Sec6/8 regulates Bcl-2 and Mcl-1, but not Bcl-xl, in malignant peripheral nerve sheath tumor cells.

Sec6 and Sec8, which are components of the exocyst complex, has been concerned with various roles independent of its role in secretion, such as cell migration, invadopodia formation, cytokinesis, glucose uptake, and neural development. Given the vital roles of the exocyst complex in cellular and developmental processes, the disruption of its function may be closely related to various diseases such as cancer, diabetes, and neuronal disorders. Malignant peripheral nerve sheath tumors (MPNSTs) have high malignant potential and poor prognosis because of aggressive progression and metastasis. To date, no chemotherapeutic agents have been validated for MPNSTs treatment because how MPNSTs are resistant to chemotherapeutic agents remains unknown. This study demonstrates that combination of doxorubicin and sorafenib induces apoptosis in MPNST cells through downregulation of B cell lymphoma protein 2 (Bcl-2), Bcl-2-related protein long form of Bcl-x (Bcl-xl), and myeloid cell leukemia 1 (Mcl-1). Moreover, both Sec6 and Sec8 levels decreased after treatment with doxorubicin and sorafenib and were found to be associated with Bcl-2 and Mcl-1 expressions, but not Bcl-xl. Although Sec8 was found to be involved in the regulation of both Bcl-2 and Mcl-1 at the mRNA level, Sec6 regulated Bcl-2 at the mRNA level and the binding affinity of F-box and WD repeat domain containing 7 and Mcl-1, thereby controlling Mcl-1 at the protein level. Bcl-2 or Mcl-1 mRNA suppression by Sec6 or Sec8 depletion resulted in significant changes in nuclear factor-kappa B, cAMP response element, and p53 transcriptional activity. These results suggest that Sec6 and Sec8 are therapeutic target molecules in MPNST.

Neurological Deficits before and after Surgical Resection of Schwannomas in the Upper Extremities.

Background Schwannomas are the most common primary solitary tumor among peripheral nerve sheath tumors. The occurrence of transient or permanent neurological deficits after schwannoma resection is more common than previously recognized. Here, the neurological deficits before and after surgical resection of schwannomas in the upper extremities were examined. Methods The study included 43 upper-extremity schwannomas that were treated surgically between January 2000 and July 2013. The neurological status of each patient (such as pain, sensory disturbances, and motor disturbances) was evaluated preoperatively, immediately postoperatively, and at the final postoperative follow-up. Results Out of the 43 cases, 34 cases exhibited neurological symptoms before the operation, and in 31 of the 34 cases, neurological symptoms were either reduced or disappeared after the surgery. In 20 of the 43 cases, new neurological deficits that had not been observed preoperatively were noted immediately postoperatively; the newly acquired neurological deficits disappeared over time in 5 of the 20 cases. Significantly, more newly acquired neurological deficits remained in cases where the tumor was located in the upper arm and elbow than in cases where the tumor was located in the distal forearm. Conclusion New neurological deficits occurred after surgery in about half of the cases. This ratio was higher than expected, suggesting that schwannoma resection is not always a complication-free operation. Therefore, patients should be informed preoperatively about the possibility of neurological deficits. Furthermore, extreme care should be taken not to damage the affected and uninvolved nerves during surgery.

An unusual location of ulnar nerve pathology: a perineurioma of the ulnar nerve in the upper arm.

A young man presented with progressive motor weakness and atrophy of the ulnar muscles of his left hand over a period of more than 2 years. Electrodiagnostic studies indicated an ulnar nerve lesion, but it was not localized. High-resolution sonography of the ulnar nerve revealed an enlarged and hypoechogenic ulnar nerve at an unusual location, namely 12.5 cm proximal to the medial epicondyle. Histology showed that this was an intraneural perineurioma. High-resolution sonography of the ulnar nerve is very useful in the discovery of this unusual location of nerve pathology and may assist in its early detection.

The role of neurofibromin in N-Ras mediated AP-1 regulation in malignant peripheral nerve sheath tumors.

Plexiform neurofibromas commonly found in patients with Neurofibromatosis type I (NF1) have a 5% risk of being transformed into malignant peripheral nerve sheath tumors (MPNST). Germline mutations in the NF1 gene coding for neurofibromin, which is a Ras GTPase activating protein (RasGAP) and a negative regulator of Ras, result in an upregulation of the Ras pathway. We established a direct connection between neurofibromin deficiency and downstream effectors of Ras in cell lines from MPNST patients by demonstrating that knockdown of NF1 expression using siRNA in a NF1 wild type MPNST cell line, STS-26T, activates the Ras/ERK1,2 pathway and increases AP-1 binding and activity. We believe this is the first time the transactivation of AP-1 has been linked directly to neurofibromin deficiency in a disease relevant MPNST cell line. Previously, we have shown that N-Ras is constitutively activated in cell lines derived from independent MPNSTs from NF1 patients. We therefore sought to analyze the role of the N-Ras pathway in deregulating AP-1 transcriptional activity. We show that STS-26T clones conditionally expressing oncogenic N-Ras show increased phosphorylated ERK1,2 and phosphorylated JNK expression concomitant with increased AP-1 activity. MAP kinase pathways (ERK1,2 and JNK) were further examined in ST88-14, a neurofibromin-deficient MPNST cell line. The basal activity of ERK1,2 but not JNK was found to increase AP-1 activity. These experiments further confirmed the link between the loss of neurofibromin and increased activity of Ras/MAP kinase pathways and the activation of downstream transcriptional mechanisms in MPNSTs from NF1 patients.

The role of angiogenesis in the transformation of plexiform neurofibroma into malignant peripheral nerve sheath tumors in children with neurofibromatosis type 1.

PURPOSE: The role of angiogenesis in the transformation of peripheral neurofibroma (PNF) to malignant peripheral nerve sheath tumor (MPNST) in neurofibromatosis type 1 (NF1) remains elusive and forms the objective of this study. EXPERIMENTAL DESIGN: Archival tissue from 5 children with NF1 and PNF, who developed MPNST between the ages of 8 and 15 years were analyzed for differences in microvasculature. The role of proangiogenic growth factors such as Vascular Endothelial Growth Factor (VEGF), and its receptors Flk-1 and Flt-1, and vessel maturity, defined as von Willebrand factor (vWf), α-smooth muscle actin+ (SMA+), were evaluated by immuno-histochemistry. RESULTS: A qualitative evaluation of the vasculature showed predominantly α-SMA+/vWf+ more stable vessels in PNF, and an irregular meshwork of α-SMA-/vWf+ endothelial cells structures in MPNST. In NF and PNF tumor cells were VEGF-, in contrast to VEGF+ tumor cells in MPNST. If present, the VEGF stain was confined mainly to the perivascular spaces in PNF, unlike the mainly stromal VEGF stain in MPNST. VEGF receptors also manifested a tumor stage-specific pattern. Flk-1 and Flt-1 were restricted to the mature, well-formed vasculature in PNF, but exhibited a diffuse pattern in MPNST. CONCLUSION: Our study provides a rare opportunity to document consistent and histologically detectable differences in the vascular organization of PNF and MPNST. It permits a pair-wise evaluation of the malignant conversion of benign PNF into its malignant counterpart, in the same patients. The phenotypic variations and characteristics of the vessels in these tumors are consistent with the idea that a strong proangiogenic drive contributes to the progressive growth in MPNST.

Surgical strategies for managing foraminal nerve sheath tumors: the emerging role of CyberKnife ablation.

Sixteen Stanford University Medical Center (SUMC) patients with foraminal nerve sheath tumors had charts reviewed. CyberKnife radiosurgery was innovative in management. Parameters were evaluated for 16 foraminal nerve sheath tumors undergoing surgery, some with CyberKnife. Three neurofibromas had associated neurofibromatosis type 1 (NF1). Eleven patients had one resection; others had CyberKnife after one (two) and two (three) operations. The malignant peripheral nerve sheath tumor (MPNST) had prior field-radiation and adds another case. Approaches included laminotomy and laminectomies with partial (three) or total (two) facetectomies/fusions. Two cases each had supraclavicular, lateral extracavitary, retroperitoneal and Wiltze and costotransversectomy/thoracotomy procedures. Two underwent a laminectomy/partial facetectomy, then CyberKnife. Pre-CyberKnife, one of two others had a laminectomy/partial facetectomy, then total facetectomy/fusion and the other, two supraclavicular approaches. The MPNST had a hemi-laminotomy then laminectomy/total facetectomy/fusion, followed by CyberKnife. Roots were preserved, except in two. Of 11 single-operation-peripheral nerve sheath tumors, the asymptomatic case remained stable, nine (92%) improved and one (9%) worsened. Examinations remained intact in three (27%) and improved in seven (64%). Two having a single operation then CyberKnife had improvement after both. Of two undergoing two operations, one had symptom resolution post-operatively, worsened 4 years post-CyberKnife then has remained unchanged after re-operation. The other such patient improved post-operatively, had no change after re-operation and improved post-CyberKnife. The MPNST had presentation improvement after the first operation, worsened and after the second surgery \and CyberKnife, the patient expired from tumor spread. In conclusion, surgery is beneficial for pain relief and function preservation in foraminal nerve sheath tumors. Open surgery with CyberKnife is an innovation in these tumors' management.

Peripheral nerve sheath tumors in Neurofibromatosis Type 2: Surgical and histopathologic features.

OBJECTIVE: Management of peripheral nerve sheath tumors (PNST) in Neurofibromatosis Type 2 (NF2) is complicated by frequent involvement of major peripheral nerves and concern that these tumors may be plexiform and/or involve multiple fascicles. Hybrid histologic features of both schwannoma and neurofibroma have been described in NF2-associated tumors, although the incidence of this phenotype in PNSTs is unknown. We sought to define the outcomes of surgery for tumors involving major peripheral nerves in NF2 and identify the rate of hybrid histology in PNSTs. PATIENTS AND METHODS: Functional outcomes of surgery for patients with tumors on major (named) peripheral nerves were recorded. Histopathologic analyses were performed on all available excised tumors. RESULTS: Nineteen operations were performed in 12 patients with NF2, for resection of 28 PNSTs. Among 11 tumors involving major peripheral nerves, 10 involved nerves related to motor function. Presenting symptoms in this group included pain (9) and weakness (4). Median tumor diameter was 3.4 cm (range:2.2-10.3 cm). Gross-total resection was achieved in 10 cases. Motor function was stable/improved in 10 cases but diminished after one case involving a small motor fascicle. All tumors involved a single fascicle. Histopathologic analyses of 21 available specimens revealed 19 pure schwannomas. In two cases (10 %) hybrid features of both schwannoma and neurofibroma were identified, with mast cells within regions consistent with neurofibroma. CONCLUSIONS: PNSTs can be resected safely in NF2, even if they involve major peripheral nerves. A small proportion (10 %) of these tumors harbor hybrid histologic features, which may explain reports of plexiform or multi-fascicular tumors in NF2.

Neuregulin-1 beta and neuregulin-1 alpha differentially affect the migration and invasion of malignant peripheral nerve sheath tumor cells.

Malignant peripheral nerve sheath tumors (MPNSTs) are the most common malignancy associated with neurofibromatosis Type 1 (NF1). These Schwann cell lineage-derived sarcomas aggressively invade adjacent nerve and soft tissue, frequently precluding surgical resection. Little is known regarding the mechanisms underlying this invasive behavior. We have shown that MPNSTs express neuregulin-1 (NRG-1) beta isoforms, which promote Schwann cell migration during development, and NRG-1 alpha isoforms, whose effects on Schwann cells are poorly understood. Hypothesizing that NRG-1 beta and/or NRG-1 alpha promote MPNST invasion, we found that NRG-1 beta promoted MPNST migration in a substrate-specific manner, markedly enhancing migration on laminin but not on collagen type I or fibronectin. The NRG-1 receptors erbB3 and erbB4 were present in MPNST invadopodia (processes mediating invasion), partially colocalized with focal adhesion kinase and the laminin receptor beta(1)-integrin and coimmunoprecipitated with beta(1)-integrin. NRG-1 beta stimulated human and murine MPNST cell migration and invasion in a concentration-dependent manner in three-dimensional migration assays, acting as a chemotactic factor. Both baseline and NRG-1 beta-induced migration were erbB-dependent and required the action of MEK 1/2, SAPK/JNK, PI-3 kinase, Src family kinases and ROCK-I/II. In contrast, NRG-1 alpha had no effect on the migration and invasion of some MPNST lines and inhibited the migration of others. While NRG-1 beta potently and persistently activated Erk 1/2, SAPK/JNK, Akt and Src family kinases, NRG-1 alpha did not activate Akt and activated these other kinases with kinetics distinct from those evident in NRG-1 beta-stimulated cells. These findings suggest that NRG-1 beta enhances MPNST migration and that NRG-1 beta and NRG-1 alpha differentially modulate this process.

Fractionated stereotactic radiation therapy in the management of primary optic nerve sheath meningiomas.

We analysed our long-term results after fractionated stereotactic radiotherapy (FSRT) in patients with primary optic nerve sheath (pONSM) meningioma, as a rare subtype of meningiomas. Between 01/1995 and 12/2007, 32 patients with pONSM were treated with FSRT. Fifteen patients received radiotherapy as primary treatment, four after biopsy, and six patients after surgical resection. Seven patients were irradiated for recurrent disease. Seventeen lesions were histologically proven and determined as WHO grade I pONSM. Median target volume was 15.7 cc, median total dose 54.9 Gy. Twenty-nine patients showed clinical symptoms before radiotherapy like reduced vision, unilateral loss of vision, or an exophthalmia. Median follow-up was 4.5 years. Overall local tumor control was 100%. Twenty-six patients had stable disease based on CT/MRI, while 6/32 had a partial remission of tumor volume. 97% of our patients showed stable vision or an improvement of visual acuity. Eleven patients (38%) showed an improvement of pre-existing clinical symptoms like double vision, exophthalmia and visual acuity. Only one patient showed an impairment of vision with progressive concentric decreasing of the visual field on the side of the irradiated ONSM. These data demonstrate that FSRT is an effective and safe treatment modality for local control in patients with pONSM with minimal risk of significant late toxicity.

Management of brachial plexus region tumours and tumour-like conditions: relevant diagnostic and surgical features in a consecutive series of eighteen patients.

BACKGROUND: Tumours of the brachial plexus region are rare and most publications are case reports or studies with a small series of patients. The aim of this study is to present our experience in managing these lesions. METHODS: We review 18 patients with tumours in the brachial plexus region submitted to surgical treatment in a 6 year period, including their clinical presentation, neuro-imaging data, surgical findings and outcome. FINDINGS: The tumours comprised a heterogeneous group of lesions, including schwannomas, neurofibromas, malignant peripheral nerve sheath tumour (MPNST), sarcomas, metastases, desmoids and an aneurysmal bone cyst. The most common presentation was an expanding lump (83.33%). Eleven tumours were benign and 7 were malignant. Neurofibromatosis was present in only 2 patients (11.11%). Gross total resection was achieved in 14 patients and sub-total resection in the others. Only 3 patients presented with new post-operative motor deficits. The incidence of complications was low (16.5 %). CONCLUSIONS: The majority of tumours were benign and most of them could be excised with a low incidence of additional deficits. Some of the malignant tumours could be controlled by surgery plus adjuvant therapy, but this category is still associated with high morbidity and mortality rates.

Prognostic and predictive markers for perineural and bone invasion of oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is a growing problem worldwide. Several biological and molecular criteria have been established for making a prognosis of OSCC. One of the most important factors affecting the risk of tumor recurrence and overall prognosis is perineural invasion and bone invasion. Perineural invasion is defined as a tumor spreading and the ability of tumor cells to penetrate around or through the nerve tissue. Perineural invasion can cause the tumor to spread to distant areas from the primary tumor location. One possible explanation for this is the formation of microenvironment in the perineural space which may contain cellular factors that act on both nerve tissue and some types of tumor tissues. Bone invasion by OSCC has major implications for tumor staging, choice of treatment, outcome and quality of life. Oral SCCs invade the mandibular or maxillary bone through an erosive, infiltrative or mixed pattern that correlates with clinical behavior. Bone resorption by osteoclasts is an important step in the process of bone invasion by oral SCCs. Some cytokines (e.g. TNFα and PTHrP) lead to receptor activator of NF-κB ligand (RANKL) expression or osteoprotegerin (OPG) suppression in oral SCC cells and in cancer stromal cells to induce osteoclastogenesis. Oral SCCs provide a suitable microenvironment for osteoclastogenesis to regulate the balance of RANKL and OPG. A more molecular-based clinical staging and tailor-made therapy would benefit patients with bone invasion by OSCC.

[18F]2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) as a diagnostic tool for neurofibromatosis 1 (NF1) associated malignant peripheral nerve sheath tumours (MPNSTs): a long-term clinical study.

BACKGROUND: Malignant peripheral nerve sheath tumours (MPNSTs) are difficult to detect in neurofibromatosis 1 (NF1) individuals. The purpose was to evaluate [(18)F]2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) and PET computed tomography (CT) as a diagnostic tool for MPNST in NF1 patients with symptomatic plexiform neurofibromas and to verify the diagnosis by pathology and clinical follow-up. PATIENTS AND METHODS: NF1 individuals with symptomatic plexiform neurofibromas underwent clinical evaluation and magnetic resonance imaging. Qualitative FDG PET and PET CT associated with semi-quantitative maximum standard uptake value (SUVmax) assessed possible malignant change. Excision/biopsy verified the diagnosis when possible and clinical follow-up was undertaken in all patients. RESULTS: In all, 116 lesions were detected in 105 patients aged 5-71 years, including 80 plexiform neurofibromas, five atypical neurofibromas, 29 MPNST and two other cancers. Biopsy confirmed the findings in 59 tumours and no MPNST was diagnosed on clinical follow-up of 23 lesions diagnosed as benign on FDG PET and PET CT. FDG PET and PET CT diagnosed NF1-associated tumours with a sensitivity of 0.89 [95% confidence interval (CI) 0.76-0.96] and a specificity of 0.95 (CI 0.88-0.98), but the SUVmax level did not predict tumour grade. CONCLUSION: FDG PET and PET CT is a sensitive and specific diagnostic tool for NF1-associated MPNST. Other PET tracers will be required to solve the problem of predicting tumour grade.

Malignant triton tumor of the gluteal region in a patient unaffected by neurofibromatosis: A case report.

Malignant triton tumor (MTT) is a rare variant of malignant peripheral nerve sheath tumor (MPNST) made up of both malignant schwannoma cells and malignant rhabdomyoblasts. A 26-years-old male patient was admitted with an asymptomatic gluteal mass. Magnetic resonance imaging showed heterogeneous soft tissue mass and he underwent open biopsy. Malignant peripheral nerve sheath tumor was diagnosed. He was given adjuvant chemotherapy following the removal of the tumor with hip disarticulation. The tumor was diagnosed as "malignant triton tumor" based on pathological examination including immunohistochemical studies. There were no signs of metastasis but recurrence was observed at 9 months follow up. MTT is usually associated with Neurofibromatosis 1 and located in head, neck region. In this case sporadic involvement of gluteal region and aggressive behavior of the lesion despite radical surgery was demonstrated.

A rare case of bilateral vagus nerve schwanomatosis.

Schwanomatosis is the third most common form of neurofibromatosis. Schwanomatosis affecting the vagus nerve is particularly rare. In this report, we describe an extremely rare case bilateral vagus nerve schwanomatosis in a 45-year-old male patient. The patient initially presented with bilateral neck tumors and hoarseness arising after thoracic surgery. We performed left neck surgery in order to diagnose and resect the remaining tumors followed by laryngeal framework surgery to improve vocal cord closure and symptoms of hoarseness. Voice recovery was successfully achieved after surgery. An appropriate diagnosis and surgical tumor resection followed by phonosurgery improved patient quality of life in this rare case.

A brief history of surgery for peripheral nerve sheath tumors.

The authors present a brief and selective history of surgery for peripheral nerve tumors to illustrate how the current understanding of the nature of disease influences the choice of surgical intervention. There was very little understanding of the anatomy and function of peripheral nerves in ancient times; consequently, surgical treatments for peripheral nerve tumors were based on the writings of authorities. The confusion between traumatic neuromas and genuine nerve sheath tumors coupled with the belief that manipulation of a peripheral nerve might be lethal to the patient stifled the development of surgical techniques for the management of nerve tumors in the 18th and 19th centuries. It was not until the 20th century, with an increased understanding of the microscopic anatomy of nerve sheath tumors, that efficacious surgical treatments for these diseases were developed. Continued advances in the understanding of the biology of these tumors will continue to impact their surgical management.

Expression and inhibition of BRD4, EZH2 and TOP2A in neurofibromas and malignant peripheral nerve sheath tumors.

Malignant peripheral nerve sheath tumors (MPNST) are rare, highly aggressive sarcomas that can occur spontaneously or from pre-existing plexiform neurofibromas in neurofibromatosis type1 (NF1) patients. MPNSTs have high local recurrence rates, metastasize easily, are generally resistant to therapeutic intervention and frequently fatal for the patient. Novel targeted therapeutic strategies are urgently needed. Standard treatment for patients presenting with advanced disease is doxorubicin based chemotherapy which inhibits the actions of the enzyme topoisomerase IIα (TOP2A). Recent molecular studies using murine models and cell lines identified the bromodomain containing protein 4 (BRD4) and enhancer of zeste homolog 2 (EZH2) as novel targets for MPNST treatment. We investigated the expression and potential use of BRD4, EZH2 and TOP2A as therapeutic targets in human NF1-derived MPNSTs. The transcript levels of BRD4, EZH2 and TOP2A were determined in paired formalin-fixed paraffin-embedded (FFPE) neurofibroma/MPNST samples derived from the same NF1 patient and in a set of plexiform neurofibromas, atypical neurofibromas and MPNST. We further examined the effect on cell viability of genetic or pharmacological inhibition of BRD4, EZH2 and TOP2A in an MPNST cell line panel. Our results indicated that in MPNST samples BRD4 mRNA levels were not upregulated and that MPNST cell lines were relatively insensitive to the bromodomain inhibitor JQ1. We corroborated that EZH2 mRNA expression is increased in MPNST but failed to confirm its reported pivotal role in MPNST pathogenesis as EZH2 knockdown by siRNA did not interfere with cellular proliferation and viability. Finally, the relation between TOP2A levels and sensitivity for doxorubicin was examined, confirming reports that TOP2A mRNA levels were overexpressed in MPNST and showing that MPNST cell lines exhibited relatively high TOP2A protein levels and sensitivity to doxorubicin. We tentatively conclude that the potential for effective therapeutic intervention in MPNST by targeting BRD4, EZH2 and TOP2A individually, may be limited. Clinical studies are necessary to ultimately prove the relevance of BRD4 and EZH2 inhibition as novel therapeutic strategies for MPNST.

Nerve ultrasound: A useful screening tool for peripheral nerve sheath tumors in NF1?

OBJECTIVE: To determine ultrasonographic peripheral nerve involvement in patients with asymptomatic neurofibromatosis type 1 (NF1). METHODS: Thirteen asymptomatic and 4 minimally symptomatic patients with NF1 were included in this cross-sectional pilot study to detect asymptomatic abnormalities of the brachial plexus and upper and lower extremity nerves. Patients underwent clinical examination, nerve conduction studies (NCS), and high-resolution ultrasonography (HRUS). RESULTS: HRUS showed abnormalities in 16 patients (94.1%). Neurofibromas were identified in 10 patients (58.8%): localized neurofibromas were found in 3 patients (17.6%), plexiform neurofibromas in 3 (17.6%), and both in 4 (23.5%). In 6 patients (35.3%), only nerve enlargement without an abnormal fascicular pattern was observed. Severe involvement of the peripheral nervous system with multiple plexiform neurofibromas was observed in 7 patients (41.2%), while 4 patients (23.5%) had no or only minor involvement. Both NCS and HRUS were performed on 73 individual nerve segments. In 5.5%, abnormalities were found with both tests; in 50.7%, only with HRUS; and in 1.4%, only with NCS. CONCLUSIONS: HRUS frequently showed subclinical involvement of the peripheral nerves in NF1, also when NCS were normal. HRUS findings ranged from normal to widespread peripheral nerve involvement. Because the presence of plexiform neurofibromas and the benign tumor load are risk factors for the development of a malignant peripheral nerve sheath tumor, HRUS may be a useful tool to identify a subgroup of patients who could benefit from regular follow-up.

Optic nerve sheath meningioma: visual improvement during radiation treatment.

PURPOSE: To describe four patients with optic nerve sheath meningioma in whom visual improvement began to occur even before completion of a standard course of radiation therapy. DESIGN: Retrospective case review. METHODS: A review was conducted of 35 patients who received stereotactic three-dimensional conformal radiotherapy for optic nerve sheath meningioma from 1990 to 2005. RESULTS: Four patients with radiographic confirmation of optic nerve sheath meningioma were identified who had neuro-ophthalmologic assessment, which included perimetry, either while radiation treatment was underway or immediately afterwards. All of the patients showed improvement in visual acuity and visual fields. CONCLUSION: A rapid response to radiation therapy may occur in some patients with optic nerve sheath meningioma. In such patients, it may be possible to customize the radiation dose by assessing of visual function during the course of therapy.

Loss of p16 (INK4A) expression is associated with allelic imbalance/loss of heterozygosity of chromosome 9p21 in microdissected malignant peripheral nerve sheath tumors.

The p16 is a tumor suppressor gene on the short arm of chromosome 9p21. The product of the p16 acts as a negative cell cycle regulator by inhibiting G1 cyclin-dependent kinases that phosphorylate the retinoblastoma protein. This study was designed to assess the frequency of genetic loss of 9p21 and to determine the role of p16 the pathogenesis of sporadic and neurofibromatosis 1 (NF1)-associated malignant peripheral nerve sheath tumors (MPNSTs). The authors examined 15 cases for p16 protein expression and 10 cases for allelic imbalance (AI)/loss of heterozygosity (LOH) of chromosome 9p. DNA was microdissected from normal and neoplastic tissues. AI/LOH analysis was performed using six microsatellite markers on the 9p region. On immunohistochemical analysis 80% of cases showed abnormal expression of p16. Similarly, 8 of 10 cases revealed genetic loss with at least one microsatellite marker. The most frequent deletion was that within the coding sequence. Of p16 at me D9S974 locus. These findings emphasize the role of loss of p16 in the development of both sporadic and NF1-associated MPNSTs.