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Malignant peripheral nerve sheath tumors (MPNSTs) are soft tissue sarcomas that frequently harbor genetic alterations in polycomb repressor complex 2 (PRC2) components-SUZ12 and EED. Here, we show that PRC2 loss confers a dedifferentiated early neural-crest phenotype which is exclusive to PRC2-mutant MPNSTs and not a feature of neurofibromas. Neural crest phenotype in PRC2 mutant MPNSTs was validated via cross-species comparative analysis using spontaneous and transgenic MPNST models. Systematic chromatin state profiling of the MPNST cells showed extensive epigenomic reprogramming or chromatin states associated with PRC2 loss and identified gains of active enhancer states/super-enhancers on early neural crest regulators in PRC2-mutant conditions around genomic loci that harbored repressed/poised states in PRC2-WT MPNST cells. Consistently, inverse correlation between H3K27me3 loss and H3K27Ac gain was noted in MPNSTs. Epigenetic editing experiments established functional roles for enhancer gains on DLX5-a key regulator of neural crest phenotype. Consistently, blockade of enhancer activity by bromodomain inhibitors specifically suppressed this neural crest phenotype and tumor burden in PRC2-mutant PDXs. Together, these findings reveal accumulation of dedifferentiated neural crest like state in PRC2-mutant MPNSTs that can be targeted by enhancer blockade., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Neuroblastoma (NB) is the common pediatric tumor of the sympathetic nervous system characterized by poor prognosis. Owing to the challenges such as high tumor heterogeneity, multidrug resistance, minimal residual disease, etc., there is an immediate need for exploring new therapeutic strategies and effective treatments for NB. Herein, in the current study, we explored the unexplored response of NB cells to the second-generation histone deacetylase inhibitor (HDACi) JNJ-26481585(JNJ) and the lysosomotropic agent, Chloroquine (CQ) alone and upon JNJ/CQ treatment as a plausible therapeutic. We identify that while JNJ alone induced autophagy in NB cells, JNJ/CQ treatment decreased the viability and proliferation of NB cells in vitro by switching from autophagy to apoptosis. Further we found that autophagy inhibition by CQ pre-treatment led to the generation of ROS and a decrease in the mitochondrial membrane potential (MMP) that subsequently caused caspase-3-mediated apoptotic cell death in NB cells. Corroborating the above observations, we found that the ROS scavenger N-acetylcysteine (NAC) countered caspase-3 activity and the cells were rescued from apoptosis. Finally, these observations establish that JNJ/CQ treatment resulted in cell death in NB cells by triggering the formation of ROS and disruption of MMP, suggesting that modulation of JNJ-induced autophagy by CQ represents a promising new therapeutic approach in NB.

Background: Secondary central nervous system involvement of non-Hodgkin's lymphoma (NHL) is rare and with poor prognosis, the most common pathological type is diffuse large B cell lymphoma (DLBCL). Although it can occur in any part of central nervous system, it rarely directly infiltrates the spinal cord or cauda equina., Case Presentation: We present the case of 64-year-old immunocompetent man with a worsening pain of waist and left lower extremity, accompanied by numbness and paresis of bilateral lower extremity for 20 days. His previous medical history included a resection of painless mass in the left groin in another hospital 7 months ago, and the pathological diagnosis was non-Hodgkin small B cell lymphoma. Gd-enhanced MRI and F-18 FDG PET-CT scan demonstrated multiple infiltrations in the cauda equina. During the operation, we removed as many as 11 subdural-extramedullary bean-size lesions involving multiple nerve roots. The paralysis of his left leg recovered rapidly after the operation. During the follow-up period of more than one year, he underwent standard R-CHOP chemical therapy, no evidence of recurrence was noted until the 13th month, the patient died because of intracranial relapse., Conclusions: Imaging examination is important in the diagnosis of multiple secondary cauda equina non-Hodgkin's lymphoma, and we highlight the significance of gadolinium-enhanced MRI and F-18 FDG-PET/CT in preoperative diagnosis as well as the previous history.

Neuroblastoma is the most common extracranical tumor of childhood and the most deadly tumor of infancy. It is characterized by early age onset and high frequencies of metastatic disease but also the capacity to spontaneously regress. Despite intensive therapy, the survival for patients with high-risk neuroblastoma and those with recurrent or relapsed disease is low. Hence, there is an urgent need to develop new therapies for these patient groups. The molecular pathogenesis based on high-throughput omics technologies of neuroblastoma is beginning to be resolved which have given the opportunity to develop personalized therapies for high-risk patients. Here we discuss the potential of developing targeted therapies against aberrantly expressed molecules detected in sub-populations of neuroblastoma patients and how these selected targets can be drugged in order to overcome treatment resistance, improve survival and quality of life for these patients and also the possibilities to transfer preclinical research into clinical testing., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

We report a case of isolated posterior tibial B-cell lymphoma of the posterior tibial nerve presenting as tarsal tunnel syndrome. This diagnosis was considered because of the clinical presentation and electrophysiologic abnormalities. It was further confirmed by the magnetic resonance imaging findings of the ankle and tissue pathologic findings. Whole body positron emission tomography confirmed this to be a localized lymphoma involving the peripheral nerve. The patient underwent chemotherapy with complete tumor resolution. She had had no relapse after 8 months of follow-up. Isolated peripheral nerve lymphomas are very rare, and involvement of the posterior tibial nerve has not been previously reported. Furthermore, the present case report highlights the importance of the clinical examination in the diagnosis of tarsal tunnel syndrome before performing surgical decompression., (Copyright © 2017 American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.)

Research of various diseases of the nervous system has shown that VEGF has direct neuroprotective effects in the central and peripheral nervous systems, and indirect effects on improving neuronal vessel perfusion which leads to nerve protection. In the tumors of the nervous system, VEGF plays a critical role in tumor angiogenesis and tumor progression. The effect of anti-VEGF treatment on nerve protection and function has been recently reported - by normalizing the tumor vasculature, anti-VEGF treatment is able to relieve nerve edema and deliver oxygen more efficiently into the nerve, thus reducing nerve damage and improving nerve function. This review aims to summarize the divergent roles of VEGF in diseases of the nervous system and the recent findings of anti-VEGF therapy in nerve damage/regeneration and function in tumors, specifically, in Neurofibromatosis type 2 associated schwannomas., (Copyright © 2017. Published by Elsevier Inc.)

Objective To study the function and potential mechanism of RAC1 inhibitors in NF2-associated schwannoma. Methods In this study, we the downregulation of RAC1 activity and tumor cell phenotypes by RAC1 inhibitor NSC23766 in vitro. And we further validated the anti-proliferation effect by this RAC1 inhibitor in subcutaneous xenograft tumor model and sciatic nerve model. Results Pharmacological inhibition of RAC1 could significantly inhibit the proliferation of both RT4 cells and human NF2-associated primary schwannoma cells by inducing apoptosis. Pharmacological inhibition of RAC1 effectively reduced Rac1 activity and down-regulated the pathway downstream of Rac. Moreover, pharmacological inhibition of RAC1 showed a potential antitumor effect, with low toxicity in vivo. Conclusion RAC1 inhibitors may play a therapeutic role in patients with schwannoma.

Background: The effectiveness of corticosteroid injection for the treatment of Morton's neuroma is unclear. In addition, most of the studies related to it are case-control or retrospective case series. The purpose of this study was to compare the effectiveness between corticosteroid injection associated with local anesthetic and local anesthetic alone (placebo control group) for the treatment of Morton's neuroma., Methods: Forty-one patients with a diagnosis of Morton's neuroma were randomized to receive 3 injections of either a corticosteroid plus a local anesthetic or a local anesthetic alone. The patients and the researcher who collected data were blinded to the treatment groups. The visual analog scale for pain and the American Orthopaedic Foot & Ankle Score (metatarsophalangeal/interphalangeal score) were obtained at baseline, after each injection, and at 3 and 6 months after the last injection., Results: There were no significant between-group differences in terms of pain and function improvement at 3 and 6 months after treatment completion in comparison with baseline values. At the end of the study, 17 (48.5%) patients requested surgical excision of the neuroma: 7 (44%) in the experimental group and 10 (53%) in the control group ( P = 1.0)., Conclusion: The injection of a corticosteroid plus a local anesthetic was not superior to a local anesthetic alone in terms of pain and function improvement in patients with Morton's neuroma., Level of Evidence: Level I, randomized controlled trial.

Neurofibromas are benign peripheral nerve tumors driven by NF1 loss in Schwann cells (SCs). Macrophages are abundant in neurofibromas, and macrophage targeted interventions may have therapeutic potential in these tumors. We generated gene expression data from fluorescence-activated cell sorted (FACS) SCs and macrophages from wild-type and mutant nerve and neurofibroma to identify candidate pathways involved in SC-macrophage cross-talk. While in 1-month-old Nf1 mutant nerve neither SCs nor macrophages significantly differed from their normal counterparts, both macrophages and SCs showed significantly altered cytokine gene expression in neurofibromas. Computationally reconstructed SC-macrophage molecular networks were enriched for inflammation-associated pathways. We verified that neurofibroma SC conditioned medium contains macrophage chemo-attractants including colony stimulation factor 1 (CSF1). Network analysis confirmed previously implicated pathways and predict novel paracrine and autocrine loops involving cytokines, chemokines, and growth factors. Network analysis also predicted a central role for decreased type-I interferon signaling. We validated type-I interferon expression in neurofibroma by protein profiling, and show that treatment of neurofibroma-bearing mice with polyethylene glycolyated (PEGylated) type-I interferon-α2b reduces the expression of many cytokines overexpressed in neurofibroma. These studies reveal numerous potential targetable interactions between Nf1 mutant SCs and macrophages for further analyses.

Aims: The objective of this double-blind randomised controlled trial was to assess whether ultrasound guidance improved the efficacy of corticosteroid injections for Morton's neuroma (MN)., Patients and Methods: In all, 50 feet (40 patients) were recruited for this study but five feet were excluded due to the patients declining further participation. The mean age of the remaining 36 patients (45 feet) was 57.8 years (standard deviation (sd) 12.9) with a female preponderance (33F:12M). All patients were followed-up for 12 months. Treatment was randomised to an ultrasound guided (Group A) or non-ultrasound guided (Group B) injection of 40 mg triamcinolone acetonide and 2 ml 1% lignocaine, following ultrasound confirmation of the diagnosis., Results: The mean visual analogue score for pain improved significantly in both groups (Group A - from 64 mm, sd 25 mm to 29 mm, sd 27; Group B - from 69 mm, sd 23 mm to 37 mm, sd 25) with no statistical difference between them at all time-points. The failure rate within 12 months of treatment was 11/23 (48%) and 12/22 (55%) in Groups A and B, respectively (p = 0.458). The improvement in Manchester Oxford Foot Questionnaire Index and patient satisfaction favoured Group A in the short-term (three months) that almost reached statistical significance (p = 0.059 and 0.066 respectively). However, this difference was not observed beyond three months., Conclusion: This study has shown that ultrasound guidance did not demonstrably improve the efficacy of corticosteroid injections in patients with MN., Take Home Message: In the presence of a clear diagnosis of MN, a trained clinician who understands the forefoot anatomy may perform an injection without ultrasound guidance with good and safe results., (©2016 The British Editorial Society of Bone & Joint Surgery.)

Primary central nervous system (CNS) lymphoma is a rare form of non-Hodgkin's lymphoma. The clinical presentation is variable, depending on its localisation within the nervous system. Only 1% of primary CNS lymphoma emerges in the spinal cord, and the prevalence of primary lymphoma of the cauda equina is unknown, but probably even rarer. Diagnosing primary lymphoma of the cauda equina is difficult, since it can mimic other more common disorders such as a herniated disc, especially in its early stages. Here we present two cases of primary cauda equina lymphoma in which diagnostic work up took a long time, as the final diagnosis was only reached after a nerve root biopsy., (2014 BMJ Publishing Group Ltd.)

Background: Previous studies have shown that the injection of dehydrated alcohol has been successful for the treatment of Morton's neuroma in the foot. In this study, we determined the cellular effect of injection of alcohol into and around the sciatic nerve of rats and measured the extent of cell necrosis and/or any associated histologic or inflammatory changes., Methods: Twenty-two male (~375 g) Wistar rats were randomized into 2 groups each receiving alcohol injections into or around the sciatic nerve after nerve exposure under sterile technique. Group 1 rats were injected with a 0.5 ml solution of 0.5% Marcaine in the left sciatic nerve as a control group. In the right sciatic nerve a 0.5 ml solution of 4% ethanol with 0.5% Marcaine was injected. Group 2 rats received 0.5 ml of 20% ethanol with 0.5% Marcaine injected into the left sciatic nerve and 0.5 ml of 30% ethanol with 0.5% Marcaine injected into the right sciatic nerve. In each group, the rats were placed in 3 subgroups: intraneural, perineural, perimuscular injections. All rats were sacrificed and tissue harvested for histologic evaluation at day 10 post injection., Results: No evidence of alcohol-associated cell necrosis, apoptosis, or apparent inflammation was observed in histologic specimens of any injected nerves, perineural tissue, or muscles in controls or experimental groups regardless of concentration of ethanol injected on day 10., Conclusion: We concluded that alcohol injection (≤30% ethanol) into and/or around the sciatic nerve or the adjacent muscle of rats has no histologic evidence of necrosis or inflammation to the nerve or surrounding tissue. There was no observable histological change in apoptosis, or cell number, in response to the alcohol injection., Clinical Relevance: The lack of any measureable changes in nerve or adjacent muscle histology with ethanol injection into the rat sciatic nerve (and surrounding tissues) raises questions about the efficacy of using ethanol injections in the treatment of Morton's neuroma in human clinical practice., (© The Author(s) 2014.)

Background: To discuss the therapeutic approach for primary neurolymphomatosis., Methods: We report all primary neurolymphomatosis cases referred to our institution, with descriptions of clinical, radiological, electrophysiological, histological features and long-term follow-up. We treated all patients with a combination of high-dose methotrexate and alkylating agents., Results: Five patients were diagnosed with histologically confirmed primary neurolymphomatosis. The majority of them presented with painful asymmetric sensory-motor neuropathy. Magnetic resonance imaging was abnormal in 4 of 5 patients, as shown with gadolinium enhancements. Electroneuromyography revealed denervation in all 4 cases with contributive examinations. All our patients received a chemotherapy combination of high-dose methotrexate and alkylating agent. Median progression-free survival was 8 months (2 complete responses and 2 partial responses), and overall survival was 24 months., Conclusions: Primary neurolymphomatosis is rare and polymorphic; it represents a difficult diagnosis of neuropathy. In our cohort, treatment with a chemotherapy combination with high-dose methotrexate showed encouraging results., (Copyright © 2014 Elsevier B.V. All rights reserved.)

About one half of malignant peripheral nerve sheath tumors (MPNST) have Neurofibromin 1 (NF1) mutations. NF1 is a tumor suppressor gene essential for negative regulation of RAS signaling. Survival for MPNST patients is poor and we sought to identify an effective combination therapy. Starting with the mTOR inhibitors rapamycin and everolimus, we screened for synergy in 542 FDA approved compounds using MPNST cells with a native NF1 loss in both alleles. We further analyzed the cell cycle and signal transduction. In vivo growth effects of the drug combination with local radiation therapy (RT) were assessed in MPNST xenografts. The synergistic combination of mTOR inhibitors with bortezomib yielded a reduction in MPNST cell proliferation. The combination of mTOR inhibitors and bortezomib also enhanced the anti-proliferative effect of radiation in vitro. In vivo, the combination of mTOR inhibitor (everolimus) and bortezomib with RT decreased tumor growth and proliferation, and augmented apoptosis. The combination of approved mTOR and proteasome inhibitors with radiation showed a significant reduction of tumor growth in an animal model and should be investigated and optimized further for MPNST therapy.

Background Context: Malignant solitary fibrous tumors (SFTs) arising from the spinal cord are extremely rare and poorly understood mesenchymal neoplasms. To date, only one malignant SFT located in the spinal canal of the sacrum has been described, but none arising from the lumbar nerve root have been reported. Although most SFTs with benign histological features can be treated by complete surgical excision alone, malignant SFTs may require adjuvant therapy. However, systemic chemotherapy and radiotherapy have not been shown effective in patients with malignant SFTs., Purpose: To describe a patient with a malignant SFT arising from the lumbar nerve root., Study Design: A case report and review of literature., Methods: We describe the clinical course of the patient and the radiological and pathological findings of the tumor. The effect of systemic chemotherapy was evaluated and the relevant literature was reviewed. This work has no disclosure of funding and was approved by the Institutional Review Board of Gifu University., Results: The tumor had been resected previously at another hospital, but it recurred and showed multiple metastatic lesions on both lungs within 3 months. Although the patient received systemic chemotherapy, both primary and metastatic lesions were found to be stable disease according to Response Evaluation Criteria in Solid Tumors. The patient died due to cachexia 6 months after her first visit., Conclusion: This patient presented with a highly unusual tumor. Even if a tumor is a dumbbell-shaped mass, similar to a neural tumor, SFT should be considered in the differential diagnosis., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Lipomatosis of nerve is a rare benign tumor-like process characterized by infiltration of the epineurium by adipose and fibrous tissue leading to nerve enlargement. We describe a case of lipomatosis of the sciatic nerve compressed by an adjacent desmoid tumor. This case supports the hypothesis that lipomatosis of nerve may form as a result of irritation or compression by adjacent structures.

Neurofibromatosis-1 (NF-1) is a relatively common autosomal dominant disease and it is caused by mutation of the NF-1 tumor suppressor gene; hence, the individuals affected have increased risk for developing familial cancer. Abdominal cavity neurofibromas are common but the simultaneous occurrence of a malignant peripheral nerve sheath tumor (MPNST) in the chest and in the abdomen is rare. Here, we present a patient with MPNST (spindle cell sarcoma) affecting simultaneously the vagus nerve in the head and neck region, mediastinum, pleura as well as celiac plexus branches near the stomach., (Published by Elsevier Ltd.)

A babygirl, aged six weeks, was hospitalized for rectal prolapse and isolated constipation. The investigation revealed a neuroblastoma (NB) inducing a medullar compression responsible for the sphincter disorders. NB is second among pediatric solid tumors, but is the most frequent cancer among infants. Its diagnosis is difficult because of its rarity and the variety of its symptoms. A new staging, based on imaging, has recently been proposed by the International Neuroblastoma Risk Group. With the exception of its localized, easily resectable forms, NB is best treated by chemotherapy.

After limb amputation, neuromas may be asymptomatic when not compressed, but can cause unexplained discomfort when a prosthesis is worn. The sonographic presentation of multiple postamputation neuromas has rarely been reported. A 40-year-old female with a left, below-elbow amputation suffered from late-onset stump pain and prosthesis intolerance. Physical examination revealed a painful nodule, whereas sonographic findings disclosed three hypoechoic masses derived from the median, ulnar, and radial nerves. Marked pain reduction was reported 2 weeks after sonography-guided steroid injection. Investigation of all damaged nerves in the residual limbs is important., (Copyright © 2012 Wiley Periodicals, Inc.)

Lymphoma of the peripheral nerve, particularly of the T-cell variety, is an extremely rare subtype of extra nodal lymphoma that has a variable response to current therapeutic regimens. Here, we present a patient with natural killer (NK)/T-cell lymphoma in remission who presented with a two-month history of right forearm swelling and paresthesia in the ulnar nerve distribution. Magnetic resonance imaging (MRI) showed an ulnar nerve mass identified as a nerve sheath tumor. Frozen section and postresection biopsies showed an Epstein-Barr virus-positive NK/T-cell lymphoma, nasal type. Consequently, the patient received chemotherapy following resection. Four months later, the patient developed a proximal leg mass, which was diagnosed as tibial nerve lymphoma. The patient was then treated with chemotherapy and follow-up was done by positron emission tomography-computed tomography (PET-CT). In conclusion, lymphoma should be considered in the differential diagnosis of a peripheral nerve mass. MRI is a useful imaging tool together with PET-CT, which plays a beneficial role in the follow-up of these patients on therapy as well as diagnosis of new lesions.

Neurofibromatosis type 1 (NF1) patients develop benign neurofibromas and malignant peripheral nerve sheath tumors (MPNST). These incurable peripheral nerve tumors result from loss of NF1 tumor suppressor gene function, causing hyperactive Ras signaling. Activated Ras controls numerous downstream effectors, but specific pathways mediating the effects of hyperactive Ras in NF1 tumors are unknown. We performed cross-species transcriptome analyses of mouse and human neurofibromas and MPNSTs and identified global negative feedback of genes that regulate Ras/Raf/MEK/ERK signaling in both species. Nonetheless, ERK activation was sustained in mouse and human neurofibromas and MPNST. We used a highly selective pharmacological inhibitor of MEK, PD0325901, to test whether sustained Ras/Raf/MEK/ERK signaling contributes to neurofibroma growth in a neurofibromatosis mouse model (Nf1(fl/fl);Dhh-Cre) or in NF1 patient MPNST cell xenografts. PD0325901 treatment reduced aberrantly proliferating cells in neurofibroma and MPNST, prolonged survival of mice implanted with human MPNST cells, and shrank neurofibromas in more than 80% of mice tested. Our data demonstrate that deregulated Ras/ERK signaling is critical for the growth of NF1 peripheral nerve tumors and provide a strong rationale for testing MEK inhibitors in NF1 clinical trials.

Neurolymphomatosis (NL) is a rare clinical entity defined as peripheral nervous system infiltration by lymphoma. The diagnosis is difficult and often elusive. Whole-body diffusion-weighted magnetic resonance imaging (DW MRI) was developed to enhance the detection of vaguely delineated tumors. Here, we describe the case of a 71-year-old male with secondary NL of diffuse large B-cell lymphoma (DLBCL) that was successfully detected by whole-body DW MRI. The patient was diagnosed with DLBCL extending from the ethmoidal sinus to the nasal cavity, orbital cavity, and anterior cranial fossa. Although he was administered R-THP-COP chemotherapy and the tumor remarkably decreased in size, he developed painful paresthesia and weakness in the left upper and bilateral lower extremities during treatment. Because lymphoma cells were detected in his spinal fluid, high-dose methotrexate (MTX) and weekly intrathecal MTX and cytarabine injections were administered. Test results for lymphoma cells in the spinal fluid became negative ; however, the neurological disorders progressed. Whole-body DW MRI was performed as whole-body screening and could localize NL at the left cervical and bilateral lumbar nerve roots. Both cervical spine plain MRI and enhanced computed tomography performed around the same time could not detect the cervical lesion. Our case report suggests that whole-body DW MRI is a useful diagnostic imaging procedure, especially as whole-body screening in facilities where PET/CT is not available.

Purpose: Assess patient discomfort during two different methods of injection of Morton's neuroma., Methods: Sixty-eight patients referred for ultrasound-guided injection of Morton's neuroma had punctures performed dorsal or plantar to the interdigital skin crease, with and without preliminary subcutaneous local anesthesia (LA). Patients rated discomfort during skin puncture (SP) and needle advancement (NA) using a visual analog scale., Results: Average pain score was 4.4 ± 2.3 (1 SD) for the plantar approach and 2.9 ± 2.0 for the dorsal approach. This difference was statistically significant during SP (p < 0.01) and NA (p < 0.05). During the plantar approach with LA, mean pain score during SP was 4.4 (± 2.1) and 3.9 (± 2.8) during NA. This plantar approach without LA resulted in a pain score of 4.3 (± 2.6) and 3.8 (± 3.1), respectively. Mean pain scores for patients injected from the dorsal approach with LA during SP were 3.8 (± 2.7) and NA were 2.2 (± 2.0) and without LA were 2.6 (± 1.9) and 3.0 (± 2.1). There was no statistical significance in mean pain score difference during SP and NA, with and without LA for either the plantar (p > 0.05) or the dorsal (p > 0.05) approach., Conclusions: Injection of Morton's neuroma was better tolerated via a dorsal approach and use of preliminary LA did not confer any benefit., (Copyright © 2012 Wiley Periodicals, Inc.)

A 69-year-old man presented with a very rare case of primary central nervous system lymphoma originating in the cauda equina manifesting as progressive paraparesis. The patient underwent a biopsy, and was treated with intravenous high-dose (3.5 g/m(2)) methotrexate chemotherapy and local irradiation. Histological study revealed large B cell type lymphoma. Follow-up magnetic resonance imaging showed complete remission of the lesion, but the patient died of pneumonia at 18 months after the initial onset without tumor recurrence, so the efficacy of this strategy remains unknown.

Adenocarcinomas and other various tumors are known to metastasize to various locations without any significant predilection and the metastasis could be the first presentation of the malignancy by the patient. Involvement of peripheral nerves without the central nervous system involvement has been rarely reported. Perineural tumor spread has been infrequently reported with soft tissue tumors without central nervous system involvement. Here we present an unusual case of an elderly gentleman presenting with symptoms consistent with peripheral neuropathy involving multiple nerves. After failure of symptomatic therapy, electromyogram, and nerve conduction study showed severe bilateral carpal tunnel syndrome. Interestingly, symptoms worsened in the left hand after bilateral release surgery. Due to persistence of significant lifestyle-limiting symptoms, biopsy of the sural nerve was done that showed metastatic poorly differentiated adenocarcinoma cells. A complete surveillance for the primary lesion has been negative so far. The peripheral neuropathy was considered to be arising from the involvement of the perineural sheaths by the metastatic tumor lesions. The patient was then started on gemcitabine therapy and after just 2 cycles of chemotherapy, the patient has shown notable improvement of his symptoms. After completion of the duration of chemotherapy, he has been symptom-free for more than 6 months. Metastatic lesions to the peripheral nervous system should be considered in patients who have persisting neuropathic symptoms because treatment of those lesions can results in improvement of symptoms.

Malignant peripheral nerve sheath tumours are rare and aggressive soft-tissue sarcomas of ectomesenchymal origin. These tumours commonly occur in patients with neurofibromatosis Type 1 with a cumulative lifetime risk of 10%. The vast majority of cases present with clinical evidence of a soft-tissue mass with or without features of nerve irritation and loss of function arising from the lesion of origin. The primary presentation of a malignant peripheral nerve sheath tumour with a pneumothorax in the absence of widespread metastatic disease in a patient with no medical or family history of neurofibromatosis has never been reported in the literature. We present a unique case of a systemically well 34-year-old male who presented with clinical evidence of a right-sided pneumothorax. The chest radiograph identified the right-sided pneumothorax and revealed an apical pleural mass that was confirmed by intravenous contrast-enhanced CT of the thorax. The patient was referred for video-assisted thorascopic surgical pleurodesis and biopsy of the lesion. Histopathology analyses confirmed the diagnosis of malignant peripheral nerve sheath tumour. To the best of our knowledge, no such case reports have been published in the literature. A diagnosis of malignant peripheral nerve sheath tumour should be considered as one of the rarer possibilities in patients presenting with pneumothoraces in association with apical pleural lesions.

Objective: Primary lymphomas of peripheral nerves are extremely rare, with the bulk of the literature being case reports. The nerve most commonly affected is the sciatic nerve, with 9 cases reported. To date, there are no reports in the English literature of isolated involvement of the radial nerve by a primary lymphoma., Clinical Presentation: A 69-year-old woman with a history of osteoporosis, irritable bowel disease, asthma, and Graves' disease presented with a 6-month history of paresthesia in her left superficial sensory radial nerve territory, weakness of thumb extension, and localized pain and swelling in the cubital fossa. Examination showed a painful tender mass in the line of the radial nerve in the cubital fossa, grade 4/5 supination, grade 4-/5 extensor carpi radialis longus and extensor carpi ulnaris, and grade 3/5 finger and thumb extension, all consistent with a radial nerve lesion at the level of the cubital fossa. Ultrasonography and computed tomography confirmed an intraneural tumor. Surgery revealed radial intraneural tumor just after the branch to the extensor carpi radialis longus. It was clearly an infiltrating lesion with no plane between tumor and nerve fascicles. Frozen section confirmed malignancy, and an incomplete excision was performed. Histopathology revealed diffuse large B-cell lymphoma. Surgery was followed with negative staging and a chemotherapy program., Conclusion: Primary B-cell lymphoma of the peripheral nerve is exceedingly rare and to date has not been reported as an isolated occurrence in the radial nerve. We present a patient who is alive and disease free 65 months after incomplete excision and limited chemotherapy.

Neurolymphomatosis (NL) is an uncommon syndrome of peripheral or cranial nerve root dysfunction secondary to infiltration by B-cell non-Hodgkin's lymphoma (NHL). A high index of suspicion is required as presenting symptoms are varied, conventional radiology has only modest sensitivity, and pathological diagnosis is often difficult. Treatment with chemotherapy alone has an objective response rate of 82%, although long-term outcomes are highly variable. This case series describes outcomes in four patients whose management incorporated PET scanning and the use of rituximab in combination with chemotherapy. PET scanning could often diagnose NL where other diagnostic modalities were non-diagnostic. Although combination therapy with rituximab and chemotherapy has been shown to be superior to chemotherapy alone in other forms of NHL, this does not appear to be the case in patients with NL. This may reflect the inability of rituximab to adequately penetrate into the central and peripheral nervous system. This is supported by the common finding that patients will relapse solely with NL despite on-going complete remission at sites outside the nervous system. The prognosis of these patients is poor, with the disease often following a progressive course despite treatment.

Neurofibromatosis type 1 (NF1) patients are prone to the development of malignant tumors, the most common being Malignant Peripheral Nerve Sheath Tumor (MPNST). NF1-MPNST patients have an overall poor survival due to systemic metastasis. Currently, the management of MPNSTs includes surgery and radiation; however, conventional chemotherapy is not very effective, underscoring the need for effective biologically-targeted therapies. Recently, the NF1 gene product, neurofibromin, was shown to negatively regulate the phosphoinositide-3-kinase (PI3K)/Protein Kinase-B (Akt)/mammalian Target Of Rapamycin (mTOR) pathway, with loss of neurofibromin expression in established human MPNST cell lines associated with high levels of mTOR activity. We developed and characterized a human NF1-MPNST explant grown subcutaneously in NOD-SCID mice, to evaluate the effect of the mTOR inhibitor rapamycin. We demonstrate that rapamycin significantly inhibited human NF1-MPNST mTOR pathway activation and explant growth in vivo at doses as low as 1.0 mg/kg/day, without systemic toxicities. While rapamycin was effective at reducing NF1-MPNST proliferation and angiogenesis, with decreased CyclinD1 and VEGF respectively, there was no increase in tumor apoptosis. Rapamycin effectively decreased activation of S6 downstream of mTOR, but there was accompanied increased Akt activation. This study demonstrates the therapeutic potential and limitations of rapamycin in NF1-associated, and likely sporadic, MPNSTs.

A 45-year-old woman presented with a rare case of metastatic cauda equina tumor from breast cancer without spinal column or brain metastasis. She had undergone resection of breast cancer 4 years previously. She presented with a 2-month history of severe low back pain. Magnetic resonance imaging showed a well-enhanced intradural extramedullary mass at the L1 level without other intradural lesions. At surgery, the tumor was partially removed to preserve the nerve root function under electrophysiological monitoring. The histological diagnosis was adenocarcinoma. The tumor was located in the subarachnoid space, suggesting hematogenous metastasis from the breast cancer. Postoperatively the pain subsided and no neurological deficit occurred. She underwent adjuvant therapy and rehabilitation. Cauda equina tumors may be relatively progressive regardless of imaging findings and clinical symptoms, so preoperative systemic investigation should be conducted, considering the possibility of metastatic tumor. A comprehensive therapeutic strategy involving adjuvant therapy after surgery is important to establish, considering the preservation of postoperative nerve function.

Neurolymphomatosis, the infiltration of the peripheral nervous system (PNS) by malignant lymphatic cells, is a rare condition whose prognosis and treatment are not fully characterized. The authors report the case of a 69-year-old, previously healthy man who had a 1-month history of progressive pain in his right arm and associated weakness of several muscles of the right upper extremity when they first examined him. Initial MR imaging of the right brachial plexus showed no abnormalities, but over 3 months, symptoms gradually progressed to almost complete plegia of his right upper extremity. Subsequent MR imaging of his right brachial plexus showed an enhancing mass of the posterior cord of the plexus that encroached on the other cords. Positron emission tomography confirmed the presence of a hypermetabolic lesion in the right axillary region and also detected an asymptomatic hot spot in the gastric wall. Biopsy of the gastric lesion demonstrated a CD20+, diffuse large B-cell lymphoma that was immunohistochemically positive for BCL-6 and negative for p16. The patient underwent 6 cycles of dose-adjusted etoposide-vincristine-doxorubicin-cyclophosphamide-prednisone (EPOCH) and rituximab, intermixed with 3 cycles of high-dose intravenous and intrathecal methotrexate, and followed by 6 monthly doses of rituximab for consolidation. Follow-up MR imaging and PET of the plexus showed complete radiological response after 3 months of treatment, as demonstrated by normalization of brachial plexus caliber, contrast enhancement, and metabolic activity. Twenty-eight months after symptom onset and 20 months after beginning therapy, the patient was disease-free, had recovered most upper extremity neurological function, and had only minimal remaining weakness of the right wrist and finger extension.

Myc family genes are often deregulated in embryonal tumors of childhood including medulloblastoma and neuroblastoma and are frequently associated with aggressive, poorly differentiated tumors. The Myc protein is a transcription factor that regulates a variety of cellular processes including cell growth and proliferation, cell cycle progression, differentiation, apoptosis, and cell motility. Potential strategies that either inhibit the proliferation-promoting effect of Myc and/or activate its pro-apoptotic function are presently being explored. In this review, we will give an overview of Myc activation in embryonal tumors and discuss current strategies aimed at targeting Myc for cancer treatment.

Background: The purpose of this study was to evaluate the efficacy of corticosteroid injection and determine the duration of symptom-free period after treatment with a single ultrasound-guided injection for a painful Morton's neuroma., Materials and Methods: From May 2002 to November 2003, 35 consecutive patients (7 males, 28 females) (mean age, 54; age range, 29 to 77 years) underwent a single ultrasound guided corticosteroid injection. Thirty-nine injections were performed as 4 patients had bilateral Morton's neuromas. The injection of 1.0 cc Celestone Chronodose (5.7 mg/ml) with 0.5 cc of 1% lidocaine was performed into the symptomatic intermetatarsal web-space. The efficacy of the injection was determined by the Johnson grading scale, and modified lower extremity functional scale., Results: On the Johnson scale, 15 of 39 (38%) neuromas showed complete satisfaction 9 months after treatment and 11 of 39 (28%) were satisfied with minor reservations. A total of 26 of 39 (66%) neuromas had a positive outcome 9 months after the injection. On the functional daily activity (FDA) scale, 20 of 39 (51%) neuromas showed no difficulty and 4 of 39 (10%) indicated minor difficulties, which was considered a positive outcome 9 months after injection. Complete pain relief was achieved in 11 of 39 (28%) neuromas 9 months after treatment. Twelve of 39 (31%) neuromas did not respond to conservative treatment and required surgery. The results of treatment suggested improvement in efficacy if injection was used early. The size of the lesion measured on ultrasound showed no correlation with pain relief after injection., Conclusion: A single corticosteroid injection can offer short-term pain relief in the conservative management of Morton's neuroma.

Objective: Identify molecular targets for development of tumor-specific pharmacotherapeutics aimed at treating vestibular schwannomas (VSs). Activated epidermal growth factor receptor B (ErbB) 2 and ErbB3 are abundantly expressed in VS. ErbB2 signaling is essential for Schwann cell differentiation, survival, and proliferation. VS arise after loss of functional merlin, a putative tumor suppressor. Merlin internalizes ErbB2 receptors in rodent Schwann cells. Unregulated ErbB signaling may contribute to VS tumorigenesis., Study Design: Molecular analyses, retrospective clinical correlation., Setting: Tertiary referral center., Patients: Thirty-eight specimens from patients operated for sporadic (n=21) and neurofibromatosis (NF) 2-related (n=17) VS., Intervention(s): VS analyses via real-time polymerase chain reaction, immunohistochemistry, and correlation with patient clinical data., Main Outcome Measure(s): ErbB signaling molecule expression, tumor size, age, and NF2 status., Results: VS upregulated epidermal growth factor (EGF) receptor in 68% (62% sporadic and 75% NF2-associated VS) and ErbB2 in 84% (76% sporadic and 94% NF2-related VS). ErbB3 was upregulated in 34%, and ErbB4 is downregulated in NF2-related VS. Of EGF receptor (EGFR) ligands, EGF was upregulated in all NF2-related VS, but none of the sporadic VS (p<0.01), and transforming growth factor alpha and beta-cellulin showed upregulation in 67% of NF2-related VS but not sporadic VS (p=0.02 and p=0.01, respectively). Neuregulin (Nrg) was upregulated in 86% of sporadic VS versus 19% of NF2-related VS (p<0.01). EGFR expression levels correlated directly with VS tumor size and inversely with patient age, whereas Nrg expression correlated directly with age (p=0.0005). EGF expression predicts NF2 status, whereas Nrg predicts non-NF2 status (p<0.01)., Conclusion: These findings implicate the ErbB pathway in VS growth and as potential molecular targets for VS pharmacotherapy.

Neurolymphomatosis is a rare condition and may be the first and only manifestation of a non-Hodgkin lymphoma. We present the case of a 59-year-old patient with fluctuating gluteal pain for 5 years and progressive palsy of the left lower extremity, leading to severe walking difficulties. The neurologic examination revealed pronounced atrophy, flaccid paresis, and sensory loss in the area of innervation of the left sciatic nerve. Electroneuromyography showed a severe sensomotoric axonal lesion of the left sciatic nerve. Biopsy of the lesion revealed diffuse large B-cell lymphoma. Fluorodeoxyglucose (FDG)-positron emission tomography/computed tomography was performed for staging, showing a high FDG uptake of the left sciatic nerve. FDG-positron emission tomography/computed tomography after six cycles of chemotherapy showed complete metabolic response.

Objective: Morton's neuroma is a common cause of forefoot pain. For this study, we assessed the efficacy of a series of sonographically guided alcohol injections into the lesion., Subjects and Methods: One hundred one consecutive patients with Morton's neuroma were included in this prospective series. An average of 4.1 treatments per person were administered, and follow-up images were obtained at a mean of 21.1 months after the last treatment (range, 13-34 months)., Results: Technical success was 100%. Partial or total symptom improvement was reported by 94% of the patients, with 84% becoming totally pain-free. The median visual assessed pain score decreased from 8 before treatment to 0 after treatment (p < 0.001). Transitory increased local pain occurred in 17 cases (16.8%). There were no major complications. Thirty patients underwent sonography at 6 months after the last injection and showed a 30% decrease in the size of the neuroma., Conclusion: We conclude that alcohol injection of Morton's neuroma has a high success rate and is well tolerated. The results are at least comparable to surgery, but alcohol injection is associated with less morbidity and surgical management may be reserved for nonresponders.

Purpose: Fenretinide [N-(4-hydroxyphenyl)retinamide (4-HPR)] is a cytotoxic retinoid that suffers from a wide interpatient variation in bioavailability when delivered orally in a corn oil capsule. The poor bioavailability of the capsule formulation may have limited responses in clinical trials, and the large capsules are not suitable for young children. To support the hypothesis that a novel organized lipid matrix, LYM-X-SORB, can increase the oral bioavailability of fenretinide, fenretinide in LYM-X-SORB matrix and in a powderized LYM-X-SORB formulation was delivered to mice., Experimental Design: Fenretinide was delivered orally to mice as the contents of the corn oil capsule, in LYM-X-SORB matrix (4-HPR/LYM-X-SORB matrix) or in a LYM-X-SORB matrix powderized with sugar and flour (4-HPR/LYM-X-SORB oral powder). Levels of 4-HPR, and its principal metabolite, N-(4-methoxyphenyl)retinamide, were assayed in plasma and tissues., Results: In a dose-responsive manner, from 120 to 360 mg/kg/d, delivery to mice of 4-HPR in LYM-X-SORB matrix, or as 4-HPR/LYM-X-SORB oral powder, increased 4-HPR plasma levels up to 4-fold (P<0.01) and increased tissue levels up to 7-fold (P<0.01) compared with similar doses of 4-HPR delivered using capsule contents. Metabolite [N-(4-methoxyphenyl)retinamide] levels mirrored 4-HPR levels. Two human neuroblastoma murine xenograft models showed increased survival (P<0.03), when treated with 4-HPR/LYM-X-SORB oral powder, confirming the bioactivity of the formulation., Conclusions: 4-HPR/LYM-X-SORB oral powder is a novel, oral drug delivery formulation, suitable for pediatric use, which warrants further development for the delivery of fenretinide in the treatment of cancer. A phase I clinical trial in pediatric neuroblastoma is in progress.

Background: Dilute alcohol injection has been described as a nonsurgical treatment option for interdigital nerve compression of the foot, also known as "Morton's neuroma." This study reviews the efficacy of the procedure in 49 feet at one treatment center., Methods: In this historical cohort study, data from 42 patients who had undergone alcohol injection therapy were obtained from clinic records. A total of 49 feet were reviewed., Results: Symptoms were improved or resolved in 30 (61%) of 49 feet. Nineteen feet (39%) were unimproved, with 12 of those progressing to surgical neurectomy. Feet that received five or more injections were more likely to improve (74%) than those that received fewer than five injections (39%). Three patients reported mild complications associated with dilute alcohol injection, all of which resolved spontaneously within 2 days of the injection., Conclusions: Dilute alcohol injection is a safe and effective treatment option for patients with Morton's neuroma who want to avoid a surgical procedure and any associated complications. The procedure may be more successful if the patient receives at least five injections.

Evidence that CD4CD25 regulatory T (Treg) cells play a role in the progression of cancer continues to mount. There is a great deal of interest as to whether transient elimination or functional inhibition of these cells can improve the efficacy of immunotherapy for cancer. Our goals in this study were to test whether treatment of mice with anti-CD25 monoclonal antibody (mAb) (PC61) could induce rejection of a murine neuroblastoma, whether anti-CD25 treatment could increase tumor immunity when administered just before cell-based vaccination, and to learn how anti-CD25 treatment influences the vaccine-induced antitumor response. Treatment of mice with anti-CD25 mAb induced rejection of the mouse neuroblastoma, Neuro-2a, as 90% of anti-CD25-treated mice survived challenge with a lethal dose of tumor cells. In vivo anti-CD25 mAb treatment before the first of 2 weekly vaccines significantly improved the survival of tumor-vaccinated/challenged mice (75% vs. 33% survival), whereas antibody treatment before each of the 2 vaccines did not, suggesting that excessive treatment with anti-CD25 mAb interferes with activated antitumor effector cells. A detailed phenotypic analysis of tissues from anti-CD25-treated mice indicated that the antibody partially depletes CD4Foxp3 Treg cells (25% to 40%) in A/J mice, and that the antibody may inhibit the remaining cells by inducing loss of CD25 expression and blocking CD25 molecules, partially confirming recent data from other investigators. Importantly, we found that in vivo anti-CD25 mAb treatment significantly decreased the contribution of asialo GM1 cells in the antitumor response. As we did not see a direct effect of anti-CD25 mAb on in vitro assays of immune cell function in spleen cells from treated animals, this indicates that inhibition of Treg cells amplifies the immune response in vivo in a manner that bypasses the requirement for innate immune activation, potentially mediated by natural killer cells, and allows for protective CD4 and CD8 cells to expand directly in response to cell-based vaccines.

Amputation neuroma is the consequence of a traumatic event that interrupt the anatomic structure of a nerve. After the lesion, the nerve begin an plerosis attempt. This condition determines hyposensitivity on its innervation area and a painful syndrome. The pattern's resolution is possible with the neuroma's tissue exeresis and the sinking of proximal stump into closer tissue. This operation reduces or eliminates axonal nerve's flux. The hyaluronic acid (Hyaloglide 0.8-1 ml) use is based on the necessity of proximal stump preservation from mechanical and thermic stimuli that are responsible of typical neuroma's symptoms. In this study we used hyaluronic acid on six painful amputation neuroma patterns on sensitive nerves of upper and lower extremities.

We performed an open-label phase II trial of oral pirfenidone in 24 patients with neurofibromatosis type 1 (NF1). Tumors were monitored by three-dimensional MRI. At the end of treatment, four patients had a decrease in tumor volume by 15% or more, three had tumor progression, and 17 remained stable. Pirfenidone warrants further investigation in NF1, which has until now lacked an effective control therapy.

A patient with primary B cell non-Hodgkin's lymphoma of the sciatic nerve is described. He presented with neuropathic symptoms in the left leg, initially diagnosed as tarsal tunnel syndrome. Magnetic resonance imaging (MRI) identified the abnormality in the sciatic nerve. A fascicular biopsy of the sciatic nerve showed a diffuse large B cell non-Hodgkin's lymphoma. The patient was treated with chemotherapy and rituximab (anti-CD20 monoclonal antibody). Four months later he was in remission, and remains so 48 months from presentation. Primary lymphoma of single peripheral nerves may be a unique subtype of extranodal lymphoma, which usually follows an aggressive course and has a variable response to current therapeutic strategies. MRI is useful, alongside electrophysiological studies, in patients with atypical peripheral nerve symptoms.

Object: Desmoid-type fibromatoses are a locally invasive soft-tissue lesion that is most commonly encountered in abdominal sites. The tumor also affects head and neck areas, particularly the supraclavicular region, where it may encase and distort the brachial plexus and compromise neurovascular structures. Neurosurgeons may be called on to treat desmoid-type fibromatoses in these sites. The authors describe their experience in treating four patients with desmoid-type fibromatoses involving the brachial plexus and report the results of immunohistochemical analysis of the tumors., Methods: Gross-total excision with nerve sparing was the first-line therapy of choice, although the surgery was challenging. Intraoperative identification of the site of tumor origin from musculoaponeurotic tissues by the neurosurgeon was necessary in two of the four cases to achieve a correct frozen section or final pathological diagnosis. Immunostaining for c-KIT (CD117) was undertaken in all cases in light of a previous report of positive CD117 immunoreactivity in abdominal desmoid-type fibromatoses. All four tumors manifested weak focal immunostaining for c-KIT. One of the patients was given adjuvant imatinib mesylate therapy, with limited success. Subsequent polymerase chain reaction testing revealed that three of the four tumors manifested a single base pair change in exon 10 of the c-KIT gene (A to C in two cases and A to G in one case). There was local recurrence in three patients, despite gross-total excision. With the combination of surgery and radiation therapy, local disease control was achieved in three of the four patients., Conclusions: This represents the first report of c-KIT sequencing in desmoid-type fibromatoses and suggests a possible biological basis for continuing to explore the use of adjuvant imatinib mesylate therapy.

A 25-year-old man was referred to our hospital with left flank pain, and computed tomography (CT) and magnetic resonance imaging (MRI) revealed large retroperitoneal masses. Physical examination revealed many café-au-lait spots and superficial neurofibromas, and a diagnosis of neurofibromatosis type 1 (von Recklinghausen's disease) was made. The tumor was resected, and the pathological diagnosis was malignant peripheral nerve sheath tumor (MPNST). Six months after the operation, lung metastases were detected. Surgical resection was incomplete, as there were too many lesions. He received four courses of chemotherapy with carboplatin and etoposide, and the metastatic lung lesions were markedly decreased. After chemotherapy, complete resection of the remaining lung lesions was performed, and there has been no recurrence to date.