheath tumors in children have a worse prognosis: A nationwide cohort study.

BACKGROUND: Malignant peripheral nerve sheath tumors (MPNST) are rare and aggressive non-rhabdomyoblastic soft-tissue sarcomas (NRSTS) in children. This study set out to investigate clinical presentation, treatment modalities, and factors associated with survival in pediatric MPNST using Dutch nationwide databases. METHODS: Data were obtained from the Netherlands Cancer Registry (NCR) and the Dutch Pathology Database (PALGA) from 1989 to 2017. All primary MPNSTs were collected. Demographic differences were analyzed between adult and pediatric (age ≤18 years) MPNST. In children, demographic and treatment differences between neurofibromatosis type 1 (NF1) and non-NF1 were analyzed. A Cox proportional hazard model was constructed for localized pediatric MPNSTs. RESULTS: A total of 70/784 MPNST patients were children (37.1% NF1). Children did not present differently from adults. In NF1 children, tumor size was more commonly large (> 5 cm, 92.3% vs 59.1%). Localized disease was primarily resected in 90.6%, and radiotherapy was administered in 37.5%. Non-NF1 children tended to receive chemotherapy more commonly (39.5% vs 26.9%). Overall, estimated five-year survival rates of localized NF1-MPNST was 52.4% (SE: 10.1%) compared with 75.8% (SE: 7.1%) in non-NF1 patients. The multivariate model showed worse survival in NF1 patients (HR: 2.98; 95% CI, 1.17-7.60, P = 0.02) and increased survival in patients diagnosed after 2005 (HR: 0.20; 95% CI, 0.06-0.69, P = 0.01). No treatment factors were independently associated with survival. CONCLUSION: Pediatric MPNSTs have presentations similar to adult MPNSTs. In children, NF1 patients present with larger tumors, but are treated similarly to non-NF1 MPNSTs. In localized pediatric MPNST, NF1 is associated with worse survival. Promisingly, survival has increased for pediatric MPNSTs after 2005.

Combined Targeting of AKT and mTOR Inhibits Proliferation of Human NF1-Associated Malignant Peripheral Nerve Sheath Tumour Cells In Vitro but not in a Xenograft Mouse Model In Vivo.

Persistent signalling via the PI3K/AKT/mTOR pathway is a major driver of malignancy in NF1-associated malignant peripheral nerve sheath tumours (MPNST). Nevertheless, single targeting of this pathway is not sufficient to inhibit MPNST growth. In this report, we demonstrate that combined treatment with the allosteric pan-AKT inhibitor MK-2206 and the mTORC1/mTORC2 inhibitor AZD8055 has synergistic effects on the viability of MPNST cell lines in comparison to the treatment with each compound alone. However, when treating animals bearing experimental MPNST with the combined AKT/mTOR regime, no influence on tumour growth was observed. Further analysis of the MPNST xenograft tumours resistant to AKT/mTOR treatment revealed a reactivation of both AKT and mTOR in several tumour samples. Additional targeting of the RAS/RAF/MEK/MAPK pathway with the allosteric MEK1/2 inhibitor AZD6244 showed synergistic effects on the viability of MPNST cell lines in vitro in comparison to the dual AKT/mTOR inhibition. In summary, these data indicate that combined treatment with AKT and mTOR inhibitors is effective on MPNST cells in vitro but tumour resistance can occur rapidly in vivo by restoration of AKT/mTOR signalling. Our data further suggest that a triple treatment with inhibitors against AKT, mTORC1/2 and MEK1/2 may be a promising treatment option that should be further analysed in an experimental MPNST mouse model in vivo.

Malignant progression of a peripheral nerve sheath tumor in the setting of rhabdoid tumor predisposition syndrome.

Malignant progression of a benign or low-grade tumor in individuals with germline alteration of SMARCB1 gene is not well characterized. In a family in which two carrier children had germline SMARCB1 mutations and atypical teratoid rhabdoid tumor, we report malignant progression of a nerve sheath tumor over a 7-year period in an affected adult family member. Prompt identification of the germline SMARCB1 alteration and the resultant rhabdoid tumor predisposition syndrome can help guide genetic counseling and surveillance in affected family members.

Bladder Dysfunction in Children with Neurofibromatosis Type I: Report of Four Cases and Review of the Literature.

AIM: Neurofibromatosis type 1 (NF1) is a rare autosomal dominant disorder. Malignant transformation into malignant peripheral nerve sheath tumors (MPNST) can occur. However, urinary tract involvement is rare. We report 4 cases of NF1 with bladder dysfunction. METHODS: A retrospective single center analysis of 4 patients was conducted over a 17-year period, focusing on urinary tract involvement. RESULTS: NF1 was diagnosed at a median of 16.5 months (4-36) and urinary involvement occurred at a median of 5.25 years (4-9) after diagnosis. Bladder dysfunction was due to spinal cord compression in 2 cases, bladder invasion in 1 case, and cerebral lesions in 1 case. Malignant transformation of neurofibromas into MPNST occurred in 2 patients. Mechanisms of urinary involvement in NF1 are diverse and no pre-established protocol of management and follow-up exists. CONCLUSION: Although rare, dysfunction of the bladder can arise in NF1 and innovative strategies then need to be considered. This is best achieved with the help of a multidisciplinary team and a national reference center when available.

Establishment and characterization of a recurrent malignant peripheral nerve sheath tumor cell line: RsNF.

Malignant peripheral nerve sheath tumor (MPNST) is a highly aggressive and recurrent soft tissue sarcoma. It most commonly occurs secondary to neurofibromatosis type I, and it has a 5-year survival rate of only 8-13%. To better study the tumor heterogeneity of MPNST and to develop diverse treatment options, more tumor-derived cell lines are needed to obtain richer biological information. Here, we established a primary cell line of relapsed MPNST RsNF cells derived from a patient diagnosed with NF1 and detected the presence of NF1 mutations and SUZ12 somatic mutations through whole-exome sequencing(WES). Through tumor molecular marker targeted sequencing and single-cell transcriptome sequencing, it was found that chromosome 7 copy number variation (CNV) was gained in this cell line, and ZNF804B, EGFR, etc., were overexpressed on chromosome 7. Therefore, RsNF cells can be used as a useful tool in NF1-associated MPNST genomic amplification studies and to develop new therapeutic strategies.

NF1-Driven Rhabdomyosarcoma Phenotypes: A Comparative Clinical and Molecular Study of NF1-Mutant Rhabdomyosarcoma and NF1-Associated Malignant Triton Tumor.

PURPOSE: Alterations of the NF1 tumor suppressor gene is the second most frequent genetic event in embryonal rhabdomyosarcoma (ERMS), but its associations with clinicopathologic features, outcome, or coexisting molecular events are not well defined. Additionally, NF1 alterations, mostly in the setting of neurofibromatosis type I (NF1), drive the pathogenesis of most malignant peripheral nerve sheath tumor with divergent RMS differentiation (also known as malignant triton tumor [MTT]). Distinguishing between these entities can be challenging because of their pathologic overlap. This study aims to comprehensively analyze the clinicopathologic and molecular spectrum of NF1-mutant RMS compared with NF1-associated MTT for a better understanding of their pathogenesis. METHODS: We investigated the clinicopathologic and molecular landscape of a cohort of 22 NF1-mutant RMS and a control group of 13 NF1-associated MTT. Cases were tested on a matched tumor-normal hybridization capture-based targeted DNA next-generation sequencing. RESULTS: Among the RMS group, all except one were ERMS, with a median age of 17 years while for MTT the mean age was 39 years. Three MTTs were misdiagnosed as ERMS, having clinical impact in one. The most frequent coexisting alteration in ERMS was TP53 abnormality (36%), being mutually exclusive from NRAS mutations (14%). MTT showed coexisting CDKN2A/B and PRC2 complex alterations in 38% cases and loss of H3K27me3 expression. Patients with NF1-mutant RMS exhibited a 70% 5-year survival rate, in contrast to MTT with a 33% 5-year survival. All metastatic NF1-mutant ERMS were associated with TP53 alterations. CONCLUSION: Patients with NF1-mutant ERMS lacking TP53 alterations may benefit from dose-reduction chemotherapy. On the basis of the diagnostic challenges and significant treatment and prognostic differences, molecular profiling of challenging tumors with rhabdomyoblastic differentiation is recommended.

Impact of CT and MRI in the diagnostic workup of malignant triton tumour-a monocentric analysis and review of the literature.

OBJECTIVES: Malignant triton tumours (MTTs) are rare but aggressive subtypes of malignant peripheral nerve sheath tumours (MPNSTs) with a high recurrence rate and 5-year survival of 14%. Systematic imaging data on MTTs are scarce and mainly based on single case reports. Therefore, we aimed to identify typical CT and MRI features to improve early diagnosis rates of this uncommon entity. METHODS: A systematic review on literature published until December 2022 on imaging characteristics of MTTs was performed. Based on that, we conducted a retrospective, monocentric analysis of patients with histopathologically proven MTTs from our department. Explorative data analysis was performed. RESULTS: Initially, 29 studies on 34 patients (31.42 ± 22.6 years, 12 female) were evaluated: Literature described primary MTTs as huge, lobulated tumours (108 ± 99.3 mm) with central necrosis (56% [19/34]), low T1w (81% [17/21]), high T2w signal (90% [19/21]) and inhomogeneous enhancement on MRI (54% [7/13]). Analysis of 16 patients (48.9 ± 13.8 years; 9 female) from our institution revealed comparable results: primary MTTs showed large, lobulated masses (118 mm ± 64.9) with necrotic areas (92% [11/12]). MRI revealed low T1w (100% [7/7]), high T2w signal (100% [7/7]) and inhomogeneous enhancement (86% [6/7]). Local recurrences and soft-tissue metastases mimicked these features, while nonsoft-tissue metastases appeared unspecific. CONCLUSIONS: MTTs show characteristic features on CT and MRI. However, these do not allow a reliable differentiation between MTTs and other MPNSTs based on imaging alone. Therefore, additional histopathological analysis is required. ADVANCES IN KNOWLEDGE: This largest published systematic analysis on MTT imaging revealed typical but unspecific imaging features that do not allow a reliable, imaging-based differentiation between MTTs and other MPNSTs. Hence, additional histopathological analysis remains essential.

Neurofibrosarcoma of the gallbladder: a case report.

Sarcoma of the gallbladder is a rare entity. This report presents an extremely rare clinical case of a neurofibrosarcoma of the gallbladder. On examination, a mass was felt in the right hypochondrium. An ultrasound of the abdomen showed a mass in the gallbladder. Computed tomography (CT) scan of the abdomen showed a grossly distended gallbladder with soft tissue mass in the gallbladder. The mass was diagnosed as carcinoma of the gallbladder and an extended cholecystectomy was performed. Histopathological examination revealed spindle-cell proliferation and the possibility of a malignant tumor of mesenchymal origin.

Spontaneous malignant transformation of trigeminal schwannoma: consideration of responsible gene alterations for tumorigenesis-a case report.

Malignant peripheral nerve sheath tumors (MPNSTs) arising from the trigeminal nerves are extremely rare (only 45 cases, including the present case, have been published) and have been reported to develop de novo from the peripheral nerve sheath and are not transformed from a schwannoma or neurofibroma. Here, we report a case of MPNSTs of the trigeminal nerve caused by the malignant transformation of a trigeminal schwannoma, with a particular focus on genetic considerations. After undergoing a near-total resection of a histologically typical benign schwannoma, the patient presented with regrowth of the tumor 10 years after the primary excision. Histopathologic and immunochemical examinations confirmed the recurrent tumor to be an MPNST. Comprehensive genomic analyses (FoundationOne panel-based gene assay) showed that only the recurrent MPNST sample, not the initial diagnosis of schwannoma, harbored genetic mutations, including NF1-p.R2637* and TP53-p.Y234H, candidate gene mutations associated with malignant transformation. Moreover, the results of reverse transcription polymerase chain reaction showed that the fusion of SH3PXD2A and HTRA1, which has been reported as one of the responsible genetic aberrations of schwannoma, was detected in the recurrent tumor. Taken together, we could illustrate the accumulation process of gene abnormalities for developing MPNSTs from normal cells via schwannomas.

Images Combined With Surgical Procedures and Pathological Identification to Distinguish a Reactive Histiocytosis With Organized Hematoma From a Malignant Peripheral Nerve Sheath Tumor.

BACKGROUND/AIM: Malignant peripheral nerve sheath tumors (MPNST) are rare soft tissue malignant tumors. To the best of our knowledge, there have been no previous reports of benign reactive histiocytosis with hematoma that mimics MPNST on medical images. CASE REPORT: A 57-year-old female with past history of hypertension came to our clinic due to low back pain with radiculopathy which was diagnosed with a tumor arising from L2 neuroforamen with L2 pedical erosion. Initial tentative diagnosis on the images was MPNST. However, after surgical resection, the pathologic report revealed no evidence of malignancy but only an organized hematoma with reactive histiocytosis. CONCLUSION: Images cannot provide enough diagnostic evidence for distinguishing a reactive histiocytosis from MPNST. Proper surgical procedures and expert pathological identification can correct the mistaking of the ambiguous identification as MPNST. Images can only provide precise and personalized medication accompanied by proper surgical procedures and expert pathological identification.

FOXM1 promotes neurofibromatosis type 1-associated malignant peripheral nerve sheath tumor progression in a NUF2-dependent manner.

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft-tissue sarcomas characterized by poor prognosis and low drug response rates. Traditional chemo/radiotherapies show only mild benefits for patients with MPNSTs, and no targeted therapy is available in the clinic. A better understanding of the molecular background of MPNSTs is critical for the development of effective targeted therapies. Forkhead box M1 (FOXM1) has been implicated in the progression of many human malignancies, though its role in MPNSTs is unclear. In this study, using four Gene Expression Omnibus (GEO) datasets and a tissue microarray, we demonstrated that FOXM1 upregulation was associated with poor prognosis in patients with MPNSTs. FOXM1 overexpression and knockdown regulated the proliferation and colony formation of MPNST cells. Using bioinformatics analysis and luciferase reporter assays, we identified NUF2 as a direct downstream target of FOXM1. Both in vitro and in vivo experiments demonstrated that the induction of MPNST cell proliferation by FOXM1 was dependent on elevated NUF2 expression, as NUF2 knockdown abolished the FOXM1-induced proliferation of MPNST cells. Our study showed that the FOXM1-NUF2 axis mediates human MPNST progression and could be a potential therapeutic target.

Experience of a single center in the treatment of rare malignant peripheral nerve sheath tumors during the years 1991-2021.

Malignant peripheral nerve sheath tumor (MPNST) is a rare sarcoma with a poor prognosis, as the aggressive types of this cancer tend to grow rapidly and metastasize frequently. MPNST is associated with neurofibromatosis type 1 gene mutation. The minority of cases arise secondary to radiation therapy or sporadically. The primary treatment for MPNST is early surgical resection of the tumor. The aim of this study was to retrospectively evaluate the outcome of the treatment of MPNST in Helsinki University Hospital from the years 1991 to 2021. Fourteen MPNST cases were evaluated in this study retrospectively. Descriptive statistical analysis was performed on the collected patient data. Marginal resection was completed in nine cases, wide margins were achieved in three cases, and in two cases the final histological examination of the specimen revealed intralesional removal. During the follow-up time of 36.7 ± 12.1 months, all patients who underwent wide margin resection were alive. One patient died 22 months after intralesional resection and six within 38.3 ± 30.9 months of marginal resection. Seventy-one percent of tumor surgeries resulted in Clavien-Dindo class 3b complications, reflecting the complexity of the surgeries. The aggressive nature of MPNST and the large size of these tumors requires extensive surgery, which can lead to complications. The prognosis of MPNST needs improvement.

Survival analysis of malignant peripheral nerve sheath tumor: Experience of a tertiary center in Taiwan.

BACKGROUND: This study aimed to analyze the demographic characteristics and prognostic factors of malignant peripheral nerve sheath tumor (MPNST) in a Taiwanese population. Single-center treatment outcomes were also presented. METHODS: This retrospective cohort study analyzed the medical records of 54 patients with pathological diagnoses of MPNSTs from 2005 to 2021 at a single institution. The primary endpoint was the 5-year overall survival rate of MPNST, and the secondary endpoint was recurrence-free 5-year survival. Variables including patient characteristics, metastasis status at initial diagnosis, and surgical outcomes were analyzed with competing risk analysis. RESULTS: Among all 41 eligible patients diagnosed with MPNST, female predominance was noted, and the median age at diagnosis was 44 years. The most common site of lesion was found at the trunk (46.34%), and eight patients were diagnosed with notable metastasis. Twelve patients were diagnosed with type 1 neurofibromatosis (NF1). The 5-year overall survival rate was 36.84% and the 5-year recurrence-free survival was 28.95%. Metastasis diagnosed at presentation, large lesion sizes, and recurrence were identified as significant poor prognostic factors of survival. Metastasis diagnosed at presentation was identified as the only significant risk factor of recurrence. CONCLUSION: In our series, metastasis diagnosed at presentation, large lesion sizes, and recurrence were identified as significant poor prognostic factors of survival. Metastasis was also identified as the only significant risk factor of recurrence. NF1-associated MPNSTs presented with significantly larger tumor sizes and additional treatment postoperatively did not significantly improve survival. The limitations of this study include its retrospective nature and sample size.

RRM2 as a novel prognostic and therapeutic target of NF1-associated MPNST.

BACKGROUND: Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas that typically develop in the setting of neurofibromatosis type 1 (NF1) and cause significant morbidity. Conventional therapies are often ineffective for MPNSTs. Ribonucleotide reductase subunit M2 (RRM2) is involved in DNA synthesis and repair, and is overexpressed in multiple cancers. However, its role in NF1-associated MPNSTs remains unknown. Our objective was to determine the therapeutic and prognostic potential of RRM2 in NF1-associated MPNSTs. METHODS: Identification of hub genes was performed by using NF1-associated MPNST microarray datasets. We detected RRM2 expression by immunochemical staining in an MPNST tissue microarray, and assessed the clinical and prognostic significance of RRM2 in an MPNST cohort. RRM2 knockdown and the RRM2 inhibitor Triapine were used to assess cell proliferation and apoptosis in NF1-associated MPNST cells in vitro and in vivo. The underlying mechanism of RRM2 in NF1-associated MPNST was revealed by transcriptome analysis. RESULTS: RRM2 is a key hub gene and its expression is significantly elevated in NF1-associated MPNST. We revealed that high RRM2 expression accounted for a larger proportion of NF1-associated MPNSTs and confirmed the correlation of high RRM2 expression with poor overall survival. Knockdown of RRM2 inhibited NF1-associated MPNST cell proliferation and promoted apoptosis and S-phase arrest. The RRM2 inhibitor Triapine displayed dose-dependent inhibitory effects in vitro and induced significant tumor growth reduction in vivo in NF1-associated MPNST. Analysis of transcriptomic changes induced by RRM2 knockdown revealed suppression of the AKT-mTOR signaling pathway. Overexpression of RRM2 activates the AKT pathway to promote NF1-associated MPNST cell proliferation. CONCLUSIONS: RRM2 expression is significantly elevated in NF1-associated MPNST and that high RRM2 expression correlates with poorer outcomes. RRM2 acts as an integral part in the promotion of NF1-associated MPNST cell proliferation via the AKT-mTOR signaling pathway. Inhibition of RRM2 may be a promising therapeutic strategy for NF1-associated MPNST.

A case report on a novel use of intraoperative Intrabeam™ radiation therapy for a recurrent malignant peripheral nerve sheath tumor with sciatic nerve involvement.

BACKGROUND: Malignant peripheral nerve sheath tumors (MPNST) are sarcomas that arise from peripheral nerves. They generally have a poor prognosis which is exacerbated by high local recurrence rates. This case report discusses the treatment of a patient with a MPNST with local recurrence. This case report is novel due to the use of intraoperative Intrabeam™ (Zeiss, Dublin, CA) radiation therapy use in the protection of neurovascular structures such as the sciatic nerve. CASE PRESENTATION: The patient was a 65-year-old male who noticed a right posterior thigh mass slowly increasing in size over two months. A planned positive margin wide-resection excision was performed due to sciatic nerve abutment. The mass was determined to be a MPNST via postoperative pathology with positive margins along the sciatic nerve. The patient began adjuvant radiation therapy to the upper and lower thigh fields over a period of three months. Thirty-two months later, the patient was found to have a hypermetabolic mass with venous congestion and hyperemia at the prior surgical site which was confirmed by core needle biopsy to be local recurrence of the MPNST. Re-excision of the tumor was planned and performed followed by intraoperative Intrabeam™ radiation therapy. At two years of follow-up, the patient was doing well with minimal pain in his right buttock region with no new or recurrent neurological deficits. Radiologic imaging was negative for local recurrence of the MPNST. CONCLUSION: We believe this case report demonstrates a novel treatment strategy for sarcoma management. The unique use of intraoperative Intrabeam™ radiation therapy, which had not previously been used for this indication, may be efficacious in cases involving neurovascular structures. In this case, focal radiation from the intraoperative Intrabeam™ radiation device was used in a way to affect the recurrent tumor yet protect the sciatic nerve.

Malignant peripheral nerve sheath tumor: models, biology, and translation.

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive, invasive cancer that comprise around 10% of all soft tissue sarcomas and develop in about 8-13% of patients with Neurofibromatosis Type 1. They are associated with poor prognosis and are the leading cause of mortality in NF1 patients. MPNSTs can also develop sporadically or following exposure to radiation. There is currently no effective targeted therapy to treat MPNSTs and surgical removal remains the mainstay treatment. Unfortunately, surgery is not always possible due to the size and location of the tumor, thus, a better understanding of MPNST initiation and development is required to design novel therapeutics. Here, we provide an overview of MPNST biology and genetics, discuss findings regarding the developmental origin of MPNST, and summarize the various model systems employed to study MPNST. Finally, we discuss current management strategies for MPNST, as well as recent developments in translating basic research findings into potential therapies.